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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
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Figure 1. The differing BP thresholds and slopes of the relationship between BP and renal damage in patients with uncomplicated hypertension (benign and malignant nephrosclerosis) and
those with diabetic and nondiabetic CKD.
Pathophysiology of Hypertensive
Renal Damage
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 pathogenetic 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 because the ambient BP profile in conscious animals is characterized 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
Figure 2. Illustration of the spectrum of pressure flow relationships in the renal vascular bed in hypertension. Pattern A represents 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 illustrates 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 dihydropyridine CCBs. Although RBF is depicted as the dependent variable, the same relationships are expected to obtain for
PGC, given that the autoregulatory resistance changes are confined to the preglomerular vasculature.
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Unresolved Issues
Despite the progress that has been achieved, certain fundamental issues of hypertensive target organ damage remain
unresolved. The term BP load is used generically because
the relative pathogenic importance of individual BP parameters (mean, systolic, diastolic, pulse pressure, and BP variability) 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 individual 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 autoregulatory responses. And fluctuations in microvascular pressures
(pressure transients and/or peak pressures) may have a greater
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 potential 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 transmission and pathogenic importance of these individual components 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 (barotrauma) 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 reductions to below the autoregulatory threshold are likely to
prevent malignant nephrosclerosis in patients with uncomplicated 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 nephrosclerosis 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 pathophysiology 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.
599
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
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Hypertension
November 2004
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 nondiabetic CKD likely accounts for their increased susceptibility to
progressive renal damage with even moderate hypertension. Moreover, 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 antihypertensives 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.
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