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Am J Hypertens. Author manuscript; available in PMC 2011 November 1.
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Am J Hypertens. 2010 November ; 23(11): 11591169. doi:10.1038/ajh.2010.174.
State of the Art: Renovascular Hypertension and Ischemic

Nephropathy
Stephen C. Textor, M.D.[Professor of Medicine] and
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
Lilach Lerman, M.D., Ph.D.[Professor of Medicine]
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
Abstract
Renovascular disease remains among the most prevalent and important causes of secondary
hypertension and renal dysfunction. Many lesions reduce perfusion pressure including
fibromuscular diseases and renal infarction, but most are caused by atherosclerotic disease.
Epidemiologic studies establish a strong association between with atherosclerotic renal artery
stenosis and cardiovascular risk. Hypertension develops in patients with renovascular disease from
a complex set of pressor signals, including activation of the renin-angiotensin system, recruitment
of oxidative stress pathways, and sympatho-adrenergic activation. Although the kidney maintains
function over a broad range of autoregulation, sustained reduction in renal perfusion leads to
disturbed microvascular function, vascular rarefaction and ultimately development of interstitial
fibrosis. Advances in antihypertensive drug therapy and intensive risk factor management
including smoking cessation and statin therapy can provide excellent blood pressure control for
many individuals. Despite extensive observational experience with renal revascularization in
patients with renovascular hypertension, recent prospective randomized trials fail to establish
compelling benefits either with endovascular stents or surgery when added to effective medical
therapy. These trials are limited and exclude many patients most likely to benefit from
revascularization. Meaningful recovery of kidney function after revascularization is limited once
fibrosis is established. Recent experimental studies indicate that mechanisms allowing repair and
regeneration of parenchymal kidney tissue may lead to improved outcomes in the future. Until
additional staging tools become available, clinicians will be forced to individualize therapy
carefully to optimize the potential benefits regarding both blood pressure and renal function for
such patients.
Keywords
Renovascular Hypertension; renal artery stenosis; renin; BOLD MR; angioplasty; stent;
atheroemboli
Introduction
Management of patients with hypertension and renovascular disease has never been more
complexor ambiguous. Continued emphasis on achieving lower goal blood pressures to
reduce cardiovascular risk forces clinicians caring for hypertensive patients to intensify
therapy and consider secondary factors, such as renovascular occlusive disease, more than
ever before. At the same time, however, a confusing array of prospective, randomized
clinical trials published in the prominent general medical literature fail to establish major
benefits from revascularizing patients with atherosclerotic renal arterial disease 1;2. Many of
these trials are seriously flawed 3. While these trial results indeed reflect major
improvements in medical management and antihypertensive drug therapy, most clinicians in
Textor and Lerman
Page 2
the field recognize the need to optimize both endovascular and medical interventions for
renovascular disease. In some cases, critical opportunities to preserve renal function are
missed, allowing patients to drift into advanced kidney failure. The goal of this review is to
summarize the current state of affairs regarding renovascular hypertension and ischemic
nephropathy for the clinician with a major interest in hypertension.
Definition and epidemiology

Renovascular hypertension refers to the rise in arterial pressure attributable to reduced
perfusion of the kidney. Most often this is from main renal arterial obstruction from either
atherosclerotic occlusion or fibromuscular dysplasia. A variety of other lesions can produce
the same syndrome, however, some of which are identified in TABLE 1. As a clinical
phenomenon, these lesions sometimes produce an unexpected rise in blood pressure in
younger subjects, e.g. less than 30 or contribute to resistant hypertension in previously
normotensive or treated hypertensive subjects Recent imaging studies indicate that
incidental vascular lesions can be identified in 3-5% of normotensive subjects, e.g.
potential living kidney donors with normal kidney function and blood pressure 4. Hence,
radiographic identification of a vascular occlusive lesion alone does not establish its
physiologic role.
A variety of fibromuscular lesions are recognized, most commonly in young women. These
sometimes first appear as unexplained rises in arterial pressure, e.g. during pregnancy. These
lesions may have varied appearance including the string-of-beads associated with medial
fibroplasia or focal banding in the mid-renal artery 5. Remarkably, these lesions often trigger
renin release without loss of renal parenchymal volume or glomerular filtration rate unless
they lead to dissection or thrombosis of the entire kidney.
By far the most common renovascular lesion is atherosclerotic renal artery stenosis (ARAS).
Atherosclerosis leading to elevated arterial velocities suggesting more than 60% stenosis can
be detected in 6.8% of community based subjects above age 65 6. The prevalence of ARAS
rises with age and with clinically manifest disease in the coronary arteries (18-20%), the
aorta, or peripheral vascular beds (35-50%), as recently reviewed 7. Development of
atherosclerotic disease relates to the magnitude of cardiovascular risk factors, including
smoking, dyslipidemia, diabetes and age, among others. Epidemiologic associations have
been proposed to suggest that individuals with refractory congestive heart failure and/or
end-stage renal disease may have demonstrable of ARAS in 40-50% of cases 7. Whether
these lesions are active causal factors in these conditions or represent an associated
biomarker of atherosclerosis remains controversial. Development and use of aortic
endovascular stent grafts, often placed adjacent to the renal arteries has produced a new
class of patients with acquired renal artery stenosis related to occlusive effects of the stent
graft 8. This may become more common as these devices become more widely used in
patients at ever older age ranges.
Pathophysiology: Renovascular hypertension and the role of reninangiotensin system

Seminal studies demonstrating the link between vascular perfusion to the kidney and the
development of hypertension remain fundamental to the field of blood pressure research
9-11. Models using renal arterial lesions have been reproduced in multiple species including
rat, dog, rabbit and swine. Studies in these models facilitated discovery and elucidation of
the renin-angiotensin system. Unilateral experimental renovascular disease with a
functioning contralateral kidney that excretes sodium as function of pressure natriuresis
(identified as 2-kidney-1-clip hypertension) remains a premier model of angiotensin-
Textor and Lerman
Page 3

dependent hypertension. When a solitary kidney is present or both kidneys are affected,
angiotensin-dependence is temporary and dependent upon sodium depletion 12. Targeted
blockade of the renin-angiotensin system 13;14 or its activation in animals without
angiotensin receptors protects against the development of renovascular hypertension 15.
Studies using kidney transplants from angiotensin receptor knockout mice indicate that both
systemic and renal effects of angiotensin participate in pressure and target organ injury in
this disorder 16. Remarkably, activation of the circulating renin-angiotensin system is
transient and leads to recruitment of additional pressor pathways, including oxidative stress,
sympatho-adrenergic activation, and impaired vasodilatory responses both within the renal
and systemic microcirculation 17. It should be emphasized that the release of circulating
renin depends upon a substantial reduction in kidney perfusion pressure. Studies using
balloon occlusion in humans indicate that this process requires development of a gradient
across the lesion such that distal pressures fall at least by 10-20% below aortic pressure 18.
Such pressure differences correspond to translesional peak systolic gradients of 15-25 mm
and develop only when the cross-sectional area of occlusion approaches 70-80% as
illustrated in FIGURE 1 19. An important corollary of this observation is that vascular
lesions that fail to generate such a gradient are unlikely to participate in renovascular
hypertension and do not benefit from measures to open the vessel. Conversely,
revascularization of vessels with lesions that produce a gradient does not invariably resolve
hypertension and renal dysfunction, which may be caused by alternative or co-existing
mechanisms.
The kidney is relatively overperfused relative to its metabolic requirements, a feature
consistent with its role as a filtering organ. Hence, blood flow and filtration may fall
considerably without jeopardizing tissue viability. Recent studies indicate that reduction of
renal blood flow sufficient to reduce kidney size and produce renin release may develop
despite preserving normal overall levels of both cortical and medullary tissue oxygenation
20. These data imply that renovascular hypertension does not depend upon true renal
ischemia per se.
Clinical manifestations of renovascular hypertension include high rates of target organ

injury as compared to similar levels of essential hypertension 21. Importantly, the presence
of ARAS also increases cardiovascular risk 22. Some target organ injury may be related
directly to activation of the renin-angiotensin-aldosterone axis. For this reason, the U.S.
Cardiovascular Outcomes for Renal Artery Lesions (CORAL) trial specifies angiotensinblockade as part of medical therapy for all patients in the study 23. Patients with ARAS
commonly have disturbed day-night blood pressures with loss of nocturnal BP fall,
increased sympathetic nerve traffic as measured in efferent nerve fibers, more severe left
ventricular hypertrophy and lower glomerular filtration rate (GFR) as compared to essential
hypertension with similar clinic blood pressures 24;25.
Loss of renal function and viability

Although the kidney overall receives more blood than needed strictly for its metabolic
activity, impaired blood flow eventually leads to tissue fibrosis. Remarkably, parenchymal
fibrosis rarely develops in patients with fibromuscular disease with the exception of those
experiencing renal infarction. This suggests that activation of remodeling mechanisms in the
post-stenotic kidney is related to the atherosclerotic milieu itself 26. Recent experimental
studies also underscore the development of renal microvascular changes distal to a stenosis
in the renal artery 27;28. An example of microvascular proliferation induced by cholesterol
feeding (a surrogate for early atherosclerosis) and subsequent rarefaction of renal small
vessels beyond a main renal artery lesion is illustrated in FIGURE 2. Numerous signaling
pathways lead to upregulation of cytokines and inflammatory mediators, including
Textor and Lerman
Page 4
transforming growth factor (TGF)-beta, within the post stenotic kidney 29;30. Over time,
rarefaction of the distal arterioles develops, associated with fibrogenesis and loss of viable
function 31. 32-34 When vascular occlusion reaches severe proportions, overt tissue ischemia
can be demonstrated as illustrated using Blood Oxygen Level Dependent (BOLD) magnetic
resonance imaging (FIGURE 3).
For many of these patients, restoring kidney blood flow alone has little effect on improving
kidney function, as emphasized by the results from recent clinical trials 35. However, some
injurious pathways responsible for renal remodeling can be modified using intensive therapy
with either anti-oxidants or statins 36, leading to improved blood flow, vascular integrity and
reduced kidney injury 32. Clinical observations suggest that statins slow the progression of
tissue injury in ARAS and are associated with substantially less interstitial fibrosis in
kidneys removed for total arterial occlusion 33;34. Remarkably, infusion of autologous
endothelial progenitor cells in a swine model produces increases in renal blood flow and
glomerular filtration rate even without renal revascularization 37. Whether additional
maneuvers, such as delivering undifferentiated progenitor cells to the kidney or mobilization
of resident kidney stem cells, can facilitate recovery of viable tissue in humans under these
circumstances remains to be seen.
Clinical manifestations and the Decision to undertake Diagnostic studies

Stenotic occlusive disease in the renal arteries is associated with a broad range of clinical
manifestations as illustrated in FIGURE 1. Many of these lesions reflect incidental or
modest disease with little clinical impact regarding renal perfusion, blood pressure or
glomerular filtration. Results from recent trials underscore the fact that the severity of many
vascular lesions, i.e. the degree of actual vessel occlusion, is overestimated from noninvasive diagnostic imaging, e.g. MR angiography, Doppler ultrasound or CT angiography.
When subjected to quantitative angiography, many of these lesions remain below the
threshold warranting vascular intervention. In the STent placement for Atherosclerotic Renal
artery stenosis (STAR) trial, for example, 28% of stenotic lesions were not subjected to
intervention despite assignment to this therapy, primarily due to identifying only clinically
trivial disease after closer scrutiny during angiography 2;3.
When reduced kidney perfusion activates pressor mechanisms, blood pressure often rises,
sometimes leading to acceleration of pre-existing essential hypertension. As a result, the
clinical manifestations of ARAS most commonly develop in previously treated hypertensive
subjects. A rapid rise in arterial pressure can be associated with target injury such as a
stroke, or when combined with reduced renal perfusion to the entire renal mass and
enhanced sodium reabsorption can lead to rapidly developing circulatory congestion
(sometimes termed flash pulmonary edema). Sodium retention in patients with leftventricular heart dysfunction contributes to refractory congestive failure, particularly when
both kidneys or the entire renal mass is affected. Finally, loss of blood flow produces
irreversible kidney fibrosis as noted above. As a practical matter, the decision whether to
initiate diagnostic studies often depends directly upon the clinical likelihood that
renovascular disease is an important contributor to the disease state of the patient. It also
depends upon whether these manifestations can be managed readily with medical therapy
alone. It may be argued that if blood pressure and kidney function are treated satisfactorily
and remain stable, little is to be gained by embarking on a path of expanded diagnostic
studies. Hence, the decision to undertake expanded diagnostic testing should be based upon
the commitment to consider renal revascularization if studies are positive. A commonly
applied algorithm is summarized in FIGURE 4.
Textor and Lerman
Page 5
It is worth emphasizing that this approach is more conservative than proposed even a decade
ago. Formal reviews of both the observational studies 38;39 and prospective trials emphasize
that surgical and endovascular renal revascularization procedures carry expense and
morbidity risks. Outcomes of these trials are summarized below (TABLE 2). The benefit to
intensive investigation and vascular intervention for most patients is modest and should be
reserved for those most likely to experience real clinical benefit.
Diagnostic Studies for Renovascular Disease

Exhaustive consideration of vascular imaging of the kidney is beyond the scope of this
review. Before initiating any of these procedures, clinicians would do well to define
precisely the goals to be achieved, as we have discussed elsewhere 40. In general, imaging
procedures are undertaken to define the presence and/or bilateral location of
hemodynamically important vascular occlusion. Optimally, one would like an estimate of
the severity, accessibility, and location of these lesions, and the functional status of the
kidney beyond. Even more importantly, one would like to define the degree to which these
vascular occlusive lesions actually are responsible for the clinical manifestations present and
the likelihood that restoring vascular patency would reverse this process. Achieving all of
these goals is difficult with any single study.
Renal artery Doppler ultrasound is a widely available method that reliably defines velocity
changes consistent with vascular narrowing. It requires attention to detail and varies
considerably between institutions, particularly in light of operator expertise, patient
preparation, and the time allowed for satisfactory study. Prospective series suggest
sensitivity and specificity above 90% in dedicated laboratories 41;42. Others have reported
sensitivity in the 60% range with more than 20% technically inadequate studies, often due to
obesity or poor preparation 43. In our experience, duplex ultrasound rarely produces false
positives, but can miss important vascular lesions, resulting in false negatives. It can be
helpful to follow previously identified lesions regarding progression of disease.
Identification of low resistive index in the affected kidney has been proposed as a marker of
likely benefit from revascularization 44, although this has not been observed universally 45.
Velocity thresholds for significant disease vary considerably (classically considered at
180-200 cm/sec Peak Systolic Velocity for hemodynamically significant lesions above
60% occlusion 46). To avoid overdiagnosis of modest lesions some authors advocate setting
the threshold at 300 cm/sec, currently the required threshold for enrollment in the
Cardiovascular Outcomes for Renal Atherosclerotic Lesions (CORAL) trial in the U.S..
CT angiography (CTA) and MR angiography (MRA) provide ever more sophisticated

imaging, allowing construction of three dimensional vascular images and estimates of
individual kidney function. Use of contrast MRA in subjects with reduced GFR has fallen
off drastically in this disease since the concerns regarding development of nephrogenic
systemic fibrosis (NSF) and the putative role of gadolinium contrast 47. While gadolinium
contrast may be safe for patients with preserved GFR, newer techniques allow improved
vascular imaging without gadolinium and may become more widely available 47. CT
angiography has both radiation and contrast exposure, but can provide excellent definition of
both vascular tree and renal function.
Functional testing based upon activation of the renin angiotensin-system
Renovascular hypertension is more closely associated with activation of the reninangiotensin system (RAAS) than any other form of hypertension. While intuitively attractive
as diagnostic tools, measurement of plasma renin activity alone and/or the blood pressure
response to angiotensin blockade are limited by interactions with drug effects, sodium
Textor and Lerman
Page 6
intake, renal dysfunction and possible alterations dependent upon age and the duration of
renovascular disease.
Angiotensin is an important determinant of filtration pressure in the kidney. Most patients

with renovascular disease tolerate RAAS blockade without evident adverse effects, although
some fall in GFR may accrue inevitably from functional removal of the angiotensin II action
that supports filtration 48. This fall in GFR is exaggerated in the presence of pre-glomerular
vascular disease and is the basis for examining changes in isotope renograms before and
after captopril. Several series derived from clinically selected populations suggest that
captopril renography can predict blood pressure and/or renal function improvements after
renal revascularization with predictive values exceeding 75% and sensitivity above 90%
49-51. These observations have not been confirmed when applied to larger populations and
may be confounded by previous drug therapy, bilateral disease and reduced kidney function
52;53. Captopril renography is less commonly used than before, but has advocates within the
hypertension community 54. It had little predictive value in the Dutch Renal Artery Stenosis
Intervention Cooperative study group (DRASTIC) trial other than to identify individuals
with progressive total occlusion 53. Renography does provide functional data regarding
blood flow and filtration, but no direct imaging regarding the renal vasculature itself. Hence,
it provides an estimate of relative function when total occlusion is present that may validate
consideration of nephrectomy of a pressor kidney, as recently revisited 55;56.
Intra-arterial angiography and renal vein renin measurements remain the gold standard.
Angiographic core laboratories indicate that visual estimates of stenosis commonly overstate
the severity of vascular occlusive lesions. As a result, some authors recommend
confirmation with translesional gradient measurement using low profile pressure transducers
57. Without a measurable gradient, it is hard to justify vascular intervention. While
measurement of renal vein renin levels has fallen into less common use, a considerable body
of data supports a predictive role of lateralizing values regarding the likely benefit of
revascularization, at least regarding improved blood pressure control 58. Careful studies of
renal vein renin levels obtained after withholding drug therapy for two weeks indicate that
lateralizing values (more than 1.7) accurately predict the fall in arterial pressure following
nephrectomy in patients with total occlusion 59. The authors argue that lateralization for
non-occluded vessels performed best (by receiver operating curves) at a level of 1.55, which
corresponded to a sensitivity of 54% with a false positive rate of 15%. In practice, many
clinicians are unwilling to withhold drug therapy before testing and results may be less
consistent. As with most diagnostic studies in this disorder, the results are most useful when
positive. Failure to demonstrate lateralization can result for many reasons, including volume
expansion commonly employed during angiography.
One might argue that ambiguous trial results should encourage more careful documentation
and evaluation before undertaking renal revascularization procedures. There is a pressing
need to refine the tools for defining the clinical impact of vascular occlusion in the kidney,
as we have discussed 40.
Medical Therapy for Renovascular Hypertension and Ischemic

Nephropathy
As noted above, much of the commitment for extensive diagnostic studies and vascular
intervention depends upon the results of medical therapy as an initial step. Particularly for
patients with accelerated or extreme hypertension, blood pressure reduction to safe levels
should be achieved before invasive diagnostic procedures. Pharmacologic therapy of
renovascular hypertension follows the basic principles of all antihypertensive drug therapy,
but especially depends on effective blockade of the renin-angiotensin-aldosterone system
Textor and Lerman
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(RAAS). Italian and Canadian registry data suggest considerable survival advantages for
patients able to employ angiotensin converting enzyme (ACE) inhibition or angiotensin
receptor blockers (ARB's) as part of their regimen 60;61. Few data address the role of direct
renin inhibition, although this is a rational alternative. Analysis of subgroups from the
HOPE and PEACE trials suggest the greatest clinical benefits from RAAS blockade accrue
to those with some degree of renal dysfunction 62;63. These groups are likely to include
some patients with unrecognized atherosclerotic RAS. A clinically important fall in GFR
associated with a rise in serum creatinine and potassium sometimes occurs with major
preglomerular vascular occlusion that precludes the use of these agents. It should be
emphasized that such a rise in creatinine develops both because blood flow is threatened and
because angiotensin II supports filtration under those conditions 64. Hence, the loss of GFR
reflects a functional signal that blood flow is threatened and filtration requires the supportive
action of angiotensin. Filtration can recover when blockade of RAAS is removed. A
corollary of this observation is that other forms of antihypertensive drug therapy may also
threaten blood flow, which in some cases constitutes a legitimate reason to move forward to
restore renal blood flow. Remarkably, most patients with hemodynamically important
ARAS tolerate RAAS blockade without difficulty. Withdrawal of ACE / ARB in the heart
failure trials occurred in less than 5% of subjects 65. Recommendations for the use of these
agents include re-evaluation of serum creatinine and potassium level soon (within a week)
after initiating therapy, particularly in patients with reduced kidney function 48. It remains
essential for the clinician to define what increase in serum creatinine can be tolerated, but
some authors indicate that a rise of 30% may be expected 66. Some investigators argue that
the cardiovascular risk is magnified by the neuro-hormonal activation associated with ARAS
57. As a result, the authors of CORAL advocate universal blockade of the RAAS as a central
component of managing this disorder.
At least equally important is the intensive and rigorous management of atherosclerosis.
Discontinuing tobacco use, statin therapy, aspirin, and diabetes management are major
components that require attention. Most of the adverse outcomes for patients with
atherosclerotic renovascular disease derive from non-renal vascular complications, including
stroke, coronary events, and peripheral vascular disease 67.
The role of Renal Revascularization
Restoring blood flow to kidneys that actively trigger pressor mechanisms in renovascular
hypertension is an intuitively rational approach 68. Indeed, both surgical or endovascular
revascularization occasionally produce normalization of arterial pressures in such cases,
leading to cure. Most cases of fibromuscular dysplasia producing hypertension in younger
individuals can be considered for angioplasty at low procedural risk, so long as no
aneurysms are present. Considering the potential need for many years of antihypertensive
therapy and the limitations on using either ACE inhibitors or ARBs in pregnancy, most
clinicians favor angioplasty as initial therapy for younger women, who are most likely to be
treated for this disorder. It is important to recognize that even with FMD, rates of cure are
limited. Recent series suggest that achieving normal blood pressures without
antihypertensive drug therapy occurs in less than 30% of subjects, although some
improvement may occur in an additional 50% or more 5. Complex disease including
aneurysmal dilatation should be approached using either surgical or medical therapy
primarily. Restenosis may occur with FMD and lead to repeat procedures in 11-23% 5;69.
Atherosclerotic RAS poses a different set of concerns, as noted above. These lesions
primarily develop in subjects with pre-existing hypertension, so revascularization rarely
lowers blood pressure to normal. Nonetheless, restoring blood flow to kidneys at critically
reduced perfusion offers the potential to recover kidney function, protect from further
Textor and Lerman
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degradation, and improve blood pressure control. Observational studies including both
surgical and endovascular repair emphasize that important improvements in kidney function
and reduced antihypertensive drug requirements can be obtained in such patients 70-74. A
formal review from the Agency for Health Quality Research (AHQR) indicates that while
prospective studies fail to define unequivocal strategies for management of atherosclerotic
RAS, clinically important improvements in kidney function and reversal of hypertension
developed only in patients with successful revascularization 38. Major improvements do not
occur frequently, however, and these procedures have both costs and risks. Because the
advances in medical therapy have been substantial, numerous prospective, randomized trials
comparing intensive medical therapy with and without renal revascularization procedures
have been undertaken in recent years 39. Some of these have been completed and published.
The main results from these trials are summarized in TABLE 2. It is notable that these trials
vary enormously in size and power estimates, ranging from less than 100 to more than 1000
for target populations. Because patients with ARAS are older and commonly have
widespread atherosclerosis, clinical events are subject to major confounding with other
comorbid diseases. Some authors argue that such populations are inherently so
heterogeneous as to be impossible to study as a single population 75. A major limitation of
these initial trials including STAR 2 and ASTRAL 1 has been the inconsistency in defining
critical vascular occlusion and the degree of stenosis. Hence, the power of several trials
has been undermined by realization that patients selected for treatment often have trivial
disease. Another key observation has been the recognition that current optimal medical
therapy appears to allow stabilization of atherosclerotic disease and renal dysfunction to a
much greater degree than originally predicted. Hence, the ability to achieve reasonably good
blood pressure control has been much better than reported in studies a decade ago 76.
Perhaps for these reasons, the results of the recent trials fail to demonstrate major
advantages to renal revascularization as a primary intervention. The largest and most
carefully performed study in this field in the U.S., the Cardiovascular Outcomes in Renal
Atherosclerotic Lesions (CORAL), remains in progress and will not provide outcome data
for several more years.
It must be recognized that revascularization procedures carry some risks, although modern
techniques have reduced these substantially. Moderate complications including bleeding,
local dissection, and branch occlusion can develop, but are reported in less than 10% of
cases 77. Restenosis remains a concern and can develop in 10-15% of subjects 78. ARAS
lesions commonly develop as part of generalized atherosclerosis, particularly in the
abdominal aorta. As a result, either surgical or endovascular manipulation carry some risk of
releasing atheroemboli. While a small amount of embolic debris may be released in nearly
any vascular procedure, including guidewire placement 79;80, the incidence of clinically
important renal infarction or systemic atheroemboli remains low, reported between 1 and
4% 77;81. When the full syndrome of systemic emboli occurs, however, it can be
devastating. Risk factors for emboli include extensive aortic plaque and/or aneurysm,
uncontrolled hypertension, and direct renal artery manipulation 82. In a series of 43 patients
developing advanced renal failure from this procedure, 31 required long-term dialysis and
33% did not survive the first year. Of those requiring dialytic support, only 12 (28%)
ultimately recovered sufficiently to withdraw from dialysis. Whether use of embolic
protection devices will improve these outcomes is uncertain. Results from a recent trial
suggest that simply having the device in place during the procedure offers little benefit for
recovery of kidney function after renal artery stenting 83. Many embolic events develop in a
stuttering fashion for days and weeks after the procedure, suggesting that temporary
vascular protection will have limited value.
Textor and Lerman
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Future Developments to recover renal function

ARAS initiates complex changes by which disturbed signaling pathways activate

inflammatory and fibrogenic processes at different times 29;30. Although the kidney
microvasculature is complex and remarkably resilient despite local environments with
reduced oxygen tension, it is likely that either recurrent or critical levels of ischemia
participate in triggering some of these responses. While restoring large vessel perfusion
alone is rarely sufficient, future studies may elucidate a role for adjunctive or alternative
measures that overcome hypoxic stimuli and allow for restoring the microvasculature. Some
may also support regeneration of functional cells to repair injured tubules and glomeruli.
Experimental studies suggest that undifferentiated cells, either local progenitor cells or those
recruited from elsewhere in the body, may foster a microenvironment where such repair can
occur. We are optimistic that newer tools to monitor tissue conditions and improved
technology to stimulate local repair mechanisms will play an important role in this process.
Summary: An integrated view of managing renovascular disease
Renovascular disease remains one of the most prevalent and important causes of secondary
hypertension and renal dysfunction. Advances in antihypertensive drug therapy and
intensive risk factor management including statin therapy can provide excellent blood
pressure control in many individuals. Despite these advances, timely recognition of vascular
occlusive disease is important to avoid progressive renal functional loss. Recent studies
emphasize important interactions between large vessel occlusive disease and changes in the
milieu or microvascular environment in the kidney. Changes in microvascular disease
appear to activate multiple mechanisms of tissue injury and repair that remain incompletely
understood 31;84. Improved therapy for this disorder will depend upon more precise
definition of the role of post-stenotic kidneys in sustaining hypertension and identification of
kidneys that are threatened by vascular occlusive disease but remain viable and salvageable.
Based on the ambiguous results of prospective treatment trials to date, clinicians will need to
examine each patient closely to consider if limited net benefits warrant the expense and
potential hazard of invasive procedures and vascular repair. We anticipate the need for more
refined tools to define the degree of actual tissue ischemia within an individual subject and
the role of adjunctive maneuvers to assist in tissue repair. Effective patient care for
renovascular disease likely will benefit from close collaboration among clinicians directly
managing medical therapy and those providing vascular intervention.
Acknowledgments
The project described was supported by Award number P01HL085307 from National Heart, Lung and Blood
Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views
of the National Heart, Lung and Blood Institute or the National Institutes of Health.
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Brenner and Rector's: The Kidney. Vol. chap 43. Philadelphia: 2008. p. 1528-1566.

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Page 16

FIGURE 1.
(a) MR Angiogram of High grade renal artery stenosis with renal vein renin measurements:
lateralization suggests high probability of pressor activity.
(b) Renal artery duplex study of distal segments on the right kidney illustrating parvus
tardus waveform and low resistive index (RI=0.42). These data suggest excellent distal
blood flow runoff' and limited parenchymal fibrosis. Severe hypertension had developed
over a three month period that was reversed by successful revascularization.
(c) Manifestations of renal arterial disease

Textor and Lerman
Page 17

FIGURE 2.
Micro-CT imaging of vascular casts obtained from a swine model of atherosclerotic renal
artery stenosis. Atherosclerosis produced by cholesterol feeding induces small vessel
proliferation and disturbed endothelial function (middle panel). The kidney beyond a main
renal arterial occlusive lesion induced by copper stent experiences dropout (rarefication)
of small vessels within both cortex and medulla and accelerated tissue fibrosis. From
Lerman and Chade, with permission 90.

Textor and Lerman
Page 18

Textor and Lerman
Page 19

FIGURE 3.
(a) T2 imaging by MR and CT angiogram demonstrating high grade renal artery stenosis to
the left kidney and a normal nephrogram on the right (with a vascular stent in place and
distal fibromuscular disease). (b) Parametric maps of R2* (reflecting the level of
deoxyhemoglobin) from Blood Oxygen Level Dependent (BOLD) MR at 3 Tesla from the
same kidneys are shown below. The right kidney has low cortical R2* (blue) with small
areas of medullary deoxygenation typical of a normal kidney. Moderate vascular stenosis
such as observed with fibromuscular disease is associated with well-preserved tissue
oxygenation as shown here 20. The small left kidney has higher levels of cortical R2* and a
large, deep area of medullary deoxygenation (red) illustrating physiologic oxygen
Textor and Lerman
Page 20
deprivation as a result of extreme vascular compromise. Hence, progressive occlusive

disease ultimately overrides compensatory changes within the kidney to produce ischemic
injury.

Textor and Lerman
Page 21

FIGURE 4.
Algorithm for evaluation and intervention in renovascular disease (from Textor, in Brenner's
Textbook, with permission 91

Textor and Lerman
Page 22
TABLE 1
Major Causes of vascular occlusion producing Renovascular Hypertension
Unilateral disease
Unilateral atherosclerotic renal artery stenosis
Unilateral fibromuscular dysplasia (FMD)
Medial fibroplasia
Perimedial fibroplasia
Intimal fibroplasia
Medial hyperplasia
Renal artery aneurysm
Arterial embolus
Arteriovenous fistula (congential / traumatic)
Segmental arterial occlusion (post-traumatic)
Extrinsic compression of renal artery, e.g pheochromocytoma
Renal compression, e.g. metastatic tumor
Bilateral Disease or Solitary Functioning Kidney
Stenosis to a solitary functioning kidney

Bilateral renal arterial stenosis
Aortic coarctation
Systemic vasculitis (e.g. Takayasu's, Polyarteritis)
Atheroembolic disease
Vascular occlusion due to endovascular aortic stent graft

Textor and Lerman
Page 23
TABLE 2
Summary of Prospective, Randomized trials of medical therapy vs renal revascularization in atherosclerotic

renal artery stenosis.
Author/No. Patients
Inclusion/BP measurement
Outcome
Weaknesses/Limitations
The ASTRAL Investigators
Uncertainty-Patient's doctor was uncertain.

Primary endpoint.
20% change in renal function.
No difference in BP, serum

creatinine, mortality, CHF at 33
months (median).
Enrollment bias: uncertainty

not defined
NEJM 361;1953, 2009
20-22% renal event
Non-standard imaging
42% <70%
58% 70%
ASTRAL *
N=806
49-51% Cardiovascular event
Nonstandard medical therapy

Only 335 of 403 patients
assigned to stents treated
6% Crossover
Bax, et al: STAR*
RAS>50%
Clearance <80 mL/min/1.73m2
Endpoint 20% change in
clearance
Ann Int Med 150:840, 2009
Uzzo, et all Transplant Proc.

34:723, 2002
No difference in rates of
developing a fall in GFR between
groups.
Minor disease 28% of assigned

stent group not treated, mainly
due to minimal stenosis
Med failure: 4/74 (46/64

randomized to stent were actually
treated)
High-grade stenosis entire renal
mass (>75% stenosis)
Creatinine 4 mg/dL
N=52
Stop points BP, doubling Cr

ESRD, CV event or death.
Enrollment bias?
Median f/u: 74mo: No difference

between groups: 67% reached stop
point.
All patients required to be

surgical candidates.
Van Jaarsveld, et al NEJM 342,

2000
Resistant: 2 drugs
DBP>95 mm Hg or creatinine
rise with ACEI
RAS>50%
No difference in BP outcomes at 3
mos between groups: Fewer drugs:
1.9 vs 2.4 in PTRA group p<.01
Large crossover for BP Control

(44%)
N=106 ASO
Exclusion: Creat 2.3

Solitary kidney/total occlusion
Kidney <8 cm
Creat Clearance (3 mos) ml/min:

PTRA: 70
Med Rx: 59
(p=.03)
Few/no stents.
BP automated oscillometric
Abnormal renograms
PTRA: 36%
Med Rx: 70%
(p=.002)
Short follow-up.
Renal artery occlusion

PTRA 0
Med Rx 8
Inadequate BP control in both

groups
No difference in BP or Creatinine
clearance between groups:
Fewer drugs (DDD) in PTRA:
PTRA 1.0
Med Rx: 1.78, p<.01
Excluded RAAS blockade.
Plouin, et al Hypertension
31:822, 1998
<75 years
Normal contralateral kidney
RAS>75% or >60%, lateralizing
study
N=49 (unilateral ASO)
Exclusion: Malig HTN CVA,

CHF, MI within 6 mos
27% crossover in Medical group
BP: Automated
Sphygomanometer, ABPM at 6
mos
Enrollment selection bias

(exclusion).
Textor and Lerman
Page 24
Author/No. Patients
Inclusion/BP measurement
Outcome
Weaknesses/Limitations
Webster, et al J. Human
Hypertens 12:329, 1998
DBP 95, 2 drugs
No BP Difference in Unilateral
ARAS:
Improved BP in bilateral
disease.
N=55 (unilateral=27)
N=135 eligible
Exclusion: CVA, MI within 3

mos:
Creat>500(mcmol/L)
RAS>50%
Lower BP in Bilateral ARAS:

PTRA: 152/83
Med Rx: 171/91
p<.01
Limited BP control by current

standards.
BP: Random Zero Device No

ACEI allowed
DDD=defined daily doses
*
ASTRAL: = Angioplasty and Stent Therapy for Renal Artery Lesions
STAR = Stent placement in patients with Atherosclerotic Renal Artery Stenosis

Overview of prospective randomized trials comparing medical therapy for renovascular hypertension to percutaneous renal artery angioplasty
(PTRA) with and without stenting or surgery. These studies contained selected patient populations that excluded highest risk groups. Each was
different, but all found less blood pressure or renal functional benefits in interventional groups than reported from previous observational studies
alone. These data highlight advances in medical therapy and relatively modest rates of renal functional loss for patients with limited disease.
Crossover rates from medical to angioplasty arms were significant in the early trials mainly related to blood pressure control, however, and
emphasize the importance of restoring blood supply in selected patients, particularly those with bilateral disease.
ASTRAL 1
STAR 85
Surgery: Uzzo 86
Webster 87
Plouin 88
Van Jaarsveld 89


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State of the Art: Renovascular Hypertension and Ischemic

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Textor and Lerman

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Definition and epidemiology

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Pathophysiology: Renovascular hypertension and the role of reninangiotensin system

Am J Hypertens. Author manuscript; available in PMC 2011 November 1.

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Clinical manifestations of renovascular hypertension include high rates of target organ

Loss of renal function and viability

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Clinical manifestations and the Decision to undertake Diagnostic studies

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Am J Hypertens. Author manuscript; available in PMC 2011 November 1.

Textor and Lerman

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Diagnostic Studies for Renovascular Disease

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NIH-PA Author Manuscript

CT angiography (CTA) and MR angiography (MRA) provide ever more sophisticated

Am J Hypertens. Author manuscript; available in PMC 2011 November 1.

Textor and Lerman

NIH-PA Author Manuscript

Angiotensin is an important determinant of filtration pressure in the kidney. Most patients

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NIH-PA Author Manuscript

Medical Therapy for Renovascular Hypertension and Ischemic

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The role of Renal Revascularization

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Am J Hypertens. Author manuscript; available in PMC 2011 November 1.

Textor and Lerman

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Am J Hypertens. Author manuscript; available in PMC 2011 November 1.

Textor and Lerman

Future Developments to recover renal function

ARAS initiates complex changes by which disturbed signaling pathways activate

Summary: An integrated view of managing renovascular disease

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Am J Hypertens. Author manuscript; available in PMC 2011 November 1.

Textor and Lerman

NIH-PA Author Manuscript

Am J Hypertens. Author manuscript; available in PMC 2011 November 1.

Textor and Lerman

NIH-PA Author Manuscript

Am J Hypertens. Author manuscript; available in PMC 2011 November 1.