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Diagnosis and Management of Renal Vascular Occlusive Disease
Historical Background
Renovascular Hypertension
In 1934, Goldblatt demonstrated that constriction of the renal artery (renal artery stenosis [RAS]) produced atrophy of the kidney and hypertension in dogs. As a clinical pathologist, Goldblatt noticed that extensive vascular disease was often present at autopsy in patients with hypertension and was frequently severe in the renal arteries. In his own words: “Contrary, therefore, to what I had been taught, I began to suspect that the vascular disease comes first and, when it involves the kidneys, the resultant impairment of the renal circulation probably, in some way, causes elevation of the blood pressure.” Goldblatt's elegant experiments introduced a new era by demonstrating that renal artery stenosis could produce a form of hypertension that may be corrected by nephrectomy.
In 1938, Leadbetter and Burkland described the first successful treatment of this correctable form of hypertension. They cured a 5-year-old child with severe hypertension by removal of an ischemic ectopic kidney. The photomicrographs published from that renal artery specimen were the first documentation of a renovascular origin of hypertension. In subsequent years, numerous patients were treated by nephrectomy, based on the findings of hypertension and a small kidney on intravenous pyelogram. Smith reviewed 575 such cases in 1956 and found that only 26% of patients were cured of hypertension by nephrectomy. This led him to suggest that nephrectomy should be limited to strictly urologic indications.
In 1954, Freeman performed an aortic and bilateral renal artery thromboendarterectomy in a hypertensive patient, which resulted in resolution of the hypertension. This first cure of hypertension by renal revascularization, in combination with the widespread use of aortography, was followed by enthusiastic reports describing blood pressure benefit after renal revascularization. Nevertheless, by 1960 it became apparent that renal revascularization in hypertensive patients with renal artery stenosis was associated with a beneficial blood pressure response in fewer than half of individuals. These clinical results fostered general pessimism regarding the value of operative renal artery reconstruction for the treatment of hypertension and have not been altered with the introduction of endovascular correction of renal artery stenosis.
Contemporary operative management of renovascular hypertension (RVH) began with the introduction of tests of functional significance. Split renal function by Howard and Connor, Stamey and associates, Page and Helmes, and others identified the role of the renin-angiotensin system in blood pressure control, thus describing the pathophysiology of RVH. After accurate assays for plasma renin activity became available, physicians could accurately predict which renal artery lesion was producing RVH.
Ischemic Nephropathy
Until the current era, the pathophysiology and management of renovascular disease (RVD) focused solely on hypertension; however, contemporary reports have emphasized the relationship between RVD and renal insufficiency.
The term ischemic nephropathy has been adopted to recognize this relationship. By definition, ischemic nephropathy describes the presence of severe occlusive disease of the extraparenchymal renal artery in combination with excretory renal insufficiency. In 1962, Morris and associates reported on eight azotemic patients with global renal ischemia who experienced improved blood pressure and renal function after renal revascularization. Novick, Libertino, and Dean and their groups found a similar beneficial functional response when bilateral renal lesions were corrected in azotemic patients. These early reports and the reports that followed suggested that ischemic nephropathy could mediate renal insufficiency that was rapidly progressive, contributing to end-stage renal disease. In this chapter, diagnostic studies and methods of management for RVD, RVH, and ischemic nephropathy are reviewed.
Pathology
The majority of interventions performed for RVD are due to atherosclerosis and fibromuscular dysplasia; however, renal artery aneurysm (RAA), aortic dissection, and traumatic injury have all been implicated in RVD. Atherosclerosis of the renal artery is not unique. The pathogenesis parallels atherosclerotic lesions elsewhere, with cholesterol-rich lipid deposition and intimal thickening. Later, this atheroma may undergo central degeneration and even calcification. Atheromas typically occur at or near the renal artery ostium ( Fig. 26.1 ). This ostial lesion reflects aortic atheroma that spills over into the renal artery orifice. Most commonly, these lesions are found on the left and account for approximately 70% of patients with RVH. Like atherosclerosis elsewhere, angiographic findings that are pathognomonic for a hemodynamically significant lesion include poststenotic dilatation and the presence of collateral vessels. Often there is simultaneous angiographic involvement of the abdominal aorta and its bifurcation. Most commonly, the renal artery lesion is only one manifestation of generalized atherosclerosis.
Fibromuscular dysplasia of the renal artery encompasses a variety of hyperplastic and fibrosing lesions of the intima, media, or adventitia. They are most frequently seen in young women. This is of no predictive value, however, because fibrodysplastic lesions can be found at any age and in either sex. Medial fibroplasia is the most common lesion, accounting for 85% of dysplastic lesions. The right renal artery is more commonly affected than the left, but bilateral involvement is present in the vast majority of patients. The basic cause of medial fibroplasia remains unknown, but its frequent occurrence in multiple arteries suggests a systemic arteriopathy. It often involves long segments of the renal artery and its branches, producing a characteristic “string-of-beads” appearance angiographically. Embryologic variations, hormonal influences, autoimmune mechanisms, and even recurrent trauma during youth have been suggested as possible causative factors. None of these explanations is adequate, however, and the supporting evidence remains mostly conjectural.
Based on the angiographic appearance of fibromuscular disease, several methods of categorization have been suggested. To establish a uniform terminology, Harrison and McCormack combined their experience and developed a classification of these lesions correlating the histologic and angiographic appearance. Depending on the layer predominantly involved, lesions may be categorized as intimal, medial, or adventitial ( Fig. 26.2 ). Clinically, however, it may be difficult to segregate individual lesions into one of these categories. The most common variety of fibromuscular dysplasia is medial fibroplasia (85%) with mural microaneurysms ( Fig. 26.3 ). Less commonly, the dysplastic lesions may appear as a single mural stenosis (see Fig. 26.2 ), which is consistent with intimal fibroplasia (5%). Perimedial dysplasia (10%) demonstrates the same gender predilection and arterial septa as medial fibroplasia; however, mural microaneurysms are absent.
With the widespread acceptance of thoracic endografting as appropriate therapy for type B aortic dissection (TBAD), surgeons are more frequently being involved in the care of these patients. Dissection can result in obstruction of the renal ostia via a dynamic or static obstruction. Dynamic obstruction occurs when the aortic flap temporarily occludes the renal ostia due to alterations in lumen pressure during the cardiac cycle. Conversely, a static obstruction can occur when the dissection flap carries out into the main renal vessel proper. Both pathologies can lead to acute renal failure and worsening of hypertensive control.
RAA has been implicated in RVH in the past. In fact, the most common reason for repair of symptomatic RAA in the Society for Vascular Surgery's Low Frequency Disease Consortium's evaluation of RAA was hypertension. No obvious causal effect has been linked between RVH and RAA; however, embolization and artery kinking are posited to play a role.
Pathophysiology
The kidney, because of its influence on circulating plasma volume and on the modulation of vasomotor tone, is a dominant site of blood pressure regulation. To examine the pathophysiology of RVH, a review of the normal homeostatic activities of the kidney in blood pressure regulation is appropriate.
Renin-Angiotensin-Aldosterone System
The renin-angiotensin-aldosterone system is a complex feedback mechanism that normally acts to maintain a stable blood pressure and blood volume under varying conditions. Richly innervated modified smooth muscle cells located along the afferent arterioles in juxtaposition to the renal glomerulus (juxtaglomerular apparatus) are sensitive monitors of perfusion pressure. Diminished perfusion pressure stimulates these cells to release renin, a proteolytic enzyme. Renin interacts with angiotensinogen, an α-globulin manufactured in the liver, to produce angiotensin I. Angiotensin I, an inactive and labile decapeptide, is converted to the potent vasoconstrictor angiotensin II by angiotensin-converting enzyme, which is abundant in the lungs and other tissues. In addition to its potent vasoconstrictor properties, angiotensin II, through its conversion to angiotensin III, also increases blood pressure by stimulating aldosterone release from the zona glomerulosa of the adrenal cortex. This, in turn, increases plasma volume by increasing sodium and water resorption in the renal tubules. Through these actions of angiotensin II and III, blood pressure, plasma volume, and plasma sodium content are increased. In addition, the adjacent cells of the distal convoluted tubule (macula densa) may play a role by acting as sensors of sodium concentration in the distal tubules and exerting a positive feedback mechanism on renin release. As these mechanisms increase perfusion pressure in the juxtaglomerular cells, further renin production and release are suppressed, and blood pressure is modulated within a narrow range.
Goldblatt Kidneys: One-Clip Two-Kidney and One-Clip One-Kidney Hypertension
Potentially, two forms of hypertension may be produced by hemodynamically significant RVD: renin-dependent hypertension and volume-dependent hypertension. In the original Goldblatt experiments, renovascular insufficiency was induced through two methods. The first mimicked unilateral RAS by creating a stenosis in one kidney and leaving the other kidney normal. Decreased perfusion activates the renin-angiotensin-aldosterone axis and the angiotensin II–mediated increase in peripheral resistance and blood pressure as well as the aldosterone-mediated volume expansion. When the contralateral renal artery and kidney are normal, the feedback mechanisms in the normal kidney produce a natriuresis and compensatory reduction in circulating plasma volume. In this scheme, an angiotensin II–vasoconstrictive source of hypertension is created.
In contrast, when the contralateral renal artery or kidney is also diseased as replicated by removing one kidney and creating a stenosis in the remaining one, this compensatory diuresis is lost and volume expansion occurs, producing an angiotensin-aldosterone–mediated, volume-dependent hypertension. Modification of renal perfusion by renal revascularization can effectively diminish or abolish the underlying mechanism producing either of these varieties of RVH.
It would be simplistic to think that these factors provide a complete description of all the mechanisms activated by the onset of renal hypoperfusion. In the clinical context, however, the pathophysiology of renal hypertension can be characterized by a sustained elevation in peripheral vascular resistance that is mediated by the activation of both the renin-angiotensin and the sympathetic nervous systems and their concomitant contribution to vascular endothelial dysfunction. Although the contribution of increased renin secretion and angiotensin II production is a sustaining stimulus for the hemodynamic and hormonal response, the actions of angiotensin II on the vascular endothelium may play the biggest role in sustained blood pressure elevation. Both the renin-angiotensin and the sympathetic nervous systems appear to act in concert to regulate the integrated hormonal response that operates to regulate sodium and potassium balance and arterial pressure.
It is well accepted that RVH is caused by increased activity of the renin-angiotensin system produced initially by hypersecretion of renin from the juxtaglomerular apparatus of the ischemic kidney. However, as hypertension evolves into a chronic stage, adaptive cardiovascular changes may become an essential mechanism for the maintenance of elevated blood pressure and peripheral vascular resistance. The effect of hypertension on precapillary resistant vessels triggers a myogenic response that is evidenced by the combination of hypertrophy and hyperplasia of the vascular smooth muscle. This augments vascular reactivity to pressor agents. There is also evidence that renin may be trapped in structural elements of the vascular wall. Local production of angiotensin II by tissue renin-angiotensin systems may contribute to the remodeling of resistance vessels. Angiotensin-converting enzyme exists in the plasma membrane of vascular endothelial and smooth muscle cells. Thus the necessary components for the production of angiotensin II may be found in both vascular and cardiac tissue. In the chronic phases of the hypertension process, hypersecretion of renin from the ischemic kidney may be less important than increased production of vascular angiotensin II as the mechanism that sustains the elevation in arterial pressure.
Ischemic Nephropathy
The pathophysiology of renovascular renal insufficiency (i.e., ischemic nephropathy) is incompletely understood. The earliest clinical reports suggested a “glomerular filtration failure” based on hypoperfusion of the kidney, but the molecular basis for ischemic nephropathy is poorly characterized. Like RVH, the renin-angiotensin system likely contributes to ischemic nephropathy through its paracrine effects—intrarenal angiotensin peptides increase efferent arteriolar tone. In the presence of a pressure-reducing renal artery lesion, this paracrine effect increases glomerular capillary pressure to support glomerular filtration. In contrast to these positive effects, angiotensin peptides have also been shown to promote tubulointerstitial injury in the presence of a renal artery lesion. This observation is supported by the induction of transforming growth factor-β and interstitial platelet-derived growth factor-β, which are associated with increased extracellular matrix and interstitial fibrosis. Disruption of the tubular cell cytoskeleton and the loss of tubular membrane polarity have also been suggested. Besides these potentially reversible contributors to excretory renal insufficiency, an atherosclerotic renovascular lesion can also be a source of atheroemboli. The inability to distinguish potentially reversible ischemic nephropathy from irreversible renal parenchymal disease has enormous clinical importance. Recovery of renal function after renovascular intervention has proved to be the strongest predictor of dialysis-free survival.
Prevalence of Renovascular Hypertension and Ischemic Nephropathy
RVH is generally thought to account for 5% to 10% of the hypertensive population. Tucker suggested an even lower prevalence. Likewise, Shapiro and colleagues suggested that the identification and successful operative treatment of RVH in patients older than 50 years are so unlikely that diagnostic investigation for a correctable cause in that group should be undertaken only when hypertension is severe and uncontrollable. Estimates of the prevalence of hypertension in the United States from all causes range from 60 to 80 million people, and hypertension may be present in 25% to 30% of the adult population.
The actual contribution of RVD to hypertension or renal insufficiency has been uncertain because the population-based prevalence of RVD was unknown. Past prevalence estimates of RVD were extrapolated from case series, autopsy examinations, or angiography obtained to evaluate diseases of the aorta or peripheral circulation.
Recently, the population-based prevalence of RVD has been estimated for participants in the Cardiovascular Health Study (CHS) sponsored by the National Heart, Lung, and Blood Institute. The CHS is a longitudinal, prospective, population-based study of coronary heart disease and stroke in elderly men and women. This study showed that hemodynamically significant RVD was present in 6.8% of this elderly, free-living cohort. Multivariate analysis demonstrated that increasing participant age ( P =.028; odds ratio [OR], 1.44; 95% confidence interval [CI], 1.03 to 1.73) and increasing systolic blood pressure at baseline ( P = .007; OR, 1.44; 95% CI, 1.10 to 1.87) were significantly and independently associated with the presence of RVD. Moreover, renal insufficiency was associated with RVD, but only when renal artery disease coexisted with significant hypertension. Contrary to historical assumptions, RVD demonstrated no significant relationships with gender or ethnicity.
As in the general population, the incidence of RVH is undoubtedly low when all patients with hypertension are considered. Because RVH tends to produce relatively severe hypertension, its prevalence in the large population of mildly hypertensive patients (diastolic blood pressure <105 mm Hg) is probably negligible. In contrast, however, it is a frequent cause of hypertension in the smaller group of patients with severe hypertension. In the Wake Forest experience, the presence of severe hypertension at the two extremes of life carried the highest probability of its being RVH. Their review of the causes of hypertension in 74 children admitted for diagnostic evaluation over a 5-year period showed that 78% of the children younger than 5 years had a correctable renin-dependent cause. In 1996, the same group screened 629 hypertensive adults older than 50 years for RVD ( Table 26.1 ). Overall, 25% of subjects demonstrated significant renal artery disease. However, 52% of those older than 60 years whose diastolic pressure was greater than 110 mm Hg had significant renal artery stenosis or occlusion. When serum creatinine was elevated in conjunction with this age and blood pressure, 71% of subjects demonstrated hemodynamically significant RVD.
TABLE 26.1
Results of Renal Duplex Sonography in 629 New Hypertensive Adults
From Deitch JS, Hansen KJ, Craven TE, et al: Renal artery repair in African-Americans. J Vasc Surg 26:465–473, 1997.
| Renal Vascular Disease | No. Present (%) | Absent (%) | Total (%) |
|---|---|---|---|
| All patients | 154 (24) | 475 (76) | 629 (100) |
| <60 years + DBP ≥110 mm Hg | 98 (52) | 91 (48) | 189 (30) |
| DBP ≥110 mm Hg + SCr ≥2.0 mg/dL | 53 (71) | 22 (29) | 75 (12) |
DBP, Diastolic blood pressure; SCr, serum creatinine.
The presence of RAS itself is fairly common in a number of disease states such as peripheral vascular disease, congestive heart failure, and abdominal aortic aneurysm. However, the presence of hemodynamically significant RAS leading to RVD is more dramatic in presentation than essential hypertension and can be predicted by thorough patient history.
Characteristics of Renovascular Hypertension
Because of the small proportion of RVH among the entire hypertensive population, many reports have focused on the value of demographic factors, physical findings, and screening tests to discriminate between essential hypertension and RVH. Most frequently cited as discriminate factors suggesting the presence of RVH and a need for further study are recent onset of hypertension, young age, lack of family history of hypertension, and presence of an abdominal bruit. The most complete study comparing the clinical characteristics of patients with RVH to those with essential hypertension was the Cooperative Study of Renovascular Hypertension. In that study, the prevalence of certain clinical characteristics in 339 patients with essential hypertension was compared with their prevalence in 175 patients with RVH secondary to atherosclerotic lesions (91 patients) and fibromuscular dysplasia (84 patients). Although the prevalence of several characteristics was significantly different in RVH compared with essential hypertension, none of the characteristics had sufficient discriminant value to be used to exclude patients from further diagnostic investigation for RVH. Certainly, the finding of an epigastric bruit in a young white female with malignant hypertension is strongly suggestive of a renovascular origin of the hypertension. The absence of such criteria, however, does not exclude the presence of RVH, and such criteria should not be used to eliminate patients from further diagnostic study.
Therefore, the decision to undertake diagnostic study should be based on the severity of hypertension. Mild hypertension has a minimal chance of being renovascular in origin. In contrast, the more severe the hypertension, the higher the probability that it is from a correctable cause. With this in mind, we evaluate all adult patients with diastolic blood pressures greater than 105 mm Hg who would be considered for intervention to evaluate for a renovascular lesion as a correctable origin of hypertension. Children are evaluated when their blood pressure exceeds the 95th percentile for height and age. Other hallmarks for RVH include sudden worsening of long-standing hypertension, acute worsening of chronic kidney disease in the absence of other inciting factors, acute pulmonary edema, and acute renal dysfunction when starting angiotensin-moderating medications.
Natural History of Atherosclerotic Renovascular Disease
Historically, RVH was thought to mimic other atherosclerotic processes and progression to occlusion was considered in decision for intervention. However, this has not been borne out in the literature. A prospective study by Pillay and colleagues described the change in blood pressure and serum creatinine among patients with atherosclerotic RVD. Ninety-eight patients in this multicenter, nonrandomized observational study were noted to have greater than 50% renal artery stenosis during aortography to evaluate peripheral vascular disease. On a minimum duration of 2 years of follow-up, 64 patients with unilateral renal stenosis and 21 patients with bilateral disease were managed medically. Twelve patients with bilateral disease underwent percutaneous intervention or open operative repair. The overall 2-year estimated mortality was 32%. Mortality was equivalent for patients treated with renal artery intervention and for those treated medically. There was no change in median blood pressure, number of anti-hypertensives, or change in renal size in follow-up among survivors. A small but statistically significant increase in serum creatinine was observed in patients who underwent renal artery intervention. Patients with bilateral RVD treated medically had stable serum creatinine over 2-year follow-up. This study lacked a specific measure of glomerular filtration; however, it demonstrated stable length and stable serum creatinine with controlled hypertension in medically managed patients who had anatomic disease but no clinical indication for RVH.
A series of consecutive reports described prospective duplex studies performed at the University of Washington. These authors first reported on serial duplex examinations performed on 80 patients with hypertension. Renal arteries were classified according to four categories: normal, stenosis less than 60%, stenosis greater than 60%, or renal artery occlusion. The rate of progression to greater than 60% stenosis during 3 years of follow-up was 8% for renal arteries that were initially classified as normal and 43% initially classified as having less than 60% diameter-reducing stenosis. Incidental renal artery occlusions were observed only in arteries previously categorized as having 60% diameter-reducing stenosis. The 3-year risk for occlusion among the entire group was 7%. Lesion progression was associated with increasing patient age, increasing systolic blood pressure, smoking, female sex, and poorly controlled hypertension.
Davis and colleagues reported on 119 participants in the Cardiovascular Health Study with 235 kidneys followed over an 8-year period. None of these subjects demonstrated severe hypertension. Controlling for within-subject correlation, the overall estimated change in RVD among all 235 kidneys was 14% (95% CI, 9.2% to 21.4%) with hemodynamically significant RVD in 4% (95% CI, 1.9% to 8.2%). No hemodynamically significant stenosis at baseline progressed to renal artery occlusion on follow-up. Increased blood pressure and decrease in renal length were not associated with RVD at baseline examination. These findings cast doubt on the value of renal artery intervention in the absence of RVH or renal insufficiency.
The most difficult decision in evaluation of RAS in patients with hypertension is parsing out essential hypertension from true RVH. As demonstrated above, the presence of RAS and hypertension together is of infrequent clinical significance. However, the systemic cardiovascular effects of true RVH, such as congestive heart failure, renal insufficiency, severe hypertension, and cerebrovascular accident, result in a significant increase in the likelihood of early cardiac death in patients with true RVH. Thus, in patients with the spectrum of symptoms that are of concern for RVH, appropriate workup is important.
Diagnostic Evaluation
The general evaluation of all hypertensive patients should include a careful medical history, physical examination, serum electrolyte and creatinine determination, and electrocardiography. Electrocardiography is important to gauge the extent of secondary myocardial hypertrophy or associated ischemic heart disease. Serum electrolyte and serial serum potassium determinations can effectively exclude patients with primary aldosteronism if potassium levels are greater than 3.0 mg/dL. One must remember, however, that hypokalemia is often due to salt-depleting diets and previous diuretic therapy. Finally, estimation of renal function is mandatory. Preexisting renal disease may reduce renal function and cause hypertension. Conversely, renal dysfunction may reflect ischemic nephropathy.
Screening Studies
Identification of a noninvasive screening test that accurately identifies all patients with RVD that may warrant interventional management remains an elusive goal. Prior methods such as peripheral plasma renin activity, rapid-sequence intravenous pyelography, and saralasin infusion have been abandoned. Screening studies are basically of two types: functional studies or anatomic studies. Of the functional type, isotope renography continues to be proposed as a valuable screening test, but the methods used are continually modified with the hope of improving its sensitivity and specificity. The newest versions of isotope renography consist of renal scans performed before and after the administration of an inhibitor to angiotensin I–converting enzyme. Of these, only captopril renal scanning has gained widespread use and acceptance as a screening tool. Anatomic screening studies include renal duplex sonography and arteriography.
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