Brenner and Rector's The Kidney, 8th ed.

CHAPTER 43. Renovascular Hypertension and Ischemic Nephropathy

Stephen C. Textor



Historical Perspective, 1528



Pathophysiology of Renovascular Hypertension and Ischemic Nephropathy, 1529



Epidemiology of Renal Artery Stenosis, 1537



Clinical Features of Renovascular Hypertension, 1539



Diagnostic Testing for Renovascular Hypertension and Ischemic Nephropathy, 1544



Management of Renal Artery Stenosis and Ischemic Nephropathy, 1551



Summary, 1562

Few clinical problems present greater challenges to nephrologists than managing renovascular hypertension and ischemic nephropathy. When successful, renal revascularization in these disorders can both improve hypertension and salvage renal function to a remarkable degree. Selecting patients for whom these benefits apply without excessive risks is rarely simple, however. Broad changes in population demographics, imaging technology, and medical therapy related to the renin-angiotensin system, combined with rapidly evolving techniques of renal revascularization, make this a dynamic clinical field.

The study and treatment of renovascular disease overlaps many medical disciplines and subspecialties, including nephrology, internal medicine, cardiovascular diseases, interventional radiology, and vascular surgery. These subspecialty groups tend to deal with widely different patient subgroups and clinical issues that shape different points of view. Cardiologists, for example, more commonly encounter patients with widespread coronary and vascular disease at risk for “flash” pulmonary edema than internists who may deal with established hypertensive patients with progressive hypertension or a rise in serum creatinine ( Fig. 43-1 ). Both of these may represent clinical manifestations of renovascular disease but present different comorbid risk and management issues. It will come as no surprise that perceptions related to renovascular hypertension and ischemic nephropathy sometimes differ among informed clinicians, even when derived from the same published data. Optimal application of endovascular stenting for atherosclerotic renal artery stenosis (ARAS), for example, is sufficiently controversial to warrant a multicenter, prospective, randomized trial funded through the National Institutes of Health (NIH) beginning in 2005. The Cardiovascular Outcomes for Renal Atherosclerotic Lesions (CORAL) trial will examine the long-term outcomes of optimal medical management with and without renal artery stenting. The fact that the NIH review committees concluded that the role of stenting is in “equipoise” such that randomization is ethical and appropriate underscores the ambiguity clinicians encounter in practice.

Nephrologists play a major role in caring for patients with these disorders. Ultimately, renovascular disease threatens blood flow to the kidney. The consequences of impaired blood flow not only affect blood pressure and cardiovascular risk but also threaten the viability of the kidney. It can lead to irreversible loss of kidney function, sometimes designated ischemic nephropathy or azotemic renovascular disease.[1] It must be recognized, however, that renal revascularization is a two-edged sword. The benefits of renal artery interventional procedures include the potential to improve systemic arterial blood pressures and to preserve or salvage renal function. Unfortunately, the risks of renal intervention are all too familiar to nephrologists. The procedures themselves may threaten the viability of the affected kidney through vascular thrombosis, dissection, restenosis, or atheroemboli. The consequences of these events sometimes precipitate the need for renal replacement therapy, including dialysis or transplantation. It is, therefore, important that nephrologists have a solid foundation related to the risks and benefits of reduced renal perfusion and the implications of both medical management and restoration of renal perfusion pressure.

This chapter undertakes to summarize our current knowledge related to the mechanisms underlying renovascular hypertension and ischemic nephropathy. It addresses the changing demographics and comorbid risk of patients with renovascular disease, the spectrum of clinical manifestations encountered, the implications of disease progression, and the risks and benefits of both medical management and renal revascularization.



FIGURE 43-1  A, Aortogram demonstrates renal artery stenosis (RAS) in multiple renal arteries in a 78-year-old man with hypertension. This image was obtained during lower extremity angiography for symptomatic claudication. Renovascular disease commonly develops in the setting of atherosclerotic disease elsewhere. Detection of an aortic aneurysm is an additional incidental finding. Understanding the role of renal artery disease in a specific patient regarding blood pressure control and kidney function is central to deciding when to consider renal revascularization. In this case, hypertension was easily treated with a single agent and serum creatinine remained stable at 1.3 mg/dL for more than 6 years. B, The spectrum of clinical manifestations of renovascular disease ranges from minimal hemodynamic effects to major acceleration of cardiovascular (CV) risk and renal injury.




Many of the earliest observations regarding blood pressure regulation focused upon the role of the kidney. The sequence of these observations has been reviewed.[2] In 1898, Tigerstedt and Bergman established that extracts of the kidney had pressor effects in the whole animal, and these authors are credited with the identification of “renin.” Identification of each element in the renin-angiotensin system together represents a remarkable series of research ventures spanning a half century and investigators in many separate countries. Goldblatt and others provided seminal experiments with the development of an animal model in which reduced renal perfusion regularly produced hypertension, published between 1932 and 1934. Numerous investigators thereafter addressed the peptide nature of angiotensin (Ang), the role of “renin-substrate” or angiotensinogen, the role of nephrectomy in sensitizing the animal to the pressor effects of Ang, and the sequential “phases” of hypertension. Activation of the renin-angiotensin system was identified as central in renovascular hypertension.[3] Hence, the renin-angiotensin system owes its discovery and nomenclature primarily to early studies related to regulation of blood pressure by the kidney. Only recently have the many additional actions of Ang become evident regarding vascular remodeling, modulation of inflammatory pathways, and interaction with fibrogenic mechanisms. Understanding that reduced renal blood flow produces sustained elevations in arterial pressure led to broad study of the mechanisms of hypertension. Experimental hypertension of two-kidney and one-kidney renal clip (two-kidney and one-kidney “Goldblatt” models) represents some of the most extensively studied models of blood pressure and cardiovascular regulation.[3]Translation of these studies to clinical medicine followed soon thereafter. Some forms of hypertension were recognized as “malignant” in character during the late 1930s and 1940s based on poor survival if patients were untreated. Few antihypertensive agents were known until the 1950s, and intervention consisted mainly of lumbar sympathectomy and/or extremely low-sodium-intake diets. Recognition that some forms of severe hypertension were secondary to occlusive vascular disease in the kidney led surgeons to undertake unilateral nephrectomy for small kidneys in 1937.[4] The fact that some of these were indeed “pressor” kidneys and blood pressure fell to normal levels provided “proof of concept” and led to more widespread use of nephrectomy. Unfortunately, achieving “cure” of hypertension after nephrectomy was rare, and Homer Smith reviewed the poor results overall in a 1956 paper discouraging this practice.

The 1960s marked the introduction of practical methods of vascular surgery that could be applied to restoration of renal blood flow. These carried substantial morbidity but offered an opportunity to restore the renal circulation and potentially to reverse renovascular hypertension. One result of this development was a series of studies to characterize the functional role of each vascular lesion in producing hypertension, thereby allowing prediction of the outcomes of vascular surgery.[4] A large, cooperative study of renovascular hypertension included major vascular centers and reported on the results of more than 500 surgical procedures.[4] These results provided limited support for vascular repair but highlighted relatively high associated morbidity and mortality, particularly in patients with atherosclerotic disease.

The 1980s and 1990s were characterized by both improved medications and the introduction of endovascular procedures, including percutaneous angioplasty and stents. These both broadened the options for treating patients with vascular disease and raised new issues regarding timing and overall goals of intervention. Recent developments highlight the need for intensive cardiovascular risk factor reduction and more stringent standards of blood pressure control. Medications have improved dramatically, as regards both efficacy and tolerability. As is emphasized later, broad application of angiotensin-converting enzyme inhibitors and Ang receptor antagonists for reasons other than hypertension alone has changed the clinical presentation of disorders associated with renal artery stenosis (RAS). Uncontrollable hypertension is now less commonly the reason to intervene in renovascular disease than before. Often, the main objective is the long-term preservation of renal function. In recent years, endovascular techniques of angioplasty and stent placement now open the possibility of renal revascularization with relatively low morbidity in many patients previously considered unacceptable surgical candidates. The central challenge for clinicians is how and when to apply these tools most effectively in the management of individual patients.[5]


Renal Artery Stenosis versus Renovascular Hypertension

As with most vascular lesions, the presence of a vascular abnormality alone does not translate directly into functional importance. Some degree of RAS can be identified in 20% to 45% of patients undergoing vascular imaging for other reasons, such as coronary angiography or lower extremity peripheral vascular disease.[6] Most of these “incidental” stenoses are of little or no hemodynamic significance. The term renovascular hypertension refers to a rise in arterial pressure induced by reduced renal perfusion. A variety of lesions can lead to the syndrome of renovascular hypertension, some of which are listed in Table 43-1 . Strictly speaking, the diagnosis of renovascular hypertension is established only in retrospect after successful reversal of hypertension with revascularization.

TABLE 43-1   -- Examples of Vascular Lesions Producing Renal Hypoperfusion and the Syndrome of Renovascular Hypertension



Unilateral disease (analogous to one-clip-two-kidney hypertension)



Unilateral atherosclerotic renal artery stenosis



Unilateral fibromuscular dysplasia



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 (analogous to one-clip-one-kidney model)



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




Studies of vascular obstruction using latex rubber casts indicate that between 70% and 80% of lumen obstruction must occur before measurable changes in blood flow or pressure across the lesion can be detected. Measurements of pressure gradients across human lesions confirm these observations.[7] When advanced stenosis is present, the fall in pressure and flow develops steeply, as illustrated in Figure 43-2 . When lesions have reached a degree of hemodynamic significance, they are deemed to have reached “critical” stenosis.



FIGURE 43-2  A and B, Measured fall in arterial pressure and blood flow across stenotic lesion induced in experimental animals. The degree of stenosis was quantitated using latex casts after completion of the experiment. These data indicate that “critical” lesions require 70% to 80% luminal obstruction before hemodynamic effects can be detected.  (From May AG, Van de Berg L, DeWeese JA, et al: Critical arterial stenosis. Surgery 54:250–259, 1963.)




When renal artery lesions reach critical dimensions, a series of events leads to a rise in systemic arterial pressure and restoration of renal perfusion pressure, as illustrated in Figure 43-3 . Hence, one can view the development of rising pressures in this context as an integrated renal response to maintain renal perfusion. It is important to distinguish between experimental models of “clip” stenosis, at which time a sudden change in renal perfusion is induced, and the more common clinical situation of gradually progressive lumen obstruction. In the latter instance, hemodynamic characteristics change slowly and are likely to produce hypertension over a prolonged time interval. The rise in systemic pressure restores normal renal perfusion, often with normal-sized kidneys and no discernible hemodynamic compromise. If the renal artery lesion progresses further (or is experimentally advanced), the cycle of reduced perfusion and rising arterial pressures recurs until malignant phase of hypertension develops. Recent experimental swine models emphasize gradually progressing vascular lesions that mimic human renovascular disease.[8]



FIGURE 43-3  Systemic arterial pressure (carotid) and poststenotic renal perfusion pressures (iliac) in an aortic coarct model with the clip placed between the right and the left renal arteries. These measurements in conscious animals during development of renovascular hypertension illustrate the fact that, despite a persistent gradient across the stenosis, renal perfusion pressure is maintained at near-normal levels at the expense of systemic hypertension. SEM, standard error of the mean.  (From Textor SC, Smith-Powell L: Post-stenotic arterial pressure, renal haemodynamics and sodium excretion during graded pressure reduction in conscious rats with one- and two-kidney coarctation hypertension. J Hypertens 6:311–319, 1988.)




A corollary to “critical” arterial stenosis is that reduction of elevated systemic pressures to normal in renovascular hypertension threatens to reduce renal pressures beyond the stenotic lesion. Poststenotic pressures may fall below levels that maintain blood flow. Such underperfusion of the kidney activates counterregulatory pathways and leads to a sequence of events directed toward restoring kidney perfusion. Foremost among these pathways is the release of renin with activation of the renin-angiotensin system.

The Role of the Renin-Angiotensin System in One-Kidney and Two-Kidney Renovascular Hypertension

Reduction in renal perfusion pressures activates the release of renin from juxtaglomerular cells within the affected kidneys. Experimental studies indicate that two-kidney-one-clip models of hypertension can be delayed indefinitely so long as agents that block this system are administered. Animals genetically modified to lack the Ang I receptor fail to develop two-kidney-one-clip hypertension as illustrated in Figure 43-4 .[9]



FIGURE 43-4  Systolic blood pressures (BPs) in mice before and after placement of a renal artery clip in experimental two-kidney-one-clip renovascular hypertension (2K1C). The rise in systolic BP (SBP) after clip placement develops rapidly only in mice with an intact angiotensin 1A receptor (AT1A+, solid circles, left panel). This rise is blocked by administration of an angiotensin receptor blocker (open circles, left panel). A genetic knockout mouse strain with no AT1A receptor (AT1A-/-) has lower SBP and no change after renal artery clipping (solid circles, right panel). No additional effect is noted with an angiotensin receptor blocker (open squares, right panel). These data reinforce the essential role of the renin-angiotensin system and an intact angiotensin 1 receptor for development of renovascular hypertension.  (Modified from Cervenka L, Horacek V, Vaneckova I, et al: Essential role of AT1-A receptor in the development of 2K1C hypertension. Hypertension 40:735–741, 2002, with permission.)




Demonstration of the role of the renin-angiotensin axis in renovascular hypertension depends in part upon whether or not a contralateral, nonstenotic kidney is present. Classically, human renovascular hypertension is considered analogous to two-kidney-one-clip experimental (Goldblatt) hypertension. The contralateral, nonstenotic kidney is subjected to elevated systemic perfusion pressures. The effect of rising perfusion pressure is to force natriuresis from the nonstenotic kidney and to suppress renin release. Hence, the nonstenotic kidney tends to prevent the rise in systemic pressures, thereby perpetuating reduced perfusion to the stenotic side and fostering continued renin release from the stenotic kidney. Blood pressure in these models is demonstrably angiotensin-dependent and associated with elevated circulating levels of plasma renin activity, as illustrated in Figure 43-5 . It is important to recognize that the two-kidney-one-clip model of renovascular hypertension provides the basis for many of the early functional studies of surgically curable hypertension in which side-to-side function was compared regarding glomerular filtration, sodium excretion, and other characteristics. This paradigm is also the basis for comparing kidneys side-to-side using radionuclide studies, such as captopril renograms, and renal vein renin determinations. Unilateral renal ischemia represents a classical model for the study of angiotensin-dependent hypertension and target organ injury.



FIGURE 43-5  A and B, Schematic view of two-kidney and one-kidney renovascular hypertension. These models differ by the presence of a contralateral kidney exposed to elevated perfusion pressures in two-kidney hypertension. The nonstenotic kidney tends to allow pressure natriuresis to ensue and produces ongoing stimulation of rennin release from the stenotic kidney. The one-kidney model eventually produces sodium retention and a fall in renin with minimal evidence of angiotensin-dependence unless sodium depletion is achieved.  (From Textor SC: Renovascular hypertension. In Johnson RJ, Feehally J (eds): Comprehensive Clinical Nephrology, 1st ed. London, Mosby [Harcourt Brace International], 2000, pp 41.1–41.12.).


When no such contralateral kidney is present, mechanisms sustaining hypertension differ. This model corresponds to the one-kidney-one-clip (one-kidney Goldblatt) hypertensive animal. Although renin release occurs initially, elevated systemic pressures develop with sodium and volume retention, as there is no sodium excretion by the contralateral kidney. Rising pressures eventually restore renin levels to normal. Hypertension in this model is not demonstrably dependent upon Ang II unless prior sodium depletion is achieved. Clinical examples of this situation are those of bilateral RASs or stenosis to a solitary functioning kidney in which the entire renal mass is affected. In such cases, diagnostic comparison of side-to-side renin release is not possible or has little meaning.

Mechanisms Leading to Sustained Renovascular Hypertension

For more than a century, the kidney has been recognized has a source of pressor materials. Recruitment of multiple pathways that raise arterial pressure increases the complexity of manag3ing hypertension in this setting. Identification of components of the renin-angiotensin system provides a crucial link to understanding several of these systems. Circulating renin is derived primarily from the kidney in response to a reduction of renal perfusion pressure detected by loss of afferent arteriolar stretch.[10] Renin itself has biologic activity directed mainly to the enzymatic release of Ang I from its circulating substrate, angiotensinogen, in plasma and possibly other sites. Two further peptides are cleaved from Ang I through the action of angiotensin-converting enzyme (ACE) to produce Ang II. Generation of Ang II in plasma occurs mainly during passage through the lung. Hence, the signal of reduced kidney pressures is amplified and transmitted to a major vasopressor system that acts throughout the body, accounting for one major mechanism by which renovascular hypertension develops.

The importance and breadth of the renin-angiotensin system in renovascular hypertension cannot be overemphasized. The actions of Ang II are multifold, as illustrated in Figure 43-6 . Activation of this system represents amplification of a local signal within the kidney to activate systemic pressor mechanisms, mediated by increased vascular resistance, sodium retention, and aldosterone stimulation. Further studies indicate that complex interactions between Ang II and tissue and cellular systems occur, leading to vascular remodeling, left ventricular hypertrophy, and activation of fibrogenic mechanisms.



FIGURE 43-6  Schematic view of activation of the renin-angiotensin system beyond a renal artery stenotic lesion. Generation of circulating and local angiotensin II leads to widespread effects, including sodium retention, efferent arteriolar vasoconstriction, and elevated systemic vascular resistance. Studies in recent years implicate angiotensin II in many other pathways of vascular and cardiac smooth muscle remodeling, activation of inflammatory and fibrogenic cytokines, coagulation factors, and induction of other vasoactive systems. ACE, angiotensin-converting enzyme; LV, left ventricular.



Hypertension and peripheral vasoconstriction reflect further complex interactions between Ang and other vasoactive systems. Renovascular disease leads to disturbances in sympathetic nerve traffic, which may differ between one-kidney and two-kidney models.[11] Muscle sympathetic nerve activity is increased in humans with renovascular hypertension, and blood pressure responses to adrenergic inhibition are magnified.[12]

A major transition occurs with recruitment of altered oxidative stress within the systemic vasculature, leading to increased oxygen free radicals. [10] [13] Experimental models of two-kidney-one-clip hypertension develop a rise in oxidative stress (reflected by F2-isoprostanes) that can be reversed in part with Ang blockade and/or antioxidants.[14] Vascular injury itself produces disturbances in endothelium-derived mechanisms, such as endothelin (ET) production, and vasodilator systems, such as prostacyclin.[15] That endothelial dysfunction and increased oxidative stress participate in human renovascular disease has been supported by clinical studies in patients with both atherosclerotic and fibromuscular RAS.[16] These data have been reinforced in atherosclerotic renovascular disease demonstrating a rise in nitric oxide (NO) and reduction in malondialdehyde within 24 hours of endovascular revascularization.[17] These studies indicate that oxidative stress can be reversed both by infusion of antioxidants and by successful revascularization, which can restore vasomotor tone toward normal.

Phases of Development

Experimental models of renovascular hypertension indicate that mechanisms sustaining hypertension change over time ( Fig. 43-7 ). An early phase is characterized by elevated circulating indices of renin activity and hypertension, both of which return to normal after the vascular lesion is removed. A second phase has been described with a return of circulating renin activity to normal or low levels, during which hypertension persists and blood pressure can still respond to clip removal. A third phase has been proposed, during which removal of the clip no longer leads to reduction in arterial pressure. These observations have been interpreted to underscore the transition between differing mechanisms of vascular control, some of which no longer depend upon reduced renal perfusion. Some data have been presented to argue that microvascular injury to the contralateral kidney sustains hypertension in this phase. Recent studies in a swine model indicate that a the fall in renin activity follows a transition to mechanisms related to oxidative stress with persistent elevation of oxidative metabolites such as isoprostanes.[13] Whether these phases apply directly to human renovascular disease is not well known.



FIGURE 43-7  Schematic depiction of phases observed in experimental renovascular hypertension. Initially high levels of renin activity fall in the chronic phase despite the fact that removal of the renal artery clip corrects hypertension. These observations support the concept of recruitment of additional vasopressor mechanisms after the initial activation of the renin-angiotensin system (see text). Whether human renovascular hypertension follows these patterns is not well known. BP, blood pressure  (From Brown JJ, Davis DL, Morten JJ, et al: Mechanism of renal hypertension. Lancet 1:1219–1221, 1976.)


Mechanisms of Ischemic Nephropathy

Reduced renal perfusion beyond “critical” stenosis ultimately leads to loss of viable kidney function, as illustrated in Figure 43-8 . Patients with stenosis affecting the entire renal mass can develop reduced blood flow and glomerular filtration when poststenotic pressures fall below the range of autoregulation. This process is reversible if pressure is restored and/or the vascular lesion is removed. If allowed to progress, recurrent reduction in kidney blood flow can produce irreversible fibrosis, as illustrated schematically in Figure 43-9A . The mechanisms by which this occurs may differ from those that govern the development of hypertension. The term ischemic nephropathy may itself be a misnomer, as we have discussed previously.[7] Unlike brain or cardiac tissue, the kidney is vastly oversupplied with oxygenated blood, consistent with its function as a filtering organ. Measurements of both renal vein oxygen saturation and erythropoietin in patients with high-grade renovascular lesions indicate that whole-organ “ischemia” is not present. There may be local areas of deranged oxygen delivery within the kidney.[18]



FIGURE 43-8  Effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) in patients with critical bilateral renal artery stenosis during pressure reduction with sodium nitroprusside (NP). Reduction to normal blood pressures (BPs) produced a reversible fall in both plasma flow and GFR. Studies in the same patients (right panel) after unilateral surgical revascularization indicate that the sensitivity of blood flow and GFR to pressure reduction can be reversed. SEM, standard error of the mean.  (From Textor SC, Novick A, Tarazi RC, et al: Critical perfusion pressure for renal function in patients with bilateral atherosclerotic renal vascular disease. Ann Intern Med 102:309–314, 1985.)






FIGURE 43-9  A, The general paradigm in clinical use, reflecting the fact that reversible injury related to hypoperfusion of the kidney becomes irreversible at some point. B, Schematic depiction of hypothetical pathways implicated in ischemic nephropathy. These pathways entail activation of apoptosis, increased oxidative stress, and fibrogenic mechanisms, some of which may be modulated by the renin-angiotensin system and other factors, such as lipid peroxidation. ATP, adenosine triphosphate; GFR, glomerular filtration rate; IL-1, interleukin-1; NF-kB, nuclear factor-kB; NO, nitric oxide; PAI-1, plasminogen activator inhibitor-1; PG, prostaglandin; TGF-b, transforming growth factor-β; TNF, tumor necrosis factor.  (From Lerman L, Textor SC: Pathophysiology of ischemic nephropathy. Urol Clin North Am 28:793–803, 2001.)




Reduction of blood flow to the kidney activates numerous pathways of vascular and tissue injury, including increased Ang II, ET release, and oxidative stress, as noted previously. Under the right conditions, these factors trigger inflammatory cytokines and fibrogenic mechanisms, leading to tissue fibrosis.

Adaptive Mechanisms to Reduced Renal Perfusion

The kidney maintains autoregulation of blood flow in the face of reduced arterial diameters of up to 75%. Under basal conditions, renal blood flow is among the highest of all organs, reflecting its filtration function. Less than 10% of delivered oxygen is sufficient to maintain renal metabolic needs. Under conditions of impaired renal perfusion, oxygen delivery is sometimes maintained by development of collateral vessels, associated with intrarenal redistribution of blood flow. The kidney medulla functions at levels closer to hypoxia than does the cortex, which is efficiently autoregulated. The outer medulla, for example, is continuously on the verge of anoxia and is sensitive to acute changes in perfusion, which produce tubular necrosis. During chronic reduction of blood flow, the medulla is protected somewhat by adaptive maintenance of tissue perfusion at the expense of cortical blood flow, which parallels whole kidney renal blood flow.[19] Hence, gradual reduction of renal perfusion pressures allows recruitment of protective mechanisms that remain incompletely understood, leading to different functional and morphologic changes from those observed after acute ischemic injury.

A fall in renal blood flow is accompanied by decreased oxygen consumption, in part due to reduced metabolic demands of filtration and tubular solute reabsorption.[20] When severe, reduced blood flow leads to accumulation of deoxygenated molecular hemoglobin.[21] Eventually, structural atrophy of the renal tubules occurs, partly due to necrosis and apoptosis (see Fig. 43-9B ). The latter is an active, programmed form of cellular death that appears to be closely regulated and differs from tissue necrosis. Tubular atrophy is potentially reversible and the kidney maintains the capacity for tubular cell regeneration under many conditions, features that support the concept that underperfused kidney tissue can achieve a “hibernating” state capable of restoring function if blood flow is restored.[22] Eventually, pathologic examination demonstrates reduced glomerular volume, loss of tubular structures near underperfused glomeruli, and areas of local inflammatory reaction, as illustrated in Figure 43-10 .



FIGURE 43-10  A and B, Photomicrographs obtained from a kidney beyond an occlusive renal artery lesion. The glomerular volume is small, with tubular atrophy and interstitial fibrosis with patchy areas of inflammatory cellular infiltrate.  (From Textor SC, Wilcox CS: Renal artery stenosis: A common, treatable cause of renal failure? Annu Rev Med 52:421–442, 2001, with permission.)




Mechanisms of Tissue Injury in Azotemic Renovascular Disease

The role of Ang II during renal hypoperfusion is complex. Generation of Ang II acts to raise perfusion pressure and to protect glomerular filtration by efferent arteriolar constriction, as noted previously. Ang II induces cellular hypertrophy and hyperplasia in several cell types, in addition to directly stimulating local hormone production and ion transport. Experimental infusion of Ang II leads to parenchymal renal injury with focal and segmental glomerulosclerosis.[23] ACE inhibition and Ang II receptor blockade in several experimental models diminish renal cell proliferation and suppress infiltration of mononuclear cells that trigger expression of extracellular matrix proteins that leads to progressive nephrosclerosis. Ang II may participate in vascular smooth muscle cell growth, platelet aggregation, generation of superoxide radicals, activation of adhesion molecules and macrophages, induction of gene transcription for proto-oncogenes, and oxidation of low-density lipoproteins (LDLs).[24] These observations underscore the dual roles of Ang II, both for adaptation and maintenance of kidney function and for modulating many steps in the pathologic cascade underlying progressive renal injury.

Recent experimental studies indicate an independent effect of hypercholesterolemia in modifying parenchymal renal injury in ischemic nephropathy. Cholesterol feeding is used as a model of “early atherosclerosis” and itself alters renal vascular reactivity to acetylcholine and changes renal tubular functional characteristics.[25] Levels of oxidized LDL rise in this model, associated with markers of oxidative stress and activation of tissue nuclear factor-kB (NF-kB), transforming growth factor-β (TGF-β), and inducible NO synthase. The effect of these changes in producing kidney fibrosis is magnified in the presence of RAS. Many of these effects can be reduced experimentally by ET blockade or antioxidants.[26]

The vascular endothelium is a source of multiple vasoactive factors, the most widely recognized of which are NO and ET. Endothelial nitric oxide is synthesized from L-arginine by a family of NO synthases and participates in the regulation of kidney function by counteracting the vasoconstrictor effects of Ang II. In addition to its effects on blood flow and tubular reabsorption of sodium, NO inhibits growth of vascular smooth muscle cells, mesangial cell hypertrophy and hyperplasia, and synthesis of extracellular matrix. These occur in part by down-regulating expression of ACE[27] and Ang I1 genes. Loss of the balance between Ang II and NO represents a disturbance of tissue homeostasis and may accelerate tissue damage.

A reduction in renal perfusion leads to diminished “shear stress” distal to the stenosis (see Fig. 43-9B ). This condition reduces production of NO and accelerates release of renin and generation of Ang II in the stenotic kidney. Hence, the effects of NO are diminished in the poststenotic kidney, allowing predominance of intrarenal vasoconstrictors, in-cluding Ang II and vasoconstrictor prostaglandins, such as thromboxane.[28] The decrease in NO allows removal of its antithrombotic effects and the inhibition of growth-related responses to tissue injury.

The ET peptides are a family of potent and long-lasting vasoconstrictor peptides produced and released from endothelial cells. ET itself is released from renal epithelial cells after simulation with a variety of substances such as thrombin and local cytokines, including TGF-b, interleukin-1, and tumor necrosis factor (TNF). It must be emphasized that renal ischemia is a potent stimulus for expression of the ET-1 gene in the kidney, which persists for days after resolution of the ischemic injury. Sustained vascular effects of ET may participate in the hypoperfusion that lasts long beyond the vascular insult to postischemic kidneys.

The kidney is a rich site for production of prostaglandins, which are cyclo-oxygenase derivatives of arachidonic acid. These materials are produced in arteries, arterioles, and glomeruli in the cortex, where they have important actions to maintain renal blood flow and filtration, particularly under conditions of elevated Ang II. Enhanced synthesis of prostacyclin and prostaglandin E2 (PGE2) occurs during tissue hypoperfusion and ischemia, which may protect against some forms of hypoxic injury. Conversely, thromboxane A2 (TXA2) is a vasoconstrictor prostaglandin that lowers GFR by reducing renal plasma flow and can accelerate structural renal damage. It is stimulated by Ang II production and by production of reactive oxygen species and may, in turn, modify hemodynamic actions of Ang II. TXA2 modulates ET in actions on vascular permeability that may contribute to interstitial matrix composition and target organ damage. Blockade of TXA2 receptors thereby can reduce severity of experimental tissue injury, including acute ischemic damage.

Oxidative stress is term reflecting an imbalance between tissue oxygen radical-generating systems and radical scavenging systems leading to a shift toward “pro-oxidant” species. This involves increased presence and toxicity of reactive oxygen species, which in turn can promote the formation of vasoactive mediators including ET-1, leukotrienes, and PGF isoprostanes, which are products of lipid peroxidation. As noted previously, these mediators affect renal function and hemodynamics, both by inducing renal vasoconstriction and by changing glomerular capillary ultrafiltration characteristics.

Reactive oxygen species can magnify ischemic renal injury by causing lipid peroxidation of cell and organelle membranes. These disrupt structural integrity and capacity for cell transport and energy production, particularly within the proximal tubule. Other cytokine pathways including activation of NF-kB and growth factors may play a role.[29]

The role of TGF-b merits emphasis. It belongs to a family of polypeptides that regulate normal cell growth, development, and tissue remodeling after injury.[30] This cytokine is an important and ubiquitous fibrogenic factor that modifies extracellular matrix synthesis by both glomerular and extraglomerular mesenchymal cells. These factors modify both tissue healing and progression to advanced renal failure. TGF-β is essential for tissue repair after many forms of injury, including ischemic injury, during which it participates in restoration of restoring extracellular matrix in proximal tubular basement membranes. However, activation of the AT1A receptor stimulates generation of TGF-b, which plays a major role in tissue fibrosis through increases in type IV collagen deposition. TGF-β acts synergistically with ET and has interactions with platelet-derived growth factor (PDGF), interleukin-1, and basic fibroblast growth factor in progressive interstitial fibrosis.[31] Some investigators propose that many forms of renal scarring represent an overabundance of TGF-β activity owing to failure to suppress its activity after repair of an original injury.[32] Activation of TGF-β develops in experimental models of RAS and is magnified by hypercholesterolemia.[25]

Although whole kidney oxygen saturation and delivery remains preserved in the poststenotic kidney, it is inescapable that local areas within the kidney likely are exposed to at least intermittent, recurrent ischemia. The potential for repetitive acute renal injury to induce long-term irreversible fibrosis is evident from studies of acute heme protein exposure.[33] The hallmark of acute ischemic injury is a rapid decline in cellular adenosine triphosphate (ATP), which in turn allows accumulation of intracellular calcium, activation of phospholipases, and generation of oxygen free radicals.

Tissue ischemia appears to be a common denominator in many forms of tubulointerstitial injury, which is the major prognostic factor in most renal diseases. Such injury is associated commonly with interstitial inflammatory reactions and activation of fibroblasts and heat shock proteins. Injury to the tubular epithelium alters the antigenic profile of these cells, initiating a cell-mediated immune response, sometimes associated with B lymphocyte, T lymphocyte, and macrophage infiltrates.[34] As noted earlier, sustained tubulointerstitial injury leads to increased TGF-b, enhanced expression of plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloprotease-1 (TIMP-1), a 1 (IV) collagen and fibronectin-EIIA, and thus to increased synthesis of extracellular matrix.

Many of the mechanisms mentioned previously interact with one another. Taken together, the kidney is subject to a wide variety of vasoactive and inflammatory mediators, which can be disrupted by loss of blood flow and perfusion pressure. These disturbances appear to activate a variety of fibrogenic and local destructive mechanisms, which can lead to irreversible parenchymal damage within the kidney.

Consequences of Restoring Renal Blood Flow

As illustrated in Figure 43-9A , restoring renal perfusion can allow recovery of renal function to the extent that these changes remain reversible. At some point, both inflammatory and fibrogenic mechanisms appear to no longer respond with recovery of renal function.

Renal Reperfusion Injury

The course of recovery after restoration of blood supply to an underperfused kidney depends upon the extent and duration of the perfusion injury, in addition to the adequacy of reperfusion.[35] Paradoxically, some tissues subjected to ischemic injury undergo morphologic and functional changes that worsen during the reperfusion phase. This is believed to reflect vascular endothelial injury and activated leukocytes, which may be “primed” to obstruct distal capillaries after restoring perfusion pressure contributing to a so-called no-reflow phenomenon. Under experimental conditions, reperfusion injury appears to require major degrees of pro-oxidant stress with excess PGFisoprostanes and free oxygen radicals, particularly with a deficit of NO.[36] Hence, antioxidants and reactive oxygen metabolite scavengers improve outcomes following experimental reperfusion. Within the kidney, ischemia-reperfusion models are most pronounced in the proximal tubules, with local necrosis and tubular obstruction as observed in acute tubular necrosis (ATN).

Ang II may participate in some of these changes because activation of AT1 receptors impairs glomerular filtration in the postischemic kidney.[37] Local imbalance of NO production is particularly prominent within the kidney; it has a dual action with the potential drawback of accelerating reoxygenation injury and initiating lipid peroxidation. However, systemic treatment with NO donors improves renal function and blunts local inflammation before reperfusion in some conditions.[36]


The syndrome of renovascular hypertension can be produced by a wide variety of lesions affecting renal blood flow. Some of these are listed in Table 43-1 . A rapidly developing form of this disorder can be seen after spontaneous or traumatic renal artery dissection. The majority of stenotic lesions are made up from atherosclerotic renal artery stenosis or “fibromuscular diseases (FMDs).” Of patients with hypertension, previous studies have produced a wide range of estimates as to the prevalence of renovascular hypertension. This range depends heavily upon differences between patient groups studied. In un-selected mild to moderate hypertensive popula tions, the frequency appears to be between 0.6% and 3%, whereas in a referral clinic of “elderly” patients, the prevalence may exceed 30%. [38] [39] As noted later, the prevalence of anatomic RAS far exceeds that of renovascular hypertension.

Fibromuscular Disease

Fibromuscular disease commonly refers to one of several conditions affecting the intima or fibrous layers of the vessel wall. In some cases, multiple layers of the vessel wall may be affected. Reports from arteriograms obtained in “normal” renal organ donors indicate that 3% to 5% of individuals may have one of these lesions, many of which are present at an early age and do not affect either renal blood flow or arterial pressure.[40] Such lesions can lead to renovascular hypertension, sometimes associated with dissection or progression. Smoking is a risk factor for disease progression. Medial fibroplasia is the most common subtype, often associated with a “string-of-beads” appearance, as illustrated in Figure 43-11A . Such lesions consist primarily of intravascular “webs,” each of which may have only moderate hemodynamic effect. The combination of multiple webs in series, however, can impede blood flow characteristics and activate responses within the kidney to reduced perfusion. FMD lesions have a modest association with dysplastic lesions in other vascular beds, most commonly the carotid artery.[41] The large preponderance of hypertensive cases coming to vascular intervention occur in women with a bias toward the right renal artery.[42] FMD lesions are classically located away from the origin of the renal artery, often in the midportion of the vessel or at the first arterial bifurcation. Some of these expand to develop small vascular aneurysms. Although less common, other dysplastic lesions, particularly intimal hyperplasia, can progress and lead to renal ischemia and atrophy. Although loss of renal function is unusual with FMD, quantitative imaging of cortical and medullary kidney volumes indicate reduction parenchymal “thinning” occurs in both the stenotic and the contralateral kidneys beyond FMD.[43] Whereas these are commonly considered as a disorder of younger women, they can present at older ages, sometimes combined with atherosclerotic lesions, which magnify the hemodynamic effects. Whereas previous estimates derived from hypertension referral clinics suggest that 25% of patients with renovascular hypertension may have FMD, more recent studies suggest that current rates may be 16% or less.[44]



FIGURE 43-11  A and B, Angiographic appearance of medial fibroplasia with serial intravascular webs with small aneurysmal dilatations between them. These lesions appear in the midportion of the vessel, have strong predilection for the right renal artery, and are most commonly found in women. As shown in B, these lesions can often be improved substantially be effective balloon angioplasty.




Atherosclerosis affecting the renal arteries is the most com-mon renovascular lesion, accounting for 75% to 84% of interventional series in recent years. ARAS can be identified commonly with vascular disease affecting other vascular beds. Recent studies in patients undergoing coronary angiography indicate that 19% to 29% have ARAS with greater than 50% narrowing of the renal artery lumen. [6] [45] [50] Aortograms obtained in patients with peripheral vascular disease indicate that 14% to 42% of such patients have renal artery lesions of some degree.[47] Table 43-2 summarizes several reports related to the coexistence of atherosclerotic lesions in various vascular territories. The prevalence of such lesions increases with age and with the presence of atherosclerotic risk factors such as elevated cholesterol, smoking, and hypertension. Recent studies indicate that the probability of identifying high-grade RAS in hypertensive patients with azotemia rises from 3.2% in the 6th decade to above 25% in the 8th decade.[48] These figures confirm previous postmortem observations indicating that many patients dying of cardiovascular disease have renal artery lesions at autopsy. The data previously discussed underscore the fact that many renal artery lesions remain undetected on clinical grounds for many years (see later).

TABLE 43-2   -- Prevalence Rates of Atherosclerotic Renal Artery Stenosis in Patients with Vascular Disease Affecting Other Regional Beds Identified by Angiography


Studied with CAD (N)

Renal Artery Stenosis (>50%)

Coronary artery disease

Vetrovec et al[45a]


22 (29%)

Harding et al[45]


164 (20%)

Rihal et al[46]


57 (19.2%)

Peripheral vascular disease

Choudhri et al[45b]


42 (42%)

Wilms et al[45c]


22 (22%)

Olin et al[45d]


122 (38%)

Swartbol et al[47]


104 (23%)




The location of atherosclerotic disease is most often near the origin of the artery ( Fig. 43-12A ), although it can be observed anywhere. Many such lesions represent a direct extension of an aortic plaque into the renal arterial segment. It should be emphasized that ARAS is strongly associated with preexisting hypertension, cardiovascular lipid risk, diabetes, smoking, and abnormal renal function. [6] [53]



FIGURE 43-12  Atherosclerotic disease commonly affects both the renal arteries and the abdominal aorta. A, Aortogram shows early aneurysm formation and high-grade stenosis of the left renal artery with poststenotic dilation. The right renal artery also contains a tight stenosis originating from an aortic plaque. B, Magnetic resonance angiogram (MRA) in a 65-year-old male demonstrates near-total aortic occlusion with encasement of the right renal artery in atherosclerotic debris. The mean age for patients undergoing renal revascularization has increased from age 50 in the early surgical literature to over 70 in recent series. Accordingly, management of these patients must factor comorbid disease risk and the determination of risk/benefit considerations differently in older patients.




This section examines the demographic and clinical presentation of RAS, primarily as caused by atherosclerotic disease. It emphasizes the role of changing population demographics within the United States, newer antihypertensive agents, and the expanding use of agents that block the renin-angiotensin system for indications other than hypertension. These factors are fundamentally changing the populations at risk for being adversely affected by renal arterial disease and its clinical manifestations. “Uncontrollable” hypertension is now less commonly the main reason for considering renal revascularization. Rather, the hazards of underperfusion to kidney tissue leading to irreversible renal failure have led many to consider revascularization for “preservation” of renal function. Most importantly, it must be emphasized that long-term clinical outcomes in such patients are commonly determined by other disease entities (termed competing risk) that may have important implications for decisions concerning invasive therapy.[50] The importance of timing therapy and following the evolution of vascular disease over time cannot be overstated.

Fibromuscular Disease versus Atherosclerosis

As noted previously, renovascular hypertension may develop as a result of many lesions (see Table 43-1 ). The two most common are the FMDs and atherosclerosis. It must be emphasized that FMDs of the renal artery differ clinically from atherosclerotic diseases in many respects. FMD represents several types of intimal or medial disorders of the vessel wall, commonly affecting midportions of the renal artery in younger individuals. These lesions rarely lead to major renal functional loss, although some progression may be seen, particularly in smokers. These lesions appear most often as hypertension of early onset (<30 yr of age) and unusual severity. Occasionally, it presents as hypertension during pregnancy. Many lesions respond well to percutaneous angioplasty (see Fig. 43-9B ).[51]

By contrast, atherosclerotic lesions more commonly arise near the origin of the renal artery and are related to the systemic disorder predisposing to atherosclerosis elsewhere. ARAS is commonly associated with reduced GFRs.[5]Renovascular hypertension is associated with high morbidity and mortality. Ambulatory blood pressure monitoring (ABPM) readings indicate exaggerated systolic pressure variability and frequent loss of the circadian pressure rhythm,[52] usually associated with left ventricular hypertrophy. Sympathetic nerve traffic recordings indicate heightened adrenergic outflow that improves after successful revascularization.[11] A population-based study of 870 subjects above age 65 indicated that those with RAS had a 2- to 3-fold increased risk for adverse cardiovascular events during the subsequent 2 years.[53] These data are supported by a review of Medicare claims data between 1999 and 2001 for a random sample of Medicare recipients above age 67.[54] The authors indicate that incidence of atherosclerotic renovascular disease was 3.7/1000 patient-years and was associated with preexisting peripheral and coronary disease. After detection, subsequent development of claims for heart disease, transient ischemic attack, renal replacement therapy, and congestive heart failure were 3- to 20-fold higher in such patients as compared with contemporaries without renovascular disease. Adverse cardiovascular events were more than 10-fold more common than the need for renal replacement therapy. As a result, one of the major current controversies in cardiovascular disease is how to identify and monitor clinically significant RAS as a modifying factor for cardiovascular outcomes. This controversy is compounded by changes produced by (1) evolving medical therapy and (2) changing population characteristics.

The Role of Changing Antihypertensive Therapy

Prior to the 1980s, the literature of renovascular disease primarily concerned identification of functionally important lesions in patients with severe hypertension. Drug therapy was limited in scope and often produced poorly tolerated side effects. Most importantly, the range of available drugs did not yet include agents capable of interrupting the renin-angiotensin system. As a result, patients commonly appeared with accelerated or malignant hypertension, a large fraction of which was related to RAS. Among 123 patients whose average age was 44 years presenting with accelerated hypertension, more than 30% of whites were identified as having renovascular hypertension. Some patients could not be effectively controlled with available medications and were subjected to “urgent” bilateral nephrectomy as a life-saving measure. Hence, the evaluation for RAS centered upon identifying those patients whose blood pressures could be improved, perhaps “cured,” by renal revascularization.

Since the early 1980s, several new classes of antihypertensive agents have become available and widely used. These include calcium channel blockers and, most importantly, drugs that functionally block the renin-angiotensin system, such as ACE inhibitors and Ang receptor blockers (ARBs). The impact of these agents cannot be overstated. Reviews of medical therapy for renovascular hypertension indicate that regimens using these agents increased the likelihood of achieving good blood pressure control from 46% to more than 90%.[5] The concept of emergency bilateral nephrectomy for control of hypertension has almost disappeared. Most importantly, it is likely that many, if not most, patients with renovascular disease and hypertension now go undetected because blood pressure and renal function are well controlled and stable.[46] This may be happening even more commonly than before with the expansion of use of ACE inhibitors for other reasons, including congestive cardiac failure, proteinuric renal disease, and other constellations of cardiovascular risk factors, particularly since the publication of the Heart Outcomes and Prevention Evaluation (HOPE) trial.[55] Whether the use of ACE inhibitors and/or ARBs delays the onset of renovascular hypertension in humans, as it does in experimental animals, cannot be established with the present data.

Changing Population Demographics

The last several decades have been characterized by longer lifespans in many Western countries. This is likely the result of several factors, including major declines in mortality related to stroke and cardiovascular disease. Population groups above age 65 are now among the most rapidly growing segments in the United States. One consequence of lower mortality from coronary and cerebrovascular events is the delayed appearance of vascular disease affecting other beds, such as the aorta and kidneys. As a result, clinical manifestations of RAS are appearing in older individuals, often combined with other comorbid diseases.[56] These features change the clinical presentation (see later) in many respects and may affect the risk/benefit considerations inherent in deciding whether to consider renal revascularization. Series with renal artery intervention now routinely include average age values between 68 and 71 years, whereas a decade ago the mean age was between 61 and 63 years.[57] These mean values are more than 15 years older than those from the 1960s and 1970s (see Fig. 43-12 ). As might be expected, the prevalence of advanced coronary disease, congestive heart failure, previous stroke/transient ischemic attack, and aortic disease as well as impaired renal function is rising in patients with atherosclerotic renal artery disease.[58]

Clinical Features of Renal Artery Stenosis

Manifestations of renal artery disease vary widely across a spectrum illustrated in Figure 43-1 and Table 43-3 . As noted previously, this spectrum may range from a purely incidental finding noted during angiography for other indications to advancing renal failure leading to the need for dialytic support. As described earlier, multiple mechanisms raise systemic arterial pressure and tend to restore renal perfusion pressures to levels close to baseline. Clinical features of patients with essential hypertension were compared with those in patients subjected to revascularization for renovascular hypertension in the Cooperative Study in the 1960s are summarized in Table 43-3 .[4] Many features including short duration of hypertension, early age of onset, fundoscopic findings, and hypokalemia were more common in those patients with renovascular hypertension but had limited discriminating or predictive value.

TABLE 43-3   -- Clinical Features of Patients with Renovascular Hypertension

Syndromes associated with renovascular HTN



Early- or late-onset HTN (<30 yr or >50 yr)



Acceleration of treated essential HTN



Deterioration of renal function in treated essential HTN



Acute kidney failure during treatment of HTN



“Flash” pulmonary edema



Progressive renal failure



Refractory congestive cardiac failure

These “syndromes” should alert the clinician to the possible contribution of renovascular disease in a given patient. The last three are most common in patients with bilateral disease, many of whom are treated as having “essential hypertension” until these characteristics appear (see text).


Clinical features of patients with renovascular HTN

Clinical Feature

Essential HTN (%)

Renovascular HTN (%)

Duration < 1 yr



Age of onset > 50 yr



Family history of HTN



Grade 3 or 4 fundi



Abdominal bruit



BUN > 20 mg/dL



Potassium < 3.4 mEq/L



Urinary casts






Clinical features that differed (P < .05) between closely matched groups of 131 patients with essential and renovascular HTN taken from the Cooperative Study of Renovascular Hypertension in the 1960s. These observations underscore the potential severity of HTN in candidates for surgery, but none of these features allows clinical discrimination with confidence (see text).


BUN, blood urea nitrogen; HTN, hypertension.




If renal artery lesions progress to critical stenosis, they can produce a rapidly developing form of hypertension, which may be severe and associated with polydipsia, hyponatremia, and central nervous system findings.[59] Such cases are most often seen with acute renovascular events, such as sudden occlusion of a renal artery or branch vessel.

More commonly, RAS presents as a progressive worsening of preexisting hypertension, often with a modest rise in serum creatinine. Because the prevalence of both hypertension and atherosclerosis rises with age, this disorder must be considered, particularly in older subjects with progressive hypertension. Some of the most striking examples of renovascular hypertension are older individuals whose previously well-controlled hypertension deteriorates to accelerated rise in systolic blood pressure and target injury, such as stroke. Studies from hypertension referral centers in the Netherlands are instructive in this regard. Of 477 patients undergoing detailed evaluation for RAS because of “treatment resistance,” 107 (22.4%) were identified with renovascular disease (>50% stenosis by angiography). Clinical features predictive of RAS included older age, recent progression, other vascular disease (e.g., claudication), an abdominal bruit, and elevated serum creatinine. The authors derive a multivariate regression equation of predictive features for the presence of angiographic RAS. They present a clinical scoring system to determine the pretest probability of identifying renal artery disease ( Fig. 43-13 ).[44] The strongest predictors include age and serum creatinine. Of note is the fact that clinical features alone could provide pretest predictive values nearly as accurate as radionuclide scans.[44]



FIGURE 43-13  Probability of identifying renal artery stenosis based upon clinical features. These data were obtained from 477 patients (Pt) in referral centers for treatment-resistant hypertension (HTN) in the Netherlands. Overall prevalence was 22.4%, illustrating that, even in “enriched” patient populations, renovascular disease is not present in the majority. Clinical features allowed selection of patients for testing with relatively high “pretest probability” of disease, which affects the validity of testing schemes. BMI, body mass index.  (From Krijnen P, van Jaarsveld BC, Steyerberg EW, et al: A clinical prediction rule for renal artery stenosis. Ann Intern Med 129:705–711, 1998, with permission.)




Declining renal function during antihypertensive therapy is a common manifestation of progressive renal arterial disease. It is recognized that beyond levels of “critical” stenosis, blood flow and perfusion pressures to the kidney fall. This can be magnified by reduction in systemic arterial pressure by any antihypertensive regimen. This phenomenon has become particularly common since the introduction of ACE inhibitors and, more recently, with ARBs. A precipitous rise in serum creatinine soon after starting these agents may occur owing to a loss of transcapillary filtration pressure produced by removing the efferent arteriolar vasoconstriction from Ang II.[60] This particular “functional” loss of GFR is reversible if detected promptly and should lead the clinician to consider large vessel renovascular disease when it occurs. Clinically important changes in serum creatinine develop mainly when the entire renal mass is affected, such as with bilateral RAS or stenosis to a solitary functioning kidney.

Other syndromes heralding occult RAS are becoming more commonly recognized. Among the most important are rapidly developing episodes of circulatory congestion (so-called “flash” pulmonary edema).[61] This usually arises in patients with hypertension and with left ventricular systolic function that may be well preserved. Underlying arterial compromise may favor volume retention and resistance to diuretics in such cases. A sudden rise in arterial pressure impairs cardiac function owing to rapidly developing diastolic dysfunction. Such episodes tend to be rapid both in onset and in resolution. Patients with treatment-resistant congestive cardiac failure, often with reduced arterial pressures, may harbor unsuspected renovascular disease.[62] Restoration of renal blood flow in such patients can improve volume control and sensitivity to diuretics with lower risk of azotemia during therapy.[63] A similar sequence of events may produce symptoms of “crescendo” angina from otherwise stable coronary disease.[64] When the role of RAS is identified, renal revascularization can prevent their recurrence. [69] [70]

Another clinical presentation of RAS is advanced renal failure, occasionally at end-stage, requiring renal replacement therapy. This manifestation has received much attention during the past decade, particularly because it raises the possibility of an undetected, potentially reversible, form of chronic renal failure. As discussed previously, this is designated by some as ischemic nephropathy or azotemic renovascular disease[1] and is defined as loss of renal function beyond an arterial stenosis owing to impaired renal blood flow. Studies in patients with bilateral RAS indicate that reduction of systemic pressures to normal levels using sodium nitroprusside can abruptly reduce both renal plasma flow and GFR, indicating that the poststenotic pressures are at critical levels beyond autoregulation (see Fig. 43-8 ). Some estimates suggest that between 12% and 14% of patients reaching end-stage renal disease (ESRD) with no other identifiable primary renal disease may have occult, bilateral RAS. [60] [71] Patients with vascular lesions affecting the entire renal mass are primarily at risk for losing kidney function on this basis. The role of vascular impairment in producing renal dysfunction is established most firmly when renal revascularization leads to restoration of renal function. Unfortunately, this does not occur commonly, as we have reviewed.[1] Patients with advanced renal dysfunction have high comorbid disease risks associated with cardiovascular disease and commonly have interstitial renal injury on biopsy. [72] [73] Radionuclide studies in patients with atherosclerotic disease commonly identify reduced function unrelated to the presence of stenosis.[70] Those with declining renal function have a poor survival rate regardless of intervention, the strongest predictor of which is low baseline GFR. Attempts to quantitate the prevalence of ischemic nephropathy as a cause of ESRD in the United States produce figures rising from 1.4% of new cases in 1991 to 2.1% in 1997. Multivariate analysis indicated that male gender and advancing age correlated positively with this disorder, whereas African American race or Asian or Native American background correlated negatively.[71]

The potential benefit of revascularization regarding salvage, or at least stabilization, of renal function is greatest when serum creatinine is less than 3 mg/dL, so this diagnosis is best considered early in its course. Remarkably, RAS can be associated with proteinuria, occasionally to nephrotic levels. [76] [77] [78] Proteinuria can diminish or resolve entirely following renal revascularization,[75] leading to the speculation that intrarenal hemodynamic changes or stimulation of local hormonal or cytokine activity alter glomerular membrane permeability in a reversible fashion. Although other glomerular diseases can develop in patients with renal artery disease, including diabetic nephropathy and focal sclerosing glomerulonephritis (FSGN), the presence of proteinuria alone does not establish a second disorder.

Clinical manifestations and prognosis differ when renovascular disease affects one of two kidneys or affects the entire functioning renal mass. Although blood pressure levels may be similar, the fall in blood pressure after renal revascularization is greater in bilateral disease.[76] Most patients with episodic pulmonary edema have bilateral disease or a solitary kidney. Long-term mortality during follow-up is higher when bilateral disease is present, regardless of whether renal revascularization is undertaken. [81] [82] [83] These data suggest that the extent and severity of renovascular disease reflects the overall atherosclerotic burden of the individual. Our observations in patients with incidental RAS (>70%) managed without revascularization reemphasize the reduced survival with bilateral disease, despite reasonable blood pressure control, as illustrated in Figure 43-14 . The causes of death were mainly related to cardiovascular disease, including stroke and congestive heart failure.



FIGURE 43-14  Kaplan-Meier survival curve of 160 patients with more than 70% renal artery stenosis managed without revascularization. Those with bilateral disease had lower survival, primarily owing to cardiovascular disease. The mean age of death was 79 years. These data underscore the close relationship between extent of vascular disease and mortality. Less than 10% of these subjects developed advanced chronic kidney disease during follow-up.  (From Textor SC: Renovascular hypertension and ischemic nephropathy. In Brenner BM [ed]: Brenner and Rector's The Kidney, 7th ed. Philadelphia, Saunders, 2004, pp 2065-2108; and Chabova V, Schirger A, Stanson AW, et al: Outcomes of atherosclerotic renal artery stenosis managed without revascularization. Mayo Clin Proc 75:437–444, 2000.)


Progressive Vascular Occlusion

Atherosclerosis is a progressive disorder. The clinical manifestations from RAS depend upon the severity and extent of vascular occlusion. The most ominous of these manifestations, for example, renal failure or pulmonary edema, are related to bilateral disease or stenosis to a solitary functioning kidney and pose the greatest hazard when total arterial occlusion develops. Hence, the impetus to intervene in RAS depends in many cases upon predicting, or establishing, the “natural history” of vascular stenosis within an individual. Retrospective studies of serial angiograms obtained in the 1970s and early 1980s indicated that atherosclerotic lesions progressed to more severe levels in 44% to 63% of patients followed from 2 to 5 years. Up to 16% of renal arteries developed total occlusion. More recent prospective studies in patients undergoing cardiac catheterization or serial Doppler ultrasound measurements suggest that current rates of progression may be lower. Zierler and co-workers[80] reported a 20% overall rate of disease progression, with 7% advancing to total occlusion over 3 years. A later report from the same group[81] using different Doppler velocity criteria suggested higher rates of progressive stenosis. Overall progression was detectable in 31%, but primarily those with the most severe baseline stenosis (>60%) and severe hypertension were more likely to progress (51%) ( Fig. 43-15 ). The occurrence of total occlusion was rare (9/295 [3%]). Data from medical treatment trials suggest that progressive occlusion can develop silently in up to 16% of treated subjects.[82]



FIGURE 43-15  Cumulative rates of disease progression in atherosclerotic renal artery stenosis, as measured by renal artery Doppler ultrasound. During a follow-up period of 5 years, overall progression was 31%, but those patients with the most severe baseline lesion progressed in 50% of cases. The progression of vascular disease was not closely related to change in serum creatinine or renal atrophy (see text).  (Modified from Caps MT, Perissinotto C, Zierler RE, et al: Prospective study of atherosclerotic disease progression in the renal artery. Circulation 98:2866–2872, 1998.)




Importantly, clinical events such as detectable changes in renal function or accelerating hypertension bear only a limited relationship to vascular progression. The occurrence of renal “atrophy” (loss in renal size by ≤1 cm by ultrasound) developed in 20.8% of the most severe lesions in the prospective series.[83] Most series of medically treated patients indicate that, despite evident progression of vascular disease, changes in kidney function are modest. Results reported during medical follow-up of 41 patients managed medically before the introduction of ACE inhibitors for an average of 36 months identified a loss of renal length in 35%, whereas a significant rise in serum creatinine developed in 8/41 (19.5%). Results of 160 patients with high-grade stenosis (>70%) identified incidentally and managed without revascularization are summarized in Table 43-4 . These patients were followed for many years and are divided into cohorts spanning the introduction of ACE inhibitors into clinical practice. Blood pressure control improved during these intervals. Medical management was associated with increased requirements for antihypertensive agents. The number developing clinical progression with refractory hypertension or progressive renal insufficiency fell from 21% in 1980 to 1984 to less than 10% in the most recent cohort. This conclusion is consistent with long-term studies from Europe in which incidental renal artery lesions could not be associated with progressive renal failure over more than 9 years of follow-up.[84] These data support the observation that renal artery lesions can remain stable in some patients over many years without adverse clinical effects or evident progression.[85] Whether the apparent lower rates of vascular disease progression in recent studies indicate a true change or differences in study methodology is not yet certain. However, it may be argued that overall rates of atherosclerotic disease progression likely will change owing to more widespread use of “statin” class drugs or aspirin, diminishing tobacco use, and more intense antihypertensive therapy. Hence, progressive vascular occlusion is an important clinical risk but does not occur in all patients.

TABLE 43-4   -- Incidental Renal Artery Stenosis: Medical Management Between 1980 and 1993[*]













Mean FU (mo)












 Last FU












 Last FU




Renal failure[‖]




BP meds at FU (no)




ACE inhibitors (%) (initial)




Subsequent revascularization




Data from Chabova V, Schirger A, Stanson AW, et al: Outcomes of atherosclerotic renal artery stenosis managed without revascularization. Mayo Clin Proc 75:437–444, 2000; and Chabova V, Schirger A, Stanson A, Textor SC: Management of renal artery stenosis without revascularization since the introduction of ACE inhibitors. J Am Soc Nephrol 10:362A, 1999.

ACE, angiotensin-converting enzyme; BP, blood pressure; FU, follow-up.



Management of renal artery stenosis without revascularization in patients with “incidentally” identified disease between 1980 and 1993. These cohorts bridged the period of introduction of ACE inhibitors in widespread use for treatment of hypertension, during which the use rose from 0% to 40.6% of patients. Achieved BPs improved during this interval and the number of patient referred for revascularization owing to refractory hypertension or progressive renal insufficiency fell from 20.6% to less than 10% during several years of follow-up. Such observations underscore the fact that some patients can be managed medically without adverse effects for many years.

P < .01 at last FU vs. initial.

P < .05 vs. 1980–1984.


P < .05 vs. 1985–1989.

Creatinine rise ≥50%.



The Role of Concurrent Diseases

ARAS rarely occurs as an isolated entity. It is a manifestation of atherosclerotic disease, which ordinarily affects multiple other sites. Follow-up studies related to survival of “incidentally” identified renal arterial disease suggest that the presence of RAS independently predicts mortality, particularly in the presence of elevated serum creatinine.[86] It bears emphasis that the mortality risk of a serum creatinine level above 1.4 mg/dL (but <2.3 mg/dL) for any reason is higher than the risk with normal creatinine levels.[55] The major causes of death are cardiovascular events, including congestive cardiac failure, stroke, and myocardial infarction. It is essential to consider the role of these “competing risks” in planning management of patients with all forms of vascular disease, especially the elderly.[50] These disorders often dominate the clinical outcomes of patients with renal arterial disease, independent of the level of renal function. As one result, it has been difficult to establish improved survival in prospective trials of patients treated with either medical therapy or renal revascularization. Whereas many patients experience blood pressure that is more easily controlled and some recover renal function, current methods of revascularization are not free of risks. Even after successful renovascular procedures, other comorbid events may obscure long-term benefit, leading some to challenge the “cost-effectiveness” of renal revascularization.[87] Reviews of Medicare claims in the United States for 2 years after identification of ARAS indicate that the risk of cardiovascular events, many of which are fatal, are more than 10-fold more likely than progression to advanced renal failure.[54] Conversely, others argue that RAS accelerates these cardiovascular risks by increasing arterial pressures and activating adverse neurohumoral pathways, predisposing to both congestive heart failure and renal dysfunction.[88] Hence, they argue that restoration of renal perfusion should be considered at an early stage.[89] There is a pressing need for more prospective data in this patient group. Whether long-term cardiovascular outcomes are affected by endovascular stent therapy is unknown and is a major aim of the CORAL trial.[90]


Goals of Evaluation

The literature related to diagnosis and evaluation of renovascular hypertension is complex and inconsistent. Some of the confusion likely reflects the widely different patient groups being considered for evaluation and divergent goals for intervention. It behooves the clinician to identify carefully the objectives of initiating expensive and sometimes ambiguous studies. As with all tests, the reliability and value of diagnostic studies depend heavily on the pretest probability of disease [95] [96] [97] ( Table 43-5 ). Furthermore, it is essential to consider from the outset exactly what is to be achieved. Is the major goal to exclude high-grade renal artery disease? Is it to exclude bilateral (as opposed to unilateral) disease? Is it to identify stenosis and estimate the potential for clinical benefit from renal revascularization? Is it to evaluate the role of renovascular disease in explaining deteriorating renal function? The specific approach to diagnosis will differ depending upon which of these is the predominant clinical objective

TABLE 43-5   -- Goals of Diagnostic and Therapeutic Intervention in Renovascular Hypertension and Ischemic Nephropathy



Goals of diagnostic evaluation



Establish presence of renal artery stenosis: location and type of lesion



Establish whether unilateral or bilateral stenosis (or stenosis to a solitary kidney) is present



Establish presence and function of stenotic and nonstenotic kidneys



Establish hemodynamic severity of renal arterial disease



Plan vascular intervention: degree and location of atherosclerotic disease



Goals of therapy



Improved blood pressure control



Prevent morbidity and mortality of high blood pressure



Improve blood pressure control and reduce medication requirement



Preservation of renal function



Reduce risk of renal adverse perfusion from use of antihypertensive agents



Reduce episodes of circulatory congestion (“flash” pulmonary edema)



Reduce risk of progressive vascular occlusion causing loss of renal function: “preservation of renal function”



Salvage renal function: recover glomerular filtration rate




Noninvasive diagnostic tests for renovascular hypertension and ischemic nephropathy remain imperfect. For the purposes of this discussion, diagnostic tests fall into general categories ( Table 43-6 ): (1) physiologic and functional studies to evaluate the role of stenotic lesions particularly related to activation of the renin-angiotensin system, (2) perfusion and imaging studies to identify the presence and degree of vascular stenosis, and (3) studies to predict the likelihood of benefit from invasive maneuvers, including renal revascularization.

TABLE 43-6   -- Noninvasive Assessment of Renal Artery Stenosis





Physiologic studies to assess the renin-angiotensin system

Measurement of peripheral plasma renin activity

Reflects the adequacy of sodium excretion

Measures the level of activation of the renin-angiotensin system

Low predictive accuracy for renovascular hypertension; results influenced by medications and many other conditions

Measurement of captopril-stimulated renin activity

Produces a fall in pressure distal to the stenosis

Enhances the release of renin from the stenotic kidney

Low predictive accuracy for renovascular hypertension; results influenced by many other conditions

Measurement of renal vein renin activity

Compares renin release from the two kidneys

Lateralization predictive of improvement in blood pressure with revascularization

Nonlateralization not predictive of the failure of blood pressure to improve with revascularization; results influenced by medications and many other conditions

Functional studies to assess overall renal function

Measurement of serum creatinine

Measures overall renal function

Readily available; inexpensive

Not sensitive to early changes in renal mass or single-kidney function


Assesses urinary sediment and proteinuria

Readily available; inexpensive

Results are nonspecific and influenced by many other diseases

Nuclear imaging with [125I] iothalamate or chromium 51Cr-labeled pentetic acid (diethylenetriaminepenta-acetic acid [DTPA]) to determine the glomerular filtration rate

Measures overall glomerular filtration rate

Useful for estimating single-kidney glomerular filtration rate in patients with normal and abnormal renal function

Expensive; not widely available

Perfusion studies to assess differential renal blood flow

Captopril renography with technetium 99mTc mertiatide (99mTc MAG3)

Captopril-mediated fall in filtration pressure amplifies differences in renal perfusion

Normal study excludes renovascular hypertension

Multiple limitations in patients with advanced atherosclerosis or creatinine > 2.0 mg/dL (177 μmol/L)

Nuclear imaging with technetium mertiatide or technetium-labeled DTPA to estimate fractional flow to each kidney

Estimates fractional flow to each kidney

Allows calculation of single- kidney glomerular filtration rate

Results may be influenced by other conditions, e.g., the presence of obstructive uropathy

Vascular studies to evaluate the renal arteries

Duplex ultrasonography

Shows the renal arteries and measures flow velocity as a means of assessing the severity of stenosis

Inexpensive; widely available

Heavily dependent on operator's experience; less useful than invasive angiography for the diagnosis of fibromuscular dysplasia and abnormalities in accessory renal arteries

Magnetic resonance angiography

Shows the renal arteries and perirenal aorta

Not nephrotoxic; useful in patients with renal failure; provides excellent images

Expensive; less useful than invasive angiography, recent concerns about toxicity of gadolinium (nephrogenic systemic fibrosis NSF])

Computed tomographic angiography

Shows the renal arteries and perirenal aorta

Provides excellent images; stents do not cause artifacts

Not widely available; the large volume of contrast medium required is potentially nephrotoxic

Modified from Safian RD, Textor SC: Medical progress: Renal artery stenosis. N Engl J Med 344:431–442, 2001, with permission.




Physiologic and Functional Studies of the Renin-Angiotensin System

Since the 1970's, efforts have been made to establish the level of activation of the renin-angiotensin system as a marker of underlying renovascular hypertension. Peripheral plasma renin activity conducted under standardized conditions of sodium intake (“renin-sodium profiling”) and the response of renin to administration of an ACE inhibitor such as captopril have been proposed.[94] Although these studies are promising when studied in patients with known renovascular hypertension, they have lower performance as diagnostic tests when applied to wider populations, as we and others have reviewed. [99] [100] In a series of 31 patients studied prior to Percutaneous transluminal renal angioplasty (PTRA), combined mathematical models to predict the clinical results indicate a sensitivity of 36% and an accuracy of 43%, too low to be used as a major determinant in decision making.[95] Plasma renin activity is sensitive to changes of sodium intake, volume status, renal function, and many medications. The sensitivity and specificity of such maneuvers are heavily dependent upon the a priori probability of renovascular hypertension. In practice, the major utility of these studies depends upon their negative predictive value, specifically the certainty with which one can exclude significant renovascular disease if the test is negative. Because negative predictive value rarely exceeds 60% to 70%, these tests offer limited value in clinical decision making.

Measurement of renal vein renin levels has been widely applied in planning surgical revascularization for hypertension. These measurements are obtained by sampling renal vein and inferior vena cava blood individually. The level of the vena cava is taken as comparable with the arterial levels into each kidney and allows estimation of the contribution of each kidney to total circulating levels of plasma renin activity. Lateralization is usually defined as a ratio exceeding 1.5 between the renin activity of the stenotic kidney and that of the nonstenotic kidney. Some authors propose detailed examination not only of the relative ratio between kidneys but also the degree of suppression of renin release from the nonstenotic or contralateral kidney. In general, the greater the degree of lateralization, the more probable that clinical blood pressure benefit will accrue from surgical or other revascularization. Results from many studies support the observation that large differences between kidneys identify high-grade RAS.[97] These observations have been reinforced by recent studies of renal vein measurements prior to considering nephrectomy for refractory hypertension and advanced renovascular occlusive disease.[98] As with many tests of hormonal activation, study conditions are crucial. A number of measures to enhance renin release and magnify differences between kidneys have been proposed, including sodium depletion with diuretic administration, hydralazine, tilt-table stimulation, or captopril. Strong and colleagues[98a] demonstrated that nonlateralization can be changed to strongly lateralizing measurements by administration of diuretics between sequential studies. A review of more than 50 studies of renal vein renin measurements indicated that, when lateralization could be demonstrated, clinical benefit regarding blood pressure control could be expected in more than 90% of patients. Failure to demonstrate lateralization, however, was still associated with significant benefit in more than 50% of patients.[77] More recent series reached similar conclusions, indicating that overall sensitivity of renal vein renin measurements was no better than 65% and that positive predictive value was 18.5%.[99] For many reasons, renal vein assays are performed less commonly than before. A major factor is that the goals of renal revascularization have shifted substantially and are often directed toward “preservation of renal function,” rather than for blood pressure control per se. In cases for which it is important to establish the degree of pressor effect of a specific kidney or site, such as before considering nephrectomy of a pressor kidney, measurement of renal vein renins can provide strong supportive evidence.

Studies of Individual Renal Function

Serum creatinine, iothalamate clearance, and other estimates of GFR are measures of total renal excretory function and do not address changes within each kidney. They may be influenced by numerous factors including body mass, protein intake, and age. A large body of literature addresses the potential for individual “split” renal function studies to establish the functional importance of each kidney in renovascular disease.

Split renal function studies utilize separate ureteral catheters to allow individual urine collection for measurement of separate GFR, renal blood flow, sodium excretion, concentrating ability, and the response to blockade of Ang II. These studies demonstrate that hemodynamic effects of renal artery lesions translate directly into functional changes, such as avid sodium retention, before major changes in blood flow occur. They emphasize that autoregulation of blood flow and GFR can occur over a wide range of pressures in humans and may be affected in both stenotic and contralateral kid-neys by the effects of Ang II. These studies require urinary tract instrumentation and provide only indirect information regarding the probability of benefit from revascularization. They are now rarely performed.

Separate renal functional measurements now can be obtained less invasively with radionuclide techniques. These methods use a variety of radioisotopes (e.g., technetium-99m mercaptoacetyltriglyicne [99mTc-MAG3] or 99mTc-diethylenetriaminepenta-acetic acid [DTPA]) to estimate fractional blood flow and filtration to each kidney. Administration of captopril beforehand magnifies differences between kidneys, primarily by delaying excretion of the filtered isotope owing to removal of the efferent arteriolar effects of ACE inhibition. Some authors rely upon such measurements to follow progressive renal artery disease and its effect on unilateral kidney function as a guide to consider revascularization.[96] Some authors indicate that serial measurements of individual renal function by radionuclide studies allows more precise identification of progressive “ischemic” injury to the affected in kidney in unilateral renal artery disease than can be determined from overall GFR. [100] [105] Recent studies indicate that single-kidney GFR measurements by this method accurately reflect changes in three-dimensional volume parameters measured by magnetic resonance imaging (MRI).[101] These authors argue that demonstrating well-preserved “parenchymal volume” with disproportionate reduction in single-kidney GFR supports the concept of “hibernating” kidney parenchyma and might provide a predictive parameter for recovery of kidney function after revascularization.[101]

Imaging of the Renal Vasculature

Advances in Doppler ultrasound, radionuclide imaging, magnetic resonance arteriography (MRA) and computed tomographic (CT) angiography continue to introduce major changes in the field of renovascular imaging. The details of these methods are beyond the scope of this discussion. They are addressed more fully elsewhere (see Chapter 27 ). What follows is a discussion of some of the specific merits and limitations of each modality as they apply to application in renovascular hypertension and ischemic nephropathy.[93]

Current practice favors limiting invasive arteriography to the occasion of endovascular intervention, for example, stenting and/or angioplasty. Although angiography remains for many the “gold standard” for evaluation the renal vasculature, its invasive nature, potential hazards, and cost make it most suitable for those in whom intervention is planned, often during the same procedure. As a result, most clinicians favor preliminary noninvasive studies beforehand. When noninvasive studies are equivocal, arterial angiography may be warranted to establish the presence of trans-stenotic pressure gradients, as recommended for treatment trials.[102]

Noninvasive Imaging

Captopril Renography

Imaging the kidneys before and after administration of an ACE inhibitior (e.g., captopril) provides a functional assessment of the change in blood flow and GFR to the kidney related to both changes in arterial pressure and removal of the efferent arteriolar effects of Ang II. The most commonly used radiopharmaceuticals are 99mTc-DTPA and 99mTc-MAG3. The latter agent has clearance characteristics similar to those of hippuran and is often taken as reflecting renal plasma flow. Both can be used, although specific interpretive criteria differ.[100] Both provide information regarding size and filtration of both kidneys, and the change in these characteristics after inhibition of ACE allows inferences regarding the dependence of glomerular filtration upon Ang II. Several series of patients studied in patient groups with prevalence rates between 35% and 64% of subjects suggest that sensitivity and specficity range between 65% to 96% and 62% to 100%, respectively.[100] With high specificity, captopril renography can be applied to populations at low pretest probability with an expectation that a normal study will exclude significant renovascular hypertension in more than 96% of cases.[103] Some series report 100% accurate negative predictive values.[94]

These studies are less sensitive and specific for renovascular disease in the presence of renal insufficiency (usually defined as creatinine > 2.0 mg/dL).[104] These performance characteristics deteriorate in patients who cannot be prepared carefully (i.e., withdrawal of diuretics and ACE inhibitors for 4-14 days before the study).[100] It should be emphasized that renography provides functional information but no direct anatomic information, that is, the location of renal arterial disease, the number of renal arteries, or associated aortic and/or ostial disease ( Fig. 43-16 ). Some authors believe that renographic screening of patients using this technique is among the most cost-effective of methods of identifying candidates for further diagnostic studies and superior to functional studies of the renin-angiotensin system.[105] The prospective studies of renovascular disease from the Netherlands did observe changes in the renogram during follow-up but did not find captopril renography predictive of angiographic findings or outcomes.[82] A prospective study of 74 patients undergoing both renography and Doppler ultrasound evaluation before renal revascularization could identify only limited predictive value of scintigraphy (sensitivity 58% and specificity of 57%) regarding blood pressure outcomes.[106]



FIGURE 43-16  A and B, Isotope renography in a patient with unilateral renal artery stenosis. A diethylenetriaminepenta-acetic acid (DTPA) scan demonstrates delayed circulation and excretion of isotope on the left. A hippuran scan (now replaced with 99 technetium mercaptoacetyltriglycine [99Tc-MAG3]) provided a renogram demonstrating a small kidney with impaired renal function on the affected side. Radionuclide scans provide a comparative estimate of function from each kidney that may facilitate selection of intervention, including the potential effect of nephrectomy (see text).



Under carefully controlled conditions, some authors argue that changes in renographic appearance correlate with changes in blood pressure to be expected after revascularization. Changes in split renal function indicate that stenotic kidneys regain GFR after revascularization, sometimes with a decrement in contralateral GFR, thereby leaving overall kidney function unchanged. [112] [113]

Doppler Ultrasound of the Renal Arteries

Duplex interrogation of the renal arteries provides measurements of localized velocities of blood flow. In many institutions, this provides an inexpensive means for measuring vascular occlusive disease at sequential time points, to establish both the diagnosis of RAS and its progression.[81] After renal revascularization, Doppler studies are commonly used to monitor restenosis and target vessel patency [114] [115] ( Fig. 43-17 ). The main drawbacks of Doppler imaging relate to the difficulties of obtaining adequate studies in obese patients. The utility and reliability of Doppler ultrasound depend partly upon the specific operator and the time allotted for optimal studies. These factors vary considerably between institutions.



FIGURE 43-17  A, Velocity measurements in a patient with high-grade renal artery stenosis affecting the proximal left renal artery (LRA PRX). Velocities reach 605 cm/sec, well above the normal upper limit of 180 cm/sec. B, Segmental branch ultrasround in the distal segmental renal arteries demonstrates “parvus” and “tardus” dampening of the signal characteristic of poststenotic waveforms. The utility of these measurements depends upon the ability to obtain reliable identification of vessel segments and the skills of the operator. Once the location of a vascular lesion is known, subsequent studies can be performed more easily to track progression of vascular occlusion, restenosis, and/or the results of endovascular intervention.



The primary criteria for renal artery studies are a peak systolic velocity above 180 cm/sec and/or a relative velocity above 3.5 as compared with the adjacent aortic flow.[111] Using these criteria, sensitivity and specificity with angiographic estimates of lesions exceeding 60% can surpass 90% and 96%, respectively, [117] [118] although not universally.[114] When main vessel velocities cannot be determined reliably, segmental waveforms within the arcuate vessels in the renal hilum can provide additional information. Damping of these waveforms, labeled as “parvus” and “tardus,” have been proposed as indirect signs of upstream vascular occlusive phenomena.[115] Recent studies challenge the use of angiographic estimates of stenosis as representing a gold standard altogether.[116] These authors argue that Doppler velocities correlate highly (r = 0.97) with a truer estimate of vascular occlusion, specifically stenosis determined by intravascular ultrasound.

In our own experience, Doppler study of the renal arteries is highly reliable when adequate imaging of the renal arteries can be obtained. Positive Doppler velocities in an artery clearly identified as the renal artery are rarely proved to be negative later. False-negative studies are more common. In subjects with accessible vessels, Doppler ultrasound provides the most practical means of following vessel characteristics sequentially over time. A drawback of renal artery Doppler studies includes frequent failure to identify accessory vessels.

Recent studies emphasize the potential for Doppler ultrasound to characterize the small vessel flow characteristics within the kidney. The resistive index provides an estimate of the relative flow velocities in diastole and systole. In a study of 138 patients with RAS, a resistive index above 80 provided an excellent tool for identification of parenchymal renal disease who did not respond to renal revascularization[117] ( Fig. 43-18 ). A sizable portion of this group eventually progressed to kidney failure. A resistive index less than 80 was associated with more than 90% favorable blood pressure response and stable or improved renal function. The authors emphasize that accurate predictive power depended upon using the highest resistive index observed, even when present in the nonstenotic kidney. A subsequent study of 215 subjects with mean preintervention serum creatinine levels of 1.51 mg/dL did not confirm the predictive value of resistive index measurements. Of 99 subjects with “improved” renal function after 1 year, 18% had resistive index above 80 before intervention, whereas 15% of 92 subjects with no improvement had index above 0.8 (not significant). In this series, preintervention level of serum creatinine itself was the strongest predictor of improved renal function.[118]



FIGURE 43-18  Blood pressure and number of antihypertensive agents used after renal revascularization in 138 patients with renal artery stenosis. These patients were divided into groups with “resistive index” of 80 or higher and those with resistive index less than 80 in the most severely affected kidney. The authors indicate that high resistive index reflects intrinsic parenchymal and small vessel disease in the kidney that does not improve after revascularization. Those with lower indices had both lower blood pressures during follow-up and lower antihypertensive medication requirements.  (From Radermacher J, Chavan A, Bleck J, et al: Use of Doppler ultrasonography to predict the outcome of therapy for renal-artery stenosis. N Engl J Med 344:410–417, 2001, with permission.)




Magnetic Resonance Angiography

Gadolinium-enhanced images of the abdominal and renal vasculature have been a mainstay of evaluating renovascular disease in many institutions. [124] [125] This technique is suitable for patients with impaired renal function, as it offers the advantage of non-nephrotoxic imaging agents. No radiation is used. Comparative studies indicate that sensitivity ranges from 83% to 100% and specificity from 92% to 97% in RAS. [126] [127] Meta-analyses of published literature including 998 subjects support more than 97% sensitivity using gadolinium-enhanced imaging.[123] The nephrogram obtained from gadolinium filtration provides an estimate of relative function and filtration, as well as parenchymal volume.[124] Quantitative measurement of parenchymal volume determined by MRI appears to correlate closely with isotopically determined single-kidney GFR in some institutions.[101]

Examples of MRA are shown in Figure 43-19 . Drawbacks include expense and the tendency to overestimate the severity of lesions, which in fact appear as a signal void.[120] The limits of resolution with current instrumentation make detection of small accessory vessels limited, and quantitating fibromuscular lesions is difficult with current technology. Both of these are improving with newer generations of scanners. High-spatial-resolution three-dimensional contrast-enhanced MRA scanners provide up to 97% sensitivity and 92% specificity for renal artery stenotic lesions.[125] Signal degradation in the presence of metallic stents renders MRA unsuitable for follow-up studies after endovascular procedures in which stents are used.



FIGURE 43-19  A, Gadolinium-enhanced MRA demonstrates a normal-appearing aorta and high-grade stenosis of the right renal artery, mild atheromatous disease of the aorta, and well-preserved nephrogram bilaterally. The renal arteries have only minimal changes and a venous phase is easily seen showing the renal vein on the left. B, MRA in an 82-year-old man with recent hypertension and stroke. The aorta has extensive atheromatous change, and both renal arteries have significant vascular lesions. No nephrogram is apparent on the left in this view. The right renal artery also has a substantial signal void near the origin, and an accessory renal artery on the right has a near-total occlusion in the midportion. MRA has the benefit of minimal nephrotoxicity from contrast.



Beginning in 1997, reports appeared of a rare, but debilitating condition identified as “nephrogenic fibrosing dermopathy” in patients with advanced renal dysfunction. This was later renamed “nephrogenic systemic fibrosis” (NSF) to emphasize the fact that muscles and joints were also involved. It only develops in patients with estimated GFR levels less than 30 ml/min/1.73 m2 and in 2006 was associated with administration of gadolinium. For that reason, the Food and Drug Administration (FDA) has issued a cautionary warning against its use in patients with advanced chronic kidney disease.[125a]

Computed Tomographic Angiography

CT angiography using “helical” and/or multiple head scanners and intravenous contrast can provide excellent images of both kidneys and the vascular tree. Resolution and reconstruction techniques render this modality capable of identifying smaller vessels, vascular lesions, and parenchymal characteristics, including stones[126] ( Fig. 43-20 ). When used for detection of renal artery stenosis, CT angiography agrees well with conventional arteriography (correlation 95%) and sensitivity may reach 98% and specificity 94%. [132] [133] Although this technique offers a noninvasive examination of the vascular tree suitable for kidney donors, for example, it has the drawback of considerable contrast requirement. As a result, it is less ideally suited for evaluation of renovascular hypertension and/or ischemic nephropathy for patients with impaired renal function. One prospective study comparing both CT angiography and MRA with intra-arterial studies in 402 subjects indicated substantially worse performance for detection of lesions greater than 50% stenosis.[128] In this study, CT angiography had sensitivity of 64% and specificity of 92%, whereas MRA had sensitivity of 62% and specificity of 84%. This was an unusual population with only 20% of the screened population having stenotic lesions, nearly half of which were FMD. The results of such studies reinforce the importance of careful patient selection for study and establishing exactly for what questions imaging is being undertaken in advance.[129]



FIGURE 43-20  Examples of computed tomography (CT) angiogram using conventional iodinated contrast with three-dimensional reconstructed views. A, View of the aorta and renal artery after successful stent placement, with the stent location clearly visible. B, The ability of CT to outline atherosclerotic calcified plaque and the extension into the origin of both right and left renal arteries. Source images for these views allow more precise estimation of the magnitude of vessel occlusion than can be seen here. These images are now standard for kidney donors and other patients with good kidney function. They have the disadvantage for patients with impaired renal function requiring iodinated contrast.



Invasive Imaging

Intra-arterial angiography remains the gold standard for definition of vascular anatomy and stenotic lesions in the kidney. Often, it is completed at the time of a planned intervention, such as endovascular angioplasty and/or stenting. What is the current role of including angiography of the renal arteries during imaging of other vascular beds, such as “drive-by” angiography during coronary artery imaging? Several studies confirm that the prevalence of renal artery lesions exceeding 50% lumen occlusion in patients with hypertension and coronary artery disease is high, usually between 18% and 24%.[88] Some of these individuals (7%–10%) will have high-grade stenoses above 70% and some will be bilateral. Accepting the fact that an intra-arterial puncture and catheterization of the aorta and coronary vessels produce some risk, the added risk from including aortography of the renal vessels appears to be small, almost negligible. Follow-up studies of individuals with identified “incidental” renal artery lesions suggest that the presence of these lesions does provide additive predictive risk for mortality.[130] No data to this point suggest that combining screening angiography with renal revascularization changes that risk. Hence, endovascular procedures for such lesions should be confined to individuals with strong indications for renal revascularization, as even the most ardent advocates of catheter-based intervention have suggested.[88]

Contrast toxicity remains an issue with conventional iodinated agents.[131] In many centers, gadolinium has been employed to reduce toxicity while still providing satisfactory imaging to complete endovascular procedures, particularly if the location and severity of the lesions have been preestablished. Intravascular ultrasound procedures have been undertaken using papaverine to evaluate “flow reserve” beyond stenotic lesions.[132] These studies confirm both a reduction in absolute flow and an impaired response to arterial vasodilators that reverse after successful revascularization in stenotic kidneys.


Considering the array of potential interventions that bear upon renovascular disease and the complexity of these patients, clinicians need to formulate a clear set of therapeutic goals. Because each mode of treatment—ranging from medical therapy alone to surgical revascularization—carries both benefits and risks, the clinician's task is to weigh the role of each of these within the context of the individual patient's comorbid disease risk. Rarely is it obvious how best to proceed. In most cases, long-term management of the patient with renovascular disease represents a balance between pharmacologic management of blood pressure and cardiovascular risk and optimal timing of renal revascularization. The objective of this section is to provide a framework by which to plan a balanced approach to the patient with unilateral or bilateral RAS. It should be emphasized that consideration of renal artery disease takes place in the broad context of managing other cardiovascular risk factors, including withdrawal of tobacco use, reduction of cholesterol levels, and treatment of diabetes and obesity.

Medical Therapy of Renovascular Disease

The overall goals of therapy are summarized in Table 43-5 . Foremost among these is the goal as stated by the Joint National Committee (JNC) of the National High Blood Pressure Education Program (NHBPEP): “The goal of treating patients with hypertension is to prevent morbidity and mortality associated with high blood pressure.”[133] This task may include the effort to simplify or potentially to eliminate long-term antihypertensive drug therapy. A further goal is to preserve kidney function and to prevent loss of kidney function related to impaired renal blood flow. In some instances, renal revascularization is undertaken to allow improved management of salt and water balance in the process of managing patients with congestive cardiac failure. This may allow safer use of diuretic agents and ACE inhibitor/ARB classes of medication in patients with critical renal artery lesions to the entire renal mass. Because prospective, randomized trial information is limited in renovascular disease, each patient must be considered individually. What cannot be taken for granted currently is the premise that renal revascularization prolongs life or prevents ESRD. [1] [5] As noted previously, the burden of atherosclerotic disease associated with RAS is often widespread and the causes of death include a broad array of cardiovascular events. Both endovascular and surgical intervention in the aorta and renal vasculatures carry substantial risk that may accelerate morbidity and loss of renal function. As a result, these measures must be considered within the entire context of patient management over time.

Unilateral versus Bilateral Renal Artery Stenosis

Consideration of these disorders differs in some respects. Bilateral in this context refers to the circumstances in which the entire functional renal mass is affected by vascular occlusion. This may be caused by either bilateral stenoses or stenosis to a solitary functioning kidney. Not only are the putative mechanisms related to blood pressure and volume control different in the presence of a nonstenosed, functioning contralateral kidney with unilateral disease (as outlined under Pathophysiology, earlier), but the potential hazards of intervention and/or medical therapy also differ. Patient survival is reduced in patients with bilateral disease or stenosis to a solitary functioning kidney. Progressive arterial disease in this group also poses the most immediate hazard of declining renal function. Patient survival depends upon the extent of vascular involvement[78] regardless of whether renal revascularization is undertaken.

Management of Unilateral Renal Artery Stenosis

Most patients with atherosclerotic renal artery disease have preexisting hypertension. As a result, they usually are exposed to antihypertensive therapy before identification of the lesion and may be well controlled with only moderate medication use.[46] As noted previously, such patients commonly come to clinical attention when recognizable clinical progression occurs. Occasionally, clinical decision-making is influenced strongly by concerns about the hazards of medical therapy and failing to achieve restored blood flow soon enough. Examination of the results of medical therapy alone is important before evaluating the role of vascular reconstruction or dilation.

Since the introduction of agents blocking the renin-angiotensin system have been introduced, most patients (86%–92%) with unilateral renal artery disease can achieve blood pressure levels below 140/90 mm Hg with medical regimens based upon these agents.[134] It must be understood that widespread application of these agents to patients with many forms of cardiovascular disease ensures that subcritical cases of renovascular disease are treated without being identified.

Do the risks of treating unidentified RASs with antihypertensive drug therapy pose a hazard to patients? This issue is at the crux of clinical debates regarding management of patients with renovascular hypertension. Early studies with experimental “clip” hypertension emphasized renal fibrosis and scarring that occurred in the stenotic kidney in animals treated with ACE inhibitors. Several studies suggest that experimental hypertension may be more prone to pressure reduction and poststenotic renal injury in ACE inhibitor-treated groups as compared with either vasodilators (such as hydralazine or minoxidil) or calcium channel blockers (such as nifedipine. [141] [142] It is well recognized that removal of the efferent arteriolar effects of Ang II pose the possibility of loss of glomerular filtration in a kidney with reduced renal perfusion ( Fig. 43-21 ). Experimental studies in two-kidney-one-clip rats indicate that the loss of kidney function is sometimes irreversible, although survival is improved in ACE inhibitor-treated animals as compared with those receiving minoxidil treatment.[135] The unique role of ACE inhibitors and ARBs must be understood in this regard. Any drug capable of reducing systemic arterial pressure has the potential to lower renal pressures beyond a critical stensosis.[137] As a result, successful antihypertensive therapy in renovascular disease has the theoretical result of reducing blood flow to the poststenotic kidney sufficient to induce vascular occlusion. The unique feature of agents that block the renin-angiotensin system is the reduction of efferent arteriolar resistance sufficient to lower transcapillary filtration pressures, despite preserved blood flow to the glomerulus (see Fig. 43-21B ). This property is central to the benefits of this class of agent in “hyperfiltration” states believed to accelerate renal damage in other settings.[138] Hence, the fall in glomerular filtration beyond a stenotic lesion can be observed despite relatively preserved plasma flows. The fall in GFR heralds an approaching degree of critical vascular compromise before blood flow itself is reduced.[139] Studies in renovascular hypertensive animals confirm that, despite a reduction in filtration, renal structural integrity can be preserved and recovered[140] after removal of the clip and/or the ACE inhibitor. Hence, it is unlikely that ACE inhibitors or ARBs themselves pose a unique hazard, beyond that attributable to reduction in renal blood flow.



FIGURE 43-21  A, Glomerular filtration rate (GFR) falls beyond a renal artery stenotic lesion during blockade of angiotensin II (produced by intrarenal infusion of Sar-1-Ala-8-angiotensin II and pressure reduction induced by sodium nitroprusside. The fall in GFR occurs despite preserved renal blood flow (RBF, measured by electromagnetic flow probe). These observations illustrate the role of angiotensin II in maintaining GFR in the poststenotic kidney at low perfusion pressures. MAP, mean arterial pressure; RAP, renal artery pressure. B, Summary of the effects of angiotensin-converting enzyme (ACE) inhibition on RBF, GFR, and filtration fraction (FF) in normal, moderate, and severe levels of renal artery stenosis. As compared with other antihypertensive agents, ACE inhibitors (and angiotensin receptor blockers ARBs) lead to a fall in GFR and FF owing to removal of the efferent arteriolar effects of angiotensin II. When stenosis is sufficiently severe that pressure reduction compromises RBF, the potential for complete occlusion is present, as with other effective antihypertensive agents as well.  (From Textor SC: Renal failure related to ACE inhibitors. Semin Nephrol 17:67–76, 1997, with permission.)




It is important to recognize that the contralateral kidney usually supports total glomerular filtration despite reduced filtration in the stenotic kidney. Changes in overall GFR may be undetectable. This may be interpreted in several ways. Some authors argue in favor of using split renal function measurements, such as radionuclide renal scans, to detect loss of individual kidney function as a means of timing revascularization.[96] Depending upon the circumstances, loss of one kidney may be an acceptable price if one can assure the patient that the remaining kidney has adequate function and blood supply, as illustrated in Figure 43-22 . The fall in GFR from a loss of one kidney represents a loss of GFR similar to that of donating a kidney for renal transplantation or nephrectomy for malignancy. In such instances, the long-term hazard to the remaining kidney is small, although not negligible. [147] [148] As the age and comorbid disease burden of the population at risk rise, the loss of one kidney may pose no great hazard if overall glomerular filtration is adequate. The experience of ACE inhibition in trials of congestive cardiac failure is reassuring in this regard. Thousands of patients with marginal arterial pressures and clinical heart failure have been treated over many years with a variety of ACE inhibitors and, more recently, ARBs. These patients are at high risk for undetected renal artery lesions as part of the atherosclerotic burden associated with coronary disease. Although a minor change in creatinine is observed in 8% to 10% of these individuals, a rise sufficient to lead to withdrawal of these agents under trial monitoring conditions occurs in only 1% to 2%.[139] Data from patients with high cardiovascular disease risk treated with ramipril included patients with creatinine levels up to 2.3 mg/dL. Those with creatinine between 1.4 and 2.3 mg/dL were at higher risk for cardiovascular mortality and had a major survival benefit from ACE inhibition. Close follow-up of kidney function indicated that withdrawal of ACE inhibition owing to deterioration of renal function was less than 5% and no greater than that attained with placebo.[55]



FIGURE 43-22  A 79-year-old man with prostate cancer and worsening hypertension and proteinuria. The arteriogram indicated virtually complete occlusion developing to the left kidney. Addition of an angiotensin receptor blocker to his diuretic regimen allowed stable blood pressure and resolution of proteinuria. This patient's renal function stabilized beyond the timepoint indicated by the arrow. This reflected the time of complete loss of function of the left kidney. Residual function in the solitary, normally perfused kidney has been stable for years. This patient has had no further difficulty for 5 years. In this case, stable renal function and blood pressure were obtained with medical therapy. The decision as to whether renal revascularization should be undertaken depends in part upon other factors, including age and comorbid disease conditions.



Medical Therapy Compared with Percutaneous Transluminal Renal Angioplasty

It follows from the previous discussion that many patients with unilateral RAS are managed without restoration of blood flow for a long period, sometimes indefinitely. The judgment about endovascular intervention in a specific case revolves about the anticipated outcome, as summarized later. There are a few prospective, randomized trials comparing medical therapy with PTRA upon which to draw. Familiarity with the available trials and their limitations is important for nephrologists. The major features of these trials are summarized in Table 43-7 .

TABLE 43-7   -- Prospective, Randomized Trials of Medical versus Interventional Therapy for Atherosclerotic Renal Artery Stenosis[*]

Author/Patients (N)

Inclusion/BP Measurement

BP Outcome (mm Hg)

Renal Outcome



DBP ≥ 95, two drugs


Creatinine (μmol/L)

“… Unable to demonstrate any benefit in respect of renal function or event free survival” (FU 40 mo).



 PTRA: 173/95



Webster et al, 1998[76]

Exclusion: CVA, MI within 3 mo; creatinine >500 μmol/L

 Med Rx: 161/88

 PTRA: 188





 Med Rx: 157


N = 55 (unilateral = 27)







 PTRA: 152/83

PTRA: 144


N = 135 eligible

BP: Random-zero device; no ACEI allowed

 Med Rx: 171/91, P < .01

Med Rx: 168


RAS >50%






Age < 75 yr

PTRA: 140/81

Creatinine clearance (mL/min): 6 mo

“BP levels and the proportion of patients given antihypertensive treatment were similar one year after randomization in the control and angioplasty groups, confirming that the BP-lowering effect of angioplasty in the short and medium terms is limited in atherosclerotic RAS.”


Normal contralateral kidney

Med Rx: 141/84

 PTRA: 77


Plouin et al, 1998[143]



 Med Rx: 74




No. drugs (DDD):



N = 49 (unilateral ASO)

MHTN CVA, CHF, MI within 6 mo

 PTRA: 1.0





 Med Rx: 1.78, P < .01

Renal artery occlusion:


RAS >75% or >60%, lateralizing study

BP: Automated sphygomanometer, ABPM at 6 mo


 PTRA: 0




Crossover to PTRA: 7/26 (27%)

 Med Rx: 0



Resistant: Two drugs

BP outcomes at 3 mo:

Creatinine clearance (mL/min): 3 mo

“In the treatment of patients with hypertension and renal artery stenosis, angioplasty has little advantage over antihypertensive drug therapy”


DBP > 95 mm Hg or creatinine rise with ACEI

 PTRA 169/89

 PTRA: 70


Van Jaarsveld et al, 2000[82]


 Med Rx: 163/88

 Med Rx: 59, P = .03



Exclusion: Creatinine ≥2.3 mg/dL

At 12 mo:



N = 106 ASO


 PTRA: 152/84



RAS >50%

Solitary kidney/total occlusion

 Med Rx: 162/88

Abnormal renograms



Kidney < 8 cm

No. drugs: 1.9 vs. 2.4, P < .01

 PTRA: 36%



BP automated oscillometric


 Med Rx: 70%, P = .002





Renal artery occlusion





 PTRA: 0





 Med Rx: 8



ABPM, ambulatory blood pressure monitoring; ACEI, angiotensin-converting enzyme inhibitor; ASO, atherosclerosis; BP, blood pressure; CHF, congestive heart failure; CVA, cerebrovascular accident; DDD, de. ned daily doses; DBP, diastolic blood pressure; FU, follow-up; HTN, hypertension; MHTN, malignant hypertension; MI, myocardial infarction; PTRA, percutaneous transluminal renal angioplasty; RAS, renal artery stenosis.



Summary of three prospective, randomized trials comparing medical therapy for renovascular HTN to PTRA. These studies were small and contained selected patient populations. However, they sought to standardize BP outcome measurement and to randomize patients prospectively. Each was different, but all found less major bene. ts accrued in PTRA groups than reported by observational studies alone. Crossover rates from medical to angioplasty arms were signi. cant, however, and emphasize the importance of restoring blood supply in selected patients, particularly those with bilateral disease.


Three small trials address the relative value of endovascular repair, specifically PTRA as compared with medical therapy for ARAS. To the credit of these investigators, care was taken to standardize blood pressure measurement before and after endovascular repair and to select antihypertensive regimens carefully. All of these trials have limitations, but they are instructive. Webster and associates[76] randomized 55 patients with ARAS to either medical therapy or PTRA. Follow-up blood pressures were obtained using a random-zero sphygmomanometer after a run-in period. The run-in period produced considerable reduction in blood pressures in all patients. Those with unilateral disease had no significant difference between medical therapy and PTRA after 6 months. There was greater blood pressure benefit after PTRA in those with bilateral RAS. The authors indicated they were “unable to demonstrate any benefit in respect of renal function or event free survival” during follow-up, which was presented up to 40 months. Plouin and colleagues[143] randomized 49 patients with unilateral ARAS greater than 75% or greater than 60% with lateralizing functional studies. Blood pressure measurements were based upon overnight ABPM readings, which are believed to yield more reproducible trial data and to be relatively free from placebo or office effects. Seven of 26 patients (27%) assigned to medical therapy eventually crossed over to the PTRA group for refractory hypertension. There were 6 procedural complications in the PTRA group, including branch dissection and segmental infarction. Final blood pressures were not different between groups, but slightly fewer medications were required in the PTRA group. Taken together, this trial suggested that PTRA produced more complications in the near term, was useful in some medical treatment failures, and required slightly fewer medications after 6 months. This study excluded agents that blocked the renin-angiotensin system (such as ACE inhibitors).[143] The largest randomized, prospective trial included 106 patients enrolled in the DRASTIC study.[82] These patients were selected for “resistance” to therapy including two drugs and were required to have serum creatinine values below 2.3 mg/dL. Blood pressures were evaluated using automated oscillometric devices at 3 and 12 months after entry. Patients were evaluated on an “intention to treat” basis. Blood pressures did not differ between groups overall at either 3 or 12 months, although the PTRA group was taking fewer medications (2.1 ± 1.3 vs. 3.2 ± 1.5 defined daily doses, P < .001). The authors concluded that, in the treatment of hypertension and RAS, “angioplasty has little advantage over antihypertensive drug therapy.”[82] It should not be overlooked, however, that 22/50 patients (44%) assigned to medical therapy were considered treatment failures and referred for PTRA after 3 months. There were eight instances of total arterial occlusion in the medical group, as compared with none in the angioplasty group. Many clinicians interpret these data to support an important role for PTRA in management of patients with refractory hypertension and RAS. Regardless of interpretation, these trials offer important insights into current management options. The benefits of endovascular procedures, even in the short term, are moderate compared with effective antihypertensive therapy. Patients failing to respond to medical therapy often improve after revascularization.[144] Some authors have combined these prospective studies into meta-analyses, indicating that, taken together, renal revascularization produced modest, but definite, reductions in blood pressures, averaging -7/-3 mm Hg. [151] [152]

These modest benefits emphasize differences between the current era and the situation a few decades ago. Reports from the 1970s underscore the fact that some patients experienced recurrent episodes of malignant phase hypertension with encephalopathy, fluid retention, and progressive renal insufficiency. Despite medical therapy, some of these cases required “urgent bilateral nephrectomy” as a life-saving measure. The mean age in several of these small series was below 50 years. Since then, malignant hypertension is becoming less prevalent in most Western countries, although not universally.[147] Introduction of ACE inhibitors and calcium channel blocking drugs in the 1980s has been associated temporally with reduced occurrence of severe hypertension and improved medical management of patients with high-renin states, including renovascular hypertension. More effective medical management, including treatment of patients with renovascular disease, largely has eliminated urgent nephrectomy for blood pressure control. Reported results from the prospective trials of angioplasty are lower than those reported from retrospective series. A representative report of more than 1000 successfully stented patients followed in a registry suggest that average blood pressure levels fell during follow-up -21/-10 mm Hg[148] ( Fig. 43-23 ). The basis for the differences between prospective trials and registry values often reflect an element of reporting bias. An important alternative possibility, however, is that enrollment in prospective trials may itself reflect selection bias in favor of more “stable” patients in less dire clinical need of restoring renal circulation. Hence, the randomized trials may underestimate the benefits of renal revascularization for the patients at the greatest risk of both accelerated hypertension and/or renal failure.



FIGURE 43-23  Comparison of blood pressure changes reported after renal revascularization from a large, observational registry (>1000 patients) and from a meta-analysis of three prospective, randomized trails (210 patients). The difference between these results is reflected in variable enthusiasm for intervention between clinicians. Whereas results from observational series may overstate the benefits, results from prospective trials likely underestimate changes, in part owing to patient crossover between treatment arms, ranging from 25% to 44% (see text).  (Data from Dorros G, Jaff M, Mathiak L, He T, Multicenter Registry Participants: Multicenter Palmaz stent renal artery stenosis revascularization registry report: Four-year follow-up of 1058 successful patients. Catheter Cardiovasc Interv 55:182–188, 2002; and Nordmann AJ, Woo K, Parkes R, Logan AG: Balloon angioplasty or medical therapy for hypertensive patients with atherosclerotic renal artery stenosis? A meta-analysis of randomized controlled trials. Am J Med 114:44–50, 2003.)




Progressive Renal Artery Stenosis in Medically Treated Patients

As noted previously, the potential for progressive vascular occlusion is central to management of patients with renovascular disease. It may be argued that failure to revascularize the kidneys exposes the individual to the hazard of undetected, progressive occlusion, potentially leading to total occlusion and/or irreversible loss of renal function. A firm understanding of the data regarding progressive atherosclerotic disease of the kidney is important for planning both endovascular and surgical revascularization.

Atherosclerosis is a variably progressive disorder. Management of disorders of the carotid, coronary, aortic, and peripheral vasculatures all recognize the potential for progression, which occurs at widely different rates between individuals. Medical therapy of all vascular disorders should incorporate measures aimed at intensive reduction of risk factors, of which smoking cessation, blood pressure control, and correction of dyslipidemias are paramount. Treatment of these risk factors reduces mortality rates related to cardiovascular disease.[149]

How does progressive renal artery occlusive disease affect management of renovascular hypertension? Moderate anatomic progression does not reliably predict functional changes in terms of deteriorating blood pressure control or renal function. In the Doppler ultrasound studies from Seattle,[83] a decrement in measured renal size by 1 cm (“renal atrophy”) developed in 5.5% of those with normal initial vessels and 20.8% of those with baseline stenosis greater than 60% during a follow-up interval of 33 months. Changes in serum creatinine were infrequent but did occur in a subset of patients, particularly those with bilateral RAS. These are in general agreement with early studies during medical therapy of renovascular hypertension in which 35% of patients had a detectable fall in measured renal length, but only 8/41 (19%) had a significant rise in creatinine during a follow-up of 33 months. Follow-up of the medical treatment arms during relatively short-term studies fails to show major changes in kidney function, although occasional loss of renal perfusion by radionuclide scan is observed.[82]

How often does management of RAS without revascularization lead to clinical progression, in terms either of refractory hypertension or advancing renal insufficiency? Follow-up of patients with incidentally identified RAS is helpful in this regard. Review of peripheral aortograms identified 69 patients with high-grade RAS (>70%) followed without revascularization for more than 6 months. Their long-term follow-up identified generally satisfactory blood pressure control (by the standards of 1990), although the requirement for further antihypertensive therapy progressed during an average of 36 months of follow-up.[85] Four of these eventually underwent renal revascularization for refractory hypertension and/or renal dysfunction. Five developed ESRD, of which only 1 was believed related to RAS directly. Overall, serum creatinine rose from 1.4 mg/dL to 2.0 mg/dL. These data indicate that many such patients can be managed without revascularization for many years and that clinical progression leading to urgent revascularization develops in between 10% to 14% of such individuals. Expansion of this data set to 160 individuals allowed comparison of different antihypertensive regimens. The rates of progression did not appear related to the introduction of ACE inhibitors, although the level of blood pressure control improved in recent years (see Table 43-4).[150] These observations are supported by a recent report of 126 patients with incidental RAS compared with 397 patients matched for age. Measured serum creatinine was higher and calculated GFR was lower in patients with RAS followed 8 to 10 years. However, none of the patients identified progressed to ESRD. These observations are entirely consistent with results of prospective trials of medical versus surgical intervention started in the 1980s and extended into the 1990s.[151] No differences in patient survival or renal function could be identified. Taken together, these studies indicate that rates of progression of renovascular disease are moderate and occur at widely varying rates. Often, such patients can be managed well for many years without revascularization. The clinical issue in a specific patient frequently hinges on whether or not the risks of revascularization are truly less than the risks of progression.

Although these reports are informative, they leave many questions unanswered. How often does suboptimal blood pressure control in renovascular hypertension accelerate cardiovascular morbidity and mortality? Does one lose the opportunity to effectively reverse hypertension by delaying renal revascularization? These issues will depend upon further prospective studies. It is equally clear that, for many patients with progressive disease, optimal long-term stability of kidney function and blood pressure control can be achieved by successful surgical or endovascular restoration of the renal blood supply.

Surgical Treatment of Renovascular Hypertension and Ischemic Nephropathy

Early experience with vascular disease of the kidney was based entirely upon surgical intervention, either nephrectomy or vascular reconstruction, with the objective of “surgical curability.”[4] For that reason, much of the original data regarding split renal function measurement was geared toward identifying “functionally” significant lesions as a guide by which patients should be selected for a major surgical procedure. Surgical intervention is less commonly performed in the current era, in part because age and comorbid risks of patients with atherosclerotic disease commonly favor endovascular procedures when feasible.

Methods of surgical intervention have changed over the decades. A review in 1982 emphasized the role for “ablative” techniques, including partial nephrectomy. Use of ablative operative means was guided by the difficulty of controlling blood pressure during this era. They are less common since the expansion of tolerable medication regimens, as noted previously. Recent introduction of laparascopic techniques, including hand-assisted nephrectomy, may return attention to nephrectomy as a means to reduce medication requirements with low morbidity in high-risk patients.

Surgical series from the 1960s and early 1970s indicated that cure of hypertension was present only in 30% to 40% of subjects, despite attempts at preselection. Survival of groups chosen for surgery appeared to be better than that in those chosen for medical management. This likely reflected the heavy disease burden and preoperative risks identified in those for whom surgery was not considered. The Cooperative Study of Renovascular Disease in the 1960s and 1970s examined many of the clinical characteristics of renovascular hypertension. These studies identified some of the limitations and hazards of surgical intervention and reported mortality rates of 6.8%, even in excellent institutions. The mean age in this series was 50.5 years. Definitions of operative mortality included events as late as 375 days after the procedure and may overestimate the hazard. Had the authors considered deaths only within the 1st week, for example, the immediate perioperative mortality was 1.7%.[77]

Subsequent development of improved techniques for patient selection including screening for coronary and carotid disease, for renal artery bypass and endarterectomy, and for combined aortic and renal artery repair represents major elements in the history of major vascular surgery.[4] Several of the options developed for renal artery reconstruction are listed in Table 43-8 . The majority of these methods now focus upon reconstruction of the vascular supply for preservation of nephron mass. Transaortic endarterectomy can effectively restore circulation to both kidneys. It requires aortic cross-clamping and is often undertaken as part of a combined procedure with aortic replacement. [62] [158]Identification and treatment of carotid and coronary disease led to reductions in surgical morbidity and mortality. By addressing associated cardiovascular risk before surgery, early surgical mortality falls below 2% in patients without other major diseases.

TABLE 43-8   -- Surgical Procedures Applied to Reconstruction of the Renal Artery and/or Reversal of Renovascular Hypertension (See Text)



Ablative surgery: removal of a “pressor” kidney



Nephrectomy: direct or laparoscopic



Partial nephrectomy



Renal artery reconstruction (requires aortic approach)



Renal endarterectomy



Transaortic endarterectomy



Resection and reanastomosis: suitable for focal lesions



Aortorenal bypass graft



Extra-anatomic procedures: may avoid direct manipulation of the aorta (require adequate alternate circulation without stenosis at celiac origin)



Splenorenal bypass graft



Hepatorenal bypass graft



Gastroduodenal, superior mesenteric, iliac-to-renal bypass grafts



Autotransplantation with ex vivo reconstruction

Modified from Libertino JA, Zinman L: Surgery for renovascular hypertension. In Breslin DL, Swinton NW, Libertino JA, Zinman L (eds): Renovascular Hypertension, 1st ed. Baltimore, Williams & Wilkins, 1982, pp 166–212.




Surgical reconstruction of the renal blood supply usually requires access to the aorta. A variety of alternative surgical procedures have been designed to avoid manipulation of the badly diseased aorta, including those for which previous surgical procedures make access difficult. These include extra-anatomic repair of the renal artery using hepatorenal or splenorenal conduits to lower the requirement of manipulation of a badly diseased aorta.[153] It should be emphasized that success with extrarenal conduits depends upon the integrity of the alternative blood supply. Hence, careful preoperative assessment of stenotic orifices of the celiac axis is undertaken before using either the hepatic or the splenic arteries. The results of these procedures have been good, both in the short-term and during long-term follow-up studies.[154] Analysis of 222 patients treated more than 10 years earlier indicates that these procedures were performed with 2.2% mortality and low rates of restenosis (7.3%) and good long-term survival. The predictors of late mortality were age above 60 years, coronary disease, and previous vascular surgery.

The durability of surgical vascular reconstruction is well established.[155] Follow-up studies after 5 and 10 years for all forms of renal artery bypass procedures indicate excellent long-term patency (>90%) for both renal artery procedures alone and when combined with aortic reconstruction.[156] Results of surgery have been good despite increasing age in the reported series. Patient selection has been important in all of these reports. Whereas long-term outcome data are established for surgery, little information is available for endovascular stent procedures, which appear more prone to restenosis and technical failure. This proven record of surgical reconstruction leads some clinicians to favor this approach for younger individuals with longer life expectancy.

Few studies have compared endovascular intervention (PTRA without stents) and surgical repair. A single study of nonostial, unilateral atherosclerotic disease in which patients were randomly assigned to surgery or PTRA indicates that, whereas surgical success rates were higher and PTRA was needed on a repeat basis in several cases, the 2-year patency rates were 90% for PTRA and 97% for surgery. The authors favored using PTRA as the initial choice of therapy with a requirement for close follow-up. [163] [164]

In our institution, surgical reconstruction of the renal arteries is most often undertaken as part of aortic surgery. Those patients with impaired renal function (creatinine ≤2.0 mg/dL) underwent simultaneous aortic and renal procedures in 75% of cases.[58] Recent experience indicates that combining renal revascularization with aortic repair does not increase the risk of the aortic operation. As with endovascular techniques, the results regarding changes in renal function include improvement in 22% to 26%, no change (some consider “stabilization”) in 46% to 52%, and progressive deterioration in 18% to 22% [165] [166] [167] [168] ( Fig. 43-24 ). Using intraoperative color-flow Doppler ultrasound allows immediate correction of suboptimal results and improved long-term patency.[163] Results from several surgical series are summarized in Table 43-9 . Using current techniques, operative risk is below 4% in good-risk candidates. [165] [174] Risk factors for higher risk include advanced age, elevated creatinine (>2.7–3.0 mg/dL), and associated aortic or other vascular disease. Combined risk when multiple comorbid risk factors are present may rise to 15%.[58] In some cases, nephrectomy of a totally infarcted kidney provides major improvement in blood pressure control at low operative risk. The introduction of laparoscopic surgical techniques makes nephrectomy technically feasible in some patients for whom vascular reconstruction is not an option. These series reflect widely variable methods of determining blood pressure benefit, as discussed later.



FIGURE 43-24  Renal functional outcomes after renal revascularization in 304 azotemic patients (creatinine ≤2.0 mg/dL) with atherosclerotic renal artery stenosis (RAS). On average, mean serum creatinine did not change during a follow-up period exceeding 36 months. Group mean values obscure major differences in clinical outcomes, as shown here. Some patients experience major clinical benefit (defined as a fall in serum creatinine of ≤1.0 mg/dL) (left panel). The largest group has minor changes (<1.0 mg/dL), which might be considered “stabilization” of renal function. The degree of benefit in these patients depends upon whether renal function is deteriorating before intervention. The data for the group in the right panel emphasize the failure to observe consistent overall improvement in function, because 18% to 22% of patients develop worsening renal function. The exact causes of this deterioration are not clear, although atherosclerotic disease is responsible for a portion. This potential hazard of revascularization must be considered when offering these procedures. LFU, latest follow-up.  (From Textor SC, Wilcox CS: Renal artery stenosis: A common, treatable cause of renal failure? Annu Rev Med: 52:421–442, 2001.)




TABLE 43-9   -- Surgical Treatment of Renovascular Hypertension and Ischemic Nephropathy


Renovascular Hypertension[*]




No Effect

Fibromuscular disease




 7 series

Mean[‡]: 59%

Mean: 29%

Mean: 12%

  N = 575 patients

Range: 43%–76%

Range: 14%–39%

Range: 1.3%–33%

Atherosclerotic disease




 7 series

Mean[‡]: 34%

Mean: 80%

Mean: 16%

  N = 631 patients

Range: 15%–58%

Range: 21%–75%

Range: 5%–38%



Ischemic Nephropathy[†]



“No Change”


Atherosclerotic disease




 7 series after 1990

Mean[‡]: 41%

Mean: 37%

Mean: 22%

  N = 805 patients

Range: 27%–63%

Range: 19%–54%

Range: 4%–42%



Modified from Stanley JC: Surgical treatment of renovascular hypertension. Am J Surg 174:102–110, 1997.

Data from Textor SC: Renovascular hypertension and ischemic nephropathy. In Brenner BM (ed): Brenner and Rector's The Kidney, 7th ed. Philadelphia, Saunders, 2004, pp 2065–2108.

Mean represents the weighted mean after factoring the number of patients reported in each series. Data modified and summarized from 1, 4, 58, 159, 163a, 163b, 163c, 163d, and 201.


Studies in patients with bilateral RAS or vascular occlusion to the entire renal mass indicate that restoration of blood flow can lead to preservation of renal function in some cases.[165] Most often, this has been undertaken when a clue of preserved blood supply, sometimes from capsular vessels, is evident by renography. Occasionally, revascularization can lead to functional recovery sufficient to eliminate the need for dialysis.

Endovascular Renal Angioplasty and Stenting

The ability to restore renal perfusion in high-risk patients with renovascular hypertension and ischemic nephropathy using endovascular methods represents a major advance in this disorder. Restoration of blood flow to the kidney beyond a stenotic lesion provides the obvious means to improve renovascular hypertension and halt the progression of vascular occlusive injury. The past 2 decades have been characterized by a major shift from surgical reconstruction toward preferential application of endovascular procedures. The total volume of renal revascularization procedures registered for the U.S. Medicare population above age 65 rose 62% from 13,380 to 21,600 between 1996 and 2000. This change reflects an increase in endovascular procedures by 2.4-fold, whereas surgical renovascular procedures fell by 45% ( Fig. 43-25 ).[166] These changes have enlarged and reconfigured the physician pool engaged in making decisions about renovascular hypertension. Interventional cardiologists increased their activity in this field nearly 4-fold during this interval.



FIGURE 43-25  A, Renal aortogram illustrates high-grade bilateral renal arterial lesions in a 63-year-old male who developed accelerated hypertension a few months earlier. B, Aortogram after placement of endovascular stents illustrates excellent vessel patency and early technical success. This was followed by resolution of his hypertension. C, Numbers of endovascular procedures recorded through Medicare claims surveys between 1996 and 2000 illustrate the rapid increase in percutaneous stenting and simultaneous decrement in surgical revascularization of the kidney.  (A and B, From Textor SC: Progressive hypertension in a patient with “incidental” renal artery stenosis. Hypertension 40:595–600, 2002, with permission; C, Murphy TP, Soares G, Kim M: Increase in utilization of percutaneous renal artery inteventions by Medicare beneficiaries 1996-2000. AJR Am J Roentgenol 183:561–568, 2004, with permission.)




Revascularizing the kidney has both benefits and risks, however. In the present era, with older patients developing RAS in the context of preexisting hypertension, the likelihood of “cure” is small, particularly in atherosclerotic disease. The morbidity of surgical procedures can be substantial, so the ability to convert a diagnostic angiogram into a therapeutic procedure at the same setting is attractive. The true risks and benefits of these procedures are sometimes difficult to ascertain from published literature. They may vary between institutions depending upon the technical expertise available. As noted later, methods of reporting results regarding clinical outcomes are inconsistent. Although complications are not common, they can be catastrophic,[167] a feature familiar to nephrologists responsible for managing kidney failure when it occurs, often related to atheroembolic disease. Wide variability in the experience with peripheral endovascular procedures is reflected by the observation that their use, combining renal and lower extremity vascular stents, varies more than 14-fold between regions in the United States.[168] The probability of renal angioplasty within 30 days of cardiac catheterization is 4-fold higher when cardiologists perform the procedure than when interventional radiologists are responsible. Knowing when to pursue renal revascularization is central to the dilemma of managing renovascular disease. The following section undertakes to summarize the available information for nephrologists active in this field.

The introduction of endovascular stents has accelerated renal revascularization, in part because of improved technical patency possible with ostial atherosclerotic lesions as compared with angioplasty alone. It should be emphasized that much of the shift to endovascular procedures relates to their applicability in elderly patients and widespread availability of interventional radiology. Whether endovascular repair is comparable with surgical intervention during long-term follow-up, at least since the advent of stents, is not yet known.

Interpretation of Observational Studies Related to Endovascular Procedures

Literature reports related to renal revascularization are made more difficult by the fact that these procedures have not been subjected to rigorous evaluation in the form of large, prospective, randomized clinical trials. The few such trials performed in recent years are summarized earlier. The primary body of literature comprises observational reports of outcomes based upon measurements before and after intervention in patients often selected by means not clearly defined. These reports vary widely, as others have noted. [179] [180] Commonly, they are limited by imprecise definitions of blood pressure measurement and goal levels, widely varied antihypertensive medication administration, time intervals for follow-up, definitions of procedural success, and complications. As a result, the enthusiasm for results of angioplasty, for example, varies according the series selected.[169] Remarkably, the reported frequency of clinical success including “cure” falls during later reports of most of these procedures, including both surgical and PTRA. [181] [182] Application of formal blood pressure measurement protocols including ABPM routinely demonstrates less effect from renal revascularization than those reported from observational studies. [80] [86] [149] Furthermore, use of standardized antihypertensive drug regimens (e.g., during a formal “run-in” period) can provide improvements in blood pressure at least equal to that achieved with revascularization. [80] [183] The same caveats apply when evaluating renal functional outcomes for ischemic nephropathy, although serum creatinine levels and progression to ESRD are more discrete end points than blood pressure levels. Several of the larger trials utilizing PTRA and stents are summarized in Table 43-10 .

TABLE 43-10   -- Outcomes of Renal Artery Stent Placement






No Change

14 series

Weighted mean: 17%

Weighted mean: 47%

Weighted mean: 36%

N = 678 patients

Range: 3%–68%

Range: 5%–61%

Range: 0%–61%

98% technical success




Renovascular hypertension




N = 472






Effect on Renal Function in Azotemic Patients





14 series reporting

Weighted mean: 30%

Weighted mean: 42%

Weighted mean: 29%

“impaired renal function”

Range: 10%–41%

Range: 32%–71%

Range: 19%–34%

N = 496 patients




Ischemic nephropathy


37% no change


N = 469




Modified from Textor SC: Renovascular hypertension and ischemic nephropathy. In Brenner BM (ed): Brenner and Rector's The Kidney, 7th ed. Philadelphia, Saunders, 2004, pp 2065–2108. Data modified and summarized from 110, 173a, 173b, 173c, 173d, 173e, 176, 177, 178, and 189.

Note: Criteria for “cured” and “improved” vary between reports. In general, the first refers to office blood pressures below 140/90 or 150/90 mm Hg without medication during clinical follow-up. “Improved” refers to lower arterial pressures and/or some reduction in antihypertensive drug therapy (see text). “Improved” renal function refers to a fall in serum creatinine or rise in “estimated GFR” during follow-up. The magnitude of change varies between studies, ranging from 0.2 mg/dL to 1.0 mg/dL.




Angioplasty for Fibromuscular Disease

Most lesions of medial fibroplasia are located at a distance away from the renal artery ostium. Many of these have multiple webs within the vessel, which can be successfully traversed and opened by balloon angioplasty. Experience in the 1980s indicated more than 94% technical success rates.[174] Some of these lesions (≈10%) developed restenosis, for which repeat procedures have been used.[51] Clinical benefit regarding blood pressure control has been reported in observational outcome studies in 65% to 75% of patients, although the rates of “cure” are less secure.[42] Cure of hypertension, defined as sustained blood pressure levels less than 140/90 mm Hg with no antihypertensive medications, may be obtained between 35% and 50% of the time. Predictors of cure (normal arterial pressures without medication at 6 months and beyond after PTRA) include lower systolic blood pressures, younger age, and shorter duration of hypertension.[175]

A large majority of patients with FMD are female. The age of detecting hypertension is usually younger than the series with atherosclerotic disease.[42] In general, such patients have relatively less aortic disease and are at less risk for major complications of angioplasty. Because the risk for major procedural complications is low, most clinicians favor early intervention for patients with FMD, with the hope of reduced antihypertensive medication requirements after successful PTRA.

Angioplasty and Stenting for Atherosclerotic Renal Artery Stenosis

Few advances in renovascular disease have been associated with the level of controversy and impact as successful endovascular stenting for atherosclerotic renovascular disease. With the introduction of PTRA, it was soon evident that ostial lesions commonly failed to respond, in part because of extensive recoil of the plaque that extended into the main portion of the aorta.[176] These lesions develop restenosis rapidly even after early success. Endovascular stents were introduced for ostial lesions in the late 1980s and early 1990s.[177] These agents have been widely accepted by interventional radiologists and cardiologists.

The technical advantage of stents is indisputable. An example of successful renal artery stenting is shown in Figure 43-25 . Prospective comparison between angioplasty alone versus angioplasty with stents indicates intermediate (6–12 mo) vessel patency was 29% and 75%, respectively. Restenosis fell from 48% to 14% in stented patients.[176] As technical success continues to improve, many reports suggest nearly 100% technical success in early vessel patency, although rates of restenosis continue to reach 14% to 25%. [92] [193] [194] [195] [196]

Demographic features of patients undergoing renal revascularization have been changing over the last four decades.[58] The mean age of patients undergoing either surgery or angioplasty (with or without stenting) has climbed from 55 years to more than 75 years. It is likely that many individuals are now offered endovascular procedures who would otherwise not be considered candidates for major surgical procedures, such as aortic or renal reconstruction.

What are the outcomes of patients undergoing renal artery stenting? These are commonly considered in terms of (1) blood pressure control and (2) preservation or salvage of renal function in ischemic nephropathy. Results from observational cohort blood pressure studies after stenting face the same limitations as those observed with angioplasty alone. Results during follow-up from 1 to 4 years are summarized for representative series in Table 43-10 . These have been reviewed elsewhere. [194] [197] Typical fall in blood pressure levels are in the range of 25 to 30 mm Hg systolic, the best predictor of which was the initial systolic blood pressure.[183] Some authors report 42% “improvement” in blood pressure with fewer medications needed, although cures were rare and renal function was unchanged.[178] Careful attention to degree of residual patency led to more than 91% patency at 1 year and 79% at 5 years in 210 patients with stents.[110] Blood pressures were “cured” or “improved” in more than 80%. In some cases, angina and recurrent congestive cardiac failure subsided. [199] [200] As noted under the trials summarized previously, prospective randomized controlled trials have been less impressive regarding the benefits of angioplasty. When standardized pressure measurement is applied to both medically treated control groups and interventional groups, the differences in blood pressure are more in the 5 to 10 mm Hg range. The ambiguity of blood pressure responses in these studies has produced widely different recommendations. These range from “we are left with whether renal angioplasty should be considered at all”[186] to a general conviction expressed within the interventional cardiology community that “open renal arteries are better than closed renal arteries” and that nearly all renal artery lesions should be opened (and probably stented).[88]

It must be emphasized that these trials face the problem of patient selection, which likely understates the benefit of revascularization. Most excluded accelerated hypertension, advancing renal dysfunction, or recent congestive cardiac failure, in which case successful revascularization can offer major benefit. Importantly, the crossover rate from medical therapy ranged between 26% and 44% in the prospective trials, [86] [149] indicating that medical therapy simply does not succeed in a subset of patients with renovascular hypertension.

Several comparisons have been made between stents and PTRA alone.[180] Remarkably, the differences in clinical outcomes have been relatively small, as regards changes in both blood pressure and kidney function between the two procedures, despite demonstrably improved vessel patency in stented patients.[180] A prospective, randomized trial comparing stenting with angioplasty for ostial lesions demonstrated nearly identical clinical results regarding both blood pressure and kidney function.[176] These observations tend to emphasize the lack of correlation between target vessel patency alone and clinical results of renal revascularization.

What are the results regarding recovery of renal function with endovascular revascularization? Table 43-10 summarizes some of the recent series. In general, changes in renal function for ARAS, as reflected by serum creatinine levels, have been small.[1] Remarkably, the changes in renal function in azotemic patients after surgical reconstruction are similar. [62] [202] As we and others have observed, overall group changes in kidney function can be misleading.[188] Careful evaluation of the literature indicates that three distinctly different clinical outcomes are routinely observed. In some instances (≈27%), revascularization produces meaningful improvements in kidney function. For this group, the mean serum creatinine may fall from a mean value of 4.5 mg/dL to an average of 2.2 mg/dL. There can be no doubt that such patients benefit from the procedure and can avoid major morbidity (and probably mortality) associated with advanced renal failure. The bulk of patients, however, have no measurable change in renal function (≈52%). Whether such patients benefit much depends upon the true clinical likelihood of progressive renal injury if the stenotic lesion were managed without revascularization, as discussed previously. For those without the risk of progression, they gain little. The most significant concern, however, is the group of patients whose renal function deteriorates further after a revascularization procedure. In most reports, this ranges from 19% to 25%. [1] [204] In some instances, this represents atheroembolic disease, or a variety of complications including vessel dissection with thrombosis.[190] Hence, nearly 20% of patients face a relatively rapid progression of renal insufficiency and the potential for requiring renal replacement therapy, including dialysis and/or renal transplantation.[194] [202] [206] Possible mechanisms for deterioration include atheroembolic injury, which may be nearly universal after any vascular intervention,[192] and acceleration of oxidative stress producing interstitial fibrosis.[193] Whether improving techniques, including the application of distal “protection” devices for endovascular catheters, will reduce these complications is not yet known.

Several studies suggest that progression of kidney failure attributed to ischemic nephropathy may be reduced by endovascular procedures. [204] [209] Harden and associates[189] presented reciprocal creatinine plots in 23 of 32 patients, suggesting that the slope of loss of GFR could be favorably changed after renal artery stenting, as illustrated in Figure 43-26 . It should be emphasized that 69% “improved or stabilized,” indicating that 31% worsened, consistent with results from other series. These reports and an interventional consensus document regarding reporting of trials promote the use of “breakpoint” analysis to consider the results of renovascular procedures. Caution must be applied regarding the use of breakpoints using reciprocal creatinine plots in this disorder, however. It must be recognized that vascular disease is not a uniform disorder affecting both kidneys symmetrically, nor is it likely to follow a constant course of progression, in contrast to diabetic nephropathy, for example. As a result, a gradual loss of renal function with subsequent stabilization can be observed with unilateral disease leading to total occlusion, as illustrated in Figure 43-22 . Perhaps the most convincing group data in this regard derived from serial renal functional measurement in 33 patients with high-grade stenosis (>70%) to the entire affected renal mass (bilateral disease or stenosis to a solitary functioning kidney) with creatinine levels between 1.5 and 4.0 mg/dL. Follow-up over a mean of 20 months indicated that the slope of GFR loss converted from negative (-0.0079 dL/mg/mo) to positive (0.0043 dL/mg/mo).[194] These studies agree with other observations that long-term survival is reduced in bilateral disease and that the potential for renal dysfunction and accelerated cardiovascular disease risk is highest in such patients (see earlier).



FIGURE 43-26  Reciprocal creatinine plots and calculated slope of declining renal function in 23 (of 32) patients followed before and after renal artery stenting. These data are presented as reflecting “stabilization” of renal function, although it might be observed that similar plots might be obtained with renal artery occlusion, as seen in Figure 43-22 . Nonetheless, some patients do improve, as observed in series with bilateral renal artery stenoses or stenosis to a solitary kidney.[194]  (From Harden PN, Macleod MJ, Rodger RS, et al: Effect of renal-artery stenting on progression of renovacular renal failure. Lancet 349:1133–1136, 1997, with permission.)


Predictors of Likely Benefit Regarding Renal Revascularization

Identification of patients most likely to obtain improved blood pressure and/or renal function after renal revascularization remains an elusive task. As noted previously, functional tests of renin release, such as measurement of renal vein renin levels, have not performed universally well. Many of these studies are most useful when positive (e.g., the likelihood of benefit improves with more evident lateralization) but have relatively poor negative predictive value—that is, when such studies are negative, outcomes of vessel repair may still be beneficial. As a clinical matter, recent progression of hypertension remains among the most consistent predictors of improved blood pressure after intervention.

Predicting favorable renal functional outcomes is also difficult. Several series indicate that either surgical or endovascular procedures are least likely to benefit those with advanced renal insufficiency, usually characterized by serum creatinine levels above 3.0 mg/dL. [165] [166] Nonetheless, occasional patients with recent progression to far advanced renal dysfunction can recover GFR with durable improvement over many years ( Fig. 43-27 ). Small kidneys, as identified by length less than 8 cm, are less likely to recover function, particularly when little function can be identified on radionuclide renography.[195] Reports of renal resistance index measured by Doppler ultrasound in 5950 patients indicate that identification of lower resistance was a favorable marker for improvement in both GFR and blood pressure, whereas elevated resistance index was an independent marker of poor outcomes[117] (see Fig. 43-18 ). None of these is absolute. A recent deterioration of kidney function portends more likely improvement with reconstruction.



FIGURE 43-27  Serum creatinine and blood pressure levels before and after percutaneous transluminal renal angioplasty (PTRA) in a patient with bilateral high-grade renal artery stenosis and recently developing renal failure. Restoration of blood supply to the kidneys led to a fall in creatinine from above 6 mg/dL to 2.1 mg/dL. Improvement in blood pressure control was achieved with administration of an angiotensin-converting enzyme (ACE) inhibitor, which had not been tolerated previously. Such cases illustrate the potential benefits of recognizing and acting to restore kidney function when possible in patients developing ischemic nephropathy. LFU, last follow-up.  (From Textor SC, Wilcox CS: Ischemic nephropathy/azotemic renal vascular disease. Semin Nephrol 20:489–502, 2000.)




Complications of Renal Artery Angioplasty and Stenting

Atherosclerotic plaque is commonly composed of multiple layers with calcified, fibrotic, and inflammatory components. Physical expansion of such a lesion applies considerable force to the wall and may lead to cracking and release of small particulate debris into the bloodstream. Effective balloon angioplasty and stenting require learning optimal techniques for limiting the damage to blood vessels during the procedure. As a result, optimal results depend upon achieving a level of competence after traversing a learning curve. Reported results vary considerably between centers and are improving with increasing experience.[196] A review of 10 published series with 416 stented vessels indicates that significant complications arise in 13% of cases, not including those that lead to the need for dialysis. These include several of the events listed in Table 43-11 , including hematomas and retroperitoneal bleeding requiring transfusion. Renal function deteriorated in these series on average 26% of the time and 50% (7/14) subjects with preprocedure creatinine levels above 400 mmol progressed to advanced kidney failure requiring dialysis.[179]Most complications are minor, including local hematomas and false aneurysms at the insertion site. Occasional severe complications develop, including aortic dissection,[190] stent migration, and vessel occlusion with thrombosis.[197] Local renal dissections can be managed by judicious application of additional stents. Mortality related directly to this procedure is small, but has been reported as a complication in 0.5%.[179]

TABLE 43-11   -- Complications After Percutaneous Transluminal Renal Angioplasty and Stenting of the Renal Arteries



Minor (most frequently reported)



Groin hematoma



Puncture site trauma



Major (reported in 71/799 treated arteries [9%][180])



Hemorrhage requiring transfusion



Femoral artery pseudoaneurysm needing repair



Brachial artery traumatic injury needing repair



Renal artery perforation leading to surgical intervention



Stent thrombosis: surgical or antithrombotic intervention



Distal renal artery embolus



Iliac artery dissection



Segmental renal infarction



Cholesterol embolism: renal



Peripheral atheroemboli



Aortic dissection[190]



Restenosis: 16% (range: 0%–39%)



Deterioration of renal function: 26% (range: 0%–45%)



Mortality attributed to procedure: 0.5%



Procedure-related complications: 51/379 patients in 10 series (13.5%)[179]

Modified and adapted from references 179, 180, 190 [194] [195] [205].



Restenosis remains a significant clinical limitation. Reported rates vary widely between 13% and 30%, most often within the first 6 to 12 months. [61] [194] [195] [213] [214] [215] [216] Most recent series report 13% to 16% sometimes leading to repeat procedures. Whether this will be changed by future use of sirolimus-coated stents, as it has for coronary restenosis, is not yet known.


Renovascular disease is common, particularly in older subjects with other atherosclerotic disease. It can produce a wide array of clinical effects, ranging from asymptomatic “incidental” disease to accelerated hypertension and progressive kidney failure. With improved imaging and in older patients, significant renal artery disease is detected more often than ever before. It is incumbent upon the clinician to evaluate both the role of renal artery disease in the individual patient and the potential risk/benefit ratio for renal revascularization. An algorithm to guide treatment and reevaluation of patients with ARAS is presented in Figure 43-28 . This process relies heavily upon considering comorbid risks and the evolution of both blood pressure control and kidney function over a period of time. Management of cardiovascular risk and hypertension is the primarily objective of medical therapy. For most patients, the realistic goals of renal revascularization are to reduce medication requirements and to stabilize renal function over time. Patients with bilateral disease or stenosis to a solitary functioning kidney may have lower risk of circulatory congestion (“flash” pulmonary edema or its equivalent) and lower risk for advancing kidney failure. It is essential to appreciate the risks inherent in either surgical or endovascular manipulation of the diseased aorta, including a hazard of atheroembolic complications and potential deterioration of renal function related to the procedure itself (estimated at 20%). Hence, the decision to undertake these procedures should include consideration of whether the potential gain warrants such risks. In many cases, improved blood pressure and recovery of renal function are entirely justified. Follow-up of both blood pressure and renal function is important, particularly because of the potential for restenosis and/or recurrent disease. Selection of the balance and timing of medical management and revascularization depends largely upon the comorbid disease risks for each patient.



FIGURE 43-28  Algorithm summarizing a management scheme for patients with renovascular hypertension and/or ischemic nephropathy. Optimizing antihypertensive and medical therapy for comorbid disease including dyslipidemia is paramount to reducing cardiovascular morbidity and mortality in atherosclerotic disease. Decisions regarding timing of renal revascularization procedures depend both upon the clinical manifestations (see text) and whether blood pressures and kidney function remain stable. ACE, angiotensin-converting enzyme; GFR, glomerular filtration rate; PTRA, percutaneous transluminal renal angioplasty; RAS, renal artery stenosis.




1. Textor SC, Wilcox CS: Renal artery stenosis: A common, treatable cause of renal failure?.  Annu Rev Med  2001; 52:421-442.

2. Basso N, Terragno NA: History about the discovery of the renin-angiotensin system.  Hypertension  2001; 38:1246-1249.

3. Martinez-Maldonado M: Pathophysiology of renovascular hypertension.  Hypertension  1991; 17:707-719.

4. Stanley JC: Surgical treatment of renovascular hypertension.  Am J Surg  1997; 174:102-110.

5. Garovic V, Textor SC: Renovascular hypertension and ischemic nephropathy.  Circulation  2005; 112:1362-1374.

6. Conlon PJ, O'Riordan E, Kalra PA: Epidemiology and clinical manifestations of athersclerotic renal artery stenosis.  Am J Kidney Dis  2000; 35:573-587.

7. Textor SC, Lerman LO: Renal artery disease: Pathophysiology.   In: Creager MA, Dzau VJ, Loscalzo J, ed. Vascular Medicine: A Companion to Braunwald's Heart Disease,  Philadelphia: Saunders-Elsevier; 2006:323-334.

8. Lerman LO, Schwartz RS, Grande JP, et al: Noninvasive evaluation of a novel swine model of renal artery stenosis.  J Am Soc Nephrol  1999; 10:1455-1465.

9. Cervenka L, Horacek V, Vaneckova I, et al: Essential role of AT1-A receptor in the development of 2K1C hypertension.  Hypertension  2002; 40:735-741.

10. Romero JC, Feldstein AE, Rodriguez-Porcel MG, Cases-Amenos A: New insights into the pathophysiology of renovascular hypertension.  Mayo Clin Proc  1997; 72:251-260.

11. Miyajima E, Yamada Y, Yoshida Y, et al: Muscle sympathetic nerve activity in renovascular hypertension and primary aldosteronism.  Hypertension  1991; 17:1057-1062.

12. Gao SA, Johansson M, Rundqvist B, et al: Reduced spontaneous baroreceptor sensitivity in patients with renovascular hypertension.  J Hypertens  2002; 20:111-116.

13. Lerman LO, Nath KA, Rodriguez-Porcel M, et al: Increased oxidative stress in experimental renovascular hypertension.  Hypertension  2001; 37:541-546.

14. Welch WJ, Mendonca M, Aslam S, Wilcox CS: Roles of oxidative stress and AT1 receptors in renal hemodynamics and oxygenation in the postclipped 2K,1C kidney.  Hypertension  2003; 41:692-696.

15. Romero JC, Reckelhoff JF: Role of angiotensin and oxidative stress in essential hypertension.  Hypertension  1999; 43(pt 2):943-949.

16. Higashi Y, Sasaki S, Nakagawa K, et al: Endothelial function and oxidative stress in renovascular hypertension.  N Engl J Med  2002; 346:1954-1962.

17. Parildar M, Parildar Z, Oran I, et al: Nitric oxide and oxidative stress in atherosclerotic renovascular hypertension: Effect of endovascular treatment.  J Vasc Interv Radiol  2004; 14:887-892.

18. Lerman L, Textor SC: Pathophysiology of ischemic nephropathy.  Urol Clin North Am  2001; 28:793-803.

19. Lerman LO, Bentley MD, Fiksen-Olsen MJ, et al: Pressure dependency of canine intrarenal blood flow within the range of autoregulation.  Am J Physiol  1995; 268:F404-F409.

20. Nielsen K, Rehling M, Henriksen JH: Renal vein oxygen saturation in renal artery stenosis.  Clin Physiol  1992; 12:179-184.

21. Juillard L, Lerman LO, Kruger DG, et al: Blood oxygen level-dependent measurement of acute intra-renal ischemia.  Kidney Int  2004; 65:944-950.

22. Abdi A, Johns EJ: Importance of the renin-angiotensin system in the generation of kidney failure in renovascular hypertension.  J Hypertens  1996; 14:1131-1137.

23. Zou LX, Imig JD, von Thun AM, et al: Receptor-mediated intrarenal angiotensin II augmentation in angiotensin II-infused rats.  Hypertension  1996; 28:669-677.

24. Matsusaka T, Hymes J, Ichikawa I: Angiotensin in progressive renal diseases: Theory and practice.  J Am Soc Nephrol  1996; 7:2025-2043.

25. Chade AR, Rodriguez-Porcel M, Grande JP, et al: Distinct renal injury in early atherosclerosis and renovascular disease.  Circulation  2002; 106:1165-1171.

26. Chade AR, Best PJ, Rodriguez-Porcel M, et al: Endothelin-1 receptor blockade prevents renal injury in experimental hypercholesterolemia.  Kidney Int  2003; 64:962-969.

27. Raij L: Nitric oxide in hypertension: Relationship with renal injury and left ventricular hypertrophy.  Hypertension  1998; 31:189-193.

28. Sigmon DH, Beierwaltes WH: Renal nitric oxide and angiotensin II interaction in renovascular hypertension.  Hypertension  1993; 22:237-242.

29. Remuzzi G, Bertani T: Pathophysiology of progressive nephropathies.  N Engl J Med  1998; 339:1448-1456.

30. Grande JP: Role of transforming growth factor-beta in tissue injury and repair.  Proc Soc Exp Biol Med  1997; 214:27-40.

31. Eddy AA: Molecular insights into renal interstitial fibrosis.  J Am Soc Nephrol  1996; 7:2495-2508.

32. Border WA, Noble NA: Interactions of transforming growth factor-beta and angiotensin II in renal fibrosis.  Hypertension  1998; 31(pt 2):181-188.

33. Nath KA, Croatt AJ, Haggard JJ, Grande JP: Renal response to repetitive exposure to heme proteins: Chronic injury induced by an acute insult.  Kidney Int  2000; 57:2423-2433.

34. Truong LD, Farhood A, Tasby J, Gillum D: Experimental chronic renal ischemia: Morphologic and immunologic studies.  Kidney Int  1992; 41:1676-1689.

35. Molitoris BA, Marrs J: The role of cell adhesion molecules in ischemic acute renal failure.  Am J Med  1999; 106:583-592.

36. Garcia-Criado FJ, Eleno N, Santos-Benito F, et al: Protective effect of exogenous nitric oxide on the renal function and inflammatory response in a model of ischemia-reperfusion.  Transplantation  1998; 66:982-990.

37. Kontogiannis J, Burns KD: Role of AT1 angiotensin II receptors in renal ischemic injury.  Am J Physiol  1998; 274:F79-F90.

38. Svetkey LP, Kadir S, Dunnick NR, et al: Similar prevalence of renovascular hypertension in selected blacks and whites.  Hypertension  1991; 17:678-683.

39. McAlister FA, Lewanczuk RZ, Teo KK: Resistant hypertension: An overview.  Can J Cardiol  1996; 12:822-828.

40. Slovut DP, Olin JW: Current concepts: Fibromuscular dysplasia.  N Engl J Med  2004; 350:1862-1871.

41. Rossi G, Rossi A, Zanin L, et al: Excess prevalence of extracranial carotid artery lesions in renovascular hypertension.  Am J Hypertens  1992; 5:8-15.

42. Bonelli FS, McKusick MA, Textor SC, et al: Renal artery angioplasty: Technical results and clinical outcome in 320 patients.  Mayo Clin Proc  1995; 70:1041-1052.

43. Mounier-Vehier C, Lions C, Jaboureck O, et al: Parenchymal consequences of fibromuscular dysplasia in renal artery stenosis.  Am J Kidney Dis  2002; 40:1138-1145.

44. Krijnen P, van Jaarsveld BC, Steyerberg EW, et al: A clinical prediction rule for renal artery stenosis.  Ann Intern Med  1998; 129:705-711.

45. Harding MB, Smith LR, Himmelstein SI, et al: Renal artery stenosis: Prevalence and associated risk factors in patients undergoing routine cardiac catheterization.  J Am Soc Nephrol  1992; 2:1608-1616.

45a. Vetrovec GW, Landwehr DM, Edwards VL: Incidence of renal artery stenosis in hypertensive patients undergoing coronary angiography.  J Interven Cardiol  1989; 2:69-76.

45b. Choudhri AH, Cleland JGF, Rowlands PC, et al: Unsuspected renal artery stenosis in peripheral vascular disease.  Br Med J  1990; 301:1197-1198.

45c. Wilms G, Marchal G, Penne P, et al: The angiographic incidence of renal artery stenosis in the arteriosclerotic population.  Eur J Radiol  1990; 10:195-197.

45d. Olin JW, Melia M, Young JR, et al: Prevalence of atherosclerotic RAS in patients with atherosclerosis elsewhere.  Am J Med  1990; 88:46N-51N.

46. Rihal CS, Textor SC, Breen JF, et al: Incidental renal artery stenosis among a prospective cohort of hypertensive patients undergoing coronary angiography.  Mayo Clin Proc  2002; 77:309-316.

47. Swartbol P, Thorvinger BOT, Parsson H, Norgren L: Renal artery stenosis in patients with peripheral vascular disease and its correlation to hypertension; a retrospective study.  Int Angiol  1992; 11:195-199.

48. Coen G, Manni M, Giannoni MF, et al: Ischemic nephropathy in an elderly nephrologic and hypertensive population.  Am J Nephrol  1998; 18:221-227.

49. Scoble JE: The epidemiology and clinical manifestations of atherosclerotic renal disease.   In: Novick AC, Scoble J, Hamilton G, ed. Renal Vascular Disease,  1st ed. London: WB Saunders; 1996:303-314.

50. Welch HG, Albertsen PC, Nease RF, et al: Estimating treatment benefits for the elderly: The effect of competing risks.  Ann Intern Med  1996; 124:577-584.

51. Surowiec SM, Sivamurthy N, Rhodes JM, et al: Percutaneous therapy for renal artery fibromuscular dysplasia.  Ann Vasc Surg  2003; 17:650-655.

52. Iantorno M, Pola R, Schinzari F, et al: Association between altered circadian blood pressure profile and cardiac end-organ damage in patients with renovascular hypertension.  Cardiology  2003; 100:114-119.

53. Edwards MS, Hansen KJ, Craven TE, et al: Associations between renovascular disease and prevalent cardiovascular disease in the elderly: A population-based study.  Vasc Endovasc Surg  2004; 38:25-35.

54. Kalra PA, Guo H, Kausz AT, et al: Atherosclerotic renovascular disease in United States patients aged 67 years or older: Risk factors, revascularization and prognosis.  Kidney Int  2005; 68:293-301.

55. Mann JFE, Gerstein HC, Pogue J, HOPE Investigators , et al: Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: The HOPE randomized trial.  Ann Intern Med  2001; 134:629-636.

56. Greco BA, Breyer JA: The natural history of renal artery stenosis: Who should be evaluated for suspected ischemic nephropathy?.  Semin Nephrol  1996; 16:2-11.

57. Tuttle KF, Chouinard RF, Webber JT, et al: Treatment of atherosclerotic ostial renal artery stenosis with the intravascular stent.  Am J Kidney Dis  1998; 32:611-622.

58. Hallett JW, Textor SC, Kos PB, et al: Advanced renovascular hypertension and renal insufficiency: trends in medical comorbidity and surgical approach from 1970 to 1993.  J Vasc Surg  1995; 21:750-759.

59. Kaneko K, Shimazaki S, Ino T, et al: Severe hyponatremia in a patient with renovascular hypertension: Case report.  Nephron  1994; 68:252-255.

60. Holm EA, Randlov A, Strandgaard S: Brief report: Acute renal failure after losartan treatment in a patient with bilateral renal artery stenosis.  Blood Press  1996; 5:360-362.

61. Missouris CG, Belli AM, MacGregor GA: “Apparent” heart failure: A syndrome caused by renal artery stenoses.  Heart  2000; 83:152-155.

62. MacDowall P, Kalra PA, O'Donoghue DJ, et al: Risk of morbidity from renovascular disease in elderly patients with congestive cardiac failure.  Lancet  1998; 352:13-16.

63. Gray BH, Olin JW, Childs MB, et al: Clinical benefit of renal artery angioplasty with stenting for the control of recurrent and refractory congestive heart failure.  Vasc Med  2002; 7:275-279.

64. Tami LF, McElderry MW, Al-Adli NM, et al: Renal artery stenosis presenting as crescendo angina pectoris.  Catheter Cardiovasc Diagn  1995; 35:252-256.

65. Messina LM, Zelenock GB, Yao KA, Stanley JC: Renal revascularization for recurrent pulmonary edema in patients with poorly controlled hypertension and renal insufficiency: A distinct subgroup of patients with arteriosclerotic renal artery occlusive disease.  J Vasc Surg  1992; 15:73-82.

66. Stack R: Procedural indications and variables that affect acute outcome.  J Invasive Cardiol  1998; 10:103-104.

67. Connolly JO, Higgins RM, Walters HL, et al: Presentation, clinical features and outcome in different patterns of atherosclerotic renovascular disease.  Q J Med  1994; 87:413-421.

68. Cheung CM, Wright JR, Shurrab AE, et al: Epidemiology of renal dysfunction and patient outcome in atherosclerotic renal artery occlusion.  J Am Soc Nephrol  2002; 13:149-157.

69. Wright JR, Duggal A, Thomas R, et al: Clinicopathological correlation in biopsy-proven atherosclerotic nephropathy: Implications for renal functional outcome in atherosclerotic renovascular disease.  Nephrol Dial Transplant  2001; 16:765-770.

70. Farmer CKT, Cook GJR, Balke GM, et al: Individual kidney function in atherosclerotic nephropathy is not related to the presence of renal artery stenosis.  Nephrol Dial Transplant  1999; 14:2880-2884.

71. Fatica RA, Port FK, Young EW: Incidence trends and mortality in end-stage renal disease attributed to renovascular disease in the United States.  Am J Kidney Dis  2001; 37:1184-1190.

72. Chen R, Novick AC, Pohl M: Reversible renin mediated massive proteinuria successfully treated by nephrectomy.  J Urol  1995; 153:133-134.

73. Docci D, Moscatelli G, Capponcini C, et al: Nephrotic-range proteinuria in patient with high renin hypertension: Effect of treatment with an ACE-inhibitor.  Am J Nephrol  1992; 12:387-389.

74. Ie EH, Karschner JK, Shapiro AP: Reversible nephrotic syndrome due to high renin state in renovascular hypertension.  Neth J Med  1995; 46:136-141.

75. Ben-Chitrit S, Korzets Z, Podjarny E, Bernheim J: Reversal of the nephrotic syndrome due to renovascular hypertension by successful percutaneous angioplasty and stenting.  Nephrol Dial Transplant  1995; 10:1460-1461.

76. Webster J, Marshall F, Abdalla M, et al: Randomised comparsion of percutaneous angioplasty vs continued medical therapy for hypertensive patients with atheromatous renal artery stenosis.  J Hum Hypertens  1998; 12:329-335.

77. Textor SC: Renovascular hypertension and ischemic nephropathy.   In: Brenner BM, ed. Brenner and Rector's The Kidney,  7th ed. Philadelphia: Saunders; 2004:2065-2108.

78. Conlon PJ, Little MA, Pieper K, Mark DB: Severity of renal vascular disease predicts mortality in patients undergoing coronary angiography.  Kidney Int  2001; 60:1490-1497.

79. Wright JR, Shurrab AE, Cheung C, et al: A prospective study of the determinants of renal functional outcome and mortality in atherosclerotic renovascular disease.  Am J Kidney Dis  2002; 39:1153-1161.

80. Zierler RE, Bergelin RO, Davidson RC, et al: A prospective study of disease progression in patients with atherosclerotic renal artery stenosis.  Am J Hypertens  1996; 9:1055-1061.

81. Caps MT, Perissinotto C, Zierler RE, et al: Prospective study of atherosclerotic disease progression in the renal artery.  Circulation  1998; 98:2866-2872.

82. van Jaarsveld BC, Krijnen P, Pieterman H, Dutch Renal Artery Stenosis Intervention Cooperative Study Group , et al: The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis.  N Engl J Med  2000; 342:1007-1014.

83. Caps MT, Zierler RE, Polissar NL, et al: Risk of atrophy in kidneys with atherosclerotic renal artery stenosis.  Kidney Int  1998; 53:735-742.

84. Leertouwer TC, Pattynama PMT, van den Berg-Huysmans A: Incidental renal artery stenosis in peripheral vascular disease: A case for treatment?.  Kidney Int  2001; 59:1480-1483.

85. Chabova V, Schirger A, Stanson AW, et al: Outcomes of atherosclerotic renal artery stenosis managed without revascularization.  Mayo Clin Proc  2000; 75:437-444.

86. Conlon PJ, Athirakul K, Kovalik E, et al: Survival in renal vascular disease.  J Am Soc Nephrol  1998; 9:252-256.

87. Butterly DW, Schwab SJ: Renal artery stenosis: The case for conservative management.  Mayo Clin Proc  2000; 75:435-436.

88. White CJ: Catheter-based therapy for atheroscerotic renal artery stenosis.  Circulation  2006; 113:1464-1473.

89. White CJ: Open renal arteries are better than closed renal arteries.  Catheter Cardiovasc Diagn  1998; 45:9-10.

90. Murphy TP, Cooper CJ, Dworkin LD, et al: The Cardiovascular Outcomes with Renal Atherosclerotic Lesions (CORAL) study: Rationale and methods.  J Vasc Interv Radiol  2005; 16:1295-1300.

91. Mann SJ, Pickering TG: Detection of renovascular hypertension: State of the art: 1992.  Ann Intern Med  1992; 117:845-853.

92. Wilcox CS: Use of angiotensin converting enzyme inhibitors for diagnosing renovascular hypertension.  Kidney Int  1993; 44:1379-1390.

93. Boudewijn G, Vasbinder C, Nelemans PJ, et al: Diagnostic tests for renal artery stenosis in patients suspected of having renovascular hypertension: A meta-analysis.  Ann Intern Med  2001; 135:401-411.

94. Canzanello VJ, Textor SC: Noninvasive diagnosis of renovascular disease.  Mayo Clin Proc  1994; 69:1172-1181.

95. Postma CT, van Oijen AH, Barentsz JO, et al: The value of tests predicting renovascular hypertension in patients with renal artery stenosis treated by angioplasty.  Arch Intern Med  1991; 151:1531-1535.

96. Safian RD, Textor SC: Medical progress: Renal artery stenosis.  N Engl J Med  2001; 344:431-442.

97. Simon G, Coleman CC: Captopril-stimulated renal vein renin measurements in the diagnosis of atherosclerotic renovascular hypertension.  Am J Hypertens  1994; 7:1-6.

98. Kane GC, Textor SC, Schirger A, Garovic VD: Revisiting the role of nephrectomy for advanced renovascular disease.  Am J Med  2003; 114:729-735.

98a. Strong CG, Hunt JC, Sheps SG, et al: Renal venous renin activity enhancement of sensitivity of lateralization by sodium depletion.  Am J Cardiol  1971; 27:602-611.

99. Roubidoux MA, Dunnick NR, Klotman PE, et al: Renal vein renins: Inability to predict response to revascularisation in patients with hypertension.  Radiology  1991; 178:819-822.

100. Taylor A: Functional testing: ACEI renography.  Semin Nephrol  2000; 20:437-444.

101. Cheung CM, Shurrab AE, Buckley DL, et al: MR-derived renal morphology and renal function in patients with atherosclerotic renovascular disease.  Kidney Int  2006; 69:715-722.

102. Rundback JH, Sacks D, Kent KC, et al: Guidelines for reporting of renal artery revascularization in clinical trials.  Circulation  2002; 106:1572-1585.

103. Mann JFE: The diagnosis of renovascular hypertension: State of the art 1995.  Nephrol Dial Transplant  1995; 10:1285-1286.

104. Fernandez P, Morel R, Jeandot R, et al: Value of captopril renal scintigraphy in hypertensive patients with renal failure.  J Nucl Med  1999; 40:412-417.

105. Elliot WJ, Martin WB, Murphy MB: Comparison of two non-invasive screening tests for renovascular hypertension.  Arch Intern Med  1993; 153:755-764.

106. Soulez G, Therasse E, Qanadli SD, et al: Prediction of clinical response after renal angioplasty: Respective value of renal Doppler sonography and scintigraphy.  AJR Am J Roentgenol  2004; 181:1029-1035.

107. La Batide-Alanore A, Azizi M, Froissart M, et al: Split renal function outcome after renal angioplasty in patients with unilateral renal artery stenosis.  J Am Soc Nephrol  2001; 12:1235-1241.

108. Meholic AJ, Saddler MC, Hallin GW, et al: The captopril renogram in percutanous transluminal angioplasty of the renal arteries.  Am J Physiol Imaging  1992; 7:36-41.

109. Bakker J, Beutler JJ, Elgersma OE, et al: Duplex ultrasonography in assessing restenosis of renal artery stents. Cardiovasc Intervent.  Radiol  1999; 22:468-474.

110. Henry M, Amor M, Henry I, et al: Stents in the treatment of renal artery stenosis: Long-term follow-up.  J Endovasc Surg  1999; 6:42-51.

111. Edwards JM, Zaccardi JM, Strandness DE: A preliminary study of the role of duplex scanning in defining the adequacy of treatment of patients with renal artery fibromuscular dysplasia.  J Vasc Surg  1992; 15:604-609.

112. Olin JW, Piedmonte MR, Young JR, et al: The utility of duplex ultrasound scanning of the renal arteries for diagnosing significant renal artery stenosis.  Ann Intern Med  1995; 122:833-838.

113. Spies KP, Fobbe F, El-Bedewi M, et al: Color-coded duplex sonography for noninvasive diagnosis and grading of renal artery stenosis.  Am J Hypertens  1995; 8:1222-1231.

114. Postma CT, van Aalen J, de Boo T, et al: Doppler ultrasound scanning in the detection of renal artery stenosis in hypertensive patients.  Br J Radiol  1992; 65:857-860.

115. Stavros AT, Parker SH, Yakes WF, et al: Segmental stenosis of the renal artery: Pattern recognition of tardus and parvus abnormalities with duplex sonography.  Radiology  1992; 184:487-492.

116. Radermacher J, Weinkove R, Haller H: Techniques for predicting favourable response to renal angioplasty in patients with renovascular disease.  Curr Opin Nephrol Hypertens  2002; 10:799-805.

117. Radermacher J, Chavan A, Bleck J, et al: Use of Doppler ultrasonography to predict the outcome of therapy for renal-artery stenosis.  N Engl J Med  2001; 344:410-417.

118. Zeller T, Muller C, Frank U, et al: Stent angioplasty of severe atherosclerotic ostial renal artery stenosis in patients with diabetes mellitus and nephrosclerosis.  Catheter Cardiovasc Interv  2003; 58:510-515.

119. Spinosa DJ, Hagspiel KD, Angle JF, et al: Gadolinium-based contrast agents in angiography and interventional radiology: Uses and techniques.  J Vasc Intervent Radiol  2000; 11:985-990.

120. King BF: Diagnostic imaging evaluation of renovascular hypertension.  Abdom Imaging  1995; 20:395-405.

121. Grist TM: Magnetic resonance angiography of renal artery stenosis.  Am J Kidney Dis  1994; 24:700-712.

122. Postma CT, Joosten FB, Rosenbusch G, Thien T: Magnetic resonance angiography has a high reliability in the detection of renal artery stenosis.  Am J Hypertens  1997; 10:957-963.

123. Tan KT, van Beek EJ, Brown PW, et al: Magnetic resonance angiography for the diagnosis of renal artery stenosis: A meta-analysis.  Clin Radiol  2002; 57:617-624.

124. Ros PR, Gauger J, Stoupis C, et al: Diagnosis of renal artery stenosis: Feasibility of combining MR angiography, MR renography and gadopentetate-based measurements of glomerular filtration rate.  AJR Am J Roentgenol  1995; 165:1447-1451.

125. Fain SB, King BF, Breen JF, et al: High-resolution contrast-enhanced MR angiography of the renal arteries: A prospective comparison to x-ray angiography.  Radiology  2001; 218:481-490.

125a. Marckmann P, Skov L, Rossen K, et al: Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging.  J Am Soc Nephrol  2006; 17:2359-2362.

126. Olbricht CJ, Paul K, Prokop M, et al: Minimally invasive diagnosis of renal artery stenosis by spiral computed tomography angiography.  Kidney Int  1995; 48:1332-1337.

127. Elkohen M, Beregi JP, Deklunder G, et al: Evaluation of the spiral computed tomography alone and combined with color Doppler ultrasonography in the detection of renal artery stenosis: A prospective study of 114 renal arteries.  Arch Mal Coeur Vaiss  1995; 88:1159-1164.

128. Vasbinder GBC, Nelemans PJ, Kessels AGH, et al: Accuracy of computed tomographic angiography and magnetic resonance angiography for diagnosing renal artery stenosis.  Ann Intern Med  2004; 141:674-682.

129. Textor SC: Pitfalls in imaging for renal artery stenosis.  Ann Intern Med  2004; 141:730-731.

130. Conlon PJ, Athirakul K, Kovalik E, et al: Long-term follow-up of asymptomatic renal vascular disease. Abstract.  J Am Soc Nephrol  1996; 7:1384.

131. Gami AS, Garovic VD: Contrast nephropathy after coronary angiography.  Mayo Clin Proc  2004; 79:211-219.

132. Mounier-Vehier C, Cocheteux B, Haulon S, et al: Changes in renal blood flow reserve after angioplasty of renal artery stenosis in hypertensive patients.  Kidney Int  2004; 65:245-250.

133. Chobanian AV: NHBPEP Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report.  JAMA  2003; 289:2560-2572.

134. Hollenberg NK: Treatment of hypertension: The place of angiotensin-converting enzyme inhibitors in the nineties.  J Cardiovasc Pharmacol  1992; 20(suppl):S29-S33.

135. Jackson B, Franze L, Sumithran E, Johnston CI: Pharmacologic nephrectomy with chronic angiotensin converting enzyme inhibitor treatment in renovascular hypertension in the rat.  J Lab Clin Med  1990; 115:21-27.

136. Mimran A: Renal effects of antihypertensive agents in parenchymal renal disease and renovascular hypertension.  J Cardiovasc Pharmacol  1992; 19(suppl 6):S45-S50.

137. Veniant M, Heudes D, Clozel JP, et al: Calcium blockade versus ACE inhibition in clipped and unclipped kidneys of 2K-1C rats.  Kidney Int  1994; 46:421-429.

138. Mackenzie HS, Brenner BM: Prevention of progressive renal failure.   In: Brady H, Wilcox C, ed. Therapy in Nephrology and Hypertension,  1st ed. Philadelphia: WB Saunders; 1999:463-473.

139. Textor SC: Renal failure related to ACE inhibitors.  Semin Nephrol  1997; 17:67-76.

140. Grone HJ, Warnecke E, Olbricht CJ: Characteristics of renal tubular atrophy in experimental renovascular hypertension: A model of kidney hibernation.  Nephron  1996; 72:243-252.

141. Kavoussi LR: Laparoscopic donor nephrectomy.  Kidney Int  2000; 57:2175-2186.

142. Lau WKO, Blute ML, Weaver AL, et al: Matched comparison of radical nephrectomy vs. nephron-sparing surgery inpatients with unilateral renal cell carcinoma and a normal contralateral kidney.  Mayo Clin Proc  2000; 75:1236-1242.

143. Plouin PF, Chatellier G, Darne B, Raynaud A: Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis: A randomized trial.  Hypertension  1998; 31:822-829.

144. Semple PF, Dominczak AF: Detection and treatment of renovascular disease: 40 years on.  J Hypertens  1994; 12:729-734.

145. Nordmann AJ, Woo K, Parkes R, Logan AG: Balloon angioplasty or medical therapy for hypertensive patients with atherosclerotic renal artery stenosis? A meta-analysis of randomized controlled trials.  Am J Med  2003; 114:44-50.

146. Ives NJ, Wheatley K, Stowe RL, et al: Continuing uncertainty about the value of percutaneous revascularization in atherosclerotic renovascular disease: A meta-analysis of randomized trials.  Nephrol Dial Transplant  2003; 18:298-304.

147. Kitiyakara C, Guzman NJ: Malignant hypertension and hypertensive emergencies.  J Am Soc Nephrol  1998; 9:133-142.

148. Dorros G, Jaff M, Mathiak L, He T: Multicenter Registry Participants. Multi-center Palmaz stent renal artery stenosis revascularization registry report: Four-year follow-up of 1058 successful patients.  Catheter Cardiovasc Interv  2002; 55:182-188.

149. White HD, Simes RJ, Anderson NE, et al: Pravastatin therapy and the risk of stroke.  N Engl J Med  2000; 343:317-326.

150. Chabova V, Schirger A, Stanson A, Textor SC: Management of renal artery stenosis without revascularization since the introduction of ACE inhibitors Abstract.  J Am Soc Nephrol  1999; 10:362A.

151. Uzzo RG, Novick AC, Goormastic M, et al: Medical versus surgical management of atherosclerotic renal artery stenosis.  Transplant Proc  2002; 34:723-725.

152. Dougherty MJ, Hallett JW, Naessens J, et al: Renal endarterectomy vs. bypass for combined aortic and renal reconstruction: Is there a difference in clinical outcome?.  Ann Vasc Surg  1995; 9:87-94.

153. Novick AC: Alternative bypass techniques for renal revascularization.   In: Novick AC, Scoble J, Hamilton G, ed. Renal Vascular Disease,  1st ed. Philadelphia: WB Saunders; 1996:465-480.

154. Steinbach F, Novick AC, Campbell S, Dykstra D: Long-term survival after surgical revascularization for atherosclerotic renal artery disease.  J Urol  1997; 158:38-41.

155. Cambria RP, Brewster DC, L'Italien GJ, et al: The durability of different reconstruc-tive techniques for atherosclerotic renal artery disease.  J Vasc Surg  1994; 20:76-87.

156. Paty PS, Darling III RC, Lee D, et al: Is prosthetic renal artery reconstruction a durable procedure? An analysis of 489 bypass grafts.  J Vasc Surg  2001; 34:127-132.

157. Weibull H, Bergqvist D, Bergentz SE, et al: Percutaneous transluminal renal angioplasty versus surgical reconstruction of atherosclerotic renal artery stenosis: A prospective randomized study.  J Vasc Surg  1993; 18:841-850.

158. Weibull H, Bergqvist D, Jonsson K, et al: Long-term results after percutaneous transluminal angioplasty of atherosclerotic renal artery stenosis—The importance of intensive follow-up.  Eur J Vasc Surg  1991; 5:291-301.

159. Chaikof EL, Smith RB, Salam AA, et al: Ischemic nephropathy and concomitant aortic disease: A ten-year experience.  J Vasc Surg  1994; 19:135-146.

160. Cambria RP, Brewster DC, L'Italien GJ, et al: Renal artery reconstruction for the preservation of renal function.  J Vasc Surg  1996; 24:371-382.

161. Alcazar JM, Rodicio JL: Ischemic nephropathy: Clinical characteristics and treatment.  Am J Kidney Dis  2000; 36:883-893.

162. Clair DB, Belkin M, Whittemore AD, et al: Safety and efficacy of transaortic renal endarterectomy as an adjunct to aortic surgery.  J Vasc Surg  1995; 21:926-933.

163. Dougherty MJ, Hallett JW, Naessens JM, et al: Optimizing technical success of renal revascularization: The impact of intraoperative color-flow duplex ultrasonography.  J Vasc Surg  1993; 17:849-857.

163a. Hansen KJ, Starr SM, Sands RE, et al: Contemporary surgical management of renovascular disease.  J Vasc Surg  1992; 16:319-330.

163b. Lamawansa MD, Bell R, House AK: Short-term and long-term outcome following renovascular reconstruction.  Cardiovasc Surg  1995; 3:50-55.

163c. Mercier C, Piquet P, Alimi Y, et al: Occlusive disease of the renal arteries and chronic renal failure: the limits of reconstructive surgery.  Ann Vasc Surg  1990; 2:166-170.

163d. Bredenberg CE, Sampson LN, Ray FS, et al: Changing patterns in surgery for chronic renal artery occlusive diseases.  J Vasc Surg  1992; 15:1018-1024.

164. Libertino JA, Bosco PJ, Ying CY, et al: Renal revascularization to preserve and restore renal function.  J Urol  1992; 147:1485-1487.

165. Hansen KJ, Thomason RB, Craven TE, et al: Surgical management of dialysis-dependent ischemic nephropathy.  J Vasc Surg  1995; 21:197-209.

166. Murphy TP, Soares G, Kim M: Increase in utilization of percutaneous renal artery inteventions by Medicare beneficiaries 1996-2000.  AJR Am J Roentgenol  2004; 183:561-568.

167. Thadhani RI, Camargo CA, Xavier RJ, et al: Atheroembolic renal failure after invasive procedures: Natural history based on 52 histologically proven cases.  Medicine  1995; 74:350-358.

168. Axelrod DA, Fendrick AM, Birkmeyer JD, et al: Cardiologists performing peripheral angioplasties: Impact on utilization.  Eff Clin Pract  2001; 4:191-198.

169. Ramsay LE, Waller PC: Blood pressure response to percutaneous transluminal angioplasty for renovascular hypertension: An overview of published series.  BMJ  1990; 300:569-572.

170. Englund R, Brown MA: Renal angioplasty for renovascular disease: A reappraisal.  J Cardiovasc Surg  1991; 32:76-80.

171. Aurell M, Jensen G: Treatment of renovascular hypertension.  Nephron  1997; 75:373-383.

172. Textor SC: Renovascular hypertension.   In: Johnson RJ, Feehally J, ed. Comprehensive Clinical Nephrology,  1st ed. London: Mosby (Harcourt Brace International); 2000:41.1-41.12.

173. Taler SJ, Textor SC, Augustine JE: Resistant hypertension: Comparing hemodynamic management to specialist care.  Hypertension  2002; 39:982-988.

173a. Kuhn FP, Kutkuhn B, Torsello G, Modder U: Renal artery stenosis: preliminary results of treatment with the Strecker Stent.  Radiology  1991; 180:367-372.

173b. Iannone LA, Underwood PL, Nath A, et al: Effect of primary balloon expandable renal artery stents on long-term patency, renal function, and blood pressure in hypertensive and renal insufficient patients with renal artery stenosis.  Cathet Cardiovasc Diagn  1996; 37:243-250.

173c. Xue F, Bettman MA, Langdon DR, Wivell WA: Outcome and cost comparison of percutaneous transluminal renal angioplasty, renal arterial stent placement, and renal arterial bypass grafting.  Radiology  1999; 212:378-384.

173d. White CJ, Ramee SR, Collins TJ, et al: Renal artery stent placement: utility in lesions difficult to treat with balloon angioplasty.  J Am Coll Cardiol  1997; 30:1445-1450.

173e. Rundback JH, Gray RJ, Rozenblit G, et al: Renal artery stent placement for the management of ischemic nephropathy.  J Vasc Intervent Radiol  1998; 9:413-420.

174. Tegtmeyer CJ, Selby JB, Hartwell GD, et al: Results and complications of angioplasty in fibromuscular disease.  Circulation  1991; 83(suppl):I155-I161.

175. Davidson RA, Barri Y, Wilcox CS: Predictors of cure of hypertension fibromuscular renovascular disease.  Am J Kidney Dis  1996; 28:334-338.

176. van de Ven PJ, Kaatee R, Beutler JJ, et al: Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: A randomised trial.  Lancet  1999; 353:282-286.

177. Blum U, Krumme B, Fluegel P, et al: Treatment of ostial renal-artery stenoses with vascular endoprostheses after unsuccessful balloon angioplasty.  N Engl J Med  1997; 336:459-465.

178. Dorros G, Jaff M, Mathiak L, et al: Four-Year follow-up of Palmaz-Schatz stent revascularization as treatment for atherosclerotic renal artery stenosis.  Circulation  1998; 98:642-647.

179. Isles CG, Robertson S, Hill D: Management of renovascular disease: A review of renal artery stenting in ten studies.  Q J Med  1999; 92:159-167.

180. Leertouwer TC, Gussenhoven EJ, Bosch JP, et al: Stent placement for renal arterial stenosis: Where do we stand? A meta-analysis.  Radiology  2000; 21:78-85.

181. Textor SC, McKusick M: Can renal artery stenting preserve renal function? An analysis of present data and issues for future investigation?.   In: Jaff MR, ed. Endovascular Therapy for Atherosclerotic Renal Artery Stenosis: Present and Future,  1st ed. Armonk, NY: Futura Publishing; 2001:121-132.

182. Bloch MJ, Pickering T: Renal vascular disease: Medical management, angioplasty and stenting.  Semin Nephrol  2000; 20:474-488.

183. Burket MW, Cooper CJ, Kennedy DJ, et al: Renal artery angioplasty and stent placement: Predictors of a favorable outcome.  Am Heart J  2000; 139:64-71.

184. Khosla S, White CJ, Collins TJ, et al: Effects of renal artery stent implantation in patients with renovascular hypertension presenting with unstable angina or congestive heart failure.  J Am Coll Cardiol  1997; 80:363-366.

185. Bloch MJ, Trost DW, Pickering TG, et al: Prevention of recurrent pulmonary edema in patients with bilateral renovascular disease through renal artery stent placement.  Am J Hypertens  1999; 12:1-7.

186. Ritz E, Mann JFE: Renal angioplasty for lowering blood pressure.  N Engl J Med  2000; 342:1042-1043.

187. Hansen KJ, Cherr GS, Craven TE, et al: Management of ischemic nephropathy: Dialysis-free survival after surgical repair.  J Vasc Surg  2000; 32:472-482.

188. Textor SC: Revascularization in atherosclerotic renal artery disease.  Kidney Int  1998; 53:799-811.

189. Harden PN, Macleod MJ, Rodger RS, et al: Effect of renal-artery stenting on progression of renovacular renal failure.  Lancet  1997; 349:1133-1136.

190. Bloch MJ, Trost DW, Sos TA: Type B aortic dissection complicating renal artery angioplasty and stent placement.  J Vasc Intervent Radiol  2001; 12:517-520.

191. Dejani H, Eisen TD, Finkelstein FO: Revascularization of renal artery stenosis in patients with renal insufficiency.  Am J Kidney Dis  2000; 36:752-758.

192. Topol EJ, Yadav JS: Recognition of the importance of embolization in atherosclerotic vascular disease.  Circulation  2000; 101:570-580.

193. Klahr S, Morrissey J: The role of vasoactive compounds, growth factors and cytokines in the progression of renal disease.  Kidney Int  2000; 57:S7-S14.

194. Watson PS, Hadjipetrou P, Cox SV, et al: Effect of renal artery stenting on renal function and size in patients with atherosclerotic renovascular disease.  Circulation  2001; 102:1671-1677.

195. Lamawansa MD, Bell R, Kumar A, House AK: Radiological predictors of response to renovascular reconstructive surgery.  Ann R Coll Surg Engl  1995; 77:337-341.

196. Beek FJ, Kaatee R, Beutler JJ, et al: Complications during renal artery stent placement for atherosclerotic ostial stenosis.  Cardiovasc Intervent Radiol  1997; 20:184-190.

197. Textor SC, McKusick MA: Renal artery stenosis.  Curr Treat Options Cardiovasc Med  2001; 3:187-194.

198. Taylor A, Sheppard D, Macleod MJ, et al: Renal artery stent placement in renal artery stenosis: Technical and early clinical results.  Clin Radiol  1997; 52:451-457.

199. Textor SC, Smith-Powell L: Post-stenotic arterial pressure, renal haemodynamics and sodium excretion during graded pressure reduction in conscious rats with one- and two-kidney coarctation hypertension.  J Hypertens  1988; 6:311-319.

200. Textor SC: Progressive hypertension in a patient with “incidental” renal artery stenosis.  Hypertension  2002; 40:595-600.

201. Libertino JA, Zinman L: Surgery for renovascular hypertension.   In: Breslin DL, Swinton NW, Libertino JA, Zinman L, ed. Renovascular Hypertension,  1st ed. Baltimore: Williams & Wilkins; 1982:166-212.

If you find an error or have any questions, please email us at Thank you!