Acute Renal Failure and Sepsis

Robert W. Schrier, M.D., and Wei Wang, M.D.

Acute renal failure occurs in approximately 19 percent of patients with

moderate sepsis, 23 percent with severe sepsis, and 51 percent with septic
shock when blood cultures are positive. A progressive increase in the acute
respiratory distress syndrome also occurs with moderate and severe sepsis
and septic shock. In the United States, an estimated 700,000 cases of sepsis
occur each year, resulting in more than 210,000 deaths; this number
accounts for 10 percent of all deaths annually and exceeds the number of
deaths due to myocardial infarction.3 The combination of acute renal failure
and sepsis is associated with a 70 percent mortality, as compared with a 45
percent mortality among patients with acute renal failure alone. Thus, the
combination of sepsis and acute renal failure constitutes a particularly
serious medical problem in the United States.4 Substantial progress has
been made toward understanding the mechanisms whereby sepsis is
associated with a high incidence of acute renal failure. Moreover, recently
identified clinical interventions may be able to decrease the occurrence of
acute renal failure and sepsis and the high associated mortality.

The cytokine-mediated induction of nitric oxide synthesis that occurs in

sepsis decreases systemic vascular resistance. This arterial vasodilatation
predisposes patients with sepsis to acute renal failure, the need for
mechanical ventilation, and ultimately, increased mortality. In this article, we
review the effects of nitric oxide–mediated arterial vasodilatation on
resistance to exogenous pressors and hypotension and we discuss the use of
arginine vasopressin in patients with septic shock. We also review the effects
of increased plasma concentrations of several endogenous vasoconstrictor
hormones, including catecholamines, angiotensin II, and endothelin, which
support arterial pressure in patients with sepsis who have vasodilatation but
also cause renal vasoconstriction and predispose patients to acute renal
failure. Patients who have a combination of sepsis and acute renal failure
may have some effects of systemic arterial vasodilatation, such as altered
Starling forces in the capillaries, pulmonary edema, and hypoxia, a need for
mechanical ventilation, acute respiratory distress syndrome, and multiple-
organ dysfunction syndrome, which together may increase mortality to more
than 80 percent. We discuss interventions that may prevent this dire
sequence of events. Finally, we review several prospective, randomized
clinical trials of interventions that have the potential to prevent or attenuate
acute renal failure in patients with sepsis and thus decrease mortality. Such
trials have addressed anticoagulant therapy, early resuscitation, the
treatment of hyperglycemia, the use of corticosteroids, a shortened duration
of mechanical ventilation, and various types of renal-replacement therapy.

Hemodynamics and Hormones

The hemodynamic hallmark of sepsis is generalized arterial

vasodilatation with an associated decrease in systemic vascular resistance.
Arterial underfilling due to arterial vasodilatation occurs in several clinical
circumstances, including sepsis, and is associated with activation of the
neurohumoral axis and an increase in cardiac output secondary to the
decreased cardiac afterload. Activation of the sympathetic nervous system
and the renin–angiotensin–aldosterone axis, the nonosmotic release of
vasopressin, and an increase in cardiac output are essential in maintaining
the integrity of the arterial circulation in patients with severe sepsis and
septic shock but may lead to acute renal failure.

The arterial vasodilatation that accompanies sepsis is mediated, at

least in part, by cytokines that up-regulate the expression of inducible nitric
oxide synthase in the vasculature. The release of nitric oxide with inducible
nitric oxide synthase, as compared with constitutive endothelial nitric oxide
synthase, is more profound and prolonged. Moreover, vascular resistance to
the pressor response to norepinephrine and angiotensin II5 occurs during
sepsis and is attributable in part to the potent vasodilatory effect of nitric
oxide. In addition, an increase in plasma concentrations of hydrogen ions
and lactate and a decrease in ATP in vascular smooth-muscle cells during
septic shock activate the ATP-sensitive potassium channels (KATP channels).
The resultant potassium efflux through the KATP channels causes
hyperpolarization of the vascular smooth-muscle cells with closure of the
voltage-gated calcium channels in the membrane. Since the vasoconstrictor
effects of norepinephrine and angiotensin II depend on open calcium
channels, vascular resistance to these pressor hormones can occur along
with lactic acidosis in patients with sepsis. Furthermore, the high
endogenous levels of these vasoactive hormones during sepsis may be
associated with down-regulation of their receptors, which would result in a
lessening of their effects on the vasculature.

The Pressor Effect of Arginine Vasopressin

There is evidence that the administration of arginine vasopressin in

patients with sepsis-related vasodilatory shock may help maintain blood
pressure despite the relative ineffectiveness of other vasopressor hormones
such as norepinephrine and angiotensin II.18,19 Specifically, arginine
vasopressin may inactivate the KATP channels20 and thereby lessen
vascular resistance to norepinephrine12 and angiotensin II. Arginine
vasopressin also decreases the synthesis of nitric oxide (as a result of a
decrease in the expression of inducible nitric oxide synthase) as well as
cyclic guanosine monophosphate (cGMP) signaling by nitric oxide,21 thus
attenuating the arterial vasodilatation and pressor resistance during sepsis.
The degree of vasoconstriction in response to arginine vasopressin relates to
its plasma levels and occupancy of the V1a arginine vasopressin receptors
on vascular smooth-muscle cells. Initially, in septic or hemorrhagic shock, the
plasma arginine vasopressin concentrations increase to 200 to 300 pg per
milliliter, but after approximately an hour, the neurohypophysial stores of
vasopressin are depleted and plasma concentrations may fall to
approximately 30 pg per milliliter.19 At that time and in the presence of
unoccupied V1a receptors, the administration of exogenous arginine
vasopressin can increase blood pressure by 25 to 50 mm Hg by returning the
plasma concentrations of antidiuretic hormones to their earlier high levels.

Arginine vasopressin is also known to be synergistic with the pressor

hormones norepinephrine and angiotensin II, since all three hormones have
in common intracellular signaling that involves an increase in the cytosolic
calcium concentration. Another advantage of using arginine vasopressin as a
pressor agent in patients with sepsis is that the sites of major arterial
vasodilatation in sepsis — the splanchnic circulation, the muscles, and the
skin — are vascular beds that contain abundant V1a arginine vasopressin
receptors.

Glomerular filtration is determined by the net difference in arterial

pressure between the afferent and efferent arterioles across the glomerular
capillary bed (termed transcapillary filtration pressure). Norepinephrine
profoundly constricts the glomerular afferent arteriole, dropping the filtration
pressure, and thus may contribute to and prolong the course of acute renal
failure in patients with sepsis. In contrast, arginine vasopressin has been
shown to constrict the glomerular efferent arteriole and therefore can
increase the filtration pressure and, consequently, the glomerular filtration
rate.

The decision to use arginine vasopressin as a pressor agent, however,

must involve consideration of several additional physiological properties.26
Increased concentrations of arginine vasopressin constrict the coronary
arteries and have been reported to cause myocardial infarction. In contrast
to norepinephrine and angiotensin II, arginine vasopressin does not have a
cardiac inotropic effect; thus, the increase in cardiac afterload during the
infusion of arginine vasopressin can decrease cardiac output. Moreover,
during sepsis, the increased cardiac output that generally occurs may be
suboptimal for the patient, given the diminished systemic vascular
resistance and cardiac afterload, because circulating cytokines such as
tumor necrosis factor that are induced by the septic state have myocardial
depressant properties.27 Furthermore, interstitial myocarditis and diastolic
dysfunction have also been reported to occur during sepsis.28 Since arginine
vasopressin is a very potent venoconstrictor that decreases splanchnic
compliance, excessive fluid that is administered is distributed more centrally,
including in the lung, and therefore can lead to noncardiogenic pulmonary
edema (pseudo–acute respiratory distress syndrome).6,29 Nevertheless,
despite the issues mentioned, the administration of arginine vasopressin
may be effective in patients with septic shock who have vasodilatation and
relative resistance to other pressor hormones.

Effects of Systemic Arterial Vasodilatation on Body-Fluid Volume and Starling

Forces
 The difference between the oncotic and hydrostatic pressures within
the vasculature and interstitium (Starling forces) determines whether plasma
water remains within the vasculature or leaks out into the interstitium.
Experimental studies in rats have examined the effect of arterial
vasodilatation on Starling forces, albumin distribution, and body-fluid volume
in normal animals.30 The administration of the potent arterial vasodilator
minoxidil was shown to cause sodium and water retention with resultant
expansion of plasma and interstitial volume. With the use of Guyton's
subcutaneous capsule, which is able to measure interstitial pressure, arterial
vasodilatation in a rat model was shown to reverse the normally negative
pressure within the interstitium.30 Moreover, during intravenous saline
loading, interstitial pressure increased in animals without vasodilatation,
whereas the elevated interstitial pressure in the animals that had
vasodilatation did not increase further. The fall in interstitial pressure that
occurred with the intravenous administration of hyperoncotic albumin in the
normal animals did not occur in the animals with vasodilatation. This latter
effect may be due to the increased distribution of albumin within the
interstitial space that occurs with arterial vasodilatation. The pulmonary bed
is particularly prone to collect interstitial fluid in this situation. If applied to
humans, these findings would indicate that patients with sepsis who have
vasodilatation are susceptible to noncardiogenic pulmonary edema. There is
indeed evidence that this is the case.

Experimental Models of Endotoxemia and Sepsis

Vasoactive Hormones

There is experimental evidence that early in sepsis-related acute renal

failure, the predominant pathogenetic factor is renal vasoconstriction with
intact tubular function, as demonstrated by increased reabsorption of tubular
sodium and water. Thus, intervention at this early stage may prevent
progression to acute tubular necrosis. For example, if endotoxin is infused
into a conscious-rat model, the early events include a fractional excretion of
sodium of less than 1 percent, indicating good tubular function.32

Another pressor hormone that has been observed to be elevated in

sepsis is endothelin, a potent vasoconstrictor. Renal vasoconstriction in
sepsis seems to be due, at least in part, to the ability of tumor necrosis
factor to release endothelin.34 Indeed, an intrarenal injection of antiserum
to endothelin-1 in a rat model was capable of reversing the decrease in the
glomerular filtration rate induced by endotoxin.35 During endotoxemia,
endothelin may also cause a generalized leakage of fluid from the capillaries
and thereby diminish plasma volume.36

Endothelial and Inducible Nitric Oxide Synthases

The vasodilatory effect of constitutive endothelial nitric oxide synthase

within the kidney might be expected to lessen the renal vasoconstriction
induced by norepinephrine, angiotensin II, and endothelin during sepsis.
However, the results of in vitro studies showed that the increase in the
plasma nitric oxide concentration stimulated by inducible nitric oxide
synthase during endotoxemia down-regulated endothelial nitric oxide
synthase within the kidney.37 When cytokines activated inducible nitric
oxide synthase, however, not only did the plasma nitric oxide concentration
increase, but also the expression of inducible nitric oxide synthase increased
in the renal cortex.38 In association with this increased expression of
inducible nitric oxide synthase, a progressive increase in cGMP in the renal
cortex occurred during the initial 16 hours after exposure to endotoxin. At 24
hours, however, the plasma nitric oxide concentration remained high, though
renal cGMP had decreased. Since cGMP is the secondary messenger for nitric
oxide–mediated arterial vasodilatation, the down-regulation of this enzyme
at 24 hours may also contribute to renal vasoconstriction during sepsis.

Endothelial damage occurs during sepsis and may be associated with

microthrombi and an increased concentration of von Willebrand factor in the
circulation.39 Sepsis-related impairment of the endothelium may also
attenuate or abolish the normal effect of endothelial nitric oxide synthase in
the kidney to counteract the vasoconstrictor effects of norepinephrine,
endothelin, and angiotensin II. The study of knockout mice, in which the
expression of either endothelial nitric oxide synthase or inducible nitric oxide
synthase has been ablated, has been helpful in elucidating the importance of
endothelial damage during sepsis. Since there is no specific inhibitor of
endothelial nitric oxide synthase, the effect of endotoxin (lipopolysaccharide)
was tested in endothelial nitric oxide synthase–knockout mice, which have a
significant increase in blood pressure and renal vascular resistance as
compared with normal (control) mice. A small dose of endotoxin, which did
not alter the glomerular filtration rate in the control mice, caused a profound
decrease in the glomerular filtration rate in these knockout mice.40

Cytokines, Chemokines, and Adhesion Molecules

The early vasoconstrictor phase of acute renal failure during

endotoxemia may be followed by a proinflammatory phase, although there is
probably an overlap in these processes. It is known that caspase activates
both interleukin-1 and interleukin-18 cytokines, and the resultant up-
regulation of adhesion molecules contributes to neutrophil infiltration during
endotoxemia. The importance of caspase in endotoxemia has been
underscored by the observation that caspase-1–knockout mice are protected
against renal failure that is induced by either ischemia45 or endotoxemia.46
Several chemokines are also expressed during endotoxemia in association
with neutrophil and macrophage infiltration into the glomeruli and
interstitium.

The complex composed of a lipopolysaccharide and the

lipopolysaccharide-binding protein activates the membrane-CD14 and toll-
like receptors on cells, which up-regulate nuclear factor-B (NF-B), a nuclear
transcription factor for the promoters of multiple cytokines, chemokines, and
adhesion molecules.47Activation of NF-B may therefore be a critical factor in
the proinflammatory phase that involves a cytokine, chemokine, and
adhesion molecule "storm," which leads to acute renal failure and an
increased rate of death. Blocking agents for NF-B exist that could protect
against endotoxemia better than targeting any individual cytokine,
chemokine, or adhesion molecule.48 These substances need to be studied
both in experimental models and in clinical studies in humans with
concurrent sepsis and acute renal failure.

Complement pathways are activated during sepsis by bacterial

products such as lipopolysaccharide, C-reactive protein, and other stimuli.
Complement C5a that is generated during sepsis seems to have
procoagulant properties, and blocking C5a and C5a receptor in a rodent
model of sepsis has been shown to improve survival.49,50,51

Although animal models of endotoxemia and sepsis have provided

insights into sepsis and acute renal failure, the translation of these
experimental results to patients with sepsis must be made with caution. Also,
the mouse models in which sepsis was induced by the administration of
lipopolysaccharide differed from the models achieved by cecal ligation and
puncture.52,53

Disseminated Intravascular Coagulation

Sepsis affects the expression of complement, coagulation, and the

fibrinolytic cascade. Sepsis can be viewed as a procoagulant state that can
lead to disseminated intravascular coagulation with consumptive
coagulopathy, thrombosis, and ultimately, hemorrhage. Disseminated
intravascular coagulation has been associated with glomerular microthrombi
and acute renal failure.54 Prospective, randomized trials have been
undertaken to evaluate methods of intervening in the procoagulant process
associated with sepsis. A major prospective, randomized study, the
PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in
Severe Sepsis) trial, showed that recombinant human activated protein C
(drotrecogin alfa) significantly improved survival in patients with severe
sepsis, as compared with those given placebo (75.3 percent vs. 68.3 percent,
P=0.006).55 Results of renal-function tests were not reported in this trial.

Early Resuscitation

Since the early vasoconstrictor phase of sepsis and acute renal failure
is potentially reversible, it should be an optimal time for intervention.
However, clinical studies performed in patients up to 72 hours after
admission to the intensive care unit, in which attempts were made to
optimize hemodynamics and monitor the patients with a pulmonary-artery
catheter, not only were negative56,57,58,59 but showed increased mortality
among patients with sepsis. In contrast, a randomized study of 263 patients
with a mean serum creatinine concentration of 2.6 mg per deciliter (230
µmol per liter) on admission to the emergency department showed that early
goal-directed therapy during the first six hours after admission was
effective.60 The central venous oxygen saturation was continuously
monitored as goal-directed therapy was instituted; in patients assigned to
such interventions, the multiorgan dysfunction score decreased significantly
and in-hospital mortality decreased (30.5 percent, as compared with 46.5
percent in the control patients, who received standard care; P=0.009). The
goal-directed approach included early volume expansion and administration
of vasopressors to maintain mean blood pressure at or above 65 mm Hg and
transfusion of red cells to increase the hematocrit to 30 percent or more if
central venous oxygen saturation was less than 70 percent. If these
interventions failed to increase central venous oxygen saturation to greater
than 70 percent, then therapy with dobutamine was instituted.

Hyperglycemia and Insulin

Hyperglycemia impairs the function of leukocytes and macrophages. A

randomized study of 1548 patients compared the use of insulin to control
blood glucose levels tightly (maintaining blood glucose levels between 80
and 110 mg per deciliter [4.4 and 6.1 mmol per liter]) with conventional
treatment (the use of insulin only if the blood glucose levels exceeded 215
mg per deciliter [11.9 mmol per liter], with the aim of maintaining glucose
levels between 180 and 220 mg per deciliter [10.0 and 12.2 mmol per
liter]).61 The group assigned to tight control of blood glucose levels showed
a decrease in mortality in the intensive care unit as compared with the group
receiving conventional treatment (4.6 percent vs. 8 percent, P<0.04), a 46
percent decrease in positive blood cultures, and a 41 percent decrease in
acute renal failure requiring dialysis or hemofiltration. Multiple-organ failure
with a proven focus of sepsis was also decreased (8 cases vs. 33 cases,
P=0.02). Recent studies further support the importance of controlling blood
glucose in critically ill patients but suggest a less stringent goal of
maintaining blood glucose at a level of 145 mg per deciliter (8.0 mmol per
liter) or less.62

Glucocorticoids and Mechanical Ventilation

Glucocorticoids have been known to enhance the pressor effects of

catecholamines, but older studies in which septic shock was treated with
large doses of glucocorticoid hormones for a short period of time did not
show any benefit.63,64 However, a recent study65 in patients with septic
shock showed that patients without a response to corticotropin (as defined
by a rise in plasma free cortisol of less than 9 µg per deciliter at 30 or 60
minutes) who were treated for 7 days with intravenous boluses of 50 mg of
hydrocortisone every 6 hours plus daily oral fludrocortisone (a 50-µg tablet)
had a decrease in mortality at 28 days as compared with the placebo group
(63 percent vs. 53 percent, P=0.02). In this randomized study, 229 of the
299 patients with septic shock who were enrolled were classified as not
having a response. There was no difference in mortality among the 70
patients with a response to the short corticotropin study. Withdrawal of
vasopressors was also significantly better at 28 days in those without a
response (40 percent vs. 57 percent, P<0.001).65 Although this study did
not report renal function results, it is known that septic shock is associated
with acute renal failure in 38 percent of patients with negative cultures and
51 percent of patients with positive cultures.2

Renal Replacement
Patients with sepsis and acute renal failure are hypercatabolic. Studies
suggesting that increased doses of dialysis improve survival in patients who
are hypercatabolic and have acute renal failure are persuasive. For example,
survival was markedly improved with aggressive hemodialysis as compared
with peritoneal dialysis in patients who had heatstroke, rhabdomyolysis, and
acute renal failure.67 Hemofiltration has been shown to produce better
survival rates than peritoneal dialysis in patients with acute renal failure
associated with malaria and other infections.68 A recent study showed that
daily hemodialysis as compared with alternate-day hemodialysis was
associated with less systemic inflammatory response syndrome or sepsis (22
percent vs. 46 percent, P=0.005), lower mortality (28 percent vs. 46 percent,
P<0.01) and a shorter duration of acute renal failure (mean [±SD], 9±2 vs.
16±6 days; P=0.001).69

Reaction
Continuous renal-replacement therapy has increasingly been used to
treat acute renal failure. A randomized study using continuous venovenous
hemofiltration suggested that the ultrafiltration rate of 35 or 45 ml per
kilogram per hour as compared with 20 ml per kilogram per hour improves
survival in acute renal failure (P<0.001).70 Moreover, in patients with sepsis-
related acute renal failure, better survival was observed with an
ultrafiltration rate of 45 ml per kilogram per hour than with a rate of 35 mg
per kilogram per hour. Meta-analysis of hemodialysis as compared with
continuous renal-replacement therapy in acute renal failure, however, has
not yet shown an advantage for either mode of renal-replacement
therapy.71 The benefit of the removal of cytokines by continuous renal-
replacement therapy also remains to be proven as a method for improving
survival in patients with sepsis and acute renal failure.
Acute renal failure is a common complication of sepsis and septic
shock. Patients who have sepsis-related acute renal failure have much higher
mortality than patients with acute renal failure who do not have sepsis.
Experimental models of endotoxemia and sepsis have provided insights into
the pathogenesis of sepsis-related acute renal failure, but results from such
models should be examined stringently before applying them to patients
with sepsis. Recent clinical studies indicate that interventions based on
several proposed pathogenetic factors in sepsis-related acute renal failure
may have a favorable effect on both the incidence of acute renal failure and
the mortality of patients with acute renal failure.
 Normotensive Ischemic Acute Renal Failure
J. Gary Abuelo, M.D.

Acute renal failure is defined as a rapid decrease in the glomerular

filtration rate, occurring over a period of minutes to days. Because the rate
of production of metabolic waste exceeds the rate of renal excretion in this
circumstance, serum concentrations of markers of renal function, such as
urea and creatinine, rise. The causes of acute renal failure are classically
divided into three categories: prerenal, postrenal (or obstructive), and
intrinsic. Prerenal azotemia is considered a functional response to renal
hypoperfusion, in which renal structure and microstructure are preserved.
Postrenal azotemia — obstruction of the urinary tract — is initially
accompanied by few microscopical changes (early hydronephrosis, with
enlargement of the pelvic cavity and minimal distention or blunting of the
renal papilla) or none. In contrast, intrinsic renal azotemia is due to
parenchymal injury of the blood vessels, glomeruli, tubules, or interstitium.
In prerenal and postrenal azotemia, complete recovery may be seen 1 to 2
days after relief of the offending lesion, provided that normal perfusion or
urinary outflow is reestablished before structural changes occur.

A research focus group organized by the American Society of

Nephrology recently recommended that the term "acute kidney injury"
replace the term "acute renal failure." However, the group left the actual
definition of acute kidney injury to be determined in the future. Thus,
whether acute kidney injury refers only to acute tubular necrosis or includes
prerenal and postrenal azotemia and parenchymal diseases such as acute
glomerulonephritis remains unclear. Most clinicians still use the term acute
renal failure as defined above.

The two forms of ischemic acute renal failure, prerenal azotemia and
acute tubular necrosis, account for more than half the cases of renal failure
seen in hospitalized patients and are familiar to most clinicians. Yet in many
patients with acute renal failure, the contribution of ischemia is initially
unrecognized. Patients with ischemic acute renal failure typically have low
systemic perfusion, sometimes caused by volume depletion, although their
blood pressure may not fall dramatically but instead may remain within the
normal range (in an adult, systolic blood pressure >90 to 100 mm Hg). In
such cases, in the absence of frank hypotension, the clinician may speculate
that an unobserved drop in blood pressure must have caused the renal
failure. Although this scenario cannot be ruled out, other causative
mechanisms can usually be identified. This type of ischemic acute renal
failure (termed normotensive, because the patient's blood pressure is — at
least temporarily — within the normal range) can occur as a result of several
processes, most of which involve increased renal susceptibility to modest
reductions in perfusion pressure. Fortunately, the factors that lead to
ischemic renal failure in patients with apparently normal blood pressure are
discernible in most instances. Recognition of these factors allows the
physician to make an early diagnosis and facilitates the interventions that
can help to reestablish normal renal hemodynamics.

The importance of addressing even mild renal failure is illustrated by a

recent study showing that hospitalized patients with a modest increase in
the serum creatinine level (0.3 to 0.4 mg per deciliter [26.5 to 35.4 µmol per
liter]) have a 70% greater risk of death than persons without any increase.5
This article reviews the renal response to ischemia, notes the risk factors for
the development of normotensive ischemic acute renal failure, and discusses
the diagnosis of this condition.

Renal Response to Ischemia

As renal perfusion pressure drops below the autoregulatory range,
endogenous vasoconstrictors increase afferent arteriolar resistance. This
reduces glomerular capillary pressure and the glomerular filtration rate,
resulting in functional prerenal azotemia. The postglomerular capillary bed,
which perfuses the tubules, has diminished blood flow and pressure, but the
tubules remain intact. However, increasing severity and duration of ischemia
may cause structural tubular injury, further impairing renal function.
Sloughed tubular epithelial cells and brush-border–membrane debris form
casts that obstruct tubules, and experimental data indicate that glomerular
filtrate leaks from the tubular lumen across denuded tubular walls into
capillaries and the circulation (a phenomenon called back-leak). In addition,
impaired sodium reabsorption by injured tubular epithelial cells increases the
sodium concentration in the tubular lumen. The increased intratubular
sodium concentration polymerizes Tamm–Horsfall protein, which is normally
secreted by the loop of Henle, forming a gel and contributing to cast
formation.

The mechanism whereby ischemia and oxygen depletion injure tubular

cells starts with ATP depletion, which activates a number of critical
alterations in metabolism. Cytoskeletal disruption leads to loss of brush-
border microvilli and cell junctions and to mislocation of integrins and
sodium–potassium ATPase from the basal surface to the apical surface. As a
result, brush-border membranes and cells slough and may obstruct tubules
downstream. ATP depletion also activates harmful proteases and
phospholipases, which, with reperfusion, cause oxidant injury to tubular cells.
Similar damage occurs in endothelial cells of the peritubular capillaries,
especially in the outer medulla, which is marginally oxygenated under
normal circumstances. This oxidant injury, together with a shift in the
balance of vasoactive substances toward vasoconstrictors such as
endothelin, results in vasoconstriction, congestion, hypoperfusion, and
expression of adhesion molecules. The expression of adhesion molecules, in
turn, initiates leukocyte infiltration, augmented by proinflammatory and
chemotactic cytokines generated by ischemic tubular cells. These leukocytes
obstruct the microcirculation and release cytotoxic cytokines, reactive
oxygen species, and proteolytic enzymes, which damage the tubular cells.

This tubular damage is commonly known as acute tubular necrosis.

The term is misleading, however, because only some tubular cells are
necrotic; most are viable (either healthy or reversibly injured), and some are
apoptotic (i.e., undergoing an orderly programmed death). "Ischemic acute
kidney" and "acute tubular injury" have been proposed as better terms14;
neither of these newer terms is in common use.

Factors Increasing Renal Susceptibility to Ischemia

The kidneys are most vulnerable to moderate hypoperfusion when

autoregulation is impaired This phenomenon may be seen in elderly patients
or in patients with atherosclerosis, hypertension, or chronic renal failure, in
whom hyalinosis and myointimal hyperplasia cause structural narrowing of
the arterioles. Increased susceptibility to renal ischemia may also occur in
malignant hypertension because of intimal thickening and fibrinoid necrosis
of the small arteries and arterioles. In addition, in chronic kidney disease,
afferent arterioles in the functioning glomeruli become dilated, which
increases their filtration rate (hyperfiltration). Although an increased
glomerular filtration rate per nephron compensates for the loss of nephrons,
the inability to vasodilate further markedly impairs the kidney's ability to
autoregulate the glomerular filtration rate in low-perfusion states.

Failure of afferent resistance to decrease can also occur when a

patient is receiving nonsteroidal antiinflammatory drugs (NSAIDs) or
cyclooxygenase-2 (COX-2) inhibitors, which reduce the synthesis of
vasodilatory prostaglandins in the kidneys (Figure 2C).16,18,19,20 When this
occurs, angiotensin II, norepinephrine, and other vasoconstrictors released in
low-perfusion states may act on the afferent arterioles unopposed, further
decreasing glomerular capillary pressure. In other situations, sepsis,
hypercalcemia, severe liver failure, calcineurin inhibitors, and radiocontrast
agents can act through various vasoconstrictor mediators to increase
afferent arteriolar resistance. In addition, sepsis and contrast agents may
have direct toxic effects on the tubules. Decreased renal perfusion may also
cause an exaggerated drop in the glomerular filtration rate — for example,
when angiotensin II does not raise efferent resistance in patients who are
receiving angiotensin-receptor blockers or angiotensin-converting–enzyme
(ACE) inhibitors.

Narrowing of the main renal arteries due to atherosclerosis can

increase susceptibility to renal ischemia. In the case of unilateral renal-artery
stenosis, the contralateral, normally perfused kidney maintains the
glomerular filtration rate; however, renal failure may occur if renal-artery
stenosis in a solitary kidney or in both kidneys is greater than 70% of the
lumen.16 Renovascular insufficiency affecting the total renal mass may not
reduce poststenotic perfusion pressure enough to impair glomerular
filtration, but lowering blood pressure with antihypertensive therapy can
worsen ischemia and reduce renal function.

Low-Perfusion States in Normotensive Renal Failure

The cause of classic ischemic acute renal failure is hypovolemic,

cardiogenic, or distributive shock, with systolic blood pressure typically
dropping below 90 mm Hg. Normotensive renal failure usually involves
milder degrees of these low-perfusion processes but azotemia occurs
because of factors that increase renal susceptibility to ischemia, as
described above.

A less common mechanism for normotensive renal failure is severe

hypoperfusion in the presence of increased levels of vasoconstrictive
substances that limit the drop in blood pressure but that may occasionally
increase the measured blood pressure. Hypoperfusion may be systemic; for
example, in acute myocardial infarction or acute pulmonary edema, low
cardiac output may be accompanied by stable or even elevated blood
pressure mediated by sympathetic discharge. Hypercalcemia may increase
afferent glomerular arteriolar resistance, as mentioned above, and may lead
to marked hypovolemia because it may increase renal fluid losses.
Hypercalcemia may simultaneously cause systemic vasoconstriction, which
may paradoxically maintain or increase blood pressure.

Conversely, the severe hypoperfusion may be local: in renal-artery

stenosis, the poststenotic drop in blood pressure causes intrarenal ischemia
but is accompanied by hypertension from hypervolemia or renin release into
the circulation. Small-vessel disease in malignant hypertension similarly
leads to renal ischemia with increased renin secretion, which worsens the
hypertension.

Diagnosis of Normotensive Ischemic Acute Renal Failure

Common conditions in which normotensive ischemic acute renal failure

may develop include hypertension, chronic kidney disease, and old age, all
of which are associated with narrowing and blunted vasodilatory capacity of
renal vessels. Other conditions include cirrhosis, infection, myocardial
infarction, and congestive heart failure, as well as decreased intake of food,
which can reduce renal perfusion. In addition, diuretics reduce extracellular
volume, which can compromise cardiac output, and medications such as ACE
inhibitors and NSAIDs interfere with autoregulation. In classic ischemic acute
renal failure, when a patient goes into shock, the physician should be vigilant
in looking for a decrease in urinary output and an increase in the serum
creatinine concentration. In the normotensive variant, when the urinary
output decreases or the creatinine concentration increases, the clinician
should look for the presence of a low-perfusion state that may not have been
readily apparent. On the first day during which the creatinine concentration
increases, the blood pressure is usually noted to be below its usual level. In
persons who have underlying hypertension, blood pressure decreases from
high to normal (e.g., a drop in systolic blood pressure from 160 to 118 mm
Hg). Since patients are normotensive when renal failure occurs, the decrease
in blood pressure may be overlooked. Frequently the patient's usual blood
pressure is not recorded alongside current blood pressures; the usual blood
pressure must be ascertained from medical records and compared with the
blood pressures when the serum creatinine concentration began to rise. In
patients with hypovolemia, blood pressure must often be measured in the
upright position to confirm the degree and orthostatic nature of the decline
in blood pressure.

The cause of the decline in blood pressure may not be apparent. The
following two scenarios are not uncommon. In the first, a patient has what
turns out to be early sepsis but at the onset does not have fever or any
localizing symptoms. Such patients usually have one or more of the following
signs or symptoms: hypothermia, confusion, cool extremities, leukocytosis,
"bandemia" (an elevated level of band forms of white cells), leukopenia, or
unexplained lactic acidosis. Especially in patients with relative hypotension
and acute renal failure, any of these clinical pictures should lead the clinician
to search for an occult infection, using physical examination, imaging, and
microbiologic studies.

Alternatively, a patient in stable condition who is receiving diuretics for

hypertension or congestive heart failure may have anorexia and stop eating
for some reason or may otherwise have decreased salt intake. Progressive
negative sodium balance results in volume depletion and a downward drift in
blood pressure. Patients may not be aware of decreases in oral intake or may
not volunteer the information spontaneously. Thus, the clinician needs to
question the patient, family, and caregivers about recent weight loss or
changes in diet.

In addition to watching for low-perfusion states, clinicians should try to

identify susceptibility factors for renal ischemia (Table 1). Because
normotensive renal failure is multifactorial, several low-perfusion states and
susceptibility factors may be present. It is important to ask about the
patient's use of over-the-counter NSAIDs that might change renal perfusion
and to obtain a measurement of the serum calcium concentration, corrected
for any degree of hypoalbuminemia that is present. Sepsis, hypercalcemia,
and the hepatorenal syndrome may all cause both low-perfusion states and
increased afferent arteriolar resistance.

Susceptibility factors may sometimes result in ischemic acute renal

failure in the absence of a low-perfusion state. In these cases, the factors
result in severe enough renal vasoconstriction to cause a critical reduction in
renal perfusion. Examples are radiocontrast agents given to patients with
chronic renal failure and cyclosporine, tacrolimus, NSAIDs, or COX-2
inhibitors given in high or supratherapeutic doses.
 Patients with malignant hypertension, renal-artery stenosis in a solitary
kidney, or bilateral renal-artery stenosis have severe hypertension on
presentation but also have compromised renal perfusion. As high blood
pressure is controlled, renal function may worsen because of a critical drop
in glomerular capillary pressure. Once low-perfusion states and susceptibility
factors are recognized, a tentative diagnosis of normotensive renal failure
can be made, supported by laboratory findings and a response to therapy.

Laboratory Findings

Low-perfusion states trigger the body's water- and sodium-conserving

mechanisms. Thus, by the time glomerular capillary pressure and glomerular
filtration rate drop, the renal tubule is reabsorbing more water and sodium,
which also increases passive reabsorption of urea. There is experimental
evidence that this increase in reabsorption is facilitated by increased
expression of urea transporters in the collecting duct, mediated by high
plasma vasopressin concentrations.37 As a result of these changes, the
specific gravity of the urine often increases to 1.015 or higher, while urinary
sodium and urea excretion decrease (urinary sodium, <20 mmol per liter;
fractional excretion of sodium, <1%; and fractional excretion of urea, <35%),
and the ratio of blood urea nitrogen to creatinine rises from the usual value
of 10:1 to 20:1 or higher. These laboratory findings strongly suggest the
presence of renal hypoperfusion, even with a blood pressure in the normal
range.

If further ischemia causes acute tubular necrosis, the injured tubules

are no longer able to increase reabsorption of water, sodium, and urea. The
specific gravity of the urine becomes isosthenuric, similar to plasma, and
urinary sodium and fractional excretion of sodium and urea increase to more
than 20 mmol per liter, greater than 1%, and greater than 35%, respectively,
while the ratio of blood urea nitrogen to creatinine falls back to 10:1. The
urinary sediment will show sloughed renal tubular epithelial cells and debris-
filled, muddy-brown, granular casts. Although these elements are easily
recognized by the nephrologist examining the urinary sediment, clinical
laboratories may fail to identify them. Laboratory personnel may not
distinguish these pigmented casts from other granular casts and may not
examine a sufficient number of fields on the slide to find them. Furthermore,
the dipstick often shows no red cells, white cells, or proteinuria, so the
clinical laboratory may not examine the sediment as part of the urinalysis.
Many patients appear to be "between" prerenal azotemia and acute tubular
necrosis because of mixed findings — for example, a ratio of blood urea
nitrogen to creatinine of 25:1 and urinary sodium excretion of 15 mmol per
liter, suggesting prerenal azotemia, but with renal tubular epithelial cells in
the urinary sediment, a finding that is consistent with acute tubular necrosis.

Low-perfusion states and risk factors for renal ischemia are often
treatable and thus should be identified and dealt with promptly. If possible,
blood pressure that is on the lower end of the normal range should be
increased by correction of any hypovolemia and by dose reduction or
discontinuation of antihypertensive medication and other medications that
may lower blood pressure (e.g., narcotics). The patient should be evaluated
for occult infection, and any such infection should be treated. If acute tubular
necrosis has not yet occurred, effective therapy can reverse the increase in
the creatinine concentration within 24 to 48 hours. Improvement may even
occur if only one of the causes is reversed — for example, stopping
treatment with NSAIDs may be beneficial in a patient with severe
cardiomyopathy. However, if acute tubular necrosis has occurred, several
days are usually required before improvement is seen, even after the
underlying causes have been treated. If the cause of acute renal failure is
not apparent or if the patient's condition does not improve, consultation with
a nephrologist may help to ensure complete assessment and appropriate
management.

Reaction

An acute increase in the serum creatinine concentration is usually due

to renal ischemia. If the patient does not have frank hypotension,
normotensive ischemic acute renal failure must be considered. A drop in
systolic blood pressure to the low-normal range (100 to 115 mm Hg) must
not be overlooked. Many cases can be treated quickly by replacing volume,
treating infection, or stopping medications such as NSAIDs, diuretics, and
antihypertensive agents, especially ACE inhibitors or angiotensin-receptor
blockers.

Adequate nutrition should be provided; malnutrition is associated with

increased complications and death in patients with acute renal failure. Such
patients frequently have accelerated protein breakdown and increased
caloric needs, especially if they are critically ill or receiving renal-
replacement therapy (hemodialysis). In general, daily intake should include
25 to 30 kcal per kilogram of body weight; catabolic patients should receive
up to 1.5 g of protein per kilogram daily. Enteral nutrition with food or
formula designed for renal failure is preferred over parenteral nutrition, when
possible, because it maintains the integrity of the gut, requires less fluid
intake, and is less expensive.41,45,46 Advice from a dietitian or a nutrition
consultant may be helpful. Although intake of potassium and phosphate is
typically restricted because of impaired renal excretion, hypokalemia and
hypophosphatemia due to cell uptake or external losses can occur, and
supplements may be required.

Indications for intermittent or continuous renal-replacement therapy

are florid uremic symptoms, volume overload, hyperkalemia, and metabolic
acidosis that cannot be managed by conservative means. How severe these
problems need to be before treatment is initiated is controversial. Arguments
in favor of starting renal-replacement therapy early may be based on the
desire to avoid the dangerous metabolic, fluid, and electrolyte derangements
of uremia47; arguments in favor of withholding renal-replacement therapy
until definite indications are present are based on the risk of hemorrhage
during vascular access, hypotension and arrhythmia during dialysis, and
possible dialysis-induced recurrent renal injury or delayed renal recovery.48
Existing data on the timing of renal-replacement therapy are inadequate to
provide clear guidance.47,49 Unfortunately, many patients with
normotensive renal failure have important complicating factors, such as old
age, sepsis, and heart disease, and progression to frank shock and death is
not unusual.

ACUTE RENAL FAILURE

The sudden interruption of renal function that can be caused by obstruction,

poor circulation or underlying kidney disease.
Causes
1. Pre-renal:
o Conditions that diminishes renal perfusion to kidneys causing
hypoperfusion.

 Cardiac  Diuretic  Arterial

arrhythmias overuse embolsim
 Cardiac  Hemorrhage  Arterial/venous
tamponade  Hypovolemic thrombosis
 Cardiogenic shock  Tumor
shock  Trauma  Disseminated
Heart failure intravascular
  Anti-
coagulation (DIC)
 Myocardial hypentensive
 Eclampsia
infarction drugs
 Malignant
 Burns  Sepsis
hypertension
 Dehydration
 Vasculitis

o When renal blood flow is diminished, so is oxygen delivery. The resulting

hypoxemia causes rapid and irreversible damages to the renal system,
especially to the tubules.
o Renal hypoperfusion results to decreased glomerular filtration rate,
azotemia and increased tubular reabsorption of sodium and water.
o The decrease in GFR causes electrolyte imbalances and metabolic
acidosis.

2. Renal:
o Also called intrinsic or parenchymal renal failure, results from damage to
the filtering structures of the kidneys.
o 3 classifications: nephrotoxic
o inflammatory
o ischemic
 Poorly treated prerenal failure
 Nephrotoxins (aminoglycosides, analgesics, heavy metals, radiographic
contrast media, organic solvents, antimicrobials)
 Obstetric complications
 Crush injuries
 Myopathy
 Transfusion reaction
 Acute glumerulonephritis
 Acute interstitial nephritis
 Acute pyelonephritis
 Bilateral renal vein thrombosis
 Malignant nephrosclerosis
 Papillary necrosis
 Polyarteritis nodosa
 Renal myeloma
 Sickle cell disease
 Systemic lupus erythematosus (SLE)
 Vasculitis
 o In nephrotoxic damage, the delicate layer under the epithelium
(basement membrane) becomes irreversibly damaged, typically leading
to chronic renal failure.
o Ischemic tissues generate toxic oxygen-free free radicals, which cause
swelling, injury and necrosis.
o Nephrotoxic drugs accumulate in the renal cortex, causing renal failure
that manifests after treatment or other exposures.
o Nephrotoxin damage tends to be limited in the proximal tubules, while
ischemic necrosis tends to distribute along parts of the nephron.
3. Post-renal:
o Bladder obstruction
 (anticholinergic drugs, autonomin nerve dysfunction,
infection, tumors)
o Ureteral obstruction – restricts urine flow from kidneys to bladder
(blood clots, calculi, edema, necrotic renal papillae, retroperitoneal
fibrosis or hemorrhage, accidental ligation, uric acid crystals,
tumors)
o Urethral obstruction –by BPH, tumors/stricture

Phases of ARF: Oliguric, Diuretic, Recovery

o Oliguric phase – urine output may remain at less than 40 mL/hour or
400 mL/day for a few days or weeks
o Diuretic phase – marked by increased urine output of more than 400
mL/day, as the kidneys become unable to conserve sodium and water.
this phase causes dehydration and electrolyte imbalances.
o Recovery phase – azotemia gradually disappears; urine output returns
to normal or near-normal renal function over 3-12 months.

Signs and Symptoms

o Early signs: oliguria, azotemia and/or anuria
o GI: anorexia, nausea, vomiting, diarrhea-constipation, stomatitis,
bleeding, hematemesis, dry mucous membranes, uremic breath
o CNS: headache, drowsiness, irritability, confusion, peripheral
neuropathy, seizures, coma
o Integument: Dryness, pruritus, pallor, purpura, uremic frost
o Cardiovascular: hypotension, then hypertension, arrhythmias, fluid
overload, heart failure, anasarca, anemia, altered clotting mechanisms
o Respiratory: pulmonary edema, Kussmaul’s respirations (indicates
metabolic acidosis)

Diagnosis
o Hyperkalemia, decreased bicarbonate levels, acidemia (low blood pH)
 o Urinalysis: casts, decreased urine specific gravity, proteinuria, urine
osmolality close to serum osmolality, urine sodium level <20 mEq/L (if
resulting in renal hypoperfusion) or > 40 mEq/L (if intrarenal cause)
o Creatinine clearance test:
o Electrocardiogram: tall, peaked T waves, widened QRS complex,
disappearing P waves (hyperkalemia)
o Ultrasonography: plain abdominal films, KUB radiography, excretory
urography, renal scan, retrograde pyelography, CT scan

Medical Management:

A. Fluid Management:
1. Push fluid + 200-500 cc NSS to rule out pre-renal azotemia; I&O catheter
and check post-void residual to rule out obstruction.
2. Furosemide (Lasix) 100-200 mg IVP or Mannitol 20% 500 cc x 2 doses.
Observe for 2 hours for complications: CHF, pulmonary edema
3. Dopamine 1 amp 200 mg + D5W 250 cc x 10 ugtts/min
4. Consider CVP insertion, maintain euvolemia
Total Fluid Intake= Urine output Yesterday + 500 cc insensible water loss
In oliguric patients (400 ml/day) limit to < 1L/day

B. Diet/Nutritional Support:
1. For weight maintenance: High Caloric Intake
Low protein = 0.5 g/kg/day (to decrease nitrogenous
wastes)
Carbohydrates: 100 g/day PO4 = 800
mg/day
NaCl = < 1 g/day Mg = none

2. For weight gain = add 1,000 kcal/day for gain of approx 1 kg/week

C. Electrolytes:
1. Hyperkalemia
2. Metabolic acidosis
3. Hypocalcemia
4. Hyperphosphatemia
5. Hyperuricemia: no treatment unless with gout (Allopurinol 300 mg/day
for 2 days then 100 mg/day)
6. Avoid Mg-containing antacids, NSAIDS and other nephrotoxins

D. Adjust all drug dosages according to GFR

E. Indications for initiating hemodialysis

o Pulmonary congestion (unresponsive to Lasix)
 o Severe metabolic acidosis
o severe hyperkalemia
o BUN >100 mg/dl or creatinine > 9 mg/dl

Nursing Management:
o Weigh daily
o Insert Foley catheter
o Avoid Mg-containing antacids, salt substitutes, NSAIDS and other
nephrotoxic agents
o Don’t take BP or insert IV line on left (or right) arm

Possible Nursing Diagnoses

• Fluid Volume Deficit r/t hypovolemia, followed by Fluid Volume
Excess r/t inability of kidneys to produce urine secondary to ARF
o Plan: Client will not develop FVD and ARF, or client will
not develop FVE, as shown by return to balanced intake
and output.
o Interventions:
o Strictly monitor client’s fluid intake and output every shift.
o Monitor client’s vital signs q1h with neurochecks, call
physician if UO <20 cc/hour
o Monitor laboratory results.
o Measure client’s weight daily at same time.
o Measure urine specific gravity every shift
o Provide oral care PRN, provide ice chips or lip balm to
patient.
o Administer medications with meals.

• Altered Nutrition: Less than Body Requirements r/t anorexia

secondary to renal failure or dietary restrictions
o Plan: The client will maintain adequate nutrition, as
shown by sufficient intake of food.
o Interventions:
o Strictly monitor client’s intake and output q shift.
o Provide pleasant environment at mealtime.
o Present food in small amounts.
o Provide medications as prescribed by physician (anti-
emetics)

• High Risk for Impaired Skin Integrity r/t disease process or poor
cellular nutrition
o Plan: The client will not develop impaired skin integrity,
as shown by intact skin.
o Interventions:
 o Monitor client for sign of skin breakdown q shift.
o Provide frequent turning of client q2h
o Encourage range-of-motion (ROM) exercises OD.

• High Risk for Infection r/t lowered resistance

o Plan: The client will not develop infection, as evidenced
by normal vital signs and white blood cell count.
o Interventions:
o Monitor laboratory results daily.
o Check client for signs of infection.
o Check Foley catheter for signs of contamination.

• Anxiety r/t progressive disease process

o Plan: The client will be able to cope with present anxiety
as shown by calmness and acceptance to present
condition.
o Interventions:
o Allow client time to ask questions.
o Give careful explanations for treatment modalities.

Drug Study

The goal of treatment is to control symptoms, reduce complications,

and slow the progression of the disease. Diseases that cause or result from
chronic kidney failure must be controlled and treated as appropriate.
Blood transfusions or medications such as iron and erythropoietin
supplements may be needed to control anemia.
Fluids may be restricted, often to an amount equal to the volume of
urine produced. Restricting the amount of protein in the diet may slow the
build up of wastes in the blood and control associated symptoms such as
nausea and vomiting.
Salt, potassium, phosphorus, and other electrolytes may be restricted.
Dialysis or kidney transplant may eventually be needed.
The medications given are directed on underlying cause of the acute
renal failure or to prevent complications.
For instance, patient may take antibiotics to prevent or treat infections,
and may take other medicines to get rid of extra fluid and prevent
electrolyte imbalances, which can be dangerous. Health care provider may
adjust the dose of medicines so that they work well.
Diuretic medications, such as furosemide, have traditionally been used
to treat acute renal failure because they quickly increase urine output. But
many experts now feel that they may not be helpful and may actually be
harmful to people who are very ill. Depending on the cause and severity of
your acute renal failure, your doctor may choose another method to get rid
of extra fluids.

Furosemide
Furosemide is a loop diuretic (water pill) that prevents your body from
absorbing too much salt, allowing the salt to instead be passed in your
urine.It treats fluid retention (edema) in people with congestive heart failure,
liver disease, or a kidney disorder such as nephrotic syndrome. This
medication is also used to treat high blood pressure (hypertension).

Side Effects:
• dry mouth, thirst, nausea, vomiting;
• feeling weak, drowsy, restless, or light-headed;
• fast or uneven heartbeat;
• muscle pain or weakness;
• urinating less than usual or not at all;
• easy bruising or bleeding, unusual weakness;
• a red, blistering, peeling skin rash;
• hearing loss; or
• nausea, stomach pain, low fever, loss of appetite, dark urine, clay-
colored stools, jaundice (yellowing of the skin or eyes).
Less serious side effects may include:
• diarrhea, constipation, or stomach pain;
• headache;
• numbness, burning, pain, or tingly feeling;
• dizziness; or
• blurred vision