Robert W. Schrier - Atlas of Diseases of The Kidney Volume 03 PDF

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Series Editor
Robert W. Schrier
Professor and Chairman Department of Medicine University of Colorado School of Medicine Denver, Colorado
Table of Contents
VOLUME ONE
VOLUME TWO
VOLUME THREE VOLUME FOUR
VOLUME FIVE
VOLUME THREE
Edited by Christopher S. Wilcox
Contents
CHAPTER 1 THE KIDNEY IN BLOOD PRESSURE REGULATION L. Gabriel Navar and L. Lee Hamm CHAPTER 2 RENAL PARENCHYMAL DISEASE AND HYPERTENSION Stephen C. Textor CHAPTER 3 RENOVASCULAR HYPERTENSION AND ISCHEMIC NEPHROPATHY Marc A. Pohl CHAPTER 4 ADRENAL CAUSES OF HYPERTENSION Myron H. Weinberger
CHAPTER 5 INSULIN RESISTANCE AND HYPERTENSION Theodore A. Kotchen CHAPTER 6 THE ROLE OF HYPERTENSION IN PROGRESSION OF CHRONIC RENAL DISEASE Lance D. Dworkin and Douglas G. Shemin CHAPTER 7 PHARMACOLOGIC TREATMENT OF HYPERTENSION Garry P. Reams and John H. Bauer CHAPTER 8 HYPERTENSIVE CRISES Charles R. Nolan
The Kidney in Blood Pressure Regulation

L. Gabriel Navar L. Lee Hamm
espite extensive animal and clinical experimentation, the mechanisms responsible for the normal regulation of arterial pressure and development of essential or primary hypertension remain unclear. One basic concept was championed by Guyton and other authors [14]: the long-term regulation of arterial pressure is intimately linked to the ability of the kidneys to excrete sufficient sodium chloride to maintain normal sodium balance, extracellular fluid volume, and blood volume at normotensive arterial pressures. Therefore, it is not surprising that renal disease is the most common cause of secondary hypertension. Furthermore, derangements in renal function from subtle to overt are probably involved in the pathogenesis of most if not all cases of essential hypertension [5]. Evidence of generalized microvascular disease may be causative of both hypertension and progressive renal insufficiency [5,6]. The interactions are complex because the kidneys are a major target for the detrimental consequences of uncontrolled hypertension. When hypertension is left untreated, positive feedback interactions may occur that lead progressively to greater hypertension and additional renal injury. These interactions culminate in malignant hypertension, stroke, other sequelae, and death [7]. In normal persons, an increased intake of sodium chloride leads to appropriate adjustments in the activity of various humoral, neural, and paracrine mechanisms. These mechanisms alter systemic and renal hemodynamics and increase sodium excretion without increasing arterial pressure [3,8]. Regardless of the initiating factor, decreases in sodium excretory capability in the face of normal or increased sodium intake lead to chronic increases in extracellular fluid volume and blood volume. These increases can result in hypertension. When the derangements also include increased levels of humoral or neural factors that directly cause vascular smooth muscle constriction, these effects increase peripheral vascular resistance or decrease vascular capacitance. Under these conditions the effects of subtle increases in blood volume are compounded because of increases in the blood volume relative to
CHAPTER
1.2
Hypertension and the Kidney

extrinsic influences and intrarenal derangements can lead to reduced sodium excretory capability. Many factors also exist that alter cardiac output, total peripheral resistance, and cardiovascular capacitance. Accordingly, hypertension is a multifactorial dysfunctional process that can be caused by a myriad of different conditions. These conditions range from stimulatory influences that inappropriately enhance tubular sodium reabsorption to overt renal pathology, involving severe reductions in filtering capacity by the renal glomeruli and associated marked reductions in sodium excretory capability. An understanding of the normal mechanisms regulating sodium balance and how derangements lead to altered sodium homeostasis and hypertension provides the basis for a rational approach to the treatment of hypertension.
the capacitance, often referred to as the effective blood volume. Through the mechanism of pressure natriuresis, however, the increases in arterial pressure increase renal sodium excretion, allowing restoration of sodium balance but at the expense of persistent elevations in arterial pressure [9]. In support of this overall concept, various studies have demonstrated strong relationships between kidney disease and the incidence of hypertension. In addition, transplantation studies have shown that normotensive recipients from genetically hypertensive donors have a higher likelihood of developing hypertension after transplantation [10]. This unifying concept has helped delineate the cardinal role of the kidneys in the normal regulation of arterial pressure as well as in the pathophysiology of hypertension. Many different
160 Aortic pressure, mm Hg
Arterial pressure, mm Hg
Isolated systolic hypertension (61 y)
120
80 Aortic blood flow, mL/s 400 0

Normotensive (56 y)
200 180 160 140 120 100 80 60 40 20
HEMODYNAMIC DETERMINANTS
For any vascular bed: Arterial pressure gradient Blood flow = Vascular resistance For total circulation averaged over time: Blood flow = cardiac output Therefore, Arterial pressure - right atrial pressure Cardiac output = Total peripheral resistance and: Mean arterial pressure = Cardiac output total peripheral resistance
PP = 72 mm Hg PP = 40 mm Hg PP = 30 mm Hg
500
600 700 800 900 Arterial volume, mL
FIGURE 1-1 Aortic distensibility. The cyclical pumping nature of the heart places a heavy demand on the distensible characteristics of the aortic tree. A, During systole, the aortic tree is rapidly filled in a fraction of a second, distending it and increasing the hydraulic pressure. B, The distensibility characteristics of the arterial tree determine the pulse pressure (PP) in response to a specific stroke volume. The normal relationship is shown in curve A, and arrows designate the PP. A highly distensible arterial tree, as depicted in curve B, can accommodate the stroke volume with a smaller PP. Pathophysiologic processes and aging lead to decreases in aortic distensibility. These decreases lead to marked increases in PP and overall mean arterial pressure for any given arterial volume, as shown in curve C. Decreased distensibility is partly responsible for the isolated systolic hypertension often found in elderly persons. Recordings of actual aortic pressure and flow profiles in persons with normotension and systolic hypertension are shown in panel A [11,12]. (Panel B Adapted from Vari and Navar [4] and Panel A from Nichols et al. [12].)
FIGURE 1-2 Hemodynamic determinants of arterial pressure. During the diastolic phase of the cardiac cycle, the elastic recoil characteristics of the arterial tree provide the kinetic energy that allows a continuous delivery of blood flow to the tissues. Blood flow is dependent on the arterial pressure gradient and total peripheral resistance. Under normal conditions the right atrial pressure is near zero, and thus the arterial pressure is the pressure gradient. These relationships apply for any instant in time and to timeintegrated averages when the mean pressure is used. The time-integrated average blood flow is the cardiac output that is normally 5 to 6 L/min for an adult of average weight (70 to 75 kg).
1.3
Dietary Insensible losses Urinary intake (skin, respiration, fecal) excretion
Net sodium and fluid balance
ECF volume Arterial pressure Blood volume Interstitial fluid volume
Arterial baroreflexes Atrial reflexes Renin-angiotensin-aldosterone Adrenal catecholamines Vasopressin Natriuretic peptides Endothelial factors: nitric oxide, endothelin kallikrein-kinin system Prostaglandins and other eicosanoids (Autoregulation) Total peripheral resistance
Neurohumoral systems
Mean circulatory pressure
Venous return
Cardiac output Cardiovascular capacitance
Heart rate and contractility
FIGURE 1-3 Volume determinants of arterial pressure. The two major determinants of arterial pressure, cardiac output and total peripheral resistance, are regulated by a combination of short- and long-term mechanisms. Rapidly adjusting mechanisms regulate peripheral vascular resistance, cardiovascular capacitance, and cardiac performance. These mechanisms include the neural and humoral mechanisms listed. On a long-term basis, cardiac output is determined by venous return, which is regulated primarily by the mean circulatory pressure. The mean circulatory pressure depends on blood volume and overall cardiovascular capacitance. Blood volume is closely linked to extracellular fluid (ECF) volume and sodium balance, which are dependent on the integration of net intake and net losses [13]. (Adapted from Navar [3].)
NaCl intake
Antidiuretic hormone release If increased
Concentrated urine: Increased free water reabsorption Thirst: Increased water intake
6 5 Blood volume, L 4 3 2 0 10
Edema
Na+ and Cl Quantity of Extracellular concentrations fluid volume = NaCl in ECF in ECF volume
If decreased NaCl losses (urine insensible) Antidiuretic hormone inhibition
Decreased water intake Increased salt intake Dilute urine: Increased solute-free water excretion
15 Extracellular fluid volume, L
20
FIGURE 1-4 A, Relationship between net sodium balance and extracellular fluid (ECF) volume. Sodium balance is intimately linked to volume balance because of powerful mechanisms that tightly regulate plasma and ECF osmolality. Sodium and its accompanying anions constitute the major contributors to ECF osmolality. The integration of sodium intake and losses establishes the net amount of sodium in the body, which is compartmentalized primarily in the ECF volume. The quotient of these two parameters (sodium and volume) determines the sodium concentration and, thus, the osmolality. Osmolality is subject to very tight regulation by vasopressin and other mechanisms. In particular, vasopressin is a very powerful regulator of plasma osmolality; however, it achieves this regulation primarily by regulating the relative solute-free water retention or excretion by the kidney [1315]. The important point is that the osmolality is rapidly regulated by adjusting the ECF volume to the total solute present. Corrections of excesses in extracellular fluid volume involve more complex interactions that regulate the sodium excretion rate.
B, Relationship between the ECF volume and blood volume. Under normal conditions a consistent relationship exists between the total ECF volume and blood volume. This relationship is consistent as long as the plasma protein concentration and, thus, the colloid osmotic pressure are regulated appropriately and the microvasculature maintains its integrity in limiting protein leak into the interstitial compartment. The shaded area represents the normal operating range [13]. A chronic increase in the total quantity of sodium chloride in the body leads to a chronic increase in ECF volume, part of which is proportionately distributed to the blood volume compartment. When accumulation is excessive, disproportionate distribution to the interstitium may lead to edema. Chronic increases in blood volume increase mean circulatory pressure (see Fig. 1-3) and lead to an increase in arterial pressure. Therefore, the mechanisms regulating sodium balance are primarily responsible for the chronic regulation of arterial pressure. (Panel B adapted from Guyton and Hall [13].)
1.4
Intrarenal Mechanisms Regulating Sodium Balance

6 Sodium excretion, normal 5 4 3 2 1 0 60 80 100 120 140 160 Renal arterial pressure, mm Hg 180 200
Normal sodium intake Reduced 1 3 Elevated sodium intake 2 4 High sodium intake Normal sodium intake Low sodium intake B
FIGURE 1-5 Arterial pressure and sodium excretion. In principle, sodium balance can be regulated by altering sodium intake or excretion by the kidney. However, intake is dependent on dietary preferences and usually is excessive because of the abundant salt content of most foods. Therefore, regulation of sodium balance is achieved primarily by altering urinary sodium excretion. It is therefore of major significance that, for any given set of conditions and neurohumoral environment, acute elevations in arterial pressure produce natriuresis, whereas
reductions in arterial pressure cause antinatriuresis [9]. This phenomenon of pressure natriuresis serves a critical role linking arterial pressure to sodium balance. Representative relationships between arterial pressure and sodium excretion under conditions of normal, high, and low sodium intake are shown. When renal function is normal and responsive to sodium regulatory mechanisms, steady state sodium excretion rates are adjusted to match the intakes. These adjustments occur with minimal alterations in arterial pressure, as exemplified by going from point 1 on curve A to point 2 on curve B. Similarly, reductions in sodium intake stimulate sodiumretaining mechanisms that prevent serious losses, as exemplified by point 3 on curve C. When the regulatory mechanisms are operating appropriately, the kidneys have a large capability to rapidly adjust the slope of the pressure natriuresis relationship. In doing so, the kidneys readily handle sodium challenges with minimal long-term changes in extracellular fluid (ECF) volume or arterial pressure. In contrast, when the kidney cannot readjust its pressure natriuresis curve or when it inadequately resets the relationship, the results are sodium retention, expansion of ECF volume, and increased arterial pressure. Failure to appropriately reset the pressure natriuresis is illustrated by point 4 on curve A and point 5 on curve C. When this occurs the increased arterial pressure directly influences sodium excretion, allowing balance between intake and excretion to be reestablished but at higher arterial pressures. (Adapted from Navar [3].)
Filtered sodium load, mol/min/g
150 100 50 0 100

Low Normal High
Fractional sodium reabsorption, %
98 96 94 92 8
FIGURE 1-6 Intrarenal responses to changes in arterial pressure at different levels of sodium intake. The renal autoregulation mechanism maintains the glomerular filtration rate (GFR) during changes in arterial pressure, GFR, and filtered sodium load. These values do not change significantly during changes in arterial pressure or sodium intake [3,16]. Therefore, the changes in sodium excretion in response to arterial pressure alterations are due primarily to changes in tubular fractional reabsorption. Normal fractional sodium reabsorption is very high, ranging from 98% to 99%; however, it is reduced by increased sodium chloride intake to effect the large increases in the sodium excretion rate. These responses demonstrate the importance of tubular reabsorptive mechanisms in modulating the slope of the pressure natriuresis relationship. (Adapted from Navar and Majid [9].)
Fractional sodium excretion, %
6 4 2 0 75 100 125 150 175 Renal arterial pressure, mm Hg
1.5
RA
ga=25
B<1 PB=20
Pg=60 ge=37
EFP=9
GFR=Kf EFP
i=8 Pi=6
Tubular reabsorption
Pc=20 RE c=37 PCU=Kr ERP
15 25 RV
FIGURE 1-7 Hemodynamic mechanisms regulating sodium excretion. Many different neurohumoral mechanisms, paracrine factors, and drugs exist that can influence sodium excretion and the pressure natriuresis relationship. These modulators may influence sodium excretion by altering changes in filtered load or changes in tubular reabsorption. Filtered load depends primarily on hemodynamic mechanisms that regulate the forces operating at the glomerulus. As shown, the glomerular filtration rate (GFR) is determined by the filtration coefficient (Kf) and the effective filtration pressure (EFP). The EFP is a distributed force determined by the glomerular pressure (Pg), the pressure in Bowmans space (PB), and the plasma colloid osmotic pressure within the glomerular capillaries (g). The g increases progressively along the length
of the glomerular capillaries as protein-free fluid is filtered such that filtration is greatest in the early segments of the glomerular capillaries, as designated by the large arrow. The glomerular forces, EFP, and blood flow are regulated by mechanisms that control the vascular smooth muscle tone of the afferent and efferent arterioles and of the intraglomerular mesangial cells. The filtration coefficient also is subject to regulation by neural, humoral, and paracrine influences [17]. Changes in tubular reabsorption can result from alterations of various processes governing both active and passive transport along the nephron segments. Peritubular capillary uptake (PCU) of the tubular reabsorbate is mediated by the net colloid osmotic pressure gradient (c - i). As a result of the filtration of protein-free filtrate, the plasma colloid osmotic pressure entering the peritubular capillaries is markedly increased. Thus, the colloid osmotic gradient exceeds the outwardly directed hydrostatic pressure gradient (Pc - Pi). Appropriate responses of one or more of these modulating mechanisms allow the kidneys to respond rapidly and efficiently to changes in sodium chloride intake [3,17]. Bcolloid osmotic pressure in Bowmans space; gacolloid osmotic pressure in initial parts of glomerular cappillaries; gecolloid osmotic pressure in terminal segments of glomerular capillaries; RAresistance of preglomerular arterioles; REefferent resistance; RVvenous resistance. (Adapted from Navar [3].)
0.6 0.4 0.2 0 20 15 10 5 0 5

RE RA
Renal blood flow, mL/ming
Vascular resistance, mm Hgming/mL
FIGURE 1-8 Renal autoregulatory mechanism. Because the glomerular filtration rate (GFR) is so responsive to changes in the glomerular forces, highly efficient mechanisms have been developed to maintain a stable intrarenal hemodynamic environment [16]. These powerful mechanisms adjust vascular smooth muscle tone in response to various extrinsic disturbances. During changes in arterial pressure, renal blood flow and the GFR are autoregulated with high efficiency as a consequence of adjustments in the vascular resistance of the preglomerular arterioles. Although efferent resistance also can be regulated by other mechanisms, it does not participate significantly over most of the autoregulatory range. The GFR, filtered sodium load, and the intrarenal pressures are maintained stable in the face of various extrarenal disturbances by the autoregulatory mechanism. (Adapted from Navar [3].)
Glomerular filtration rate, mL/ming
4 3 2 1 0 0 50 100 150 200 Renal arterial pressure, mm Hg
1.6
Arterial pressure

Plasma colloid Proximal tubular osmotic pressure and loop of Henle reabsorption Macula densa Glomerulotubular balance Collection pipette Wax blocking pipette
Perfusion pipette Early distal tubule: flow-related changes in fluid composition Proximal tubule
Glomerular pressure and plasma flow
Glomerular filtration rate
Proximal to distal tubule flow
Distal tubule
Preglomerular resistance
Vascular effector (afferent arteriole)
Macula densa: Sensor mechanism Transmitter
B vasoconstriction, whereas decreases in flow cause afferent vasodilation [16,18,19]. Blocking flow to the distal tubule or interrupting the feedback loop attenuates the autoregulatory efficiency of the glomerular filtration rate (GFR), glomerular pressure, and renal blood flow. B, Individual tubules can be blocked and perfused downstream, while collections are made or pressure measured in an early tubular segment. C, When the tubule is perfused at increased flows, the glomerular pressure and GFR of that nephron decrease. The shaded area in the normal relationship represents the normal operating level of the TGF mechanism. This mechanism helps stabilize the filtered load and the solute and sodium load to the distal nephron segment. The responsiveness of the TGF mechanism is modulated by changes in sodium intake and in extracellular fluid (ECF) volume status. At high sodium intake and ECF volume expansion the sensitivity of the TGF mechanism is low, thus allowing greater spillover of salt to the distal nephron. During low sodium intake and other conditions associated with ECF volume contraction, the sensitivity of the TGF mechanism is markedly increased to minimize spillover into the distal nephron and maximize sodium retention. The hormonal and paracrine mechanisms responsible for regulating TGF sensitivity are discussed subsequently. The myogenic mechanism is intrinsic to the vessel wall and responds to changes in wall tension to regulate vascular smooth muscle tone. Preglomerular arteries and afferent arterioles but not efferent arterioles exhibit myogenic responses to changes in wall tension [16,20]. The residual autoregulatory capacity that exists during blockade of the tubuloglomerular feedback mechanism indicates that the myogenic mechanism contributes about half to the autoregulatory efficiency of the renal vasculature. (Figure adapted from Navar [3].)
40
30 Single nephron GFR, nL/min

High sodium intake, ECF volume expansion
20
Normal
10
Low sodium intake Decreased ECF volume
0 0 10
20 30 Late proximal perfusion rate, nL/min
40
FIGURE 1-9 Tubuloglomerular feedback (TGF) and myogenic mechanisms. Two mechanisms are responsible for efficient renal autoregulation: the TGF and myogenic mechanisms. The TGF mechanism is explained here. A, Increases in distal tubular flow past the macula densa generate signals from the macula densa cells to the afferent arterioles to elicit

Agents that increase cytosolic calcium: Angiotensin II, vasopressin, epinephrine (), TXA2, leukotrienes, adenosine (A1), ATP, norepinephrine, endothelin VoltageReceptoroperated operated channel 2+ Ca channel 2+ Ca
1.7
Chloride channel_ Cl +
Calcium-activated potassium channel K+
Agents that increase cAMP (or cGMP): Epinephrine (), PTH, PGI2, PGE2, ANP, dopamine, nitric oxide, adenosine (A2) Ca2+ Ca2+
R Gq PLC Phosphoinositides Ca2+ DAG + IP3 Ca2+ SR PKC Calmodulin Ca2+-Cal MLCK Active MLCK MLC Phosphorylated MLCK (inactive) PKA cAMP cAMP Na+ Gi Gs Ad Cy R
Phosphorylated MLC Actin
Tension development
Smooth muscle cell
FIGURE 1-10 Cellular mechanisms of vascular smooth muscle contraction. The vascular resistances of different arteriolar segments are ultimately regulated by the contractile tone of the corresponding vascular smooth muscle cells. Shown are the various membrane activation mechanisms and signal transduction events leading to a change in cytosolic calcium ions (Ca2+), cyclic AMP (cAMP), and phosphorylation of myosin light chain kinase. Many of the circulating hormones and paracrine factors that increase or decrease vascular smooth muscle
tone are identified. Ad Cyadenylate cyclase; ANPatrial natriuretic protein; Calcalmodulin; cGMPcyclic GMP; DAG1,2-diacylglycerol; Gq, Gi, GsG proteins; IP3inositol 1,4,5-triphosphate; MLCmyosin light chain; MLCKmyosin light chain kinase; PGE2prostaglandin E2; PGI2prostaglandin I2; PKAprotein kinase A; PKCprotein kinase C; PLCphospholipase C; PTHparathyroid hormone; Rreceptor; SRsarcoplasmic reticulum; TXA2 thromboxane A2. (Adapted from Navar et al. [16].)
FIGURE 1-11 Differential activating mechanisms in afferent and efferent arterioles. The relative contributions of the activation pathways are different in afferent and efferent arterioles. Increases in cytosolic Ca2+ in afferent arterioles appear to be primarily by calcium ion (Ca2+) entry by way of receptor- and voltage-dependent Ca2+ channels. The efferent arterioles are less dependent on voltage-dependent Ca2+ channels. These differential mechanisms in the renal vasculature are exemplified by comparing the afferent and efferent arteriolar responses to angiotensin II before and after treatment with Ca2+ channel blockers. A, These experiments were done using the juxtamedullary nephron preparation that allows direct visualization of the renal microcirculation [21]. AAafferent arteriole; ArAarcuate artery; PCperitubular capillaries; Vvein; VRvasa recta. (Continued on next page)
1.8

FIGURE 1-11 (Continued) B, Both afferent and efferent arterioles constrict in response to angiotensin II [22]. Ca2+ channel blockers, dilate only the afferent arterioles and prevents the afferent vasoconstriction responses to angiotensin II. In contrast, Ca2+ channel blockers do not significantly vasodilate efferent arterioles and do not block the vasoconstrictor effects of angiotensin II. Thus, afferent and efferent arterioles can be differentially regulated by various hormones and paracrine agents. (Panel A from Casellas and Navar [21]; panel B from Navar et al. [23].)
30 25 Diameter,
Afferent arteriole
Efferent arteriole
20 15 10
Control Ca2+ channel blockers 0.1 nM 10 nM 0.1 nM 10 nM
Control
Angiotensin II
Control
Angiotensin II
Smooth muscle cell Vasodilation Vasoconstriction
EDHF
NO PGI 2 Relaxing factors
TXA2
EDCF PGF2 Endothelin Constricting factors

ACE
Angiotensin II
Endothelial cell Angiotensin I Shear stress Bradykinin Platelet activating ATP-ADP Serotonin Leukotrienes factor Acetylcholine Thrombin Insulin Histamine
FIGURE 1-12 Endothelial-derived factors. In addition to serving as a diffusion barrier, the endothelial cells lining the vasculature participate actively in the regulation of vascular function. They do so by responding to various circulating hormones and physical stimuli and releasing
paracrine agents that alter vascular smooth muscle tone and influence tubular transport function. (Examples are shown.) Angiotensinconverting enzyme (ACE) is present on endothelial cells and converts angiotensin I to angiotensin II. Nitric oxide is formed by nitric oxide synthase, which cleaves nitric oxide from L-arginine. Nitric oxide diffuses from the endothelial cells to activate soluble guanylate cyclase and increases cyclic GMP (cGMP) levels in vascular smooth muscle cells, thus causing vasodilation. Agents that can stimulate nitric oxide are shown. The relative amounts of the various factors released by endothelial cells depend on the physiologic circumstances and pathophysiologic status. Thus, endothelial cells can exert vasodilator or vasoconstrictor effects. At least one major influence participating in the normal regulation of vascular tone is nitric oxide. EDCFendothelial derived constrictor factor; EDHFendothelial derived hyperpolarizing factor; PGF2 prostaglandin F2 ; PGI2prostaglandin I2; TXA2 thromboxane A2. (Adapted from Navar et al. [16].)
Renal arterial pressure normal
Shear stress
Endothelial nitric oxide release Diffusion to tubules
Vascular dilation but counteracted by autoregulation
3 2 1
Control NOS inhibition
Epithelial cGMP Decreased sodium reabsorption Sodium excretion
50 75 100 125 150 Renal arterial pressure, mm Hg
FIGURE 1-13 Nitric oxide in mediation of pressure natriuresis. Several recent studies have demonstrated that nitric oxide also directly affects tubular sodium transport and may be an important mediator of the changes induced by arterial pressure in sodium excretion, as described in Figure 1-5 [9,24]. Increases in arteriolar shear stress caused by increases in arterial pressure stimulate production of nitric oxide. Nitric oxide may exert direct effects to inhibit tubule sodium reabsorptive mechanisms and may elicit vasodilatory actions. Nitric oxide increases intracellular cyclic GMP (cGMP) in tubular cells, which leads to a reduced reabsorption rate through cGMP-sensitive sodium entry pathways [24,25]. When formation of nitric oxide is blocked by agents that prevent nitric oxide synthase activity, sodium excretion is reduced and the pressure natriuresis relationship is markedly suppressed. Thus, nitric oxide may exert a critical role in the regulation of arterial pressure by influencing vascular tone throughout the cardiovascular system and by serving as a mediator of the changes induced by the arterial pressure in tubular sodium reabsorption. (Adapted from Navar [3].)
Sodium excretion,
1.9
PCT 60%
DCT
7% CCD PST 2% 3%
TALH 30%
OMCD
DLH ALH
IMCD
< 1% Filtered NA+ load = Plasma Na Glomerular filtration rate = 140 mEq/L 0.120 L/min = 16.8 mEq/min 1440 min/d = 24,192 mEq/min Urinary Na+ excretion = 200 mEq/d Fractional Na excretion = 0.83% Fractional Na reabsorption = 99.17%
FIGURE 1-14 Tubular transport processes. Sodium excretion is the difference between the very high filtered load and net tubular reabsorption rate such that, under normal conditions less than 1% of the filtered sodium load is excreted. The percentage of reabsorption of the filtered load occurring in each nephron segment is shown. The end result is that normally less than 1% of the filtered load is excreted; however, the exact excretion rate can be changed by many mechanisms. Despite the lesser absolute sodium reabsorption in the distal nephron segments, the latter segments are critical for final regulation of sodium excretion. Therefore, any factor that changes the delicate balance existing between the hemodynamically determined filtered load and the tubular reabsorption rate can lead to marked alterations in sodium excretion. ALHthin ascending limb of the loop of Henle; CCDcortical collecting duct; DCTdistal convoluted tubule; DLHthin descending limb of the loop of Henle; IMCDinner medullary collecting duct; OMCDouter medullary collecting duct; PCTproximal convoluted tubule; PSTproximal straight tubule; TALHthick ascending limb of the loop of Henle.
Peritubular capillary Lateral intercellular P space
()
Na K
Na Active transcellular
[K ]
+
Na
K K
Cells Paracellular (passive)
Na+ () [Na+]
Tubule lumen
FIGURE 1-15 Proximal tubule reabsorptive mechanisms. The proximal tubule is responsible for reabsorption of 60% to 70% of the filtered load of sodium. Reabsorption is accomplished by a combination of both active and passive transport mechanisms that reabsorb sodium and other solutes from the lumen into the lateral spaces and interstitial compartment. The major driving force for this reabsorption is the basolateral sodium-potassium ATPase (Na+-K+ ATPase) that transports Na+ out of the proximal tubule cells in exchange for K+. As in most cells, this maintains a low intracellular Na+ concentration and a high intracellular K+ concentration. The low intracellular Na+ concentration, along with the negative intracellular electrical potential, creates the electrochemical gradient that drives most of the apical transport mechanisms. In the late proximal tubule, a lumen to interstitial chloride concentration gradient drives additional net solute transport. The net solute transport establishes a small osmotic imbalance that drives transtubular water flow through both transcellular and paracellular pathways. In the tubule, water and solutes are reabsorbed isotonically (water and solute in equivalent proportions). The reabsorbed solutes and water are then further reabsorbed from the lateral and interstitial spaces into the peritubular capillaries by the colloid osmotic pressure, which establishes a predominant reabsorptive force as discussed in Figure 1-7. Ptranscapillary hydrostatic pressure gradient; transcapillary colloid osmotic pressure gradient.
1.10

pathways across the apical membrane may include a coupled sodium chloride entry step or chloride anion exchange that is coupled with sodium-hydrogen exchange. Major transport pathways at the basolateral membrane include the ubiquitous and preeminent sodium-potassium ATPase (Na+-K+ ATPase) that creates the major driving force. The other major pathway is a sodium-bicarbonate transport system that transports the equivalent of one sodium ion coupled with the equivalent of three bicarbonate ions (HCO-3). Because this transporter transports two net charges out the electrically negative cell, membrane voltage partially drives this transport pathway. A basolateral sodium-calcium exchanger is important in regulating cell calcium. Not shown are several other pathways that predominantly transport protons or other ions and organic substrates. Several major regulatory factors are listed.
Lumen
Proximal tubule cells

Regulation of reabsorption _
Na+ Glucose
ATP
3Na+ 2 K+ Na+ _ HCO3 CO3 Ca2+
ADP Na+ H+ Anion

_ _
Stimulation Angiotensin II Adrenergic agents or increased renal nerve activity Increased luminal flow or solute delivery Increased filtration fraction Inhibition Volume expansion (via increased backleak) Atrial natriuretic peptide Dopamine Increased interstitial pressure
Cl
3Na+
FIGURE 1-16 Major transport pathways across proximal tubule cells. At the apical membrane, sodium is transported in conjunction with organic solutes (such as glucose, amino acids, and citrate) and inorganic anions (such as phosphate and sulfate). The major mechanism for sodium entry into the cells is sodium-hydrogen exchange (the isoform NHE3). Chloride transport
Lumen
Furosemide Cell _ K+ or NH4+ +10mv K+ Na+ H+ 2ClNa
Thick ascending limb cells

ATP
ADP CI
_
Regulation of reabsorbtion Stimulation Antidiuretic hormone 3Na+ -adrenergic agents 2 K+ Mineralocorticoids Inhibition Hypertonicity Prostaglandin E2 Acidosis Calcium
FIGURE 1-17 Sodium transport mechanisms in the thick ascending limb of the loop of Henle. The major sodium chloride reabsorptive mechanism in the thick ascending limb at the apical membrane is the sodiumpotassium-chloride cotransporter. This electroneutral transporter is inhibited by furosemide and other loop diuretics and is stimulated by a variety of factors. Potassium is recycled across the apical membrane into the lumen, creating a positive voltage in the lumen. An apical sodium-hydrogen exchanger also exists that may function to reabsorb some sodium bicarbonate. The sodium-potassium ATPase (Na+-K+ ATPase) at the basolateral membrane again is the driving force. The basolateral chloride channel and possibly other chloride cotransporters are important in mediating chloride efflux across the basolateral membrane. Sodium and chloride are reabsorbed without water in this segment because water is impermeable across the apical membrane of the thick ascending limb. Thus, the tubular fluid osmolality in this nephron segment is hypotonic.
1.11
Thiazides _ Na _ Cl Na+ Amiloride _
Distal tubule and connecting tubule cells
ATP 3Na+ 2 K+ ADP
FIGURE 1-18 Mechanisms of sodium chloride reabsorption in the distal tubule. The distal convoluted tubule and subsequent connecting tubule have a variety of sodium transport mechanisms. The distal tubule has predominantly a sodium chloride cotransporter, which is inhibited by thiazide diuretics. In the connecting tubule, sodium channels and a sodium-hydrogen exchange mechanism also are present. Amiloride inhibits sodium channel activity. Again the sodium-potassium ATPase (Na+-K+ ATPase) on the basolateral membrane provides most of the driving force for sodium reabsorption.
Na+ H+
Collecting duct principal cell Lumen Cell

ATP Regulation of reabsorbtion Stimulation Aldosterone 3Na+ Antidiuretic hormone 2 K+ Inhibition Prostaglandins Nitric oxide Atrial natriuretic peptide Bradykinin Na+_ 2CI K+ (IMCD)
Na+ _ Amiloride K+
ADP
FIGURE 1-19 Mechanism of sodium chloride reabsorption in collecting duct cells. Sodium transport in the collecting duct is mainly via amiloridesensitive sodium channels in the apical membrane. Some evidence for other mechanisms such as an electroneutral sodium-chloride cotransport mechanism and a different sodium channel also has been reported. Again, the basolateral sodium-potassium ATPase (Na+-K+ ATPase) creates the driving force for overall sodium transport. There are some differences between the cortical collecting duct and the deeper inner medullary collecting duct (IMCD). In the cortical collecting duct, sodium transport occurs in the predominant principal cell type interspersed between acid-base transporting intercalated cells. The principal cell also is an important site of potassium secretion by way of apical potassium channels and water transport via antidiuretic sensitive water channels. Regulation of sodium channels may involve either insertion (from subapical compartments) or activation of preexisting sodium channels.
1.12
Systemic Factors Regulating Arterial Pressure and Sodium Excretion

Medulla NTS Baroreceptor firing rate, impulses/s
Normal
I
Resetting
Glossopharyngeal nerve Afferents Carotid sinus Efferents NA DN
Bulbospinal pathway epinephrine
100 Arterial pressure, mm Hg
Arterial pressure
Vagus nerve
Atrial receptors
Aortic arch Heart rate Preganglionic sympathetics (acetylcholine)
Postganglionic Sympathetics Vascular smooth muscle TPR Norepinephrine Kidney

RBF GFR Reabsorption Na+ excretion
Adrenal medulla
Epinephrine
FIGURE 1-20 Neural and sympathetic influences. The neural reflexes serve as the principal mechanisms for the rapid regulation of arterial pressure. The neural reflexes also exert a long-term role by influencing sodium excretion. The pathways and effectors of the arterial baroreflex and atrial pressure-volume reflex are depicted. The arrows indicate increased or decreased activity in response to an acute reduction in arterial pressure which is sensed by the baroreceptors in the aortic arch and carotid sinus. The insert depicts the relationship between the arterial blood pressure and baroreflex primary afferent firing rate. At the normal level of mean arterial pressure of approximately 100 mm Hg, the sensitivity ( I/ P) is set at the maximum level. After chronic resetting of the baroreceptors, the peak sensitivity and threshold of activation are shifted to a higher level of arterial pressure. The cardiovascular reflexes involve high-pressure arterial receptors in the aortic arch and carotid sinus and low-pressure atrial receptors. In response to decreases in arterial pressure or vascular volume, increased sympathetic stimulation participates in shortterm control of arterial pressure. This increased stimulation does
so by enhancing cardiac performance and stimulating vascular smooth muscle tone, leading to increased total peripheral resistance and decreased capacitance. The direct effects of the sympathetic nervous system on kidney function lead to decreased sodium excretion caused by decreases in filtered load and increases in tubular reabsorption [26]. The decreases in the glomerular filtration rate (GFR) and filtered sodium load are due to increases in both afferent and efferent arteriolar resistances and to decreases in the filtration coefficient (see Fig. 1-7). Sympathetic activation also enhances proximal sodium reabsorption by stimulating the sodium-hydrogen (Na+-H+) exchanger mechanism (see Fig. 1-16) and by increasing the net chloride reabsorption by the thick ascending limb of the loop of Henle. The indirect effects include stimulation of renin secretion and angiotensin II formation, which, as discussed next, also stimulates tubular reabsorption. Ichange in impulse firing; Pchange in pressure; DNdorsal motor nucleus; NAnucleus ambiguous; NTSnucleus tractus solitarii; RBFrenal blood flow; TPRtotal peripheral resistance. (Adapted from Vari and Navar [4].)
1.13
Angiotensinogen Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Val-Tyr-Ser-R Renin NaCl intake Arterial pressure ECF volume Stress trauma Angiotensin I Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu Angiotensinconverting enzyme, chymase (heart) Angiotensin II Juxtaglomerular apparatus Cytosolic Ca2+ cAMP Renin release Asp-Arg-Val-Tyr-Ile-His-Pro-Phe Angiotensinases
Macula densa mechanism Baroreceptor mechanism Sympathetic nervous system
Metabolites Angiotensin (17) Angiotensin (28) Angiotensin (38) Inactive fragments
AT1, AT2, AT? Receptor binding and Biologic actions
FIGURE 1-21 Renin-angiotensin system. The renin-angiotensin system serves as one of the most powerful regulators of arterial pressure and sodium balance. In response to various stimuli that compromise blood volume, extracellular fluid (ECF) volume, or arterial pressureor those associated with stress and traumathree major mechanisms are activated. These mechanisms stimulate renin release by the cells of the juxtaglomerular apparatus that act on angiotensinogen to form angiotensin I. Angiotensinogen is an 2 globulin formed primarily in the liver and to a lesser extent by the kidney. Angiotensin I is a decapeptide that is rapidly converted by angiotensin-converting enzyme (ACE) and to a lesser extent by chymase (in the heart) to angiotensin II, an octapeptide. Recent studies have indicated that other angiotensin metabolites such as angiotensin (28), angiotensin (17), and angiotensin (38) have biologic actions.
Angiotensin II and/or active metabolites
Adrenal cortex
Kidney
Intestine
Central nervous system
Peripheral nervous system
Vascular smooth muscle
Heart
Growth factors
Aldosterone Distal nephron reabsorption
Vasoconstriction transport effects
Adrenergic facilitation Sympathetic discharge Thirst, salt appetite Vasopressin release Water reabsorption Vasoconstriction
Contractility Proliferation
Proximal and distal sodium + water Reabsorption by intestine Maintain or increase extracellular fluid volume
Total peripheral resistance
Cardiac output
Hypertrophy
FIGURE 1-22 Multiple actions of angiotensin. Angiotensin II and some of the other angiotensin II metabolites have a myriad of actions on many different vascular beds and organ systems. Angiotensin II exerts short- and long-term actions, including vasoconstriction and stimulation of aldosterone release. Angiotensin II also
interacts with the sympathetic nervous system by facilitating adrenergic transmission and has long-term actions on vascular smooth muscle proliferation by interacting with growth factors. Angiotensin II exerts several important effects on the kidney that contribute to sodium conservation. (Adapted from Navar [3].)
1.14

Enhance proximal tubular reabsorption PT
BS
Decrease Kf
GC
FIGURE 1-23 Angiotensin II actions on renal hemodynamics. Systemic and intrarenal angiotensin II exert powerful vasoconstrictive actions on the kidney to decrease renal blood flow and sodium excretion. At the level of the glomerulus, angiotensin II is a vasoconstrictor of both afferent (AA) and efferent arterioles (EA) and decreases the filtration coefficient Kf. Angiotensin II also directly inhibits renin release by the juxtaglomerular apparatus. Increased intrarenal angiotensin II also is responsible for the increased sensitivity of the tubuloglomerular feedback mechanism that occurs with decreased sodium chloride intake (see Fig. 1-9) [17,27,28]. BSBowmans space; GCglomerular capillaries; PCperitubular capillaries; PTproximal tubule; TALthick ascending limb; TGFtubuloglomerular feedback mechanism. (Adapted from Arendshorst and Navar [17].)
EA
Inhibit renin release
PC
Efferent arteriolar vasoconstriction
Afferent arteriolar vasoconstriction TAL Increased sensitivity of TGF mechanism AA
Angiotensin
Angiotensin
G PLA
_ + cAMP
H+ Tubule lumen
Na+
HCO3 Na+
K+ Na+
FIGURE 1-24 Angiotensin II actions on tubular transport. Angiotensin II receptors are located on both the luminal and basolateral membranes of the proximal and distal nephron segments. The proximal effect has been studied most extensively. Activation of angiotensin II-AT1 receptors leads to increased activities of the sodium-hydrogen (Na+-H+) exchanger and the sodium-bicarbonate (Na+-HCO-3) cotransporter. These increased activities lead to augmented volume reabsorption. Higher angiotensin II concentrations can inhibit the tubular sodium reabsorption rate; however, the main physiologic role of angiotensin II is to enhance the reabsorption rate [28]. cAMPcyclic AMP; GG protein; PLAphospholipase A. (Adapted from Mitchell and Navar [28].)
1.15
A. SYNERGISTIC RENAL ACTIONS OF ANGIOTENSIN II

Enhancement of proximal reabsorption rate Stimulation of apical amiloride-sensitive Na-H exchanger Stimulation of basolateral Na-HCO3 cotransporter Sustained changes in distal volume and sodium delivery Increased sensitivity of afferent arteriole to signals from macula densa cells
Reabsorption 60 Proximal SNGFR Glomerular pressure, mm Hg 55 50 45 40 35 30 0
Distal delivery
Proximal reabsorption 60 SNGFR Glomerular pressure, mm Hg 55 50 45 40 35 30 0
10 20 30 End proximal fluid flow, nL/min
40
Distal delivery
10 20 30 End proximal fluid flow, nL/min
40
FIGURE 1-25 AC, Synergistic effects of angiotensin II on proximal reabsorption and tubuloglomerular feedback mechanisms. The actions of angiotensin II on proximal nephron reabsorption and the ability of angiotensin II to enhance the sensitivity of the tubuloglomerular feedback (TGF) mechanism prevent a compensatory increase in glomerular filtration rate caused by the reduced distal tubular flow. These actions allow elevated angiotensin II levels to exert a sustained reduction in sodium delivery to the distal nephron segment. This effect is shown here by the shift of operating levels to a lower proximal fluid flow under the influence of elevated angiotensin II [27]. The effects of angiotensin II to enhance TGF sensitivity allow the glomerular pressure (GP) and nephron filtration rate to be maintained at a reduced distal volume delivery rate that would occur as a consequence of the angiotensin II effects on reabsorption. SNGFRsingle nephron glomerular filtration rate. (Panels B and C adapted from Mitchell et al. [27].) FIGURE 1-26 Effects of aldosterone on distal nephron sodium reabsorption. A, Mechanism of action of aldosterone. Angiotensin II also is a very powerful regulator of aldosterone release by the adrenal gland. The increased aldosterone levels synergize with the direct effects of angiotensin II to enhance distal tubule sodium reabsorption. Aldosterone increases sodium reabsorption and potassium secretion in the distal segments of the nephron by binding to the cytoplasmic mineralocorticoid receptor (MR). On binding, the receptor complex migrates to the nucleus where it induces transcription of a variety of messenger RNAs (mRNAs). The mRNAs encode for proteins that stimulate sodium reabsorption by increasing sodium-potassium ATPase (Na+-K+ ATPase) protein and activity at basolateral membranes, increasing mitochondrial ATP formation, and increasing the sodium and potassium channels at the luminal membrane [29]. Growing evidence also exists for nongenomic actions of aldosterone to activate sodium entry pathways such as the amiloride-sensitive sodium channel [30]. (Continued on next page)
Lumen
Principal cell
Mitochondria
ATP
Na+ Proteins mRNA ADP
3Na+ 2 K+
K+ Nucleus MR Aldosterone _ Spironolactone
1.16
14 12 Filtered sodium remaining, % 10 8 6 4 2 0 0

FIGURE 1-26 (Continued) B, The net effect of aldosterone is to stimulate sodium reabsorption along the distal nephron segment, decreasing the remaining sodium to only 2% or 3% of the filtered load. The direct action of aldosterone can be blocked by drugs such as spironolactone that bind directly to the mineralocorticoid receptor.
Aldosterone blockade
Normal
20
40 60 Distal nephron length, %
80
100
Lumen
Principal cell
Mitochondria
ATP
Na+
3Na+ 2 K+
Proteins ADP mRNA MR

Nucleus Cortisone
K+
Aldosterone Cortisol II-_OHSD defect or glycyrrhizic acid or carbenoxolone
FIGURE 1-27 Syndrome of apparent mineralocorticoid excess and hypertension. Aldosterone increases sodium reabsorption and potassium secretion in the distal segments of the nephron by binding to the cytoplasmic mineralocorticoid receptor (MR). Cortisol, the glucocorticoid that circulates in plasma at much higher concentrations than does aldosterone, also binds to MR. However, cortisol normally is prevented from this by the action of 11- -hydroxysteroid dehydrogenase (11-OHSD), which metabolizes cortisol to cortisone in mineralocorticoid-sensitive cells. A deficiency or defect in this enzyme has been found to be responsible for a rare form of hypertension in persons with the hereditary syndrome of apparent mineralocorticoid excess. In these persons, cortisol binds to the MR receptor, causing sodium retention and hypertension [31]. This enzyme also is blocked by glycyrrhizic acid (in some forms of licorice) and carbenoxolone. The diuretic spironolactone acting by way of inhibition of MR is able to block this excessive action of cortisol on the MR receptor.
Lumen
Principal cell
Mitochondria ATP
Na+ Proteins mRNA ADP
3Na+ 2K+ Primary hyperaldosteronism Adrenal enzymatic disorder Adenoma Glucorticoid-remediable aldosteronism Aldosterone
K+ Nucleus MR
FIGURE 1-28 Hyperaldosteronism and glucocorticoid-remediable aldosteronism. Hypertension can result from increased aldosterone or from increases in other closely related steroids derived from abnormal adrenal metabolism (11- -hydroxylase deficiency and 17- hydroxylase deficiency). The most common cause is an aldosterone-producing adenoma; bilateral hyperplasia of the adrenal zona glomerulosa is the next most common cause. In glucocorticoid-remediable aldosteronism, a DNA crossover mutation results in a chimeric gene in which aldosterone production is regulated by adrenocorticotropic hormone (ACTH). Increases in aldosterone also can result secondarily from any state of increased renin such as renal artery stenosis, which leads to increased circulating concentrations of angiotensin II and stimulation of aldosterone release [31]. MRmineralocorticoid receptor; mRNAmessenger RNA.
1.17
Lumen Cell Liddle's syndrome

Na+
pp pp
pp
ATP ADP K+
3Na+ 2 K+
Liddle's syndrome
FIGURE 1-29 Excess epithelial sodium channel activity in Liddles syndrome. The epithelial sodium channel responsible for sodium reabsorption in much of the distal portions of the nephron is a complex of three homologous subunits, , , and each with two membrane-spanning domains. Liddles syndrome, an autosomal dominant disorder causing low renin-aldosterone hypertension often with hypokalemia, results from mutated or subunits. These mutations increase the sodium reabsorptive rate by way of these channels by keeping them open longer, increasing sodium channel density on the membranes, or both. The specific problem appears to reside with proline (P)-rich domains in the carboxyl terminal region of or that are involved in regulation of the channel membrane localization or activity. The net result is excess sodium reabsorption and a reduced capability to increase sodium excretion in response to volume expansion [31,32].
Extracellular fluid volume Blood volume

Na Cl
Intrathoracic blood volume
Atrial stretch receptors
Gitleman's syndrome
Na+
Sodium excretion
Aldosterone Renin Tubular sodium reabsorption
Atrial natriuretic peptide
L Na+2Cl _ Cl K+ K+
Pseudohypoaldosteronism
Vascular resistance
Vasodilation
Bartter's syndrome
FIGURE 1-30 Syndromes of diminished sodium reabsorption and hypotension. Recently, a variety of syndromes associated with salt wasting, and usually hypotension, have been attributed to specific molecular defects in the distal nephron. Bartters syndrome, which usually is accompanied by metabolic alkalosis and hypokalemia, has been found to be associated with at least three separate defects (the three transporters shown) in the thick ascending limb. These defects are at the level of the sodium-potassium-2chloride (Na+-K+-2Cl-) cotransporter, apical potassium channel, and basolateral chloride channel (see Fig. 1-17). Malfunction in any of these three proteins results in diminished sodium chloride reabsorption similar to that occurring with administration of loop diuretics. Gitelmans syndrome, which was originally described as a variant of Bartters syndrome, represents a defect in the sodium chloride cotransport mechanism in the distal tubule. Pseudohypoaldosteronism results from a defect in the apical sodium channels in the collecting ducts. In contrast to Bartters and Gitelmans syndromes, hyperkalemia may be present. These rare disorders illustrate that defects in sodium chloride reabsorptive mechanisms can result in abnormally low blood pressure as a consequence of excessive sodium excretion in the urine. Although these conditions are rare, similar but more subtle defects of the heterozygous state may contribute to protection from hypertension in some persons [31]. Bbasolateral side; Llumen of tubule.
FIGURE 1-31 Atrial natriuretic peptide (ANP). In response to increased intravascular volume, atrial distention stimulates the release of ANP from the atrial granules where the precursor is stored. Extracellular fluid volume expansion is associated with increased ANP levels, whereas reductions in vascular volume and dehydration elicit decreases in plasma ANP levels. ANP participates in arterial pressure regulation by sensing the degree of vascular volume expansion and exerting direct vasodilator actions and natriuretic effects. ANP has been shown to markedly increase the slope of the pressure natriuresis relationship (see Figs. 1-5 and 1-6). The vasorelaxant and transport actions are mediated by stimulation of membrane-bound guanylate cyclase, leading to increased cyclic GMP levels. ANP also inhibits renin release, which reduces circulating angiotensin II levels [3335]. Related peptides, such as brain natriuretic peptides, have similar effects on sodium excretion and renin release [36].
1.18

States of volume depletion and hypoperfusion stimulate prostaglandin synthesis [16,17,38]. The vasodilator prostaglandins attenuate the influence of vasoconstrictor substances during activation of the renin-angiotensin system, sympathetic nervous system, or both [33]. These prostaglandins also have transport effects on renal tubules through activation of distinct prostaglandin receptors [40]. In some pathophysiologic conditions, enhanced production of TXA2 and other vasoconstrictor prostanoids may occur. The vasoconstriction induced by TXA2 appears to be mediated primarily by calcium influx [17,40]. Leukotrienes are hydroperoxy fatty acid products of 5-hydroperoxyeicosatetraenoic acid (HPETE) that are synthesized by way of the lipoxygenase pathway. Leukotrienes are released in inflammatory and immunologic reactions and have been shown to stimulate renin release. The cytochrome P450 monooxygenases produce several vasoactive agents [16,37,41,42] usually referred to as EETs and hydroxy-eicosatetraenoic acids (HETEs). These substances exert actions on vascular smooth muscle and epithelial tissues [16,41,42]. (Adapted from Navar [3].)
Membrane phospholipids Phospholipase A2

COOH
Arachidonic acid Cytochrome P450 monooxygenases EETs (vasodilation ) HETEs (vasoconstriction)
Cyclooxygenase Endoperoxides
Lipoxygenases HPETEs Leukotrienes (vasoconstriction)
PGI2/PGE2 (vasodilation, natriuresis)
TXA2/PGH2 (vasoconstriction)
HETEs Lipoxins
FIGURE 1-32 Arachidonic acid metabolites. Several eicosanoids (arachidonic acid metabolites) are released locally and exert both vasoconstrictor and vasodilator effects as well as effects on tubular transport [16,37]. Phospholipase A2 catalyzes formation of arachidonic acid (an unsaturated 20-carbon fatty acid) from membrane phospholipids. The cyclooxygenase pathway and various prostaglandin synthetases are responsible for the formation of endoperoxides (PGH2), prostaglandins E2 (PGE2) and I2 (PGI2), and thromboxane (TXA2) [38,39].
Kallikrein-kinin system Low molecular weight kininogen Tissue kallikrein Bradykinin Kininase I Des Arg-bradykinin Kininase II (ACE) NEP Kinin degradation products B2-receptor Endothelium-dependent Nitric oxide PGE2 Vasodilation natriuresis High molecular weight kininogen Plasma kallikrein
B1-receptor
FIGURE 1-33 Kallikrein-kinin system. Plasma and tissue kallikreins are functionally different serine protease enzymes that act on kininogens (inactive 2 glycoproteins) to form the biologically active kinins (bradykinin and lysyl-bradykinin [kallidin]). Kidney kallikrein and kininogen are localized in the distal convoluted and cortical collecting tubules. Release of kallikrein into the tubular fluid and interstitium can be stimulated by prostaglandins, mineralocorticoids, angiotensin II, and diuretics. B1 and B2 are the two major bradykinin receptors that exert most of the vascular actions. Although glomerulus and distal nephron segments contain both B1 and B2 receptors, most of the renal vascular and tubular effects appear to be mediated by B2-receptor activation [16,17,43,44]. Bradykinin and kallidin elicit vasodilation and stimulate nitric oxide, prostaglandin E2 (PGE2) and I2 (PGI2), and renin release [45,46]. Kinins are inactivated by the same enzyme that converts angiotensin I to angiotensin II, angiotensin-converting enzyme (ACE). The kallikrein-kinin system is stimulated by sodium depletion, indicating it serves as a mechanism to dampen or offset the effects of enhanced angiotensin II levels [47,48]. Des Arg bradykinin; NEPneutral endopeptidase.
1.19
10 Plasma vasopressin, pg/mL 8 6 4 2 0 260

Decreased ECF volume
Normal ECF volume
Increased ECF volume
280 300 320 Plasma osmolality, mOsm/kg
340
FIGURE 1-34 Vasopressin. Vasopressin is synthesized by the paraventricular and supraoptic nuclei of the hypothalamus. Vasopressin is stored in the posterior pituitary gland and released in response to osmotic or volume-dependent baroreceptor stimuli, or both. Atrial filling inhibits vasopressin release. Increases in plasma osmolality increase vasopressin release; however, the relationship is shifted by the status of extracellular fluid (ECF) volume, with decreases in the ECF volume increasing the sensitivity of the relationship. Stress and trauma also increase vasopressin release [15]. Therefore, when ECF volume and blood volume are diminished, vasopressin is released to help guard against additional losses of body fluids. (Adapted from Navar [8].)
Collecting duct principal cell
Plasma membrane ATP cAMP + PPi Protein kinase A

GTP
Tubule lumen
Adenylate cyclase
GTP G G G G V2
Circulating vasopressin
GDP
H 2O Aquaporin 2 water channels Aquaporin 2
FIGURE 1-35 Vasopressin receptors. Vasopressin exerts its cellular actions through two major receptors. Activation of V1 receptors leads to vascular smooth muscle constriction and increases peripheral resistance. Vasopressin stimulates inositol 1,4,5-triphosphate and calcium ion (Ca2+) mobilization from cytosolic stores and also increases Ca2+ entry from extracellular stores as shown in Figure 1-10. The vasoconstrictive action of vasopressin helps increase total peripheral resistance and reduces medullary blood flow, which enhances the concentrating ability of the kidney. V2 receptors are located primarily on the basolateral side of the principal cells in the collecting duct segment. Vasopressin activates heterotrimeric G proteins that activate adenylate cyclase, thus increasing cyclic AMP levels. Cyclic AMP (cAMP) activates protein kinase A, which increases the density of water channels in the luminal membrane. Water channels (aquaporin proteins) reside in subapical vesicles and on activation fuse with the apical membrane. Thus, vasopressin markedly increases the water permeability of the collecting duct and allows conservation of fluid and excretion of a concentrated urine. An intact vasopressin system is essential for the normal regulation of urine concentration by the kidney that, in turn, is the major mechanism for coupling the solute to solvent ratio (osmolality) of the extracellular fluid. As discussed in Figure 1-4, this tight coupling allows the confluence of homeostatic mechanisms regulating sodium balance with those regulating extracellular fluid volume. G and Gproteins; PPi inorganic pyrophosphate. (Adapted from Vari and Navar [4].)
1.20
Hypertensinogenic Process
Initial increase in vascular resistance Neurogenic or humoral stimuli Vasoconstrictor effects Renal volume retention Effective blood volume Initial increase in volume Volume
Cardiac output Tissue blood flow Autoregulatory resistance adjustments
Capacitance Increased vascular resistance Increased arterial blood pressure
FIGURE 1-36 Overview of mechanisms mediating hypertension. From a pathophysiologic perspective, the development of hypertension requires either a sustained absolute or relative overexpansion of the blood volume, reduction of the capacitance of the cardiovascular system, or both [4,49,50]. One type of hypertension is due primarily to overexpansion of either the actual or the effective blood volume compartment. In such a condition of volume-dependent hypertension,
either one or more of the physiologic mechanisms described in this chapter fails to respond appropriately to intravascular expansion or some pathophysiologic process causes excess production of one or more sodium-retaining factors such as mineralocorticoids or angiotensin II [51,52]. Through mechanisms delineated earlier, overexpansion leads to increased cardiac output that results in overperfusion of tissues; the resultant autoregulatory-induced increases in peripheral resistance contribute further to an increase in total peripheral resistance and elevated arterial pressure [2,53,54]. Hypertension also can be initiated by excess vasoconstrictor influences that directly increase peripheral resistance, decrease cardiovascular capacitance, or both. Examples of this type of hypertension are enhanced activation of the sympathetic nervous system and overproduction of catecholamines such as that occurring with a pheochromocytoma [45,54,55]. When hypertension caused by a vasoconstrictor influence persists, however, it must also exert significant renal vasoconstrictor and sodium-retaining actions. Without a renal effect the elevated arterial pressure would cause pressure natriuresis, leading to a compensatory reduction in extracellular fluid volume and intravascular volume. Thus, the elevated systemic arterial pressure would not be sustained [2,8,54]. Derangements that activate both a vasoconstrictor system and produce sodium-retaining effects, such as inappropriate elevations in the activity of the renin-angiotensin-aldosterone system, lead to an even more powerful hypertensinogenic mechanism that is not easily counteracted [27]. These dual mechanisms are why the reninangiotensin system has such a critical role in the cause of many forms of hypertension, leaving only the option to increase arterial pressure and elicit a pressure natriuresis. (Adapted from Navar [3].)
180 Mean arterial pressure, mm Hg 160 140 120 100 80 14 12 10 8 6 4 2 0

Aldosterone Renal perfusion pressure Reduce renal perfusion pressure Angiotensin II + Aldosterone
Angiotensin II + Aldosterone
Aldosterone
1 2 3 4 Reduced renal pressure, d
FIGURE 1-37 Predominance of the renin-angiotensin-aldosterone mechanisms. Collectively, the various mechanisms discussed provide overlapping influences responsible for the highly efficient regulation of sodium balance, extracellular fluid (ECF) volume, blood volume, and arterial pressure. Nevertheless, the synergistic actions of the renin-angiotensin-aldosterone system on both vasoconstrictor as well as sodium-retaining mechanisms exert a particularly powerful influence that is not easily counteracted. In a recent study by Seeliger and coworkers [56], renal perfusion pressure was lowered to 90 to 95 mm Hg. The angiotensin II and aldosterone levels were not allowed to decrease and were fixed at normal levels by continuous infusions. The results demonstrated that all compensatory mechanisms (such as increased release of atrial natriuretic peptide and reduced activity of the sympathetic system) could not overcome the hypertensinogenic influence of maintained aldosterone or aldosterone plus angiotensin II as long as renal perfusion pressure was not allowed to increase. Thus, under conditions of increased activity of the renin-angiotensin system, an increased renal arterial pressure seems essential to reestablish sodium balance. In conclusion, regardless of the specific intrarenal mechanism involved, the net effect of a long-term hypertensinogenic derangement is a reduced capability for sodium excretion at normotensive arterial pressures that cannot be completely compensated by other neural, humoral, or paracrine mechanisms, leaving only the option to increase arterial pressure and elicit a pressure natriuresis. (Adapted from Seeliger et al. [56].)
Cumulative sodium balance, mmol/kg BW
1.21
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Lifton RP: Molecular genetics of human blood pressure variation. Science 1996, 272:676680. 32. Warnock DG: Liddle syndrome: an autosomal dominant form of human hypertension. Kidney Int 1998, 53:1824. 33. Jamison RL, Canaan-Kuhl S, Pratt R: The natriuretic peptides and their receptors. Am J Kidney Dis 1992, 20:519530. 34. Paul RV, Kirk KA, Navar LG: Renal autoregulation and pressure natriuresis during ANF-induced diuresis. Am J Physiol 1987, 253:F424F431. 35. Knepper MA, Lankford SP, Terada Y: Renal tubular actions of ANF. Can J Physiol Pharmacol 1991, 69:15371545. 36. Jensen KT, Carstens J, Pedersen EB: Effect of BNP on renal hemodynamics, tubular function and vasoactive hormones in humans. Am J Physiol (Renal Fluid Electrolyte Physiol 43) 1998, 274:F63F72. 37. Capdevila JH, Falck JR, Estabrook RW: Cytochrome P450 and the arachidonate cascade. FASEB J 1992, 6:731736. 38. Smith WL: Prostanoid biosynthesis and mechanisms of action. Am J Physiol (Renal Fluid Electrolyte Physiol 32) 1992, 263:F181F191. 39. Frazier LW, Yorio T: Eicosanoids: their function in renal epithelia ion transport. Proceedings of the Society for Experimental Biology and Medicine 1992, 201:229243. 40. Breyer MD, Jacobson HR, Breyer RM: Functional and molecular aspects of renal prostaglandin receptors. J Am Soc Nephrol 1996, 7:817. 41. McGiff JC: Cytochrome P-450 metabolism of arachidonic acid. Ann Rev Pharmacol Toxicol 1991, 31:339369. 42. Imig JD, Zou A-P, Stec DE, et al.: Formation and actions of 20hydroxyeicosatetraenoic acid in rat renal arterioles. Am J Physiol (Regulat Integrative Comp Physiol 39) 1996, 270:R217R227. 43. Bhoola KD, Figueroa CD, Worthy K: Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev 1992, 44:180. 44. El-Dahr SS: Development biology of the renal kallikrein-kinin system. Pediatr Nephrol 1994, 8:624631. 45. Carretero OA, Scicli AG: Local hormonal factors (intracrine, autocrine, and paracrine) in hypertension. Hypertension 1991, 18 (suppl I):I-58I-69. 46. Siragy HM, Jaffa AA, Margolius HS: Bradykinin B2 receptor modulates renal prostaglandin E2 and nitric oxide. Hypertension 1997, 29:757762. 47. Margolius HS: Kallikreins and kinins: molecular characteristics and cellular and tissue responses. Diabetes 1996, 45:S14S19.
1.22

53. Coleman TG, Guyton AC: Hypertension caused by salt loading in the dog. Circ Res 1969, XXV:153160. 54. Guyton AC, Hall JE, Coleman TG, et al.: The dominant role of the kidneys in long-term arterial pressure regulation in normal and hypertensive states. In Hypertension: Pathophysiology, Diagnosis, and Management, edn 2. Edited by Laragh JH, Brenner BM. New York: Raven Press; 1995, 78:13111326. 55. Julius S, Nesbitt S: Sympathetic overactivity in hypertension: a moving target. Am J Hypertens 1996, 9:113S120S. 56. Seeliger E, Boemke W, Corea M, et al.: Mechanisms compensating Na and water retention induced by long-term reduction of renal perfusion pressure. Am J Physiol (Regulat Integrative Comp Physiol 42) 1997, 273:R646R654.
48. Siragy HM: Evidence that intrarenal bradykinin plays a role in regulation of renal function. Am J Physiol (Endocrinol Metab28) 1993, 265:E648E654. 49. Ploth DW, Navar LG: Physiologic control of arterial blood pressure and mechanisms of hypertension. In Clinical Approaches to High Blood Pressure in the Young. Edited by Kotchen TA, Kotchen JM. Boston: John Wright, PSG; 1983:2378. 50. Guyton AC, Manning RA, Normon RA, et al.: Current concepts and perspectives of renal volume regulation in relationship to hypertension. J Hypertens 1986, 4(suppl 4):S49S56. 51. DeWardener HE: The primary role of the kidney and salt intake in the aetiology of essential hypertension: part II. Clin Sci 1990, 79:289297. 52. Hamlyn JM, Blaustein MP: Sodium chloride, extracellular fluid volume, and blood pressure regulation. Am J Physiol (Renal Fluid Electrolyte Physiol 20) 1986, 251:F563F575.
Renal Parenchymal Disease and Hypertension

Stephen C. Textor
ypertension and parenchymal disease of the kidney are closely interrelated. Most primary renal diseases eventually disturb sodium and volume control sufficiently to produce clinical hypertension. Both on theoretical and practical grounds, many authors argue that any sustained elevation of blood pressure depends ultimately on disturbed renal sodium excretion, ie, altered pressure natriuresis. Hence, some investigators argue that a clinical state of hypertension represents de facto evidence of disturbed (or reset) renal function even before changes in glomerular filtration can be measured. Many renal insults further induce inappropriate activation of vasoactive systems such as the renin-angiotensin system, adrenergic sympathetic nerve traffic, and endothelin. These mechanisms may both enhance vasoconstriction and act as mediators of additional tissue injury by altering the activity of inflammatory cytokines and promoters of interstitial fibrosis. Arterial hypertension itself accelerates many forms of renal disease and hastens the progression to advanced renal failure. Recent studies have firmly established the importance of blood pressure reduction as a means to slow the progression of many forms of renal parenchymal injury, particularly those characterized by massive proteinuria. Over the long term, damage to the heart and cardiovascular system resulting from hypertension represents the major causes of morbidity and mortality for patients with end-stage renal disease. Here are illustrated the roles of renal parenchymal disease in sustaining hypertension and of arterial pressure reduction in slowing the progression of renal injury. As discussed, parenchymal renal disease may refer to either unilateral (uncommon) or bilateral conditions.
CHAPTER
2.2

FIGURE 2-1 Forms of unilateral renal parenchymal diseases related to hypertension. Many unilateral abnormalities, such as congenital malformations, renal agenesis, reflux nephropathy, and stone disease, do not commonly produce hypertension. However, some unilateral lesions can produce blood pressure elevation. Data for each of these are based primarily on demonstrating unilateral secretion of renin and resolution with unilateral nephrectomy. It should be emphasized that unilateral renal disease does not reduce the overall glomerular filtration rate beyond that expected in patients with a solitary kidney. It follows that additional reductions in the glomerular filtration rate must reflect bilateral renal injury.
FORMS OF UNILATERAL RENAL PARENCHYMAL DISEASE RELATED TO HYPERTENSION

Renal artery stenosis Atherosclerosis and fibromuscular lesions (Chapter X) Small vessel disease Vasculitis Atheroembolic renal infarction Thrombosis and infarction Traumatic injury Renal fracture Perirenal fibrosis (Page kidney) Radiation injury Arteriovenous malformation or fistulas Other diseases Renal carcinoma Enlarging renal cyst Multiple renal cysts Renin-secreting tumors (rare)
FIGURE 2-2 Angiogram and nephrogram of a persistent fractured kidney. The kidney damage shown here produced hypertension in a young woman 2 years after a motor vehicle accident. Measurement of renal vein renins confirmed unilateral production of renin from the affected side. Blood pressure control was achieved with blockade of the renin-angiotensin system using an angiotensin II receptor antagonist (losartan). Many traumatic injuries to the kidney produce temporary hypertension when a border of viable but underperfused renal tissue remains.
Prevalence of Hypertension in Chronic Renal Disease

80 Prevalence of hypertension, % 70 60 50 40 30 20 10 0 CIN APKD MCN IgA MGN DN MPGN FSGN
FIGURE 2-3 Prevalence of hypertension in chronic renal parenchymal disease. Most forms of renal disease are associated with hypertension. This association is most evident with glomerular diseases, including diabetic nephropathy (DN) and membranoproliferative glomerulonephritis (MPGN), in which 70% to 80% of patients are affected. Minimal change nephropathy (MCN) is a notable exception. Tubulointerstitial disorders such as analgesic nephropathy, medullary cystic diseases, and chronic reflux nephropathies are less commonly affected. APKDadult-onset polycystic kidney disease; CINchronic interstitial nephritis; FSGNfocal segmental glomerulonephritis; MGN membranous glomerulonephritis. (Data from Smith and Dunn [1].)
2.3
100 90
Mean GFR=39 mL/min/1.73 m2
*n=255 patients Mean GFR=18.5 mL/min/1.73 m2
80 70 60 % 50 40 30 20 10 0
MDRD: Study B*
MDRD: Study A
NHANES estimates
FIGURE 2-4 Prevalence of hypertension requiring therapy as a function of the degree of chronic renal failure in the Modification of Diet in Renal Disease (MDRD) trial on progressive renal failure. The mean age of these patients was 52 years, with glomerular disease (25%) and polycystic disease (24%) being the most common renal diagnoses in this trial. In Study B, more than 90% of patients were treated with antihypertensive agents, including diuretics, to achieve an overall average blood pressure of 133/81 mm Hg. In general, the more severe the level of renal dysfunction, the more antihypertensive therapy is required to achieve acceptable blood pressures. Patients with glomerular filtration rates (GRFs) below 10 mL/min were hypertensive in 95% of cases. NHANESNational Health and Nutrition Examination Survey. (Data from Klahr and coworkers [2].)
US Population
80 Prevalence of hypertension, % 70 60 50 40 30 20 10 0 Acute GN Acute IN
Early Late
FIGURE 2-5 Hypertension in acute renal disease. Acute renal failure is defined as transient increases in serum creatinine above 5.0 mg/dL. During the course of acute renal failure, worsening of preexisting levels or newly detected hypertension (>140/90 mm Hg) is common and almost universally observed in patients with acute glomerulonephritis (GN). Many of these patients have lower pressures as the course of acute renal injury subsides, although residual abnormalities in renal function and sediment may remain. Blood pressure returns to normal in some but not all of these patients. Overall, 39% of patients with acute renal failure develop new hypertension. INinterstitial nephritis. (Adapted from RodriguezIturbe and coworkers [3]; with permission.)
FIGURE 2-6 (see Color Plate) Micrograph of an onion skin lesion from a patient with malignant hypertension.
2.4
Pathophysiology of Hypertension in Renal Disease

x
FIGURE 2-7 Pathophysiologic mechanisms related to hypertension in parenchymal renal disease: schematic view of candidate mechanisms. The balance between cardiac output and systemic vascular resistance determines blood pressure. Numerous studies suggest that cardiac output is normal or elevated, whereas overall extracellular fluid volume is expanded in most patients with chronic renal failure. Systemic vascular resistance is inappropriately elevated relative to cardiac output, reflecting a net shift in vascular control toward vasoconstricting mechanisms. Several mechanisms affecting vascular tone are disturbed in patients with chronic renal failure, including increased adrenergic tone and activation of the reninangiotensin system, endothelin, and vasoactive prostaglandins. An additional feature in some disorders appears to depend on reduced vasodilation, such as in impaired production of nitric oxide.
Blood pressure =
Cardiac output
Systemic vascular resistance
Increased extracellular fluid volume Decreased glomerular filtration rate Impaired sodium excretion Increased renal nerve activity Ineffective natriuresis, eg, atrial natriuretic peptide resistance
Increased contraction Increased adrenergic activation
Increased vasoconstriction Increased adrenergic stimuli Inappropriate renin-endothelin release Increased endothelin-derived contracting factor Increased thromboxane
Decreased vasodilation Decreased prostacyclin Decreased nitric oxide
7 Intake and output of water and salt (x normal) Intake and output of water and salt (x normal) 6 5 4 3
Normal
D
7
kid G o ld ne blat t ys Al do ste ron e-s tim ula ted
6 5 4 3 2 1 0
Normal intake Low intake A H B
High intake
E s se n hyp tial erte nsio n
Normal
High intake
F G
2 1 0 0 50
Normal intake Low intake
A C
ss ma al ren of ss D Lo C
100 150 Arterial pressure, mm Hg
200
50
100 150 Arterial pressure, mm Hg
200
FIGURE 2-8 A, The relationship between renal artery perfusion pressure and sodium excretion (which defines pressure natriuresis) has been the subject of extensive research. Essential hypertension is characterized by higher renal perfusion pressures required to achieve daily sodium balance. B, Distortion of this relationship routinely occurs in patients with parenchymal renal disease, illustrated here
as loss of renal mass. Similar effects are observed in conditions with disturbed hormonal effects on sodium excretion (aldosterone-stimulated kidneys) or reduced renal blood flow as a result of an arterial stenosis (Goldblatt kidneys). In all of these instances, higher arterial pressures are required to maintain sodium balance.

200 Percentage of body weight, kg Total blood volume, mL/cm 130
Hemodialysis
2.5
40
Cumulative daily sodium intake
0
Cumulative urinary sodium loss
126
35
400 Sodium, mEq 800
122
30
118 F 10.0 S S M T W TH Days F S S M
Sodium losses during hemodialysis or ultrafiltration Net sodium loss
1200
1600
Plasma renin activity, mg/mL/h
5.0
Uremic control subjects
Total net loss of sodium=1741 mEq
M T
W TH F Days
S M
Blood pressure, mm Hg
180
Captopril, 25 mg
140
100
FIGURE 2-9 Sodium expansion in chronic renal failure. The degree of sodium expansion in patients with chronic renal failure can be difficult to ascertain. A, Shown are data regarding body weight, plasma renin
activity, and blood pressure (before and after administration of an ACE inhibitor) over 11 days of vigorous fluid ultrafiltration. Sequential steps were undertaken to achieve net negative sodium and volume losses by means of restricting sodium intake (10 mEq/d) and initiating ultrafiltration to achieve several liters of negative balance with each treatment. A negative balance of nearly 1700 mEq was required before evidence of achieving dry weight was observed, specifically a reduction of blood pressure. Measured levels of plasma renin activity gradually increased during sodium removal, and blood pressure became dependent on the renin-angiotensin system, as defined by a reduction in blood pressure after administration of the angiotensin-converting enzyme inhibitor captopril. Achieving adequate reduction of both extracellular fluid volume and sodium is essential to satisfactory control of blood pressure in patients with renal failure. B, Daily and cumulative sodium balance.
Plasma renin Cumulative sodium balance, mEq activity, ng/mL/hr
Angiotensin II inhibitor, g/kg/min 5 10 50 100 10 10 Saline infusion L40
200
150 100
200
FIGURE 2-10 Interaction between sodium balance and angiotensin-dependence in malignant hypertension. Studies in a patient with renal dysfunction and accelerated hypertension during blockade of the renin-angiotensin system using Sar-1-ala-8-angiotensin II demonstrate the interaction between angiotensin and sodium. Reduction of blood pressure induced by the angiotensin II antagonist was reversed during saline infusion with a positive sodium balance and reduction in circulating plasma renin activity. Administration of a loop diuretic (L40 [furosemide], 40 mg intravenously) induced net sodium losses, restimulated plasma renin activity, and restored sensitivity to the angiotensin II antagonist. Such observations further establish the reciprocal relationship between the sodium status and activation of the renin-angiotensin system [5]. (From Brunner and coworkers [5]; with permission.)
100 0 100 50 0 0 1 11 35 38 41 Hours 65 67
2.6

FIGURE 2-11 A, Sympathetic neural activation in chronic renal disease. Adrenergic activity is disturbed in chronic renal failure and may participate in the development of hypertension. Microneurographic studies in patients undergoing hemodialysis demonstrate enhanced neural traffic (panel A) that relates closely to peripheral vascular tone [6]. Studies in patients in whom native kidneys are removed by nephrectomy demonstrate normal levels of neural traffic, suggesting that afferent stimuli from the kidney modulate central adrenergic outflow. B, Delayed onset hypertension in denervated rats. Panel B shows evidence from experimental studies in denervated animals subjected to deoxycorticosteronesalt hypertension. The role of the renal nerves in modifying the development of hypertension is supported by studies of renal denervation that show a delayed onset of hypertension, although no alteration in the final level of blood pressure was achieved. NSnot significant. (Panel A from Converse and coworkers [6]; with permission. Panel B from Katholi and coworkers [7]; with permission.)
15 s
Normal person
Hemodialysis, bilateral nephrectomy
Hemodialysis, no nephrectomy
Neurogram
Electrocardiogram
3s
200 Systolic blood pressure, mm Hg 190 180 170 160 150 140 130 120 110
NS
Sham Renal denervated
NS
<0.01 <0.001 <0.001 <0.01 <0.05 <0.05 <0.05
NS
5 10 15 20 25 30 Deoxycorticosterone acetatesalt administration, d
35
2.7
MAJOR CANDIDATE MECHANISMS THAT MAY ELEVATE PERIPHERAL VASCULAR RESISTANCE IN RENAL PARENCHYMAL DISEASE
Increased vasoconstrictors
Renin-angiotensin system Endothelin Prostanoids: thromboxane Arginine vasopressin Endogenous digitalis-like substance: ouabain (?)
Impaired or relatively inadequate vasodilators

Nitric oxide: inadequate compensation Vasodilator prostaglandins: prostacyclin 2 Natriuretic peptides: atrial natriuretic peptide Kallikrein-kinin system
FIGURE 2-12 Major candidate mechanisms that may elevate peripheral vascular resistance in renal parenchymal disease. Some data support each of these pathways, although rarely does one mechanism predominate. Experimental studies suggest that endothelin-1 may magnify interstitial fibrosis and contribute to hypertension in some models; however, rarely is the effect major [8,9]. Most levels of vasodilators, including nitric oxide, prostacyclin, and atrial natriuretic peptide, are normal or elevated in patients with renal disease. The vasodilators appear to buffer the vasoconstrictive actions of angiotensin II, which may be increased abruptly if the vasodilator is removed, as occurs with inhibition of cyclo-oxygenase with the use of nonsteroidal antiinflammatory drugs.
Sham-operated rats
Rats with renal mass reduction
80 Urinary endothelin, ng/d 60 40
Urinary endothelin excretion, pg/d
Mean SEM *P<0.01 vs pretransplantation P<0.01 vs normal subjects
200 160 120 80 40 0
Horizontal bars=mean values P<0.01 vs basal
20 0
Normal
Pretransplantation
12 mo
24 mo
Basal
Day 45
Basal
Day 45
FIGURE 2-13 Urinary endothelin in renal disease. A, Urinary endothelin levels in patients with cyclosporine-induced renal dysfunction and hypertension before and after liver transplantation. These patients had near-normal kidney function before liver transplantation, after which their glomerular filtration rates decreased from 85 to 55 mL/min, on average. These data underscore the observation that the kidney itself is a rich source of vasoactive materials and that renal excretion of substances such as endothelin is independent of circulating blood levels [10]. Endothelin has properties that both facilitate vasoconstriction and enhance mitogenic and fibrogenic responses, perhaps accelerating interstitial fibrosis in the kidney. Early withdrawal of cyclosporine leads to reversal of a
diminished glomerular filtration rate. With time, however, these changes lose the feature of reversibility [11]. B, Renal ablation. Urinary endothelin levels in rats exposed to reduced renal mass achieved by 5/6 nephrectomy. As in humans, plasma levels of endothelin were dissociated from urinary levels, and injected endothelin was not excreted. These results suggest that urinary levels were of renal origin. These studies further support the concept that the diminished nephron number elicits production of potent vasoactive and inflammatory materials that may accelerate irreversible parenchymal injury. (Panel A from Textor and coworkers [10]; with permission. Data in panel B from Benigni and coworkers [12].)
2.8
Renal parenchymal disease
PHARMACOLOGIC AGENTS THAT COMMONLY AGGRAVATE OR INDUCE HYPERTENSION IN PARENCHYMAL RENAL DISEASE
Increased cytokine Increased growth factors Cellular proliferation Corticosteroids Cyclosporine Erythropoietin Nonsteroidal anti-inflammatory drugs
Decreased afferent resistance Decreased efferent resistance Impaired autoregulation
Increased angiotensin Increased norepinephrine Increased endothelin Systemic hypertension
Other agents
Over-the-counter sympathomimetic agents, eg, phenylpropanolamine Supplements containing ephedrine Oral contraceptives (less common with low-dose forms) Amphetamines and stimulants, eg, methylphenidate hydrochloride and cocaine
Increased glomerular pressure
Increased glomerular volume
Increased glomerular pressure
FIGURE 2-14 Mechanisms of glomerular injury in hypertension and progressive renal failure. This schematic diagram summarizes the general mechanisms by which disturbances linked to elevated arterial pressure in patients with parenchymal renal disease may lead to further tissue injury. Hemodynamic changes lead to increased glomerular perfusion pressures, whereas local activation of growth factors, angiotensin, and probably several other factors both worsen peripheral resistance and increase tissue fibrotic mechanisms. (From Smith and Dunn [1].)
FIGURE 2-15 Many pharmacologic agents affect blood pressure levels or the effectiveness of antihypertensive therapy. Shown here are several agents that commonly lead to worsening hypertension and are likely to be administered to patients with renal disease.
Mean arterial pressure, mL/min
160 150 140 130 120 110 * *
120 90 60 30 1 min
* *
Control 10 g LNAME 50 g LNAME
Heart rate, bpm
280 240 200

L-NAME L-Arginine
Renal plasma flow, mL/min
4.0 3.0 2.0 1.0 1.2 1.0 0.8 Control 60' 120' * * * * * * * *
Results=meansstandard error *P<0.05 compared with controls
100 mg kg-1
300 mg kg-1
* *
FIGURE 2-16 Increase in arterial pressure induced by inhibition of nitric oxide. A, Intra-arterial pressure in rabbits during N-nitro-L-arginine methyl ester (L-NAME) infusion. B, Decrease in renal plasma flow and glomerular filtration rate in the blood pressures of rats during nitric oxide inhibition. (Continued on next page)
Glomerular filtration rate, mL/min
180'
2.9
21 Urinary sodium excretion, Eq/min 19 17 15 13 11 9 140 Urinary flow rate, mL/min 120 100 80
Control 10 g/kg/min L NAME 50 g/kg/min L NAME
* *
Results=meansstandard error *P<0.05 compared with controls
FIGURE 2-16 (Continued) C, Urine flow rate and urinary sodium excretion over time. Inhibition of nitric oxide synthesis from L-arginine by a competitive substrate such as L-NAME produces dose-dependent and widespread vasoconstriction, leading to an increase in blood pressure [13]. Within specific regional beds such as the kidney, inhibition of nitric oxide produces a decrease in renal plasma flow, diminished glomerular filtration, and sodium retention [14]. The magnitude of these changes in normal animals and humans suggests that tonic nitric oxide production is a major endothelial buffering mechanism preserving vascular tone. The degree to which renal parenchymal disease alters the production of nitric oxide is not known precisely. In some situations, such as nephrotoxicity associated with cyclosporine administration, endothelial production of nitric oxide appears to be substantially impaired [15]. (Panel A from Rees and coworkers [13]; with permission. Panel B from Lahera and coworkers [14]; with permission.)
* 60
Control
60'
120'
180'
Clinical Features of Hypertension in Renal Disease

A. HYPERTENSION IN PARENCHYMAL RENAL DISEASE: CLINICAL MANIFESTATIONS OF HYPERTENSIVE DISEASE
Cardiovascular disease
Myocardial infarction Congestive heart failure Atherosclerotic vascular disease Claudication and limb ischemia Aneurysm 100 90 80 70 60 50 40 30 20 10 0
Cardiac Vascular Infection Other
Central nervous system

Stroke Intracerebral hemorrhage
Progressive renal injury

End-stage renal disease Increased proteinuria
B FIGURE 2-17 A and B, Major target organ manifestations of hypertension producing cardiovascular morbidity and mortality in patients with renal disease. More than half of deaths are related to cardiovascular disease in both patients on dialysis and transplantation recipients. These observations underscore the major risk for cardiovascular morbidity and mortality associated with hypertension in the population with chronic renal failure. (From Whitworth [16]; with permission.)
Percentage of total
Transplantation Dialysis
2.10
Blood pressure
Left ventricular hypertrophy
Congestive heart failure Percentage of total
40 35 30 25 20 15 10 5
Blood pressure
Death: Congestive heart failure Overall mortality
A FIGURE 2-18 Based on average blood pressure values, a strong direct relationship was found between arterial pressure and left ventricular hypertrophy, left ventricular chamber dilation (by echocardiography), and systolic dysfunction in patients undergoing dialysis for end-stage renal disease. After prolonged follow-up, blood pressures fell with the onset of congestive heart failure and manifest coronary artery disease. With the onset of cardiac failure, there appeared to be an inverse relationship between arterial pressure and mortality. From the outset, the strongest predictor of congestive heart failure was elevated blood pressure. (Adapted from Foley and coworkers [17].)
0 Left ventricular Systolic Left ventricular chamber dilation dysfunction hypertrophy
250
Awake: 156/101 mm Hg Nocturnal: 167/100 mm Hg
200
Blood pressure values Heart rate
150 140 100 90 50

MMMM Rx F d MMMM Fd ZZZZZ Rx RxZZZ ZZZZZZZZZZZZZZZZZZ MMMM
0 0.0 10a 12n 2p 4p 6p 8p 10p 12m Real time data 2a 4a 6a 8a
FIGURE 2-19 Around-the-clock ambulatory blood pressure monitoring in a patient with renal disease. Loss of diurnal blood pressure patterns have been implicated in increased rates of target organ injury in patients with hypertension. In normal persons with essential hypertension, nocturnal pressures decreased by at least 10% and were associated with a decrease in heart rate. Several conditions have been associated with a loss of the nocturnal decrease in pressure, particularly chronic steroid administration and chronic renal failure. Such a loss in normal circadian rhythm, in particular loss of the nocturnal decrease in blood pressure is more commonly associated with left ventricular hypertrophy and lacunar strokes (manifested as enhanced T-2 signals in magnetic resonance images) and increased rates of microalbuminuria. Data from a single subject with end-stage renal disease studied with are depicted here.
2.11
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 May 1979 Feb 1982 Nov 1984 Aug 1987 May 1990 Date Jan 1993 Oct 1995 Jul 1998
A
FIGURE 2-20 (see Color Plate) Hypertension accelerates the rate of progressive renal failure in patients with parenchymal renal disease. A, Photomicrograph of malignant phase hypertension. Regardless of the cause of renal disease, untreated hypertension leads to more rapid loss of remaining nephrons and decline in glomerular filtration rates. A striking example of pressure-related injury may be observed in patients with malignant phase hypertension. This image is an open biopsy specimen obtained from a patient with papilledema, an expanding aortic aneurysm, and
blood pressure level at approximately 240/130 mm Hg. The biopsy specimen shows the following features of malignant nephrosclerosis: these patients develop vascular and glomerular injury, which can progress to irreversible renal failure. Before the introduction of antihypertensive drug therapy, patients with malignant phase hypertension routinely proceeded to uremia. Effective antihypertensive therapy can slow or reverse this trend in some but not all patients. B, Progressive renal failure in malignant hypertension over 8 years.
1/Creatinine 0.12 0.10 Proportion with ESRD 0.08 0.06

165<SBP180 n=11,912 men P<0.001
100
SBP>180 White=300,645 Black=20,222 83.1
Incidence per 100,000 person-years, %
80
N=332,544 men
60
40
27.34 26.18 14.22 5.41 9.1
37.21 32.37
0.04 0.02
SBP165
20
5.43
15.83
0.00 0 1 2
0 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Years from beginning therapy to ESRD <117
117123 124130 131140 Systolic blood pressure, mm Hg
>140
FIGURE 2-21 Blood pressure levels and rates of end-stage renal disease (ESRD). A, Line graph showing Kaplan-Meier estimates of ESRD rates; 15-year follow-up. B, Age-adjusted 16-year incidence of all-cause ESRD in men in the Multiple Risk Factor Intervention Trial (MRFIT). Largescale epidemiologic studies indicate a progressive increase in the risk for developing ESRD as a function of systolic blood pressure levels. Follow-up of nearly 12,000 male veterans in the United States established that systolic blood pressure above 165 mm Hg at the initial visit was predictive of progressively higher risk of ESRD over a 15-year
follow-up period [18]. Similarly, follow-up studies after 16 years of more than 300,000 men in MRFIT demonstrated a progressive increase in the risk for ESRD, most pronounced in blacks [19]. These data suggest that blood pressure levels predict future renal disease. However, it remains uncertain whether benign essential hypertension itself induces a primary renal lesion (hypertensive renal disease nephrosclerosis) or acts as a catalyst in patients with other primary renal disease, otherwise not detected at initial screening. SBPsystolic blood pressure. (Panel A from Perry and coworkers [18]; with permission.)
2.12
50
0 Ccr, mL/min 40 30 20 4 mL/mmol-1 3 2 1 400 200 Days 0 +200 +400

Chronic glomerulonephritis: Rates of progression over time decrease after reduction of BP from 149/102 mm Hg to treated level, 136/90 mm Hg.
0 3 6
Protein excretion, g/d 00.25 1.03.0 0.251 3.0 Study A: mean GFR: 39 mL/min/1.73 m2 N=585: range: 2555 mL/min
Decrease in glomerular filtration rate, mL/min/y
3 6 9
9 12 15 18 107
12 15
Cr-1/s,
18
86
92 98 Mean follow-up MAP, mm Hg
FIGURE 2-22 Rates of progression in glomeruloneophritis. The decrease in glomerular filtration rate is illustrated. The rates of decline decreased considerably with administration of antihypertensive drug therapy. Among other mechanisms, the decrease in arterial pressure lowers transcapillary filtration pressures at the level of the glomerulus [20]. This effect is correlated with a reduction in proteinuria and slower development of both glomerulosclerosis and interstitial fibrosis. A distinctive feature of many glomerular diseases is the massive proteinuria and nephron loss associated with high single-nephron glomerular filtration, partially attributable to afferent arteriolar vasodilation. The appearance of worsening proteinuria (>3 g/d) is related to progressive renal injury and development of renal failure. Reduction of arterial pressure can decrease urinary protein excretion and slow the progression of renal injury. Ccrcreatinine clearance rate; Cr-1/sreciprocal creatinine, expressed as 1/creatinine. (From Bergstrom and coworkers [20]; with permission.)
FIGURE 2-23 Blood pressure, proteinuria, and the rate of renal disease progression: results from the Modification of Diet in Renal Disease (MDRD) trial. Shown are rates of decrease of glomerular filtration rate (GFR) for patients enrolled in the MDRD trial, depending on level of achieved treated blood pressure during the trial [21]. A component of this trial included strict versus conventional blood pressure control. The term strict was defined as target mean arterial pressure (MAP) of under 92 mm Hg. The term conventional was defined as MAP of under 107 mm Hg. The rate of decline in GFR increased at higher levels of achieved MAP in patients with significant proteinuria (>3.0 g/d). No such relationship was evident over the duration of this trial (mean, 2.2 years) for patients with less severe proteinuria. These data emphasize the importance of blood pressure in determining disease progression in patients with proteinuric nondiabetic renal disease. No distinction was made in this study regarding the relative benefits of specific antihypertensive agents. (From Peterson and coworkers [21]; with permission.)
Effects of Antihypertensive Therapy on Renal Disease Progression

FIGURE 2-24 Blood pressure and rate of progressive renal failure. Rates of disease progression (defined as the slope of 1/creatinine) were determined in 86 patients who reached end-stage renal disease and dialytic therapy. The rates of progression were defined between mean creatinine levels of 3.8 mg/dL (start) and 11.4 mg/dL (end) over a mean duration of 33 months [22]. Brazy and coworkers [22] demonstrated that the slope of disease progression appeared to be related to the range of achieved diastolic blood pressure during this interval. Hence, these authors argue that more intensive antihypertensive therapy may delay the need for replacement therapy in patients with end-stage renal disease. As noted in the Modification of Diet in Renal Disease trial, such benefits are most apparent in patients with proteinuria over a shorter follow-up period. (From Brazy and coworkers [22]; with permission.)
Slope of 1/creatinine vs time, dL/mg mo
0.006 0.008 0.010 0.012 0 8590 7085 9096 96113 Range of diastolic blood pressure (mm Hg) for each quartile of the population
2.13
CLASSES OF ANTIHYPERTENSIVE AGENTS USED IN TREATMENT OF CHRONIC RENAL DISEASE

Diuretics: Thiazide class Loop diuretics Potassium-sparing agents Adrenergic inhibitors Peripheral agents, eg, guanethidine Central -agonists, eg, clonidine, methyldopa, and guanfacine -Blocking agents, eg, doxazosin -Blocking agents Combined - blocking agents, eg, labetalol Vasodilators Hydralazine Minoxidil Classes of calcium-channel blocking agents Verapamil Diltiazem Dihydropyridine Angiotensin-converting enzyme inhibitors Angiotensin receptor blockers
FIGURE 2-25 The current classification of agents applied for chronic treatment of hypertension as summarized in the report by the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure [23]. Attention must be given to drug accumulation and limitations of individual drug efficacy as glomerular filtration rates decrease in chronic renal disease. Potassium levels may increase during administration of potassium-sparing agents and medications that inhibit the renin-angiotensin system, especially in patients with impaired renal function [24].
60 55 GFR, mL/min/1.73 m2/y 50 45 40 35 30 25 6 0 6 12 18
4
Conventional Strict n=87 patients Bars=95% confidence intervals for GFR estimates
Rate of change in GFR, mL/min/1.73 m2/y
3 2
Mean SEM
0 1 2 3
24 30 Time, mo
36
42
48
Strict Conventional Blood pressure control group
FIGURE 2-26 Strict blood pressure control and progression of hypertensive nephrosclerosis. Whether vigorous blood pressure reduction reduces progression of early parenchymal renal disease in blacks with nephrosclerosis is not yet certain. A and B, A randomized prospective trial comparing strict (panel A) blood pressure control (defined as diastolic blood pressure [DBP] <80 mm Hg) with conventional (panel B) levels of diastolic control between 85 and 95 mm Hg for more than 3 years could not identify a reduction in rates of disease progression [25]. Of patients, 68 of 87 were black. Rates of progression in
these patients were low. It should be emphasized that entry criteria excluded patients with diabetes and massive proteinuria. Initial studies from the African American Study of Kidney Disease trial confirm that biopsy findings in most patients with clinical features of hypertension were considered consistent with primary hypertensive disease [26]. Whether lower than normal levels of blood pressure in these patients will prevent progression to end-stage renal disease over longer time periods remains to be determined. GFRglomerular filtration rate. (From Toto and coworkers [25]; with permission.)
2.14
100 90 80 Patients who died or needed dialysis or transplantation, % 70 60 50 40 30 20 10 0 0.0

FIGURE 2-27 Angiotensin-converting enzyme (ACE) inhibitors and chronic renal disease. Progression of type I diabetic nephropathy to renal failure was reduced in the ACE inhibitor arm of a trial comparing conventional antihypertensive therapy with a regimen containing the ACE inhibitor captopril. All patients in this trial had significant proteinuria (>500 mg/d). The most striking effect of the ACE inhibitor regimen was seen in patients with higher serum creatinine levels (>1.5 mg/dL) as shown in the top two lines. It should be noted that calcium channel blocking drugs were excluded from this trial and the ACE inhibitor arm had somewhat lower arterial pressures during treatment. These data offer support to the concept that ACE inhibition lowers intraglomerular pressures, reduces proteinuria, and delays the progression of diabetic nephropathy by more mechanisms than can be explained by pressure reduction alone. (Data from Lewis and coworkers [27].)
P=0.002
P=0.14
0.5
1.0 44 52 148 152
1.5 40 51 146 150
Creatinine 1.5 mg/dL Placebo 49 48 Captopril 53 53 Creatinine <1.5 mg/dL Placebo 153 150 Captopril 154 154
2.0 2.5 Years of follow-up 33 48 138 147 23 36 98 104
3.0 16 25 84 78
3.5 7 17 52 47
4.0 1 8 25 29
2.6
Benazepril: n=583 patients; creatinine=1.54.0 Placebo
2.6
Benazepril: n=583 patients; creatinine=1.54.0 Placebo 117
2.4
239
2.4
137
262
2.2
2.2
2.0
2.0
Years
Years
FIGURE 2-28 Angiotensin-converting enzyme (ACE) inhibition in nondiabetic renal disease. A and B, Shown here are serum creatinine levels from the 12-month (panel A) and 36-month (panel B) cohorts followed in the benazepril trial. In this trial, 583 patients were randomized to therapy with or without benazepril [28]. Slight reductions in the rates of increase in creatinine and of stop points in the ACE inhibitor group occurred; however, these reductions were modest. Whereas these
data support a role for ACE inhibition, the results are considerably less convincing than are those for diabetic nephropathy. These results argue that some groups may not experience major benefit from ACE inhibition over the short term. Preliminary reports from recent studies limited to patients with proteinuria suggest that rates of progression were substantially reduced by treatment with ramipril [29]. (From Maschio and coworkers [28]; with permission.)
2.15
CONCLUSIONS AND RECOMMENDATIONS OF THE SIXTH REPORT OF THE JOINT NATIONAL COMMITTEE ON PREVENTION, DETECTION, EVALUATION AND TREATMENT OF HIGH BLOOD PRESSURE, 1997
1. Hypertension may result from renal disease that reduces functioning nephrons. 2. Evidence shows a clear relationship between high blood pressure and end-stage renal disease. 3. Blood pressure should be controlled to 130/85 mm Hg (<125/75 mm Hg) in patients with proteinuria in excess of 1 g/24 h. 4. Angiotensin-converting enzyme inhibitors work well to lower blood pressure and slow progression of renal failure.
FIGURE 2-29 Conclusions and Recommendations of the Sixth Report of the Joint National Committee (JNC) on Prevention, Detection, Evaluation and Treatment of High Blood, 1997 [23]. The JNC Committee has emphasized the importance of vigorous blood pressure control with any agents needed, rather than specific classes of medication. Angiotensin-converting enzyme inhibitors in proteinuric disease are the exception.
References
1. Smith MC, Dunn MJ: Hypertension in renal parenchymal disease. In Hypertension: Pathophysiology, Diagnosis and Management. Edited by Laragh JH, Brenner BM. New York: Raven Press; 1995:20812102. 2. Klahr S, Levey AS, Beck GJ, et al.: The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N Engl J Med 1994, 330:877884. 3 Rodriguez-Iturbe B, Baggio B, Colina-Chouriao J, et al.: Studies on the renin-aldosterone system in the acute nephritic syndrome. Kidnet Int 1981, 445453 4. Curtiss JJ, Luke RG, Dustan HP, et al.: Remission of essential hypertension after renal transplantation. N Engl J Med 1983, 309:10091015. 5. Brunner HR, Gavras H, Laragh JH: Specific inhibition of the reninangiotensin system: a key to understanding blood pressure regulation. Prog Cardiovasc Dis 1974; 17:8798. 6. Converse RL, Jacobsen TN, Toto RD, et al.: Sympathetic overactivity in patients with chronic renal failure. N Engl J Med1992, 327:19121918. 7. Katholi RE, Nafilan AJ, Oparil S: Importance of renal sympathetic tone in the development of DOCA-salt hypertension in the rat. Hypertension 1980, 2:266273. 8. Benigni A, Zoja C, Cornay D, et al.: A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression. Kidney Int 1993, 44:440444. 9. Levin ER: Mechanisms of disease: endothelins. N Engl J Med 1995, 333:356363. 10. Textor SC, Burnett JC, Romero JC, et al.: Urinary endothelin and renal vasoconstriction with cyclosporine or FK506 after liver transplantation. Kidney Int 1995, 47:14261433. 11. Sandborn WJ, Hay JE, Porayko MK, et al.: Cyclosporine withdrawal for nephrotoxicity in liver transplant recipients does not result in sustained improvement in kidney function and causes cellular and ductopenic rejection. Hepatology 1994, 19:925932. 12. Benigni A, Perico N, Gaspari F, et al.: Increased renal endothelin production in rats with renal mass reduction. Am J Physiol 1991, 260:F331F339. 13. Rees DD, Palmer RMJ, Moncada S: Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci U S A 1989, 86:33753378. 14. Lahera V, Salom MG, Miranda-Guardiola F, et al.: Effects of N-nitroL-arginine methyl ester on renal function and blood pressure. Am J Physiol 1991, 261:F1033F1037. 15. Gaston RS, Schlessinger SD, Sanders PW, et al.: Cyclosporine inhibits the renal response to L-arginine in human kidney transplant recipients. J Am Soc Nephrol 1995, 5:14261433. 16. Whitworth JA: Renal parenchymal disease and hypertension. In Clinical Hypertension. Edited by Robertson JIS. Amsterdam: Elsevier, 1992:326350. 17. Foley RN, Parfrey PS, Harnett JD, et al.: Impact of hypertension on cardiomyopathy, morbidity and mortality in end-stage renal disease. Kidney Int 1996, 49:13791385. 18. Perry HM, Miller JP, Fornoff JR, et al.: Early predictors of 15-year end-stage renal disease in hypertensive patients. Hypertension 1995, 25(part 1):587594. 19. Klag MJ, Whelton PK, Randall BL, et al.: End-stage renal disease in African-American and White men. JAMA 1997, 277:12931298. 20. Bergstrom J, Alvestrand A, Bucht H, Guttierrez A: Progression of chronic renal failure in man is retarded with more frequent clinical follow-ups and better blood pressure control. Clin Nephrol 1986, 25:16. 21. Peterson JC, Adler S, Burkart JM, et al.: Blood pressure control, proteinuria and the progression of renal disease. Ann Intern Med 1995; 123:754762. 22. Brazy PC, Stead WW, Fitzwilliam JF: Progression of renal insufficiency: role of blood pressure. Kidney Int 1989, 35:670674. 23. JNC Committee: Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Bethesda, MD: National Institutes of Health Publication; 1997. 24. Textor SC: Renal failure related to ACE inhibitors. Semin Nephrol 1997, 17:6776. 25. Toto RD, Mitchell HC, Smith RD, et al.: Strict blood pressure control and progression of renal disease in hypertensive nephrosclerosis. Kidney Int 1995, 48:851859. 26. Fogo A, Breyer JA, Smith MC, et al.: Accuracy of the diagnosis of hypertensive nephrosclerosis in African-Americans: a report from the African American Study of Kidney Disease (ASSK) trial. Kidney Int 1997; 51:244252. 27. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993, 329:14561462. 28. Maschio G, Alberti D, Janin G, et al.: Effect of the angiotensin-converting enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996, 334:939945. 29. Ruggenenti P, Perna A, Mosconi M, et al.: The angiotensin converting enzyme inhibitor ramipril slows the rate of GFR decline and the progression to end-stage renal failure in proteinuric, non-diabetic chronic renal diseases [abstract]. J Am Soc Nephrol 1997, 8:147A. 30. Giatras I, Lau J, Levey AS: Effect of angiotensin-converting enzyme inhibitors on the progression of non-diabetic renal disease: a metaanalysis of randomized trials. Ann Intern Med 1997, 127:345.
Renovascular Hypertension and Ischemic Nephropathy

Marc A. Pohl
he major issues in approaching patients with renal artery stenosis relate to the role of renal artery stenosis in the management of hypertension, ie, renovascular hypertension, and to the potential for vascular compromise of renal function, ie, ischemic nephropathy. Ever since the original Goldblatt experiment in 1934, wherein experimental hypertension was produced by renal artery clamping, countless investigators and clinicians have been intrigued by the relationship between renal artery stenosis and hypertension. Much discussion has focused on the pathophysiology of renovascular hypertension, the renin angiotensin system, diagnostic tests to detect presumed renovascular hypertension, and the relative merits of surgical renal revascularization (SR), percutaneous transluminal renal angioplasty (PTRA), and drug therapy in managing patients with renal artery stenosis and hypertension. Hemodynamically significant renal artery stenosis, when bilateral or affecting the artery to a solitary functioning kidney, can also lead to a reduction in kidney function (ischemic nephropathy). This untoward observation may be reversed by interventive maneuvers, eg, surgical renal revascularization, PTRA, or renal artery stenting. The syndrome of ischemic renal disease or ischemic nephropathy now looms as an important clinical condition and has attracted the fascination of nephrologists, vascular surgeons, and interventional cardiologists and radiologists. The detection of renal artery stenosis in a patient with hypertension usually evokes the assumption that the hypertension is due to the renal artery stenosis. However, renal artery stenosis is not synonymous with renovascular hypertension. On the basis of autopsy studies and clinical angiographic correlations, high-grade atherosclerotic renal artery stenosis (ASO-RAS) in patients with mild blood pressure elevation or in patients with normal arterial pressure is well recognized. The vast majority of patients with ASO-RAS who have hypertension have essential hypertension, not renovascular hypertension. These hypertensive patients with ASO-RAS are rarely cured of their hypertension by interventive procedures that either bypass or
CHAPTER
3.2

chronic subcapsular hematoma, and unilateral ureteral obstruction may also be associated with hypertension that is relieved when the affected kidney is removed. These clinical analogues of the experimental Page kidney reflect the syndrome of renovascular hypertension (RVHT), but without main renal artery stenosis. Takayasus arteritis and atheroembolic renal disease are additional examples of RVHT without main renal artery stenosis. Accordingly, the anatomic presence of renal artery stenosis should not be equated with renovascular hypertension and the syndrome of RVHT need not reflect renal artery stenosis. This chapter reviews the types of renal arterial disease associated with RVHT, the pathophysiology of RVHT, clinical features and diagnostic approaches to renal artery stenosis and RVHT, evolving concepts regarding ischemic nephropathy, and management considerations in patients with renal artery stenosis, presumed RVHT, and ischemic renal disease.
dilate the stenotic lesion. Thus, it is critical to distinguish between the anatomic presence of renal artery stenosis, in which a stenotic lesion is present but not necessarily causing hypertension, and the syndrome of renovascular hypertension in which significant arterial stenosis is present and sufficient to produce renal tissue ischemia and initiate a pathophysiologic sequence of events leading to elevated arterial pressure. In the final analysis, proof that a patient has the entity of renovascular hypertension rests with the demonstration that the hypertension, presumed to be renovascular, can be eliminated or substantially ameliorated following removal of the stenosis by surgical or endovascular intervention, or by removing the kidney distal to the stenosis. Although the great majority of patients diagnosed as having renovascular hypertension have this syndrome because of main renal artery stenosis, hypertension following unilateral renal trauma,
CLASSIFICATION OF RENAL ARTERY DISEASE

Disease
Atherosclerosis Fibrous dysplasia Medial (30%) Perimedial (5%) Intimal (5%) *Percent of renal artery lesions.
Incidence, %*
6080 2040
FIGURE 3-1 Classification of renal artery disease. Two main types of renal arterial lesions form the anatomic basis for renal artery stenosis. Atherosclerotic renal artery disease (ASO-RAD) is the most common cause of renal artery disease, accounting for 60% to 80% of all renal artery lesions. The fibrous dysplasias are the other major category of renal artery disease, and as a group account for 20% to 40% of renal artery lesions. Arterial aneurysm and arteriovenous malformation are rarer types of renal artery disease.
FIGURE 3-2 Angiographic examples of atherosclerotic renal artery disease (ASO-RAD). A, Aortogram demonstrating severe nonostial atherosclerotic renal artery disease of the left main renal artery. B, Intra-arterial digital subtraction aortogram showing severe proximal right renal artery stenosis (ostial lesion) and moderately severe narrowing of the left renal artery due to atherosclerosis.
Atherosclerotic renal artery disease is typically associated with atherosclerotic changes of the abdominal aorta (see panel B). ASORAD predominantly affects men and women in the fifth to seventh decades of life but is uncommon in women under the age of 50. Anatomically, the majority of these patients demonstrate atherosclerotic plaques located in the proximal third of the main renal artery. In the majority of cases (70% to 80%), the obstructing lesion is an aortic plaque invading the renal artery ostium (ostial lesion). Twenty to 30 percent of patients with ASORAD demonstrate atherosclerotic narrowing 1 to 3 cm beyond the takeoff of the renal artery (nonostial lesion). Nonostial lesions are technically more amenable to percutaneous transluminal renal angioplasty (PTRA) than ostial ASO-RAD lesions, which are technically difficult to dilate and have a high restenosis rate after PTRA. Renal artery stenting has gained wide acceptance for ostial lesions. Endovascular intervention for nonostial lesions includes both PTRA and stents. Surgical renal revascularization is used for both ostial and nonostial ASO-RAD lesions. (From Pohl [1]; with permission.)
3.3
NATURAL HISTORY OF ATHEROSCLEROTIC RENOVASCULAR DISEASE: REPORTS OF SERIAL ANGIOGRAMS

First author
Wollenweber Meaney Dean Schreiber Tollefson Total
Year
1968 1968 1981 1984 1991
Months of follow-up, n/n

12/88 6/120 6/102 12/60 15/180
Patients, n
30 39 35 85 48 237
Progression, n (%)
21 (70) 14 (36) 10 (29) 37 (44) 34 (71) 116 (49)
Total occlusion
NA 3 (8) 4 (11) 14 (I6) 7 (15) 28 (14)
FIGURE 3-3 Natural history of atherosclerotic renovascular disease. Retrospective studies, based on serial renal angiograms, suggest that atherosclerotic renal artery disease (ASO-RAD) is a progressive disorder. This figure summarizes retrospective series on the natural history of ASO-RAD. A large series from the Cleveland Clinic in nonoperated patients indicated progression of renal artery obstruction in 44%; progression to total occlusion occurred in 16% of these patients. Reduction in ipsilateral renal size is associated with angiographic evidence of progression in contrast to patients with nonprogressive (angiographically) ASO-RAD. Zierler and coworkers have prospectively studied the progression of ASO-RAD by sequential duplex ultrasonography. The
cumulative incidence of progession of lesions with less than 60% reduction in lumen diameter progressing to more than 60% reduction in lumen diameter was 30% at 1 year, 44% at 2 years, and 48% at 3 years. Progression to total occlusion occurred only in arteries with a baseline reduction in lumen diameter of more than 60%. The cumulative incidence of progression to total occlusion in patients with baseline stenosis of 60% or greater was 4% at 1 year, 4% at 2 years, and 7% at 3 years. Blood pressure control and serum creatinine were not predictors of progression. The risk of renal parenchymal atrophy over time in kidneys with ASO-RAD has also been described. (Table adapted from Rimmer and Gennari [2]; with permission.) the second most common type of fibrous dysplasia, accounting for 10% to 25% of fibrous renal artery lesions. This lesion also occurs predominantly in women, is diagnosed between the ages of 15 and 30, is frequently bilateral and highly stenotic, and may progress to total arterial occlusion. These patients should undergo surgical renal revascularization to relieve hypertension and to avoid loss of renal function. Intimal fibroplasia and medial hyperplasia (usually indistinguishable angiographically) are not common, accounting for only 5% to 10% of fibrous renal artery lesions. Intimal fibroplasia occurs primarily in children and adolescents. Medial hyperplasia is found predominantly in adolescents; angiographically it appears as a smooth linear stenosis that may extend into the primary renal artery branches. Medial hyperplasia, like intimal fibroplasia, is a progressive lesion and is associated with ipsilateral renal atrophy. Surgical renal revascularization is recommended for patients with either intimal fibroplasia or medial hyperplasia to avoid lifelong antihypertensive therapy and to avert renal atrophy.
FREQUENCY AND NATURAL HISTORY OF FIBROUS RENAL ARTERY DISEASES

Lesion
Intimal fibroplasia and medial hyperplasia Perimedial fibroplasia Medial fibroplasia
Frequency, %*
10 1025 7085
Risk of progression
++++ ++++ ++
Threat to renal function

++++ ++++
*Frequency relates to frequency of only the fibrous renal artery diseases.
FIGURE 3-4 Frequency and natural history of fibrous renal artery diseases. There are four types of fibrous renal artery disease (fibrous dysplasias): medial fibroplasia, perimedial fibroplasia, intimal fibroplasia, and medial hyperplasia. Although the true incidence of these specific types of fibrous renal artery disease is not clearly defined, medial fibroplasia is the most common, estimated to account for 70% to 85% of fibrous renal artery disease. The majority of patients with medial fibroplasia are almost exclusively women who are diagnosed between the ages of 25 to 50 years. Although medial fibroplasia progresses to higher degrees of stenosis in about one third of cases, complete arterial occlusion or ischemic atrophy of the involved kidney is rare. Intervention on this type of fibrosis dysplasia is for relief of hypertension because the threat of progressive medial fibroplasia to renal function is negligible. Perimedial fibroplasia is
3.4

FIGURE 3-5 Arteriogram and schematic diagrams of medial fibroplasia. A, Right renal arteriogram demonstrating weblike stenosis with interposed segments of dilatation (large beads) typical of medial fibroplasia (string of beads lesion). B, Schematic diagram of medial fibroplasia. The lesion of medial fibroplasia characteristically affects the distal half of the main renal artery, frequently extending into the branches, is often bilateral, and angiographically gives the appearance of multiple aneurysms (string of beads). Histologically, this beaded lesion is characterized by areas of proliferation of fibroblasts of the media surrounded by fibrous connective tissue (stenosis) alternating with areas of medial thinning (aneurysms). Inspection of the renal angiogram in panel A indicates that the width of areas of aneurysmal dilatation is wider than the nonaffected proximal renal artery, an angiographic clue to medial fibroplasia. (Panel A from Pohl [1]; with permission.) FIGURE 3-6 Arteriogram and schematic diagram of perimedial fibroplasia. A, Selective right renal arteriogram shows a tight stenosis in the mid portion of the renal artery with a small string of beads appearance, typical of perimedial fibroplasia. B, Schematic diagram of perimedial fibroplasia. Perimedial fibroplasia, accounting for 10% to 25% of the fibrous renal artery diseases, is also observed almost exclusively in women. The stenotic lesion occurs in the mid and distal main renal artery or branches and may be bilateral. Angiographically, serial stenoses are observed with small beads, which are smaller in diameter than the unaffected portion of the renal artery. This highly stenotic lesion may progress to total occlusion; collateral blood vessels and renal atrophy on the involved side are frequently observed. Pathologically, the outer layer of the media varies in thickness and is densely fibrotic, producing a severe reduction in lumen diameter (panel B). Renal artery dissection and/or thrombosis are common. (Panel A from Pohl [1]; with permission.)
3.5
FIGURE 3-7 Arteriogram and schematic diagram of intimal fibroplasia. A, Selective right renal arteriogram demonstrating a localized, highly stenotic, smooth lesion involving the distal renal artery, from intimal fibroplasia. B, Schematic diagram of intimal fibroplasia. Intimal fibroplasia occurs primarily in children and adolescents and angiographically gives the appearance of a localized, highly stenotic, smooth lesion, with poststenotic dilatation. It may occur in the proximal portion of the renal artery as well as in the mid and distal portions of the renal artery, is progressive, and is occasionally associated with dissection or renal infarction. Pathologically, idiopathic intimal fibroplasia is due to a proliferation of the intimal lining of the arterial wall. Intimal fibroplasia of the renal artery may also occur as an event secondary to atherosclerosis or as a reactive intimal fibroplasia consequent to an inciting event such as prior endarterectomy or balloon angioplasty. (Panel A from Pohl [1]; with permission.) kidney beyond the stenosis are relatively common with ASO-RAD, but ischemic atrophy of the kidney ipsilateral to the medial fibroplasia lesion is rare. Surgical intervention or pecutaneous transluminal renal angioplasty (PTRA) typically produce good cure rates for the hypertension in medial fibroplasia and these lesions are technically quite amenable to PTRA. In contrast, ASO-RAD is, technically, much less amenable to PTRA (particularly ostial lesions), and surgical intervention or PTRA produce mediocre-to-poor cure rates of the hypertension. ASO-RAD and medial fibroplasia may cause hypertension and when the hypertension is cured or markedly improved following intervention, the patient may be viewed as having renovascular hypertension. This sequence of events is far more likely to occur in patients with medial fibroplasia than in patients with ASO-RAD. ASO-RAD and medial fibroplasia involve both main renal arteries in approximately 30% to 40% of patients.
ATHEROSCLEROTIC RENAL ARTERY DISEASE VERSUS MEDIAL FIBROPLASIA

Atherosclerotic
Men and women Age >5055 y Total occlusion common Ischemic atrophy common Surgical intervention or angioplasty: Mediocre cure rates of the hypertension Less amenable to PTRA
Medial fibroplasia
Women Age 2040 y Total occlusion rare Ischemic atrophy rare Surgical intervention or angioplasty: Good cure rates of the hypertension More amenable to PTRA
FIGURE 3-8 A comparison of atherosclerotic renal artery disease and medial fibroplasia. The most common types of renal artery disease (atherosclerotic renal artery disease [ASO-RAD] and medial fibroplasia) are compared here. In general, ASO-RAD is observed in men and women older than 50 to 55 years of age, whereas medial fibroplasia is observed primarily in younger white women. Total occlusion of the renal artery and, hence, atrophy of the
3.6
Pathophysiology of Renovascular Hypertension

This diagram shows the classic model of two-kidney, one clip (2K,1C) Goldblatt hypertension, wherein one renal artery is constricted and the contralateral kidney is left intact. In the presence of hemodynamically sufficient unilateral renal artery stenosis, the kidney distal to the stenosis is rendered ischemic, activating the renin angiotensin system, and producing high levels of angiotensin II, causing a vasoconstrictor type of hypertension. Numerous studies have established the causal relationship between angiotensin IImediated vasoconstriction and hypertension in the early phase of this experimental model. In addition, the high levels of angiotensin II stimulate the adrenal cortex to elaborate larger amounts of aldosterone such that the stenotic kidney demonstrates sodium retention. This secondary aldosteronism also produces hypokalemia. The degree of renal artery stenosis necessary to produce hemodynamically significant reductions in perfusion, triggering renal ischemia and activation of the renin angiotensin system, generally does not occur until a reduction of 80% or more in both lumen diameter and cross-sectional area of the renal artery takes place. Lesser degrees of renal artery constriction do not initiate this sequence of events. This model of 2K,1C Goldblatt hypertension implies that the contralateral (nonaffected) kidney is present, and that its renal artery is not hemodynamically significantly narrowed. As illustrated, the contralateral kidney demonstrates suppressed renin production and undergoes a pressure natriuresis, presumably because of angiotensin IIinitiated vasoconstriction and sodium retention, leading to systemic elevation of blood pressure that then results in suppression of renin release and enhanced excretion of sodium (pressure natriuresis) by the contralateral kidney.
Stenotic kidney
Contralateral kidney Supressed renin Pressure natriuresis
Ischemia Renin Angiotensin II Vasoconstriction Aldosterone
Intrarenal hemodynamics Sodium retention
FIGURE 3-9 Schematic representation of renovascular hypertension. Renovascular hypertension may be defined as the secondary elevation of blood pressure produced by any of a variety of conditions that interfere with the arterial circulation to kidney tissue and cause renal ischemia. Almost always, renovascular hypertension is caused by obstruction of the renal artery or its branches, and demonstration of causality between the renal artery lesion and the hypertension is essential to this definition.
3.7
Clip Blood pressure
Phase II
III
Renin Change in blood pressure on removing clip
FIGURE 3-10 Sequential phases in two-kidney, one-clip (2K,1C) experimental renovascular hypertension. The schematic representation of renovascular hypertension depicted in Figure 3-9 is an oversimplification. In fact, the course of experimental 2K,1C hypertension may be divided into three sequential phases. In phase I, renal ischemia and activation of the renin angiotensin system are of fundamental importance, and in this early phase of experimental hypertension, the blood pressure elevation is renin- or angiotensin IIdependent. Acute administration of angiotensin II antagonists, administration of angiotensin-converting enzyme (ACE) inhibitors, removal of the renal artery stenosis (ie, removal of the clip in the experimental animal or removal of the stenotic kidney) promptly normalizes blood pressure. Several days after renal artery clamping, renin levels fall, but blood pressure remains elevated. This second phase of experimental 2K,1C hypertension may be viewed as a pathophysiologic transition phase that, depending on the experimental model and species, may last from a few days to several weeks. During this transition phase (phase II), salt and water retention are observed as a consequence of the effect of hypoperfusion of the stenotic kidney;
augmented proximal tubular reabsorption of sodium and water and angiotensin IIinduced stimulation of aldosterone secretion contribute to this sodium and water retention. In addition, the high levels of angiotensin II stimulate thirst, which further augments expansion of the extracellular fluid volume. The expanded extracellular fluid volume results in a progressive suppression of peripheral renin activity. During this transition phase, the hypertension is still responsive to removal of the unilateral renal artery stenosis, to angiotensin II blockade, or unilateral nephrectomy, although these maneuvers do not normalize the blood pressure as promptly and consistently as in the acute phase. After several weeks, a chronic phase (phase III) ensues wherein unclipping the renal artery of the experimental animal does not lower the blood pressure. This failure of unclipping to lower the blood pressure in this chronic phase (III) of 2K,1C hypertension is due to widespread arteriolar damage to the contralateral kidney, consequent to prolonged exposure to high blood pressure and high levels of angiotensin II. In this chronic phase of 2K,1C renovascular hypertension, extracellular fluid volume expansion and systemic vasoconstriction are the main pathophysiologic abnormalities. The pressure natriuresis of the contralateral kidney blunts the extracellular fluid volume expansion caused by the stenotic kidney; but as the contralateral kidney suffers vascular damage from extended exposure to elevated arterial pressure, its excretory function diminishes and extracellular fluid volume expansion persists. In this third phase of experimental 2K,1C hypertension, acute blockade of the renin angiotensin system fails to lower blood pressure. Sodium depletion may ameliorate the hypertension but does not normalize it. The clinical surrogate of phase III experimental 2K,1C hypertension is duration of hypertension. Widespread clinical experience indicates that major improvements in blood pressure control or cure of the hypertension following renal revascularization or even removal of the kidney ipsilateral to the renal artery stenosis are rarely observed in patients with a long duration (ie, >5 years) of hypertension. (Adapted from Brown and coworkers [3]; with permission.) FIGURE 3-11 Schematic representation of two types of experimental hypertension. The discussion so far of the pathophysiology of renovascular hypertension has focused on the two-kidney, one-clip model of renovascular hypertension (two-kidney hypertension), wherein the artery to the contralateral kidney is patent and the contralateral nonaffected kidney is present. Elevated peripheral renin activity, normal plasma volume, and hypokalemia are typically associated with the elevated arterial pressure. There is another type of renovascular hypertension known as one-kidney hypertension, wherein in the experimental model, one renal artery is constricted and the contralateral kidney is removed. Although there is an initial increase in renin release responsible for the early rise in blood pressure in one-kidney hypertension as in two-kidney hypertension, the absence of an unclipped contralateral kidney allows for sodium retention early in the course of this one-kidney, one-clip (1K,1C) model. Renin levels are suppressed to normal levels in conjunction with high blood pressure which is maintained by salt and water retention. Thus, extracellular fluid volume expansion is a prime feature of one-kidney hypertension.
Two-kidney hypertension
One-kidney hypertension
Blood pressure
Renin High
Volume Normal
Blood pressure
Renin Normal
Volume High
3.8

FIGURE 3-12 Lesions producing the syndrome of renovascular hypertension. A, Two-kidney hypertension. The most common clinical counterpart to two-kidney hypertension is unilateral renal artery stenosis due to either atherosclerotic or fibrous renal artery disease. Unilateral renal trauma, with development of a calcified fibrous capsule surrounding the injured kidney causing compression of the renal parenchyma, may produce renovascular hypertension; this clinical situation is analogous to the experimental Page kidney, wherein cellophane wrapping of one of two kidneys causes hypertension, which is relieved by removal of the wrapped kidney. B, One-kidney hypertension. Clinical counterparts of experimental one-kidney, one-clip (one kidney) hypertension include renal artery stenosis to a solitary functioning kidney, bilateral renal arterial stenosis, aortic coarctation, Takayasus arteritis, fulminant polyarteritis nodosa, atheroembolic renal disease, and renal artery stenosis in a transplanted kidney. In some parts of the world, eg, China and India, Takayasus arteritis is a frequent cause of renovascular hypertension.
A. LESIONS PRODUCING THE SYNDROME OF RENOVASCULAR HYPERTENSION (TWO-KIDNEY HYPERTENSION)*

Unilateral atherosclerotic renal arterial disease Unilateral fibrous renal artery disease Renal artery aneurysm Arterial embolus Arteriovenous fistula (congenital and traumatic) Segmental arterial occlusion (traumatic) Pheochromocytoma compressing renal artery Unilateral perirenal hematoma or subcapsular hematoma (compressing renal parenchyma) *Implies contralateral (nonaffected) kidney present.
B. LESIONS PRODUCING THE SYNDROME OF RENOVASCULAR HYPERTENSION (ONE-KIDNEY HYPERTENSION)*

Stenosis to a solitary functioning kidney Bilateral renal arterial stenosis Aortic coarctation Vasculitis (polyarteritis nodosa and Takayasus arteritis) Atheroembolic disease *Implies total renal mass ischemic.
STEPS IN MAKING THE DIAGNOSIS OF RENOVASCULAR HYPERTENSION

1. Demonstration of renal arterial stenosis by angiography 2. Determination of pathophysiologic significance of the stenotic lesion 3. Cure of the hypertension by intervention, ie, revascularization, percutaneous transluminal angioplasty, nephrectomy
FIGURE 3-13 Steps in making the diagnosis of renovascular hypertension (RVHT). With the exception of oral contraceptive use and alcohol ingestion, RVHT is the most common cause of potentially remediable secondary hypertension. RVHT is estimated to occur with a prevalence of 1% to 15%. Some hypertension referral clinics have estimated a prevalence of RVHT as high as 15%, whereas other prevalence data suggest that less than 1% to 2% of the hypertensive population has RVHT.
Although elderly atherosclerotic hypertensive individuals often have atherosclerotic renal artery disease, their hypertension is usually essential hypertension, not RVHT. On balance, the prevalence of RVHT in the general hypertensive population is probably no more than 2% to 3%. The particular appeal of diagnosing RVHT centers around its potential curability by an interventive maneuver such as surgical revascularization, percutaneous transluminal renal angioplasty (PTRA), or renal artery stenting. Whether or not to use these interventions for the goal of improving blood pressure depends on the likelihood such intervention will improve the blood pressure. The overwhelming majority of patients with RVHT will have this syndrome because of main renal artery stenosis. Therefore, the first step in making the diagnosis of RVHT is to demonstrate renal artery stenosis by one of several imaging procedures and, eventually, by angiography. The second step in establishing the probability that the renal artery stenosis is instrumental in promoting hypertension is to determine the pathophysiologic significance of the stenotic lesion. Finally, the hypertension, presumed to be renovascular in origin, is proven to be RVHT when the elevated blood pressure is cured or markedly ameliorated by an interventive maneuver such as surgical revascularization, PTRA, renal artery stent, or nephrectomy.
3.9
DIAGNOSIS OF RENAL ARTERIAL STENOSIS

Clinical clues
Age of onset of hypertension <30 y or >55 y Abrupt onset of hypertension Acceleration of previously well-controlled hypertension Hypertension refractory to an appropriate three-drug regimen Accelerated retinopathy Systolic-diastolic abdominal bruit Evidence of generalized atherosclerosis obliterans Malignant hypertension Flash pulmonary edema Acute renal failure with use of angiotensin-converting enzyme inhibitors or angiotensin II receptor-blockers
Diagnostic tests
Duplex ultrasonography Radionuclide renography Captopril renography Captopril provocation test Intravenous digital subtraction angiography Rapid sequence IVP Magnetic resonance angiography Spiral CT angiography CO2 angiography Conventional (contrast) angiography
FIGURE 3-14 Diagnosis of renal artery stenosis. Clinical clues suggesting renal artery stenosis, some of which suggest that the stenosis is the cause of the hypertension, are listed on the left. The well-documented age of onset of hypertension in an individual under the age of 30 or over age 55 years, particularly if the hypertension is severe and requiring three antihypertensive drugs, is a strong clinical clue to renal artery stenosis and predicts that the stenosis is causing the hypertension. The patient with a long history of mild hypertension, easily controlled with one or two drugs, who, particularly in older age, develops severe and refractory hypertension, is likely to have developed atherosclerotic renal artery stenosis as a contributor to underlying
longstanding essential hypertension. Grade III hypertensive retinopathy, malignant hypertension, and flash pulmonary edema all suggest renal artery stenosis with or without renovascular hypertension. The observation of a diastolic bruit in the abdomen of a young white women suggests fibrous renal artery disease and, further, is a reliable clinical clue that the hypertension will be helped substantially by surgical renal revascularization or percutaneous transluminal renal angioplasty. The diagnostic tests listed along the right side are used mainly to detect renal artery stenosis (ie, the anatomic presence of disease). Captopril renography is also used to predict physiologic significance of the stenotic lesion. The popularity of these diagnostic tests in detecting renal artery stenosis varies from institution to institution; correlations with percent stenosis by comparative angiography are widely variable. A substantial fall in blood pressure following initiation of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker suggests RVHT. With the exception of a diastolic abdominal bruit and accelerated retinopathy, no clear-cut physical findings definitely discriminate patients with RVHT from the larger pool of patients with essential hypertension.
FIGURE 3-15 Renal duplex ultrasound for diagnosis of renal artery stenosis. Duplex ultrasound scanning of the renal arteries is a noninvasive screening test for the detection of renal artery stenosis. It combines direct visualization of the renal arteries (B-mode imaging) with measurement of various hemodynamic factors in the main renal arteries and within the kidney (Doppler), thus providing both an anatomic and functional assessment. Unlike other noninvasive screening tests (eg, captopril renography), duplex ultrasonography does not require patients to discontinue any antihypertensive medications before the test. The study should be performed while the patient is fasting. The white arrow indicates the aorta and the black arrow the left renal artery, which is stenotic. Doppler scans (bottom) measure the corresponding peak systolic velocities in the aorta and in the renal artery. The peak systolic velocity in the left renal artery was 400 cm/s, and the peak systolic velocity in the aorta was 75 cm/s. Therefore, the renalaortic ratio was 5.3, consistent with a 60% to 99% left renal artery stenosis. (From Hoffman and coworkers [4]; with permission.)
3.10

FIGURE 3-16 Comparison of duplex ultrasound with arteriography. A total of 102 consecutive patients with both duplex ultrasound scanning of the renal arteries and renal arteriography were prospectively studied. All patients in this study had difficult-to-control hypertension, unexplained azotemia, or associated peripheral vascular disease, giving them a high pretest likelihood of renovascular hypertension. Sixty-two of 63 arteries that showed less than 60% stenosis by formal arteriography, were identified by duplex ultrasound scanning. Twenty-two of 23 arteries with total occlusion on arteriography were correctly identified by duplex ultrasound. Thirty-one of 32 arteries with 60% to 79% stenosis using arteriography were identified as having 60% to 99% stenosis on duplex ultrasound and 67 of 69 arteries with 80% to 99% stenosis on arteriography were detected to have 60% to 99% stenosis on ultrasound. A current limitation of duplex ultrasound is the inability to consistently distinguish between more than and less than 80% stenosis (considered to be the magnitude of stenosis required for hemodynamic significance of the lesion). Nevertheless, duplex ultrasound is currently highly sensitive and specific in patients with a high likelihood of renovascular disease in detecting patients with more or less than 60% renal artery stenosis. Accessory renal arteries are difficult to identify by ultrasound and remain a limitation of this test. (Adapted from Olin and coworkers [5]; with permission.) renogram not only suggest the anatomic presence of renal artery stenosis but also imply that the stenosis is instrumental in producing the hypertension. Reductions of lumen diameter of less than 70% to 80% generally do not initiate renal ischemia or activation of the renin angiotensin system; thus, before recommending a renal revascularization procedure, severe renal artery stenosis (>75% reduction in lumen diameter) should be observed on the renal angiogram. A lateralizing renal vein renin ratio (a comparison of renin harvested from the renal vein ipsilateral to the renal artery stenosis with the renin level from renal vein of the contralateral kidney), particularly when renin production from the contralateral kidney is suppressed, suggests that an intervention on the renal artery stenosis will cure or markedly ameliorate the hypertension in about 90% of cases. Conversely, cure or marked improvement in blood pressure following renal revascularization has been reported in nearly 50% of cases in the absence of lateralizing renal vein renins. Hypokalemia, in the absence of diuretic therapy, strongly suggests that the hypertension is renovascular in origin, consequent to secondary aldosteronism. The sensitivity of an IVP in detecting unilateral RVHT is relatively poor (about 75%) and the overall sensitivity in detecting patients with bilateral renal artery disease is only about 60%. Because RVHT has a low prevalence in the general population, a negative IVP provides strong evidence (98% to 99% certainty) against RVHT.
COMPARISON OF DUPLEX ULTRASOUND WITH ARTERIOGRAPHY

Percent stenosis by arteriogram
059 62 1 0 63 6079 0 31 1 32 8099 1 67 1 69 100 1 0 22 23 Total 64 99 24 187
Percent stenosis by ultrasound

059 6099 100 Total
Sensitivity, 0.98. Specificity, 0.98. Positive predictive value, 0.99. Negative predictive value, 0.97.
DETERMINATION OF PATHOPHYSIOLOGIC SIGNIFICANCE OF THE STENOTIC LESION

Duration of hypertension <35 y Appearance of lesion on angiogram (>75% stenosis) Systolic-diastolic bruit in abdomen Renal vein renin ratio >1.5 Positive captopril provocation test or captopril renogram Abnormal rapid sequence IVP Hypokalemia
FIGURE 3-17 Determination of pathophysiologic significance of the stenotic lesion. The second step in making the diagnosis of renovascular hypertension (RVHT) is to determine the pathophysiologic significance of the stenotic lesion demonstrated by angiography. The likelihood of cure of the hypertension by an interventive maneuver is greatly enhanced when one or more of the items listed here are present. A positive captopril provocation test, abnormal rapid sequence intravenous pyelogram (IVP), or positive captopril
3.11
RENIN CRITERIA FOR CAPTOPRIL TEST THAT DISTINGUISH PATIENTS WITH RVHT FROM THOSE WITH ESSENTIAL HYPERTENSION
Stimulated PRA of 12 ng/mL/h or more Absolute increase in PRA of 10 ng/mL/h or more Percent increase in PRA Increase in PRA of 150% if baseline PRA >3 ng/mL/h Increase in PRA of 400% if baseline PRA <3 ng/mL/h
FIGURE 3-18 The captopril test: renin criteria that distinguish patients with renovascular hypertension from those with essential hypertension. The captopril provocation test evolved because the casual measurement of peripheral plasma renin activity (PRA) has been of little
value as a diagnostic screening test for renovascular hypertension (RVHT). The notion that patients with high PRA, even in the face of high urinary sodium excretion, might turn out to have RVHT has not been supported by numerous clinical observations. However, the short-term (60- to 90-minute) response of blood pressure and PRA to an oral dose (25 to 50 mg) of captopril has gained recent popularity as a screening test for presumed RVHT. Preparation of patients for this test is vital; ideally patients should discontinue their antihypertensive medications, maintain a diet adequate in salt, and have good renal function. A baseline blood pressure and PRA are obtained after which captopril is administered; 60 minutes after captopril administration, a postcaptopril PRA is obtained along with repeat measurements of blood pressure. Early reports with this test indicated a high sensitivity and specificity (95% to 100%) in identifying RVHT if all three of the renin criteria listed here were met. Subsequent reports have not been as encouraging such that the overall sensitivity of this captopril test is only about 70%, with a specificity of approximately 85%. (Adapted from Muller and coworkers [6]; with permission.)
1.0
1.0
0.8 Relative acidity Relative acidity

Bladder Right kidney Left kidney
0.8
0.6
0.6
0.4
0.4
0.2
0.2
Bladder Right kidney Left kidney
0 0 8 16
0 24 Time, min 32 40 48
16
24 Time, min
32
40
48
FIGURE 3-19 Captopril renography. A, TcDPTA time-activity curves during baseline. B, TcDPTA time-activity curves after captopril administration. These curves represent a captopril renogram in a patient with unilateral left renal artery stenosis. This diagnostic test has been used to screen for renal artery stenosis and to predict renovascular hypertension. Captopril renography appears to be highly sensitive and specific for detecting physiologically significant renal artery stenosis. Scintigrams and time-activity curves should both be analyzed to assess renal perfusion, function, and size. If the renogram following captopril administration is abnormal (panel B, demonstrating delayed time to maximal activity and retention of the radionuclide in the right kidney), another renogram may be obtained without captopril for comparison. The diagnosis of renal artery stenosis is based on
asymmetry of renal size and function and on specific, captoprilinduced changes in the renogram, including delayed time to maximal activity (11 minutes), significant asymmetry of the peak of each kidney, marked cortical retention of the radionuclide, and marked reduction in the calculated glomerular filtration rate of the kidney ipsilateral to the stenosis. One must interpret the clinical and renographic data with caution, as protocols are complex and diagnostic criteria are not well standardized. Nevertheless, captopril renography appears to be an improvement over the captopril provocation test, with many reports indicating sensitivity and specificity from 80% to 95% in predicting an improvement in blood pressure following intervention. (Adapted from Nally and coworkers [7]; with permission.)
3.12

now available to detect renal artery stenosis and several tests designed to predict the physiologic significance of the stenotic lesion, the index of clinical suspicion for RVHT remains the focal point of the work-up for RVHT. A brief duration of moderately severe hypertension is the most important clue directing subsequent work-up for RVHT. If the index of clinical suspicion (see Fig. 3-14) is high, it is reasonable to proceed directly to formal renal arteriography with renal vein renin determination. Alternatively, in patients highly suspected to have RVHT, a captopril renogram followed by a renal arteriogram may be recommended. Strong arguments against RVHT include 1) long duration (more than 5 years) of hypertension, 2) old age, 3) generalized atherosclerosis, 4) increased serum creatinine, and 5) a normal serum potassium concentration. For these patients, particularly if the blood pressure is only minimally elevated or easily controlled with one or two antihypertensive medications, further work-up for RVHT is not indicated. (Adapted from Mann and Pickering [8]; with permission.)
Suggested work-up for renovascular hypertension Index of clinical suspicion
Low (<1%) Low
PRA Normal or high
Moderate (5%15%)
High (>25%)
Captopril test, or captopril renogram, or stimulated renal vein renins, or (?) duplex ultrasound
No further work-up
Negative
Positive
Arteriogram + renal vein renins
FIGURE 3-20 Suggested work-up for renovascular hypertension. Because the prevalence of renovascular hypertension (RVHT) among hypertensive persons in general is approximately 2% or less, widespread screening for renovascular disease is not justified. Despite the proliferation of diagnostic tests
Ischemic Nephropathy
FIGURE 3-21 Aortogram in a 62-year-old white woman demonstrating subtotal occlusion of the left main renal artery supplying an atrophic left kidney and high-grade ostial stenosis of the proximal right renal artery from atherosclerosis. This patient presented in 1977 with a recent appearance of hypertension and a blood pressure of 170/115 mm Hg. Three years previously, when diagnosed with polycythemia vera, an IVP was normal. She was followed closely between 1974 and 1977 by her physician and was always normotensive until the hypertension suddenly appeared. A repeat rapid sequence IVP demonstrated a reduction in the size of the left kidney from 14 cm in height (1974) to 11.5 cm in height (1977). The serum creatinine was 2.6 mg/dL. The renal arteriogram shown here indicates high-grade bilateral renal artery stenosis with the left kidney measuring 11.5 cm in height, and the right kidney measuring 14.5 cm in height. Renal vein renins were obtained and lateralized strongly to the smaller left kidney. The blood pressure was well controlled with inderal and chlorthalidone. Right aortorenal reimplantation was undertaken solely to preserve renal function. Postoperatively the serum creatinine fell to 1.5 mg/dL and remained at this level for the next 13 years. Blood pressure continued to require antihypertensive medication, but was controlled to normal levels with inderal and chlorthalidone.
3.13
12.0 11.0 10.0 9.0 8.0 Serum creatinine, mg/dL 7.0 6.0
Pt. 3 Pt. 8 Pt. 7
5.0
Pt. 6
4.0 3.0 2.0 1.0 0 Admission Medical therapy Surgery or angioplasty

Pt. 2 Pt. 1 Pt. 4 Pt. 3
FIGURE 3-22 Effects of medical therapy and surgery or angioplasty on serum creatinine levels. This figure describes eight patients hospitalized because of severe hypertension and renal insufficiency. With medical management of the hypertension (antihypertensive drug therapy), four of the eight patients developed substantial worsening of their renal function as measured by serum creatinine; three of these four patients demonstrated improvement following surgery or angioplasty. The other four patients (patients one to four) did not demonstrate a worsening serum creatinine level with medical therapy; but three of these four patients showed improved renal function following surgery or angioplasty. (Adapted from Ying and coworkers [9]; with permission.)
B
FIGURE 3-23 Improved renal function demonstrated by intravenous pyelography following left renal revascularization. A, preoperative IVP (5-minute film) in a 65-year-old white man with a 15-year history of hypertension; serum creatinine 2.6 mg/dL. Note poorly functioning left kidney, which measured 11.5 cm in height. B, post operative IVP (5-minute film) obtained following left aortorenal saphenous vein bypass grafting to the left kidney. Note the prompt function and increased height (14.0 cm) of the revascularized left kidney versus the preoperative IVP. (From Novick and Pohl [10]; with permission.) The clinical story of the patient in Figure 3-21, the benefits of surgical renal revascularization or pecutaneous transluminal renal angioplasty (Fig. 3-22), and the radiographic evidence of improved renal function after renal revascularization (Fig. 3-23) are examples of ischemic nephropathy. Two definitions of ischemic nephropathy are suggested herein: 1) clinically significant reduction in renal function due to compromise of the renal circulation; and 2) clinically significant reduction in glomerular filtration rate due to hemodynamically significant obstruction to renal blood flow, or renal failure due to renal artery occlusive disease.
3.14

FIGURE 3-24 Atherosclerotic renal artery stenosis in patients with generalized atherosclerosis obliterans and in patients with coronary artery disease (CAD). Atherosclerotic renal artery stenosis is common in older patients with and without hypertension simply as a consequence of generalized atherosclerosis obliterans. Approximately 40% of consecutively studied patients undergoing arteriography for routine evaluation of abdominal aortic aneurysm, aorto-occlusive disease, or lower extremity occlusive disease have associated renal artery stenosis (more than 50% unilateral renal artery stenosis) and nearly 30% of patients undergoing coronary angiography may have incidentally detected unilateral renal artery stenosis. Approximately 4% to 13% of patients with CAD or peripheral vascular disease have more than 75% bilateral renal artery stenosis. Correlations of hypercholesterolemia and cigarette smoking with renal artery atherosclerosis are not unequivocally clear, but they probably represent risk factors for renal artery atherosclerosis just as they represent risk factors for atherosclerosis in other vascular beds. (Adapted from Olin and coworkers [11]; with permission.)
ATHEROSCLEROTIC RENAL ARTERY STENOSIS IN 395 PATIENTS WITH GENERALIZED ATHEROSCLEROSIS OBLITERANS AND IN PATIENTS WITH CORONARY ARTERY DISEASE
Patients, n
Abdominal aortic aneurysm Aorto-occlusive disease Lower extremity disease Suspected renal artery stenosis Coronary artery disease 109 21 189 76 76 817
Percent of patients with >50% stenosis

38 33 39* 70 29 20
*50% in diabetic patients. Data from Vetrovec and coworkers [12]. Data from Harding [13].
CLINICAL PRESENTATIONS OF ISCHEMIC RENAL DISEASE

Acute renal failure, frequently precipitated by a reduction in blood pressure (ie, angiotensin-converting enzyme inhibitors plus diuretics) Progressive azotemia in a hypertensive patient with known renal artery stenosis treated medically Progressive azotemia in a patient (usually elderly) with refractory hypertension Unexplained progressive azotemia in an elderly patient Hypertension and azotemia in a renal transplant patient
FIGURE 3-25 Clinical presentations of ischemic renal disease. The clinical presentation of a patient likely to develop renal failure from atherosclerotic ischemic renal disease is that of an older (more than 50 years) individual demonstrating progressive azotemia in conjunction with antihypertensive drug therapy, risk factors for generalized atherosclerosis obliterans, known renal artery disease, refractory hypertension, and generalized atherosclerosis. Acute renal failure precipitated by a reduction in blood pressure below a critical perfusion pressure, and particularly with the use of angiotensin convertingenzyme inhibitors (ACEI) or angiotensin II receptor blockers plus diuretics, strongly suggests severe intrarenal ischemia from arteriolar nephrosclerosis and/or severe main renal artery stenosis. Unexplained progressive azotemia in an elderly patient with clinical signs of vascular disease with minimal proteinuria and a bland urinary sediment also suggest ischemic nephropathy. (Adapted from Jacobson [14]; with permission.)
3.15
FIGURE 3-26 Mild stenosis (less than 50%) due to atherosclerotic disease of the left main renal artery (panel A) that has progressed to high-grade (75% to 99%) stenosis on a later arteriogram (panel B). Underlying the concept of renal revascularization for preservation of renal function is the notion that atherosclerotic renal artery disease (ASO-RAD) is a progressive disorder. The sequential angiograms in Figures 3-26 and 3-27 show angiographic progression of ASO-RAD over time. In patients demonstrating progressive renal artery stenosis by serial angiography, a decrease in kidney function as measured by serum creatinine and a decrease in ipsilateral kidney size correlate significantly with progressive occlusive disease. Patients demonstrating more than 75% stenosis of a renal artery are at highest risk for progression to complete occlusion. (From Novick [15]; with permission.)
A
FIGURE 3-27 A, Normal right main renal artery and minimal atherosclerotic irregularity of left main renal artery on initial (1974) aortogram. B, Repeat aortography (1978) showed progression to moderate
B
stenosis of the right main renal artery (arrow) and total occlusion of left main renal artery (arrow). (From Schreiber and coworkers [16]; with permission.)
3.16

entire renal functioning mass is not threatened by large vessel occlusive disease. Clinical clues to the high-risk patient are similar to the clinical presentations of ischemic renal disease shown in Figure 3-25. Nearly 75% of adults with a unilateral small kidney have sustained this renal atrophy due to large vessel occlusive disease from atherosclerosis. One third of these patients with a unilateral small kidney have high-grade stenosis of the artery involving the contralateral normalsized kidney. Flash pulmonary edema is another clue to bilateral renovascular disease or high-grade stenosis involving a solitary functioning kidney. These patients, usually hypertensive and with documented coronary artery disease and underlying hypertensive heart disease, present with the abrupt onset of pulmonary edema. Left ventricular ejection fractions in these patients are not seriously impaired. Flash pulmonary edema is associated with atherosclerotic renal artery disease and may occur with or without severe hypertension. Renal revascularization to preserve kidney function or to prevent life-threatening flash pulmonary edema may be considered in patients with high-grade arterial stenosis to a solitary kidney or high-grade bilateral renal artery stenosis. Pecutaneous transluminal renal angioplasty (PTRA), renal artery stenting, or surgical renal revascularization may be employed. Patients with chronic total renal artery occlusion bilaterally or in a solitary functioning kidney are candidates for surgical renal revascularization, but are not candidates (from a technical standpoint) for PTRA or renal artery stents. potential for salvable renal function. Clinical clues suggesting renal viability include 1) kidney size greater than 9 cm (pole-topole length) by laminography (tomography); 2) some function of the kidney on either urogram or renal flow scan; 3) filling of distal renal arteries (by collaterals) angiographically, when the main renal artery is totally occluded proximally (see Fig. 3-30); and 4) well-preserved glomeruli with minimal interstitial scarring (see Fig. 3-31) on renal biopsy. Patients with moderately severe azotemia, eg, serum creatinine more than 3-4 mg/dL, are likely to have severe renal parenchymal scarring (see Fig. 3-32), which renders improvement in renal function following renal revascularization unlikely. Exceptions to this observation are cases of total main renal artery occlusion wherein kidney viability is maintained via collateral circulation (see Figure 3-30). A kidney biopsy may guide subsequent decision making regarding renal revascularization for the goal of improving kidney function. FIGURE 3-30 This abdominal aortogram reveals complete occlusion of the left main renal artery (panel A) with filling of the distal renal artery branches from collateral supply on delayed films (panel B). The observation of collateral circulation when the main renal artery is totally occluded proximally suggests viable renal parenchyma. (From Novick and Pohl [10]; with permission.)
CLINICAL CLUES TO BILATERAL ATHEROSCLEROTIC RENOVASCULAR DISEASE

Generalized atherosclerosis obliterans Presumed renovascular hypertension Unilateral small kidney Unexplained azotemia Deterioration in renal function with BP reduction and/or ACE inhibitor therapy Flash pulmonary edema
FIGURE 3-28 Clinical clues to bilateral atherosclerotic renovascular disease. The patient at highest risk for developing renal insufficiency from renal artery stenosis (ischemic nephropathy) has sufficient arterial stenosis to threaten the entire renal functioning mass. These highrisk patients have high-grade (more than 75%) arterial stenosis to a solitary functioning kidney or high-grade (more than 75%) bilateral renal artery stenosis. Patients with two functioning kidneys with only unilateral renal artery stenosis are not at significant risk for developing renal insufficiency because the
PREDICTORS OF KIDNEY SALVAGEABILITY
Kidney size >9 cm (laminography) Function on either urogram or renal flow scan Filling of distal renal arteries (by collaterals) angiographically, with total proximal occlusion Glomerular histology on renal biopsy
FIGURE 3-29 Predictors of kidney salvageability. In evaluating patients as candidates for renal revascularization to preserve or improve renal function, some determination should be made of the
3.17
FIGURE 3-31 Renal biopsy of a solitary left kidney in a 67-year-old woman who had been anuric and on chronic dialysis for 9 months. The biopsy shows hypoperfused retracted glomeruli consistent with ischemia. There is no evidence of active glomerular proliferation or glomerular sclerosis. Note intact tubular basement membranes and negligible interstitial scarring. Left renal revascularization resulted in recovery of renal function and discontinuance of dialysis with improvement in serum creatinine to 2.0 mg/dL. (From Novick [15]; with permission.)
FIGURE 3-32 Pathologic specimen of kidney beyond a main renal artery occlusion in a patient with severe bilateral renal artery stenosis and a serum creatinine of 4.5 mg/dL. The biopsy demonstrates glomerular sclerosis, tubular atrophy, and interstitial fibrosis. The magnitude of glomerular and interstitial scarring predict irreversible loss of kidney viability. (From Pohl [1]; with permission.)
FIGURE 3-33 Severe atherosclerosis involving the abdominal aorta, renal, and iliac arteries. This abdominal aortogram demonstrates a ragged aorta, total occlusion of the right main renal artery, and subtotal occlusion of the proximal left main renal artery. Such patients are at high-risk for atheroembolic renal disease following aortography, selective renal arteriography, pecutaneous transluminal renal angioplasty, renal artery stenting, or surgical renal revascularization.
FIGURE 3-34 (see Color Plate) Purple toe syndrome reflecting peripheral atheroembolic disease in the patient in Figure 3-33 (ragged aorta), following an abdominal aortogram.
3.18

FIGURE 3-35 Pathologic specimen of kidney demonstrating atheroembolic renal disease (AERD). Microemboli of atheromatous material are readily identified by the characteristic appearance of cholesterol crystal inclusions that appear in a biconvex needle-shaped form. In routine paraffin-embedded histologic sections, the cholesterol is not seen because the methods used in preparing sections dissolve the crystals; the characteristic biconvex clefts in the glomeruli (or blood vessels) persist, allowing easy identification. Several patterns of renal failure in patients with AERD are recognized: 1) insult (eg, abdominal aortogram) leads to end-stage renal disease (ESRD) over weeks to months; 2) insult leads to chronic stable renal insufficiency; 3) multiple insults (repeated angiographic procedures) lead to a step-wise rise in serum creatinine eventuating in end-stage renal failure; and 4) insult leading to ESRD over several weeks to months with recovery of some renal function allowing for discontinuance of dialysis. FIGURE 3-36 Renal biopsy demonstrating severe arteriolar nephrosclerosis. Arteriolar nephrosclerosis is intimately associated with hypertension. The histology of the kidney in arteriolar nephrosclerosis shows considerable variation in intensity and extent of the arteriolar lesions. Thickening of the vessel wall, edema of the smooth muscle cells, hypertrophy of the smooth muscle cells, and hyaline degeneration of the vessel wall may be apparent depending on the severity of the nephrosclerosis. In addition to the vascular lesions of arteriolar nephrosclerosis there are abnormalities of glomeruli, tubules, and interstitial areas that are believed to be secondary to the ischemia that results from arteriolar insufficiency. Arteriolar nephrosclerosis is observed in patients with longstanding hypertension; the more severe the hypertension, the more severe the arteriolar nephrosclerosis. Arteriolar nephrosclerosis may also be seen in elderly normotensive individuals and is frequently observed in elderly patients with generalized atherosclerosis or essential hypertension. FIGURE 3-37 Schematic representation of ischemic nephropathy. Patients with atherosclerotic renal artery disease (ASO-RAD) often have coexisting renal parenchymal disease with varying degrees of nephrosclerosis (small vessel disease) or atheroembolic renal disease. Whether or not the renal insufficiency is solely attributable to renal artery stenosis, nephrosclerosis, or atheroembolic renal disease is difficult to determine. The term ischemic nephropathy is more complex than being simply due to atherosclerotic renal artery stenosis. In addition, in the azotemic patient with ASORAD, one should exclude other potential or contributing causes of renal insufficiency such as obstructive uropathy, primary glomerular disease (suggested by heavy proteinuria), drug-related renal insufficiency (eg, nonsteroidal anti-inflammatory drugs), and uncontrolled blood pressure.
Atherosclerosis
Nephrosclerosis
Atheroembolism

4% Miscellaneous
3.19
11% Other
12% CGN
36% DM 29% High blood pressure
5% Urology 3% Cyst
FIGURE 3-38 Distribution of endstage renal disease diagnoses. Atherosclerotic renal artery disease (ASORAD) has been claimed to contribute to the ESRD population. This diagram from the US Renal Data System Coordinating Center 1994 report indicates that 29% of calendar year 1991 incident patients entered ESRD programs because of hypertension (HBP). No renovascular disease diagnosis is listed. Crude estimates of the percentage of patients entering ESRD programs because of ASO-RAD range from 1.7% to 15%. Precise bases for making these estimates are both unclear and confounded by the high likelihood of coexisting arteriolar nephrosclerosis, type II diabetic nephropathy, and atheroembolic renal disease. ASO-RAD as a major contributor to the ESRD population is probably small on a percentage basis, occupying some portion of the ESRD diagnosis hypertension (HBP). For dialysis-dependent patients with ASO-RAD, predictors of recovery of renal function following renal revascularization and allowing for discontinuance of dialysis (temporary or permanent) include 1) bilateral (vs unilateral) renal artery stenosis, 2) a relatively fast rate of decline of estimated glomerular filtration rate (less than 6 months) prior to initiation of dialysis; and 3) mild-tomoderate arteriolar nephrosclerosis angiographically.
Treatment of Renovascular Hypertension and Ischemic Nephropathy

TREATMENT OPTIONS FOR RENOVASCULAR HYPERTENSION AND ISCHEMIC NEPHROPATHY
Pharmacologic antihypertensive therapy PTRA Renal artery stents Surgical renal revascularization
FIGURE 3-39 Treatment options for renovascular hypertension and ischemic nephropathy. The main goals in the treatment of renovascular hypertension or ischemic nephropathy are to control the blood pressure, to prevent target organ complications, and to avoid the loss of renal function. Although the issue of renal function may be viewed as mutually exclusive from the issue of blood pressure control, uncontrolled hypertension may hasten a decline in renal function, and renal insufficiency may produce worsening hypertension. Even in the presence of excellent blood pressure control, progressive arterial stenosis might worsen renal ischemia and promote renal atrophy and fibrosis. Therapeutic options include pharmacologic antihypertensive therapy, percutaneous transluminal renal angioplasty (PTRA), renal artery stents, and surgical renal revascularization. Pharmacologic antihypertensive therapy is covered in more detail separately in this Atlas. FIGURE 3-40 Comorbidity in patients undergoing renovascular surgery. Patients presenting for renovascular surgery or endovascular renal revascularization are at high-risk for complications during intervention because of age, and frequently associated coronary, cerebrovascular, or peripheral vascular disease. As the population ages, the percentage of patients being considered for interventive maneuvers on the renal artery has increased significantly. Approximately 30% of patients currently undergoing interventive approaches to renal artery disease have angina, or have had a previous myocardial infarction. Congestive heart failure, cerebrovascular disease (eg, carotid artery stenosis), diabetes mellitus, and claudication are frequent comorbid conditions in these patients. Their aortas are often laden with extensive atherosclerotic plaque (Fig. 3-33), making angiographic investigation or endovascular renal revascularization hazardous. (Adapted from Hallet and coworkers [17]; with permission.)
INCREASING COMORBIDITY IN PATIENTS UNDERGOING RENOVASCULAR SURGERY

Comorbidity, % Condition
Angina Prior MI CHF Cerebrovascular disease Diabetes Claudication *P <0.001.
19701980
21.4 16.3 12.2 11.2 7.1 35.7
19801993
29.9 27.0 23.7* 24.8* 18.1* 56.4*
3.20

bypass with saphenous vein grafting is a frequently used surgical approach in patients with nondiseased abdominal aortas. Severe atherosclerosis of the abdominal aorta may render an aortorenal bypass or renal endarterectomy technically difficult and potentially hazardous to perform. Effective alternate bypass techniques include splenorenal bypass for left renal revascularization, hepatorenal bypass for right renal revascularization, ileorenal bypass, bench surgery with autotransplantation, and use of the supraceliac or lower thoracic aorta (usually less ravaged by atherosclerosis). Simultaneous aortic replacement and renal revascularization are associated with an increased risk of operative mortality in comparison to renal revascularization alone. Some surgeons advocate unilateral renal revascularization in patients with bilateral renovascular disease. FIGURE 3-42 Schematic diagram of alternate bypass procedures. A, Hepatorenal bypass to right kidney. B, Splenorenal bypass to left kidney. C, Ileorenal bypass to left kidney. D, Autotransplantation.
DIMINISHED OPERATIVE MORBIDITY AND MORTALITY FOLLOWING SURGICAL REVASCULARIZATION FOR ATHEROSCLEROTIC RENOVASCULAR DISEASE
Preoperative screening and correction of coronary and carotid artery disease Avoidance of operation on severely diseased aorta Unilateral revascularization in patients with bilateral renovascular disease
FIGURE 3-41 Diminished operative morbidity and mortality following surgical revascularization for atherosclerotic renovascular disease. Operative morbidity and mortality in patients undergoing surgical revascularization have been minimized by selective screening and/or correction of significant coexisting coronary and/or carotid artery disease before undertaking elective surgical renal revascularization for atherosclerotic renal artery disease. Screening tests for carotid artery disease include carotid ultrasound and carotid arteriography. Screening tests for coronary artery disease include thallium stress testing, dipyridamole stress testing, dobutamine echocardiography, and coronary arteriography. Aortorenal
3.21
A
FIGURE 3-43 Percutaneous transluminal renal angioplasty (PTRA) of the renal artery. A, High-grade (more than 75%) nonostial atherosclerotic stenosis of the left main renal artery in a patient with a solitary functioning kidney (right renal artery totally occluded). Note gradient of 170 mm Hg across the stenotic lesion. B, Balloon angioplasty of the left main renal artery was successfully performed with reduction in the gradient across the stenotic lesion from 170 mm Hg pre-PTRA to 15 mm Hg post-PTRA. Repeat aortogram 3 years later demonstrated patency of the left renal artery. FIGURE 3-44 High-grade atherosclerotic renal artery stenosis at the ostium of the right main renal artery in a 68-year-old man with a totally occluded left main renal artery. Several attempts at balloon dilatation were unsuccessful. Over the subsequent 10 days, severe renal insufficiency developed (serum creatinine increasing from 2.0 to 12.0 mg/dL) requiring dialysis. Renal function never improved and the patient remained on dialysis.
B
PTRA of the renal artery has emerged as an important interventional modality in the management of patients with renal artery stenosis. PTRA is most successful and should be the initial interventive therapeutic maneuver for patients with the medial fibroplasia type of fibrous renal artery disease (eg, Fig.3-5A). Excellent technical success rates have also been attained for nonostial atherosclerotic lesions of the main renal artery, as shown here.
FIGURE 3-45 Palmaz stent, expanded. Because percutaneous transluminal renal angioplasty (PTRA) has suboptimal long-term benefits for atherosclerotic ostial renal artery stenosis, endovascular stenting has gained wide acceptance. Renal artery stenting may be performed at the time of the diagnostic angiogram, or at some time thereafter, depending on the physicians preference and the risk to the patient of repeated angiographic procedures. From a technical standpoint, indications for renal artery stenting include 1) as a primary procedure for ostial atherosclerotic renal artery disease (ASO-RAD), 2) technical difficulties in conjunction with attempted PTRA, 3) post-PTRA dissection, 4) post-PTRA abrupt occlusion, and 5) restenosis following PTRA. It is unclear what the long-term patency and restenosis rates will be for renal artery stenting for ostial disease. Preliminary observations suggest that the 1-year patency rate for stents is approximately twice that for PTRA.
3.22

FIGURE 3-46 Abdominal aortogram in a 63-year-old male, 6 months following placement of a Palmaz stent. Note wide patency of the left main renal artery.
A. SURGICAL REVASCULARIZATION VERSUS PTRA FOR ATHEROSCLEROTIC RENAL ARTERY DISEASE

Successful surgical revascularization, %
90 90
B. SURGICAL REVASCULARIZATION VERSUS PTRA FOR FIBROUS RENAL ARTERY DISEASE

Successful surgical revascularization, %
90 90
Lesion
Nonostial (20%) Ostial (80%)
Successful PTRA, %
8090 2530
Lesion
Main (50%) Branch (50%)
Successful PTRA, %
8090 NA
FIGURE 3-47 Surgical revascularization vs percutaneous transluminal renal angioplasty (PTRA) for renal artery disease. A, Success rates for atherosclerotic renal artery disease (ASO-RAD). B, Success rates for fibrous renal artery disease. Success of either PTRA or surgical renal revascularization is viewed in terms of technical success and clinical success. For PTRA, technical success reflects a lumen patency with less than 50% residual stenosis (ie, successful establishment of a patent lumen). For surgical revascularization, technical success is the demonstration of good blood flow to the revascularized kidney determined during surgery, or postoperatively by DPTA renal scan or other immediate postoperative imaging procedures. Technical success with either PTRA or surgical revascularization is rarely defined by postoperative angiography. Clinical success may be defined as improved blood pressure or improvement in kidney function, and/or resolution of flash pulmonary edema. Technical and clinical successes do not necessarily occur together because technical success may be apparent, but without improvement in blood pressure or renal function.
The percent success for PTRA and surgical revascularization depicted above are estimates, and reflect primarily technical success for both nonostial and ostial lesions in ASO-RAD. Technical success rates for surgical revascularization are high, approximating 90%, with little difference in the technical success rates between ostial and nonostial lesions. For PTRA, technical success rates are much higher for nonostial lesions. There is a high rate of restenosis at 1 year (50% to 70%) for ostial ASO-RAD, which has promoted the use of renal artery stents for these lesions. The success rates of surgical renal revascularization and PTRA for stenosis of the main renal artery in fibrous renal artery disease are comparable, approximately 90%. Hypertension is more predictably improved with surgical revascularization and PTRA in fibrous renal artery disease in comparison with ASO-RAD. Technical success rates with surgical renal revascularization are high for branch fibrous renal artery disease, but long-term technical and clinical success rates are not available for PTRA of branch lesions due to fibrous dysplasia. NAnot available. (Adapted from Pohl [18]; with permission.)
3.23
COMPLICATIONS OF TRANSLUMINAL ANGIOPLASTY OF THE RENAL ARTERIES

Contrast-induced ARF (mild or severe) Atheroembolic renal failure Rupture of the renal artery Dissection of the renal artery Thrombotic occlusion of the renal artery Occlusion of a branch renal artery Balloon malfunction (may lead to inability to remove balloon) Balloon rupture Puncture site hematoma, hemorrhage, or vessel tear Median nerve compression (axillary approach) Renal artery spasm Mortality (1%)
FACTORS TO CONSIDER IN SELECTION OF TREATMENT FOR PATIENTS WITH RENAL ARTERY DISEASE
Is renal artery disease causing hypertension? Severity of hypertension Specific type of renal artery disease and threat to renal function General medical condition of patient Relative efficacy and risk of medical antihypertensive therapy, PTRA, renal artery stenting, surgical revascularization
FIGURE 3-48 Complications of transluminal angioplasty of the renal arteries. The more common complications of PTRA are contrast-induced acute renal failure (ARF) and atheroembolic renal failure. Dissection of the renal artery, occlusion of a branch renal artery, and occasionally thrombotic occlusion of the main renal artery may occur. In experienced hands, rupture of the renal artery is rare. Minor complications relate primarily to the puncture site. When the axillary approach is used (because of severe iliac and lower abdominal aortic atherosclerosis), median nerve compression may transpire. Some of these complications of percutaneous transluminal renal angioplasty, particularly atheroembolic renal failure and/or contrast-induced acute renal failure (ARF) may also be observed with renal artery stent procedures.
FIGURE 3-49 Selection of treatment for patients with renal artery disease. In selecting treatment options for patients with renal artery disease, there are several factors to consider: what is the likelihood that the renal artery disease is causing the hypertension? For patients with fibrous renal artery disease the likelihood is high; for patients with atherosclerotic renal artery disease (ASO-RAD), the likelihood for a cure of hypertension is small. The more severe the hypertension, the greater the inclination to intervene with either surgery or balloon angioplasty. For children, adolescents, and younger adults, most of whom will have fibrous renal artery disease, intervention is usually recommended to avoid lifelong antihypertensive therapy. Cardiovascular comorbidity is high for patients with ASO-RAD and appropriate caution in approaching these patients is warranted, weighing the relative efficacy and risk of medical antihypertensive therapy, percutaneous transluminal renal angioplasty (PTRA), renal artery stenting, and surgical revascularization. Local experience and expertise of the treating physicians must be considered as well in selection of treatment options for these patients.
References
1. Pohl MA: Renal artery stenosis, renal vascular hypertension and ischemic nephropathy. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown & Co; 1997: 13671427. 2. Rimmer JM, Gennari FJ: Atherosclerotic renovascular disease and progressive renal failure. Ann Intern Med 1993, 118:712719. 3. Brown JJ, Davies DL, Morton JJ, et al.: Mechanism of renal hypertension. Lancet 1976, 1:12191221. 4. Hoffmann U, Edwards JM, Carter S, et al.: Role of duplex scanning for the detection of atherosclerotic renal artery disease. Kidney Int 1991, 39:12321239. 5. Olin JW, Piedmonte MR, Young JR, et al.: The utility of duplex ultrasound scanning of the renal arteries for diagnosing significant renal artery stenosis. Ann Intern Med 1995, 122:833838. 6. Muller FB, Sealey JE, Case DB, et al.: The captopril test for identifying renovascular disease in hypertensive patients. Am J Med 1986, 80:633644. 7. Nally JV, Olin JW , Lammert MD: Advances in noninvasive screening for renovascular hypertension disease. Cleve Clin J Med 1994, 61:328336. 8. Mann SJ, Pickering TG: Detection of renovascular hypertension: state of the art: 1992. Ann Intern Med 1992, 117:845853. 9. Ying CY, Tifft CP, Gavras H, Chobanian AV: Renal revascularization in the azotemic hypertensive patient resistant to therapy. N Engl J Med 1984, 311:10701075. 10. Novick AC, Pohl MA: Atherosclerotic renal artery occlusion extending into branches: successful revascularization in situ with a branched saphenous vein graft. J Urol 1979, 122:240242. 11. Olin JW, Melia M, Young JR, et al.: Prevalence of atherosclerotic renal artery stenosis in patients with atherosclerosis elsewhere. Am J Med 1990, 88:46N51N. 12. Vetrovec GW, Landwehr DM, Edwards VL: Incidence of renal artery stenosis in hypertensive patients undergoing coronary angiography. J Intervent Cardiol 1989, 2:6976. 13. Harding MB, Smith LR, Himmelstein SI, et al.: Renal artery stenosis: prevalence and associated risk factors in patients undergoing routine cardiac catheterization. J Am Soc Nephrol 1992, 2:16081616. 14. Jacobson HR: Ischemic renal disease: an overlooked clinical entity? [clinical conference]. Kidney Int 1988, 34:729743. 15. Novick AC: Patient selection for intervention to preserve renal function in ischemic renal disease. In Renovascular Disease. Edited by Novick AC, Scoble J, Hamilton G. London: WB Saunders; 1996:323335. 16. Schreiber MJ, Pohl MA, Novick AC: The natural history of atherosclerotic and fibrous renal artery disease. Urol Clin North Am 1984, 11:383392. 17. Hallett JW Jr, Textor SC, Kos PB, et al.: Advanced renovascular hypertension and renal insufficiency: trends in medical comorbidity and surgical approach from 1970 to 1993. J Vasc Surg 1995, 21:750759. 18. Pohl MA: Renovascular hypertension: An internists point of view. In Hypertension. Edited by Punzi HA, Flamenbaum W. Mt. Kisco, NY: Futura Publishing Co Inc; 1989:367393.
3.24
Selected Bibliography
Goldblatt H, Lynch J, Hanzal RF, Summerville WW: Studies on experimental hypertension. I. The production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med 1934, 59:347381. Morris GC Jr, DeBakey ME, Cooley MJ: Surgical treatment of renal failure of renovascular origin. JAMA 1962, 182:113116. Novick AC, Ziegelbaum M, Vidt DG, et al.: Trends in surgical revascularization for renal artery disease: ten years experience. JAMA 1987, 257:498501. Dustan HP, Humphries AW, DeWolfe VG, et al.: Normal arterial pressure in patients with renal arterial stenosis. JAMA 1964, 187:10281029. Holley KE, Hunt JC, Brown ALJ, et al.: Renal artery stenosis: a clinicalpathological study in normotensive and hypertensive patients. Am J Med 1964, 34:1422. Page IH: The production of persistent arterial hypertension by cellophane perinephritis. JAMA 1939, 113:20462048. McCormack LJ, Poutasse EF, Meaney TF, et al.: A pathologic-arteriographic correlation of renal arterial disease. Am Heart J 1966, 72:188198. Pohl MA, Novick AC: Natural history of atherosclerotic and fibrous renal artery disease: clinical implications. Am J Kidney Dis 1985, 5:A120A130. Zierler RE, Bergelin RO, Davidson RC, et al.: A prospective study of disease progression in patients with atherosclerotic renal artery stenosis. Am J Hypertens 1996, 9:10551061. Caps MT, Zierler RE, Polissar NL, et al.: Risk of atrophy in kidneys with atherosclerotic renal artery stenosis. Kidney Int 1998, 53:735742. Goncharenko V, Gerlock AJ Jr, Shaff MI, Hollifield JW: Progression of renal artery fibromuscular dysplasia in 42 patients as seen on angiography. Radiology 1981, 139:4551. Vaughan ED Jr, Carey RM, Ayers CR, et al.: A physiologic definition of blood pressure response to renal revascularization in patients with renovascular hypertension. Kidney Int 1979, 15:S83S92. Textor SC: Renovascular hypertension. Curr Opin Nephrol Hyperten 1993, 2:775783. Working Group on Renovascular Hypertension: Detection, evaluation, and treatment of renovascular hypertension. Final report. Arch Intern Med 1987, 147:820829. Hughes JS, Dove HG, Gifford RW Jr, Feinstein AR: Duration of blood pressure elevation in accurately predicting surgical cure of renovascular hypertension. Am Heart J 1981, 101:408413. Svetkey LP, Himmelstein SI, Dunnick NR, et al.: Prospective analysis of strategies for diagnosing renovascular hypertension. Hypertension 1989, 14:247257. Setaro JF, Saddler MC, Chen CC, et al.: Simplified captopril renography in diagnosis and treatment of renal artery stenosis. Hypertension 1991, 18:289298. Novick AC, Pohl MA, Schreiber M, et al.: Revascularization for preservation of renal function in patients with atherosclerotic renovascular disease. J Urol 1983, 129:907912. Gifford RW Jr, McCormack LJ, Poutasse EF: The atrophic kidney: its role in hypertension. Mayo Clin Proc 1965, 40:834852. Pickering TG, Herman L, Devereux RB, et al.: Recurrent pulmonary oedema in hypertension due to bilateral renal artery stenosis: treatment by angioplasty or surgical revascularisation. Lancet 1988, 2:551552. United States Renal Data System Coordinating Center: Incidence and causes of treated ESRD. In The USRDS 1994 Annual Data Report. Edited by Agodoa LYC, Held PJ, Port FK. Bethesda: USRDS Coordinating Center; 1994:4354. Mailloux LU, Napolitano B, Bellucci AG, et al.: Renal vascular disease causing end-stage renal disease, incidence, clinical correlates, and outcomes: a 20-year clinical experience. Am J Kidney Dis 1994, 24:622639. Appel RG, Bleyer AJ, Reavis S, Hansen KJ: Renovascular disease in older patients beginning renal replacement therapy. Kidney Int 1995, 48:171176. Hansen KJ, Thomason RB, Craven TE, et al.: Surgical management of dialysisdependent ischemic nephropathy. J Vasc Surg 1995, 21:197209. Hallett JW Jr, Fowl R, OBrien PC, et al.: Renovascular operations in patients with chronic renal insufficiency: do the benefits justify the risks? J Vasc Surg 1987, 5:622627. Conlon PJ, Athirakul K, Kovalik E, et al.: Survival in renal vascular disease. J Am Soc Nephrol 1998, 9:252256. Textor SC, McKusick MA, Schirger AA, et al.: Atherosclerotic renovascular disease in patients with renal failure. Adv Nephrol Necker Hosp 1997, 27:281295. Novick AC, Straffon RA, Stewart BH, et al.: Diminished operative morbidity and mortality in renal revascularization. JAMA 1981, 246:749753. Khauli RB, Novick AC, Ziegelbaum M: Splenorenal bypass in the treatment of renal artery stenosis: experience with sixty-nine cases. J Vasc Surg 1985, 2:547551. Chibaro EA, Libertino JA, Novick AC: Use of the hepatic circulation for renal revascularization. Ann Surg 1984, 199:406411. Novick AC, Stewart R: Use of the thoracic aorta for renal revascularization. J Urol 1990, 143:7779. Tarazi RY, Hertzer NR, Beven EG, et al.: Simultaneous aortic reconstruction and renal revascularization: risk factors and late results in eighty-nine patients. J Vasc Surg 1987, 5:707714. Hollenberg NK: Medical therapy of renovascular hypertension: efficacy and safety of captopril in 269 patients. Cardiovasc Rev Rpts 1983, 4:852879. Pohl MA: Medical management of renovascular hypertension. In Renal Vascular Disease. Edited by Novick AC, Scoble J, Hamilton G. London: WB Saunders; 1996, 339349. Palmaz JC, Kopp DT, Hayashi H, et al.: Normal and stenotic renal arteries: Experimental balloon-expandable intraluminal stenting. Radiology 1987, 164:705708. Blum U, Krumme B, Flugel P, et al.: Treatment of ostial renal-artery stenoses with vascular endoprostheses after unsuccessful balloon angioplasty. N Engl J Med 1997, 336:459465. Harden PN, MacLeod MJ, Rodger RSC, et al.: Effect of renal-artery stenting on progression of renovascular renal failure. Lancet 1997, 349:11331136. Fiala LA, Jackson MR, Gillespie DL, et al.: Primary stenting of atherosclerotic renal artery ostial stenosis. Ann Vasc Surg 1998, 12:128133. Canzanello VJ, Millan VG, Spiegel JE, et al.: Percutaneous transluminal renal angioplasty in management of atherosclerotic renovascular hypertension: results in 100 patients. Hypertension 1989, 13:163172. Plouin PF, Chatellier G, Darne B, Raynaud A, for the Essai Multicentrique Medicaments vs. Angioplastie (EMMA) Study Group: Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis: a randomized trial. Hypertension 1998, 31:823829. Textor SC: Revascularization in atherosclerotic renal artery disease [clinical conference]. Kidney Int 1998, 53:799811.
Adrenal Causes of Hypertension

Myron H. Weinberger
he adrenal gland is involved in the production of a variety of steroid hormones and catecholamines that influence blood pressure. Thus, it is not surprising that several adrenal disorders may result in hypertension. Many of these disorders are potentially curable or responsive to specific therapies. Therefore, identifying adrenal disorders is an important consideration when elevated blood pressure occurs suddenly or in a young person, is severe or difficult to treat, or is associated with manifestations suggestive of a secondary form of hypertension. Because these occurrences are relatively rare, it is necessary to have a high index of suspicion and understand the pathophysiology on which the diagnosis and treatment of these problems is based. Three general forms of hypertension that result from excessive production of mineralocorticoids, glucocorticoids, or catecholamines are reviewed in the context of their normal production, metabolism, and feedback systems. The organization of this chapter provides the background for understanding the normal physiology and pathophysiologic changes on which effective screening and diagnosis of adrenal abnormalities are based. Therapeutic options also are briefly considered. Primary aldosteronism, Cushings syndrome, and pheochromocytoma are discussed.
CHAPTER
4.2
Adrenal Hypertension
PHYSIOLOGIC MECHANISMS IN ADRENAL HYPERTENSION
Disorder
Primary aldosteronism
Cause
Autonomous hypersecretion of aldosterone (hypermineralocorticoidism)
Pathophysiology
Increased renal sodium and water reabsorption, increased urinary excretion of potassium and hydrogen ions Increased activation of mineralocorticoid receptor (?), increased angiotensinogen (renin substrate) concentration Vasoconstriction, increased heart rate
Pressure mechanism
Extracellular fluid volume expansion, hypokalemia (?), alkalosis
FIGURE 4-1 The causes and pathophysiologies of the three major forms of adrenal hypertension and the proposed mechanisms by which blood pressure elevation results.
Cushings syndrome
Hypersecretion of cortisol (hyperglucocorticoidism)
Pheochromocytoma
Hypersecretion of catecholamines
Extracellular fluid volume expansion (?), increased angiotensin II (vasoconstriction and increased peripheral resistance) Increased peripheral resistance, increased cardiac output
Histology of the Adrenal

Capsule Zona glomerulosa
Zona fasciculata
Zona reticularis Medulla Normal human suprarenal gland Human suprarenal gland after administration of crude ACTH
FIGURE 4-2 Histology of the adrenal. A cross section of the normal adrenal before (left) and after (right) stimulation with adrenocorticotropic hormone (ACTH) [1]. The adrenal is organized into the outer adrenal cortex and the inner adrenal medulla. The outer adrenal cortex is composed of the zona glomerulosa, zona fasciculata, and zona reticularis. The zona glomerulosa is responsible for production of aldosterone and other mineralocorticoids and is chiefly under the control of angiotensin II (see Figs. 4-3 and 4-5). The zona fasciculata and zona reticularis are influenced primarily by ACTH and produce glucocorticoids and some androgens (see Figs. 4-3 and 4-19). The adrenal medulla produces catecholamines and is the major source of epinephrine (in addition to the organ of Zuckerkandl located at the aortic bifurcation) (see Fig. 4-25.)
4.3
Adrenal Steroid Biosynthesis

CH3 C=O CH3 C=O OH O
HO
Pregnenolone
HO 17-Hydroxypregnenolone
HO
Dehydroepiandrosterone
3 -OH-Dehydrogenase: 5 4 Isomerase CH3 C=O CH3 C=O OH O
FIGURE 4-3 Adrenal steroid biosynthesis. The sequence of adrenal steroid biosynthesis beginning with cholesterol is shown as are the enzymes responsible for production of specific steroids [2]. Note that aldosterone production normally occurs only in the zona glomerulosa (see Fig. 4-2). (From DeGroot and coworkers [2]; with permission.)
17Hydroxylase
Pregnenolone 21-Hydroxylase OH2OH C=O
O 17-Hydroxypregnenolone
O 4 Androstene 3,17-dione
CH2OH C=O OH
O 11-Deoxycorticosterone 11-Hydroxylase CH2OH HO C=O
11-Deoxycortisol
CH2OH HO O C=O OH
Corticosterone
Cortisol
18-Hydroxylase 18-OH-Dehrydrogenase CH2OH HO OHC C=O
Aldosterone
Zona glomerulosa only
4.4

FIGURE 4-4 Circadian rhythmicity of steroid production and major stimulatory factors. Aldosterone and cortisol and their respective major stimulatory factors, plasma renin activity (PRA) and adrenocorticotropic hormone (ACTH), demonstrate circadian rhythms. The lowest values for all of these components are normally seen during the sleep period when the need for active steroid production is minimal. ACTH levels increase early before awakening, stimulating cortisol production in preparation for the physiologic changes associated with arousal. PRA increases abruptly with the assumption of the upright posture, followed by an increase in aldosterone production and release. Both steroids demonstrate their highest values through the morning and early afternoon. Cortisol levels parallel those of ACTH, with a marked decline in the afternoon and evening hours. Aldosterone demonstrates a broader peak, reflecting the postural stimulus of PRA. sodium and water reabsorption (8) at the expense of increased potassium and hydrogen ion excretion in the urine. The increase in sodium and volume then increase systemic blood pressure and renal perfusion pressure and sodium content (9), thereby suppressing further renin release (10) and angiotensin II production (11). Thus, in contrast to the normal situation depicted in panel A, the levels of angiotensin II are highly suppressed and therefore do not contribute to an increase in systemic blood pressure (12). In primary aldosteronism, ACTH (13) has a dominant modulatory role in influencing aldosterone production and hypokalemia, resulting from increased urinary potassium exchange for sodium, which has a negative effect on aldosterone production (14).
ACTH PRA
Aldosterone Cortisol Morning 6 AM Noon 6 PM Morning
Kidney Perfusion pressure 1 Sodium content 6 Renin 2 Extracellular fluid volume 8 Sodium reabsorption 4 Aldosterone Zona glomerulosa Adrenal complex 7 Aldosterone Sodium reabsorption Juxtaglomerular apparatus Perfusion pressure 9 Sodium content 12
Kidney Juxtaglomerular apparatus Renin
10
Extracellular fluid volume 5
Angiotensin II
Angiotensin II 11 Adrenal complex
Zona glomerulosa 14 13 ACTH
Normal
K+
ACTH
Primary aldosteronism
K+
FIGURE 4-5 Control of mineralocorticoid production. A, Control of aldosterone production under normal circumstances. A decrease in renal perfusion pressure or tubular sodium content (1) at the level of the juxtaglomerular apparatus and macula densa of the kidney triggers renin release (2). Renin acts on its substrate angiotensinogen to generate angiotensin I, which is converted rapidly by angiotensin-converting enzyme to angiotensin II. Angiotensin II then induces peripheral vasoconstriction to increase perfusion pressure (6) and acts on the zona glomerulosa of the adrenal cortex (3) (see Fig. 4-2) to stimulate production and release of aldosterone (4). Potassium and adrenocorticotropic hormone (ACTH) also play a minor role in aldosterone production in some circumstances. Aldosterone then acts on the cells of the collecting duct of the kidney to promote reabsorption of sodium (and passively, water) in exchange for potassium and hydrogen ions excreted in the urine. This increased secretion promotes expansion of extracellular fluid volume and an increase in renal tubular sodium content (5) that further suppresses renin release, thus closing the feedback loop (servomechanism). B, Abnormalities present in primary aldosteronism. Autonomous hypersecretion of aldosterone (7) leads to increased extracellular fluid volume expansion and increased renal tubular sodium content. These elevated levels are a result of increased renal
4.5
Aldosteronism
TYPES OF PRIMARY ALDOSTERONISM
Types
Solitary adrenal adenoma Bilateral adrenal hyperplasia Unilateral adrenal hyperplasia Glucocorticoid-remediable aldosteronism Bilateral solitary adrenal adenomas Adrenal carcinoma
SCREENING TESTS FOR PRIMARY ALDOSTERONISM

Test
Serum potassium 3.5 mEq/L Plasma renin activity 4 ng/mL/90 min Urinary aldosterone 20 g/d Plasma aldosterone 15 ng/dL Plasma aldosteroneplasma renin activity ratio 15 Plasma aldosteroneplasma renin activity ratio 30
Relative frequency, %
65 30 2 <1 <1 <1
Sensitivity, %
75 >99 70 90 99.8 96
Specificity, %
20 4060 60 60 98 100
FIGURE 4-6 Types of primary aldosteronism. (Data from Weinberger and coworkers [3].)
FIGURE 4-7 Screening tests for primary aldosteronism. Serum potassium levels range from 3.5 to normal levels of patients with primary aldosteronism. Most hypertensive patients with hypokalemia have secondary rather than primary aldosteronism. The plasma aldosterone-to-plasma renin activity (PRA) ratio (disregarding units of measure) is the most sensitive and specific single screening test for primary aldosteronism. However, because of laboratory variability, normal ranges must be developed for individual laboratory values. A random peripheral blood sample can be used to obtain this ratio even while the patient is receiving antihypertensive medications, when the effects of the medications on PRA and aldosterone are considered. (Data from Weinberger and coworkers [3,4].)
LOCALIZING TESTS FOR PRIMARY ALDOSTERONISM

Test
Adrenal computed tomographic scan Adrenal isotopic scan Adrenal venography Adrenal magnetic resonance imaging Adrenal venous blood sampling with adrenocorticotropic hormone infusion
Sensitivity, %
50 50 70 ? >92
Specificity, %
60 65 80 ? >95
FIGURE 4-8 Localizing tests for primary aldosteronism. Adrenal venous blood sampling with determination of both aldosterone and cortisol concentrations during adrenocorticotropic hormone stimulation provides the most accurate way to identify unilateral hyperaldosteronism. This approach minimizes artefact owing to episodic steroid secretion and to permit correction for dilution of adrenal venous blood with comparison of values to those in the inferior vena cava. (see Fig. 4-12). (Data from Weinberger and coworkers [3].)
A
FIGURE 4-9 Normal and abnormal adrenal isotopic scans. A, Normal scan. Increased bilateral uptake of I131-labeled iodo-cholesterol of normal adrenal tissue is shown above the indicated renal outlines. (Continued on next page)
4.6

FIGURE 4-9 (Continued) B, Intense increase in isotopic uptake by the left adrenal (as viewed from the posterior aspect) containing an adenoma.
B
FIGURE 4-10 Adrenal venography in primary aldosteronism. A, Typical leaflike pattern of the normal right adrenal venous drainage. B, In contrast, marked distortion of the normal venous anatomy by a relatively large (3-cmdiameter) adenoma of the left adrenal. Most solitary adenomas responsible for primary aldosteronism are smaller than 1 cm in diameter and thus usually cannot be seen using anatomic visualizing techniques.
B
In normal persons the increase in plasma renin activity associated with upright posture results in a marked increase in plasma aldosterone at noon compared with that at 8 AM (see Fig. 4-4). In adenomatous primary aldosteronism, the plasma renin activity is markedly suppressed and does not increase appreciably with upright posture. Moreover, aldosterone production is modulated by adrenocorticotropic hormone (which decreases from high levels at 8 AM to lower values at noon (see Fig. 4-4). Thus, these patients typically demonstrate lower levels of aldosterone at noon than they do at 8 AM. In patients with bilateral adrenal hyperplasia, the plasma renin activity tends to be more responsive to upright posture and aldosterone production also is more responsive to the renin-angiotensin system. Thus, postural increases in aldosterone usually are seen. Exceptions to these changes occur in both forms of primary aldosteronism, however, making the postural test less sensitive and specific [3].
60 Plasma aldosterone, ng/dL 50 40 30 20 10 0
Normal
Adenoma
Hyperplasia
8 AM Supine
Noon Upright
8 AM Supine
Noon Upright
8 AM Supine
Noon Upright
FIGURE 4-11 Changes in plasma aldosterone with upright posture. AC, Depicted are individual data for persons showing temporal and postural changes in plasma aldosterone concentration in normal persons (panel A), and in patients with primary aldosteronism owing to a solitary adrenal adenoma (panel B) or to bilateral adrenal hyperplasia (panel C). Blood is sampled at 8 AM, while the patient is recumbent, and again at noon after 4 hours of ambulation.
4.7
AC TH
A C A C
A C
A C
A C
A C
Bilateral aldosteronism
Unilateral aldosteronism
FIGURE 4-12 Adrenal venous blood sampling during infusion of adrenocorticotropic hormone (ACTH) [3]. A, Bilateral aldosteronism. A schematic representation of the findings in primary aldosteronism owing to bilateral adrenal hyperplasia is shown on the left. When blood is sampled from both adrenal veins and the inferior vena cava during ACTH infusion, the aldosterone-to-cortisol ratio is similar in both adrenal effluents and higher than that in the inferior vena cava. In such cases, medical therapy (potassium-sparing diuretic combinations such as hydrochlorothiazide plus triamterene, amiloride, or spirolactone and calcium channel entry blockers) usually is effective. B, Unilateral aldosteronism. On the right is depicted the findings in a patient with a unilateral right adrenal lesion. This lesion can be diagnosed by an elevated aldosterone-to-cortisol ratio in right adrenal
venous blood compared with that of the left adrenal and the inferior vena cava. Even if the venous effluent cannot be accurately sampled from one side (as judged by the levels of cortisol during ACTH infusion), when the contralateral adrenal venous effluent has an aldosterone-to-cortisol ratio lower than that in the inferior vena cava, it can be inferred that the unsampled side is the source of excessive aldosterone production (unless there is an ectopic source). In such cases, surgical removal of the solitary adrenal lesion usually results in normalization of blood pressure and the attendant metabolic abnormalities. Medical therapy also is effective but often requires high doses of Aldactone (GD Searle & Co., Chicago) (200 to 800 mg/d), which may be intolerable for some patients because of side effects. Aaldosterone; Ccortisol.
AC TH
TH AC
TH AC
4.8

FIGURE 4-13 (see Color Plate) A section of a typical adrenal adenoma in primary aldosteronism pathology. A relatively large (2-cm-diameter) adrenal adenoma with its lipid-rich (bright yellow) content is shown.
180 160 140 120 100 80 60
Father
A
160 Blood pressure 140 120 100 80 60 Son 1
Dexamethasone
mg 200 100
FIGURE 4-14 Glucocorticoid-remediable aldosteronism. AC, Seen are the effects of dexamethasone and spironolactone on blood pressure in a father (panel A) and two sons, one aged 6 years (panel B) and the other aged 8 years (panel C). Blood pressure levels are shown before and after treatment with dexamethasone (left) or spironolactone (right) [5]. Note that the maximum blood pressure reduction with dexamethasone required more than 2 weeks of treatment. Similarly, the maximum response to spironolactone was both time- and dose-dependent.
Spironolactone
40 160 140 120 100 80 60 40 Son 2
200 100
200 100
3 4 Weeks
4 6 Months

Changes with dexamethasone
Plasma cortisol, g/ 100 mL 25 Urinary aldosterone, g/ 24 h 20 15 10 5 25 20 15 10 5 Dexamethasone
4.9
A
Plasma renin activity, ng AI/mL- 3hr 1.0
B
50 Plasma aldosterone, ng/100 mL 40 30 20 10
5 7 6 5 4 3
0.8 0.6 0.4 0.2 0
2 Weeks
FIGURE 4-15 Humoral changes in glucocorticoid-remediable aldosteronism with dexamethasone. AE, Depicted are the changes in plasma cortisol (panel A), urinary aldosterone (panel B), plasma renin activity (PRA) (panel C), plasma aldosterone (panel D), and serum potassium (panel E) before and after dexamethasone administration in the patients in Figure 4-14. Note that before dexamethasone administration, serum cortisol was in the normal range and was markedly suppressed after treatment. Urinary aldosterone was completely normal and plasma aldosterone was
elevated in only one patient before dexamethasone administration. The diagnosis was made by demonstrating that the plasma aldosterone concentration failed to suppress normally after intravenous saline infusion (2 L/4 h) [6]. After dexamethasone administration, both plasma and urinary aldosterone levels decreased markedly (except for one occasion when it is suspected that the patient did not comply with dexamethasone therapy). PRA, which was markedly suppressed before treatment, increased with dexamethasone. Note also that serum potassium levels were normal in two of the three patients before treatment with dexamethasone but increased with therapy in all three [5]. All of these changes reverted to control baseline values when dexamethasone therapy was discontinued.
Serum potassium, mEq/L
Glomerulosa AII Aldosterone Aldosterone AII
Glomerulosa
Aldosterone
Aldosterone
ACTH Cortisol
ACTH
Chimeric Aldos
Cortisol + Aldosterone + 18OH cortisol + 18OXO cortisol
Fasciculata
Fasciculata
FIGURE 4-16 Normal and chimeric aldosterone synthase in glucocorticoid-remedial aldosteronism (GRA). A, Normal relationship between the stimuli and site of adrenal cortical steroid production. Aldosterone synthase normally responds to angiotensin II (AII) in the zona glomerulosa, resulting in aldosterone synthesis and release (see Figs. 4-2 and 4-3). B, In GRA, a chimeric aldosterone synthase gene results from a mutation, which stimulates production of aldosterone and other steroids from the zona glomerulosa under the control of adrenocorticotropic hormone (ACTH) (Fig. 4-17). Thus, when ACTH production is suppressed by steroid administration, aldosterone production is reduced.
4.10

FIGURE 4-17 Mutation of the (11-OHase) chimeric aldosterone synthase gene [8]. The unequal crossing over between aldosterone synthase and 11-hydroxylase genes resulting in the mutated gene responsible for glucocorticoid-remedial aldosteronism is described.
11OHase
5' 3' 5' 3'
Unequal crossing over 5' 3' 5' 3'
5'
3'
5' Chimeric gene
3'
5' 11OHase
3'
Aldosterone synthase
Cushings Syndrome
B
FIGURE 4-18 (see Color Plate) Physical characteristics of Cushings syndrome. A, Side profile of a patient with Cushings syndrome demonstrating an increased cervical fat pad (so-called buffalo hump), abdominal obesity, and thin extremities and petechiae (on the wrist). The round (so-called moon) facial appearance, plethora, and acne cannot be seen readily here. B, Violescent abdominal striae in a patient with Cushings syndrome. Such striae also can be observed on the inner parts of the legs in some patients.
4.11
Pituitary
CRF
Pituitary
Pituitary
() () ()
ACTH
Cortisol ACTH Cortisol ACTH Cortisol
Adrenal cortex (zona fasciculata zona reticularis)
FIGURE 4-19 Normal pituitary-adrenal axis. Corticotropinreleasing factor (CRF) acts to stimulate the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH then stimulates the adrenal zona fasciculata and zona reticularis to synthesize and release cortisol (see Figs. 4-2 and 4-3). The increased levels of cortisol feed back to suppress additional release of ACTH. As shown in Figure 4-4, ACTH and cortisol have circadian patterns.
FIGURE 4-20 Pituitary Cushings disease. Pituitary Cushings disease results from excessive production of adrenocorticotropic hormone (ACTH), typically owing to a benign adenoma. Excess ACTH stimulates both adrenals to produce excessive amounts of cortisol and results in bilateral adrenal hyperplasia. The increased cortisol production does not suppress ACTH release, however, because the pituitary tumor is unresponsive to the normal feedback suppression of increased cortisol levels. The diagnosis usually is made by demonstration of elevated levels of ACTH in the face of elevated cortisol levels, particularly in the afternoon or evening, representing loss of the normal circadian rhythm (see Fig. 4-4). Radiographic studies of the pituitary (computed tomographic scan and magnetic resonance imaging) will likely demonstrate the source of increased ACTH production. When the pituitary is the source, surgery and irradiation are therapeutic options.
FIGURE 4-21 Adrenal Cushings syndrome. Adrenal Cushings syndrome typically is caused by a solitary adrenal adenoma (rarely by carcinoma) producing excessive amounts of cortisol autonomously. The increased levels of cortisol feed back to suppress release of adrenocorticotropic hormone (ACTH) and corticotropin-releasing factor. The finding of very low ACTH levels in the face of elevated cortisol values and a loss of the circadian pattern of cortisol confirm the diagnosis (see Fig. 4-4). Additional anatomic studies of the adrenal (computed tomographic scan and magnetic resonance imaging) usually disclose the source of excessive cortisol production. Surgical removal usually is effective.
4.12
Cushing's syndrome: ectopic etiology

Ectopic Tumor Pituitary
SCREENING TESTS FOR CUSHINGS SYNDROME

Test
Elevated PM serum cortisol Elevated urinary 17-hydroxy corticosteroids Elevated urinary free cortisol ()
Sensitivity, %
75 >90 >95
Specificity, %
60 60 >95
ACTH ACTH
Cortisol
FIGURE 4-23 Screening tests for Cushings syndrome. Whereas elevated evening plasma cortisol levels typically indicate abnormal circadian rhythm, other factors such as stress also can cause increased levels late in the day. Urinary levels of 17-hydroxy corticosteroids may be increased in association with obesity. In such cases, repeat measurement after a period of dexamethasone suppression may be required to distinguish this form of increased glucocorticoid excretion from Cushings syndrome. The measurement of urinary-free cortisol is the most sensitive and specific screening test.
FIGURE 4-22 Ectopic etiology of Cushings syndrome. Rarely, Cushings syndrome may be due to ectopic production of adrenocorticotropic hormone (ACTH) from a malignant tumor, often in the lung. In such cases, hypercortisolism is associated with increased levels of ACTH-like peptide; however, no pituitary lesions are found. Patients with ectopic Cushings syndrome often are wasted and have other manifestations of malignancy. the morning hours (see Fig. 4-4). In pituitary Cushings disease and ectopic forms of Cushings syndrome, elevated values are observed, especially in the afternoon and evening. The next step in differentiation is an anatomic evaluation of the pituitary. When no abnormality is found, the next step is a search for a malignancy, typically in the lung. The finding of low ACTH levels points to the adrenal as the source of excessive cortisol production, and anatomic studies of the adrenal are indicated. CT computed tomography; MRImagnetic resonance imaging.
FIGURE 4-24 Algorithm for differentiation of Cushings syndrome. The first step in the differentiation of Cushings syndrome after diagnosing hypercortisolism is measurement of plasma adrenocorticotropic hormone (ACTH) levels. Typically, these should be reduced after
4.13
Catecholamines
FIGURE 4-25 Synthesis, actions, and metabolism of catecholamines. Depicted is the synthesis of catecholamines in the adrenal medulla [9]. Epinephrine is only produced in the adrenal and the organ of Zuckerkandl at the aortic bifurcation. Norepinephrine and dopamine can be produced and released at all other parts of the sympathetic nervous system. The kidney is the primary site of excretion of
catecholamines and their metabolites, as noted here. The kidney also can contribute catecholamines to the urine. The relative contributions of norepinephrine and epinephrine to biologic events is noted by the plus signs. BMRbasal metabolic rate; CNScentral nervous system; NEFAnonesterified fatty acids; VMAvanillylmandelic acid.
4.14
Pheochromocytoma
Blood pressure taken at 2-min intervals 5-min intervals Calibrate 250 Blood pressure, mm Hg 200 150 100 0 8:30
PM 240 230 220 210 190 180 170 160 140 130 120 110 90 80 70 60 40 30 20 10
50
10
PM
2
AM
5:00
AM
7:45
AM
9
AM
10
AM
11
AM
12 Noon
1
PM
During the attack: Blood pressure, 192/100 mm Hg Pulse 108 Respirations, 24
FIGURE 4-26 Paroxysmal blood pressure pattern in pheochromocytoma. Note the extreme variability of blood pressure in this patient with pheochromocytoma during ambulatory blood pressure monitoring [9]. Whereas most levels were within the normal
range, episodic increases to levels of 200/140 mm Hg were observed. Such paroxysms can be spontaneous or associated with activity of many sorts. (Adapted from Manger and Gifford [9]; with permission.) FIGURE 4-28 Caf au lait lesions in a patient with pheochromocytoma. These light-browncolored (coffeewith-cream-colored) lesions, sometimes seen in patients with pheochromocytoma, usually are larger than 3 cm in the largest dimension. In this particular patient, neurofibromas also are present and can be seen in profile.
FIGURE 4-27 (see Color Plate) Neurofibroma associated with pheochromocytoma. Neurofibromas are sometimes found in patients with pheochromocytoma. These lesions are soft, fluctuant, and nontender and can appear anywhere on the surface of the skin. These lesions can be seen in profile in Figure 4-28.
4.15
DISORDERS ASSOCIATED WITH PHEOCHROMOCYTOMA

Cholelithiasis Renal artery stenosis Neurofibromas Caf au lait lesions Multiple endocrine neoplasia, types II and III Von Hippel-Lindau syndrome (hemangioblastoma and angioma) Mucosal neuromas Medullary thyroid carcinoma
FIGURE 4-29 Disorders associated with pheochromocytoma. In addition to the neurofibromas and caf au lait lesions depicted in Figures 4-27 and 4-28, several other associated abnormalities have been reported in patients with pheochromocytoma. (From Ganguly et al. [9]; with permission.)
COMMON SYMPTOMS AND FINDINGS IN PHEOCHROMOCYTOMA

Patients, %
Symptoms Severe headache Perspiration Palpitations, tachycardia Anxiety Tremulousness Chest, abdominal pain Nausea, vomiting Weakness, fatigue Weight loss Dyspnea Warmth, heat intolerance Visual disturbances Dizziness, faintness Constipation Finding Hypertension: Sustained Paroxysmal Pallor Retinopathy: Grades I and II Grades III and IV Abdominal mass Associated multiple endocrine adenomatosis 82 67 60 45 38 38 35 26 15 15 15 12 7 7
FIGURE 4-30 Common symptoms and findings in pheochromocytoma. Note that severe hypertensive retinopathy, indicative of intense vasoconstriction, frequently is observed. (Adapted from Ganguly et al. [10].)
SCREENING AND DIAGNOSTIC TESTS IN PHEOCHROMOCYTOMA

Test
Elevated 24-h urinary catecholamines, vanillylmandelic acid, homovanillic acid, metanephrines Abnormal clonidine suppression test Elevated urinary sleep norepinephrine
Sensitivity, %
85 75 >99
Specificity, %
80 85 >99
61 24 44 40 53 9 6
FIGURE 4-31 Screening and diagnostic tests in pheochromocytoma. Drugs, incomplete urine collection, and episodic secretion of catecholamines can influence the tests based on 24-hour urine collections in a patient with a pheochromocytoma. The clonidine suppression test is fraught with false-negative and false-positive results that are unacceptably high for the exclusion of this potentially fatal tumor. The sleep norepinephrine test eliminates the problems of incomplete 24-hour urine collection because the patient discards all urine before retiring; saves all urine voided through the sleep period, including the first specimen on arising; and notes the elapsed (sleep) time [10]. The sleep period is typically a time of basal activity of the sympathetic nervous system, except in patients with pheochromocytoma (see Fig. 4-32).
4.16

FIGURE 4-32 Nocturnal (sleep) urinary norepinephrine. The values for urinary excretion of norepinephrine are shown for normal persons and patients with essential hypertension as mean plus or minus SD [10]. Values for patients with pheochromocytoma are indicated by symbols. Note that the scale is logarithmic and the highest value for patients with normal or essential hypertension was less than 30 g, whereas the lowest value for a patient with pheochromocytoma was about 75 g. Most patients with pheochromocytomas had values an order of magnitude higher than the highest value for patients with essential hypertension.
1000
Sleep urinary norepinephrine excretion, g
100
Patient I Patient II Patient III Patient IV Patient V Patient VI
Maximum for normal Maximum for hypertensive
10 Normal mean + SD
Hypertensive mean + SD
LOCALIZATION OF PHEOCHROMOCYTOMA
Test
Abdominal plain radiograph Intravenous pyelogram Adrenal isotopic scan (meta-iodobenzoylguanidine) Adrenal computed tomographic scan
Sensitivity, %
40 60 85 >95
Specificity, %
50 75 85 >95
FIGURE 4-34 Intravenous pyelogram in pheochromocytoma. Note the displacement of the left kidney (right) by a suprarenal mass.
FIGURE 4-33 Localization of pheochromocytoma. Once the diagnosis of pheochromocytoma has been made it is very important to localize the tumor preoperatively so that the surgeon may remove it with a minimum of physical manipulation. Computed tomographic scan or MRI appears to be the most effective and safest techniques for this purpose [10]. The patient should be treated with -adrenergic blocking agents for 7 to 10 days before surgery so that the contracted extracellular fluid volume can be expanded by vasodilation.
4.17
C
FIGURE 4-35 AD, Computed tomographic scans in four patients with pheochromocytoma [10]. The black arrows identify the adrenal tumor in
D
these four patients. Three patients have left adrenal tumors, and in one patient (panel B) the tumor is on the right adrenal.
A
FIGURE 4-36 (see Color Plates) A and B, Pathologic appearance of pheochromocytoma before (panel A) and after (panel B) sectioning. This 3.5-cm-diameter
B
tumor had gross areas of hemorrhage noted by the dark areas visible in the photographs.
4.18
References
1. 2. 3. Netter FH: Endocrine system and selected metabolic diseases. In Ciba Collection of Medical Illustrations, vol. 4; 1981:Section III, Plates 5, 26. DeGroot LJ, et al.: Endocrinology, edn 2. Philadelphia: WB Saunders; 1989:1544. Weinberger MH, Grim CE, Hollifield JW, et al.: Primary aldosteronism: diagnosis, localization and treatment. Ann Intern Med 1979, 90:386395. Weinberger MH, Fineberg NS: The diagnosis of primary aldosteronism and separation of subtypes. Arch Intern Med 1993, 153:21252129. Grim CE, Weinberger MH: Familial, dexamethasone-suppressible normokalemic hyperaldosteronism. Pediatrics 1980, 65:597604. Kem DC, Weinberger MH, Mayes D, Nugent CA: Saline suppression of plasma aldosterone and plasma renin activity in hypertension. Arch Intern Med 1971, 128:380386. 7: Lifton RP, Dluhy RG, Powers M: Hereditary hypertension caused by chimeric gene duplications and ectopic expression of aldosterone synthase. Nat Genet 1992, 2:6674. 8. Lifton RP, Dluhy RG, Powers M: A glucocorticoid-remediable aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992, 355:262265. 9. Manger WM, Gifford RW Jr: Pheochromocytoma. New York: Springer-Verlag; 1977:97. 10. Ganguly A, Henry DP, Yune HY, et al.: Diagnosis and localization of pheochromocytoma: detection by measurement of urinary norepinephrine during sleep, plasma norepinephrine concentration and computed axial tomography (CT scan). Am J Med 1979, 67:2126.
4. 5. 6.
Insulin Resistance and Hypertension

Theodore A. Kotchen
esistance to insulin-stimulated glucose uptake is associated with increased risk for cardiovascular disease [1]. Risk factors for cardiovascular disease tend to cluster within individuals, and insulin resistance may be the link between hypertension and dyslipidemia. Depending on the populations studied and methodologies used for defining insulin resistance, approximately 25% to 40% of nonobese nondiabetic patients with hypertension are insulin-resistant [2]. Insulin resistance also has been observed in genetic and acquired animal models of hypertension. A constellation of insulin resistance, reactive hyperinsulinemia, increased triglycerides, decreased high-density lipoprotein cholesterol, and hypertension was designated as syndrome X by Reaven in 1988 [3]. Although a number of putative mechanisms have been proposed, it is unclear whether insulin resistance or reactive hyperinsulinemia, or both, actually cause hypertension. The recent observations that insulinsensitizing agents attenuate the development of hypertension lend credence to this hypothesis [4]. As discussed subsequently, however, these agents may lower blood pressure by different mechanisms. Whatever mechanism may be involved, the observation that a single agent may have the capacity to both increase insulin sensitivity and lower blood pressure is potentially of considerable clinical significance. Noninsulin-dependent diabetes mellitus represents an extreme of insulin resistance. Among diabetics, a two- to threefold increased prevalence of hypertension exists. Hypertension is associated with a fourfold increase in mortality among patients with noninsulin-dependent diabetes, and antihypertensive drug therapy has a beneficial impact on both macrovascular and microvascular disease [5]. Despite the potential concern that diuretics may augment insulin resistance, diabetic patients benefit from antihypertensive therapy with diuretics. The renal protective effect of antihypertensive drugs varies among different classes of agents. Angiotensin-converting enzyme inhibitors decrease proteinuria and retard the progression of renal insufficiency in diabetic patients with normal blood pressure and hypertension.
CHAPTER
5.2

dihydropyridine calcium antagonists accelerate the progression of diabetic nephropathy, particularly in the short term. Additional studies are required to evaluate the antihypertensive potential of insulin-sensitizing agents in patients with noninsulin-dependent diabetes.
This benefit is independent of an effect on blood pressure and may be related specifically to the capacity of these agents to dilate the efferent renal arteriole. Results of studies evaluating the effects of calcium antagonists on the progression of diabetic nephropathy are varied. Some studies suggest that
7.0
5054 y
Men
Women
Total cholesterol, mmol/L
6.5 6.0 5.5
4049 y 4049 y 3039 y 3039 y 2029 y 2029 y
B. NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY II

1. Persons with blood pressure >140/90 mm Hg or taking medication for hypertension: 40% have cholesterol >240 mg/dL 2. Persons with blood cholesterol >240 mg/dL: 46% have blood pressure >140/90 mm Hg 100
5.0 70 80 90 100 70 80 90 Diastolic blood pressure, mm Hg
FIGURE 5-1 Hyperlipidemia and hypertension. A, Epidemiologic studies document an association between serum cholesterol and blood pressure in men and women. B, Based on data from the National Health
and Nutrition Examination Survey II, persons with hypertension have a high prevalence of hyperlipidemia and vice versa [6]. (Panel A from Bonna and Thelle [7]; with permission.) FIGURE 5-2 Insulin resistance and hypertension. A, Genetic and nutritional factors contribute to insulin resistance and resultant hyperinsulinemia. In addition to obesity and type II diabetes, hyperlipidemia and hypertension also may be associated with insulin resistance. Insulin resistance may account for the association of hyperlipidemia with hypertension. B, Insulin resistance is associated with hypertension in a number of clinical and experimental settings. (Panel A from Ferrari and Weidmann [8]; with permission.)
Epidemiologic + clinical association Hereditary + acquired mechanisms
B. HYPERTENSION AND INSULIN RESISTANCE

Type II diabetes mellitus Obesity Essential hypertension Salt sensitive (?) Experimental hypertension Dahl-salt-sensitive rats Spontaneously hypertensive rats
Obesity
Insulin-resistance Hyperinsulinemia
Glucose tolerance Diabetes type II
Dyslipidemia, hypertension

140 Plasma glucose, mg/100 mL
5.3
FIGURE 5-4 Salt sensitivity. Persons who have salt-sensitive hypertension tend to be more insulinresistant than are those who are saltresistant. That is, patients who are saltsensitive have higher plasma glucose and insulin responses to a glucose load than do those who are salt-resistant. (From Bigazzi and coworkers [10]; with permission.)
Hypertensive patients
120
*
80 40 0 60
Control group
40 20 0 0 30 60 Time, min 90
120
FIGURE 5-3 Insulin resistance based on glucose and insulin responses to glucose load. In response to an oral glucose load of 75 g, compared with persons with normal blood pressure, patients with hypertension tend to have higher plasma glucose and insulin levels. These data suggest that patients with hypertension are insulin resistant. (From Ferrannini and coworkers [9]; with permission.)
10 Glucose, mmol/L
1 mmol/l = 0.0555 mg/dL
8 6
Salt-sensitive Salt-resistant
4 0 800 Insulin, pmol/L 600 400 200 0 0 30 60 90 Time, min 120 150 30 60 90 120 150
Plasma insulin, U/mL
1 pmol/L = 7.175 U/mL
16 14 12 10 Count 8 6 4 2 0 0 2 4 6 8 10 12 14 M value at clamp, mg/kg/min

Hypertensive subjects Control subjects
FIGURE 5-5 Insulin sensitivity. Insulin sensitivity also may be assessed using the euglycemic insulin clamp technique. The frequency distribution for insulin-mediated glucose disposal during euglycemic insulin clamping (M value) differs in persons with normal blood pressure and those with hypertension. The percentage of persons with hypertension considered insulin-resistant depends on the definition of insulin resistance. In this study, 27% of patients with hypertension were classified as being insulin-resistant based on an M value over two SDs above the mean for persons with normal blood pressure. (From Lind and coworkers [2]; with permission.)
SYNDROME X AND ASSOCIATED CONDITIONS

Hypertension Hyperinsulinemia Increased triglycerides Decreased high-density lipoprotein cholesterol Increased low-density lipoprotein cholesterol Decreased plasminogen activator Increased plasminogen activator inhibitor Increased blood viscosity Increased uric acid Increased fibrinogen (?)
FIGURE 5-6 As originally defined, syndrome X includes hypertension, hyperinsulinemia, increased plasma triglycerides, and decreased HDL cholesterol. The syndrome also may be associated with clustering of additional cardiovascular disease risk factors.
5.4

FIGURE 5-7 Hypertension associated with insulin resistance. It is unclear whether hyperinsulinemia associated with insulin resistance causes hypertension, although a number of potential mechanisms have been proposed.
Obesity
Nutrition
Genetic predisposition
Compensatory hyperinsulinemia
Resistance to insulin-stimulated glucose uptake Increased 1 adrenegic receptors
Hyperglycemia Hyperlipidemia
Increased sympathetic nervous system activity
Vascular growth
Antinatriuresis
Impaired endotheliumdependent vasodilation
Hypercholesterolemia (low-density lipoprotein, lipoprotein (a))
Endothelial injury
Increased endothelial superoxide anion production
Increased degradation of nitric oxide
FIGURE 5-8 Metabolic consequences of insulin resistance. These consequences also may affect peripheral vascular resistance. Hypercholesterolemia may result in vascular endothelial injury and, hence, impaired vasodilation.
High glucose Decreased nitric oxide production Protein kinase C activation Increased sodium-hydrogen antiport activity
FIGURE 5-9 Results of high glucose concentrations. High glucose concentrations may inhibit nitric oxide production and alter ion transport in vascular smooth muscle cells, favoring vasoconstriction.
Impaired endothelium-dependent vasodilation
Sulfonylureas R1 R2
Biguanides
Thiazolidinediones
R1
SO2 NH C NH R2
N C NH C NH2 NH NH
R1 O
CH2 O
O NH CH2 O S
C1
O C NH CH2CH2 SO2 NH C NH O Glyburide
H 3C H 3C
N N C NH C NH2 NH Metformin NH Pioglitazone CH3CH2 CH2CH2 O O NH
FIGURE 5-10 Effects of chemically distinct oral hypoglycemic agents on blood pressure. Sulfonylureas stimulate endogenous insulin secretion and do not lower blood pressure. In contrast, biguanides and thiazolidinediones increase insulin sensitivity without stimulating endogenous insulin secretion, and drugs in these classes lower blood pressure.
160 Systolic blood pressure, mm Hg

Control Pioglitazone
140 120 100 80 0 2 4 6 8 10
FIGURE 5-11 Pioglitazone in the treatment of hypertension in rats. A, Systolic blood pressures in Dahl-salt-sensitive rats treated with either vehicle or pioglitazone (a thiazolidinedione) for 3 weeks. Pioglitazone attenuated development of hypertension in this animal model. Weight gain did not differ in the two groups. (Continued on next page)
12 Day
14
16
18
20
22
5.5
B. HEMODYNAMIC MEASUREMENTS IN DAHL-SALT-SENSITIVE RATS

Mean intra-arterial pressure, mm Hg
Control group Group treated with pioglitazone 129 1 121 3*
MODELS IN WHICH THIAZOLIDINEDIONES LOWER BLOOD PRESSURE

Dahl-S rat 1-Kidney, 1-clip rat Obese Zucker rat Fructose-fed rat L-NNAtreated rat SHR Obese rhesus monkey Watanabe hyperlipidemic rabbit Obese human
Cardiac index, mL/min/100 g

51.4 1.6 59.11.7*
Total peripheral resistance, mm Hg/mL/min/100 g

2.50 0.07 2.07 0.07*
*P<0.05
FIGURE 5-11 (Continued) B, Direct intra-arterial pressure and cardiac index (thermodilution) in these same chronically instrumented, conscious pioglitazone-treated and control rats. Compared with control animals, rats treated with pioglitazone had lower mean arterial pressure, higher cardiac index, and lower total peripheral resistance. Thus, attenuation of hypertension by pioglitazone is due to a reduction of peripheral resistance. (From Dubey and coworkers [11]; with permission.)
FIGURE 5-12 Thiazolidinediones lower blood pressure in several models of experimental hypertension and in obese humans. FIGURE 5-13 Agents that increase insulin sensitivity, decrease plasma lipid concentrations, and lower blood pressure in animal models and preliminary studies in humans.
AGENTS THAT INCREASE INSULIN SENSITIVITY, DECREASE PLASMA LIPID CONCENTRATIONS, AND LOWER BLOOD PRESSURE IN ANIMAL MODELS AND PRELIMINARY STUDIES IN HUMANS
Thiazolidinediones Metformin Spontaneously hypertensive rats Humans (?) Vanadyl sulfate Spontaneously hypertensive rats Fructose-fed rats Etomoxir Spontaneously hypertensive rats Clofibrate Dahl-salt-sensitive rats Fenfluramine derivatives Fructose-fed rats Humans Lovastatin/pravastatin Dahl-salt-sensitive rats Spontaneously hypertensive rats Human (?)
200 Mean arterial pressure, mm Hg 180 160 140 120 100 80 Clofibrate Vehicle Clofibrate Vehicle Dahl-S Dahl-R
EFFECT OF CHOLESTEROL REDUCTION ON BLOOD PRESSURE RESPONSE TO MENTAL STRESS IN PATIENTS WITH NORMAL BLOOD PRESSURE AND HIGH CHOLESTEROL
Systolic blood pressure Baseline
Placebo group Group treated with lovastatin 122 119
Diastolic blood pressure Baseline

69 67
Stress
141 133*
Stress
78 75
FIGURE 5-14 Clofibrate in prevention of hypertension in rats. Clofibrate prevents the development of hypertension in Dahl salt-sensitive rats. This agent does not affect blood pressure in Dahl salt-resistant rats. (From Roman and coworkers [12]; with permission.)
FIGURE 5-15 In humans with normal blood pressure who have high serum cholesterol concentrations, treatment with lovastatin lowers serum cholesterol and attenuates the systolic blood pressure response to mathematics-induced stress. (From Sung and coworkers [13]; with permission.)
5.6

FIGURE 5-16 Insulin-sensitizing and lipid-lowering agents may lower blood pressure by a number of different mechanisms. Different agents may act through different mechanisms.
ANTIHYPERTENSIVE MECHANISMS OF INSULIN-SENSITIZING AGENTS

Block agonist-induced calcium ion entry into vascular smooth muscle cells Inhibit agonist-mediated vasoconstriction Inhibit growth of vascular smooth muscle cells Augment endothelium-dependent vasodilation Direct effect Metabolic effect Natriuresis Increase 20-hydroxy-eicosatetraenoic acid production Increase renal medullary blood flow
1.05 1.00 Intracellular [Ca2+]i
R172 #18 + 20 ng/mL PDGF
0.95 0.90 Intracellular [Ca2+]i 0.85 0.80 0.75 0.70 0.65 0.60
R172 #3141 + 2 ug/mL ciglitazone + 20 ng/mL PDGF
Arginine vasopressin
350 300 [Ca2+]i(nM) 250 200 150 100 50 0

(286) (290)
(73) (59)
0.95 0.90 0.85 0.80 0.75 0.70 0.65 0 100 200 300 400 500 600 700 800
Control Metformin
* P<0.05
0 100 200 300 400 500 600 700 800
Basal 450 400
Peak
Thrombin (213) (231)
Delta
* P<0.05
Time, s
Time, s
FIGURE 5-17 Use of ciglitazone to abolish calcium concentration elevation. Ciglitazone, a thiazolidinedione, abolishes agonist-stimulated sustained elevations of intracellular calcium concentrations. Shown are time-dependent plots of changes in intracellular calcium (in arbitrary units; [Ca2+]i) induced by platelet-derived growth factor (PDGF) in human gliobastoma cells with and without preincubation with ciglitazone. A, Addition of PDGF to control cells is indicated by the vertical line. B, An identical experiment conducted on cells pretreated with ciglitazone. The capacity of this agent to shorten the duration of agonist-stimulated increases in intracellular calcium may result in attenuation of both growth of vascular smooth muscle cells and vasoconstriction. (From Pershadsingh and coworkers [14]; with permission.)
350 300 [Ca2+]i(nM) 250 200 150 100 50 0 Basal

(286) (290)
Peak
Delta
FIGURE 5-18 Use of metformin to attenuate intracellular calcium concentration elevation. Metformin is a biguanide that attenuates agonist-stimulated increases of intracellular calcium concentrations in vascular smooth muscle. (From Bhalla and coworkers [15]; with permission.)

28 24 Cell number (x104) 20 16 12 8 4 0 0 2 4 6 8 10 Days in culture 12 14
Insulin + pioglitazone 0.4% FCS Insulin Insulin + pioglitazone (days 06)
5.7
FIGURE 5-19 Effect of pioglitazone on insulin-induced proliferation of arterial smooth muscle cells. Inhibition of insulin-stimulated vascular hyperplasia and hypertrophy is one potential mechanism by which insulin-sensitizing and lipid-lowering agents may decrease peripheral resistance. Two kinds of evidence suggest that thiazolidinediones inhibit the growth of vascular smooth muscle cells in vitro. Shown here, pioglitazone inhibits insulin-stimulated proliferation of vascular smooth muscle cells. Pioglitazone also inhibits 3H-thymidine incorporation in vascular smooth muscle cells (Fig. 5-19). FCSfetal calf serum. (From Dubey and coworkers [11]; with permission.)
120 H-Thymidine incorporation, % of control 100 80 60 40 20 0 0.001

Insulin = 1 mU/mL EGF = 100 mg/mL 5% FCS
FIGURE 5-20 Effect of pioglitazone on 3H-thymidine incorporation in vascular smooth muscle cells. 3H-thymidine incorporation is stimulated by insulin, fetal calf serum (FCS), and epidermal growth factor (EGF). Pioglitazone inhibits 3H-thymidine incorporation stimulated by each of these mitogens. Similar observations have been made with pravastatin and lovastatin. (From Dubey and coworkers [11]; with permission.)
0.01
0.1
10
100
Pioglitazone concentration, uM
50 Percent of change 40 30 20 10 0 0
50 Percent of change 40 30 20 10 0
FIGURE 5-21 Decreases in mean arterial pressure in rats treated with pioglitazone and control Dahl-salt-sensitive rats in response to graded infusions of norepinephrine and angiotensin II. In vivo, pressor responses to norepinephrine and angiotensin are II attenuated in Dahl-salt-sensitive rats treated with pioglitazone [16]. (From Kotchen and coworkers [16]; with permission.)
100 200 300 400 500 Norepinephrine, ng/kg/min
100 200 300 400 500 Angiotensin II, ng/kg/min
Norepinephrine x 108 (log M)
2 1
FIGURE 5-22 Half-maximal values for norepinephrine-induced contraction in aortic strips preincubated with insulin, pioglitazone, or both. In vitro, pressor responsiveness of aortic strips to norepinephrine-induced contraction is inhibited by preincubation with insulin plus pioglitazone [16]. The half-maximal value is increased for strips incubated with insulin plus pioglitazone (ie, higher concentrations of norepinephrine are required to achieve half-maximal contraction) but not in strips incubated with insulin alone or pioglitazone alone.
0 Control Insulin Pioglitazone Insulin + pioglitazone
5.8

Substance P Bradykinin Acetylcholine B Sodium P Gq protein M nitroprusside Endothelium Gi protein Nitric oxide L-arginine synthase Nitric oxide EDRF-nitric oxide Smooth muscle
FIGURE 5-23 Impaired endothelium-dependent vascular relaxation and insulin resistance. Insulin resistance is associated with impaired endothelium-dependent vascular relaxation, which is a defect that may be corrected by insulin-sensitizing agents. One approach to evaluating vascular endothelial function is to measure vascular relaxation in response to acetylcholine. EDRFendothelium derived relaxing factor.
Acetylcholine x 107 (log M)
5 4 Protein, pmol/min/mg 3 2 1 0 Control Insulin Pioglitazone Insulin + pioglitazone * 60 50 40 30 20 10 0
20-Hydroxy-eicosotetraenoic acid * P<0.05 Control, n = 9 Clofibrate, n = 12 *
(+) 2 Cl + Na + K K
+
Na K Ca2 Mg2 AA PLA 20-HETE K

+
PLC 3 Na
+
All bradykinin vasopressin + Ca2
* Cortex Outer medulla Liver
2K Cl
FIGURE 5-24 Half-maximal values for acetylcholineinduced vasodilation in aortic strips preincubated with insulin, pioglitazone, or both. In the presence of insulin, pioglitazone augments endothelium-dependent vasodilation. In vitro, the half-maximal values for acetylcholineinduced vasodilation is less in aortic strips incubated with insulin plus pioglitazone (ie, the strips are more responsive to acetylcholine) than in control strips or strips incubated with insulin alone or pioglitazone alone [16].
FIGURE 5-25 Effect of clofibrate on 20-hydroxy-eicosatetraenoic (20-HETE) production in Dahlsalt-sensitive rats. Insulin stimulates sodium reabsorption in the proximal tubule. Consequently, lowering plasma insulin concentrations by increasing insulin sensitivity would potentially result in less sodium retention. In addition, clofibrate induces renal P-450 fatty acid w-hydroxylase activity and, hence, increases metabolism of arachidonic acid to 20-HETE. (From Roman and coworkers [12]; with permission.)
FIGURE 5-26 20-Hydroxy-eicosotetraenoic acid inhibits chloride transport in the thick ascending limb of the loop of Henle. This inhibition results in a natriuretic effect in the Dahl-salt-sensitive rat. This may be the mechanism by which clofibrate prevents hypertension in this animal model.
BENEFITS OF CONTROL OF HYPERTENSION AND DIABETES

Hypertension Decreased nephropathy Decreased retinopathy Decreased stroke, myocardial infarction Drug specific (?) Diabetes (type I) Decreased nephropathy Decreased retinopathy Decreased neuropathy
FIGURE 5-27 Benefits of hypertension control and blood glucose controls are well established in diabetic patients. Noninsulin-dependent diabetes mellitus represents an extreme of insulin resistance, and hypertension is a major contributor to the cardiovascular complications of diabetes. Despite the potential concern that diuretics increase insulin resistance, overall cardiovascular disease morbidity and mortality are reduced in diabetic patients with hypertension by antihypertensive therapy with regimens that include diuretics.

FIGURE 5-28 Course of diabetic nephropathy during effective antihypertensive treatment in patients with overt diabetic nephropathy. Effective antihypertensive therapy with regimens that include diuretics also decreases the rate of progression of renal failure (both the glomerular filtration rate and albumin excretion) in patients with diabetic nephropathy. (From Parving and coworkers [17]; with permission.)
5.9
Mean arterial blood pressure, mm Hg
Start of antihypertensive treatment
125 115 105 95 105 95 85 75 65 55

GFR: 0.94 (mL/min/mo) GFR: 0.29 (mL/min/mo) GFR: 0.10 (mL/min/mo)
EFFECT OF ANTIHYPERTENSIVE AGENTS ON INSULIN SENSITIVITY AND RENAL FUNCTION IN DIABETIC PATIENTS
Agent
Angiotensin-converting enzyme inhibitors Diuretics -Blockers 1-Blockers Calcium ion antagonists Dihydropyridines Others
Insulin sensitivity Renal protection

Increase Decrease Decrease Increase 0 Increase + ? 0 0 -? +?
Albuminuria, g/min
Glomerular filtration rate, mL/min/1-73 m2
1250 750 250 2 1 0 1 2 Time, y 3 4 5 6
FIGURE 5-29 Different antihypertensive agents have different effects on insulin sensitivity, and in diabetic patients, on renal function. Question mark indicates inconsistent study results; plus sign indicates a protective effect; minus sign indicates no protection.
50 45 40 35 30 25 20 15 10 5 0 0.0
Percent doubling of baseline creatinine
Placebo Captopril Percent risk reduction = 48.5% (1669) P = 0.007
0.5 Proportion with event 0.4 0.3 0.2 0.1 0.0

Captopril Placebo Risk reduction = 50.5% P = 0.006
0.5
1.0
1.5 2.0 2.5 Years of follow-up
3.0
3.5
4.0
2 3 Years from randomization
4.5
FIGURE 5-30 Cumulative incidence of events in patients with diabetic nephropathy in captopril and placebo groups. A, Time to doubling of serum creatinine. B, Time to end-stage renal disease or death. In type I diabetic patients with nephropathy and either normal blood pressure or hypertension, treatment with angiotensin-converting enzyme inhibitors
decreases proteinuria and retards the rate of progression of renal insufficiency. The cumulative incidence of doubling of serum creatinine concentrations over time and development of end-stage renal disease are less in patients treated with captopril than in those treated with placebo. (From Lewis and coworkers [18]; with permission.)
5.10
CHANGES OF MEAN BLOOD PRESSURE, PROTEINURIA, AND GLOMERULAR FILTRATION RATE IN TREATMENT WITH DIFFERENT ANTIHYPERTENSIVE AGENTS IN PATIENTS WITH INSULIN-DEPENDENT DIABETES MELLITUS AND NONINSULIN-DEPENDENT DIABETES MELLITUS WHO HAVE MICROALBUMINURIA OR MACROALBUMINURIA
Treatment type
Placebo Conventional (diuretics and -blockers) Angiotensin-converting enzyme inhibitors Calcium antagonists: All except nifedipine and nitrendipine Nifedipine Nitrendipine
Patients, n
244 213 489 63 63 39
MBP, %
-2 -10 -16 -16 -12 -17
UProt, %
+39 -20 -52 -42 +2 -48
GFR, %
-8 -9 -1 +2 -48 +30
FIGURE 5-31 Despite similar control of hypertension, different classes of antihypertensive agents have different effects on renal function in patients with
diabetic nephropathy. GFRglomerular filtration rate; MBPmean blood pressure; Uproturine protein. (From Bretzel [19]; with permission.)
References
1. Kotchen TA, Kotchen JM, OShaughnessy IM: Insulin and hypertensive cardiovascular disease. Curr Opin Cardiol 1996, 11:483489. 2. Lind L, Berne C, Lithell H: Prevalence of insulin resistance in essential hypertension. J Hypertens 1995, 17:14571462. 3. Reaven GM: Role of insulin resistance in human disease. Diabetes 1988, 37:15951607. 4. Kotchen TA: Attenuation of hypertension by insulin-sensitizing agents. Hypertension 1996, 28:219223. 5. Nadig V, Kotchen TA: Insulin sensitivity, blood pressure and cardiovascular disease. Cardiol Rev 1997, 5:213219. 6. National High Blood Pressure Education Program and National Cholesterol Education Program: Working Group Report on Management of Patients with Hypertension and High Blood Cholesterol. National Institutes of Health Publication No. 90-2361. National Institutes of Health, 1990. 7. Bonna KH, Thelle DJ: Association between blood pressure and serum lipids in a population: the Tromso study. Circulation 1991, 83:13051324. 8. Ferrari P, Weidmann P: Insulin, insulin sensitivity and hypertension. J Hypertens 1990, 8:491500. 9. Ferrannini E, Buzzigoli E, Bonadonna R, et al.: Insulin resistance in essential hypertension. N Engl J Med 1987, 317:350357. 10. Bigazzi R, Bianchi S, Baldari G, et al.: Clustering of cardiovascular risk factors in salt-sensitive patients with essential hypertension: role of insulin. Am J Hypertens 1996, 9:2432. 11. Dubey RK, Zhang HY, Reddy SR, et al.: Pioglitazone attenuates hypertension and inhibits growth in renal arteriolar smooth muscle in rats. Am J Physiol 1993, 265:R726R732. 12. Roman RJ, Ma Y-H, Frohlich B, et al.: Clofibrate prevents the development of hypertension in Dahl salt-sensitive rats. Hypertension 1993, 21:985988. 13. Sung BH, Izzo JL, Wilson MF: Effects of cholesterol reduction on BP response to mental stress in patients with high cholesterol. Am J Hypertens 1997, 10:592599. 14. Pershadsingh H, Szollosi J, Benson S, et al.: Effects of ciglitazone on blood pressure and intracellular calcium metabolism. Hypertension 1993, 21:10201023. 15. Bhalla RC, Toth KF, Tan EQ, et al.: Vascular effects of metformin: possible mechanisms for its antihypertensive action in the spontaneously hypertensive rat. Am J Hypertens 1996, 9:570576. 16. Kotchen TA, Zhang HY, Reddy S, et al.: Effect of pioglitazone on vascular reactivity in vivo and in vitro. Am J Physiol 1996, 260:R660R666. 17. Parving H-H, Andersen AR, Smidt UM, et al.: Effect of antihypertensive treatment on kidney function in diabetic nephropathy. Br Med J 1987, 294:14431447. 18. Lewis EJ, Hunsicker LG, Bain RP, et al.: The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993, 329:14561462. 19. Bretzel RG: Effects of antihypertensive drugs on renal function in patients with diabetic nephropathy. Am J Hypertens 1997, 10:208S217S.
The Role of Hypertension in Progression of Chronic Renal Disease

Lance D. Dworkin Douglas G. Shemin
ypertension is a cause and consequence of chronic renal disease. Data from the United States Renal Data System (USRDS) identifies systemic hypertension as the second most common cause of end-stage renal disease, with diabetes mellitus being the first. Renal failure in patients with hypertension has many causes, including functional impairment secondary to vascular disease and hypertensive nephrosclerosis. Even in those in whom hypertension is not the primary process damaging the kidney, elevations in systemic blood pressure may accelerate the rate at which kidney function is lost. This accelerated loss of kidney function occurs particularly in patients with glomerular diseases and clinically evident proteinuria. Hypertension may damage the kidney by several mechanisms. Because autoregulation of glomerular pressure is impaired in chronic renal disease, elevations in systemic blood pressure also are associated with increased glomerular capillary pressure. Glomerular hypertension results in increased protein filtration and endothelial damage, causing increased release of cytokines and other soluble mediators that promote replacement of normal kidney tissue by fibrosis. An important factor contributing to progressive renal disease is activation of the renin-angiotensin system, which not only tends to increase blood pressure but also promotes cell proliferation, inflammation, and matrix accumulation. Numerous studies in experimental animals suggest that antihypertensive drugs can slow the progression of chronic renal disease. Drugs that inhibit the renin-angiotensin system may be more effective than are other agents in retarding renal disease progression. For many reasons, the effects of angiotensin II receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors may not
CHAPTER
6.2

classes of calcium channel blockers have equivalent renal protective effects is uncertain. Patients with hypertension and chronic renal disease should be treated aggressively. A 24-hour urine collection determines the extent of proteinuria. The patient who excretes more than 1 g/24 h of protein or who has diabetes mellitus should receive an ACE inhibitor. The target in this group of patients is to reduce the blood pressure to lower than 120/80 mm Hg. Most often, reaching this goal requires the use of combinations of antihypertensive agents, diuretics, or calcium channel blockers. Patients who excrete less than 1 g/24 h of protein may be treated according to standard recommendations with diuretics, beta blockers, ACE inhibitors, or other agents. The target blood pressure for this group of patients is lower than 130/85 mm Hg.
be identical. Calcium channel blockers also are beneficial in some settings; however, this effect is critically dependent on the degree of blood pressure reduction. The relationship between hypertension and progression of chronic renal disease has been examined in a number of clinical trials. Individuals with systemic hypertension are at increased risk for developing end-stage renal disease. The rate at which kidney function is lost increases in patients with poorly controlled systemic hypertension. Antihypertensive therapy can slow the rate of loss of kidney function in patients with diabetic and nondiabetic renal disease. Studies suggest that ACE inhibitors are particularly useful in patients with hypertension and proteinuria of over 1g/24 h. Calcium channel blockers also may slow the progression of renal disease; however, whether all
Hypertension and Kidney Damage

Partial loss of function
Fibrosis apoptosis
Compensatory growth
Renin AII activation
Afferent vasodilation
Systemic hypertension Release of cytokines and growth factors
Increased wall tension
Glomerular hypertension
Capillary injury
Proteinuria
FIGURE 6-1 Hypothesis identifying systemic hypertension as a central factor contributing to the progression of chronic renal disease. After partial loss of kidney function resulting from an undefined primary renal disease, a number of secondary processes develop that promote progressive kidney failure. Activation of the renin-angiotensin system is a common event in patients with chronic renal disease. In these patients, renin levels are either elevated or at least not
appropriately suppressed for the degree of volume expansion, elevation in blood pressure, or both. Activation of the reninangiotensin system and the relative salt and water excess contribute to the development of systemic hypertension in most patients with chronic renal disease. Systemic hypertension and a decrease in preglomerular vascular resistance lead to an increase in hydraulic pressure within the glomerular capillaries. Glomerular hypertension has a number of adverse effects, including increased protein filtration, which promotes release of cytokines and growth factors by mesangial cells and downstream tubular epithelial cells. A partial loss of kidney function also is a potent stimulus for compensatory renal growth. Glomerular hypertrophy and hypertension combine to increase capillary wall tension, promoting endothelial cell activation and injury, again causing release of cytokines and growth factors and recruitment of inflammatory cells. These mediators stimulate processes such as apoptosis, causing loss of normal kidney cells and increased matrix production, which leads to glomerular and interstitial fibrosis and scarring. As additional nephrons are damaged secondarily the cycle is repeated and amplified, causing progression to endstage renal failure. AIIantiotensin II.
6.3
Typical autoregulatory response in normal kidneys RPF, GRF, and PGC vary with perfusion pressure in chronic renal failure PGC, RPF, or GFR
FIGURE 6-2 Imaginary autoregulation curves in normal and diseased kidneys. Plotted on the y-axis are renal plasma flow (RPF), glomerular filtration rate (GFR), and glomerular capillary hydraulic pressure (PGC) with undefined units. Ordinarily, RPF, GFR, and PGC remain relatively constant over a wide range of perfusion pressures within the physiologic range, from approximately 80 to 140 mm Hg. Because autoregulatory ability is impaired in the kidneys of persons with chronic renal disease, these patients who develop systemic hypertension also are likely to have glomerular hypertension.
40
60
80
100
120
140
160
180
Renal perfusion pressure, mm Hg
PGC = PGC
MAP RA Baseline
RE
MAP
RE RA
Increased perfusion pressure
FIGURE 6-3 Mechanism of autoregulation of glomerular capillary pressure in a single glomerulus from a normal kidney. A, Baseline. B, Increased perfusion pressure. Glomerular pressure is determined by three factors: mean arterial pressure (MAP) or perfusion pressure, and the relative resistance of both the afferent and efferent arterioles. The initial response to an increase in MAP is an increase in afferent arteriolar resistance (RA), preventing transmission of the elevated systemic pressure to the glomerular capillaries. Efferent arteriolar resistance (RE) also may decline. This decrease decompresses the glomerulus, helping to limit the increase in glomerular capillary hydraulic pressure (PGC), and maintains constant renal plasma flow.
PGC < PGC
MAP
RE RA Baseline
MAP
RE RA
FIGURE 6-4 Mechanism of failure of autoregulation in a glomerulus from a damaged kidney. A, Baseline. B, Increased perfusion pressure. To compensate for a partial loss of function, surviving glomeruli undergo adaptive changes to increase the filtration rate. These include a reduction in afferent (RA) and efferent (RE) arteriolar resistances, tending to increase renal plasma flow and the glomerular filtration rate. In this setting, an increase in mean arterial pressure (MAP) is transmitted directly to the glomerular capillaries, resulting in glomerular capillary hypertension, increased protein filtration, and hemodynamically mediated capillary injury. PGC glomerular capillary hydraulic pressure.
Increased perfusion pressure
6.4
Effects of Antihypertensive Agents on Experimental Kidney Injury

60 40 20 Change in sclerosis, % 0 -20 -40 -60 -80 -100 -1 -2 -3 -4 -5 -6 -7 -8 -9 -10 Change in PGC, mm Hg
UnxSHR RemnantHD RemnantLD Docsalt NSN Results of the linear regression analysis Effects of going from low to high dose of triple therapy
FIGURE 6-5 Effects of triple therapy on glomerular pressure and injury. Relationship between the change in glomerular capillary hydraulic pressure (PGC) and the extent of glomerular injury (sclerosis) in
five separate studies. In these studies, rats with experimental renal disease were given similar antihypertensive agents. Studies were conducted in several different animal models of hypertension and renal disease, including the following: uninephrectomized spontaneously hypertensive rats (Unx SHR); rats with a remnant kidney given either relatively high-dose (remnant-HD) or low-dose (remnant-LD) drug therapy; rats with desoxycorticosteronesaltinduced hypertension (Doc-salt); and rats with nephrotoxic serum nephritis (NSN), an immune-mediated form of glomerular disease (NSN) [15]. In all these studies, untreated rats were compared with those receiving a combination of three antihypertensive agents (triple therapy), including hydralazine, reserpine, and a thiazide diuretic. In rats with remnant kidneys, separate studies examined the effects of low or high doses of these agents. A close correlation was revealed between the degree of reduction in glomerular capillary pressure produced by triple therapy and subsequent development of glomerular sclerosis. The data are consistent with the hypothesis that antihypertensive agents lessen glomerular injury by reducing glomerular capillary pressure. In the studies in rats with remnant kidneys, only a relatively high dose of the drugs was effective in reducing pressure and injury, suggesting that aggressive antihypertensive therapy is more likely to slow progression of renal disease. This finding is particularly true for antihypertensive combinations that include direct vasodilators, such as the triple-therapy regimen. By dilating the afferent arteriole, regimens such as these tend to further impair autoregulation of glomerular pressure in the setting of chronic renal disease. (From Weir and Dworkin [6]; with permission.) FIGURE 6-6 Correlation between systolic blood pressure and glomerular injury in rats with remnant kidneys. In these rats, blood pressure was continuously monitored by implanting a blood pressure sensor in the abdominal aorta connected telemetrically to a receiver. The timeaveraged blood pressure in rats with remnant kidneys that were untreated or given the angiotensin-converting enzyme inhibitor enalapril or triple therapy (combination of hydralazine, reserpine, and a thiazide diuretic) was correlated with morphologic evidence of glomerular injury. A close correlation was found between the average blood pressure and extent of glomerular injury that developed in these rats. It is proposed that, because of impaired autoregulation in chronic renal disease, elevations in systemic blood pressure are associated with glomerular hypertension in these rats. The higher the systemic pressure, the higher the glomerular pressure is predicted to be and the more glomerular injury is observed. These data provide additional evidence that systemic hypertension produces glomerular injury by causing elevation in glomerular pressure, and that antihypertensive therapy reduces injury by reducing glomerular capillary pressure. (From Griffen and coworkers [7]; with permission.)
400 350 Glomerular injury score 300 250 200 150 100 50 0 80 100 120 140 160 180 200 Overall averaged systolic blood pressure at final 8 week, mm Hg
No treatment Enalapril Low dose triple therapy High dose triple therapy
6.5
Tension=pressure x radius
PGC T
RGC
RGC PGC
FIGURE 6-7 The wall tension hypothesis. A, Normal. B, Chronic renal failure. After a partial loss of kidney function, compensatory adaptations within surviving nephrons include renal vasodilation. Vasodilation leads to an increase in glomerular capillary pressure and compensatory renal growth associated with an increase in the radius of the glomerular capillaries. According to the LaPlace equation, wall tension in a blood vessel is equal to the product of the transmural pressure and the radius of the vessel. In a surviving glomerular capillary of a damaged kidney, therefore, wall tension increases not only because of the increase in glomerular pressure but also because of an increase in capillary radius. Elevations in wall tension contribute to progressive renal disease by damaging the endothelial and epithelial cells lining the glomerular capillaries. By reducing wall tension, maneuvers that decrease either glomerular pressure or glomerular capillary radius are predicted to be beneficial. PGCglomerular capillary hydraulic pressure; RGCglomerular capillary radius; Ttension. (From Dworkin and Benstein [8]; with permission.) FIGURE 6-8 Scanning electron micrographs of vascular casts of glomeruli from normal or uninephrectomized rats. A, A glomerulus from a rat having had a sham operation, showing a uniform capillary pattern. (Panels BD display casts from uninephrectomized rats.) B, A uniform pattern with most capillaries being approximately the same size. C and D, Nonuniform patterns in which individual capillary loops (indicated by asterisks) are markedly dilated. In dilated capillary loops, wall tension is elevated and capillary wall damage is most likely to occur. The segmental nature of the capillary dilation may explain why glomerular sclerosis that eventually develops in remnant kidneys is also focal in early stages of the disease process. (Panels AD 320.) (From Nagata and coworkers [9]; with permission.)
6.6
Role of the Renin Angiotensin System

Release of cytokines and growth factors
Increased protein filtration
A II
Hyperplasia and hypertrophy
Systemic and glomerular hypertension
FIGURE 6-9 The central role of angiotensin II(AII) in promoting progressive kidney failure. Based on studies in which the renin-angiotensin system has been blocked and renal injury ameliorated, it has been suggested that activation of this system is a crucial factor promoting progressive kidney failure. Increased activity of the renin-angiotensin system also may help explain the association between hypertension
and progression of renal disease. AII may promote renal injury by several mechanisms. Activation of the renin-angiotensin system is one mechanism leading to an increase in systemic blood pressure, the result of peripheral vasoconstriction. Glomerular hypertension results not only from the increase in systemic blood pressure but also because of the ability of AII to constrict efferent arterioles, contributing to an increase in glomerular pressure. Glomerular hypertension damages the glomerular capillary wall and promotes injury by multiple mechanisms (see Fig. 6-1). An increase in glomerular pressure tends to increase protein filtration directly. In addition, evidence suggests that AII alters the permeability of the glomerular capillary wall to macromolecules, directly increasing protein filtration. By activating mesangial and epithelial cells, proteinuria itself is a factor promoting progressive kidney failure. Evidence also exists that AII directly stimulates production of various growth factors and cytokines by kidney cells, including fibrogenic cytokines such as transforming growth factor-beta and platelet-derived growth factor. Release of these factors has been linked to the development of glomerular sclerosis and interstitial fibrosis. AII also stimulates proliferation and growth of kidney cells that contribute to progression of renal disease. FIGURE 6-10 Angiotensin-converting enzyme (ACE) inhibitors and low-dose triple therapy. The effects of ACE inhibitors are compared with those of low-dose triple therapy on systemic and glomerular pressure, proteinuria, and morphologic evidence of glomerular injury in rats with remnant kidneys. Both ACE inhibitors and triple therapy caused similar reductions in mean arterial pressure in rats with remnant kidneys; however, glomerular pressure declined only in the group treated with ACE inhibitors, by approximately 10 mm Hg. ACE inhibitorinduced reductions in systemic and glomerular pressure were associated with a reduction in proteinuria and morphologic evidence of glomerular injury. The data suggest that ACE inhibitors are superior to low-dose triple therapy in preventing glomerular injury in chronic renal disease. The data support the importance of increased glomerular pressure as a determinant of glomerular injury. ACE inhibitors may be more effective than are other agents, specifically because of their ability to reduce glomerular pressure. It should be noted, however, that significant reductions in glomerular pressure and injury may be achieved even with the triple-therapy regimen when significantly higher doses than those used in the current study are administered (see Figs. 6-5 and 6-6). Asterisk indicates P < 0.05 versus remnant. (Data from Anderson and coworkers [10].)
120 Mean arterial pressure, mm Hg 100 80 60 40
80 Glomerular pressure, mm Hg Glomerular inj ry, % u
60
40
20 20 0 Remnant 120 AC E I Triple Remnant AC I E Triple 30 0
Proteinuria, g/24 h
100 80 60 40 20 0 Remnant AC E I Triple Remnant 10 20
*
AC I E Triple
6.7
Fractional volume flux at CA=0
at CA=0
Small selective pores
Small
selective pores
volume flux
0.1
0.1
0.01
Large nonselective pores
0.01
Large nonselective pores
Fractional
0.001
0.001
0.0001 0.0005 30 40 50 60 Effective pore radius, A
0.0001 0.0005 30 40 50 60 Effective pore radius,
FIGURE 6-11 Effect of renal vein constriction on glomerular protein filtration. The role of angiotensin II (AII) in modulating macromolecular clearance across the glomerular capillary wall has been examined by Yoshioka and coworkers [11]. These authors used a model of renal vein constriction to increase glomerular pressure and markedly increase protein filtration. They calculated the volume flux through the small selective pores (effective pore radius, 4050 ) within the glomerular capillary wall and through the large nonselective pores. A, Volume fluxes under control conditions (hatched bars) and during renal vein
constriction (open bars). Renal vein constriction causes an increase in filtration through large nonselective pores, which accounts for increased protein filtration. B, Effects of renal vein constriction were again examined, alone (open bars) and during administration of the AII receptor antagonist saralasin (hatched bars). Saralasin reduced volume flux through the large pores, indicating that increased endogenous AII action was largely responsible for proteinuria during renal vein constriction. (From Yoshioka and coworkers [11]; with permission.) FIGURE 6-12 (see Color Plate) Local activation of the renin-angiotensin system and production of fibrogenic cytokines in experimental chronic renal disease. In situ reverse transcriptase was performed in rats with remnant kidneys to examine the level of gene expression for angiotensinogen and transforming growth factor-beta (TGF-beta). Rats still had not developed widespread morphologic evidence of glomerular injury 24 days after subtotal nephrectomy. A, At this point in time (arrows), staining for angiotensinogen messenger RNA (mRNA) was observed along the wall of a dilated capillary loop (CL) and in an adjacent cluster of mesangial cells. B, TGFbeta mRNA was present in an identical pattern in a contiguous section (arrows). C and D, Staining for angiotensinogen (panel C) and TGF-beta (panel D) is examined in kidneys from rats treated with the angiotensin receptor antagonist losartan from the time of nephrectomy. Administration of losartan markedly reduced expression of both factors in remnant kidneys. The findings are consistent with the hypothesis that endothelial injury is associated with increased angiotensinogen production and local activation of the renin-angiotensin system, leading to increased expression of TGFbeta and progressive glomerular fibrosis. (From Lee and coworkers [12]; with permission.)
6.8
100 90 80 fg RANTES/ 104 cells 70 60 50 40 30 20 10 0
**
**
Migrated monocytes
* P< 0.05 vs cells treated with A II alone ** P< 0.01 vs unstimulated controls
15
* P<0.05 vs control medium ** P<0.05 vs A II medium without antibody *
10 ** 5
* *
m trol Con
Control A II CGP CGP+ A II PD PD + A II los los + A II
m Ab Ab IgG -6 M A II diu TE S TE S oat me 0 AN al g R AN A II +1 m ii-R ant EM ant nor DM +m m+ m+ m diu diu diu me me me rol A II A II ont C ediu m
FIGURE 6-13 Angiotensin II (AII) may be a proinflammatory molecule. The effect of AII on production of the chemokine RANTES was examined in cultured glomerular endothelial cells. A, Effects of AII on secretion of RANTES by cultured glomerular endothelial cells. AII markedly stimulated RANTES secretion. Of note is that AII-induced RANTES secretion was prevented by incubation with the AT2 receptor antagonists SCP-42112A (CGP) or PD 1231777 (PD) but not by the AT1 receptor antagonist losartan (los). These finding suggest AT2 receptors mediate the increase in secretion of RANTES. B, Results of a chemotactic assay for human monocytes. Migration of monocytes
was assessed using a modified Boyden chamber. Migration of monocytes was stimulated by conditioned medium from glomerular endothelial cells that were exposed to AII. This effect was blocked by incubation of the medium with an anti-RANTES antibody but not by control serum. The anti-RANTES antibody alone was also without effect, as was AII in the absence of conditioned media. The findings are consistent with the hypothesis that AII promotes glomerular inflammation by binding to AT2 receptors, promoting RANTES secretion and infiltration of inflammatory monocytes and macrophages. fgfemtograms. (From Wolf and coworkers [13]; with permission.) FIGURE 6-14 Renin-angiotensin systems. For many reasons the effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (AII) type 1 AT1 receptor antagonists on the progression of chronic renal disease may not be identical. In the classic pathway, renin cleaves angiotensinogen to form AI, which is further cleaved by ACE to form biologically active AII. ACE inhibitors inhibit the renin-angiotensin system by reducing the activity of ACE and decreasing AII formation. ACE also catalyzes other important pathways, however, including the breakdown of vasodilator substances such as bradykinin, substance P, and enkephalin. Increased levels of these substances might account for some of the biologic effects of ACE inhibition. Levels of these substances would not increase after administration of an AT1 receptor antagonist. In contrast, inhibition of the reninangiotensin system by ACE inhibitors may be incomplete because other proteases may catalyze to conversion of angiotensinogen to AII (on the right). CAGE chymostatin-sensitive angiotensin IIgenerating enzyme; t-PAtissue plasminogen activator. (Adapted from Dzau and coworkers [14].)
Renin-angiotensin systems
Angiotensinogen Bradykinin Substance P Enkephalin Renin Angiotensin I CAGE Cathepsin G Tonin Angiotensin II Other proteases Angiotensin III and IV tPA Cathepsin G Tonin
ACE
Inactive fragments
6.9
Vasoconstriction AT 1 Aldosterone Growth Angiotensin II Clearance Apoptosis
Proteases
AT 2
Angiotensin III and IV
Vasodilation AT 4
FIGURE 6-15 Subclasses of angiotensin receptors. Another theoretic reason the actions of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (AII) receptor antagonists may differ. All of the AII receptor antagonists currently available for clinical use selectively block the AT1 receptor. This receptor appears to transduce most of the wellknown effects of AII, including vasoconstriction, stimulation of cell growth, and secretion of aldosterone. Increasingly, however, potentially important actions of other angiotensin receptors are being discovered. For example, AT2 receptors may be involved in regulation of apoptosis and modulation of inflammation by way of secretion of RANTES (see Fig. 6-13) [13,15]. AT4 receptors bind other angiotensins preferentially and may promote endothelially mediated vasodilatation [16]. Activity of all pathways is reduced after administration of ACE inhibitors, whereas only AT1 receptormediated events are blocked by drugs currently available. Whether these differences will have important consequences for progression of renal disease is currently unknown. FIGURE 6-16 Shown are results of studies comparing the effects of angiotensin II (AII) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors on experimental renal injury. AII receptor antagonists were as effective as were ACE inhibitors in the remnant kidney model; streptozotocin-induced diabetic rats; the puromycin aminonucleoside model of progressive glomerular sclerosis, preventing interstitial fibrosis associated with obstructive uropathy; and an inherited model of glomerular sclerosis, the Munich-Wistar Furth/Ztm rat [1721]. In contrast, AII receptor antagonists were somewhat less effective than were ACE inhibitors in several other animal models of chronic renal disease, including uninephrectomized spontaneously hypertensive rats, obese Zucker rats, and the passive Heymann nephritis model of membranous glomerulonephritis [2224]. Clinical trials are necessary to determine whether these classes of drugs will be equally effective in preventing progressive renal disease in humans.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS VERSUS ANGIOTENSIN II ANTAGONISTS IN EXPERIMENTAL RENAL DISEASE

Angiotensin II antagonists equivalent to angiotensin-converting enzyme inhibitors
Remnant kidney Passive Heymann nephritis Chronic rejection Two-kidney, one-clip hypertension Streptozocin-induced diabetes Puromycin aminonucleoside Obstructive uropathy Munich-Wistar Furth/Ztm rat
Angiotensin II antagonists inferior to angiotensin-converting enzyme inhibitors

Uninephrectomized spontaneously hypertensive rats Obese Zucker rats Passive Heymann nephritis
MAP 0 Reduction, % -20 -40 -60 -80
PGC
PROT
SCLER
Nifedipine Felodipine Amlodipine
FIGURE 6-17 Three calcium channel blockers and their effects in experimental animals. The results of several studies examining the effects of three different dihydropyridine calcium channel blockers on hemodynamics and injury in the uninephrectomized spontaneously hypertensive rat model of progressive glomerular sclerosis are summarized. The three drugs produced graded declines in mean arterial pressure (MAP), with nifedipine causing the greatest and amlodipine the least reduction in systemic pressure. Micropuncture determinations of glomerular capillary hydraulic pressure (PGC) revealed that only nifedipine and felodipine caused glomerular pressure to decline significantly. These drugs reduced both the protein excretion rate (PROT) and morphologic evidence of glomerular injury (SCLER). The data are consistent with the hypothesis that antihypertensive agents ameliorate renal damage by reducing glomerular pressure and that, for calcium channel blockers, significant reductions in PGC occur only when drug administration causes a marked decline in systemic pressure. (From Dworkin [25,26]; with permission.)
6.10
The Effect of Hypertension on Renal Disease

ROLE OF HYPERTENSION IN CHRONIC RENAL DISEASE
Cause
Renal artery stenosis or occlusion Atheroembolic disease Hypertensive nephrosclerosis 100 90
Contributors to disease progression

Hypertensive persons, % Diabetes mellitus Glomerulonephritis Tubulointerstitial disease (?) Adult-onset polycystic kidney disease (?)
80 70 60 50 40 30 20 10 0 0 10 20 30 40 50 60
2
FIGURE 6-18 The impact of hypertension on the incidence of end-stage renal disease (ESRD) is vastly underestimated if one considers only those patients in whom systemic hypertension is the primary process resulting in loss of kidney function. The group of patients in whom ESRD is attributed to hypertension undoubtedly includes persons with renal disease of several causes. Some of these causes are occlusive disease of the main renal arteries as a result of atherosclerotic disease, atheroembolic disease of the kidneys, and hypertensive nephrosclerosis. The exact incidence of these processes within the hypertensive population with chronic renal disease is unknown. Even more commonly, poorly controlled systemic hypertension accelerates the rate of loss of kidney function in many patients in whom the primary cause of renal injury is another process altogether. This fact is particularly true in patients with glomerular diseases such as diabetic nephropathy and chronic glomerulonephritis [27,28]. Whether systemic hypertension also contributes to loss of kidney function in patients with tubulointerstitial or cystic disease of the kidney is less certain [29].
70
80
90
Mean GFR, mL/min/1.73m
FIGURE 6-19 Hypertension prevalence corresponds with decreased glomerular filtration rate (GFR). Hypertension is common in glomerular, tubular, vascular, and interstitial renal disease and becomes increasingly prevalent as renal function declines. In almost 200 patients screened for the Modification of Diet in Renal Disease study, the prevalence of hypertension increased as the GFR decreased and hypertension was almost universal as the GFR approached 10 mL/min [29].
Volume/ total body sodium excess
FIGURE 6-20 Multifactorial mechanisms for hypertension in clinical renal disease. An increased intravascular volume, owing to decreased renal excretion of sodium and water as the glomerular filtration rate declines, is probably the primary cause. Activation of sympathetic tone and involvement of the renin-angiotensin system, which is inappropriately stimulated in the setting of volume expansion, have been demonstrated in renal failure. Decreased activity of nitric oxide and other vasorelaxants and increased activity of endothelin and other endogenous vasoconstrictors also are probably contributory.
Stimulation of renin-angiotensin system
Augmented sympathetic tone
6.11
100 80 60 40 20 0 0
(53) (30) (18) (17)
1.0
Free of renal failure, %
0.8 Probability of survival
(7) (2) Normotensive (n=79) Hypertensive (n=69)
0.6
HBP before age 35
NBP after age 35
0.4
10 Time since biopsy, y
15 0.2
FIGURE 6-21 Consistent relationship between hypertension and progressive renal disease. Analysis of the Modification of Diet in Renal Disease study, which involved patients with a heterogeneous miscellany of renal diagnoses, showed that the degree of elevation of the mean arterial blood pressure correlated with the decline in the glomerular filtration rate [30]. This finding has been confirmed in cohorts of patients with the same renal disease. In immunoglobulin A (IgA) nephropathy, eg, the presence of high blood pressure at diagnosis is a strong predictor for development of end-stage renal disease. In this study by Radford and coworkers [31] of 148 patients with IgA nephropathy, 69 patients with hypertension had a much higher risk of proceeding to renal failure than did the 79 patients who were normotensive.
0 0 10 20 30 40 50 Age, y 60 70 80 90
FIGURE 6-22 Relationship between hypertension and renal failure. Johnson and Gabow [32] studied over one thousand patients with autosomal dominant polycystic kidney disease. These authors demonstrated that the time of renal survival was much shorter for patients with hypertension compared with patients whose blood pressure was normal (see Fig. 6-21). Renal survival was defined as the time period before the need for dialysis. HBPhigh blood pressure; NBPnormal blood pressure.
Systolic blood pressure 100
80 Free of renal endpoints, % P<0.001
FIGURE 6-23 Hypertension accelerates progression of renal failure in children and adults. For 2 years, Wingen and coworkers [33] followed almost 200 children and adolescents with renal disease, aged 2 to 18 years. Here, renal survival is defined as stability of the creatinine clearance rate. Compared with patients with systolic blood pressures lower than 120 mm Hg, those with systolic blood pressures higher than 120 mm Hg had more rapid development of renal death. Renal death was defined as a decrease in the creatinine clearance rate by 10 mL/min/1.73 m2.
60
40
<120 mm Hg >120 mm Hg 0 0 1 Time, y 2
6.12
4.0 3.5 ESRD due to any cause, % 3.0 2.5 2.0 1.5 1.0 0.5 0 0

hypertension to later development of renal failure. In over 300,000 men screened for the Multiple Risk Factor Intervention Trial, Klag and coworkers [34] showed that a single blood pressure measurement was strongly correlated with the risk of endstage renal disease (ESRD) later in life. Even men with high-normal blood pressures (defined as a systolic pressure of 130 to 139 mm Hg or a diastolic blood pressure of 85 to 89 mm Hg) were at a statistically significant greater risk for ESRD than were men with blood pressures under 120/80 mm Hg. This risk increases sequentially with the higher stage of hypertension. This study used definitions of hypertension discussed in the Fifth Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC-5). Stage I hypertension is defined as a systolic pressure of 140 to 159 mm Hg and a diastolic pressure of 90 to 99 mm Hg. Stage II hypertension is defined as a systolic pressure of 160 to 179 mm Hg and a diastolic pressure of 100 to 109 mm Hg. Stage III hypertension is a systolic pressure of 180 to 209 mm Hg and a diastolic pressure of 110 to 119 mm Hg. Stage IV hypertension is a systolic pressure of 210 mm Hg or higher and a diastolic blood pressure of 120 mm Hg or greater. The highest relative risk for renal failure was among persons with stage III or IV hypertension. FIGURE 6-25 Hypertension and impact on progression of renal disease caused by hypertension. In a study of 94 patients with essential hypertension and an initially normal serum creatinine concentration, Rostand and coworkers [35] showed that hypertension control apparently had little impact on progression of renal disease. When patients were divided into those with diastolic blood pressures higher and lower than 90 mm Hg, the percentage whose renal function deteriorated was equivalent in both groups. Blacks were at especially high risk; 23% of black patients with diastolic blood pressures below 90 mm Hg had worsened renal function over time, compared with 11% of white patients with diastolic blood pressures lower than 90 mm Hg.
Optimal Normal but not optimal High normal Stage 1 hypertension Stage 2 hypertension Stage 3 hypertension Stege 4 hypertension
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Years since screening
FIGURE 6-24 There long has been controversy over whether hypertension alone, without renal disease, can cause renal failure, especially in whites. Recent convincing epidemiologic evidence, however, links
Deteriorating renal function Stable renal function 16% Stable renal function 12%
Deteriorating renal function
Controlled diastolic blood pressure <90 min Hg
Uncontrolled diastolic blood pressure <90 min Hg
0 Decline in GFR mL/min 3 6 9 12 15 B3 F4 F12
Blood pressure
Low BP group Usual BP group
F20 Time, mo
F28
F36
FIGURE 6-26 Lower-than-usual blood pressure (BP) target. The Modification of Diet in Renal Disease study [36] also prospectively examined the effect of a lower-than-usual BP target in a larger cohort of patients with renal insufficiency. Patients were randomized to two target BPs: a usual mean arterial pressure (MAP) target of 107 mm Hg, corresponding to a BP of 140/90 mm Hg; or a low MAP target of 92 mm Hg, corresponding to a BP of 125/75 mm Hg. The changes in the glomerular filtration rate (GFR) in the two groups over a 3year follow-up period are depicted. (The y-axis depicts the changes in GFR, and the x-axis represents months. For example, F36 means 36 months after initiation of the study.) Patients in the two groups had statistically equivalent declines in GFR. Over the last 6 months of the study, however, a trend toward greater stabilization in renal function occurred in the group randomized to the lower target.
6.13
Patients randomized to low BP target Patients randomized to the usual BP target Study 1 0
Mean rate of GFR decline, mL/min/y
Study 2 0
12
n=420
n=101
n=54
n=136
n=63
n=32
<1
1<3
<1
1<3
12
Baseline urinary protein, g/d
FIGURE 6-27 Two patient groups in the study of diet in renal disease. The Modification of Diet in Renal Disease (MDRD) study involved two patient groups. The group in which patients had moderate renal dysfunction (glomerular filtration rate [GFR] between 25 and 55 mL/min) was called Study 1. The other group, which included patients who had more severe renal dysfunction (with a GFR between 13 and 24 mL/min) was called Study 2. The effects of the lower blood pressure (BP) target on patients with proteinuria in Studies 1 and 2 are shown. The y-axis divides patients in Studies 1 and 2 into three groups, depending on urinary protein excretion. The x-axis represents the rate of GFR decline. In the subset of patients in the MDRD trial in both Studies 1 and 2 who had massive proteinuria (protein over 3 g/24 h), the lower blood pressure had an especially salutary effect: the decline in GFR was much slower [37].
Renal survival
1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0 6 12 18 Time, mo 24 30
Proteinuria: <1g/24h mean BP: <107 mm Hg Proteinuria: <1g/24h mean BP: >107 mm Hg Proteinuria: <13g/24h mean BP: <107 mm Hg Proteinuria: <13g/24h mean BP: >107 mm Hg
100 90 80 Creatinine clearance, mL/min 70 60 50 40 30 20 10 -12 Group A -6 0 6 Group B Evolution of creatinine clearance 12 18 24 30 36
FIGURE 6-28 Proteinuria as a marker for progressive renal disease. Nephrotic proteinuria may be a more important and independent marker for progression of renal disease than is hypertension. That is, patients in whom massive proteinuria and hypertension coexist have the worst renal prognosis. In a study of over 400 patients with renal insufficiency followed over 2 years, Locatelli and coworkers [38] found that patients who had both a mean blood pressure (BP) higher than 107 mm Hg and protein excretion of 1 to 3 g/24 h had the lowest rates of renal survival.
FIGURE 6-29 The effect of reduction of proteinuria on the stabilization of renal function. The observations that the potentially correctable factors of hypertension and proteinuria predict the decline of renal function lead to the hypothesis that antihypertensive agents in the angiotensin-converting enzyme (ACE) inhibitor class may be especially important in treatment of hypertension in renal disease. Praga and coworkers [39] investigated 46 patients with nondiabetic renal disease and massive proteinuria treated with the ACE inhibitor captopril. These authors found that proteinuria was decreased by about half. In patients with the greatest reduction in proteinuria (group A), a greater stabilization of renal function occurred over time when compared with those (group B) whose reduction in proteinuria was less.
6.14
50 45 Percentage with doubling of baseline creatinine 40 35 30 25 20 15 10 5 0 0
1.6
Ramipril Placebo
1.4 Mean rate of GFR, mL/min/mo 1.2 1.0 0.8 0.6 0.4
Placebo
P=0.007
Captopril
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Years of follow-up
FIGURE 6-30 Large study of patients with diabetes mellitus and renal disease randomly assigned to captopril or placebo. Lewis and coworkers [40] have studied the use of the angiotensin-converting enzyme inhibitor captopril in patients with type I diabetes mellitus who have diabetic nephropathy and proteinuria. Captopril provides strong protection against progression of renal disease. Those patients treated with captopril had a significant decrease in proteinuria and a slower rate of disease progression, as defined by the time to doubling of the serum creatinine, as compared with patients randomized to placebo.
0.2 0
n=61
n=36
n=20
Baseline urinary protein excretion, 1g/24h
FIGURE 6-31 Study of patients with renal disease not associated with diabetes randomly assigned to ramipril or placebo. A study structured similarly to that in Figure 6-30 examined the use of the angiotensinconverting enzyme inhibitor ramipril in over 150 patients with nondiabetic renal disease [41]. The primary conclusion of the study is summarized. Blood pressure and proteinuria decreased more significantly in the patients treated with ramipril. This group had significantly lower rates of decline in glomerular filtration rate (GFR) over time. This effect was increasingly striking as the baseline level of proteinuria increased and was most pronounced in patients with a urinary protein excretion of over 7 g per 24 hours. FIGURE 6-32 Meta-analysis of over 1500 patients with renal insufficiency. A recent meta-analysis examined randomized studies comparing an angiotensin-converting enzyme inhibitor (ACE) to other antihypertensive agents [42]. None of the individual studies showed that the relative risk for development of end-stage renal disease (ESRD) was statistically lower in patients treated with ACE inhibitors. The pooled relative risk, incorporating data from all the studies, however, was lower in the cohort groups treated with ACE inhibitors.
Favors ACE inhibitors Favors other drugs Reference Country Year 1992 1992 1993 1993 1994 1994 1994 1995 1996 Patients, n 121 70 112 124 103 100 51 260 70
IT Zucchelli et al. [43] DEN Kamper et al. [44] Brenner (Unpublished data) USA Toto (Unpublished data) USA HOL van Essen et al. [45] Hannedouche et al. [46] FR AUS Bannister et al. [47] Himmelmann et al. [48] SW AUS Becker et al. and Ihle et al. [49,50] EUR Maschio et al. [51] Overall
1996 583
0.01 0.02 0.05 0.1 0.2
0.5 1
10
20 50 100
Relative risk for ESRD

Podocytes Renal survival, % Glomerular basement membrane
6.15
100 80 60 40 20 0 0 6 12 18 24 30 36 42 Time, mo Captopril Nifedipine
No change in proteinuria
Decreased proteinuria
Dihydropyridine calcium channel blockers Nifedipine Amlodipine Felodipine Isradipine Nisolodipine
Non-dihydropyridine calcium channel blockers Diltiazem Verapamil
FIGURE 6-33 Calcium channel blockers. Calcium channel blockers are prescribed widely to patients with normal renal function and affect renal protein excretion variably. The general consensus is that the nondihydropyridine calcium channel blockers diltiazem and verapamil decrease proteinuria, whereas the dihydropyridine agents have minimal or minor effects on proteinuria.
FIGURE 6-34 The effect of calcium channel blockers on preservation of renal function. Most studies of angiotensin-converting enzyme (ACE) inhibitors versus other agents did not examine calcium channel blockers. In a paper by Zucchelli and coworkers [43], patients with nondiabetic renal diseases and hypertension initially were treated with adrenergic antagonists, diuretics, and vasodilators. These patients were then randomized to treatment with the dihydropyridine calcium entry antagonist nifedipine or to the ACE inhibitor enalapril. The rate of decline in renal function was most rapid in the pre-randomization phase in patients treated with conventional antihypertensive agents, mostly adrenergic antagonists. The rate of decline then slowed after randomization. No significant difference in rates of decline was seen in patients treated with nifedipine compared with those treated with captopril. (From Zucchelli and coworkers [43]; with permission.) FIGURE 6-35 The effect of angiotensin-converting enzyme inhibitors and other antihypertensive agents on stabilization of renal function in noninsulin-dependent diabetes. Bakris and coworkers [52] studied patients with noninsulin-dependent diabetes mellitus, hypertension, proteinuria, and presumed diabetic nephropathy. These patients were randomized to treatment with the angiotensin-converting enzyme inhibitor lisinopril; the beta-blocker atenolol; or a nondihydropyridine calcium channel blocker (NDCCB), either verapamil or diltiazem. The primary conclusion of the study is summarized. The change in glomerular filtration rate as a function of time is depicted in groups of patients receiving lisinopril, calcium channel blockers, or atenolol. The creatinine clearance rate declined in all three groups. However, the slope of the decline was significantly greater in the group treated with atenolol and not significantly different between the groups treated with lisinopril and the calcium entry antagonist.
60 Creatinine clearance, mL/min/1.73 m2 Lisinopril
NDCCBs 40
20
Atenolol
Lisinopril NDCCBs Atenolol
1998 18 18 16
1989 18 18 16
1990 18 18 16
1991 18 17 15
1992 16 16 13
1993 16 15 11
1994 15 15 11
6.16
120 115 110 Mean BP, mm Hg 105 100 95 90 0

FIGURE 6-36 Race and ethnicity in choice of antihypertensive agents. Racial and ethnic differences also may be important in determining the choice of antihypertensive agent to delay progression of chronic renal disease. Blacks are at much higher risk than are whites for progression of renal disease. In addition, a more aggressive antihypertensive program may be beneficial to blacks. In the Modification of Diet in Renal Disease study, a trend toward a more gradual decline in renal function in blacks randomized to the low mean blood pressure target was seen [36]. Blacks tend to have a better blood pressure response to administration of diuretics than do whites. In a large study of patients with normal renal function, blacks also responded well to calcium channel blockers [53]. The AfricanAmerican Study of Kidney Disease and Hypertension (AASK), currently in progress, is examining the hypothesis that a lower-thanusual blood pressure goal will have a renal protective effect in renal disease with hypertension. A preliminary finding from the study is depicted. The study randomized blacks with hypertension to the beta-blocker atenolol, the dihydropyridine calcium channel blocker amlodipine, or the angiotensin-converting enzyme enalapril. In the initial 6 months of the study, the mean arterial blood pressure decreased most significantly in the short term with amlodipine [54]. GFRglomerular filtration rate.
Atenolol Amiodipine Enalapril Baseline GFR1 GFR2 RV FV3 FV6
Time, mo
Management of Hypertension in Clinical Renal Disease

Blood pressure:> 130/185 mm HG or higher with renal disease Blood pressure: 130/85 mm Hg or higher with renal disease Proteinuria: 1g/24h or less Proteinuria: 1G/24h or more Diabetic or primary glomerular disease Begin ACE inhibitor Target blood pressure: 125/75 mm Hg or lower Yes No
If hyperkalemia or acute renal failure develops, evaluate possible causes If no other precipitant, decrease ACE inhibitor dose Add diuretic, calcium channel blocker
Treatment with ACE inhibitor Target blood pressure: 125/75 mm Hg or lower
Treatment with diuretic, ACE inhibitor, or calcium channel blocker
A FIGURE 6-37 Treatment of patients with renal disease and high-normal or elevated blood pressure (BP). A, All patients should have a measurement of 24-hour protein excretion. If the protein excretion is over 1 g/24 h, an angiotensin-converting enzyme (ACE) inhibitor should be started. The goal of hypertension control in patients with azotemia who have massive proteinuria should be a blood pressure of 125/75 mm Hg or lower. It is unlikely that an ACE inhibitor alone will be able to decrease the blood pressure to this level before hyperkalemia or hemodynamically mediated acute renal failure intervenes. A diuretic and medications from other classes, such as a calcium channel blocker, should then be added.
B, When protein excretion is less than 1 g/24 h, the blood pressure should be lowered to at least 130/85 mm Hg. No conclusive evidence exists to support the use of one antihypertensive agent or class of agents over another. However, in patients at risk for progressive proteinuria (eg, diabetic patients with microalbuminuria), ACE inhibitors should be used. Given the importance of sodium retention in the hypertension in renal disease, a loop or thiazide diuretic is a reasonable initial treatment. An ACE inhibitor or calcium channel blocker should be added as a second-line agent.
6.17
References
1. Dworkin LD, Grosser M, Feiner HD, et al.: Renal vascular effects of antihypertensive therapy in uninephrectomized spontaneously hypertensive rats. Kidney Int 1989, 35:790798. 2. Anderson S, Meyer T, Rennke HG, Brenner BM: Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass. J Clin Invest 1985, 76:612619. 3. Kakinuma Y, Kawamura T, Bills T, et al.: Blood pressure independent effect of angiotensin inhibition on the glomerular and nonglomerular vascular lesions of chronic renal failure. Kidney Int 1996, 42: 4655. 4. Dworkin LD, Feiner HD, Randazzo J: Glomerular hypertension and injury in desoxycorticosterone-salt rats on antihypertensive therapy. Kidney Int 1987, 31:718724. 5. Neugarten J, Kaminetsky B, Feiner H, et al.: Nephrotoxic serum nephritis with hypertension: amelioration by antihypertensive therapy. Kidney Int 1985, 28:135139. 6. Weir MR, Dworkin LD: Antihypertensive drugs, dietary salt and renal protection: How low should you go and with which therapy. Am J Kidney Dis 1998, 32:122. 7. Griffen KA, Picken M, Bidani AK: Radiotelemetric BP monitoring, antihypertensives and glomeruloprotection in remnant kidney model. Kidney Int 1994, 46:10101018. 8. Dworkin LD, Benstein JA: Antihypertensive agents, glomerular hemodynamics and glomerular injury. In Calcium Antagonists and the Kidney. Edited by Epstein M, Loutzenhiser R. Philadelphia, Hanley & Belfus; 1990:155176. 9. Nagata M, Scharer K, Kriz W: Glomerular damage after uninephrectomy in young rats. I. Hypertrophy and distortion of the capillary architecture. Kidney Int 1992, 42:136147. 10. Anderson S, Rennke HG, Brenner BM: Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension. J Clin Invest 1986, 77:19932000. 11. Yoshioka T, Mitarai T, Kon V, et al.: Role for angiotensin II in an overt functional proteinuria. Kidney Int 1986, 30:538545. 12. Lee LK, Meyer TM, Pollock AS, Lovett DH: Endothelial cell injury initiates glomerular sclerosis in the rat remnant kidney. J Clin Invest 1995, 96:953964. 13. Wolf G, Ziyadeh FN, Thaiss F, et al.: Angiotensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells. J Clin Invest 1997, 100:10471058. 14. Dzau VJ, Sasamura H, Hein L: Heterogeneity of angiotensin synthetic pathways and receptor subtypes: physiological and pharmacological implications. J Hypertension 1993, 11(suppl 3):S13S18. 15. Yamada T, Horiuchi M, Dzau VJ: Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci U S A 1996, 93:156160. 16. Prsti I, Bara AT, Busse R, Hecker M: Release of nitric oxide by angiotensin (1-7) from porcine coronary endothelium: implications for a novel angiotensin receptor. Br J Pharmacol 1994, 111:652654. 17. Lafayette RA, Mayer G, Park SK, Meyer TM: Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass. J Clin Invest 1992, 90:766771. 18. Remuzzi A, Perico N, Amuchastegui CS, et al.: Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes. J Am Soc Nephrol 1993, 4:4049. 19. Tanaka R, Kon V, Yoshioka T, et al.: Angiotensin converting enzyme inhibitor modulates glomerular function and structure by distinct mechanisms. Kidney Int 1994, 45:537543. 20. Ishidoya S, Morrissey J, McCracken R, et al.: Angiotensin receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction. Kidney Int 1995, 47:12851294. 21. Remuzzi A, Malanchini B, Battaglia C, et al.: Comparison of the effects of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade on the evolution of spontaneous glomerular injury in male MWF/Ztm rats. Experimental Nephrol 1996, 4:1925. 22. Anderson AE, Tolbert EM, Esparza AR, Dworkin LD: Effects of an ACE inhibitor vs. an AII antagonist on hemodynamics, growth and injury in spontaneously hypertensive rats. J Am Soc Nephrol 1996, 7:A3014. 23. Crary GS, Swan SK, ODonnell MP, et al.: The angiotensin II receptor antagonist losartan reduces blood pressure but not renal injury in obese Zucker rats. J Am Soc Nephrol 1995, 6:12951299. 24. Hutchinson FN, Webster SK: Effect of ANGII receptor antagonist on albuminuria and renal function in passive Heymann nephritis. Am J Physiol 1992, 263:F311F318. 25. Dworkin LD, Feiner HD, Parker M, Tolbert E: Effects of nifedipine and enalapril on glomerular structure and function in uninephrectomized spontaneously hypertensive rats. Kidney Int 1991, 39:11121117. 26. Dworkin LD, Tolbert E, Recht PA, et al.: Effects of amlodipine on glomerular filtration, growth, and injury in experimental hypertension. Hypertension 1996, 27:245250. 27. Breyer JA, Bain RP, Evans JK, et al.: Predictors of the progression of renal insufficiency in patients with insulin-dependent diabetes and overt diabetic nephropathy. Kidney Int 1996, 50:16511658. 28. Gisen Group: Randomized placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997, 349:18571863. 29. Klahr S, Levey AS, Beck GJ, et al.: The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 1994, 330:877884. 30. Modification of Diet in Renal Disease Study Group: Predictors of the progression of renal disease in the modification of diet in renal disease study. Kidney Int 1997, 51:19081919. 31. Radford MG, Donadio JV, Bergstralh EJ, Grande JP: Predicting renal outcome in IgA nephropathy. J Am Soc Nephrol 1997, 8199207. 32. Johnson AM, Gabow PA: Identification of patients with autosomal dominant polycystic kidney disease at highest risk for end-stage kidney disease. J Am Soc Nephrol 1997, 8:15601567. 33. Wingen A-M, Fabian-Bach C, Shaefer F, Mehls O for the European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood. Lancet 1997, 349:11171123. 34. Klag MJ, Whelton PK, Randall BL, et al.: Blood pressure and endstage renal disease in men. N Engl J Med 1996, 334:1318. 35. Rostand SG, Brown G, Kirk KA, et al.: Renal insufficiency in treated essential hypertension. N Engl J Med 1989, 320:684688. 36. Klahr S, Levey A, Beck GJ, et al. for the Modification of Diet in Renal Disease Study Group. N Engl J Med 1994, 330:877884. 37. Peterson JC, Adler S, Burkart JM, et al. for the Modification of Diet in Renal Disease Study Group. Ann Intern Med 1995, 123:754762. 38. Locatelli F, Marcelli D, Comelli M, et al. for the Northern Italian Cooperative Study Group: proteinuria and blood pressure as causal components of progression to end-stage renal failure. Nephrol Dial Transplant 1996, 11:461467. 39. Praga M, Hernandez E, Montoyo C, et al.: Long-term beneficial effects of angiotensin-converting enzyme inhibition in patients with nephrotic proteinuria. Am J Kidney Dis 1992, 20:240248. 40. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD for the Collaborative Study Group: The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993, 329:14561462.
6.18

48. Himmelmann A, Hansson L, Hannson BG, et al.: ACE inhibition preserves renal function better than beta-blockers in the treatment of essential hypertension. Blood Pressure 1995, 4:8590. 49. Becker GJ, Whitworth JA, Ihle BU, et al.: Prevention of progression in non-diabetic chronic renal failure. Kidney Int Suppl 1994, 45:S167S170. 50. Ihle BU, Whitworth JA, Shahinfar S, et al.: Angiotensin-converting enzyme inhibition in nondiabetic progressive renal insufficiency: a controlled double-blind trial. Am J Kidney Dis 1996, 27:489495. 51. Maschio G, Aliberti D, Janin G, et al.: Effect of the angiotensinconverting enzyme inhibitor benazepril on the progression of renal insufficiency. N Engl J Med 1996, 334:939945. 52. Bakris GL, Copley JB, Vicknair N, et al.: Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int 1996, 50:16411650. 53. Materson BJ, Reda DJ, Cushman WC, et al.: Single-drug therapy for hypertensive men: a comparison of six antihypertensive agents with placebo. N Engl J Med 1993, 328:914921. 54. Hall WD, Kusek JW, Kirk KA, et al. for the African-American Study of Kidney Disease and Hypertension Pilot Study Investigators. Am J Kidney Dis 1997, 29:720728.
41. Gruppo Italiano di Studi Epidemiologici in Nefrologia: Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997, 349:18571863. 42. Giatras I, Lau J, Levey AS for the Angiotensin-Converting Enzyme Inhibition and Progressive Renal Disease Study Group: Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Ann Intern Med 1997, 127:337345. 43. Zucchelli P, Zuccala A, Borghi M, et al.: Long-term comparison between captopril and nifedipine in the progression of renal insufficiency. Kidney Int 1992, 42:452458. 44. Kamper AI, Strandgaard S, Leyssac PP: Effect of enalapril on the progression of chronic renal failure: a randomized controlled trial. Am J Hypertens 1992, 5:423430. 45. van Essen GG, Apperloo AJ, Sluiter WJ, et al.: Is ACE inhibition superior to conventional antihypertensive therapy in retarding progression in non-diabetic renal disease? J Am Soc Nephrol 1996, 7:1400. 46. Hannedouche T, Landais P, Goldfarb B, et al.: Randomized controlled trial of enalapril and beta-blockers in non-diabetic chronic renal failure. BMJ 1994, 309:833837. 47. Bannister KM, Weaver A, Clarkson AR, Woodroffe AJ: Effect of angiotensin-converting enzyme and calcium channel inhibition on progression of IgA nephropathy. Contrib Nephrol 1995, 111:184193.
Pharmacologic Treatment of Hypertension

Garry P. Reams John H. Bauer
his chapter reviews the currently available classes of drugs used in the treatment of hypertension. To best appreciate the complexity of selecting an antihypertensive agent, an understanding of the pathophysiology of hypertension and the pharmacology of the various drug classes used to treat it is required. A thorough understanding of these mechanisms is necessary to appreciate more fully the workings of specific antihypertensive agents. Among the factors that modulate high blood pressure, there is considerable overlap. The drug treatment of hypertension takes advantage of these integrated mechanisms to alter favorably the hemodynamic pattern associated with high blood pressure.
CHAPTER
7.2
Pathogenesis of Hypertension
Pathogenesis of hypertension Autoregulation B LO O D PR E SSUR E = C AR D I AC O U T P U T PE R IPHER AL VA SCUL AR RE SISTAN CE H y p er tens i o n = I n c re a s e d CO and/or I n c re a s e d P V R
Preload
Contractility
Functional constriction
Structural hypertrophy
Fluid volume
Volume redistribution
Renal sodium retention
Decreased filtration surface
Sympathetic nervous overactivity
Reninangiotensin excess
Cell membrane alteration
Hyperinsulinemia
Excess sodium intake
Genetic alteration
Stress
Genetic alteration
Obesity
Endotheliumderived factors
FIGURE 7-1 Pathogenesis of hypertension. Mean arterial pressure (MAP) is the product of cardiac output (CO) and peripheral vascular resistance
(PVR). There are a large number of control mechanisms involved in every type of hypertension. (From Kaplan [1]; with permission.)
20 Increase, %
FIGURE 7-2 Blood pressure changes and diet. Many hypertensive patients appear to be sodium sensitive, as first suggested by studies in 19 hypertensive subjects who were observed after normal (109 mmol/d), low (9 mmol/d), and high (249 mmol/d) sodium intake [2]. This figure shows the percent increase in mean blood pressure in salt-sensitive (SS) and nonsalt-sensitive (NSS) patients with hypertension when their diet was changed from low sodium to high sodium. Vertical lines indicate mean standard deviation. (From Kawasaki et al. [2]; with permission.)
10
0 SS NSS Mean arterial pressure
7.3
20 19 18 17 16 15 6.0 5.5 5.0 16 14 12 10 13 12 11 10 70 65 60 55 50 40 35 30 25 20 15 150 140 130 120 110 100
33 %
4%
20 % 5%
Pressure gradient Mean circulatory for venous filling pressure, return, mm Hg mm Hg
60 % 20 %
FIGURE 7-3 Cardiac output. An increase in cardiac output has been suggested as a mechanism for hypertension, particularly in its early borderline phase [3,4]. Sodium and water retention have been theorized to be the initiating events. Sequential changes following salt loading are depicted [3]. The resultant high cardiac output perfuses the peripheral tissues in excess of their metabolic requirements, resulting in a normal autoregulatory (vasoconstrictor) pressure. The early phase of high cardiac output and normal peripheral vascular resistance gradually changes to the characteristic feature of the sustained hypertensive state: normal cardiac output and high peripheral vascular resistance. Shown here are segmental changes in the important cardiovascular hemodynamic variables in the first few weeks following the onset of short-term salt-loading hypertension. Note especially that the arterial pressure increases ahead of the increase in total peripheral resistance. (From Guyton and coworkers [3]; with permission.)
Blood volume, L
Extracellular fluid volume, L
35 %
44 %
Cardiac output, L/min
40 %
5%
Total peripheral resistance, mm Hg/L/min
38 %
11 % Set-point elevated 45 % 22.5 %
4 Days
12
16
7.4
4000
SAP
HR beats min1
150
TPRI dyn s cm5 m2 500 1000
200
3000
180
100
2000
160 BP, mm Hg 60 140

MAP
1000
70 CI L min1 m2 120
DAP
10
SI mL stroke1 m2
50
100
30
500
1000
500
1000
VO2 mL min1 m2
VO2 mL min1 m2
VO2 mL min1 m2
FIGURE 7-4 Peripheral vascular resistance. Most established cases of hypertension are associated with an increase in peripheral vascular resistance [5]. These alterations may be related to a functional constriction, the type observed under the influence of circulating or tissue-generated vasoconstrictors, or may be a result of structural alterations in the blood vessel. Solid line indicates values at start of the study [9];
dashed line indicates results after 10 years; dotted line indicates results after 20 years. BPblood pressure; CIcardiac index; DAPdiastolic arterial blood pressure; HRheart rate; MAPmean arterial pressure; SAPsystolic arterial blood pressure; SIstroke index; TPRItotal peripheral resistance index; VO2oxygen consumption. (From LundJohansen [5]; with permission.)
7.5
Classes of Antihypertensive Drugs and Their Side Effects

CLASSES OF ANTIHYPERTENSIVE DRUGS
Diuretics: benzothiadiazides, loop, and potassium-sparing -adrenergic and 1/ -adrenergic antagonists Central 2-adrenergic agonists Central/peripheral adrenergic neuronal-blocking agent Peripheral 1-adrenergic antagonists Moderately selective peripheral 1-adrenergic antagonist Peripheral adrenergic neuronal blocking agents Direct-acting vasodilators Calcium antagonists Angiotensin-converting enzyme inhibitors Tyrosine hydroxylase inhibitor Angiotensin II receptor antagonists
FIGURE 7-5 Classes of antihypertensive drugs. There are 12 currently available classes of antihypertensive agents.
BP
PV ISF CO TPR Rx PRA Time No Rx
CO TPR
FIGURE 7-6 Hemodynamic response to diuretics. Diuretics reduce mean arterial pressure by their initial natriuretic effect [6]. Acutely, this is achieved by a reduction in cardiac output mediated by a reduction in plasma and extracellular fluid volumes [7]. Initially, peripheral vascular resistance is increased, mediated in part by stimulation of the reninangiotensin system. During sustained diuretic therapy, cardiac output returns to pretreatment levels, probably reflecting restoration of plasma volume. Chronic blood pressure control now correlates with a reduction in peripheral vascular resistance. BPblood pressure; COcardiac output; ISFinterstitial fluid; PRAplasma renin activity; PVplasma volume; Rxtreatment; TPRtotal peripheral resistance. (Adapted from Tarazi [7].)
7.6
A. DIURETICS: BENZOTHIADIAZIDES (PARTIAL LIST) AND RELATED DIURETICS

Generic (trade) name
Hydrochlorothiazide (G) (Hydrodiuril, Microzide) Chlorthalidone (G) (Hygroton) Indapamide (Lozol) Metolazone (Mykrox)*; (Zaroxolyn) *Marketed only for treatment of hypertension. (G)generic available.
First dose, mg
12.5 12.5 1.25
Usual dose
12.550 mg QD 12.550 mg QD 2.55.0 mg
Maximum dose
100 100 5
Duration of action, h
612 4872 1518
0.5 2.5
0.51.0 2.510 mg QD
1 20
1224 1224
B. DIURETICS: LOOP
Bumetanide (G) (Bumex) Ethacrynic Acid (Edecrin) Furosemide (G) (Lasix) Torsemide (Demadex) (G)generic available.
First dose, mg
0.5 25 20 5
Usual dose
0.52 mg bid 2550 mg bid 20120 mg bid 550 mg bid
Maximum dose
10 200 600 100
46 68 68 68
C. DIURETICS: POTASSIUM-SPARING DIURETICS

Spironolactone (G) (Aldactone) Amiloride (G) (Midamor) Triamterene (G) (Dyrenium) (G)generic available.
First dose, mg
25 5 50
Usual dose
501 00 mg QD 510 mg QD 50-100 mg bid
Maximum dose
400 20 300
4872 24 79
FIGURE 7-7 AC. Diuretics: benzothiadiazides and related agents, loop diuretics, and potassium-sparing agents. A partial list of benzothiadiazides and their related agents is given [6]. With the exception of indapamide and metolazone, their dose-response curves are shallow; they should not be used when the glomerular filtration rate is less than 30 mL/min/1.73 m2. The second group listed is loop
diuretics. Because of their steep dose-response curves and natriuretic potency, they are especially useful when the glomerular filtration rate is less than 30 mL/min/1.73 m2. The third group is the potassium-sparing diuretics. The major therapeutic use of these drugs is to attenuate the loss of potassium induced by the other diuretics.

Lumen Blood Lumen Na DCT diuretics Na Cl 3Na ~ 2K Na channel blockers 3Na K ~ 2K Blood
7.7
DCT PT DT
PC
Lumen HCO3 Na H H2CO3 CA H2O + CO2 HCO3 H2CO3 CA H2O + CO2 PT 3Na ~
Blood Lumen Blood
2K
CAI
CAI
Loop diuretics
Na K 2Cl
3Na
2K CD
TAL
LH
FIGURE 7-8 Mechanisms of action of diuretics. This figure depicts the major sites and mechanisms of action of diuretic drugs [8]. The diuretic/natriuretic action of benzothiadiazide-type diuretics is predicated on their gaining access to the luminal side of the distal convoluted tubule and inhibiting Na+ - Cl- cotransport by competing for the chloride site. The diuretic/natriuretic action of loop diuretics is predicated on their gaining access to the luminal side of the thick ascending limb of the loop of Henle and inhibiting Na+ - K+ -2Cl- electroneutral cotransport by competing for the chloride site.
The diuretic/natriuretic action of potassium-sparing diuretics is predicated on their gaining access to the luminal side of the principal cells located in the late distal tubule and cortical collecting duct and blocking luminal sodium channels. Because Na+ uptake is blocked, the lumen negative voltage is reduced, inhibiting K+ secretion. The potassium-sparing diuretic spironolactone does this indirectly by competing with aldosterone for its cytosolic receptor. CAcarbonic anhydrase; CAIcarbonic anhydrase inhibitor; CDcollecting duct; DCTdistal convoluted tubule; DTdistal tubule; LHloop of Henle; PCprincipal cell; PTproximal tubule; TALthick ascending limb. (From Ellison [8]; with permission.)
7.8

FIGURE 7-9 The side effect profile of diuretic therapy. The complications of diuretic therapy are typically related to dose and duration of therapy, and they decrease with lower dosages. This table lists the most common side effects of diuretics and their proposed mechanism of action [6].
THE SIDE EFFECT PROFILE OF DIURETIC THERAPY

Side effects
Thiazide-type diuretic Azotemia Hypochloremia, hypokalemia, metabolic alkalosis
Mechanisms
Enhanced proximal fluid and urea reabsorption secondary to volume depletion Increased delivery of sodium to distal tubule facilitating Na+K+ and Na+-H+ exchange; increased net acid excretion; increased urinary flow rate; secondary aldosteronism Increase fractional Mg2+ excretion by inhibiting reabsorption in ascending limb of loop of Henle Impaired free water clearance (distal cortical diluting segment) May reflect an increased protein-bound fraction secondary to volume depletion Impair enhanced proximal fluid and urate reabsorption secondary to volume depletion Hypokalemia impairing insulin secretion; decreased insulin sensitivity May be due to extracellular fluid depletion
Hypomagnesemia Hyponatremia Hypercalcemia Hyperuricemia Carbohydrate intolerance Hyperlipidemia Increased total triglyceride Increased total cholesterol Loop-type diuretics Ototoxicity Hypocalcemia Potassium-sparing diuretics Hyperkalemia Decreased sexual function, gynecomastia, menstrual irregularity, hirsutism Renal stone
High plasma concentration of furosemide or ethacrynic acid Increase fractional excretion of calcium by interfering with reabsorption in loop of Henle Blocks potassium excretion Spironolactone only; lower circulatory testosterone levels by increasing metabolic clearance and/or preventing compensatory rise in testicular androgen production Triamterene only
7.9
Adrenal gland
Heart CO 1 -blockers E NE Effector cell Kidney BP
2 +
Blood vessels TPR NE
FIGURE 7-10 -adrenergic antagonists. -adrenergic antagonists attenuate sympathetic activity through competitive antagonism of catecholamines at both 1- and 2-adrenergic receptors [6,9]. In the absence of partial agonist activity (PAA), the acute systemic hemodynamic effects are a decrease in heart rate and cardiac output and an increase in peripheral vascular resistance proportional to the degree of cardiodepression; blood pressure is unchanged. Chronically, there is a gradual decrease in blood pressure proportional to the fall in peripheral vascular resistance, which is dependent on the degree of cardiac sympathetic drive. -adrenergic antagonists with sufficient partial agonist activity to maintain heart rate and cardiac output may not evoke acute reflex vasoconstriction: Blood pressure falls proportional to the decrease in peripheral resistance (see Fig. 7-11) [10]. BPblood pressure; COcardiac output; Eepinephrine; NE norepinephrine; TPRtotal peripheral resistance.
Sympathetic neuron
MAP, %
100 90 80
Cardiac output, %
100 90 80 130
FIGURE 7-11 Hemodynamic changes associated with -adrenergic blockade. Time course of hemodynamic changes after treatment with a -adrenergic blocker devoid of partial agonist activity (PAA) (solid line) as compared with hemodynamic changes after administration of a -adrenergic blocker with sufficient PAA to replace basal sympathetic tone (eg, pindolol) (broken line). MAPmean arterial pressure. (From Man int Veld and Schalekamp [10]; with permission.)
Vascular resistance, %
120 110 100 90 80 Time (hours to days)
7.10
A. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: NON-SELECTIVE ( ADRENERGIC ANTAGONISTS THAT LACK PARTIAL AGONIST ACTIVITY
Nadolol (G) (Corgard) Propranolol (G) (Inderal) (Inderal LA) Timolol (G) (Blockadren) Ggeneric available.
AND
2)
First dose, mg
40
Usual daily dose, mg

40240 QD
Maximum daily dose, mg

320
>24
40 80 10
40120 bid 80240 QD 1030 bid
480 480 60
>12 >12 >12
B. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: NON-SELECTIVE ( 1 AND 2) ADRENERGIC ANTAGONISTS WITH PARTIAL AGONIST ACTIVITY
Pindolol (G) (Visken) Carteolol (Cartrol) Penbutolol (Levatol) Ggeneric available.
First dose, mg
5 2.5 10

1030 bid 2.510 QD 1020 QD

60 10 40
12 24 24
C: DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: 1-SELECTIVE ADRENERGIC ANTAGONISTS THAT LACK PARTIAL AGONIST ACTIVITY
Atenolol (G) (Tenormin) Metoprolol Tartrate (G) (Lopressor) Metoprolol Succinate (Toprol-XL) Betaxolol (Kerlone) Bisoprolol (Zebeta) Ggeneric available.
First dose, mg
50 50 50 5 5

50100 QD 50150 bid 100300 QD 1020 QD 520 QD

200 400 400 40 40
24 12 12 >24 12
FIGURE 7-12 Dosing schedules for -adrenergic antagonists. A, Nonselective adrenergic antagonists that lack partial agonist activity. B, Nonselective
-adrenergic antagonists with partial agonist activity. C, adrenergic antagonists that lack partial agonist activity.
1-selective
(Continued on next page)
7.11
D. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: 1-SELECTIVE ADRENERGIC ANTAGONISTS WITH WEAK PARTIAL AGONIST ACTIVITY
Acebutolol (Sectrol)
First dose, mg
200

400800 QD

1200
24
E. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: 1-NONSELECTIVE -ADRENERGIC ANTAGONISTS LABETALOL (G)
Labetalol (G) (Normodyne) (Trandate) Carvedilol (Coreg) Ggeneric available.
First dose, mg
100

100-600 bid

2400
12
6.25
6.25-25 bid
50
FIGURE 7-12 (Continued) D, 1-selective adrenergic antagonists with weak partial agonist activity. E, 1-nonselective -adrenergic antagonists.
7.12
PHARMACOKINETICS OF -ADRENERGIC ANTAGONISTS

First-pass hepatic metabolism
<10% 60% 80% 50% <10% <10% <10% <10% 50% 50% <10% 20% 30% 60% 7080%
Solubility
Nadolol Propranolol Propranolol LA Timolol Pindolol Carteolol Penbutolol Atenolol Metoprolol tartrate Metoprolol succinate Betaxolol Bisoprolol Acebutolol Labetalol Carvedilol Hydrophilic Lipophilic Lipophilic Lipophilic Lipophilic Hydrophilic Lipophilic Hydrophilic Lipophilic Lipophilic Lipophilic Equal Lipophilic Lipophilic Lipophilic
Absorption
30%40% >90% >90% >90% >90% >90% >90% 5060% >90% >90% >90% >90% 70% >90% >90
Peak concentration, h
24 13 6 12 12 13 23 24 12 7 1.56 24 24 12 12
Active metabolite
None Yes Yes None None Yes Yes None None None None None Yes None Yes
Plasma half-life, h
2024 34 10 34 34 56 5 67 37 37 1422 912 34 34 710
Dose reduction in renal failure

Yes No No No Yes Yes Yes Yes No No Yes Yes Yes No No
FIGURE 7-13 Pharmacokinetics of -adrenergic antagonists. FIGURE 7-14 The side effect profile of -adrenergic antagonists. The side effect profile of betablockers is related to the specific blockade of 1 or 2 receptors. This table lists the more common side effects and their proposed mechanism(s) of action [6,9].
THE SIDE EFFECT PROFILE OF -ADRENERGIC ANTAGONISTS

Side effects
Bronchospasm Bradycardia Congestive heart failure; decrease in exercise tolerance Claudication Constipation, dyspepsia Central nervous system manifestations (sleep disturbances, depression) Sexual dysfunction (impotence, decrease libido) Impaired glucose tolerance Prolonged insulin-induced hypoglycemia Hepatocellular necrosis Withdrawal syndrome Unstable angina Myocardial infarction Dyslipidemia Increased total triglycerides Decreased high-density lipoproteins cholesterol
Mechanisms
Blockade of 2-adrenergic receptors; increased airway resistance Blockade of atrial 1/ 2-adrenergic receptors; decrease in heart rate Blockade of ventricular 1-adrenergic receptors Blockade of peripheral vascular 2-adrenergic receptors Blockade of gastrointestinal 1/ 2-adrenergic receptors; decreased motility and relaxation of sphincter tone Blockade of CNS 1/ 2-adrenergic receptors Unknown Impaired 2-adrenergicmediated islet cell insulin secretion; increase hepatic glucose, and/or decrease insulin-stimulated glucose disposal Block epinephrine-mediated counterregulatory mechanisms Labetalol only, idiosyncratic reaction Acute overshoot in heart rate with increased myocardial oxygen demand due to increase in number and/or sensitivity of -adrenergic receptors during chronic blockade Increased -adrenergic tone; reduced lipoprotein lipase activity

Phsysiologic effect of central 2-adrenergic agonists -Methyldopa guanfacine guanabenz Stimulates Central 2 adrenoceptor
7.13
Clonidine Stimulates I1-Imidazoline receptor
FIGURE 7-15 Central 2-adrenergic agonists. Central 2-adrenergic agonists cross the blood-brain barrier and stimulate 2-adrenergic receptors in the vasomotor center of the brain stem [6,9]. Stimulation of these receptors decreases sympathetic tone, brain turnover of norepinephrine, and central sympathetic outflow and activity of the preganglionic sympathetic nerves. The net effect is a reduction in norepinephrine release. The central 2-adrenergic agonist clonidine also binds to imidazole receptors in the brain; activation of these receptors inhibits central sympathetic outflow. Central 2-adrenergic agonists may also stimulate the peripheral 2adrenergic receptors that mediate vasoconstriction; this effect predominates at high plasma drug concentrations and may precipitate an increase in blood pressure. The usual physiologic effect is a decrease in peripheral resistance and slowing of the heart rate; however, output is either unchanged or mildly decreased. Preservation of cardiovascular reflexes prevents postural hypotension.
NTS Nucleus tractus solitarii
RVLM Rostral ventrolateral medulla Inhibition of central sympathetic activity
Blood pressure reduction
CENTRAL 2-ADRENERGIC ANTAGONISTS

-Methyldopa (G) (Aldomet) Clonidine (G) (Catapres) Clonidine TTS (Catapres-TTS) Guanabenz (Wytensin) Guanfacine (Tenex) Ggeneric available; TTStransdermal patch.
First dose, mg
250 0.1 2.5 mg (TTS-1) 4 1
Usual daily dose

2501000 mg bid 0.10.6 mg bid/tid 2.57.5 mg (TTS1 to TTS3) qwk 416 mg bid 13 mg QD
Maximum daily dose

3000 2.4 15 mg (TTS-3x2) 9 wk 64 3
Duration of action
2448 h 68 h 7d 12 h 36 h
FIGURE 7-16 Central 2-adrenergic agonists. -Methyldopa is a methyl-substituted amino acid that is active only after decarboxylation and conversion to -methyl-norepinephrine. The antihypertensive effect results from accumulation of 2-adrenergic receptors, displacing and competing with endogenous catecholamines. Methyldopa is absorbed poorly (<50%); peak plasma concentrations occur in 2 to 4 hours. It is metabolized in the liver and excreted in the urine mainly as the inactive O-sulfate conjugate. The plasma half-life of methyldopa (1 to 2 hours) and its metabolites is prolonged in patients with renal insufficiency; dose reduction is required. Clonidine, an imidazoline derivative, acts by stimulating either central 2-adrenergic receptors or imidazole receptors. Clonidine may be administered orally or by a transdermal delivery system (TTS). When given orally, it is absorbed well (>75%); peak plasma concentrations occur in 3 to 5 hours. Clonidine is metabolized mainly in the liver; fecal excretion ranges from 15% to 30%, and 40% to 60% is excreted unchanged in the urine. In patients with renal
insufficiency, the plasma half-life (12 to 16 hours) may be extended to more than 40 hours; dose reduction is required. When clonidine is administered transdermally, therapeutic plasma levels are achieved within 2 to 3 days. Guanabenz, a guanidine derivative, is highly selective for central 2-adrenergic receptors. It is absorbed well (>75%); peak plasma levels are reached in 2 to 5 hours. Guanabenz undergoes extensive hepatic metabolism; less than 2% is excreted unchanged in the urine. The plasma half-life (approximately 6 hours) is not prolonged in patients with renal insufficiency. Guanfacine is a phenylacetyl-guanidine derivative with a longer plasma half-life than guanabenz. It is absorbed well (>90%); peak plasma concentrations are reached in 1 to 4 hours. The drug is primarily metabolized in the liver. Guanfacine and its metabolites are excreted primarily by the kidneys; 24% to 37% is excreted as unchanged drug in the urine. The plasma half-life (15 to 17 hours) is not prolonged in patients with renal insufficiency [6,9].
7.14

FIGURE 7-17 The side effect profile of central 2-adrenergic agonists. The side effect profile of these agents is diverse [6,9].
THE SIDE EFFECT PROFILE OF CENTRAL 2-ADRENERGIC AGONISTS

Side effects
Sedation/drowsiness Xerostoniia (dry mouth) Gynecomastia in men, galactorrhea in women Drug fever, hepatotoxicity, positive Coombs test with or without hemolytic anemia Sexual dysfunction, depression, decreased mental acuity Overshoot hypertension Restlessness Insomnia Headache Tremor Anxiety Nausea and vomiting A feeling of impending doom
Mechanisms
Stimulation of 2-adrenergic receptors in the brain Centrally mediated inhibition of cholinergic transmission Reduced central dopaminergic inhibition of prolactin release (methyldopa only) Long-term tissue toxicity (methyldopa only) Stimulation of 2-adrenergic receptor in the brain Acute excessive sympathetic discharge in the face of chronic downregulation of central 2-adrenergic receptors in an inhibitory circuit during chronic treatment when treatment is stopped
Indicates blockade Brain stem Preganglionic neuron Ganglion
NE
Postganglionic adrenergic nerve ending
FIGURE 7-18 Central and peripheral adrenergic neuronal blocking agents. Rauwolfia alkaloids act both within the central nervous system and in the peripheral sympathetic nervous system [6,9]. They effectively deplete stores of norepinephrine (NE) by competitively inhibiting the uptake of dopamine by storage granules and by preventing the incorporation of norepinephrine into the protective chromaffin granules; the free catecholamines are destroyed by monoamine oxidase. The predominant pharmacologic effect is a marked decrease in peripheral resistance; heart rate and cardiac output are either unchanged or mildly decreased.
NE
NE
NE
2 Vascular smooth muscle cells
7.15
CENTRAL PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENT

Reserpine (G) (Serpasil)
First dose, mg
0.1

0.1.25 QD

0.5
Duration of action
23 wk
FIGURE 7-19 Central and peripheral adrenergic neuronal blocking agents. Reserpine is the most popular rauwolfia product used. It is absorbed poorly (approximately 30%); peak plasma concentrations occur in 1 to 2 hours. Catecholamine depletion begins within 1 hour of drug administration and is maximal in 24 hours. Catecholamines are restored slowly. Chronic doses of reserpine are cumulative. Blood
pressure is maximally lowered 2 to 3 weeks after beginning therapy. Reserpine is metabolized by the liver; 60% of an oral dose is recovered in the feces. Less than 1% is excreted in the urine as unchanged drug. The plasma half-life (12 to 16 days) is not prolonged in patients with renal insufficiency.
THE SIDE EFFECT PROFILE OF RESERPINE

Side effects
Altered CNS function Inability to concentrate Decrease mental acuity Sedation Sleep disturbance Depression Nasal congestion/rhinitis Increased GI motility, increased gastric acid secretion Increased appetite/weight gain Sexual dysfunction Impotence Decreased libido
Peripheral adrenergic nerve ending
Indicates blockade
Mechanisms
Depletion of serotonin and/or catecholamine NE
NE
NE
Cholinergic effects Cholinergic effects Unknown Unknown 1 NE
NE
NE
NE 2 1 Vascular smooth muscle cells
FIGURE 7-20 The side effect profile of the central and peripheral adrenergic neuronal blocking agents [10,13]. Reserpine is contraindicated in patients with a history of depression or peptic ulcer disease. CNScentral nervous system; GIgastrointestinal.
FIGURE 7-21 Peripheral 1-adrenergic antagonists. 1-Adrenergic antagonists induce dilation of both resistance (arterial) and capacitance (venous) vessels by selectively inhibiting postjunctional 1-adrenergic receptors [6,9]. The net physiologic effect is a decrease in peripheral resistance; reflex tachycardia and the attendant increase in cardiac output do not predictably occur. This is due to their low affinity for prejunctional 2-adrenergic receptors, which modulate the local control of norepinephrine release from sympathetic nerve terminals by a negative feedback mechanism (see Fig. 7-22) [11]. NEnorepinephrine.
7.16

FIGURE 7-22 Adrenergic synapse. Nerve activity releases the endogenous neurotransmitter noradrenaline (NA) and also adrenaline from the varicosities. Noradrenaline and adrenaline reach the postsynaptic -adrenoceptors (or -adrenoceptors) on the cell membrane of the target organ by diffusion. On receptor stimulation, a physiologic or pharmacologic effect is initiated. Presynaptic 2-adrenoceptors on the membrane (enlarged area), when activated by endogenous noradrenaline as well as by exogenous agonists, inhibit the amount of transmitter noradrenaline released per nerve impulse. Conversely, the stimulation of presynaptic 2-receptors enhances noradrenaline release from the varicosities. Once noradrenaline has been released, it travels through the synaptic cleft and reaches both - and -adrenoceptors at postsynaptic sites, causing physiologic effects such as vasoconstriction or tachycardia. (Adapted from Van Zwieten [11].)
Varicosity Postganglionic sympathetic neuron Nerve impulse induces exocytotic NA release + Presynaptic -receptor NA Varicosities Synaptic cleft Postsynaptic -receptor
Vesicle containing NA
Sympathetic C-fiber Presynaptic -receptor Synaptic cleft Effector cell
Response
NA
Postsynaptic - receptors
Target organ
PERIPHERAL
1-ADRENERGIC
ANTAGONISTS
2-6 bid/tid 2-5 QD/bid 2-4 QD

Prazosin (G) (Minipress) Terazosin (Hytrin) Doxazosin (Cardura) Ggeneric available.
First dose, mg
1 1 1

20 20 16
Duration of action
6-12 w 12-24 h 24 h
FIGURE 7-23 Peripheral 1-adrenergic antagonists. Prazosin is a lipophilic highly selective 1-adrenergic antagonist. It is absorbed well (approximately 90%) but undergoes variable first-pass hepatic metabolism. Peak plasma concentrations occur in 2 to 3 hours. It is extensively metabolized by the liver and predominantly excreted in the feces. The plasma half-life of prazosin (2 to 4 hours) is not prolonged in patients with renal insufficiency. Terazosin is a water-soluble quinazoline analogue of prazosin with about one third of its potency. It is completely absorbed and undergoes minimal first-pass hepatic metabolism. Peak plasma concentrations occur in 1 to 2 hours. It is extensively
metabolized by the liver and predominantly excreted in the feces. The plasma half-life of terazosin (approximately 12 hours) is not prolonged in patients with renal insufficiency. Doxazosin is also a water-soluble quinazoline analogue of prazosin, with about half its potency. It is absorbed well but undergoes significant first-pass hepatic metabolism; bioavailability is approximately 65%. Peak concentrations occur in 2 to 3 hours. It is extensively metabolized by the liver and primarily eliminated in the feces. The plasma half-life of doxazosin (approximately 22 hours) is not prolonged in patients with renal insufficiency [6,9].
7.17
150 140 Mean BP, mm Hg 130 120 110 100
Placebo
Lying Standing
Day 0
FIGURE 7-24 The side effect profile of the peripheral 1-adrenergic antagonists. 1-Adrenergic antagonists are associated with relatively few side effects [6,9]; the most striking is the first-dose effect [12]. It occurs 30 to 90 minutes after the first dose and is dose dependent. It is minimized by initiating therapy in the evening and by careful dose titration. The first-dose effect is exaggerated by fasting, upright posture, volume contraction, concurrent -adrenergic antagonism, or excessive catecholamine activity (eg, pheochromocytoma). (From Graham and coworkers [12]; with permission.)
140 130 120 Mean BP, mm Hg 110 100 90 80 70 60 50
Prazosin, 2 mg
Day 1
140 130 Mean BP, mm Hg 120 110 100 90 80
Prazosin, 2 mg
Day 4
0700
0900
1100 1300 Time, h
1500
1700
7.18

Peripheral adrenergic nerve ending Indicates blockade
NE
NE
2
NE
NE
NE
NE
FIGURE 7-25 Moderately selective peripheral 1-adrenergic antagonists. Phenoxybenzamine is a moderately selective peripheral 1-adrenergic antagonist [6,9]. It is 100 times more potent at 1-adrenergic receptors than at 2-adrenergic receptors. Phenoxybenzamine binds covalently to -adrenergic receptors, interfering with the capacity of sympathomimetic amines to initiate action at these sites. Phenoxybenzamine also increases the rate of turnover of norepinephrine (NE) owing to increased tyrosine hydroxylase activity, and it increases the amount of norepinephrine released by each nerve impulse owing to blockade of presynaptic 2-adrenergic receptors [11]. The net physiologic effect is a decrease in peripheral resistance and increases in heart rate and cardiac output. Postural hypotension may be prominent, related to blockade of compensatory responses to upright posture and hypovolemia. The degree of vasodilation is dependent on the degree of adrenergic vascular tone.
NE 2 1 1 Vascular smooth muscle cells
MODERATELY SELECTIVE PERIPHERAL

Phenoxybenzamine (Dibenzyline)
1-ADRENERGIC
ANTAGONIST
Maximum of action, mg
120
First dose, mg
10

20-40 bid
Duration of action
34 d
FIGURE 7-26 Moderately selective peripheral 1-adrenergic antagonists. Phenoxybenzamine is the only drug in its class. Absorption is variable and incomplete (20% to 30%). Peak blockade occurs in 3 to 4 hours. Its plasma half-life is 24 hours. The duration of action is
approximately 3 to 4 days. Phenoxybenzamine is primarily used in the management of preoperative or inoperative pheochromocytoma. Efficacy is dependent on the degree of underlying excessive -adrenergic vascular tone [6,9].
7.19
THE SIDE EFFECT PROFILE OF PHENOXYBENZAMINE

Side effects
Nasal congestion Miosis Sedation Weakness, lassitude Sexual dysfunction Inhibition of ejaculation Tachycardia
FIGURE 7-27 The side effect profile of phenoxybenzamine. The common side effects are listed [6,9].
Mechanisms
-adrenergic receptor blockade -adrenergic receptor blockade Unknown Impairment of compensatory vasoconstriction producing orthostatic hypotension -adrenergic receptor blockade Uninhibited effects of epinephrine, norepinephrine and direct or reflex sympathetic nerve stimulation on the heart
Indicates blockade
NE
NE
NE NE
FIGURE 7-28 Peripheral adrenergic neuronal blocking agents. Peripheral adrenergic neuronal blocking agents are selectively concentrated in the adrenergic nerve terminal by an active transport mechanism, or norepinephrine pump [6,9]. They act by interfering with the release of norepinephrine (NE) from neuronal storage sites in response to nerve stimulation and by depleting norepinephrine from nerve endings. Acutely, cardiac output is reduced, caused by diminished venous return and by blockade of sympathetic -adrenergic effects on the heart; peripheral resistance is unchanged. Following chronic therapy, peripheral resistance is decreased, along with modest decreases in heart rate and cardiac output.
7.20
PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENTS

Guanethidine (Ismelin) Guanadrel (Hylorel)
First dose, mg
10 5

2575 QD 1050 bid

150 150
Duration of action
721 d 414 h
FIGURE 7-29 Peripheral adrenergic neuronal blocking agents. Guanethidine is the prototype peripheral adrenergic neuronal blocking agent. Absorption is incomplete and variable; only 3% to 30% is absorbed over 12 hours. Peak plasma levels are reached in 6 hours. The drug rapidly leaves the plasma for extravascular storage sites, including sympathetic neurons. Guanethidine is eliminated with a plasma half-life of 4 to 8 days, a time course that corresponds with its antihypertensive effect. Approximately 24% of the drug is excreted unchanged in the urine; the remainder is metabolized by the liver into more polar, less active, metabolites that are excreted in the urine and feces. When therapy is initiated or the dosage is changed, three half-lives (approximately 15 days) are required to accumulate
87.5% of a steady-state level. By administering loading doses of guanethidine at 6-hour intervals (the nearly maximal effect from a single oral dose), blood pressure can be lowered in 1 to 3 days. In patients with severe renal insufficiency, drug excretion is decreased; dose reduction is required. Guanadrel is a guanethidine derivative with a short therapeutic half-life. Absorption is greater than 85%; peak plasma concentrations are reached in 1 to 2 hours. Guanadrel is metabolized by the liver. Elimination occurs through the kidney; approximately 40% of the drug is excreted unchanged in the urine. In patients with renal insufficiency, the plasma half-life (10 to 12 hours) is prolonged; dose reduction is required [6,9]. FIGURE 7-30 The side effect profile of peripheral adrenergic neuronal blocking agents. The specific side effects of this class are related to either excessive sympathetic blockade or a relative increase in parasympathetic activity. GFR glomerular filtration rate.
THE SIDE EFFECT PROFILE OF PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENTS

Side effects
Decrease renal function (GFR) Fluid retention/weight gain Dizziness/weakness Syncope Intestinal cramping/diarrhea Sexual dysfunction Retrograde ejaculation Impotence Decreased libido Sinus bradycardia Atrioventricular block Bronchospasm Congestive heart failure
Mechanisms
Decreased renal perfusion; effect is magnified in the upright position Decreased filtered load and fractional excretion of sodium; diuretic should be used in combination Postural hypotension accentuated by hot weather, alcohol ingestion, and/or physical exercise Unopposed parasympathetic activity, increasing gastrointestinal motility Inhibition of bladder neck closure, unknown
Interferes with cardiac sympathetic compensating reflexes Catecholamine depletion aggravates airway resistance Decreased cardiac output
7.21
Plasma membrane
VGC
Leak
ROC
VGC
Ca2+ Altered calcium metabolism (?)
Ca2+ Ca2+
Ca2+
SR
Ca2+
SR
FIGURE 7-31 Direct-acting vasodilators. Direct-acting vasodilators may have an effect on both arterial resistance and venous capacitance vessels; however, the currently available oral drugs are highly selective for resistance vessels [6,9]. Their specific mechanism of vascular relaxation and reason for selectivity are unknown. By altering cellular calcium metabolism, they interfere with the calcium movements responsible for initiating or maintaining a contractile state. The net physiologic effect is a decrease in peripheral vascular resistance associated with increases in heart rate and cardiac output. These increases in heart rate and cardiac output are related directly to sympathetic stimulation and indirectly to the baroreceptor reflex response. ROCreceptor-operated channel; SRsarcoplasmic reticulum; VGCvoltage-gaited channels.
Activation of Myofilaments
Contraction of vascular smooth muscle
Hypertension
DIRECT-ACTING VASODILATORS
Hydralazine (G) (Apresoline) Minoxidil (G) (Loniten) Ggeneric available.
First dose, mg
10 5

50100 bid/tid 1020 QD/bid

300 80
1012 75
FIGURE 7-32 Direct-acting vasodilators. Hydralazine is the prototype of directacting vasodilators. Absorption is more than 90%. Peak plasma levels occur within 1 hour but may vary widely among individuals. This is because hydralazine is subject to polymorphic acetylation; slow acetylators have higher plasma levels and require lower drug doses to maintain blood pressure control compared with rapid acetylators. Bioavailability for slow acetylators ranges from 30% to 35%; bioavailability for rapid acetylators ranges from 10% to 16%. Hydralazine undergoes extensive hepatic metabolism; it is mainly excreted in the urine in the form of metabolites or as unchanged drug. The plasma half-life is 3 to 7 hours. Dose reduction may be required in the slow acetylator with renal insufficiency.
Minoxidil is a substantially more potent direct-acting vasodilator than hydralazine. Absorption is greater than 95%. Peak plasma levels occur within 1 hour. Following a single oral dose, blood pressure declines within 15 minutes, reaches a nadir between 2 and 4 hours, and recovers at an arithmetically linear rate of 30% per day. Approximately 90% is metabolized by conjugation with glucuronic acid and by conversion to more polar products. Known metabolites, which are less pharmacologically active than minoxidil, are excreted in the urine. The plasma half-life of minoxidil is approximately 4 hours; dose adjustments are unnecessary in patients with renal insufficiency. Minoxidil and its metabolites are removed by hemodialysis and peritoneal dialysis; replacement therapy is required [6,9].
7.22

Side effects of direct-acting vasodilators Heart rate Myocardial contractility Venous capacitance Peripheral vascular resistance Cardiac output
VASODILATORS
Sympathetic function
Peripheral vascular resistance
PROPRANOLOL
Arterial pressure
Plasma renin activity
Circulating angiotensin
Aldosterone secretion
DIURETICS Sodium excretion Plasma and extracellular fluid volume
FIGURE 7-33 The side effect profile of direct-acting vasodilators. The most common and most serious effects of hydralazine and minoxidil are related to their direct or reflex-mediated hemodynamic actions, including flushing, headache, palpitations, anginal attacks, and electrocardiographic changes of myocardial ischemia [6,9]. These effects may be prevented by concurrent administration of a -adrenergic antagonist. Sodium retention with expansion of extracellular fluid volume is a significant problem. Large doses of potent diuretics may be required to prevent fluid retention and the development of pseudotolerance [13]. (From Koch-Weser [13]; with permission.) Repeated administration of hydralazine can lead to a reversible syndrome that resembles disseminated lupus erythematosus. The incidence is dose dependent; it rarely occurs in patients receiving less than 200 mg/day. Hypertrichosis is a common troublesome but reversible side effect of minoxidil; it develops during the first 3 to 6 weeks of therapy in approximately 80% of patients.
Plasma membrane
VGC
ROC
VGC
Ca2+
Ca2+ Ca2+
Ca2+
SR
Ca2+
SR
Myofilaments
FIGURE 7-34 Calcium antagonists. The calcium antagonists share a common antihypertensive mechanism of action: inhibition of calcium ion movement into smooth muscle cells of resistance arterioles through L-type (long-lasting) voltage-operated channels [6,9]. The ability of these drugs to bind to voltage-operated channels, causing closure of the gate and subsequent inhibition of calcium flux from the extracellular to the intracellular space, inhibits the essential role of calcium as an intracellular messenger, uncoupling excitation to contraction. Calcium ions may also enter cells through receptor-operated channels. The opening of these channels is induced by binding neurohumoral mediators to specific receptors on the cell membrane. Calcium antagonists inhibit the calcium influx triggered by the stimulation of either -adrenergic or angiotensin II receptors in a dose-dependent manner, inhibiting the influence of -adrenergic agonist and angiotensin II on vascular smooth muscle tone. The net physiologic effect is a decrease in vascular resistance. Although all the calcium antagonists share a basic mechanism of action, they are a highly heterogeneous group of compounds that differ markedly in their chemical structure, pharmacologic effects on tissue specificity, pharmacologic behavior side-effect profile, and clinical indications [6,9,14]. Because of this, calcium antagonists have been subdivided into several distinct classes: phenylalkamines, dihydropyridines, and benzothiazepines. ROCreceptor-operated channel; SRsarcoplasmic reticulum; VGCvoltage-gaited channels.
7.23
A. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: PHENYLALKAMINE DERIVATIVE

Verapamil (G) (Isoptin, Calan) Verapamil SR (Isoptin SR, Calan SR) Verapamil SRpellet (Veralan) Verapamil COER-24 (Covera HS) Ggeneric available.
First dose, mg
80 90 120 180
Usual dose, mg
80120 tid 90240 bid 240480 QD 180480 qhs

480 480 480 480
8 1224 24 24
B. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: DIHYDROPYRIDINE DERIVATIVES

Amlodipine (Norvasc) Felodipine (Plendil) Isradipine (DynaCirc) Isradipine CR (DynaCirc CR) Nicardipine SR (Cardine SR) Nifedipine Caps (G) (Procardia) Nifedipine ER (Adalat CC) Nifedipine GITS (Procardia XL) Nisoldipine (Sular) Ggeneric available.
First dose, mg
5 5 2.5 5 30 10 30 30 20
Usual dose, mg
510 QD 51 0 QD 2.5-5 bid 520 QD 3060 bid 1030 tid/qid 3090 QD 3090 QD 2040 QD

10 20 20 20 120 120 120 120 60
24 24 12 24 12 46 24 24 24
C. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: BENZODIAZEPINE DERIVATIVE

Diltiazem (G) (Cardizem) Diltiazem SR (Cardizem SR) Diltiazem CD (Cardizem CD) Diltiazem XR (Dilacor XR) Diltiazem ER (Tiazac) Ggeneric available.
First dose, mg
60 180 180 180 180
Usual dose, mg
60120 tid/qid 120240 bid 240480 QD 180480 QD 180480 QD

480 480 480 480 480
8 12 24 24 24
FIGURE 7-35 AC. Dosing schedules for calcium antagonists: phenylalkamine derivatives, dihydropyridine derivatives, and benzothiazepine derivatives.
7.24
PHARMACOKINETICS OF CALCIUM ANTAGONISTS

Absorption, %
Verapamil >90
First-pass hepatic
70%80%
Peak concentration
12 h (tablet) 5 h (SR caplet) 79 h (SR pellet) 11 h (COER) 612 h 2.55 h 12 h (tablet) 718 h (CR) 14 h (SR) <30 min (cap) 2.55 h (ER) 6 h GITS) 612 h 23 h (tablet) 611 h (SR) 1014 h (CD) 46 h (XR) 7 h (ER)
Route of elimination Active metabolite Plasma half-life, h Dose reduction

Liver Yes 412 (tablet) 12 (SR pellet) No
Amlodipine Felodipine Isradipine Nicardipine Nifedipine
>90 >90 >90 >90 >90
Minimal Extensive Extensive Extensive 20%30%
Liver Liver Liver Liver Liver
No No No No No
3050 1116 8 89 2 24 24 712 46 57 58 510 410
No No No No No
Nisoldipine Diltiazem
>85 >80
Extensive 50%
Liver Liver
Yes Yes
No Yes
FIGURE 7-36 Pharmacokinetics of the calcium antagonists: phenylalkamine derivatives, dihydropyridine derivatives, and benzothiazepine derivatives. FIGURE 7-37 The side effect profile of calcium antagonists [10,13,18]. AVatrioventricular.
THE SIDE EFFECTS PROFILE OF CALCIUM ANTAGONISTS

Side effects
Dihydropyridine Headache, flushing, palpitation, edema Phenylalkylamine Constipation Bradycardia, AV block congestive heart failure Benzodiazepine Bradyarrhythmia, AV block congestive heart failure
Mechanism
Potent peripheral vasodilator Negative inotropic, dromotropic, chronotropic effects
Negative inotropic, dromotropic, chronotropic effects

ACE inhibition and angiotensin II type I receptor antagonists: mechanisms for decrease in peripheral vascular resistance + + Functions:: Renal tubular sodium reabsorption Aldosterone release Vasoconstriction, vascular smooth muscle Remodeling, vascular smooth muscle Sympathetic activity (central and peripheral) Baroreceptor sensitivity +
7.25
Angiotensinogen (renin substrate) 1 Renin Angiotensin I (decapeptide)
Non-renin enzymes
AT1 receptor 3 Angiotensin II (octapeptide)
Blood pressure
Non-ACE enzymes
+ 4
2 ACE
Inactive fragments + Bradykinin Nitric oxide Prostaglandin E2 Prostaglandin I2
AT2 receptor
? Function
FIGURE 7-38 Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type I receptor antagonists. Angiotensin-converting enzyme inhibitors and angiotensin II type I receptor antagonists lower blood pressure by decreasing peripheral vascular resistance; there is usually little change in heart rate or cardiac output [6,9,15].
Mechanisms proposed for the observed decrease in peripheral resistance are shown [15]. Sites of pharmacologic blockade in the renin angiotensin system: 1) renin inhibitors, 2) ACE inhibitors, 3) angiotensin II type I receptor antagonists, 4) angiotensin II type II receptor antagonists.
7.26
A. DOSING SCHEDULES FOR SULFHYDRYL-CONTAINING ACE INHIBITOR

Captopril (G) (Capoten)
First dose, mg
12.5
Usual dose, mg
12.550 bid/tid
Maximum dose, mg
150
612
B. DOSING SCHEDULES FOR CARBOXYL-CONTAINING ACE INHIBITORS

Benazepril (Lotensin) Enalapril (Vasotec) Lisinopril (Prinivil,Zestril) Moexipril (Univasc) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik)
First dose, mg
10 5 10 7.5 510 2.5 1
Usual dose, mg
1020 QD 510 QD/bid 2040 QD 7.515 QD/bid 2040 QD 2.520 QD/bid 24 QD
Maximum dose, mg
40 40 40 30 40 40 8
24 1224 24 24 24 24 24
C. DOSING SCHEDULES FOR PHOSPHINIC ACIDCONTAINING ACE INHIBITOR

Fosinopril (Monopril) Ggeneric available.
First dose, mg
10
Usual dose, mg
2040 QD/bid
Maximum dose, mg
40
24
FIGURE 7-39 AC. Classification of and dosing schedule for angiotensin-converting enzyme (ACE) inhibitors. Angiotensin-converting enzyme inhibitors differ in prodrug status, ACE affinity, potency, molecular weight and
conformation, and lipophilicity [6,9]. They are generally classified into one of three main chemical classes according to the ligand of the zinc ion of ACE: sulfhydryl, carboxyl, or phosphinic acid.
7.27
PHARMACOKINETICS OF ACE INHIBITORS

Peak concentration (active component), h
1 12 34 68 12 2 24 410 3
Absorption, %
Captopril Benazepril Enalapril Lisinopril Moexipril Quinapril Ramipril Trandolapril Fosinopril 6075 37 5575 25 > 20 60 5060 70 36
Prodrug
No Yes Yes Yes Yes Yes Yes Yes Yes
Route of elimination
Kidney Kidney/liver Kidney Kidney Kidney Kidney Kidney/liver Kidney/liver Kidney/liver
Plasma half-life, h
2 1011 11 12 29 25 1317 1624 12
Dose reduction (renal disease)

Yes Yes Yes Yes Yes Yes Yes Yes No
FIGURE 7-40 Pharmacokinetics of angiotensin-converting enzyme (ACE) inhibitors: sulfhydrylcontaining, carboxyl-containing, and phosphinic acidcontaining. FIGURE 7-41 The side effect profile of angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors are well tolerated; there are few side effects [6,9].
THE SIDE EFFECTS PROFILE OF ACE INHIBITORS

Side effects
Cough, angioedema Laryngeal edema Lightheadedness, syncope Hyperkalemia Acute renal failure
Mechanisms
Potentiation of tissue kinins Excessive hypotension in patients with high basal peripheral vascular resistance high renin states, like volume contraction, impaired cardiac output Decreased aldosterone; potassium-containing salt substitutes and supplements should be avoided Extreme hypotension with impaired efferent arteriolar autoregulation
7.28

FIGURE 7-42 Angiotensin-converting enzyme (ACE) inhibition in acute renal failure. ACE inhibitors may produce functional renal insufficiency in patients with essential hypertension and hypertensive nephrosclerosis, in patients with severe bilateral renal artery stenosis, or in patients with stenosis of the renal artery of a solitary kidney. The postulated mechanism for this effect is diminished renal blood flow (decrease in systemic pressure, compromising flow through a fixed stenosis) in combination with diminished postglomerular capillary resistance (ie, decrease in angiotensin IImediated efferent arteriolar tone). In unilateral renal artery stenosis, a drop in the critical perfusion and filtration pressures may result in a marked drop in single-kidney glomerular filtration rate (GFR); however, the contralateral kidney may show an increase in both effective renal plasma flow (ERPF) and GFR due to attenuation of the intrarenal effects of angiotensin II on vascular resistance and mesangial tone. Thus, total net GFR may be normal, giving the false appearance of stability [16]. Although ACE inhibition may invariably decrease the GFR of the stenotic kidney, it is unlikely to cause renal ischemia owing to preservation of ERPF; GFR usually returns to pretreatment values following cessation of therapy. Shown is the effect of captopril (50 mg) on total clearances of 131I-sodium iodohippurate (ERPF) and 126I-thalamate (GFR) in 14 patients with unilateral renal artery stenosis and in 17 patients with essential hypertension. The effects after 60 minutes of captopril on systolic and diastolic intra-arterial pressure (P < 0.001) and of renin were significant. (From Wenting and coworkers [16]; with permission.)
230 190 150 110 70
Renal artery stenosis
Essential hypertension
Total effective renal plasma flow, mL/min Total glomerular filtration rate, mL/min Plasma renin, mU/L
440 360 280 110 100 90 80 1000
100
10 15 0
Captopril 50 mg
Captopril 50 mg
30
60 15 0 Time, min
30
60
Indicates blockade
Tyrosine Tyrosine hydroxylase Dihydroxyphenylalanine NE
FIGURE 7-43 Tyrosine hydroxylase inhibitor. Metyrosine ( -methyl-para-tyrosine) is an inhibitor of tyrosine hydroxylase, the enzyme that catalyzes the conversion of tyrosine to dihydroxyphenylalanine [6,9]. Because this first step is rate limiting, blockade of tyrosine hydroxylase activity results in decreased endogenous levels of circulating catecholamines. In patients with excessive production of catecholamines, metyrosine reduces biosynthesis 36% to 79%; the net physiologic effect is a decrease in peripheral vascular resistance and increases in heart rate and cardiac output resulting from the vasodilation. The degree of vasodilation is dependent on the degree of blockade of adrenergic vascular tone. NEnorepinephrine.
7.29
TYROSINE HYDROXYLASE INHIBITOR

Metyrosine (Demser)
First dose, mg
250

25 qid
Maximum dose, mg
1000 qid
34
FIGURE 7-44 Tyrosine hydroxylase inhibitor. Metyrosine is the only drug in its class. The initial recommended dose is 1 g/d, given in divided doses. This may be increased by 250 to 500 mg daily to a maximum of 4 g/d. The usual effective dosage is 2 to 3 g/d. The maximum biochemical effect occurs within 2 to 3 days. In hypertensive patients in whom there is a response, blood pressure decreases progressively during the first days of therapy. In patients who are usually normotensive, the dose should be titrated to the amount that will reduce circulating or urinary catecholamines by 50% or more.
Following discontinuation of therapy, the clinical and biochemical effects may persist 2 to 4 days. Metyrosine is variably absorbed from the gastrointestinal tract; bioavailability ranges from 45% to 90%. Peak plasma concentrations are reached in 1 to 3 hours. The plasma half-life is 3 to 4 hours. Metyrosine is not metabolized; the unchanged drug is recovered in the urine. Drug dosage should be reduced in patients with renal insufficiency. Metyrosine is exclusively used in the management of preoperative or inoperative pheochromocytoma [6,9]. FIGURE 7-45 The side effect profile of metyrosine. The adverse reactions observed with metyrosine are primarily related to the central nervous system and are typically dose dependent [6,9]. Metyrosine crystalluria (needles or rods), which is due to the poor solubility of the drug in the urine, has been observed in patients receiving doses greater than 4 g/d. To minimize this risk, patients should be well hydrated. CNScentral nervous system.
THE SIDE EFFECTS PROFILE OF METYROSINE

Side effects
CNS symptoms Sedation Extrapyramidal signs Drooling Speech difficulty Tremor Trismus Parkinsonian syndrome Psychic dysfunction Anxiety Depression Disorientation Confusion Crystalluria, uroliathiasis Diarrhea Insomnia (temporary)
Mechanisms
Depletion of CNS dopamine
Poor urine solubility Direct irritant to bowel mucosa Following drug withdrawal
7.30
ANGIOTENSIN II RECEPTOR ANTAGONISTS

Losartan (Cozaar) Valsartan (Diovan) Irbesaftan (Avapro)
First dose, mg
50 80 150
Usual dose, mg
50100 QD/bid 80160 QD 150300 QD
Maximum dose, mg
100 320 300
1224 24 24
FIGURE 7-46 Angiotensin II receptor antagonists. These drugs antagonize angiotensin IIinduced biologic actions, including proximal sodium reabsorption, aldosterone release, smooth muscle vasoconstriction, vascular remodeling, and baroreceptor sensitivity. Antihypertensive efficacy appears dependent on an activated renin-angiotensin system; bilateral nephrectomy and volume expansion abolish their activity. Losartan is a nonpeptide, specific angiotensin II receptor antagonist acting on the antagonist AT1 subtype receptor. Peak response occurs within 6 hours of dosing. It is readily absorbed; peak plasma concentrations are achieved within 1 hour. It has a relatively short terminal half-life of 1.5 to 2.5 hours. Oral bioavailability is approximately 33%. Losartan undergoes extensive first-pass hepatic metabolism to the predominant circulatory form of the drug Exp-3174. This metabolite is 15 to 30 times more potent than losartan with a
longer half-life (between 4 and 9 hours). The metabolite is cleared equally by the liver and the kidney; there may be enhanced hepatic clearance in renal insufficiency [15]. Dose reduction is not required in patients with renal insufficiency. Valsartan is a nonpeptide, specific angiotensin II antagonist acting on the AT1 subtype receptor. Peak response occurs within 6 hours of dosing. Peak plasma concentrations are reached 2 to 4 hours after dosing. The average elimination half-life is about 6 hours. Oral bioavailability is approximately 25%. Dose reduction is not required in patients with renal insufficiency [15]. Irebsartan is a nonpeptide, specific angiotensin II antagonist acting on the AT1 subtype receptor. Peak response occurs in 4 to 8 hours. There is no active metabolite. Dose reduction is not required in patients with renal insufficiency [15]. FIGURE 7-47 The side effect profile of angiotensin II receptor antagonists. Angiotensin II receptor antagonists are well tolerated. In contrast to the angiotensin-converting enzyme (ACE) inhibitors, cough and angioedema are rarely (if at all) associated with this class of antihypertensive drug. Similar to ACE inhibitors, however, hyperkalemia and acute renal failure may occur in patients at risk [15].
THE SIDE EFFECTS PROFILE OF ANGIOTENSIN II RECEPTOR ANTAGONISTS

Side effects
Hyperkalemia Acute renal dysfunction
Mechanisms
Blockade of angiotensin II Reduced aldosterone secretion Hypotension with impaired efferent anteriolar autoregulation
7.31
Prevention and Treatment of High Blood Pressure

JNC VI CLASSIFICATION OF HYPERTENSION
Category*
Optimal Normal High normal Hypertension Stage 1 Stage 2 Stage 3
Systolic (mm Hg)

<120 <130 130139 140/159 160/179 -180 and and or or or or
Diastolic (mm Hg)

<80 <85 8589 90/99 100/109 110
*Not taking anithypertensive drugs and not acutely ill. When systolic and diastolic blood pressures fall into different categories, the higher category should be selected to classify the individuals blood pressure status. For example, 160/92 mm Hg should be classified as stage 2 hypertension, and 174/120 mm Hg should be classified as stage 3 hypertension. Isolated systolic hypertension is defined as systolic blood pressure of 140 mm Hg or greater and diastolic blood pressure of less than below 90 mm Hg and staged appropriately (eg, 170/82 mm Hg is defined as stage 2 isolated hypertension). In addition to classifying stages of hypertension on the basis of average blood pressure levels, clinicians should specify presence of target organ disease and additional risk factors. This specifically is important for risk classification. Optimal blood pressure with respect to cardiovascular risk is below 120/80 mm Hg. Unusually low readings should be evaluated for clinical significance. Based on the average of two or more readings taken at each of two or more visits after an initial screening. JNCJoint National Committee.
FIGURE 7-48 Prevention and treatment of high blood pressure. The aim of antihypertensive therapy is risk reduction. Since the relationship between blood pressure and cardiovascular risk is continuous, the goal of treatment might be the maximum tolerated reduction in blood pressure. There is controversy concerning what constitutes hypertension and how far systolic or diastolic blood pressure should be lowered, however. The Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) [17] provides a new classification of hypertension and recommends that risk stratification be used to determine if lifestyle modification or drug therapy with adjunctive lifestyle modification be initiated according to the patients blood pressure classification (see Fig. 7-50). Major risk factors include smoking, dyslipidemia, diabetes mellitus, an age of 60 or older, male sex or postmenopausal state for women, and a family history of cardiovascular disease in women younger than 65 and in men younger than 55. Target organ damage includes heart disease (left ventricular hypertrophy, angina pectoris, prior myocardial infarction, heart failure), stroke or transient ischemic attack, and nephropathy. Prevention and management of hypertension-related morbidity and mortality may best be accomplished by achieving a systolic blood pressure below 140 mm Hg and a diastolic blood pressure below 90 mm Hg; lower if tolerable. Recently, more aggressive blood pressure control has been advocated in patients with renal disease and hypertension, particularly in those patients with a urinary protein excretion of greater than 1 g/d. Blood pressure control in the range of 125/80 mm Hg (mean arterial pressure of 108 mm Hg) has been shown to slow the progression of renal disease [18,19]. This targeted blood pressure control may therefore be advisable in the majority of patients with hypertension. Regardless, each patient should be treated according to their cerebrovascular, cardiovascular, or renal risks; their specific pathophysiology or target organ damage; and their concurrent disease states. A uniform blood pressure goal (target) probably does not exist for all hypertensive patients, and lower may not always be better.
7.32

FIGURE 7-49 Decision analysis for treatment based on the Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) [17].
JNC VI DECISION ANALYSIS FOR TREATMENT

Risk group B (at least 1 risk factor, not including diabetes; no TOD/ CCD)
Lifestyle modification Lifestyle modification (up to 6 months) Drug therapy
Blood pressure stages (mm Hg)

High normal (130139/8589) Stage 1 (140159/9099) Stages 2 and 3 (>160/100)
Risk group A (no risk factors, no TOD/CCD)*

Lifestyle modification Lifestyle modification (up to 12 months) Drug therapy
Risk Group C (TOD/CCD and/or diabetes, with or without other risk factors)
Drug therapy Drug therapy Drug therapy
Lifestyle modification should be adjunctive therapy for all patients recommended for pharmacologic therapy. *TOD/CCD indicates target organ disease/clinical cardiovascular disease. For patients with multiple risk factors, clinicians should consider drugs as initial therapy plus lifestyle modifications. For those with heart failure, renal insufficiency, or diabetes.
CRITERIA FOR INITIAL DRUG THERAPY

Reduce peripheral vascular resistance No sodium retention No compromise in regional blood flow No stimulation of the renin-angiotensin-aldosterone system Favorable profile with concomitant diseases Once a day dosing Favorable adverse effect profile Cost effective (low direct and indirect cost)
FIGURE 7-50 Selection of initial drug therapy. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) recommends that either a diuretic or a -blocker be chosen as initial drug therapy, based on numerous randomized controlled trials that show reduction in morbidity and mortality with these agents [17]. Not all authorities agree with this recommendation. In selecting an initial drug therapy to treat a hypertensive patient, several criteria should be met [6,9]. The drug should decrease peripheral resistance, the pathophysiologic hallmark of all hypertensive diseases. It should not produce sodium retention with attendant pseudotolerance. The drug should neither stimulate nor suppress the heart, nor should it compromise regional blood flow to target organs such as the heart, brain, or the kidney. It should not stimulate the renin-angiotensin-aldosterone axis. Drug selection should consider concomitant diseases such as arteriosclerotic cardiovascular and peripheral vascular disease, chronic obstructive pulmonary disease, diabetes mellitus, hypertensive cardiovascular disease, congestive heart failure, and hyperlipidemia. Drug dosing should be infrequent. The drugs side effect profile, including its effect on physical state, emotional well-being, sexual and social function, and cognitive activity, should be favorable. Drug costs, both direct and indirect, should be reasonable. It is readily apparent that no current class of antihypertensive drug fulfills all these criteria.
7.33
CANDIDATES FOR INITIAL DRUG THERAPY OF MILD TO MODERATE HYPERTENSIVE DISEASE

Angiotensin II type I receptor antagonists
Decrease Increase/no change No change No No change Preserve No change Increase Increase Decrease/no change No effect No effect No effect May benefit No effect Benefit
ACE inhibitors
Peripheral vascular resistance Sodium homeostasis Urinary sodium excretion Extracellular fluid volume Pseudotolerance Target organ function Heart rate, cardiac output Cerebral function Renal function (GFR) Renin-angiotensin-aldosterone Plasma renin activity Plasma angiotensin II Plasma aldosterone Concurrent disease efficacy Coronary disease Peripheral vascular disease Obstructive airway disease Diabetes mellitus Dyslipidemia Systolic dysfunction Decrease Increase/no change No change No No change Preserve No change/increase Increase Decrease Decrease/no change No effect No effect No effect May benefit No effect Benefit
1-adrenergic antagonists
1-adrenergic antagonists
Thiazide-type Calcium antagonists diuretics

Decrease Increase/no change No change No Class specific Preserve No change/increase No change No change No change Benefit May benefit No effect No effect No effect No effect Decrease Increase Decrease No No change Preserve No change Increase Increase Increase No effect No effect No effect May aggravate Aggravate Benefit
Decrease May decrease May increase No May increase Preserve No change No change No change No change No effect No effect No effect No effect Benefit No effect
Decrease No change No change No Decrease Preserve No change/decrease Decrease Decrease Decrease/no change Benefit May aggravate May aggravate May aggravate May aggravate May aggravate
FIGURE 7-51 Options for monotherapy. Given the drugs that we have and their pharmacologic profiles, what are the best classes for initial drug therapy? Alphabetically, they include 1) angiotensin-converting enzyme (ACE) inhibitors, 2) 1-adrenergic antagonists, 3) angiotensin II type I receptor antagonists, 4) 1-adrenergic antagonists, 5) calcium antagonists, and
6) thiazide-type diuretics [6,9,15]. All these drugs, given as monotherapy, are effective in lowering blood pressure in 50% to 60% of patients with mild to moderate hypertension. 1-adrenergic antagonists, ACE inhibitors, and angiotensin II receptor antagonists are less efficacious in blacks than in whites.
7.34

Options for subsequent antihypertensive therapy
Not at goal blood pressure (<140/<90 mm Hg); lower goal in patients with diabetes mellitus or renal disease
No response or troublesome side effects
Inadequate response but well tolerated
Sustitute another drug from a different class
Add a second agent from a different class (diuretic if not already used)
Not a goal blood pressure
FIGURE 7-52 Options for subsequent antihypertensive therapy. The majority of patients with mild to moderate hypertension can be controlled with one drug. If, after a 1- to 3-month interval, the response to the initial choice of therapy is inadequate, however, three options for subsequent antihypertensive drug therapy may be considered: 1) increase the dose of the initial drug, 2) discontinue the initial drug and substitute a drug from another class, or 3) add a drug from another class (combination therapy). Recommendations from the Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) are provided [17].
Continue adding agents from other classes Consider referral to a hypertension specialist
COMBINATION THERAPIES
Mild to moderate (stage 1 or 2) hypertension
Addition of low-dose thiazide-type diuretic to: ACE inhibitor 1-adrenergic antagonist 1-adrenergic antagonist Angiotensin III receptor antagonist Severe (Stage 3) hypertension Classic triple drug therapy Diuretic 1-adrenergic antagonist Direct-acting vasodilator ACE inhibitor plus calcium antagonist 1-adrenergic antagonist plus 1-adrenergic antagonist 1-adrenergic antagonist plus dihydropyridine calcium antagonist
FIGURE 7-53 Combination therapies. If a second drug is required, the addition of a low-dose thiazidetype diuretic to a nondiuretic drug will usually enhance the effectiveness of the first drug [6,9,17]. Newly developed formulations, using combinations of low doses of two agents from different classes, are available and effective and may minimize the likelihood of a dose-dependent adverse effect. The fixed doses used in these formulations were chosen to control mild to moderate (JNC VI stage 1 or 2) hypertension. More severe (JNC VI stage 3) cases of hypertension that are unresponsive to this therapeutic strategy may respond either to a variety of combination therapies given together as separate formulations or to classic triple-drug therapy (ie, diuretic, -adrenergic antagonist, and direct-acting vasodilator) [6,9]. ACEangiotensin-converting enzyme; JNCJoint National Committee.
7.35
JNC VI LIFE STYLE MODIFICATIONS

Lose weight if overweight Limit alcohol intake to no more than 1 oz (30 mL) ethanol (eg, 24 oz [720 mL] beer, 10 oz [300 mL] wine, or 2 oz [60 mL] 100-proof whiskey) per day or 0.5 oz (15 mL) ethanol per day for women and lighter weight people Increase aerobic physical activity (30 to 45 minutes most days of the week) Reduce sodium intake to no more than 100 mmol/d (2.4 g sodium or 6 g sodium chloride) Maintain adequate intake of dietary potassium (approximately 90 mmol/d) Maintain adequate intake of dietary calcium and magnesium for general health Stop smoking and reduce intake of dietary saturated fat and cholesterol for overall cardiovascular health
FIGURE 7-54 Follow-up in antihypertensive therapy. During follow-up visits, pharmacologic therapy should be reconfirmed or readjusted. As a rule, antihypertensive therapy should be maintained indefinitely. Cessation of therapy in patients who were correctly diagnosed as hypertensive is usually (but not always) followed by a return of blood pressure to pretreatment levels. After blood pressure has been controlled for 1 year and at least four visits, however, attempts should be made to reduce antihypertensive drug therapy in a deliberate, slow, and progressive manner; such step-down therapy may be successful in patients following lifestyle modification [17]. Patients for whom drug therapy has been reduced or discontinued should have regular follow-up, since blood pressure may increase again to hypertensive levels. JNCJoint National Committee.
CAUSES OF RESISTANT HYPERTENSION

Patients failure to adhere to drug therapy Physicians failure to diagnose a secondary cause of hypertension Renal parenchymal hypertension Renovascular hypertension Mineralocorticoid excess state (eg, primary aldosteronism) Pheochromocytoma Drug-induced hypertension (eg, sympathomimetic, cyclosporine) Illicit substances (eg, cocaine, anabolic steroids) Glucocortoid excess state (eg, Cushings syndrome) Coarctation of the aorta Hormonal disturbances (eg, thyroid, parathyroid, growth hormone, serotonin) Neurologic syndromes (eg, Guillain-Barr syndrome, porphyria, sleep apnea) Physicians failure to recognize an adverse drugdrug interaction See Physicians Desk Reference Physicians failure to recognize the development of secondary drug resistance Sodium retention with pseudotolerance, secondary to diuretic resistance or excess sodium intake Increased heart rate, cardiac output secondary to drug-induced reflex tachycardia Increased peripheral vascular resistance secondary to drug-induced stimulation of the renin-angiotensin system
FIGURE 7-55 Resistant hypertension. Causes of failure to achieve or sustain control of blood pressure with drug therapy are listed [6,9].
7.36

FIGURE 7-56 Diuretic resistance. Diuretic resistance may result from patient noncompliance, impaired bioavailability in an edematous syndrome, impaired diuretic secretion by the proximal tubule, protein binding in the tubule lumen (eg, nephrotic syndrome), reduced glomerular filtration rate, or enhanced sodium chloride reabsorption [7,8]. Resultant fluid retention will attenuate the effectiveness of most antihypertensive drugs. Renal mechanisms, problems, and solutions are provided in this table [6,8,9].
DIURETIC RESISTANCE
Problem Mechanism Solution
Limits active transport of diuretics Reduced renal blood flow Use of large doses of a diuretic and into proximal tubular fluid, reducing appropriate dosing interval to achieve inhibitory effect at a more distal a therapeutic tubular drug concentration intraluminal membrane site Reduced glomerular filtration rate Use loop diuretics with steep dose Limits absolute amount of sodium filtered response curve and/or block multiple sites of sodium reabsorption: loop diuretic with thiazide-like diuretic Secondary hyperaldosteronism Sodium recaptured at late distal Addition of a potassium-sparing diuretic tubule and collecting duct to above, to maintain urine sodium/potassium ratio > 1
References
1. Kaplan NM: Clinical Hypertension, edn 6. Baltimore: Williams & Wilkins; 1994:50. 2. Kawasaki T, Delea CS, Bartter FC, Smith H: The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension. Am J Med 1978, 64:193198. 3. Guyton AC, Coleman TG, Yang DB, et al.: Salt balance and long-term blood pressure control. Annu Rev Med 1980, 31:1527. 4. Julius S, Krause L, Schork NJ: Hyperkinetic borderline hypertension in Tecumseh, Michigan. J Hypertens 1991, 9:7784. 5. Lund-Johansen P: Cetra haemodynamics in essential hypertension at rest and during exercise: a 20-year follow-up study. J Hypertens 1989, 7(suppl 6): 552555. 6. Bauer JH, Reams GP: Mechanisms of action, pharmacology, and use of antihypertensive drugs. In The Principles and Practice of Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: Mosby; 1995:399415. 7. Tarazi RC: Diuretic drugs: mechanisms of antihypertensive action. In Hypertension: Mechanisms and Management. The 26th Hahnemann Symposium. Edited by Oneti G, Kim KE, Moer JH. New York: Grune and Stratton; 1973:255. 8. Ellison DH: The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med 1991, 114:886894. 9. Bauer JH, Reams GP: Antihypertensive drugs. In The Kidney, edn 5. Edited by Brenner BM. Philadelphia: W.B. Saunders Co.; 1995: 23312381. 10. Man int Veld AJ, Schalekamp MADH: How intrinsic sympathomimetic activity modulates the haemodynamic responses to -adrenoceptor antagonists: a clue to the nature of their antihypertensive mechanism. Br J Clin Pharmac 1982, 13:24552575. 11. Van Zwieten PA: Antihypertensive drug interacting with -and -adrenoceptors: a review of basic pharmacology. Drugs 1988, 35(suppl 6):619. 12. Graham RM, Thornell IR, Gain JM, et al.: Prazosin: the first dose phenomenon. Br Med J 1976, 2:12931294. 13. Koch-Weser J: Vasodilation drugs in the treatment of hypertension. Arch Intern Med 1974, 133:10171025. 14. Entel SI, Entel EA, Clozel J-P: T-type Ca2+ channels and pharmacological blockade: potential pathophysiological relevance. Cardiovasc Drugs Ther 1997, 11:723739. 15. Bauer JH, Ream GP: The angiotensin II type 1 receptor antagonists. Arch Intern Med 1995, 155:13611368. 16. Wenting GJ, Tan-Tjiong HL, Derkx FMH, et al.: Split renal function after captopril in unilateral renal artery stenosis. Br Med J 1974, 288:886890. 17. JNC VI: The Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1993, 153:154183. 18. Peterson JC, Adler S, Burkart JM, et al.: Blood pressure control, proteinuria, and the progression of renal disease. Ann Intern Med 1995, 123:754762. 19. Hebert LA, Kusek JW, Greene T, et al.: Effects of blood pressure control on progressive renal disease in blacks and whites. Hypertension 1997, 30 (part 1):428435.
Hypertensive Crises
Charles R. Nolan
ost patients with hypertension remain asymptomatic for many years, until complications from atherosclerosis, cerebrovascular disease, or congestive heart failure supervene. In some patients, this so-called benign course is punctuated by a hypertensive crisis. Hypertensive crisis is defined as the turning point in the course of an illness at which acute management of the elevated blood pressure plays a decisive role in the eventual outcome [1]. The haste with which blood pressure must be controlled varies with the type of hypertensive crisis. If the patients outcome is to be optimal, however, the crucial role of hypertension in the disease process must be identified and a plan for management of the blood pressure successfully implemented. The absolute level of the blood pressure clearly is not the most important factor in determining the existence of a hypertensive crisis. For example, in children, pregnant women, and other previously normotensive persons in whom mild to moderate hypertension develops suddenly, a hypertensive crisis can occur at a level of blood pressure that normally is well-tolerated by adults with chronic hypertension. Furthermore, a crisis can occur in adults with mild to moderate hypertension with the onset of acute end-organ dysfunction involving the heart or brain.
CHAPTER
8.2

FIGURE 8-1 Malignant hypertension is a clinical syndrome characterized by marked elevation of blood pressure, with widespread acute arteriolar injury (hypertensive vasculopathy). Funduscopy reveals hypertensive neuroretinopathy with flame-shaped hemorrhages, cottonwool spots (soft exudates), and sometimes papilledema. Regardless of the severity of blood pressure elevation, malignant hypertension cannot be diagnosed in the absence of hypertensive neuroretinopathy. Thus, hypertensive neuroretinopathy is an extremely important clinical finding, indicating the presence of a hypertension-induced arteriolitis that may involve the kidneys, heart, and central nervous system. In malignant hypertension, rapid and relentless progression to end-stage renal disease occurs if effective blood pressure control is not implemented. Mortality can result from acute hypertensive heart failure, intracerebral hemorrhage, hypertensive encephalopathy, or complications of uremia. Malignant hypertension represents a hypertensive crisis given that adequate control of blood pressure clearly prevents these morbid complications. Even in patients with so-called benign (nonmalignant) hypertension, in which hypertensive neuroretinopathy is absent, a hypertensive crisis may occur based on the development of concomitant acute end-organ dysfunction. Hypertensive crises caused by benign hypertension with acute complications include hypertension in the setting of hypertensive encephalopathy, acute hypertensive heart failure, acute aortic dissection, intracerebral hemorrhage, subarachnoid hemorrhage, severe head trauma, acute myocardial infarction or unstable angina, and active bleeding. Poorly controlled hypertension in patients requiring surgery increases the risk of intraoperative cerebral or myocardial ischemia and postoperative acute renal failure. Severe postoperative hypertension, including postcoronary artery bypass hypertension and postcarotid endarterectomy hypertension, increases the risk of postoperative bleeding, hypertensive encephalopathy, pulmonary edema, and myocardial ischemia. The various catecholamine excess states can cause a hypertensive crisis with hypertensive encephalopathy or acute hypertensive heart failure. Preeclampsia and eclampsia represent hypertensive crises unique to pregnancy. Scleroderma renal crisis is a hypertensive crisis because failure to adequately control blood pressure with a regimen that includes a converting enzyme inhibitor results in rapid irreversible loss of renal function. Hypertensive crises as a result of autonomic hyperreflexia induced by bowel or bladder distention also can occur in patients with quadriplegia. The sudden onset of hypertension in this setting can lead to hypertensive encephalopathy or acute pulmonary edema. Each hypertensive crisis is discussed in more detail in the figures that follow.
HYPERTENSIVE CRISES
Malignant hypertension (Hypertensive neuroretinopathy present) Benign (nonmalignant) hypertension with acute complications (Acute organ system dysfunction without hypertensive neuroretinopathy) Hypertensive encephalopathy (also common in malignant hypertension) Acute hypertensive heart failure (also common in malignant hypertension) Acute aortic dissection Central nervous system catastrophe Intracerebral hemorrhage Subarachnoid hemorrhage Severe head trauma Acute myocardial infarction or unstable angina Active bleeding, including postoperative bleeding Uncontrolled hypertension in patients requiring surgery Severe postoperative hypertension Postcoronary artery bypass hypertension Postcarotid endarterectomy hypertension Catecholamine excess states Pheochromocytoma Monoamine oxidase inhibitortyramine interactions Miscellaneous hypertensive crises Preeclampsia and eclampsia Scleroderma renal crisis Autonomic hyperreflexia in quadriplegic patients
Hypertensive Crises
8.3
HYPERTENSIVE SYNDROMES SOMETIMES MISDIAGNOSED AS HYPERTENSIVE CRISES

Severe uncomplicated hypertension (Severe hypertension without hypertensive neuroretinopathy or acute end-organ dysfunction, formerly known as urgent hypertension) Benign hypertension with chronic end-organ complications Chronic renal insufficiency from primary renal parenchymal disease Chronic congestive heart failure from systolic or diastolic dysfunction Atherosclerotic coronary vascular disease (previous myocardial infarction, stable angina) Cerebrovascular disease (history of transient ischemic attack or cerebrovascular accident)
FIGURE 8-2 Hypertensive syndromes sometimes misdiagnosed as hypertensive crises. It should be noted that the finding of severe hypertension does not always imply the presence of a hypertensive crisis. In patients with severe uncomplicated hypertension (formally known as urgent hypertension) in which severe hypertension is not accompanied by evidence of malignant hypertension or acute end-organ dysfunction, eventual complications due to stroke, myocardial infarction, or congestive heart failure tend to occur over months to years, rather than hours to days. Long-term control of blood pressure can prevent these eventual complications. However, a hypertensive crisis cannot be diagnosed because no evidence exists that acute reduction of blood pressure results in improvement in short- or long-term prognosis. Moreover, the presence of chronic hypertensive end-organ complications in a patient with nonmalignant hypertension does not imply the existence of a hypertensive crisis requiring rapid control of blood pressure. The category of benign hypertension with chronic complications includes hypertensive patients with chronic renal insufficiency due to underlying primary renal parenchymal disease, chronic congestive heart failure as a result of either systolic or diastolic dysfunction, atherosclerotic coronary vascular disease (stable angina or previous myocardial infarction), or chronic cerebrovascular disease (previous transient ischemic attacks or cerebrovascular accident). Long-term inadequate blood pressure control increases the risk of further deterioration of endorgan function in each of these conditions. However, no evidence exists that rapid control of blood pressure is necessary to prevent further complications. Therefore, a true hypertensive crisis does not exist.
8.4

in thickening and remodeling of arteriolar walls that may be an adaptive mechanism to prevent vascular damage from the mechanical stress of hypertension. However, when the blood pressure increases suddenly or increases to a critical level, these adaptive mechanisms may be overwhelmed, resulting in vascular damage. As a result of the mechanical stress of increased transmural pressure, focal segments of the arteriolar vasculature become dilated, producing a sausage-string pattern. Endothelial permeability increases in the dilated segments, leading to extravasation of fibrinogen, fibrin deposition in the media, and necrosis of smooth muscle cells (fibrinoid necrosis). Platelet adherence to damaged endothelium with release of platelet-derived growth factor induces migration of smooth muscle cells to the intima where they proliferate (neointimal proliferation) and produce mucopolysaccharide. These cells also produce collagen, resulting in proliferative endarteritis, musculomucoid hyperplasia, and eventually, fibrotic obliteration of the vessel lumen. Occlusion of arterioles leads to accelerated glomerular obsolescence and end-stage renal disease. Other factors may synergize with hypertension to damage the arterial vasculature. Renal ischemia leads to activation of the renin-angiotensin system that can cause further elevation of blood pressure and progressive vascular damage. Spontaneous natriuresis early in the course of malignant hypertension leads to volume depletion with activation of the renin-angiotensin system or catecholamines that further elevates blood pressure. It also is possible that angiotensin II may be directly vasculotoxic. Activation of the clotting cascade within the lumen of damaged vessels may lead to fibrin deposition with localized intravascular coagulation. Thus, microangiopathic hemolytic anemia is a common finding in malignant hypertension. Cigarette smoking and oral contraceptive use may contribute to development of malignant hypertension by decreasing prostacyclin production in the vessel wall and thereby inhibiting repair of hypertensioninduced vascular injury. Low dietary intake of potassium may help promote vascular smooth muscle proliferation and therefore predisposes to the development of malignant hypertension in Blacks with severe essential hypertension. PDGFplateletderived growth factor.
Pathophysiology of malignant hypertension Renal parenchymal disease Renal artery stenosis Endocrine hypertension
Essential hypertension
Severe hypertension
Spontaneous natriuresis
Critical level or Rate of increase
Volume depletion Catecholamines Vasopressin Renin/Angiotensin II
Forced vasodilation (sausage-string) Decreased prostacyclin Oral contraceptives Cigarette smoking
Vascular damage
Denudation of epithelium
Endothelial permeability Localized intravascular coagulation
Platelet adherence PDGF release Low potassium diet Smooth muscle proliferation Deposition of mucopolysaccharide Renal ischemia Musculomucoid intimal hyperplasia
Extravasation Fibrinogen Fibrin deposition Arteriolar wall Necrosis of smooth muscle Fibrinoid necrosis
Lumen
Narrowing of vascular lumen
Renal ischemia
Accelerated glomerular obsolescence
Tubular atrophy
Interstitial fibrosis
Chronic renal failure
FIGURE 8-3 Pathophysiology of malignant hypertension. The vicious cycle of malignant hypertension is best demonstrated in the kidneys. This cycle also applies equally well to the vascular beds of the retina, pancreas, gastrointestinal tract, and brain [1]. In this scheme, severe hypertension is central. Hypertension may be either essential or secondary to any one of a variety of causes. Because not all patients develop malignant hypertension despite equally severe hypertension, the interaction between the level of blood pressure and the adaptive capacity of the vasculature may be important. In this regard, chronic hypertension results
Hypertensive Crises
8.5
Vascular lesions in malignant hypertension Malignant hypertension
Fibrinoid necrosis
Proliferative endarteritis
Occlusion of vessels
Ischemia
Retinal Hemorrhages Cotton-wool spots Papilledema
CNS Intracerebral hemorrhage Hypertensive encephalopathy
Cardiac Left ventricular dysfunction
Renal Glomerulosclerosis Tubular atrophy Interstitial fibrosis
GI Hemorrhage Bowel necrosis
Pancreatic Necrosis Hemorrhage
FIGURE 8-4 Distribution of vascular lesions in malignant hypertension. Malignant hypertension is essentially a systemic vasculopathy induced by severe hypertension. Fibrinoid necrosis and proliferative endarteritis occur throughout the body in numerous vascular beds, leading to ischemic changes. In the retina, striate hemorrhages and cotton-wool spots develop. The finding of hypertensive neuroretinopathy is the clinical sine qua non of malignant hypertension. Vascular lesions in the gastrointestinal tract (GI) can lead to hemorrhage or bowel necrosis. Hemorrhagic pancreatitis also can occur. Cerebrovascular lesions can lead to cerebral infarction or intracerebral hemorrhage. Hypertensive encephalopathy also can develop as a result of failure of autoregulation with cerebral overperfusion and edema (Fig. 8-22). Vascular lesions also can develop in the myocardium; however, acute hypertensive heart failure is largely the result of acute diastolic dysfunction induced by the marked increase in afterload that accompanies malignant hypertension (Figs. 824 and 8-25). CNScentral nervous system.
COMMON CAUSES OF MALIGNANT HYPERTENSION

Primary (essential) malignant hypertension* Secondary malignant hypertension Primary renal disease Chronic glomerulonephritis* Chronic pyelonephritis* Analgesic nephropathy* Immunoglobulin A nephropathy* Acute glomerulonephritis Radiation nephritis Renovascular hypertension* Oral contraceptives Atheroembolic renal disease (cholesterol embolism) Scleroderma renal crisis Antiphospholipid antibody syndromes Chronic lead poisoning Endocrine hypertension Aldosterone-producing adenoma (Conns syndrome) Cushings syndrome Congenital adrenal hyperplasia Pheochromocytoma
*Most common causes of malignant hypertension.
FIGURE 8-5 Malignant hypertension is not a single disease entity but, rather, a syndrome in which the hypertension can be either primary (essential) or secondary to any one of a number of different causes [2]. Among Black patients the underlying cause is almost always essential hypertension that has entered a malignant phase. The most common secondary causes of malignant hypertension are primary renal parenchymal disorders. Chronic glomerulonephritis is thought to be the cause of malignant hypertension in up to 20% of cases. Unless a history of an acute nephritic episode or long-standing hematuria or proteinuria is available, the underlying glomerulonephritis may only
become apparent when a renal biopsy is performed. Recently, immunoglobulin A (IgA) nephropathy has been reported as an increasingly frequent cause of malignant hypertension. In one series of 66 patients with IgA nephropathy, 10% developed malignant hypertension [3]. Chronic atrophic pyelonephritis in children, often a result of underlying vesicoureteral reflux, is the most common cause of malignant hypertension [4]. In Australia, malignant hypertension complicates up to 7% of cases of analgesic nephropathy [5]. Transient malignant hypertension responsive to volume expansion has been reported in analgesic nephropathy. It has been suggested that interstitial disease with salt-wasting is important in the pathogenesis by causing profound volume depletion with activation of the renin-angiotensin axis. Malignant hypertension is both an early and late complication of radiation nephritis that can occur up to 11 years after radiotherapy. Renovascular hypertension from either fibromuscular dysplasia or atherosclerosis is a well-recognized cause of malignant hypertension. In a series of 123 patients with malignant hypertension, renovascular hypertension was found in 43% of Whites and 7% of Blacks [6]. Among women of childbearing age, oral contraceptives can cause malignant hypertension [7]. In the absence of underlying renal disease, with discontinuation of the drug, long-term prognosis is excellent. Severe hypertension that may become malignant is a common complication of atheroembolic renal disease. In patients presenting with malignant hypertension in the weeks to months after an arteriographic procedure, a careful history and physical should be performed to look for evidence of atheroembolism. Scleroderma renal crisis is the most life-threatening complication of progressive systemic sclerosis. Scleroderma renal crisis is characterized by hypertension that may enter the malignant phase. Even in the absence of hypertensive neuroretinopathy suggesting malignant hypertension, the renal lesion in scleroderma renal crisis is virtually indistinguishable from primary malignant nephrosclerosis [8]. Patients with antiphospholipid antibody syndrome, either primary or secondary to systemic lupus erythematosus, can develop malignant hypertension with renal insufficiency as a result of thrombotic microangiopathy [9]. The endocrine causes of hypertension only rarely lead to malignant hypertension. Pheochromocytoma can cause hypertensive crises owing to hypertensive encephalopathy or acute hypertensive heart failure in the absence of hypertensive neuroretinopathy (malignant hypertension).
8.6

FIGURE 8-6 Tertiary hyperaldosteronism after treatment of malignant hypertension. The diagnosis of primary hyperaldosteronism must be made with caution in patients with a history of malignant hypertension. After successful treatment of malignant hypertension, plasma renin activity rapidly normalizes, whereas aldosterone secretion may remain elevated for up to a year. This phenomenon has been attributed to persistent adrenal hyperplasia induced by long-standing hyperreninemia during the malignant phase [10]. During this phase of tertiary hyperaldosteronism, despite suppressed renin activity, hypokalemia, metabolic alkalosis, and aldosterone levels that are not suppressible, mimic primary hyperaldosteronism. Adrenal imaging studies reveal bilateral nodular adrenal hyperplasia. With continued long-term control of blood pressure this hyperaldosteronism remits spontaneously.
Tertiary hyperaldosteronism after treatment of malignant hypertension Malignant hypertension Vascular lesions heal Antihypertensive treatment with resolution of malignant hypertension
Renal ischemia
Activation of reninangiotensin axis Bilateral adrenal hyperplasia
Renin levels decrease rapidly Resolves slowly over 1 year after control of blood pressure
Nonsuppressible aldosteronism
Renal potassium-wasting with hypokalemia
Metabolic alkalosis
RENAL CHANGES IN HYPERTENSION

Retinal arteriosclerosis and arteriosclerotic retinopathy (benign hypertension) Focal or diffuse arteriolar narrowing Arteriovenous crossing changes Broadening of the light reflex Copper or silver wiring Perivasculitis (parallel white lines around the arteries) Solitary round hemorrhages Hard exudates Central or branch venous occlusion Hypertensive neuroretinopathy (malignant hypertension) Generalized arteriolar narrowing Striate (flame-shaped) hemorrhage* Cotton-wool spots* Papilledema* Star figure at the macula
*Features that distinguish hypertensive neuroretinopathy from retinal arteriosclerosis.
FIGURE 8-7 Funduscopic findings are pivotal in the diagnosis of malignant hypertension. Keith and Wagener [11] graded retinal findings in hypertensive patients as follows: grade I, arteriolar narrowing; grade II, arteriovenous crossing changes; grade III, hemorrhages and exudates; grade IV, the changes in grade III plus papilledema. Although this classification of hypertensive retinopathy is of great historical importance, its clinical utility has several limitations, eg, it is extremely difficult to quantify arteriolar narrowing. In this regard, a tendency exists for significant observer bias such that patients with mild hypertension and questionable narrowing are invariably assigned to grade I. More importantly, this classification does not distinguish the retinal changes of benign and malignant hypertension. For example, the clinical significance of a cottonwool spot appearing in the fundus of a young man with severe
hypertension (diagnostic of malignant hypertension) is quite different from the clinical significance of a hard exudate in the fundus of a 60-year-old man with moderate hypertension. The prognostic and therapeutic implications of these two types of exudates clearly are different, although both would be classified as grade III. For this reason, the Keith and Wagener classification has been supplanted by the more clinically useful classification of hypertensive retinopathy shown here. This classification system draws a distinction between retinal arteriosclerosis with arteriosclerotic retinopathy, which is characteristic of benign hypertension, and hypertensive neuroretinopathy, which defines the existence of malignant hypertension [12,13]. Retinal arteriosclerosis, which is characterized histologically by the accumulation of hyaline material in arterioles, occurs in elderly normotensive persons or in the setting of long-standing benign hypertension. Funduscopic findings reflecting retinal arteriosclerosis include arteriolar narrowing, arteriovenous crossing changes, perivasculitis, and changes in the light reflex with copper or silver wiring. Arteriosclerotic retinopathy manifests as solitary round hemorrhages in the periphery of the fundus and hard exudates. The finding of retinal arteriosclerosis is of no prognostic significance with regard to the risk of coronary atherosclerosis or cerebrovascular disease. The arteries visualized with the ophthalmoscope are technically arterioles with a diameter of 0.1 mm. Hyaline arteriolosclerosis of the retinal vessels is a process entirely distinct from the atherosclerotic process that affects larger muscular arteries. Thus, the finding of retinal arteriosclerosis cannot predict the presence of atherosclerosis of the coronary or cerebral vessels. This lack of clinical significance of retinal arteriosclerosis in hypertensive patients contrasts dramatically with the importance and prognostic significance of the finding of hypertensive neuroretinopathy. This finding is the clinical sine qua non of malignant hypertension. The appearance of striate hemorrhages or cottonwool spots with or without papilledema closely parallels the development of fibrinoid necrosis and proliferative endarteritis in the kidney and other organs. Thus, the presence of hypertensive neuroretinopathy predicts the development of end-stage renal disease, or other life-threatening hypertensive complications, within a year if adequate control of the blood pressure is not achieved.
Hypertensive Crises
8.7
FIGURE 8-8 (see Color Plate) Fundus photography of retinal arteriosclerosis in benign hypertension. Funduscopy in a 60-year-old man reveals the characteristic changes of retinal arteriosclerosis, including arteriolar narrowing, mild arteriovenous crossing changes, copper wiring, and perivasculitis (parallel white lines around blood columns). The striate hemorrhages, cotton-wool spots, and papilledema characteristic of malignant hypertension are absent.
FIGURE 8-9 (see Color Plate) Fundus photography of arteriosclerotic retinopathy in benign hypertension. Funduscopy in a 52-year-old woman with benign hypertension demonstrates a solitary round hemorrhage characteristic of arteriosclerotic retinopathy.
FIGURE 8-10 (see Color Plate) Fundus photography of striate hemorrhages in hypertensive neuroretinopathy. Funduscopic findings in a 53-year-old woman with secondary malignant hypertension as a result of underlying immunoglobulin A nephropathy, demonstrating striate or flame-shaped hemorrhages (arrows). The appearance of small striate hemorrhages often is the first sign that malignant hypertension has developed. These hemorrhages are most commonly observed in a radial arrangement around the optic disc. The retinal circulation is under autoregulatory control such that under normal circumstances as blood pressure increases, arterioles constrict to maintain constant retinal blood flow. The appearance of striate hemorrhages implies that autoregulation has failed. Striate hemorrhages are a result of bleeding from superficial capillaries in the nerve fiber bundles near the optic disc. These capillaries originate directly from arterioles so that when autoregulation fails, the high systemic pressure is transmitted directly to the capillaries. This process leads to breaks in the continuity of the capillary endothelium. The resultant hemorrhages extend along nerve fiber bundles parallel to the retinal surface. The hemorrhages often have a frayed distal border owing to extravasation of blood between nerve fiber bundles.
8.8

FIGURE 8-11 (see Color Plate) Fundus photography of cotton-wool spots in hypertensive neuroretinopathy. Cotton-wool spots (arrows) are the most characteristic feature of malignant hypertension. They usually surround the optic disc and most commonly occur within three disc-diameters of the optic disc. Cotton-wool spots result from ischemic infarction of retinal nerve fiber bundles owing to arteriolar occlusion caused by proliferative arteriopathy in retinal vessels. Fluorescein angiography demonstrates that cotton-wool spots are areas of retinal nonperfusion. Embolization of pig retina with glass beads produces immediate neuronal cell edema followed by accumulation of mitochondria and other subcellular organelles in ischemic nerve fibers. It has been postulated that the normal axoplasmic flow of subcellular organelles is disrupted by retinal ischemia such that accumulation of organelles in ischemic nerve fiber bundles results in a visible white patch. Cotton-wool spots tend to distribute around the optic disc because nerve fiber bundles are most dense in this region. The detection of cotton-wool spots is a crucial clinical finding because they are the retinal manifestation of the malignant hypertension-induced systemic vasculopathy that also causes proliferative endarteritis and ischemia in the kidney and other organs. (This is the same patient as in Fig. 8-10.) FIGURE 8-12 (see Color Plate) Fundus photography of papilledema in hypertensive neuroretinopathy. Funduscopic findings in a 23-year-old Black man noted incidentally to be severely hypertensive during a routine dental clinic visit. Papilledema of the optic disc is apparent, with surrounding cotton-wool spots and striated hemorrhages. The pathogenesis of papilledema in hypertensive neuroretinopathy is unclear. Intracranial pressure is not always increased in patients with malignant hypertension and papilledema. Papilledema has been produced experimentally in Rhesus monkeys by occlusion of the long posterior ciliary artery that supplies the optic nerve. As in cotton-wool spots, indeed papilledema may result from hypertensive vasculopathyinduced ischemia of nerve fiber bundles in the optic disc. Thus, in hypertensive neuroretinopathy, papilledema essentially may represent a giant cotton-wool spot resulting from ischemia of the optic nerve. When papilledema occurs in malignant hypertension, it almost always is accompanied by striated hemorrhages and cotton-wool spots. When papilledema occurs alone, the possibility of a primary intracranial process such as tumor or cerebrovascular accident should be considered. FIGURE 8-13 (see Color Plate) Fundus photography of far-advanced hypertensive neuroretinopathy. Funduscopy in this 30-year-old man with malignant hypertension demonstrates all the characteristic features of hypertensive neuroretinopathy. These features include striate hemorrhages, cotton-wool spots, papilledema, and a star figure at the macula.
Hypertensive Crises
8.9
10
No papilledema Papilledema
08 Estimated survival
06
04
96 43 74 28 45 16 26 10 14 6 No. with papilledema No. without papilledema
FIGURE 8-14 Prognosis in accelerated hypertension versus malignant hypertension. In the original Keith and Wagener [11] classification of hypertensive retinopathy, malignant hypertension (grade IV) was defined by the presence of papilledema, whereas the term accelerated hypertension (grade III) was used when hemorrhages and exudates occurred in the absence of papilledema. However, more recent studies indicate that the prognosis is the same in hypertensive patients with striate hemorrhages and cotton-wool spots whether or not papilledema is present. In this regard, the World Health Organization has recommended that accelerated hypertension and malignant hypertension be regarded as synonymous terms for the same disease. Demonstrated are the effects of the presence or absence of papilledema on survival among 139 hypertensive patients with hypertensive neuroretinopathy (striated hemorrhages and cotton-wool spots) [14]. By multivariate analysis, after controlling for age, gender, smoking habit, initial serum creatinine concentration, and initial and achieved blood pressure, the presence of papilledema did not influence prognosis. (From McGregor [14] et al.; with permission.)
0 0 2 4 6 Years 8 10
FIGURE 8-15 (see Color Plate) Micrograph of fibrinoid necrosis in malignant hypertension. Fibrinoid necrosis of the afferent arterioles and interlobular arteries has traditionally been regarded as the hallmark of malignant hypertension. The characteristic finding is the deposition in the arteriolar wall of a granular material that is a bright-pink color on hematoxylin and eosin staining. On Masson trichrome staining, as illustrated, the granular fibrinoid material is bright red (arrow). The fibrinoid material usually is found in the media of the vessel; however, deposition in the intima also may occur. Whole or fragmented erythrocytes may be extravasated into the arteriolar wall. These hemorrhages account for the petechial hemorrhages that give rise to the peculiar flea-bitten appearance of the capsular surface of the kidney in malignant hypertension. Fibrinoid necrosis is thought to result from the mechanical stress placed on the vessel wall by severe hypertension. Forced vasodilation occurs when there is failure of autoregulation of renal blood flow, which leads to endothelial injury with seepage of plasma proteins into the vessel wall. Contact of plasma constituents with smooth muscle cells activates the coagulation cascade, and fibrin is deposited in the wall. Fibrin deposits then cause necrosis of smooth muscle cells (fibrinoid necrosis). (Masson trichrome stain, original magnification 100.)
8.10
SPECTRUM OF CLINICAL RENAL INVOLVEMENT IN MALIGNANT HYPERTENSION

Progressive subacute deterioration of renal function to end-stage renal disease Transient deterioration of renal function with initial blood pressure control Oliguric acute renal failure Established renal failure
FIGURE 8-16 (see Color Plate) Micrograph of proliferative endarteritis in malignant hypertension (musculomucoid intimal hyperplasia). In malignant nephrosclerosis, the interlobular (cortical radial) arteries reveal characteristic lesions. These lesions are variously referred to as proliferative endarteritis, endarteritis fibrosa, musculomucoid intimal hyperplasia, or the onionskin lesion. The typical finding is marked thickening of the intima that obstructs the vessel lumen. In severely affected vessels the luminal diameter may be reduced to the caliber of a single erythrocyte. Occasionally, complete obliteration of the lumen by a superimposed fibrin thrombus occurs. Traditionally, three patterns of intimal thickening have been described [15]. (1) The onionskin pattern consists of pale layers of elongated concentrically arranged myointimal cells along with delicate connective tissue fibrils that give rise to a lamellar appearance. The media often appears as an attenuated layer stretched around the expanded intima. (2) In the mucinous pattern, intimal cells are sparse. Seen is an abundance of lucent, faintly basophilic-staining amorphous material. (3) In fibrous intimal thickening, seen are few cells with an abundance of hyaline deposits, reduplicated bands of elastica, and coarse layers of collagen. The renal histology in Blacks with malignant hypertension demonstrates a characteristic finding in the larger arterioles and interlobular arteries known as musculomucoid intimal hyperplasia, with an abundance of cells and a small amount of myxoid material (that is light blue in color on hematoxylin and eosin staining) between the cells [16, 17]. These various intimal findings may represent progression over time from an initially cellular lesion to fibrosis of the intima. Electron microscopy demonstrates that in each type of intimal thickening the most abundant cellular element is a modified smooth muscle cell. This cell is called a myointimal cell. Proliferative endarteritis is thought to occur as a result of phenotypic modulation of medial smooth muscle cells that dedifferentiate from the normal contractile phenotype to acquire a more embryologic proliferative-secretory phenotype. It has been proposed that the endothelial injury in malignant hypertension results in attachment of platelets with release of plateletderived growth factor (PDGF) that may induce the phenotypic change in smooth muscle cells. PDGF stimulates chemotaxis of medial smooth muscles to the intima, where they proliferate and secrete mucopolysaccharide and later collagen and other extracellular matrix proteins, resulting in proliferative endarteritis, musculomucoid hyperplasia, and ultimately fibrous intimal thickening. (Hematoxylin and eosin stain, original magnification 100.)
FIGURE 8-17 Malignant hypertension is a progressive systemic vasculopathy in which renal involvement is a relatively late finding. In this regard, patients with malignant hypertension can present with a spectrum of renal involvement ranging from normal renal function with minimal albuminuria to end-stage renal disease (ESRD) indistinguishable from that seen in primary renal parenchymal disease. In patients initially exhibiting preserved renal function, in the absence of adequate blood pressure control, it is common to observe subacute deterioration of renal function to ESRD over a period of weeks to months. Transient deterioration of renal function with initial control of blood pressure is a well-documented entity in patients initially exhibiting mild to moderate renal impairment. Occasionally, patients with malignant hypertension initially exhibit oliguric acute renal failure, necessitating initiation of dialysis within a few days of hospitalization. Because erythrocyte casts sometimes appear in the urine sediment, malignant nephrosclerosis initially may be misdiagnosed as a rapidly progressive glomerulonephritis or systemic vasculitis [18]. Careful examination of the fundus for evidence of hypertensive neuroretinopathy confirms the diagnosis of malignant hypertension. Patients with malignant hypertension can also present with established renal failure. Often, it is impossible to determine clinically whether a patient initially exhibiting hypertensive neuroretinopathy and renal failure has primary malignant hypertension or secondary malignant hypertension with underlying primary renal parenchymal disease. The presence of normal-sized kidneys on ultrasonography supports a diagnosis of primary malignant nephrosclerosis that potentially is reversible with long-term blood pressure control. However, a renal biopsy may be required for definitive diagnosis. All patients with malignant hypertension should receive aggressive antihypertensive therapy to prevent further renal damage, regardless of the degree of renal impairment. Control of blood pressure in patients with malignant hypertension and renal insufficiency often causes further deterioration of renal function, especially when the initial glomerular filtration rate (GFR) is less than 20 mL/min. However, a fall in GFR is not a contraindication to intensive blood pressure control aimed at normalization of blood pressure. Control of hypertension protects other vital organs, such as the heart and brain, whose function cannot be replaced. Moreover, with rigid blood pressure control, renal function may eventually recover over the ensuing months, even in patients with apparent ESRD owing to primary malignant nephrosclerosis [19,20].
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8.11
FIGURE 8-18 (see Color Plate) Micrograph of hyaline arteriolar nephrosclerosis in benign hypertension. It is important to draw a clear distinction between malignant hypertension and benign hypertension with regard to renal histology and clinical renal involvement. In benign arteriolar nephrosclerosis caused by benign hypertension, the characteristic histologic lesion is hyaline arteriosclerosis. In hyaline arteriosclerosis there is expansion of the intima of afferent arterioles with hyaline material that stains a pale-pink color on periodic acidSchiff staining (large arrow). Patchy (focal) ischemic atrophy of the glomeruli usually is seen. Many glomeruli appear normal, whereas some are completely hyalinized. Atrophic tubules (small arrows), sometimes filled with amorphous material, may be seen in the vicinity of ischemic glomeruli. The severity of the glomerular and tubular changes generally reflect the extent of vascular involvement with hyaline arteriosclerosis. On gross examination, the kidneys are small with a granular-appearing capsular surface (contracted granular kidney). The loss of renal mass primarily is due to a thinning of the cortex. In untreated malignant hypertension, relentless progression to end-stage renal disease (ESRD) occurs within a year. In contrast, in benign hypertension, without underlying renal disease or superimposed malignant hypertension, despite well-established folklore to the contrary, ESRD seldom develops [21,22]. In benign hypertension, there is a usually a long asymptomatic phase, with eventual complications resulting from cerebrovascular disease, atherosclerotic disease, or congestive heart failure, in the absence of significant renal impairment despite histologic evidence of benign nephrosclerosis. In this regard, patients classified as having ESRD owing to hypertensive nephrosclerosis typically exhibit advanced disease initially, making the original process that initiated the renal disease difficult to detect. Moreover, significant racial bias may occur in the clinical diagnosis of the cause of ESRD [23]. Nephrologists presented with identical case histories of hypothetical patients with ESRD and hypertension in which the race is arbitrarily stated to be Black or White, tend to diagnose hypertensive nephrosclerosis in Blacks and chronic glomerulonephritis in Whites. It has been proposed that many of the patients presumed clinically to have ESRD owing to benign hypertension, actually have occult intrinsic renal disease with chronic glomerulonephritis, unrecognized bilateral atherosclerotic renal artery stenosis with ischemic nephropathy, atheroembolic renal disease, or episodes of malignant hypertension that had gone undetected [21,22]. (Periodic acidSchiff stain, original magnification 100.)
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FIGURE 8-19 Malignant hypertension must be treated expeditiously to prevent complications such as hypertensive encephalopathy, acute hypertensive heart failure, and renal failure. The traditional approach to patients with malignant hypertension has been the initiation of potent parenteral agents. Listed are the settings in which parenteral antihypertensive therapy is mandatory in the initial management of malignant hypertension. Parenteral therapy generally should be used in patients with evidence of acute end-organ dysfunction or those unable to tolerate oral medications. Nitroprusside is the treatment of choice for patients requiring parenteral therapy. Diazoxide, employed in minibolus fashion to avoid sustained overshoot hypotension, may be advantageous in patients for whom monitoring in an intensive care unit is not feasible. It generally is safe to reduce the mean arterial pressure by 20% or to a level of 160 to 170 mm Hg systolic over 100 to 110 mm Hg diastolic. The use of a short-acting agent such as nitroprusside has obvious advantages because blood pressure can be stabilized quickly at a higher level if complications develop during rapid blood pressure reduction. When no evidence of vital organ hypoperfusion is seen during this initial reduction, the diastolic blood pressure can be lowered gradually to 90 mm Hg over a period of 12 to 36 hours. Oral antihypertensive agents should be initiated as soon as possible to minimize the duration of parenteral therapy. The nitroprusside infusion can be weaned as the oral agents become effective. The cornerstone of initial oral therapy should be arteriolar vasodilators such as calcium channel blockers, hydralazine, or minoxidil. Usually, -blockers are required to control reflex tachycardia, and a diuretic must be initiated within a few days to prevent salt and water retention, in response to vasodilator therapy, when the patients dietary salt intake increases. Diuretics may not be necessary as a part of initial parenteral therapy because patients with malignant hypertension often present with volume depletion (Fig. 8-20). Many patients with malignant hypertension definitely require initial parenteral therapy. However, some patients may not yet have evidence of cerebral or cardiac dysfunction or rapidly deteriorating renal function and therefore do not require instantaneous control of blood pressure. These patients often can be managed with an intensive oral regimen, often with a -blocker and minoxidil, designed to bring the blood pressure under control within 12 to 24 hours. After the immediate crisis has resolved and the patients blood pressure has been controlled with initial parenteral therapy, oral therapy, or both, lifelong surveillance of blood pressure is mandatory. If blood pressure control lapses, malignant hypertension can recur even after years of successful antihypertensive therapy. Triple therapy with a diuretic, -blocker, and a vasodilator often is required to maintain satisfactory long-term blood pressure control.
INDICATIONS FOR PARENTERAL THERAPY IN MALIGNANT HYPERTENSION

Hypertensive encephalopathy Rapidly failing vision Pulmonary edema Intracerebral hemorrhage Rapid deterioration of renal function Acute pancreatitis Gastrointestinal hemorrhage or acute abdomen from mesenteric vasculitis Patients unable to tolerate oral therapy because of intractable vomiting
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8.13
Role of diuretics to treat malignant hypertension
Malignant hypertension
Abrupt increase in blood pressure Pressure-induced natriuresis and diuresis Vicious circle
Intravascular volume depletion
Activation of the renin-angiotensin axis
Angiotensin IImediated vasoconstriction
FIGURE 8-20 Role of diuretics in the treatment of malignant hypertension. Traditionally, it had been taught that patients with malignant hypertension require potent parenteral diuretics in conjunction with potent vasodilator therapy during the initial phase of management of malignant hypertension. However, evidence now exists to suggest that parenteral diuretic therapy during the acute management phase actually may be deleterious. In experimental animals, spontaneous natriuresis appears to be the initiating event in the transition from benign to malignant hypertension, and treatment with volume expansion leads to resolution of the malignant phase [24]. Rapid weight loss often occurs in patients with malignant hypertension, which is consistent with a pressure-induced natriuresis. In analgesic nephropathy, profound volume depletion often accompanies malignant hypertension, perhaps owing to tubular dysfunction with salt-wasting [5]. In this setting, restoration of normal volume status actually lowers blood pressure and leads to resolution of the malignant phase. Thus, some patients with malignant hypertension may benefit from a cautious trial of volume expansion. Volume depletion should be suspected when there is exquisite sensitivity to vasodilator therapy with a precipitous decrease in blood pressure at relatively low infusion rates. Even patients with malignant hypertension complicated by pulmonary edema may not be total-body salt and water overloaded. Pulmonary congestion in this setting may result from acute hypertensive heart failure caused by an acute decrease in left ventricular (LV) compliance precipitated by severe hypertension. In this setting, pulmonary edema occurs owing to a high LV end-diastolic pressure with normal LV end-diastolic volume (Fig. 8-24). Thus, the need for diuretic therapy during the initial phases of management of malignant hypertension depends on a careful assessment of volume status. Unless obvious fluid overload is present, diuretics should not be given initially. Overdiuresis may result in deterioration of renal function owing to superimposed volume depletion. Moreover, volume depletion may further activate the renin-angiotensin system and other pressor hormone systems. Although vasodilator therapy will eventually result in salt and water retention by the kidneys, an increase in total body sodium content cannot occur unless the patient is given sodium. Eventually, during long-term treatment with oral vasodilators, the use of diuretics becomes imperative to prevent fluid retention and adequately control blood pressure.
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FIGURE 8-21 Pathogenesis and treatment of hypertensive encephalopathy. Hypertensive encephalopathy is a hypertensive crisis in which acute cerebral dysfunction is attributed to sudden or severe elevation of blood pressure [2527]. Hypertensive encephalopathy is one of the most serious complications of malignant hypertension. However, malignant hypertension (hypertensive neuroretinopathy) need not be present for hypertensive encephalopathy to develop. Hypertensive encephalopathy also can occur in the setting of severe or sudden hypertension of any cause, especially if an acute elevation of blood pressure occurs in a previously normotensive person, eg, from postinfectious glomerulonephritis, catecholamine excess states, or eclampsia. Under normal circumstances, autoregulation of the cerebral microcirculation occurs, and therefore, cerebral blood flow remains constant over a wide range of perfusion pressures. However, in the setting of sudden severe hypertension, autoregulatory vasoconstriction fails and there is forced vasodilation of cerebral arterioles with endothelial damage, extravasation of plasma proteins, and cerebral hyperperfusion with the development of cerebral edema. This breakthrough of cerebral autoregulation underlies the development of hypertensive encephalopathy. In patients with chronic hypertension, structural changes occur in the cerebral arterioles that lead to a shift in the autoregulation curve such that much higher blood pressures can be tolerated without breakthrough. This phenomenon may explain the clinical observation that hypertensive encephalopathy occurs at much lower blood pressure in previously normotensive persons than it does in those with chronic hypertension. Clinical features of hypertensive encephalopathy include severe headache, blurred vision or occipital blindness, nausea, vomiting, and altered mental status. Focal neurologic findings can sometimes occur. If aggressive blood pressure reduction is not initiated, stupor, convulsions, and death can occur within hours. The sine qua non of hypertensive encephalopathy is the prompt and dramatic clinical improvement in response to antihypertensive drug therapy. When a diagnosis of hypertensive encephalopathy seems likely, antihypertensive therapy should be initiated promptly without waiting for the results of time-consuming radiographic examinations. The goal of therapy, especially in previously normotensive patients, should be reduction of blood pressure to normal or near-normal levels as quickly as possible. Theoretically, cerebral blood flow could be jeopardized by rapid reduction of blood pressure in patients with chronic hypertension in whom the lower limit of cerebral blood flow autoregulation is shifted to a higher blood pressure. However, clinical experience has shown that prompt blood pressure reduction with the avoidance of frank hypotension is beneficial in patients with hypertensive encephalopathy [25]. Of the conditions in the differential diagnosis of hypertension with acute cerebral dysfunction, only cerebral infarction might be adversely affected by the abrupt reduction of blood pressure. Pharmacologic agents that have rapid onset and short duration of action such as sodium nitroprusside should be used so that the blood pressure can be titrated carefully, with close monitoring of the patients neurologic status. A prompt improvement in mental status with blood pressure reduction confirms the diagnosis of hypertensive encephalopathy. Conversely, when blood pressure reduction is associated with new or progressive focal neurologic deficits, the presence of a primary central nervous system event, such as cerebral infarction, should be considered.
Pathogenesis and treatment of hypertensive encephalopathy Malignant hypertension (hypertensive neuroretinopathy present) Sudden or severe nonmalignant hypertension (hypertensive neuroretinopathy absent)
Sudden onset or severe hypertension
Failure of autoregulation of cerebral blood flow (breakthrough of autoregulation)
Forced vasodilation of cerebral arterioles
Endothelial damage (increased permeability to plasma proteins)
Cerebral hyperperfusion (increased capillary hydrostatic pressure)
Cerebral edema
Hypertensive encephalopathy (headache, vomiting, altered mental status, seizures)
Prompt blood pressure reduction with nitroprusside
New or progressive focal findings (suspect primary central nervous system process)
Dramatic clincal improvement (diagnostic of hypertensive encephalopathy)
Hypertensive Crises
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CAUSES OF HYPERTENSIVE ENCEPHALOPATHY

Malignant hypertension of any cause Acute glomerulonephritis, especially postinfectious Eclampsia Catecholamine-induced hypertensive crises Pheochromocytoma Monoamine oxidase inhibitortyramine interactions Abrupt withdrawal of centrally acting 2-agonists Phenylpropanolamine overdose Cocaine-hydrochloride or alkaloid (crack cocaine) intoxication Phencyclidine (PCP) poisoning Acute lead poisoning in children High-dose cyclosporine for bone marrow transplantation in children Femoral lengthening procedures Scorpion envenomation in children Acute renal artery occlusion from thrombosis or embolism Atheroembolic renal disease (cholesterol embolization) Recombinant erythropoietin therapy Transplantation renal artery stenosis Acute renal allograft rejection Paroxysmal hypertension in acute or chronic spinal cord injuries Postcoronary artery bypass or postcarotid endarterectomy hypertension
FIGURE 8-22 Hypertensive encephalopathy can complicate malignant hypertension of any cause. However, not all patients with hypertensive encephalopathy have hypertensive neuroretinopathy, indicating the presence of malignant hypertension. In fact, hypertensive encephalopathy most commonly occurs in previously normotensive persons who experience a sudden onset or worsening of hypertension. In acute postinfectious glomerulonephritis, the abrupt onset of even moderate hypertension may cause breakthrough of autoregulation of cerebral blood flow, resulting in hypertensive encephalopathy. Eclampsia can be viewed as a variant of hypertensive encephalopathy that complicates preeclampsia. Moreover, hypertensive encephalopathy is a common complication of catecholamine-induced hypertensive crises such as pheochromocytoma, monoamine oxidase inhibitortyramine interactions, clonidine withdrawal, phencyclidine (PCP) poisoning, and phenylpropanolamine overdose. Cocaine use also can induce a sudden increase in blood pressure accompanied by hypertensive encephalopathy. In children, acute lead poisoning, high-dose cyclosporine for bone marrow transplantation, femoral lengthening procedures, and scorpion envenomation may be accompanied by the sudden onset of hypertension with hypertensive encephalopathy. Acute renal artery occlusion resulting from thrombosis or renal embolism can induce hypertensive encephalopathy. Likewise, atheroembolic renal disease (cholesterol embolization) can cause a sudden increase in blood pressure complicated by encephalopathy. Recombinant erythropoietin therapy occasionally results in encephalopathy and seizures. This complication is unrelated to the extent or rate of increase in hematocrit; however, it is associated with a rapid increase in blood pressure, especially if the patient was normotensive previously. Transplantation renal artery stenosis or acute renal allograft rejection may cause sudden severe hypertension with encephalopathy. Hypertensive encephalopathy may complicate acute or chronic spinal cord injury. Sudden elevation of blood pressure occurs owing to autonomic stimulation by bowel or bladder distention or noxious stimulation in a dermatome below the level of the injury. Hypertensive encephalopathy also may complicate the rebound hypertension that follows coronary artery bypass procedures or carotid endarterectomy.
8.16

Cardiac index, L/min/m2 5.0 Mean arterial pressure, mm Hg 200 150 100 50 0 0 Cardiac output, L/min NS LVEDP, mm Hg 60 45 200 NS LVEDV, mL/m2 P<0.005 P<0.005 40 LVEDP, mm Hg 9
NP B NP B NP
MAP, mm Hg 200
Heart rate, beats/min 120 90
AHHF NF
100 AHHF 0 NS Stroke work index, g m/m2 150 NF
60 30 0
2.5
30 20 10 0
NP B NP
6 3 0
75
30 15
100
NP
0 0 NS P<0.005 NS A Baseline hemodynamics in acute hypertensive heart failure (AHHF) vs no failure (NF)
P<0.005
NS
P<0.005
P<0.025
Hemodynamic parameters at baseline (B) and during nitroprusside (NP) infusion
60 50
AHHF: baseline AHHF: with nitroprusside No failure: baseline No failure: with nitroprusside
LVFP, mm Hg
40
30 20
10 0 40 80 120 160 LVEDV, mL/m2 200 240
Left ventricular compliance at baseline and with nitroprusside
FIGURE 8-23 Pathogenesis of acute hypertensive heart failure. Both malignant hypertension and severe benign hypertension can be complicated by acute pulmonary edema caused by isolated diastolic dysfunction. In acute hypertensive heart failure the compromise of left ventricular (LV) diastolic function occurs as a result of a decrease in LV compliance caused by an increased workload imposed on the heart by the marked elevation in systemic vascular resistance. Illustrated are the hemodynamic derangements in acute hypertensive heart failure in a study that compared five patients with severe essential hypertension complicated by acute pulmonary edema with a control group of five patients with equally severe hypertension but no pulmonary edema [28]. Patients
in both groups had electrocardiographic evidence of LV hypertrophy caused by long-standing hypertension. A, Baseline hemodynamic measurements before treatment revealed that the following measurements were the same in both groups: mean arterial pressure (MAP), heart rate, cardiac index, systemic vascular resistance, and stroke work index. Likewise, the LV end-diastolic volume (LVEDV) was similar in both groups. In fact, the only hemodynamic difference between the groups was a significant elevation of LV filling pressure (LVFP) (pulmonary capillary wedge pressure) in the group with pulmonary edema. In acute hypertensive heart failure the finding of elevated LV end-diastolic pressures (LVEDPs), despite normal ejection fraction and cardiac index, implies the presence of isolated diastolic dysfunction. The increased LV end-diastolic pressure (LVEDP), despite similar LVEDV, can only be explained by a decrease in LV compliance in patients with acute hypertensive heart failure. B, The importance of an acute decrease in LV compliance in the pathogenesis of acute hypertensive heart failure (AHHF) was confirmed in these patients by the hemodynamic response to vasodilator therapy. Sodium nitroprusside infusion resulted in prompt resolution of pulmonary edema in the group having AHHF, with the LVEDP decreasing from a mean of 43 to 18 mm Hg. C, The decrease in filling pressure during nitroprusside therapy in patients with AHHF was not caused by venodilation with decreased venous return because the LVEDV actually increased during nitroprusside infusion. Thus, the response to sodium nitroprusside therapy was mediated through a decrease in systemic vascular resistance that led to an immediate improvement in LV compliance and reduction in wedge pressure despite an increase in LVEDV. These findings suggest that the proximate cause of AHHF is an elevation of the systemic vascular resistance that precipitates acute diastolic dysfunction (decreased LV compliance) with elevated pulmonary capillary wedge pressure, resulting in pulmonary edema. NS not significant. (Adapted from Cohn and coworkers [28]; with permission.)
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60 Left ventricular end-diastolic pressure, mm Hg 50 40

Nitroprusside
30
HF
20 10 0 40 80
No
rm
al
120
160
200
240
Left ventricular end-diastolic volume, mL/m2
FIGURE 8-24 Treatment of acute hypertensive heart failure. The left ventricular (LV) end-diastolic pressure-volume relationships (compliance curves) in acute hypertensive heart failure (AHHF) before and after treatment with sodium nitroprusside are represented schematically. In AHHF, the pressure-volume curve is shifted up and to the left, reflecting an acute decrease in LV compliance caused by severe systemic hypertension. In this setting, a higher than normal LV end-diastolic pressure (LVEDP) is required to achieve any given level of LV end-diastolic volume (LVEDV). Normal LV systolic function (ejection fraction and cardiac output) is maintained but at the expense of a very high wedge pressure that results in acute pulmonary edema. Treatment with sodium nitroprusside causes a reduction in the elevated systemic vascular resistance, with a concomitant decrease in impedance to LV ejection. As a result, LV compliance improves. Pulmonary edema resolves owing to a reduction in LVEDP, despite the fact that LVEDV actually increases during treatment. Sodium nitroprusside is the preferred drug for treatment of AHHF. There is no absolute blood pressure goal. The infusion should be titrated until signs and symptoms of pulmonary edema resolve or the blood pressure decreases to hypotensive levels. Rarely is it necessary to lower the blood pressure to this extent, however, because reduction to levels still within the hypertensive range is usually associated with dramatic clinical improvement. Although hemodynamic monitoring is not always required, it is essential in patients in whom concomitant myocardial ischemia or compromised cardiac output is suspected. After the hypertensive crisis has been controlled and pulmonary edema has resolved, oral antihypertensive therapy can be substituted as the patient is weaned from the nitroprusside infusion. As in the treatment of hypertensive patients with chronic congestive heart failure symptoms owing to isolated diastolic dysfunction, agents such as blockers, angiotension-converting enzyme inhibitors, or calcium channel blockers may represent logical first-line therapy. These agents directly improve diastolic function in addition to reducing systemic blood pressure. In patients with malignant hypertension or resistant hypertension, however, adequate control of blood pressure may require therapy with more than one drug. Potent directacting vasodilators such as hydralazine or minoxidil may be used in conjunction with a -blocker to control reflex tachycardia and a diuretic to prevent reflex salt and water retention.
AH
8.18

FIGURE 8-25 Aortic dissection. Classification of aortic dissection is based on the presence or absence of involvement of the ascending aorta [29]. The dissection is defined as proximal if there is involvement of the ascending aorta. The primary intimal tear in proximal dissection may arise in the ascending aorta, transverse aortic arch, or descending aorta. In distal dissections, the process is confined to the descending aorta without involvement of the ascending aorta, and the primary intimal tear occurs most commonly just distal to the origin of the left subclavian artery. Proximal dissections account for approximately 57% and distal dissections 43% of all acute aortic dissections. Acute aortic dissection is a hypertensive crisis requiring immediate antihypertensive treatment aimed at halting the progression of the dissecting hematoma. The three most frequent complications of aortic dissection are acute aortic insufficiency, occlusion of major arterial branches, and rupture of the aorta with fatal hemorrhage (location of rupture-hemorrhage: ascending aortahemopericardium with tamponade, aortic archmediastinum, descending thoracic aortaleft pleural space, abdominal aorta retroperitoneum). Patients with acute dissection should be stabilized with intensive antihypertensive therapy to prevent life-threatening complications before diagnostic evaluation with angiography. The initial therapeutic goal is the elimination of pain that correlates with halting of the dissection, and reduction of the systolic pressure to the 100 to 120 mm Hg range or to the lowest level of blood pressure compatible with the maintenance of adequate renal, cardiac, and cerebral perfusion [30]. Even in the absence of systemic hypertension the blood pressure should be reduced. Antihypertensive therapy should be designed not only to lower the blood pressure but also to decrease the steepness of the pulse wave. The most commonly used treatment regimens consist of initial treatment with intravenous -blockers such as propranolol, metoprolol, or esmolol followed by treatment with sodium nitroprusside. After control of the blood pressure, angiography or transesophageal echocardiography, or both, should be performed. The need for surgical intervention is determined based on involvement of the ascending aorta. In proximal dissections, surgical therapy is clearly superior to medical therapy alone (70% vs 26% survival, respectively). In contrast, in patients with distal dissection, intensive drug therapy alone leads to an 80% survival rate compared with only 50% in patients treated surgically. The explanation for the advantage of surgical therapy in proximal dissection is probably that the risks of complications such as cerebral ischemia, acute aortic insufficiency, and cardiac tamponade are higher and managed more effectively with surgery. Because these complications do not occur in distal dissection, in the absence of occlusion of a major arterial branch or development of a saccular aneurysm during long-term follow-up, medical therapy is preferred. Patients with distal dissection tend to be elderly with more advanced aortic atherosclerosis and therefore are at higher risk of complications from operative intervention. (Adapted from Wheat [29]; with permission.)
Aortic dissection Transverse aortic arch Ascending aorta Descending aorta
Proximal (Type A)
Distal (Type B)
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Poorly controlled hypertension in surgical patients Postpone elective surgery until blood pressure adequately controlled for 23 weeks Inadequate preoperative blood pressure control (diastolic blood pressure >110 mm Hg or mild to moderate hypertension in patients with history of cerebrovascular accident, myocardial ischemia, heart failure, or renal insufficiency General anesthesia Decreased cardiac output (30%) Decreased systemic vascular resistance (27%) Hypotension (45% Decrease in mean arterial pressure) Increased risks of Cerebral ischemia Myocardial ischemia Acute renal failure Increased perioperative morbidity and mortality
Administer blood pressure and antianginal medications the morning of surgery
Manage intraoperative hypertension with sodium nitroprusside
Manage postoperative hypertension with nitroprusside in patients with complications or labetalol in patients without complications
Carefully institute oral antihypertensives at low-dose and titrate based on orthostatic blood pressure measurements
FIGURE 8-26 Poorly controlled hypertension in the patient requiring surgery. Hypertension in the preoperative patient is a common problem. Poor control of preoperative hypertension, with a diastolic blood pressure higher than 110 mm Hg, is a relative contraindication to elective surgery. In such patients, perioperative morbidity and mortality are increased because of a higher incidence of intraoperative hypotension accompanied by myocardial ischemia and a heightened risk of acute renal failure [31]. Malignant hypertension clearly represents an excessive surgical risk and all but lifesaving emergency surgery should be deferred until the blood pressure can be controlled and organ function stabilized. Mild to moderate uncomplicated hypertension with diastolic blood pressure less than 110 mm Hg does not appear to increase the risk of surgery significantly and therefore is not an absolute indication to postpone elective surgery. However, patients with mild to moderate hypertension and preexisting complications such as ischemic heart disease, cerebrovascular disease, congestive heart failure, or chronic renal insufficiency, represent a subgroup with significantly increased perioperative risk. In these patients, adequate preoperative control of blood pressure
is imperative [32]. Even though the blood pressure in patients with severe or complicated hypertension usually can be controlled within hours using aggressive parenteral therapy, such precipitous control of blood pressure carries the risk of significant complications such as hypovolemia, electrolyte abnormalities, and marked intraoperative blood pressure lability. General anesthesia is accompanied by a 30% decrease in cardiac output. In normotensive persons and patients with adequately treated hypertension, anesthesia is not associated with a decrease in systemic vascular resistance. Therefore, the decrease in mean arterial pressure (MAP) is modest (2530%). However, in patients with inadequate preoperative blood pressure control, anesthesia is associated with a concomitant decrease in systemic vascular resistance (SVR) of approximately 27%. The combined decrease in cardiac output and SVR leads to a profound decrease in MAP (45%) during anesthesia [33]. This intraoperative hypotension predisposes to myocardial ischemia, cerebrovascular accidents, and acute renal failure. Therefore, in patients with diastolic blood pressure over 110 mm Hg or these other high-risk groups, elective surgery should be postponed and blood pressure brought under control for a few weeks before surgery, if possible. Ideally, sustained adequate preoperative blood pressure control should be the goal in all hypertensive patients [34]. In patients with adequately treated hypertension, oral antihypertensive, and antianginal medications should be continued up to and including the morning of surgery, administered with small sips of water. Because hypovolemia increases the risk of intraoperative hypotension and postoperative acute renal failure, diuretics should be withheld for 1 to 2 days preoperatively except in patients with overt heart failure or fluid overload. Adequate potassium repletion should be given to correct hypokalemia well in advance of surgery. Continuation of -blockers to within a few hours of surgery does not impair cardiac function and has been shown to decrease the risks of dysrhythmia and myocardial ischemia during surgery. In patients with complications and a history of cardiovascular disease or heart failure, or after coronary artery bypass surgery, postoperative hypertension should be managed with short-acting agents such as nitroglycerin or nitroprusside. In patients without complications, intermittent intravenous infusions of labetalol may be useful for management of mild to moderate postoperative hypertension until the preoperative oral antihypertensive agents can be resumed. Many patients with long-standing hypertension, even if severe, require much smaller doses of antihypertensive medications in the early postoperative course. Thus, the preoperative regimen should not be restarted automatically. Measurement of orthostatic blood pressures should be used as a guide to dosage adjustment during the postoperative recovery period. In most instances, the need for antihypertensive medications will gradually increase over a few days to weeks to eventually equal the preoperative requirement.
8.20

may develop precipitous hypotension with even low-dose infusions of nitroglycerin or nitroprusside. Hypertension in this setting should be treated using careful volume expansion with crystalloid solutions or blood if required. Postcoronary artery bypass hypertension represents a hypertensive crisis because the heightened SVR increases the impedance to left ventricular (LV) ejection (afterload) that can result in an acute decrease in ventricular compliance with elevation of LV end-diastolic pressure (LVEDP) and acute hypertensive heart failure with pulmonary edema (Figs. 8-23 and 8-24). The increase in LVEDP also impairs subendocardial perfusion and can cause myocardial ischemia. Moreover, the elevated blood pressure increases the risk of mediastinal bleeding in these recently heparinized patients. The initial management of postbypass hypertension should focus on attempts to ameliorate reversible causes of sympathetic activation, including patient agitation on emergence from anesthesia, tracheal or nasopharyngeal irritation from the endotracheal tube, pain, hypothermia with shivering, ventilator asynchrony, hypoxia, hypercarbia, and volume depletion. If these general measures fail to control the blood pressure, further therapy should be guided by measurement of systemic hemodynamics. Intravenous nitroglycerin or nitroprusside is the drug of choice to provide a controlled decrease in SVR and blood pressure. Nitroglycerin may be the preferred drug because it dilates intracoronary collateral arteries [35,36]. Therapy with -blockers is not indicated in this setting and may be detrimental because these drugs impair cardiac output and cause a further increase in SVR. Labetalol also has been shown to cause a significant reduction in cardiac output in postbypass hypertension. Postbypass hypertension is usually transient and resolves by 6 to 12 hours postoperatively, so that the vasodilatory therapy can be weaned. The hypertension usually does not recur after the initial episode in the immediate postoperative period.
Hypertensive crises after bypass surgery
Coronary artery bypass graft surgery Paradoxical hypertensive response to intravascular volume depletion Increased sympathetic tone owing to activation or pressor reflexes from heart, coronary arteries, or great vessels
Increased systemic vascular resistance Treat with nitroprusside or intravenous nitroglycerin
Systemic hypertension
Increased risk of postoperative mediastinal bleeding
Increased impedance to left ventricular ejection
Hypertensive encephalopathy (Fig. 8-21)
Acute diastolic dysfunction (decreased left ventricular compliance)
Increased left ventricular end-diastolic pressure
Impaired subendocardial perfusion causing myocardial ischemia
Acute hypertensive heart failure with pulmonary edema (Figs. 8-23 and 8-24)
FIGURE 8-27 Hypertensive crisis after coronary artery bypass surgery. Paroxysmal hypertension in the immediate postoperative period is a frequent and serious complication of cardiac surgery [35,36]. Paroxysmal hypertension is the most frequent complication of coronary artery bypass surgery, occurring in 30% to 50% of patients. It occurs just as often in normotensive patients as it does in those with a history of chronic hypertension. The increase in blood pressure usually occurs during the first 4 hours after surgery. The hypertension results from a dramatic increase in systemic vascular resistance (SVR) without a change in the cardiac output and is most commonly mediated by an increase in sympathetic tone owing to activation of pressor reflexes from the heart, great vessels, or coronary arteries. Hypervolemia, although often cited as a potential mechanism of postoperative hypertension, is a rare cause of postbypass hypertension except in patients with renal failure. In fact, increased SVR owing to marked sympathetic overreaction to volume depletion is a common, often unrecognized, cause of severe postoperative hypertension [37]. Patients with this paradoxical hypertensive response to hypovolemia are exquisitely sensitive to vasodilator therapy and
Hypertensive Crises
8.21
Hypertensive crises after carotid endarterectomy Carotid endarterectomy
Postoperative hypertension (mechanism unknown)
Repair of high-grade stenosis
Sudden increase in perfusion pressure in arteriocapillary bed that was previously protected from hypertension
Failure of autoregulation of cerebral blood flow (breakthrough of autoregulation)
Overperfusion of cerebral circulation Vessel rupture (hemorrhage and infarction)
FIGURE 8-28 Hypertensive crisis after carotid endarterectomy. Hypertension in the immediate postoperative period occurs in up to 60% of patients after carotid endarterectomy [38]. A history of chronic hypertension, especially if the blood pressure is poorly controlled preoperatively, dramatically increases the risk of postoperative hypertension. The mechanism of post-endarterectomy hypertension is unknown. The incidence of hypertension is the same whether or not the carotid sinus nerve is preserved. Hypertension after endarterectomy is a hypertensive crisis because it is associated with increased risk of intracerebral hemorrhage and increases the postoperative mortality rate [39]. A mechanism for the development of postcarotid endarterectomy cerebral hemorrhage owing to postoperative hypertension has been proposed. In patients with high-grade carotid artery stenosis, the distal cerebral circulation has been relatively protected from systemic hypertension. In this regard, the autoregulatory curve may be shifted to a lower threshold to compensate for reduced perfusion pressure. After repair of the obstructing lesion, a relative increase in perfusion pressure occurs in the cerebral arteriocapillary bed. In the setting of systemic hypertension the increased blood flow and perfusion pressure may overwhelm the autoregulatory mechanisms. Overperfusion and rupture may then occur, resulting in hemorrhagic infarction. Because poor preoperative blood pressure control increases the risk of postoperative hypertension, strict blood pressure control is essential before elective carotid endarterectomy. Furthermore, intra-arterial pressure should be monitored in the operating room and in the immediate postoperative period. Ideally, the patient should be awake and extubated before reaching the recovery room so that serial neurologic examinations can be performed to assess for the development of focal deficits. When the systolic blood pressure exceeds 200 mm Hg, an intravenous infusion of sodium nitroprusside should be initiated to maintain the systolic blood pressure between 160 and 200 mm Hg. The use of a short-acting parenteral agent is imperative to avoid overshoot hypotension and cerebral hypoperfusion.
8.22

infarction, hypertension tends to be very labile and exquisitely sensitive to hypotensive therapy. Thus, even modest doses of oral antihypertensive agents can lead to profound and devastating overshoot hypotension with extension of the infarct [42]. An additional rationale for not treating hypertension in the acute setting is based on evidence that local autoregulation of cerebral blood flow is impaired in the so-called ischemic penumbra, which surrounds the area of acute infarction [43]. Without intact autoregulation, the regional blood flow in this marginal zone of ischemia becomes critically dependent on the perfusion pressure. Thus, the presence of mild to moderate systemic hypertension may actually be protective, and acute reduction of blood pressure may cause a regional reduction in blood flow with extension of the infarct. Thus, in most cases of cerebral infarction it is prudent to allow the blood pressure to seek its own level during the first few days to weeks after the event. In most cases the hypertension tends to resolve spontaneously, without any specific therapy, over the first week as brain function recovers. When hypertension persists for more than 3 weeks after a completed infarction, reduction of the blood pressure into the normal range with oral antihypertensives is appropriate. Although benign neglect of mild to moderate hypertension is prudent in acute cerebral infarction, there may be certain indications for active treatment of blood pressure. When the diastolic blood pressure is sustained at over 130 mm Hg, cautious reduction of blood pressure into the ranges of 160 to 170 mm Hg systolic and 100 to 110 mm Hg diastolic may be appropriate. In stroke patients requiring anticoagulation therapy, moderate control of severe hypertension also should be considered. Cautious blood pressure reduction is indicated when stroke is accompanied by other hypertensive crises such as acute myocardial ischemia or acute hypertensive heart failure. Stroke caused by carotid occlusion by a proximal aortic dissection mandates aggressive blood pressure reduction into the normal range to halt the dissection process. In the setting of sudden severe hypertension, it may be difficult to distinguish hypertensive encephalopathy with focal neurologic findings from cerebral infarction. Because rapid reduction of blood pressure is lifesaving in patients with hypertensive encephalopathy, a cautious diagnostic trial of blood pressure reduction may be warranted (Fig. 821). If blood pressure reduction is deemed necessary in patients with acute cerebral infarction, treatment should be initiated using small doses of a short-acting parenteral agent such as sodium nitroprusside. Use of oral or sublingual nifedipine is associated with excessive risk of prolonged overshoot hypotension. Oral clonidine loading also is contraindicated because of the risk of hypotension and because sedative side effects interfere with the assessment of mental status.
Risks of antihypertensive therapy in acute cerebral infarction Acute cerebral infarction
Reflex increase in systemic blood pressure Even with cautious blood pressure reduction using parenteral agents
Altered blood flow autoregulation in the ischemic penumbra surrounding the infarct
Exaggerated response to oral antihypertensives Spontaneous resolution within first week Failure of autoregulation with worsening ischemia
Extension of infarct
FIGURE 8-29 Risks of antihypertensive therapy in acute cerebral infarction. Cerebral infarction results from partial or complete occlusion of an artery by an atherosclerotic plaque or embolization of atherothrombotic debris from a more proximal plaque. These atherothrombotic infarcts typically involve the cerebral cortex, cerebellar cortex, or pons; these infarcts are to be contrasted with hypertension-induced lipohyalinosis of the small penetrating cerebral end-arteries that is the principal cause of the small lacunar infarcts occurring in the basal ganglia, pons, thalamus, cerebellum, and deep hemispheric white matter. Hypertension occurs in up to 85% of patients with acute cerebral infarction, even in previously normotensive persons [40]. This early elevation of blood pressure probably represents a physiologic response to brain ischemia. Because of the known benefits of antihypertensive therapy with regard to stroke prevention, it previously had been assumed that acute reduction of blood pressure would also be of benefit in acute cerebral infarction. However, no evidence exists to suggest that acute reduction of blood pressure is beneficial in this setting. In fact, reports exist of worsening neurologic status, apparently precipitated by emergency treatment of hypertension in patients with cerebral infarction [41]. In the setting of acute cerebral
Hypertensive Crises
8.23
Hypertensive crises from intracerebral hemorrhage
Intracerebral hemorrhage
Reflex increase in blood pressure (Cushing's reflex) Hypertension may help maintain blood flow in ischemic areas Cerebral hyperperfusion with cerebral edema Impairment of autoregulation of blood flow in ischemic area surrounding hematoma (shift of lower limit of autoregulation) Increased risk of rebleeeding (expansion of hematoma)
Sodium nitroprusside Cautious blood pressure reduction by no more than 20% of presenting mean arterial pressure (intra-arterial and intracranial pressure monitoring to ensure adequate cerebral perfusion pressure)
FIGURE 8-30 Hypertensive crises due to intracerebral hemorrhage. Chronic hypertension is the major risk factor for intracerebral hemorrhage. The most common sites of hemorrhage are the small-diameter penetrating cerebral end-arteries in the basal ganglia, pons, thalamus, cerebellum, and deep hemispheric white matter. Lacunar infarcts arise from the same vessels and are similarly distributed. Intracerebral hemorrhage characteristically begins abruptly with headache and vomiting followed by steadily increasing focal neurologic deficits and alteration of consciousness [44]. More than 90% of hemorrhages rupture through brain parenchyma into the ventricles, producing bloody cerebrospinal fluid. Patients presenting with intracerebral hemorrhage are invariably hypertensive. In contrast to cerebral infarction, the hypertension does not tend to decrease spontaneously during the first week. The patients condition worsens steadily over a period of minutes to days until either the neurologic deficit stabilizes or the patient dies. When death occurs, most often it is due to herniation caused by the expanding hematoma and surrounding edema. Treatment of hypertension in the setting of intracerebral hemorrhage is controversial. An increase in intracranial pressure accompanied by a reflex increase in systemic blood pressure almost always occurs. Because cerebral perfusion pressure is a function of the difference between arterial pressure and intracranial pressure, reduction of blood pressure could compromise cerebral perfusion. Moreover, as in cerebral infarction, autoregulation is impaired in the area of marginal ischemia surrounding the hemorrhage. In contrast, cerebral vasogenic edema may be exacerbated by hypertension. Moreover, hypertension may increase the risk of rebleeding with expansion of the hematoma. Thus, in deciding to treat hypertension in the setting of intracerebral hemorrhage, a precarious balance must be struck between beneficial reduction in cerebral edema on the one hand, and deleterious reduction of cerebral blood flow on the other. Studies have shown that the lower limit of autoregulation after intracerebral hemorrhage is approximately 80% of the initial blood pressure; therefore, a 20% decrease in mean arterial pressure should be considered the maximal goal of blood pressure reduction during the acute stage [45]. Antihypertensive therapy should be undertaken only in conjunction with intracranial and intra-arterial pressure monitoring to allow for assessment of cerebral perfusion pressure. The short duration of action of nitroprusside makes its use preferable over other agents with a longer duration of action and the risk of sustained overshoot hypotension, despite the theoretic concern that nitroprusside treatment could lead to an increase in intracranial pressure by way of dilation of cerebral veins and arteries.
8.24
Hypertensive crisis with pheochromocytoma Pheochromocytoma Episodic release of catecholamines Paroxysmal hypertension Acute hypertensive heart failure with pulmonary edema (Figs. 8-23 and 8-24) Acute treatment with nitroprusside or phentolamine followed by -blockers
Pressure-induced natriuresis and diuresis Intravascular volume depletion Increased risk of intraoperative and postoperative hypotension
FIGURE 8-31 Hypertensive crisis with pheochromocytoma. In most patients, pheochromocytoma causes sustained hypertension that sometimes becomes malignant as evidenced by the presence of hypertensive neuroretinopathy. Paroxysmal hypertension is present in approximately 30% of patients. Spontaneous paroxysms consist of severe hypertension, headache, profuse diaphoresis, pallor, coldness of hands and feet, palpitations, and abdominal discomfort. Paroxysmal hypertension in pheochromocytoma represents a hypertensive crisis because it can lead to intracerebral hemorrhage, hypertensive encephalopathy, or acute hypertensive heart failure with pulmonary edema. Prompt control of the blood pressure is mandatory to prevent these life-threatening complications. Although the nonselective -blocker phentolamine often is cited as the treatment of choice for pheochromocytoma-related hypertensive crises, sodium nitroprusside is equally effective and easier to administer [46]. Only after blood pressure has been controlled with nitroprusside or phentolamine can intravenous -blockers, such as esmolol, labetalol, or propranolol, be used to control tachycardia or arrhythmias. After resolution of the hypertensive crisis, oral antihypertensive agents should be instituted as the parenteral agents are weaned. The nonselective -blocker phentolamine usually is administered orally for 1 to 2 weeks before elective surgery. After adequate -blockade is achieved, based on the presence of moderate orthostatic hypotension, oral -blocker therapy can be initiated as needed to control tachycardia. Oral or intravenous -blockers should never be administered before adequate -blockade. Doing so can precipitate a hypertensive crisis as the result of intense -adrenergic vasoconstriction that is no longer opposed by -adrenergic vasodilatory stimuli. Careful attention to volume status also is mandatory in the preoperative period. Catecholamine-induced hypertension induces a pressure natriuresis with volume depletion. Moreover, alleviation of the chronic state of vasoconstriction by -blockade results in increases in both arterial and venous capacitances. Preoperative volume expansion, guided by measurement of central venous pressure or wedge pressure often is advocated to reduce the risk of intraoperative hypotension [47]. During surgery, rapid and wide fluctuations in blood pressure should be anticipated. Careful intraoperative monitoring of intra-arterial pressure, cardiac output, wedge pressure, and systemic vascular resistance is mandatory to manage the rapid swings in blood pressure. Despite adequate preoperative -blockade with phenoxybenzamine, severe hypertension can occur during intubation or intraoperatively as a result of catecholamine release during tumor manipulation. Sodium nitroprusside is the treatment of choice for controlling acute hypertension owing to pheochromocytoma during surgery. At the opposite end of the spectrum, profound intraoperative hypotension can occur. Hypotension or even frank shock can supervene after isolation of tumor venous drainage from the circulation, with resultant abrupt decrease in circulating catecholamine levels. Volume expansion is the treatment of choice for intraoperative and postoperative hypotension [46]. Pressors only should be employed when hypotension is unresponsive to volume repletion.
Hypertensive Crises
8.25
Hypertension crises secondary to monoamine oxidase inhibitortyramine interactions Monoamine oxidase inhibitor therapy
Impaired degradation of intracellular amines (epinephrine, norepinephrine, dopamine) Accumulation of catecholamines in nerve terminal storage granules
Increased circulating tyramine level
Ingestion of tyramine-containing food
Hepatic monamine oxidase inhibition with decreased oxidative metabolism of tyramine
Massive release of catecholamines
Tachyarrhythmias
Vasoconstriction (increased systemic vascular resistance)
Severe paroxysm of hypertension
Acute hypertensive heart failure with pulmonary edema (Figs. 8-24 and 8-25)
FIGURE 8-32 Hypertensive crises secondary to monoamine oxidase inhibitortyramine interactions. Severe paroxysmal hypertension complicated by intracerebral or subarachnoid hemorrhage, hypertensive encephalopathy, or acute hypertensive heart failure can occur in patients treated with monoamine oxidase (MOA) inhibitors after ingestion of certain drugs or tyraminecontaining foods [48,49]. Because MAO is required for degradation of intracellular amines, including epinephrine, norepinephrine, and dopamine, MAO inhibitors lead to accumulation of catecholamines within storage granules in nerve terminals. The amino acid tyramine is a potent inducer of neurotransmitter release from nerve terminals. As a result of inhibition of hepatic MAO, ingested tyramine escapes oxidative degradation in the liver. In addition, the high circulating levels of tyramine provoke massive catecholamine release from nerve terminals, resulting in vasoconstriction and a paroxysm of severe hypertension. A hyperadrenergic syndrome resembling pheochromocytoma then ensues. Symptoms include severe pounding headache, flushing or pallor, profuse diaphoresis, nausea, vomiting, and extreme prostration. The mean increase in blood pressure is 55 mm Hg systolic and 30 mm Hg diastolic [49]. The duration of the attacks varies from 10 minutes to 6 hours. Attacks can be provoked by the ingestion of foods known to be rich in tyramine: natural or aged cheeses, Chianti wines, certain imported beers, pickled herring, chicken liver, yeast, soy sauce, fermented sausage, coffee, avocado, banana, chocolate, and canned figs. Sympathomimetic amines in nonprescription cold remedies also can provoke neurotransmitter release in patients treated with an MAO inhibitor. Either sodium nitroprusside or phentolamine can be used to manage this type of hypertensive crisis. Because most patients are normotensive before onset of the crisis the goal of blood pressure treatment should be normalization of the blood pressure. After blood pressure control, intravenous -blockers may also be required to control heart rate and tachyarrhythmias. Because the MAO inhibitortyramine hypertensive crisis is self-limited, parenteral antihypertensive agents can be weaned without institution of oral antihypertensive agents.
8.26

FIGURE 8-33 Mechanism of action and metabolism of nitroprusside. Sodium nitroprusside is the drug of choice for management of virtually all hypertensive crises, including malignant hypertension, hypertensive encephalopathy, acute hypertensive heart failure, intracerebral hemorrhage, perioperative hypertension, catecholamine-related hypertensive crises, and acute aortic dissection (in combination with a -blocker) [1,50]. Sodium nitroprusside is a potent intravenous hypotensive agent with immediate onset and brief duration of action. The site of action is the vascular smooth muscle. Nitroprusside has no direct action on the myocardium, although it may affect cardiac performance indirectly through alterations in systemic hemodynamics. Nitroprusside is an iron (Fe) coordination complex with five cyanide moieties and a nitroso (NO) group. The nitroso group combines with cysteine to form nitrosocysteine and other short-acting S-nitrosothiols. Nitrosocysteine is a potent activator of guanylate cyclase, thereby causing cyclic guanosine monophosphate (cGMP) accumulation and relaxation of vascular smooth muscle [51,52]. Nitroprusside causes vasodilation of both arteriolar resistance vessels and venous capacitance vessels. Its hypotensive action is a result of a decrease in systemic vascular resistance. The combined decrease in preload and afterload reduces myocardial wall tension and myocardial oxygen demand. The net effect of nitroprusside on cardiac output and heart rate depends on the intrinsic state of the myocardium. In patients with left ventricular (LV) systolic dysfunction and elevated LV end-diastolic pressure, nitroprusside causes an increase in stroke volume and cardiac output as a result of afterload reduction and heart rate may actually decrease in response to improved cardiac performance. In contrast, in the absence of LV dysfunction, venodilation and preload reduction can result in a reflex increase in sympathetic tone and heart rate. For this reason, nitroprusside must be used in conjunction with a -blocker in acute aortic dissection. The hypotensive action of nitroprusside appears within seconds and is immediately reversible when the infusion is stopped. The cGMP in vascular smooth muscle is rapidly degraded by cGMP-specific phosphodiesterases. Nitroprusside is rapidly metabolized with a half-life (t1/2) of 3 to 4 minutes. Cyanide is formed as a short-lived intermediate product by direct combination with sulfhydryl (SH) groups in erythrocytes and tissues. The cyanide groups are rapidly converted to thiocyanate by the liver in a reaction in which thiosulfate acts as a sulfur donor. Thiocyanate is excreted by the kidneys, with a half-life of 1 week in patients with normal renal function. Thiocyanate accumulation and toxicity can occur when a high-dose or prolonged infusion is required, especially in patients with renal insufficiency. When these risk factors are present, thiocyanate levels should be monitored and the infusion stopped if the level is over 10 mg/dL. Thiocyanate toxicity is rare in patients with normal renal function requiring less than 3 g/kg/min for less than 72 hours [50]. Cyanide poisoning is a very rare complication, unless hepatic clearance of cyanide is impaired by severe liver disease or massive doses of nitroprusside (over 10 g/kg/min) are used to induce deliberate hypotension during surgery [50].
Mechanism of action and metabolism of nitroprusside

+
NO CNt1/2=34 min
CNFe++ CNCNNitroprusside Combination of nitroso group with cysteine
CN-
Metabolized by direct combination with -SH groups in erythrocytes and tissues
Free cyanide (CN-)
Thiocyanate t1/2=1 wk Renal excretion
Nitrosocysteine
Activation of guanylate cyclase

t1/2=23min
cGMP accumulation in vascular smooth muscle
Metabolized by cGMP-specific phosphodiesterases
Venodilation (increased venous capacitance)
Dilation of arteriolar resistance vessels (decreased systemic vascular resistance)
Decreased blood pressure
Afterload reduction
VARIOUS ANTIHYPERTENSIVE DRUGS FOR PARENTERAL USE IN THE MANAGEMENT OF MALIGNANT HYPERTENSION AND OTHER HYPERTENSIVE CRISES
Drug Advantages Disadvantages

Instantaneous Immediate
Mechanism of action Onset of action Peak effect Method of Duration of action administration Side effects Comments
Sodium Direct arteriolar nitroprusside vasodilation and venodilation
Diazoxide
Direct arteriolar vasodilation
12 min
1015 min
Trimethaphan camsylate
Minutes Ganglionic blockage with venodilation and arteriolar vasodilation
Minutes
Discontinue if 23 min after infusion Continuous infusion: Precise titration of Monitoring in ICU Nausea, vomiting, required apprehension. stopped Initial, 0.5 g/kg/min BP. Consistently thiocyanate level Thiocyanate toxic- >10 mg/dL Average, 3 g/kg/min effective when ity with prolonged Maximum, 10 g/kg/min other drugs fail. infusion, renal Parenteral agent insufficiency of choice for hypertensive crises Sustained Nausea, vomiting, Contraindicated in 424 h IV minibolus: 50100 mg Long duration of hypotension with hyperglycemia, IV given rapidly over action. Constant aortic dissection, CNS and myocarmyocardial 510 min. Total dose, monitoring not cerebrovascular ischemia, uterine 150600 mg required after ini- dial ischemic can disease, myocardial occur. Reflex sym- atony tial titration ischemia pathetic cardiac stimulation Dry mouth, blurred Tilt-bed enhances 510 min after infuContinuous infusion: Blocks barorecep- Parasympathetic blockade vision, urinary sion stopped Initial, 0.5 mg/min tor-mediated effect; tachyphylaxis retention, paralyt- after 2448 h; Maximum, 5.0 mg/min sympathetic ic ileus, respiratocardiac stimulation contraindicated ry arrest in respiratory
FIGURE 8-34 Sodium nitroprusside remains the treatment of choice in virtually all hypertensive crises requiring rapid blood pressure control with
Minutes 15 min after infusion Continuous infusion: stopped Initially, 5 g/min Increase by 5 g/min over 35 min 1618 h Minutes
insufficiency and glaucoma; potentiates succinylcholine Dilates intracoronary collaterals
Nitroglycerin
Labetalol
Direct venodilation at low doses; combined venodilation and arteriolar dilation at higher doses Selective 1- and noncardioselective -blocker; arteriolar and venous dilation Minutes 550 min
Fails to control BP Headache, nausea, Theoretic advanin some patients vomiting, tages over nitropalpitations, prusside in setting abdominal pain of myocardial ischemia -blockage can Nausea, vomiting, IV minibolus: Initial, 20 Continuous worsen congestive paresthesias, mg over 2 min Then monitoring not heart failure, headache, 4080 mg over 10 min. required bronchospasm, bradycardia Maximum, 300 mg heart block Useful in catecholaminerelated crises Short duration of action
Phentolamine 1530 min
Nonselective -blocker
23 min
5 min
IV bolus: 15 mg over 5 min
Contraindicated in pheochromocytoma, heart failure, asthma, heart block >1 degree, after coronary artery bypass graft surgery Nitroprusside equally efficacious in catecholaminerelated crises
Hydralazine 39 h
Direct arteriolar vasodilation
1030 min
3060 min
Tachycardia, arrhythmias, nausea, vomiting, diarrhea, exacerbation of peptic ulcer disease Headache, angina Contraindicated in
aortic dissection, atherosclerotic coronary vascular disease Contraindicated in hypertensive encephalopathy, CNS catastrophe
Hypertensive Crises
Methyldopa
46 h
46 h
Delayed onset IV bolus: 510 mg over Proven efficacy of action, 2030 min or continuand safety in ous infusion 400 g/mL hypertensive crises unpredictable hypotensive effect solution Loading dose: of pregnancy 200300 g/min for 3060 min Maintenance infusion: 50150 g/min Delayed onset Sedation IV of 250500 mg Nonenot over 68 h recommended for of action, unpredictable use in hypertenhypotensive effect sive crises 28 h Intramuscular: Initial, 0.51.0 mg 24 mg over 3 h 24 mg over 312 h
parenteral therapy. However, other parenteral antihypertensive agents may be useful in certain circumstances.
24 h
Reserpine
24 h Decrease sympathetic nervous system activity via CNS 2 stimulation, decrease systemic vascular resistance 24 h Sympathetic dysfunction owing to central and peripheral catecholamine dysfunction; decreased SVR, decreased CO
Delayed onset Nasal congestion, Nonenot CNS sedation, recommended for of action, unpredictable bradycardia, use in hypertenhypotensive effect exacerbates pepsive crises tic ulcer disease, depression
Contraindicated in hypertensive encephalopathy, CNS catastrophe, cumulative hypotensive response
8.27
BPblood pressure; CNScentral nervous system; COcardiac output; ICUintensive care unit; IVintravenous; SVRsystemic vascular resistance.
8.28

blood pressure required to reach the autoregulatory limit. Thus, a reduction in MAP of approximately 20% to 25% was required in each group to reach the threshold. This result indicates that a considerable safety margin exists for blood pressure reduction before cerebral autoregulation of blood flow fails, even in patients with severe untreated hypertension. Moreover, symptoms of cerebral ischemia did not develop until the blood pressure was reduced substantially below the autoregulatory threshold because even in the face of reduced blood flow, cerebral metabolism can be maintained and ischemia prevented by an increase in oxygen extraction by the tissues. The lowest tolerated MAP, defined as the level at which mild symptoms of brain hypoperfusion developed (ie, yawning, nausea, and hyperventilation), was 65 10 mm Hg in patients with uncontrolled hypertension, 53 18 mm Hg in persons with treated hypertension, and 43 8 mm Hg in normotensive persons. The numbers on the bars illustrate that these MAP values were approximately 45% of the baseline blood pressure level in each group. Thus, symptoms of cerebral hypoperfusion did not occur until the MAP was reduced by an average of 55% from the presenting level. In the reported cases of neurologic sequelae sustained during rapid reduction of blood pressure in patients with hypertensive crises, the MAP was reduced by more than 55% of the presenting blood pressure. This frank hypotension was sustained for a period of hours to days, mostly as a result of treatment with bolus diazoxide, which has long duration of action [54]. The general guideline for acute blood pressure reduction in the treatment of hypertensive crises is reduction of systolic blood pressure to 160 to 170 mm Hg and diastolic pressure to 100 to 110 mm Hg, which equates to MAPs of 120 to 130 mm Hg. Alternatively, the initial goal of antihypertensive therapy can be a 20% reduction of the MAP from the patients initial level at presentation. This level should be above the predicted autoregulatory threshold. Once this goal is obtained the patient should be evaluated carefully for evidence of cerebral hypoperfusion. Further reduction of blood pressure can then be undertaken in a controlled fashion based on the overall clinical status of the patient. Of course, in previously normotensive persons in whom hypertensive crises develop, such as patients with acute glomerulonephritis complicated by hypertensive encephalopathy, the autoregulatory curve should not yet be shifted. Therefore, the initial goal of therapy should be normalization of blood pressure. In terms of avoiding sustained overshoot hypotension in the treatment of hypertensive crises, the use of potent parenteral agents with short duration of action, such as sodium nitroprusside or intravenous nitroglycerin, has obvious advantages. If neurologic sequelae develop during blood pressure reduction with these agents, these sequelae can be reversed quickly by tapering the infusion and allowing the blood pressure to stabilize at a higher level. Agents with a long duration of action have an inherent disadvantage in that excessive reduction of blood pressure cannot be reversed easily. Thus, bolus diazoxide, labetalol, minoxidil, hydralazine, converting enzyme inhibitors, calcium channel blockers, and central 2-agonists should be used with extreme caution in patients requiring rapid but controlled blood pressure reduction in the setting of hypertensive crises. (Adapted from Strandgaard [53]; with permission.)
200 Mean arterial pressure, mm Hg
Uncontrolled hypertensives (n=13) Controlled hypertensives (n=9) Normotensives (n=10)
150
100
79 72 74 10% 29% 12%
50
45 6%
0 Baseline mean arterial pressure Lower limit of autoregulation
46 45 16% 12%
Lowest tolerated mean arterial pressure
FIGURE 8-35 Risks of rapid blood pressure reduction in hypertensive crises. It has been argued over the years that rapid reduction of blood pressure in the setting of hypertensive crises may have a detrimental effect on cerebral perfusion because the autoregulatory curve of cerebral blood flow is shifted upward in patients with chronic hypertension. Conversely, this upward shift protects the brain from hypertensive encephalopathy in the face of severe hypertension. However, this autoregulatory shift could be deleterious when the blood pressure is reduced acutely because the lower limit of autoregulation is shifted to a higher level of blood pressure. Theoretically, aggressive reduction of the blood pressure in chronically hypertensive patients could induce cerebral ischemia. Nonetheless, in clinical practice, moderately controlled reduction of blood pressure in patients with hypertensive crises rarely causes cerebral ischemia. This clinical observation may be explained by the fact that even though the cerebral autoregulatory curve is shifted in patients with chronic hypertension, a considerable difference still exists between the initial blood pressure at presentation and the lower limit of autoregulation. Illustrated are the differences in the lower autoregulatory threshold during blood pressure reduction with trimethaphan in patients with uncontrolled hypertension and treated hypertension, and those in the control group [53]. At least eight of the 13 patients with uncontrolled hypertension had hypertensive neuroretinopathy consistent with malignant hypertension. The control groups included nine patients with a history of severe hypertension in the past whose blood pressure was effectively controlled at the time of study and a group of 10 normotensive persons. Baseline mean arterial pressures (MAPs) in the three groups were 145 17 mm Hg, 116 18 mm Hg, and 96 17 mm Hg, respectively. The lower limit of blood pressure at which autoregulation failed was 113 17 mm Hg in persons with uncontrolled hypertension, 96 17mm Hg in persons with treated hypertension, and 73 9 mm Hg in normotensive persons. Although the absolute level at which autoregulation failed was substantially higher in patients with uncontrolled hypertension, the percentage reduction in blood pressure from the baseline level required to reach the autoregulatory threshold was similar in each group. The numbers on the bars indicate the percentage reduction from the baseline
Hypertensive Crises
8.29
Severe uncomplicated hypertension Severe hypertension (diastolic blood pressure > 115 mm Hg)
Hypertensive neuroretinopathy present (striate hemorrhages, cotton-wool spots with or without papilledema) Treat malignant hypertension (Fig. 8-20)
Hypertensive neuroretinopathy absent
No acute end-organ dysfunction
Acute end-organ dysfunction Treat as hypertensive crisis (see preceding figures)
Severe uncomplicated hypertension Step 1 Patient education regarding the chronic nature of hypertension and importance of long-term compliance and blood pressure control to prevent complications Step 2 Evaluate reason for inadequate blood pressure control and adjust maintenance antihypertensive drug regimen
Step 3 Arrange outpatient follow-up to document adequate blood pressure control over the ensuing days to weeks and change drug treatment regimen as required
Noncompliant
Compliant with current blood pressure regimen
"Ran out" of medications
Drug side effects Switch to drug of another class
Cannot afford drugs Switch to generic thiazide diuretic
Add low-dose thiazide diuretic to existing monotherapy with CCB, CEI, -blocker, 2-agonist
Restart
FIGURE 8-36 Severe uncomplicated hypertension. The benefits of acute reduction in blood pressure in the setting of true hypertensive crises are obvious. Fortunately, true hypertensive crises are relatively rare events that almost never affect hypertensive patients. Another type of presentation that is much more common than are true hypertensive crises is that of the patient who initially exhibits severe hypertension (diastolic blood pressure >115 mm Hg) in the absence of hypertensive neuroretinopathy or acute end-organ damage that would signify a true crisis. This entity, known as severe uncomplicated hypertension, is very commonly seen in the emergency department or other acute-care settings. Of patients with severe uncomplicated hypertension, 60% are entirely asymptomatic and present for prescription refills or routine blood pressure checks, or are found to have elevated pressure during routine physical examinations. The other 40% of patients initially exhibit nonspecific findings such as headache, dizziness, or weakness in the absence of evidence of acute end-organ dysfunction. In the past, this entity was referred to as urgent hypertension, reflecting the erroneous notion that acute reduction of blood pressure, over a few hours before discharge from the acute-care facility, was essential to minimize the risk of short-term complications from severe hypertension. Commonly employed treatment regimens included oral clonidine loading or sublingual nifedipine. However, in recent years the practice of acute blood pressure reduction in severe uncomplicated hypertension has been questioned [55,56]. In the Veterans Administration Cooperative Study of patients with severe hypertension, there were 70 placebo-treated patients who had an average diastolic blood pressure of 121 mm Hg at entry. Among these untreated patients, 27 experienced morbid events at a mean of 11 8 months of follow-up. However, the earliest morbid event occurred only after 2 months [57]. These data suggest that in patients with severe uncomplicated hypertension in which severe hypertension is not accompanied by evidence of malignant hypertension or acute end-organ dysfunction, eventual complications from stroke, myocardial infarction, or congestive
heart failure tend to occur over months to years, rather than hours to days. Although long-term control of blood pressure clearly can prevent these eventual complications, a hypertensive crisis cannot be diagnosed because no evidence exists that acute reduction of blood pressure results in an improvement in short- or long-term prognosis. Acute reduction of blood pressure in patients with severe uncomplicated hypertension with sublingual nifedipine or oral clonidine loading was once the de facto standard of care. This practice, however, often was an emotional response on the part of the treating physician to the dramatic elevation of blood pressure or motivated by the fear of medico-legal repercussions in the unlikely event of a hypertensive complication occurring within hours to days [55]. Although observing and documenting the dramatic decrease in blood pressure is a satisfying therapeutic maneuver, there is no scientific basis for this approach. At present, no literature exists to support the notion that some goal level of blood pressure reduction must be achieved before the patient with severe uncomplicated hypertension leaves the acute-care setting [58]. In fact, acute reduction of blood pressure often is counterproductive because it can produce untoward side effects that render the patient less likely to comply with long-term drug therapy. Instead, the therapeutic intervention should focus on tailoring an effective welltolerated maintenance antihypertensive regimen with patient education regarding the chronic nature of the disease process and the importance of long-term compliance and medical follow-up. If the patient has simply run out of medicines, reinstitution of the previously effective drug regimen should suffice. If the patient is thought to be compliant with an existing drug regimen, a sensible change in the regimen is appropriate, such as an increase in a suboptimal dosage of an existing drug or the addition of a drug of another class. In this regard, addition of a low dose of a thiazide diuretic as a second-step agent to existing monotherapy with converting enzyme inhibitor (CEI), angiotensin II receptor blocker, calcium channel blocker (CCB), -blocker, or central 2-agonist often is remarkably effective. Another essential goal of the acute intervention should be to arrange suitable outpatient follow-up within a few days. Gradual reduction of blood pressure to normotensive levels over the next few days to a week should be accomplished in conjunction with frequent outpatient visits to modify the drug regimen and reinforce the importance of lifelong compliance with therapy. Although less dramatic than acute reduction of blood pressure in the acute-care setting, this type of approach to the treatment of chronic hypertension is more likely to prevent long-term hypertensive complications and recurrent episodes of severe uncomplicated hypertension.
8.30
References
1. Nolan CR, Linas SL: Malignant hypertension and other hypertensive crises. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1997:14751554. 2. Derow HA, et al.: The nature of malignant hypertension. Ann Intern Med 1941, 14:1768. 3. Perez-Fontan M, et al.: Idiopathic IgA nephropathy presenting as malignant hypertension. Am J Nephrol 1986, 6:482. 4. Holland NH, et al.: Hypertension in children with chronic pyelonephritis. Kidney Int 1975, 8(suppl):S234. 5. Nanra RS, et al.: Analgesic nephropathy: etiology, clinical syndrome, and clinicopathologic correlations in Australia. Kidney Int 1978, 13:79. 6. Davis BA, et al.: Prevalence of renovascular hypertension in patients with grade III or grade IV hypertensive neuroretinopathy. N Engl J Med 1979, 301:1273. 7. Lim K, et al.: Malignant hypertension in women of childbearing age and its relation to the contraceptive pill. Br Med J 1987, 294:1057. 8. Traub YM, et al.: Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis. Medicine 1983, 62:335. 9. Cacoub P, et al.: Malignant hypertension with antiphospholipid syndrome without overt lupus nephritis. Clin Exp Rheumatol 1993, 11:479485. 10. McAllister RG, et al.: Malignant hypertension: effect of therapy on renin and aldosterone. Circ Res 1971, 28(suppl II):II160. 11. Keith NM, Wagener HP, Barker NW: Some different types of essential hypertension: their course and prognosis. Am J Med Sci 1939, 197:332. 12. Kirkendall WM: Retinal changes of hypertension. In The Eye in Systemic Disease. Edited by Mausolf FA. St Louis: Mosby; 1975:212222. 13. Dollery CT: Hypertensive retinopathy. In Hypertension: Pathophysiology and Treatment. Edited by Genest O, Kuchel O, Hamet P. New York: McGraw-Hill; 1983:723732. 14. McGregor E, Isles CG, Jay JL, et al.: Retinal changes in malignant hypertension. Br Med J 1986, 292:233234. 15. Sinclair RA, Antonovych TT, Mostofi FL: Renal proliferative arteriopathies and associated glomerular changes: a light and electron microscopy study. Hum Pathol 1976, 7:565. 16. Pitcock JA, et al.: Malignant hypertension in blacks: malignant intrarenal arterial disease as observed by light and electron microscopy. Hum Pathol 1976, 7:33. 17. Jones DB: Arterial and glomerular lesions associated with severe hypertension. Lab Invest 1974, 31:303. 18. Mattern WD, Sommers SC, Kassiere JP: Oliguric acute renal failure in malignant hypertension. Am J Med 1972, 52:187. 19. Isles CG, McLay A, Boulton-Jones JM: Recovery in malignant hypertension presenting as acute renal failure. Q J Med 1984, 53:439. 20. Bacon BR, Ricanatie ES: Severe and prolonged renal insufficiency. Reversal in a patient wit malignant hypertension. JAMA 1978, 239:1159. 21. Shirley D, et al.: Clinical documentation of end-stage renal disease due to hypertension . Am J Kidney Dis 1994, 23:655. 22. Freedman BI, Iskander SS, Appel RG: The link between hypertension and nephrosclerosis. Am J Kidney Dis 1995, 25:207. 23. Rerneger TV, et al.: Diagnosis of hypertensive end-stage renal disease: effect of patients race. Am J Epidemiol 1995, 141:10. 24. Mhring J, et al.: Effects of saline drinking on the malignant course of renal hypertension in rats. Am J Physiol 1976, 230:849. 25. Gifford RW Jr, et al.: Hypertensive encephalopathy: mechanisms, clinical features, and treatment. Progr Cardiovasc Dis 1974, 17:115. 26. Dinsdale HB: Hypertensive encephalopathy. Neurol Clin 1983, 1:83. 27. Ziegler DK, et al.: Hypertensive encephalopathy. Arch Neurol 1965, 12:472. 28. Cohn JN, Rodriguera E, Guiha NH: Left ventricular function in hypertensive heart disease. In Hypertension Mechanisms and Management. Edited by Onesti O, Kim KE, Moyer JH. New York: Grune & Stratton; 1973:191197. 29. Wheat MW Jr: Acute dissecting aneurysms of the aorta: diagnosis and treatment, 1979. Am Heart J 1980, 99:373. 30. 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Skydell JL, et al.: Incidence and mechanism of post-carotid endarterectomy hypertension. Arch Surg 1987, 122:1153. 39. Towne JB, Bernhard VM: The relationship of postoperative hypertension to complications after carotid endarterectomy. Surgery 1980, 88:575. 40. Wallace JD, et al.: Blood pressure after stroke. JAMA 1981, 246:2177. 41. Britton M, et al.: Hazards of therapy for excessive hypertension in acute stroke. Acta Med Scand 1980, 207:253. 42. Lavin P: Management of hypertension in patients with acute stroke. Arch Intern Med 1986, 146:66. 43. Meyer JS, et al.: Impaired neurogenic cerebrovascular control and dysautoregulation after stroke. Stroke 1973, 4:169. 44. Cuneo RA, et al.: The neurologic complications of hypertension. Med Clin North Am 1977, 61:565. 45. Kaneko T, et al.: Lower limit of blood pressure in treatment of acute hypertensive intracranial hemorrhage. J Cerebral Blood Flow Metab 1983, 3(suppl 1):S51. 46. Shapiro B, Rig LM: Management of pheochromocytoma. 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VOLUME THREE VOLUME FOUR

The Kidney in Blood Pressure Regulation

Hypertension and the Kidney

160 Aortic pressure, mm Hg

Isolated systolic hypertension (61 y)

80 Aortic blood flow, mL/s 400 0

200 180 160 140 120 100 80 60 40 20

600 700 800 900 Arterial volume, mL

The Kidney in Blood Pressure Regulation

Dietary Insensible losses Urinary intake (skin, respiration, fecal) excretion

Net sodium and fluid balance

ECF volume Arterial pressure Blood volume Interstitial fluid volume

Mean circulatory pressure

Cardiac output Cardiovascular capacitance

Heart rate and contractility

Antidiuretic hormone release If increased

If decreased NaCl losses (urine insensible) Antidiuretic hormone inhibition

15 Extracellular fluid volume, L

Hypertension and the Kidney

Intrarenal Mechanisms Regulating Sodium Balance

Filtered sodium load, mol/min/g

150 100 50 0 100

Fractional sodium reabsorption, %

Fractional sodium excretion, %

6 4 2 0 75 100 125 150 175 Renal arterial pressure, mm Hg

The Kidney in Blood Pressure Regulation

Pc=20 RE c=37 PCU=Kr ERP

0.6 0.4 0.2 0 20 15 10 5 0 5

Renal blood flow, mL/ming

Vascular resistance, mm Hgming/mL

Glomerular filtration rate, mL/ming

4 3 2 1 0 0 50 100 150 200 Renal arterial pressure, mm Hg

Hypertension and the Kidney

Glomerular pressure and plasma flow

Glomerular filtration rate

Proximal to distal tubule flow

Vascular effector (afferent arteriole)

Macula densa: Sensor mechanism Transmitter

30 Single nephron GFR, nL/min

20 30 Late proximal perfusion rate, nL/min

The Kidney in Blood Pressure Regulation

Calcium-activated potassium channel K+

Phosphorylated MLC Actin

Smooth muscle cell

Hypertension and the Kidney

Smooth muscle cell Vasodilation Vasoconstriction

NO PGI 2 Relaxing factors

EDCF PGF2 Endothelin Constricting factors

Renal arterial pressure normal

Endothelial nitric oxide release Diffusion to tubules

Vascular dilation but counteracted by autoregulation

Epithelial cGMP Decreased sodium reabsorption Sodium excretion

50 75 100 125 150 Renal arterial pressure, mm Hg

The Kidney in Blood Pressure Regulation

Peritubular capillary Lateral intercellular P space

Cells Paracellular (passive)

Hypertension and the Kidney

Proximal tubule cells

3Na+ 2 K+ Na+ _ HCO3 CO3 Ca2+

ADP Na+ H+ Anion

Thick ascending limb cells