Nephrotic-range proteinuria in patients with renovascular disease

Nephrotic-range Proteinuria in Patients with Renovascular Disease Jean-Michel Halimi, MD, PhD, Jean Ribstein, MD, Guilhem Du Cailar, MD, Albert Mimran, MD PURPOSE: Proteinuria is usually considered a manifestation of glomerular disease. We sought to describe the characteristics of patients with nephrotic-range proteinuria resulting from renovascular disease and to compare them with those of patients who had glomerulonephritis. SUBJECTS AND METHODS: We identified 14 patients with nephrotic-range proteinuria and renovascular disease and compared them with 14 patients who had nephrotic-range proteinuria and biopsy-proven glomerulonephritis, matched for sex, age, and glomerular filtration rate. RESULTS: Patients with renovascular disease were more likely to have known atherosclerotic vascular disease [13 of 14 (93%) vs 3 of 14 (21%), P ⬍0.0001] and were usually smokers [12 of 14 (85%) vs 3 of 14 (21%), P ⬍0.0001]. They also had a greater mean (⫾ SD) difference between the lengths of their kidneys (29 ⫾ 10 vs 5 ⫾ 5 mm, P ⬍0.001); greater systolic blood pressure (203 ⫾ 22 vs 174 ⫾ 25 mm Hg, P ⬍0.005), plasma renin

activity (17 ⫾ 19 vs 2 ⫾ 2 ng/mL/h, P ⫽ 0.005), and plasma aldosterone concentration (40 ⫾ 23 vs 11 ⫾ 10 ng/dL, P ⫽ 0.0001); and lower serum potassium levels (3.3 ⫾ 0.5 vs 3.8 ⫾ 0.5, P ⬍0.05). Effective renal plasma flow was lower (139 ⫾ 68 vs 307 ⫾ 185 mL/min/1.73 m3) and filtration fraction was markedly greater (0.28 ⫾ 0.04 vs 0.15 ⫾ 0.07, P ⫽ 0.0001) in the patients with renovascular disease. After the oral administration of captopril, blood pressure, effective renal plasma flow, and glomerular filtration rate decreased only among patients with renovascular disease. Of the 14 patients with renovascular disease, 13 had evidence of renal artery thrombosis seen at angiography; 2 patients required dialysis, and 3 others died during follow-up. CONCLUSION: Our findings suggest that the patients with nephrotic-range proteinuria resulting from renovascular disease have distinct characteristics and a poor prognosis. Am J Med. 2000;108:120 –126. 䉷2000 by Excerpta Medica, Inc.

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range proteinuria resulting from renovascular disease. A better understanding of these patients might help physicians distinguish them from patients with glomerulonephritis and therefore conduct a more appropriate workup, such as a renal angiogram, and treatment. We performed a comprehensive assessment of the biochemical, hormonal, and morphologic characteristics, and prognosis, in patients with nephrotic-range proteinuria associated with renovascular disease, as compared with well-matched patients who had biopsy-proven glomerulonephritis.

enovascular disease is a common cause of curable hypertension in the elderly and may be an important cause of reversible renal failure (1). Revascularization of ischemic kidneys may improve renal function in selected patients (2– 4). Renovascular disease may present with refractory hypertension, an abdominal bruit, peripheral vascular disease, unequal-sized kidneys, decreases in renal function after the use of an angiotensin-converting enzyme (ACE) inhibitor, or recurrent pulmonary edema (5– 8). Renovascular disease was not mentioned among the possible causes of the nephrotic syndrome in two recent reviews (9,10), although there are several case reports of patients with both conditions (11–14). This is perhaps because nephrotic-range proteinuria is considered a marker of glomerular disease, and the initial work-up of adult patients with nephrotic syndrome usually includes an assessment for systemic diseases (ie, diabetes mellitus, infections, systemic lupus erythematosus, and other forms of vasculitis), followed by percutaneous renal biopsy for histology and immunofluorescence (9). Little is known about the clinical presentation, natural history, and long-term prognosis of patients with nephrotic-

From the Department of Medicine and Hypertension, Hoˆpital Lapeyronie, Centre Hospitalier Universitaire, Montpellier, France. Requests for reprints should be addressed to Albert Mimran, MD, Department of Medicine and Hypertension, Hoˆpital Lapeyronie, Centre Hospitalier Universitaire, 34295 Montpellier cedex 5, France. Manuscript submitted March 4, 1999, and accepted in revised form September 13, 1999. 120

䉷2000 by Excerpta Medica, Inc. All rights reserved.

MATERIAL AND METHODS Patient Selection From January 1986 to December 1995, 20 patients with nephrotic-range proteinuria (defined as greater than 3.5 g per day) were admitted to our ward and found to have renal artery stenosis (defined as a reduction in internal diameter greater than 60%) or thrombosis (defined as a complete obstruction of the vessel without vascularization or function of the kidney) seen at renal arteriography. The initial work-up included laboratory parameters (blood glucose and hemoglobin levels, leukocyte and platelet counts, immunoelectrophoresis, serum levels of complement, rheumatoid factor, hepatitis B antigen, anti-nuclear antibodies, and cryoglobulins), throat culture, chest radiograph, and abdominal sonogram. Six patients were excluded from the analysis, 5 of whom had 0002-9343/00/$–see front matter PII S0002-9343(99)00411-8

Nephrotic-range Proteinuria in Patients with Renovascular Disease/Halimi et al

systemic diseases that could cause proteinuria [diabetes mellitus type II (n ⫽ 2), systemic lupus erythematosus (n ⫽ 1), chronic glomerulonephritis (n ⫽ 1), or chronic lymphocytic leukemia (n ⫽ 1)] and 1 of whom had already developed end-stage renal failure. All patients were hypertensive (blood pressure 160/95 mm Hg or higher) and were 50 years of age or older. At our institution, which is an internal medicine and hypertension center, renovascular disease was thus associated with 19% (14 of 74) of the patients with nephrotic-range proteinuria whom we cared for among nondiabetic patients 50 years of age or older. As controls, we selected 14 hypertensive patients who had nephrotic-range proteinuria resulting from biopsyproven glomerular disease, matched for sex, age (within 5 years), and glomerular filtration rate (within 5 mL/min/ 1.73 m2). The cause of the glomerular disease was membranous nephropathy (n ⫽ 4), undetermined chronic glomerulonephritis (n ⫽ 3), IgA nephropathy (n ⫽ 1), diffuse proliferative glomerulonephritis associated with cryoglobulinemia (n ⫽ 1), diffuse endocapillary proliferative glomerulonephritis (n ⫽ 1), membranoproliferative glomerulonephritis (n ⫽ 1), glomerulonephritis associated with sarcoidosis (n ⫽ 1), focal and segmental glomerulonephritis (n ⫽ 1), or minimal change disease associated with use of nonsteroidal anti-inflammatory drugs (n ⫽ 1). In addition, Doppler sonogram of the renal arteries [and helical computed tomographic (CT) scan in 1 patient] was performed in all of the control patients with glomerulonephritis; none had renal artery stenosis.

Measurements We obtained information about prior history of stroke, coronary artery disease, or peripheral vascular disease; smoking habits; dyslipidemia; duration of hypertension; and history of proteinuria and hematuria. Patients also underwent Doppler evaluation of peripheral arteries and electrocardiography, and renal length was measured by ultrasound. Renovascular disease was assessed by renal arteriogram in all 14 patients with renal artery disease. A biopsy of the affected kidney was performed in the 4 patients with renovascular disease who underwent surgery. Renal clearance studies were performed between 8 and 12 AM (15). After a priming dose of 99mTc-diethylenetriaminopentaacetic acid (for assessment of glomerular filtration rate) and 131I-orthoiodohippurate (for assessment of effective renal plasma flow), patients received an infusion of both substances dissolved in 5% dextrose at a constant rate of 4 mL/min. After a 60-minute equilibration period, three 30-minute urine collections were obtained by spontaneous voiding. At the end of each urine collection, patients drank a volume of water equal to that voided. A 50 mg captopril tablet was then given, and two 30-minute urine collections were obtained. Blood was

drawn at baseline and 45 minutes after the captopril dose, and at the midpoint of each urine collection period for the determination of hematocrit, serum electrolytes and creatinine level, plasma renin activity, and plasma aldosterone concentration. Blood pressure and heart rate were recorded with a semiautomatic device (Dynamap 845XT; Cre´teil, France). Serum creatinine, electrolytes, triglyceride, and total and high-density lipoprotein (HDL) cholesterol levels were determined by standard methods. Plasma renin activity, aldosterone concentration (both CEA-Sorin, Saclay, France), urinary albumin level (Pharmacia Diagnostics AB, Uppsala, Sweden), and urinary ␤2-microglobulin level (Immunotech, Marseille, France) excretion were measured by radioimmunoassay.

Follow-up Studies Ten of 14 patients with renovascular disease were treated medically, whereas the remaining 4 underwent surgery (unilateral nephrectomy in 2 patients and unilateral nephrectomy with contralateral vascular reconstructive surgery in 2 patients). Patients with glomerulonephritis were treated medically (13 patients received nonspecific treatment, and 1 patient was treated with a single course of glucocorticoids). At early [5 ⫾ 5 (mean ⫾ SD) months] and late (24 ⫾ 14 months) follow-up, blood pressure, serum creatinine level, and proteinuria were measured.

Statistical Analysis Comparisons of means were performed using paired or unpaired Student’s t test, as appropriate. Qualitative variables were compared using a chi-square test. We performed a logistic regression analysis to determine which factors were associated with a renovascular origin of nephrotic-range proteinuria. Potential variables, selected after univariate analysis, included smoking habits, history of atherosclerotic complications, systolic blood pressure, filtration fraction, plasma aldosterone concentration, and absolute difference in kidney size. We set the significance levels for variable entry and removal at 0.10. A P value ⬍0.05 was considered significant. Results for continuous variables are expressed as mean ⫾ SD.

RESULTS Comparison of the Patients with Renovascular Disease or Glomerular Disease The two groups of patients had similar age, duration of hypertension, and history of hypercholesterolemia (Table 1). However, patients with renovascular disease were more frequently smokers and more likely to have a history of atherosclerotic cardiovascular disease, including coronary artery disease and stroke. In contrast, a history of proteinuria and microscopic hematuria were February 2000

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Table 1. Baseline Characteristics of Patients with Nephrotic-range Proteinuria Who Had Renovascular or Glomerular Disease Renovascular Disease (n ⫽ 14)

Glomerular Disease (n ⫽ 14)

P Value

Number (percent) or Mean ⫾ SD Female sex Age (year) Body mass index (kg/m2) Duration of hypertension (months) Smoking (past or present) Alcohol (more than 80 g/day) Coronary artery disease Stroke Other atherosclerotic disease History of hypercholesterolemia History of proteinuria Microscopic hematuria (⫹⫹ or more) at presentation

3 (21) 66 ⫾ 10 22.7 ⫾ 3.2 123 ⫾ 123 12 (85) 5 (36) 9 (64) 4 (29) 13 (93) 4 (29) 2 (14) 2 (14)

more common at presentation among patients with glomerulonephritis. There were no differences between the two groups of patients in serum creatinine levels, 24-hour creatinine clearance, hematocrit, proteinuria, lipid profile, and urinary excretion of sodium, potassium, and urea nitrogen. Lower serum potassium levels and greater total protein

3 (21) 62 ⫾ 8 25.7 ⫾ 3.3 90 ⫾ 146 3 (21) 0 1 (7) 0 3 (21) 4 (29) 6 (43) 9 (64)

— 0.10 ⬍0.05 0.52 ⬍0.0005 0.01 ⬍0.001 ⬍0.05 0.0001 1.0 0.09 ⬍0.005

and serum albumin levels were observed in patients with renovascular disease (Table 2). In the patients with renovascular disease, the kidney length of the affected (or more affected) side was smaller than the contralateral kidney (76 ⫾ 12 vs 103 ⫾ 11 mm, P ⬍0.05). In the patients with glomerulonephritis, the kidney lengths were 103 ⫾ 10 mm in the right kidney and

Table 2. Biochemical Characteristics of Patients with Nephrotic-range Proteinuria Who Had Renovascular or Glomerular Disease Renovascular Disease (n ⫽ 14)

Glomerular Disease (n ⫽ 14)

P Value

Mean ⫾ SD Serum creatinine (␮mol/L) 24-hr creatinine clearance (mL/min/1.73 m2) Uric acid (␮mol/L) Serum sodium (mmol/L) Serum potassium (mmol/L) Total proteins (g/L) Serum albumin (g/L) Hematocrit (%) Total cholesterol (mg/dL) HDL-cholesterol (mg/dL) Triglycerides (mg/dL) 24-hour urine sodium excretion (mmol/day) 24-hr urine potassium excretion (mmol/day) 24-hr urine urea nitrogen (mmol/day) Proteinuria (g/day) Urinary albumin excretion (mg/day) ␤2-microglobulin (mg/day) HDL ⫽ high-density lipoprotein. 122

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198 ⫾ 86 38 ⫾ 19 422 ⫾ 107 138 ⫾ 2 3.3 ⫾ 0.5 70 ⫾ 3 32 ⫾ 7 40 ⫾ 5 310 ⫾ 82 42 ⫾ 13 170 ⫾ 70 95 ⫾ 39 52 ⫾ 16 251 ⫾ 91 6.2 ⫾ 3.7 1,812 ⫾ 1,182 16 ⫾ 15

145 ⫾ 55 51 ⫾ 23 417 ⫾ 189 139 ⫾ 3 3.8 ⫾ 0.5 55 ⫾ 12 26 ⫾ 8 42 ⫾ 6 340 ⫾ 120 52 ⫾ 19 230 ⫾ 33 101 ⫾ 64 53 ⫾ 20 234 ⫾ 100 8.0 ⫾ 4.4 1,893 ⫾ 1,567 11 ⫾ 18

0.06 0.09 0.55 0.49 ⬍0.05 ⬍0.01 ⬍0.05 0.29 0.45 0.10 0.51 0.76 0.80 0.64 0.25 0.88 0.41

Nephrotic-range Proteinuria in Patients with Renovascular Disease/Halimi et al

Table 3. Systemic and Renal Hemodynamic Measurements and Hormonal Values in Patients with Nephrotic-range Proteinuria Who Had Renovascular or Glomerular Disease Renovascular Disease (n ⫽ 14)

Glomerular Disease (n ⫽ 14)

P Value

Mean ⫾ SD Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) Glomerular filtration rate (mL/min/1.73 m2) Effective renal plasma flow (mL/min/1.73 m2) Filtration fraction Plasma renin activity (ng/mL/h) Plasma aldosterone concentration (ng/dL)

104 ⫾ 14 mm in the left kidney. The mean absolute difference in kidney length was greater in patients with renovascular disease than in those with glomerular disease (29 ⫾ 10 vs 5 ⫾ 5 mm, P ⬍0.001). The mean absolute difference in kidney length was 15 mm or greater in 13 of the 14 patients with renovascular disease, but in none of the 14 patients with glomerulonephritis. Among the 14 patients with renovascular disease, 11 had thrombosis of a renal artery (on the right in 8 patients), 2 had thrombosis of one renal artery with stenosis of the other renal artery, and 1 had stenosis of a single renal artery. Mean systolic blood pressure was greater in patients with renovascular disease (Table 3). Although baseline glomerular filtration rates were similar, patients with renovascular disease had lower effective renal plasma flows and greater filtration fractions. The filtration fraction was 0.23 or greater in 13 of the 14 patients with renovascular disease, but in only 2 of the 14 patients with glomerulonephritis. As expected, plasma renin activity and plasma aldosterone concentration were greater in patients with renovascular disease.

203 ⫾ 22 111 ⫾ 23 71 ⫾ 12 39 ⫾ 20 139 ⫾ 68 0.28 ⫾ 0.04 17 ⫾ 19 40 ⫾ 23

174 ⫾ 25 99 ⫾ 12 65 ⫾ 16 43 ⫾ 26 307 ⫾ 185 0.15 ⫾ 0.07 2⫾2 11 ⫾ 10

⬍0.005 0.09 0.28 0.65 ⬍0.005 0.0001 0.005 0.0001

Multivariate Analysis The absolute difference in kidney size was strongly associated with renovascular disease: it ranged from 14 to 48 mm in patients with renovascular disease to 0 to 14 mm in patients with glomerular disease. Thus, this variable could not be included in multivariate models (16). Among the remaining variables, only filtration fraction was independently associated with the odds of having renovascular disease (odds ratio ⫽ 1.7; 95% confidence interval, 1.1 to 2.6; P ⫽ 0.02).

Acute Response to Captopril After the administration of captopril (50 mg orally), systolic and diastolic blood pressure, effective renal plasma flow, glomerular filtration rate, and plasma aldosterone concentration decreased, and plasma renin activity increased in patients with renovascular disease (Table 4). These variables remained unchanged in patients with glomerular disease. Reversible anuria after captopril was observed in 2 patients with renovascular disease, both of whom had unilateral renal artery thrombosis.

Table 4. Absolute Changes in Systemic and Renal Hemodynamic Measurements and Hormonal Values after Administration of Captopril (50 mg) in Patients with Renovascular and Glomerular Disease

Change in . . .

Renovascular Disease (n ⫽ 14)

Glomerular Disease (n ⫽ 14)

P Value

Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) Glomerular filtration rate (mL/min/1.73 m2) Effective renal plasma flow (mL/min/1.73 m2) Filtration fraction Plasma renin activity (ng/mL/h) Plasma aldosterone concentration (ng/dL)

⫺31 ⫾ 18 ⫺21 ⫾ 12 ⫺3 ⫾ 4 ⫺12 ⫾ 13 ⫺32 ⫾ 46 ⫺0.04 ⫾ 0.04 ⫹11 ⫾ 16 ⫺16 ⫾ 13

⫺8 ⫾ 13 ⫺3 ⫾ 10 ⫹2 ⫾ 4 ⫹2 ⫾ 13 ⫹40 ⫾ 83 ⫺0.1 ⫾ 0.3 ⫹1 ⫾ 13 ⫺4 ⫾ 8

⬍0.001 ⬍0.0005 0.01 0.01 0.01 0.20 ⬍0.05 ⬍0.01

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Table 5. Early (5 ⫾ 5 months) and Late (24 ⫾ 14 months) follow-up in Patients with Renovascular and Glomerular Disease Early follow-up

Late follow-up

Renovascular Glomerular Renovascular Glomerular Disease Disease Disease Disease (n ⫽ 10) P Value (n ⫽ 11) P Value (n ⫽ 10) (n ⫽ 11) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Serum creatinine (␮mol/L) Proteinuria (g/day)

182 ⫾ 21

150 ⫾ 16

⬍0.001

180 ⫾ 26

138 ⫾ 20

⬍0.001

93 ⫾ 11

86 ⫾ 8

0.11

96 ⫾ 12

80 ⫾ 7

⬍0.005

235 ⫾ 109

131 ⫾ 55

0.01

295 ⫾ 140

154 ⫾ 136 ⬍0.05

1.6 ⫾ 0.5

3.1 ⫾ 2.5

0.09

2.8 ⫾ 3.4

2.5 ⫾ 3.5

Histologic Findings Four patients underwent surgery and had kidney biopsy specimens obtained (all from a kidney affected by a renal artery thrombosis). All showed evidence of benign nephroangiosclerosis. Glomerulosclerosis and tubular atrophy, along with some degree of interstitial fibrosis, were also seen, but there was no evidence of glomerulonephritis or fibrinoid necrosis. Immunofluorescence stains were negative.

Follow-up Studies The clinical course of the disease was less favorable in the patients with renovascular disease than in those with glomerular disease at early (5 ⫾ 5 months) and late (24 ⫾ 14 months) follow-up (Table 5). Blood pressure and serum creatinine levels remained greater in patients with renovascular disease than in those with glomerular disease, whereas no significant difference in proteinuria was detected. Postintervention proteinuria was measured in 3 of the 4 patients with renovascular disease who underwent revascularization. In all 3 patients, proteinuria decreased markedly (⫺58% in 1 patient, ⫺64% in another, and ⫺91% in the last patient, as compared with baseline values). Because of the small size of the sample, it was not possible to assess the effect of the different antihypertensive medications on renal function. In patients with renovascular disease, 3 died and 2 required dialysis. Of the 4 patients who underwent surgery, 1 died within a month after intervention of a mesenteric infarction, and 2 others developed end-stage renal disease. Of the 10 patients treated medically, 2 died (1 of a stroke within 3 months and 1 of a myocardial infarction within 4 years). Among patients with glomerular disease, 1 died of a gastrointestinal complication after steroid therapy was initiated, and 1 began dialysis within 18 months. Thus, 50% (7 of 14) of the patients with renovascular disease and nephrotic-range proteinuria, as compared with only 21% (3 of 14) of those with glomerular disease, had a twofold increase in serum creatinine 124

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level, developed end-stage renal disease, or died during follow-up (P ⬍0.05).

DISCUSSION Among patients with nephrotic-range proteinuria, those with renovascular disease have distinct characteristics compared with patients who have glomerulonephritis. Renovascular disease occurs in patients 50 years of age and older, is usually associated with atherosclerotic renal artery thrombosis, and has a poor prognosis. Although two recent reviews (9,10) failed to mention renovascular disease as a cause of nephrotic syndrome, more than 40 cases of massive proteinuria in patients with renovascular disease, usually resulting from atherosclerosis, have been reported (11–14,17–33), suggesting that this cause of nephrotic syndrome may not be rare, especially in the elderly. Thrombosis was usually the cause (17–19,33), but stenosis of a renal artery has also been observed (20). Most patients with renovascular disease were smokers or former smokers, and they frequently had evidence of atherosclerosis, including coronary artery, peripheral, and cerebrovascular disease. Indeed, renovascular disease was seen in 15% of patients undergoing cardiac catheterization (34) and in 37% of patients with peripheral vascular disease (6). In addition, our patients with renovascular disease were severely hypertensive and had a substantial difference in the length of their kidneys. They also had low serum potassium levels despite mild-to-moderate renal failure, normal total protein levels despite massive proteinuria, and surprisingly high filtration fractions (35). Blood pressure and renal function appeared to be renin dependent only in patients with renovascular disease. Taken together, these characteristics can help physicians to identify patients with nephrotic-range proteinuria who may have renovascular disease, and in whom screening tests for renovascular disease or renal angiography would be appropriate (1). The 6 patients who were excluded from the analysis because of systemic disease or

Nephrotic-range Proteinuria in Patients with Renovascular Disease/Halimi et al

end-stage renal disease had similar clinical characteristics: all of them were older than 50 years of age, 4 were smokers, and 5 had widespread atherosclerosis. The cause of the excessive proteinuria is probably the renal artery lesion, because reversal of the nephrotic syndrome has been seen after nephrectomy (11,17,18,22), revascularization by surgery (12,18,22), percutaneous angioplasty (11,21), or stenting (32). The gradual, rather than sudden, disappearance of proteinuria after unilateral nephrectomy points to a predominant role of the kidney that is contralateral to the main lesion as the origin of protein losses (11,17,22). One of the limitations of our investigation is that percutaneous biopsy of the kidney was not performed in 10 of the 14 patients because of severe hypertension associated with known renal artery disease. It is possible that some of these patients had a superimposed renal disease, such as focal and segmental glomerulosclerosis or undiagnosed cholesterol emboli (14). Even in the 4 patients who had a renal biopsy, focal and segmental glomerulosclerosis may have been present in the contralateral kidney, as recently reported (11,12,25–28). This type of glomerulonephritis has also been reported in patients with other conditions, including massive obesity or sickle cell disease. In a recent study of 24 patients who were 50 years or older and who had focal segmental glomerulosclerosis, 8 had renovascular disease (29). However, we found benign nephrosclerosis in the 4 patients who had a renal biopsy, as reported in some patients with nephroticrange proteinuria and renovascular disease (17,18,24), even when the kidney contralateral to a renal artery occlusion was examined (17). No evidence of glomerulonephritis or atheroembolic disease (13,14) was detected. The mechanism of the massive proteinuria in patients with renovascular disease is not clear. However, the effects of angiotensin II on the glomerular permeability, combined with severe hypertension, are probably involved. Infusion of angiotensin II can cause proteinuria in animals (36,37). Several authors have reported a decrease in proteinuria after the use of an ACE inhibitor, but not other antihypertensive medications, in patients with renovascular disease and massive proteinuria (20). It is also possible that kidneys with renal artery thrombosis are more ischemic, and therefore release much more renin, than kidneys with renal artery stenosis. This would lead to greater plasma levels of angiotensin II—and greater blood pressure—and therefore more proteinuria. This may explain why renal artery thrombosis was common among patients with massive proteinuria in a previous study (21). In the present study, nephrotic syndrome associated with renovascular disease carried a poor prognosis for kidney function and for patient survival. Three of the 14 patients with renovascular disease died within 2 years. Excessive albuminuria has also been associated with in-

creased cardiovascular morbidity in diabetic (38) and nondiabetic (39) patients; this may also be true for patients with renovascular disease. Furthermore, 4 patients with renovascular disease began dialysis or had a twofold increase in their serum creatinine level during follow-up, which is associated with a poor renal outcome (40). Moderate-to-severe hypertension at presentation, which was associated with high plasma renin and aldosterone levels and was sensitive to acute blockade of the reninangiotensin system, appeared to be resistant to treatment. Whether further lowering of blood pressure would preserve renal function remains to be determined (41). We did not address the problem of the optimal treatment for renal artery disease associated with heavy proteinuria. It was recently suggested that preoperative albuminuria was an important predictor of renal function after intervention in patients with atherosclerotic renovascular disease (42). In a study that included patients with a wide range of urinary albumin excretion rates, none of those with preintervention macroalbuminuria had improved renal function after surgery or angioplasty (42). Interestingly, an inverse relation between urinary albumin excretion and subsequent renal function was also observed in diabetic (43) as well as nondiabetic (44) nephropathy. We conclude that renovascular disease is a common cause of nephrotic range proteinuria among patients 50 years of age and older, especially in the presence of known atherosclerotic vascular disease. A difference in kidney size of 14 mm or more is strongly associated with renovascular disease.

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