Brief Reviews

Pathophysiology of Hypertensive Renal Damage

Implications for Therapy
Anil K. Bidani, Karen A. Griffin

Abstract—Unlike the majority of patients with uncomplicated hypertension in whom minimal renal damage develops in
the absence of severe blood pressure (BP) elevations, patients with diabetic and nondiabetic chronic kidney disease
(CKD) exhibit an increased vulnerability to even moderate BP elevations. Investigations in experimental animal models
have revealed that this enhanced susceptibility is a consequence of an impairment of the renal autoregulatory
mechanisms that normally attenuate the transmission of elevated systemic pressures to the glomeruli in uncomplicated
hypertension. The markedly lower BP threshold for renal damage and the steeper slope of relationship between BP and
renal damage in such states necessitates that BP be lowered into the normotensive range to prevent progressive renal
damage. When BP is accurately measured using radiotelemetry in animal models, the renal protection provided by
renin-angiotensin system (RAS) blockade is proportional to the BP reduction with little evidence of BP-independent
protection. A critical evaluation of the clinical data also suggests that the BP-independent renoprotection by RAS
blockade has been overemphasized and that achieving lower BP targets is more important than the selection of
antihypertensive regimens. However, achievement of such BP goals is difficult in CKD patients without aggressive
diuresis, because of their proclivity for salt retention. The effectiveness of RAS blockers in lowering BP in patients who
have been adequately treated with diuretics, along with their potassium-sparing and magnesium-sparing effects,
provides a more compelling rationale for the use of RAS blockade in the treatment of CKD patients than any putative
BP-independent renoprotective superiority. (Hypertension. 2004;44:595-601.)
Key Words: nephrosclerosis 䡲 autoregulation 䡲 telemetry 䡲 antihypertensive agents
䡲 renin-angiotensin system 䡲 glomerulosclerosis
Downloaded from http://ahajournals.org by on October 5, 2019

T he relative risk of serious renal damage in patients with

uncomplicated essential hypertension is low as compared
with other cardiovascular complications.1,2 Nevertheless,
given the huge prevalence of hypertension in the general
population, it still remains the second leading cause of
end-stage renal disease (ESRD), with the risk being substan-
tially higher in blacks.2 Historically, hypertension-induced
renal damage in patients with uncomplicated essential hyper-
tension has been separated into the 2 distinct clinical and
histological patterns of “benign” and “malignant” nephro-
sclerosis.3 Benign nephrosclerosis is the pattern observed in
the majority of patients with uncomplicated primary hyper-
tension. The somewhat nonspecific vascular lesions of hya-
line arteriosclerosis develop slowly without overt proteinuria.
Although focal ischemic glomerular obscelence and nephron
loss occur over time, renal function is not seriously compro-
mised except in susceptible individuals such as blacks in
whom the process tends to follow a more severe and
accelerated course. By contrast, “malignant” nephrosclerosis
is observed with very severe hypertension (malignant phase
of essential hypertension) and has a characteristic renal
phenotype of acute disruptive vascular and glomerular injury
with prominent fibrinoid necrosis and thrombosis. Ischemic
glomeruli are frequent because of vascular injury. Renal
failure can develop rapidly in the absence of adequate
therapy. Although episodes of malignant nephrosclerosis
undoubtedly contribute to the development of ESRD in
untreated, noncompliant, or cocaine-abusing patients, the
full-blown clinical phenotype has fortunately become uncom-
mon with the wide availability of effective antihypertensives.
A major advance over the past 2 decades has been the
recognition that the spectrum of hypertension-induced renal
damage extends beyond benign and malignant nephrosclero-
sis. There is abundant evidence that coexistent hypertension
plays a predominant role in the progression of most chronic
kidney diseases (CKD), including diabetic nephropathy, pres-
ently the leading cause of ESRD.3–5 These deleterious effects
are observed with even mild-to-moderate blood pressure (BP)
elevations in CKD patients, indicating an enhanced vulnera-
bility to hypertensive renal damage with a lower BP threshold
for damage and a steeper slope of the relationship between BP
increase and renal damage (Figure 1). However, it has been
difficult to quantitate the contribution of hypertension to
progressive renal disease because of the lack of a specific

Received August 5, 2004; first decision August 11, 2004; revision accepted September 3, 2004.
From Loyola University Medical Center and Edward Hines Jr. VA Hospital, Maywood, Ill.
Correspondence to Anil K. Bidani, MD, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153. E-mail abidani@lumc.edu
© 2004 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org DOI: 10.1161/01.HYP.0000145180.38707.84

595
 596 Hypertension November 2004
Figure 1. The differing BP thresholds and slopes of the relation-
ship between BP and renal damage in patients with uncompli-
cated hypertension (benign and malignant nephrosclerosis) and
those with diabetic and nondiabetic CKD.
histological phenotype. Vascular pathology, considered the
hallmark of hypertensive injury, often is not prominent in this
setting of CKD. Instead, an accelerated segmental or global
glomerulosclerosis (GS) seems to be superimposed on the
intrinsic phenotype of the underlying renal disease.3,5 Never-
theless, recent investigations in experimental animal models
have increased our understanding of the mechanisms that
underlie the observed differences in histological phenotypes
and susceptibility to hypertensive renal damage illustrated in
Figure 1.
Pathophysiology of Hypertensive
Renal Damage
Downloaded from http://ahajournals.org by on October 5, 2019
The direct adverse consequences of hypertension on any
vascular bed are expected to be a function of the degree to
which it is exposed to the increased pressures. The pathoge-
netic determinants of hypertensive renal damage can thus be
broadly separated into 3 categories: (1) the systemic BP
“load”; (2) the degree to which such load is transmitted to the
renal vascular bed; and (3) local tissue susceptibility to any
given degree of barotrauma. It seems self-evident that be-
cause the ambient BP profile in conscious animals is charac-
terized by spontaneous, rapid, and often large fluctuations in
BP, conventional isolated BP measurements are inherently
inadequate to define quantitative relationships between BP
and renal damage.5– 8 The availability of BP radiotelemetry by
allowing chronic BP monitoring in conscious unrestrained
animals has provided a major advance in hypertensive target
organ damage research.5– 8
BP Load and Its Transmission to the
Renal Microvasculature
Normally, increases in systemic BP, episodic or sustained, are
prevented from fully reaching the renal microvasculature by
proportionate autoregulatory vasoconstriction of the preglo-
merular vasculature such that renal blood flow and glomer-
ular hydrostatic pressures (PGC) are maintained relatively
constant (Figure 2; pattern A).5,9 These autoregulatory re-
sponses therefore provide the primary protection against
hypertensive renal damage.5,10 As long as BP remains below
a certain limit (within the autoregulatory range), only benign
nephrosclerosis is observed; however, if this threshold is
Figure 2. Illustration of the spectrum of pressure flow relation-
ships in the renal vascular bed in hypertension. Pattern A repre-
sents the normal renal autoregulatory responses observed in
uncomplicated hypertension and shows the constancy of renal
blood flow (RBF) despite BP changes within the autoregulatory
range. Pattern B indicates the ambient renal vasodilation but
preserved autoregulation after uninephrectomy. Pattern C illus-
trates the impaired RBF autoregulatory responses observed in
the 5/6 renal ablation model. Pattern D shows the complete loss
of renal autoregulation in 5/6 renal-ablated rats treated with di-
hydropyridine CCBs. Although RBF is depicted as the depen-
dent variable, the same relationships are expected to obtain for
PGC, given that the autoregulatory resistance changes are con-
fined to the preglomerular vasculature.
exceeded, acute disruptive injury (malignant nephrosclerosis)
is expected to result despite intact autoregulation.5 However,
once vascular injury develops, autoregulatory responses can
be secondarily compromised and result in the amplification of
renal damage (vide-infra).11,12 A clear illustration of such a
threshold relationship between BP and malignant nephro-
sclerosis has recently been demonstrated using BP radiote-
lemetry in the stroke-prone spontaneously hypertensive rat
model.13 Moreover, as would be predicted, even modest BP
reductions to below this threshold were shown to prevent
such damage.13 In general, chronic hypertension tends to shift
both the upper and lower limits of autoregulation to the right
and represents a protective adaptation.5,14 Therefore, an acute
severe elevation in BP is more likely to exceed the autoreg-
ulatory threshold and cause injury than equally severe hyper-
tension that develops more gradually.5,13
However, even in the absence of severe hypertension, renal
damage can still develop if there is an enhanced transmission
of elevated systemic pressures to the renal microvasculature
as illustrated in Figure 2. Any significant preglomerular
vasodilation, as observed after uninephrectomy or in early
type 1 diabetes (before significant nephropathy), is expected
to result in a greater fractional transmission of the ambient
systemic pressures (Figure 2; pattern B).15 However, if such
vasodilation is not accompanied by impaired renal autoregu-
lation or severe hypertension, only a modest increase in the
vulnerability to hypertensive injury is expected.15 This may
account for the largely benign renal course in most unine-
phrectomized individuals and possibly the long delay in the
development of overt diabetic nephropathy.15,16 However, if
 Bidani and Griffin
renal autoregulation is additionally impaired, as seen after
more severe (ⱖ75%) renal mass reduction in animals or in
humans with diabetic or nondiabetic CKD10,17–19 (Figure 2;
pattern C), the susceptibility to hypertensive injury is mark-
edly enhanced with the greatly reduced BP threshold for
damage and the steeper relationship between BP and renal
damage as illustrated in Figure 1. Additionally, such en-
hanced glomerular pressure transmission in the absence of
hypertension severe enough to cause vascular injury primar-
ily leads to accelerated GS.3,5
The clearest demonstration of this phenomenon has been
provided in the most extensively investigated model of CKD,
the rat 5/6 renal ablation model.4 – 6 Through the use of BP
radiotelemetry, it has been shown that the progressive GS of
the initially normal remnant glomeruli in these rats follows
the quantitative relationships with BP shown in Figure 1 and
predicted by Figure 2.6,17 The importance of autoregulatory
capacity as a determinant of the susceptibility to hypertensive
injury is further illustrated by the effects of the dihydropyr-
idine calcium channel blockers (CCBs) in this model. Given
the critical dependence of autoregulatory response on
voltage-gated calcium channels, these agents, not unexpect-
edly, further impair the already impaired renal autoregulation
in the 5/6 ablation model5,20 (Figure 2; pattern D). And
predictably, CCBs also further reduce the BP threshold and
increase the slope of the relationship between GS and BP
(percent increase in GS/mm Hg in BP) such that greater GS is
observed at any given BP elevation as compared with
untreated rats, and protection is not achieved without achiev-
Downloaded from http://ahajournals.org by on October 5, 2019
ing normotension.5,20 Conversely, if preglomerular vasodila-
tion and autoregulatory impairment are prevented in this
model through the substitution of a low-protein diet, GS is
also ameliorated despite continued hypertension.10,21 How-
ever, if CCBs are given to the low-protein diet–fed rats, renal
autoregulation is impaired and the protection against GS is
also abolished.21 Similar adverse effects of dihydropyridine
CCBs, and protective effects of a low-protein diet on GS,
have also been noted in the streptozotocin-induced diabetes
model.4,22
Of note, differences in autoregulatory efficiency have also
been postulated to account for some of the strain (genetic)
differences in susceptibility to hypertensive injury.5,11,23
However, it needs to be emphasized that these adverse effects
of impaired renal autoregulation on susceptibility to hyper-
tensive renal damage are only observed in a vasodilated
vascular bed. In a vasoconstricted bed, the consequences of
impaired autoregulation primarily result in a diminished
capacity to maintain renal blood flow and glomerular filtra-
tion rate (GFR) when systemic pressures are reduced, with an
enhanced potential for ischemic tubulointerstitial injury. A
similar ischemic pathogenesis may underlie the tubulointer-
stitial injury observed in angiotensin infusion models.12
Local BP-Independent Determinants of
Tissue Susceptibility
Although still poorly defined, genetic or acquired differences
in intrinsic structure or function may result in differences in
the severity of damage expressed at any given degree of
increased pressure exposure (barotrauma).5,8,11 For instance,
Hypertensive Renal Damage 597
there is evidence that glomerular hypertrophy may be an
independent risk factor for GS.5,21,24 In addition to the
expected increase in wall tension (Laplace Law:
tension⫽pressure⫻radius), hypertrophy of glomerular capil-
laries may also compromise their ability to withstand me-
chanical stress.25,26 It has been proposed that the glomerular
capillary epithelial cell (podocyte) through its interdigitating
foot processes provides structural support against pressures
that are substantially higher than in systemic capillaries (⬇45
versus ⬇20 mm Hg). The limited replication potential of this
terminally differentiated cell during glomerular hypertrophy
may limit its ability to maintain physical integrity and
mechanical support during hypertensive stress.
However, of the local mechanisms, the BP-independent
tissue damage promoting effects of angiotensin II and, more
recently, aldosterone have received the greatest empha-
sis.4,12,24,27–29 The triggering of several downstream deleteri-
ous cellular and molecular pathways is postulated to lead to
oxidative stress and the activation of growth factors and
fibrogenic mediators such as transforming growth factor-␤
and plasminogen activator inhibitor-1. Despite the consider-
able in vitro data demonstrating these pathways, the primary
evidence to support their in vivo importance is derived from
the very large number of studies in animal models that have
claimed to show glomeruloprotection by renin-angiotensin
system (RAS) blockade and/or aldosterone antagonists over
and beyond that achieved by “equivalent” BP reductions with
other antihypertensive regimens.4,24,27–30 However, when BP
has been measured more continuously by radiotelemetry
instead of intermittently by tail-cuff, the renoprotection can
be entirely accounted for by the achieved BP reductions with
little evidence of additional BP-independent protection.5,31,32
This is true of both the malignant nephrosclerosis and the
accelerated GS models (5/6 ablation). No evidence of a shift
to a higher BP threshold for damage or a decrease in the slope
of the relationship between BP and GS is seen with RAS
blockade, as would be expected with significant BP-
independent protection. In this context, it is relevant to note
that isolated PGC measurements like isolated BP measure-
ments may not accurately reflect chronic pressure exposure.
Such limitations probably account for the lack of consistent
correlations between PGC and GS,24 even in models demon-
strating excellent correlation with radiotelemetrically mea-
sured systemic BP.5,6
Collectively, these data suggest that the activation of
downstream molecular mediators of tissue injury may not be
exclusive to angiotensin II and/or aldosterone but may rep-
resent a response to tissue stress and/or injury per se. There is
evidence that pressure alone can activate many of these
downstream pathways,32–35 and the histological phenotype of
hypertensive renal damage exhibits little difference in models
with or without overt RAS activation.3 Conversely, little
evidence of the activation of these deleterious pathways or
renal damage is observed in the absence of elevated pressures
despite substantial angiotensin and aldosterone increases
during low salt intake, congestive heart failure, or cirrhosis,
or in the clipped kidney of the 2-kidney–1-clip model of
Goldblatt hypertension.36 In fact, the administration of even
very large amounts of exogenous aldosterone results in little
 598 Hypertension November 2004
target organ damage in animals maintained normotensive on
a low-salt diet. Moreover, investigations into the pathogenic
role of aldosterone have usually not adequately controlled for
changes in potassium balance, which can independently
impact renal damage.37 Thus, although it remains possible
that angiotensin II and aldosterone may amplify hypertensive
renal damage through BP-independent mechanisms in certain
situations and/or models, definitive evidence remains to be
obtained.
Unresolved Issues
Despite the progress that has been achieved, certain funda-
mental issues of hypertensive target organ damage remain
unresolved. The term “BP load” is used generically because
the relative pathogenic importance of individual BP parame-
ters (mean, systolic, diastolic, pulse pressure, and BP vari-
ability) remains undefined.5 Although recent clinical data
have indicated that systolic and possibly pulse pressures are
more closely correlated with target organ damage than mean
arterial or diastolic pressures,1 the pathophysiological basis of
such empirical observations remains unknown. It is also
possible that the relative pathogenic potential of these indi-
vidual BP parameters may differ for different target organs.
Moreover, the transmission of fluctuating systemic pressures
to target organs in real time must also be a dynamic process
with the transmission of individual BP fluctuations depending
on their rate (frequency) and the kinetics of the autoregula-
tory responses. And fluctuations in microvascular pressures
(pressure transients and/or peak pressures) may have a greater
Downloaded from http://ahajournals.org by on October 5, 2019
pathogenic potential than sustained steady elevations. The
unusually rapid activation kinetics of the afferent arteriolar
myogenic response noted recently seem to be consistent with
this protective function.38 Moreover, the fact that systolic,
rather than mean, BP seems to be the trigger signal for this
response38 may be indicative of a greater pathogenetic poten-
tial of systolic (peak) pressures. Biophysical approaches are
being developed to separate the BP energy into its component
parts and to assess the potential renal microvascular trans-
mission and pathogenic importance of these individual com-
ponents of BP power (energy/unit time).5,15,38
Therapeutic Implications
The pathophysiology of hypertensive renal damage discussed
suggests 3 broad targets for therapeutic interventions: (1)
reduction of BP load; (2) reduction of pressure transmission
to the renal microvasculature; and (3) interruption and/or
modification of the local cellular/molecular pathways that
mediate eventual tissue injury and fibrosis.
Reduction of BP Load
Given the substantial evidence that local hypertension (baro-
trauma) plays a major role in the initiation and progression of
renal damage, it seems self-evident that the most effective
preventive strategy would be to treat the proximate cause of
such increased pressures, ie, effectively reduce the systemic
arterial pressures. However, the relative success of such BP
reductions in preventing renal damage will vary with the
clinical context. Even modest and easily achieved BP reduc-
tions to below the autoregulatory threshold are likely to
prevent malignant nephrosclerosis in patients with uncompli-
cated hypertension.5,13 By contrast, BP may need to be
lowered well into the normotensive range in CKD patients to
prevent additional GS. The more limited success against
progressive renal disease as compared with malignant neph-
rosclerosis and hypertensive stroke is thus not unexpected.1,2
The systolic BP goal of 140 to 150 mm Hg that was
considered acceptable until recently in patients with CKD,
because even if achieved, it might not have been low enough
to prevent continued glomerular barotrauma. The pathophys-
iology of hypertensive glomerular injury in these states
predicts that the more advanced the CKD (the greater the
vasodilation and autoregulatory impairment), the lower the
achieved BP will need to be to normalize intrarenal pressures.
Moreover, even transient episodes of BP elevations are
predicted to be more freely transmitted to the glomerular
capillaries, suggesting the need for around-the-clock BP
control.39 The recognition of the need for more aggressive BP
control for such patients in the recent guidelines is consistent
with these insights.1,40 Even within the CKD population, the
impact of BP reductions may differ because of intrinsic
differences in susceptibility because of disease cause and
severity, as well as genetic and environmental factors.5,7,8 The
steeper the slope of the relationship between BP and renal
damage, the greater the impact of any given BP reduction.
Thus, it is not surprising that greater benefits from aggressive
BP control are seen in proteinuric than in nonproteinuric
CKD patients,40 because proteinuria may reflect increased
glomerular pressure transmission or may be a biologic marker
of enhanced intrinsic glomerular susceptibility.
Class Differences Between Antihypertensives
As for experimental models, the relative merits of individual
antihypertensive classes and the ability of RAS blockade to
provide BP-independent target organ protection have been
the subject of much clinical investigation and debate.1,40 – 44
However, the claims for the therapeutic superiority of RAS
blockade have not been sustained, at least for cardiovascular
disease and stroke, most recently by the very large landmark
ALLHAT trial.1,41– 44 Therefore, recent guidelines now stress
the primary importance of BP reductions per se in preventing
target organ damage.1 In fact, based on their cost and
effectiveness in the ALLHAT trial, the thiazide diuretics,
despite their expected stimulation of RAS, have been recom-
mended as the initial regimen of choice for most patients with
hypertension, with other classes of drugs being added for
comorbid conditions.1 Patients with CKD, however, remain a
notable exception, with continued emphasis on RAS blockade
as the initial regimen of choice.1,40 These recommendations
are based on the results of several randomized controlled
clinical trials in diabetic and nondiabetic nephropathy that
have shown better renoprotection with RAS blockade, with
15% to 50% relative risk (RR) reductions in renal disease
endpoints (doubling of serum creatinine, ESRD) in compar-
ison to other antihypertensive regimens.1,40,45– 48 Given that
the primary importance of optimal BP control is now ac-
knowledged by even the most avid advocates of RAS
blockade, and that most CKD patients usually require at least
2 agents for such BP control, the issue of BP-independent
 Bidani and Griffin
renoprotective superiority of RAS blockade is more of
scientific than clinical practice relevance because RAS block-
ers are excellent antihypertensive agents when combined with
diuretics in this population (vide-infra).
Nevertheless, a critical analysis of the clinical trial evi-
dence shows that the interpretations are not as definitive and
the much emphasized BP-independent benefits of RAS
blockade are much smaller than have been implied. A
re-examination of the landmark clinical trial in type 1 diabetic
nephropathy patients by the Collaborative Study Group illus-
trates this issue.45 A very impressive ⬇50% RR reduction by
RAS blockade was reported (25 renal end-points in 207
captopril-treated patients versus 43 in 202 conventionally
treated controls), with almost all of the end-points and RR
reductions being observed in the higher-risk patients with a
serum creatinine of ⱖ1.5 mg/dL at entry. Although the
control group had greater proteinuria at entry, and BP during
the course exhibited small but statistically significant differ-
ences favoring the captopril group, these large RR reduction
estimates were claimed to not be significantly altered by
statistical adjustment for these differences. However, a sub-
sequently published substudy of the 108 nephrotic patients
considered to be at greatest risk in the original cohort49 casts
considerable doubts on the validity of the interpretations in
the parent study. Although its implications were not ad-
dressed, this substudy revealed that these high-risk nephrotic
patients had been disproportionately randomized, with 42
being entered in the captopril versus 66 in the placebo group
(P⬍0.002 by ␹2). The high-risk status of these patients was
Downloaded from http://ahajournals.org by on October 5, 2019
confirmed by the fact that remission in proteinuria was only
achieved in 8 patients (7 in the captopril group) who also
exhibited very substantial BP reductions, in contrast to the
essentially unchanged BP in the 100 nonresponders whose
average serum creatinine more than doubled during the study.
Of note, of the 16 black nephrotic patients, none of whom
responded, 14 were assigned to the control group (P⬍0.03).
It is likely that this flawed randomization of the 24 nephrotic
patients at very high risk to the placebo group largely
accounted for the difference of 18 more end-points in the
control group described in the initial report.
With respect to the relative magnitude of the BP-dependent
versus BP-independent effects of RAS blockade, some in-
sights may be provided by the results of the more recent
IDNT and RENAAL trials of angiotensin receptor blockers
(ARBs) in type 2 diabetic nephropathy.46,47 The additional
renoprotection (slower decline in GFR) provided by ARBs
compared with control antihypertensive regimens was ⬇1
mL/min per year (⬇5 versus ⬇6 mL/min per year/1.73m2).
However, given the GFR decline rates of 12 mL/min per year
that have been observed historically in untreated patients,16
BP reductions per se in the conventionally treated groups
reduced the rate of GFR decline by 6 mL/min per year.
Therefore, ⬇85% of the total benefit conferred by ARBs may
be attributable to their antihypertensive effects. Moreover, the
BP independence of even this residual additional renoprotec-
tion by ARBs may be questioned by the fact that the achieved
clinic BP in the RAS blockade-treated groups, as in other
clinical trials in diabetic and nondiabetic nephropathy pa-
tients, tended to be 2 to 4 mm Hg lower than in the control
Hypertensive Renal Damage 599
groups. Although such small differences have generally been
felt to be insufficient to explain the 15% to 35% RR
reductions observed in these studies, recent data including
that from the ALLHAT study suggest that such small but
significant differences in clinic pressures may have greater
impact on outcomes than generally assumed.41,43 It is possible
that such differences in clinic BP reflect larger differences in
ambient and/or nocturnal BP, as revealed in a HOPE sub-
study.50 Reductions of 3/2 mm Hg in clinic pressures in a
subset of 38 ramipril-treated patients translated into a reduc-
tion of 10/4 mm Hg in an average 24-hour ambulatory BP
(ABP) in the same patients because of a large decrease in
nocturnal BP of 17/8 mm Hg (ramipril was dosed in the
evening). Thus, as in animals, BP-independent effects of RAS
blockade are difficult to demonstrate when ABP monitoring
is used,5,8 suggesting a need for caution when inferring BP
independence based solely on clinic pressures, which are
usually not controlled for the time of day and/or relationship
to drug dosing. Such effects may be particularly important in
diabetic hypertensive patients, who often do not exhibit the
normal nocturnal decline in BP.16 Given the experimental
animal data, it is not surprising that significantly better
correlations are observed between 24-hour ABP measure-
ments than clinic pressures with markers of cardiovascular
target organ damage, including proteinuria.5,8 Therefore, even
though intermittent 24-hour ABP monitoring may not provide
as complete an assessment of the total chronic BP burden as
is possible with radiotelemetry in experimental models, its
incorporation in future clinical trials, at least in subsets of
patients, should be strongly considered.
Caution also needs to be exercised when drawing conclusions
regarding BP-independent effects based on a comparison be-
tween antihypertensive regimens. For instance, there is evidence
to suggest that ␤-blockers, because of their effects on heart rate
and the augmentation of the pressure wave reflection, may not
lower central pressures as effectively as other agents, despite
similar peripheral pressure measurements.51 Similarly, the supe-
rior renal outcomes with RAS blockade as compared with CCBs
as in the AASK trial,48 might in fact reflect the adverse effects of
CCBs on BP transmission to the microcirculation.20,21 However,
it should be acknowledged that unlike rodent models, the
evidence for deleterious effects of dihydropyridine CCBs in
humans for hard end-points, rather than proteinuria, is more
mixed.52 This may reflect the limitation of clinic BP measure-
ments combined with the fact that the adverse effects of CCBs
on renal autoregulation and BP transmission are counteracted by
the achieved BP reductions, ie, the greater the BP reduction, the
less the deleterious impact. Moreover, the deleterious effects of
CCBs may be significant only in the accelerated GS models in
which the capillary bed is the primary site of injury and may not
be relevant to more proximal vascular injury. The effectiveness
of CCBs in protecting against malignant nephrosclerosis as well
as cardiovascular and cerebrovascular hypertensive target organ
damage is consistent with such interpretations.1,41– 43
Achievement of BP Goals
Over and beyond the issues of the recognition of the need to
pursue lower BP targets for CKD patients, the difficulty of
achieving such BP goals has proved to be a major therapeutic
 600 Hypertension November 2004
challenge, with 3 to 4 drugs often deemed necessary.40
Nevertheless, there is reason to suspect that at least some of
this difficulty has stemmed from an underuse of aggressive
diuretic use in these patients,53 in part because of some
justifiable concerns about their adverse impact on renal
function parameters.54 However, hypertension in most CKD
patients is volume-dependent with relative RAS suppression
and exhibits an increased BP salt sensitivity because of
altered pressure natriuresis.55,56 As a consequence, BP reduc-
tion by agents other than diuretics usually tends to amplify
the salt retention. Such pathophysiology explains why mono-
therapy in CKD patients, including that with RAS blockers, is
generally ineffective. Therefore, adequate BP control in CKD
patients usually cannot be achieved without effective diuresis,
and some hemodynamically mediated elevations in blood
urea nitrogen and creatinine levels are unavoidable and,
unless severe, may need to be considered acceptable. Effec-
tive diuresis also activates the RAS and restores the antihy-
pertensive effects of RAS blockade.57 The fact that diuretics
and RAS blockers counteract each other’s side effects on
potassium and magnesium balance but are synergistic for BP
reductions renders their combination a logical antihypertensive
regimen for these patients. In fact, a better case can be made for
such use of RAS blockade in achieving BP goals than for any
putative BP-independent protection. It is possible that some of
the BP-independent beneficial effects of both RAS blockade and
the relatively small doses of Aldactone on cardiovascular mor-
bidity and mortality in patients with congestive heart failure58
may in part stem from minimizing the potassium and magne-
Downloaded from http://ahajournals.org by on October 5, 2019
sium depletion in these diuretic-treated patients.
Nonantihypertensive Interventions to Reduce
Hypertensive Renal Damage
As noted, it is theoretically possible to mitigate renal damage by
hemodynamically reducing the intrarenal transmission of systemic
pressures such as through protein restriction. However, unlike its
demonstrated effectiveness in rodent models, the benefits in clinical
trials have been fairly modest and only discernible in those with
more advanced renal disease.59 The reasons remain unclear, but it is
possible that the impact of dietary protein may only become
quantitatively significant after a substantial loss of functional renal
mass and autoregulatory capacity.
Theoretically, other pharmacological agents that preferentially
vasoconstrict the preglomerular vasculature also have the potential
for reducing PGC and GS. However, the clinical usefulness of agents
such as nonsteroidal anti-inflammatory drugs and cyclosporine A is
limited by their tendency to exacerbate hypertension in addition to
their potential for other side effects, including tubulointerstitial
disease. Hopefully, future investigations will suggest methods to
reduce preglomerular vasodilation and improve autoregulatory ca-
pacity without adverse effects. Similarly, it may also become
possible to independently modulate the downstream molecular
mediators of tissue injury. Such additional interventions may be
necessary to completely arrest the progression of CKD. Even if
complete systemic arterial normotension is clinically achieved, it
may not be sufficient to completely normalize glomerular hydro-
static pressures, given the enhanced fractional BP transmission in
these patients.
Conclusions
Recent investigations have provided substantial insights into the
pathogenesis of hypertensive renal damage and have indicated that
the severity of such damage depends on the degree to which renal
autoregulatory mechanisms fail to prevent the BP elevations from
being transmitted to the renal microvasculature. An impairment of
these protective mechanisms in patients with diabetic and nondia-
betic CKD likely accounts for their increased susceptibility to
progressive renal damage with even moderate hypertension. More-
over, such renal damage is likely to initiate a vicious cycle of
hypertension that is more difficult to control, resulting in more
nephron loss and further enhancement of glomerular pressure
transmission. Therefore, achieving normotension in CKD patients,
although difficult, remains the primary clinical strategy to interrupt
this vicious cycle, as recognized in recent guidelines. Little evidence
for the much emphasized BP-independent protection by RAS
blockade has been found in experimental animal models, when BP
load has been accurately assessed using radiotelemetry. Similarly,
the clinical evidence is also less definitive than has been claimed. In
any event, the controversy is of greater scientific than clinical
practice import. Most CKD patients require aggressive diuresis to
achieve BP control and RAS blockers are very effective antihyper-
tensives in effectively diuresed CKD patients. This antihypertensive
synergy combined with their counteracting effects on potassium and
magnesium balance provides a compelling rationale for combined
diuretic/RAS blockade use in most CKD patients. In any event,
finding more effective methods to achieve the lower BP goals is
likely to have a greater impact on the still-escalating incidence of
ESRD than a continued focus on BP-independent mechanisms to
prevent hypertensive renal damage.
Acknowledgments
This work was supported by National Institutes of Health grants
DK-40426, DK-61653, HL-64807, and a Merit Review Award from
the Office of Research and Development of the Department of
Veterans Affairs.
References
1. Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. The seventh report of the Joint
National Committee on Prevention, Detection, Evaluation and Treatment
of High Blood Pressure. JAMA. 2003;289:2560 –2572.
2. USRDS. 2002 Annual Data Report. Atlas of end-stage renal disease in the United
States: incidence and prevalence. Am J Kidney Dis. 2003;41:S41–S56.
3. Olson JL. Hypertension: essential and secondary forms. In: Jennette JC, Olson JL,
Schwartz MM, Silva FG, eds. Heptinstall’s Pathology of the Kidney, vol. 2, ed.
5. Philadelphia: Lippincott-Raven; 1998:943–1002.
4. Neuringer JR, Brenner BM. Hemodynamic theory of progressive renal disease: a
10-year update in brief review. Am J Kidney Dis. 1993;22:98–104.
5. Bidani AK, Griffin KA. Long-term renal consequences of hypertension for
normal and diseased kidneys. Curr Opin Nephrol Hypertens. 2002;11:73–80.
6. Bidani AK, Griffin KA, Picken M, Lansky DM. Continuous telemetric BP
monitoring and glomerular injury in the rat remnant kidney model. Am J Physiol.
1993;265:F391–F398.
7. Dominiczak AF, Clark JS, Jeffs B, Anderson NH, Negrin CD, Lee WK, Brosnan
MJ. Genetics of experimental hypertension. J Hypertens. 1998;16:1859–1869.
8. Kurtz T. False claims of blood pressure-independent protection by blockade of
the renin angiotensin aldosterone system? Hypertens. 2003;41:193–196.
9. Navar LG. Renal autoregulation: perspectives from whole kidney and single
nephron studies. Am J Physiol. 1978;234:F357–F370.
10. Bidani AK, Schwartz MM, Lewis EJ. Renal autoregulation and vulnerability to
hypertensive injury in remnant kidney. Am J Physiol. 1987;252:F1003–F1010.
11. Karlsen FM, Andersen CB, Leyssac PP, Holstein-Rathlou N-H. Dynamic auto-
regulation and renal injury in Dahl rats. Hypertens. 1997;30:975–983.
12. Long DA, Price KL, Herrera-Acosta J, Johnson RJ. How does angiotensin II
cause renal injury? Hypertens. 2004;43:722–723.
 Bidani and Griffin
13. Griffin KA, Abu-Amarah I, Picken M, Bidani AK. Renoprotection by ACE
inhibition or aldosterone blockade is blood pressure dependent. Hypertens. 2003;
41:201–206.
14. Iversen BM, Sekse I, Ofstad J. Resetting of renal blood flow autoregulation in
spontaneously hypertensive rats. Am J Physiol. 1987;252:F480–F486.
15. Bidani AK, Hacioglu R, Abu-Amarah I, Williamson GA, Loutzenhiser R, Griffin
KA. “Step” vs. “Dynamic” autoregulation: implications for susceptibility to
hypertensive injury. Am J Physiol. 2003;285:F113–F120.
16. Parving H-H, Osterby R, Anderson PW, Hsuch WA. Diabetic Nephropathy. In:
Brenner BM, ed. The Kidney. 5th ed. Philadelphia: WB Saunders Company;
1996:1864–1892.
17. Griffin KA, Picken M and Bidani AK. Method of renal mass reduction is a critical
determinant of subsequent hypertension and glomerular injury. J Am Soc
Nephrol. 1994;4:2023–2031.
18. Christensen PK, Hansen HP. Impaired autoregulation of GFR in hypertensive
non-insulin dependent diabetic patients. Kidney Int. 1997;52:1369–1374.
19. Christensen PK, Hommel EE. Impaired autoregulation of the glomerular filtration
rate in patients with nondiabetic nephropathy. Kidney Int. 1999;56:1517–1523.
20. Griffin KA, Picken MM, Bidani AK. Deleterious effects of calcium channel
blockade on pressure transmission and glomerular injury in rat remnant kidneys.
J Clin Invest. 1995;96:798–800.
21. Griffin KA, Picken M, Giobbie-Hurder A, Bidani AK. Low protein diet mediated
renoprotection in remnant kidneys: renal autoregulatory vs. hypertrophic mech-
anisms. Kidney Int. 2003;63:607–616.
22. Anderson S, Rennke HG, Brenner BM, Zayas MA, Lafferty HM, Troy JL,
Sandstrom DJ. Nifedipine versus fosinopril in uninephrectomized diabetic rats.
Kidney Int. 1992;41:891–897.
23. van Rodijnen WF, van Lambalgen TA, Tangelder GJ, van Dokkum RP, Provoost
AP, ter Wee PM. Reduced reactivity of renal microvessels to pressure and
angiotensin II in fawn-hooded rats. Hypertens. 2002;39:111–115.
24. Fogo AB. Glomerular hypertension, abnormal glomerular growth, and pro-
gression of renal diseases. Kidney Int. 2000;57:S15–S21.
25. Kriz W, Elger M, Mundel P, Lemley KV. Structure-stabilizing forces in the
glomerular tuft. J Am Soc Nephrol. 1995;5:1731–1739.
26. Pavenstadt H, Kriz W, Kretzler M. Cell Biology of the glomerular podocyte.
Physiol Rev. 2003;83:253–307.
27. Ketteler M, Noble NA, Border WA. Transforming growth factor and angiotensin
Downloaded from http://ahajournals.org by on October 5, 2019
II: the missing link from glomerular hyperfiltration to glomerulosclerosis? Annu
Rev Physiol. 1995;57:279–295.
28. Fogo AB. The role of angiotensin II and plasminogen activator inhibitor-1 in
progressive glomerulosclerosis. Am J Kidney Dis. 2000;35:179–188.
29. Epstein M. Aldosterone as a mediator of progressive renal disease: pathogenetic
and clinical implications. Am J Kidney Dis. 2001;37:677–688.
30. Taal MW, Brenner BM. Renoprotective benefits of RAS inhibition from ACEI
to angiotensin II antagonists. Kidney Int. 2000;57:1803–1817.
31. Griffin KA, Picken M, Bidani AK. Radiotelemetric BP monitoring, antihyper-
tensives and glomeruloprotection in remnant kidney model. Kidney Int. 1994;46:
1010–1018.
32. Bidani AK, Picken MM, Bakris G, Griffin KA. Lack of evidence of
BP-independent protection by renin-angiotensin system blockade after renal
ablation. Kidney Int. 2000;57:1651–1661.
33. Xu Q, Liu Y, Gorospe M, Udelsman R, Holbrook NJ. Acute hypertension
activates mitogen-activated protein kinases in arterial wall. J Clin Invest. 1996;
97:508–514.
34. Sjögren LS, Doroudi R, Gan Li, Jungersten L, Hrafnkelsdóttir T, Jern S. Elevated
intraluminal pressure inhibits vascular tissue plasminogen activator secretion and
downregulates its gene expression. Hypertens. 2000;35:1002–1008.
35. Griffin KA, Picken MM, Churchill M, Churchill P, Bidani AK. Functional and
structural correlates of glomerulosclerosis after renal mass reduction in the rat.
J Am Soc Nephrol. 2000;11:497–506.
36. Hall JE, Henegar JR, Dwyer TM, Liu J, daSilva AA, Kuo JJ, Tallam L. Is obesity
a major cause of chronic kidney disease? Adv in Renal Replacement Therap.
2004;11:41–54.
37. Tobin L, Lange J, Ulm K, Wold L, Iwai J. Potassium reduces cerebral hemor-
rhage and death rate in hypertensive rats, even when blood pressure is not
lowered. Hypertens. 1985;7:I110–I114.
38. Loutzenhiser R, Bidani A, Chilton L. Renal myogenic response: kinetic attributes
and physiological role. Circ Res. 2002;90:1316–1324.
39. Griffin KA, Picken MM, Bidani AK. Blood pressure lability and glomeruloscle-
rosis after normotensive 5/6 renal mass reduction in the rat. Kidney Int. 2004;65:
209–218.
40. Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Tuttle K,
Douglas J, Hsuch W, Sower J. Preserving renal function in adults with hyper-
tension and diabetes: a consensus approach. Am J Kidney Dis. 2000;36:646–661.
Hypertensive Renal Damage 601
41. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group. Major outcomes in high-risk hypertensive patients randomized
to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuret-
ic: the antihypertensive and lipid-lowering treatment to prevent heart attach trial
(ALLHAT). JAMA. 2002;2981–2997.
42. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of dif-
ferent blood-pressure-lowering regimens on major cardiovascular events:
results of prospectively-designed overviews of randomized trials. Lancet.
2003;362:1527–1535.
43. Staessen JA, Wang J-G, Birkenhäger WH. Outcomes beyond blood pressure
control? European Heart J. 2003;24:504–514.
44. Jones DW, Hall JE. Seventh report of the Joint National Committee on pre-
vention, detection, evaluation and treatment of high blood pressure and evidence
from new hypertension trials. Hypertens. 2004;43:1–3.
45. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, for the Collaborative Study
Group. The effects of angiotensin-converting-enzyme inhibition on diabetic ne-
phropathy. N Engl J Med. 1993;329:1456–1462.
46. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins
RC, Rohde R, Raz L. Renoprotective effect of the angiotensin receptor antagonist
irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med.
2001;345:851–860.
47. Brenner BM, Cooper ME, de Zeuw D, Keane WF, Mitch WE, Parving HH,
Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S. Effect of losartan on renal and
cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl
J Med. 2001;345:861–869.
48. Wright JW, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, Cheek D,
Douglas-Baltimore JC, Gassman J, Glassock R, Hebert L, Jamerson K, Lewis J,
Phillips RA, Toto RD, Middleton JP, Rostand SG, for the AASK Collaborative
Research Group. Effect of blood pressure lowering and antihypertensive class on
progression of hypertensive kidney disease: results from the AASK trial. JAMA.
2002;288:2421–2431.
49. Hebert LA, Bain RP, Verme D, Cattran D, White FC, Tolchin N, Rohde RD,
Lewis EJ, for the Collaborative Study Group. Remission of nephrotic range
proteinuria in type I diabetes. Kidney Int. 1994;46:1688–1693.
50. Svensson P, de Faire U, Sleight P, Salim Yusuf S, Ostergren J. Comparison of the
effects of ramipril on ambulatory and office blood pressures. A HOPE substudy.
Hypertens. 2001;38:E28–E32.
51. Asmar RG, London GM, O’Rourke ME, Safar ME, for the REASON Project
coordinators and investigators. Improvement in blood pressure, arterial
stiffness and wave reflections with a very-low-dose perindopril/indapamide
combination in hypertensive patient. A comparison with atenolol. Hypertens.
2001;38:922–926.
52. Kloke HJ, Braten AJ, Hyysmans FT, Wetzels JF. Antihypertensive treatment of
patients with proteinuric renal disease: risks or benefits of calcium channel
blockers? Kidney Int. 1998;53:1559–1573.
53. Lea JP, Contreras G, Kopple JD, Schulman G, Wang S-R, Lightfoot T,
Richardson A, for the AASK Study Group. The use of diuretic therapy in
achievement of blood pressure goals in the African-Am study of kidney disease
and hypertension. J Am Soc Nephrol. 2001;12:A2515.
54. Palmer BF. Renal dysfunction complicating the treatment of hypertension.
N Engl J Med. 2002;347:1256–1261.
55. Guyton AC, Hall JE, Coleman TG, Manning RD Jr, Norman RA Jr. The
dominant role of the kidneys in long-term arterial pressure regulation in
normal and hypertensive states. In: Laragh JH, Brenner BM, eds. Hyper-
tension: Pathophysiology, Diagnosis, and Management, vol. 1. New York:
Raven Press; 1995:1311–1326.
56. Johnson RJ, Herrera J, Schreiner G, Rodriguez-Iturbe B. Acquired and subtle
renal injury as a mechanism for salt-sensitive hypertension: bridging the
hypothesis of Goldblatt and Guyton. N Engl M Med. 2002;346:913–923.
57. Laragh JH, Sealey JE. Renin-angiotensin-aldosterone system and the renal reg-
ulation of sodium, potassium and blood pressure homeostasis. In: Windhager EE,
ed. Handbook of Physiology, vol II. New York: Oxford University Press for
American Physiological Society; 1992.
58. Pitt B, Zannd F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J,
Wittes J, for the Randomized Aldactone Evaluation Study Investigators. The
effect of spironolactone on morbidity and mortality in patients with severe
heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl
J Med. 1999;341:709–717.
59. Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker G,
for the Modification of Diet in Renal Disease Study Group. 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;330:877–884.