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Membranous glomerulopathy associated with captopril therapy
Membranous Glomerulopathy Associated with Captopril Therapy
STEPHEN C. TEXTOR, M.D. GORDON N. GEPHARDT, M.D. EMMANUEL L. BRAVO, M.D. ROBERT
C. TARAZI,
M.D.
FETNAT
M. FOUAD,
M.D.
RAYMOND JAMES
TUBBS,
D.O.
T. McMAHON,
Ph.D.
Clevelend, Ohio
From the Research Division and the Department of Pathology, The Cleveland Clink Foundation. Cleveland, Ohio. Requests for reprints should be addressed to Cr. Stephen C. Textor, Research Division, The Cleveland Clinic Foundation. 9500 EudMAvenue, Clevebxl, Ohio 44106. Manusaipt acceptedMay 12, 1982.
Two cases of nephrotic syndrome and biopsy-proved membranous glomerulopathy (membranous glomerulonephritls) were encountered during captoprii treatment of 53 hypertensive subjects in our instltution. Both patients had impaired renal function before treatment and were treated with 600 mg per day. Discontinuation of captoprii led to transient partial remission of proteinuria but was followed by a recurrent, fluctuating course over one year later. Repeat biopsies, eight and 12 months after discontinuation of the drug, demonstrated persistent subepftheliai deposits in the glomeruiar basement membrane. There has been a decline in giomeruiar fiitration rate since dlscontinuatlon of the drug, apparently due to arterionephragcierosts. These stud& suggest that gtomeruiar basement membrane deposits in captopril-associated membranous glomeruionefHtis are not readity revef-sibk and may be associated with persistent proteinuria, contrary to some previous reports. inhibition of angiotensin-converting enzyme is an effective therapy for the treatment of hypertension and congestive heart failure [l-3]. In conditions with increased activity of the renin-angiotensin system, such as malignant hypertension caused by scleroderma involving the kidney, this form of therapy may have unique applications [4]. At present, captopril (Capote@, Squibb Pharmaceutical Company) is the only orally active compound evaluated clinically and has been associated with relatively few adverse effects. One complication has been the development of proteinuria and the nephrotic syndrome in 1 to 3 percent of patients [ 5,6]. In some of these cases, renal biopsies have shown changes of membranous glomerulonephritis, characterized by subepithelial glomerular basement membrane deposits. The significance of proteinuria and anatomic changes observed in renal biopsies of captoprll-treated patients has been disputed. Some investigators reported proteinuria as a transient occurrence that was not generally associated with progressive renal failure and occasionally regressed without discontinuation of the drug [ 51. Other investigators suggested that pathologic changes in the kidney during captopril administration were more ominous and might appear without proteinuia, and they recommended renal biopsy as a routine procedure before institution of treatment with captopril [6]. In most cases of proteinuria that developed during captopril therapy, discontinuation of the drug led to its resolution. This is not universally true, however, and there has been only one report of a repeat biopsy in captoprii-treated patients with nephrotic proteinuria and membranous glomerulonephritis to document the subsequent course of basement membrane deposits [7]. The purpose of this report is to
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hematoxylin and eosin, Masson trichrome, periodic-acid Schiff, and Jones’ silver stain. The second piece was minced and fixed in 3 percent cold glutaraldehyde, postfixed in osmium tetroxide, dehydrated in graded alcohols, and embedded in Epon@. Ultrathin sections were then stained with lead citrate and uranyl acetate for electron microscopy. The third piece was frozen in liquid nitrogen, 2 to 4 mm sections cut on a Lipshaw cryostat, and immunofluorescence and immunoperoxidase techniques performed to detect IgA, IgG, IgM, and C3, as previously described [6].
CASE REPORTS Patient 1.
lgure 1. Patient 1. Blood pressure, serum creatinine levels, and urine protein excretion measurements are shown before, during, and after captopril therapy. Times of renal biopsy are indicated (6x). Deterioration of renal function appeared after discontinuation of captopril.
present the clinical course and repeat biopsy findings in two patients in whom the nephrotic syndrome and membranous glomerulonephritis developed during captopril therapy. METHODS Nephrotic range proteinuria (more than 3 g per day) developed in only two of 53 hypertensive patients treated with captopril between 1976 and 1979. Before initiation of therapy, all procedures were explained and the investigational nature of therapy was described in order to obtain informed consent, as approved by the Institutional Review Committee of the Cleveland Clinic. During these studies, urine collections for protein excretion were obtained daily in the hospital and at least once a month thereafter. Both patients had impaired renal function before captopril therapy. Neither patient previously had nephrotic range proteinuria nor any condition associated with membranous glomerulonephritis, including systemic lupus erythematosus, syphilis, hepatitis B, neoplasia, or exposure to penicillamine, gold, or mercury compounds. Two other hypertensive patients had mild proteinurla (I to 1.5 g per day) before therapy, which diminished in both during subsequent evaluation. Abnormal protein excretion (more than 250 mg per day) did not develop in any patients receiving captopril for congestive heart failure in our se-
ries. Each renal biopsy was divided into three parts. The first was fixed In modified Zenker’s solution and stained with
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This patient was a 61-yearaId Caucasian woman
in good general health with no known renal disease or hypertension until March 1978, when she presented with malignant hypertension characterized by visual loss, transient leg weakness, and retinal hemorrhages and exudates. Blood pressure was 2701140 mm Hg. The serum creatinine level ranged between 2.0 and 3.9 mg/dl. Creatinine clearance was 20 ml per minute (uncorrected). Twenty-four-hour urine protein excretion measurements were 1.1 to 1.9 g. Renal arteriography revealed arteriolar changes consistent with nephrosclerosis and bilateral diminution of renal perfusion. Plasma renin activity was 42 ng/ml per hour (normal = 0.4 to 2.6 ng/ml per hour on 100 mEq sodium intake). Hypertension was poorly controlled with methyldopa, hydralazine, ‘and diuretic agents. After obtaining informed consent, captopril was administered in doses of 400 to 600 mg per day. Beginning April 3, 1978, blood pressure decreased to 140160 mm Hg and urine protein excretion to less than 100 mg per 24 hours (Figure 1). The serum creatinine level remained between 2.9 and 3.4 mg/dl. Neurologic findings and retinal changes were reversed over several weeks. After six months of therapy, blood pressure remained well controlled with captopril and furosemide (blood pressure 140182 mm Hg), but the urine protein level increased to 2.4 g per 24 hours and subsequently ranged between 4.0 and 6.0 g per 24 hours. Mild edema developed (associated with a 5 kg weight gain) in spite of diuretic therapy. The serum albumin level ranged between 3.2 and 4.4 mg/dl. The serum cholesterol level was 200 mg/dl. Results of urinalysis revealed oval fat bodies and free lipid droplets. Creatinine clearance was 20 ml per minute. A renal biopsy was performed on November 28, 1979, and demonstrated membranous glomerulonephritis and severe arterionephrosclerosis. Results of antinuclear antibody tests, anti-DNA tests, and lupus erythematosus preparations were negative. The C3 level was 118 mg/dl (normal 70 to 190 mg/dl). VDRL test results were negative. Renal venography revealed no evidence of thrombosis. Results of tests for serum hepatitis B surface antigen and antibody were negative. Captopril therapy was discontinued on January 21, 1980. The urine protein excretion measurement decreased to 1.4 g per 24 hours by April 1980, but has varied between 2.6 and 5.0 g over the subsequent 12 months. Blood pressure has ranged between 180/70 and 150170 mm Hg during treatment with propranolol, hydralazine, furosemide, and minoxidil. The serum creatinine level increased to 6.0 mg/dl and creatinlne clearance decreased to 13 ml per minute during the following year. A second open renal biopsy was performed on August 27, 1980, which again demonstrated subepithelial deposits
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6 5 4
Figure 2. Patient 2. Blood pressure, serum creatinine levels, and urine protein excretion measurements are shown before, during, and after captopril therapy. Times of renal biopsy are indicated(6x). Deterioration of renal function appeared after discontinuation of captopril.
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in some but not all glomerular segments, as well as persistent arterionephrosclerosis. Patient 2. This patient was a %-year-old Caucasian man referred for severe hypertension (240/ 135 mm Hg) complicated by a remote stroke and azotemia. Previous medications included alpha-methyldopa, furosemide, spironolactone, propranolol, and minoxidil. Renal arteriography in 1972 demonstrated mild renal artery stenosis (30 percent). Serum creatinine levels between 1971 and 1976 ranged between 3.9 and 4.5 mg/dl (Figure 2). Creatinine clearance was 28 ml per minute. Urinary protein excretion measurements ranged between 0.2 and 0.9 g per 24 hours. Plasma renin activity was 15 ng/ml per hour. Antinuclear antibody titer was 1: 160, while results of anti-DNA tests and lupus erythematosus preparations were negative. Captopril therapy was initiated on November 2, 1978. After three months of therapy, the urine protein excretion level increased to 6.0 to 13.0 g per 24 hours with no change in the serum creatinine level. Serum albumin levels were between 3.8 and 4.4 g/dl. The serum cholesterol level was 180 mg/dl. Ankle edema was present. A renal biopsy performed on March 13, 1979 dem-
onstrated membranous glomerulonephritis and severe arterionephrosclerosis. Captopril was discontinued and hypertension was treated again with minoxidil, propranolol, furosemide, and thiazide diuretics. Proteinuria decreased over several months, but after nine months, increased to 5.7 g per 24 hours. Since then, it has varied from 1.6 to 3.4 g per 24 hours. Creatinine clearance gradually decreased to 13 ml per minute. By April 1980, the serum creatinine level was 6.5 mg/dl despite improved blood pressure control (150140/100-90 mm Hg). Results of VDRL tests were negative. Antinuclear antibody titer was 1:320, results of lupus erythematosus preparations and anti-DNA antibody tests were
CAPTOPRIL-
negative, and C3 was normal. Total hemolytic complement (CHss) was 134 units/ml (normal 70 to 190 units/ml). Antistreptolysin 0 (ASO) was 50 Todd units. Results of tests for hepatitis B antigen were negative. Clq binding assay was 177 units (normal less than 140 units). A second renal biopsy was performed on April 1, 1980, which was more than one year after discontinuation of captopril. This biopsy revealed persistent membranous glomerulonephritis and arterionephrosclerosis.
BIOPSY RESULTS Patient 1. First biopsy (Figure 3): The open biopsy contained 50 glomeruli. One third of the glomeruli exhibited global sclerosis. Two glomeruli exhibited segmental sclerosis. There was no glomerular hypercellularity. There was extensive interstitial fibrosis and lymphocytic infiltrates with associated tubular atrophy in a patchy distribution. Arterioles and small arteries exhibited severe thickening of the muscularis. The Jones’ silver stain demonstrated no glomerular basement membrane defects or spikes. The peripheral glomerular basement membrane appeared wrinkled. lmmunofluorescence and immunoperoxidase demonstrated a granular deposit of IgM and C3 (-I- 1) in glomeruli (most of which were sclerotic) and in arterioles and small arteries. All structures were negative for IgG and IgA. Electron microscopy demonstrated wrinkling of the peripheral glomerular basement membrane, increased mesangial matrix, but no glomerular hypercellularity. Epimembranous dense deposits were present in most but not all segments of the peripheral glomerular
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ular basement membrane. There was no amyloid deposit. In summary, the findings were characteristic of membranous glomerulonephritis and arterionephrosclerosis. Second biopsy (Figure 7): Light microscopic, immunofluorescence, and immunoperoxidase findings were similar to the first biopsy. Electron microscopy again demonstrated epimembranous deposits in all segments of glomerular basement membrane. COMMENTS
Figure 3. Patient 1, first biopsy. Electron microscopy demonstrates epimembranous dense deposits in the peripheral glomerular basement membrane characteristic of membranous glomerulonephritis {uranyl acetate, lead citrate; magnification X 20,400, reduced by IO percent).
basement membrane. There was no amyloid deposit. In summary, the findings were characteristic of membranous glomerulonephritis and arterionephrosclerosis. Second biopsy (Figure 4): Light microscopic, immunofluorescence, and immunoperoxidase findings were similar to the first biopsy. Electron microscopy demonstrated epimembranous deposits in some peripheral glomerular basement membranes, but apparently in fewer segments than the first biopsy. Patient 2. First biopsy (Figures 5 and 6): The needle biopsies contained 17 glomeruli. Twelve exhibited global sclerosis. The remaining glomeruli appeared unremarkable, with the exception of a moderate increase in the mesangial matrix. There was extensive tubular atrophy and associated interstitial lymphoid infiltrates. Arterioles and small arteries exhibited thickening and hyalinization. The Jones’ silver stain demonstrated no spikes or defects in the glomerular basement membrane. lmmunofluorescence and immunoperoxidase stains demonstrated granular deposits of IgG and C3 (i-1) in sclerotic glomeruli and in small arteries. Electron microscopy demonstrated epimembranous dense deposits in all segments of the glomer-
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Nephrotic range proteinuria and membranous glomerulonephritis developed in these two patients during captopril therapy: both conditions failed to remit upon discontinuation of the drug, contrary to previously described cases in the literature. Repeat biopsies, eight and 12 months after discontinuation of the drug, demonstrated persistent changes of membranous glomerulonephritis. These represent the only instances of nephrotic proteinuria observed during treatment of 53 hypertensive subjects and 35 patients with normotensive congestive heart failure at the Cleveland Clinic. Both of our patients had impaired renal function before treatment with captopril, and both had diminution of proteinuria transiently upon discontinuation of the drug; however, proteinuria recurred and followed a fluctuating course thereafter. These cases differ in some respects from those previously described. Hoorntje et al [6] performed renal biopsies on 13 patients treated with captopril and found subepithelial deposits in four. Only one patient had nephrotic syndrome; the others were selected at random or because of “serum sickness”-like syndrome and immunologic abnormalities (positive antinuclear factor). None had diminution of renal function reported either before or during captopril therapy. These investigators proposed an immunologic basis for the lesion because of the serologic findings and the occasional occurrence of arthralgias and rash. Because glomerular deposits were occasionally observed in asymptomatic patients, they recommended renal biopsies before treatment. This recommendation has been challenged [9]. By contrast, Case et al [5] reported proteinuria without associated illness or arthralgias in six of 81 hypertensive patients during captopril administration; the proteinuria subsided in four despite continued therapy over nine months. Nephrotic syndrome and membranous glomerulonephritis developed in the remaining two patients; in one of these patients, proteinuria remitted during continued treatment. A single patient had an increase in the creatinine level, prompting withdrawal of captopril, which was followed by a return to pretreatment levels. Neither of our subjects had symptoms of rash, ar-
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Flgure 4. Patient 1, second biopsy. There are persistent epimembranous dense deposits in the peripheral glomerular basement membrane (uranyl acetate, lead citrate; magnification X 26,900, reduced by 10 percent).
Figure 5. Patient 2, first biopsy. The glomerulus exhibits no abnormality. The glomerular basement membrane is not thickened (periodic-acid Schiff; magnification X 400, reduced by 7 percent).
Ffgwe 6. Patient 2, first biopsy. Electron microscopy demonstrates epimembranous dense deposits characteristic of membranous glomerulonephritis (uranyl acetate, lead citrate; magnification X 19,800, reduced by 10 percent).
Patient 2, second biopsy. There are persistent Figure 7. epimembranous dense deposits (uranyl acetate, lead citrate; magnification X 3 1,300, reduced by 10 percent).
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thralgia, or “serum sickness,” although these were observed occasionally in other patients receiving captopril in this institution. Antinuclear antibody titers were slightly elevated in Patient 2, but these values had been present before therapy; anti-DNA titers were negative. There was no associated illness or exposure to other drugs known to induce membranous glomerulonephritis, nor was there evident activation of complement. In contrast to most of the cases reported by Case et al, proteinuria did not subside spontaneously, and although there was partial remission during the six to nine months after discontinuation of the drug, further follow-up demonstrated a fluctuating, recurrent course, entirely consistent with the observation of persistent subepithelial deposits in the glomerular basement membrane in the second biopsies. Because no changes in the glomerular basement membrane were evident by light microscopy (Figure 5), these lesions would be classified as stage I membranous glomerulonephritis [ 10,111. Although their occurrence may have been coincidental, these two patients appeared to have membranous glomerulonephritis associated with captopril that persisted after discontinuation of the drug. The pathogenesis of captopril-associated membranous glomerulonephritis has not been elucidated. It has been speculated in the case of penicillamine and gold nephropathy that drug binding to circulating native protein may induce an immune response and glomerular deposition of immune complexes [ 12-141. Although the findings of arthralgias, vasculitis, and antinuclear factors have been cited as indirect evidence of such complexes, direct demonstration of their presence during captopril administration is lacking. In the more common condition of idiopathic membranous glomerulonephritis, it is unusual to detect circulating antigenantibody complexes, despite their presence in glomerular basement membrane [ 151. Alternatively, it has been demonstrated that under some conditions, identical subepithelial deposits may be formed in situ [ 161. One might speculate that a particular property of gold, penicillamine, or captopril, such as the sulfhydryl or heavy metal binding characteristics, directly alters the glomerular basement membrane, allowing deposition of antigenic material in the subepithelial space secondarily. Whatever the mechanisms, it would appear that in our patients, basement membrane deposits were not readily reversible upon discontinuation of the drug. Other factors that may have predisposed these patients to nephrotoxic effects of the drug were pre-existing renal impairment, severe arterionephrosclerosis, and the dosage of the captopril administered. The incidence of proteinuria reported by the manufacturer in patients treated at least eight months with captopril
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dropped from 2.4 percent to 0.7 percent if those with pre-existing renal disease, including renovascular hypertension and/or proteinuria, were excluded [J. Stritar, E. R. Squibb 8 Sons, Inc., personal communication]. Significant adverse reactions to captopril, including proteinuria and leukopenia, have generally been reported in patients receiving 300 to 600 mg per day, although the nephrotic syndrome developed in one patient with a normal glomerular filtration rate (96 ml per minute) while the patient was taking only 150 mg per day. Since captopril is extreted primarily by the kidneys, the recommended dosage has been adjusted recently, based on individual creatinine clearance. Whether or not this dosage adjustment will affect the incidence of adverse reactions is not yet known. Captopril shares a sulfhydryl group and other structural similarities with D-penicillamine, and there is a striking similarity in the types of adverse rections associated with these two drugs (including membranous glomerulonephritis). The incidence of adverse reactions appears at least partially dose-related in the case of penicillamine [ 171. Of major clinical importance is the observation that both of these patients had progressive deterioration of renal function after withdrawal of captopril, a problem that has not been previously reported. Repeat biopsies were performed because of this deterioration and because of the failure of proteinuria to resolve. Although basement membrane deposits were still identifiable, there was no evident progression of the membranous lesion in either case and the relatively rapid loss of glomerular filtration rate observed is distinctly unusual for membranous glomerulonephritis of any cause [ 11,181. For these reasons, we believe it unlikely that renal failure in these patients represents a direct effect of membranous glomerulonephritis associated with captopril, although this possibility cannot be excluded. Although other causes of renal failure such as ureteral obstruction, renal vein thrombosis, and renal artery stenosis were considered in these patients, they were not detected by diagnostic studies. After discontinuation of captopril, both patients were treated with propranolol, which has been found occasionally to impair renal hemodynamics and renal function [ 19,201. Alternatively, some cases of advanced hypertensive renal disease have progressed to end stage despite apparently adequate blood pressure control [21,22]. Repeat renal biopsies in both of our patients demonstrated severe arteiionephrosclerosis, consistent with the hypothesis that renal failure after discontinuation of captopril was caused by progressive ischemic injury. The development of nephrotic syndrome and membranous glomerulonephritis in captopril-treated patients has posed a substantial clinical dilemma. Both of our patients had severe hypertension resistant to therapy;
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their condition was characterized by renal impairment and elevated plasma renin activity. They are typical of persons most likely to benefit from inhibitors of angiotensin-converting enzyme. Blood pressure control was judged to be excellent or markedly improved and, in the case of Patient 1, to reverse malignant hypertension. In this instance, treatment with captopril was continued for more than one year despite the development of proteinuria. It is possible that continued exposure to the drug may have contributed to the persistence of membranous glomerulonephritis later. The development of proteinuria nonetheless led to discontinuation of an otherwise well-tolerated, effective agent that is presently the only orally effective medication that interrupts the renin-angiotensin system. The physicians responsible for managing these patients ultimately concluded that the potential nephrotoxicity made manifest by membranous glomerulonephritis required discontinuation of therapy, although no evidence of progressive renal insufficiency had been reported after captoprilassociated membranous glomerulonephritis. No such progression was evident at the time of discontinuation of captopril therapy in these patients. However, a gradual but relentless reduction in glomerular filtration rate has occurred since withdrawal of captopril; this reduction is apparently related to hypertensive vascular disease. Angiotensin is recognized as a potent vasoconstrictor and may cause local necrosis at high doses
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[23]. One might speculate that preventing the formation of angiotensin with a converting enzyme inhibitor under conditions of underlying vascular disease may be of additional value in preventing further renal damage, beyond the benefits of lowering blood pressure alone. Considering the relatively less threatening course of membranous glomerulonephritis, it could be argued that in selected cases the risk of proteinuria is less than the benefits accrued by continued administration of the drug. CONCLUSION Altogether, nephrotic syndrome and membranous glomerulonephritis developed in two of 88 patients receiving captopril in our institution. Proteinuria followed a fluctuating course after discontinuation of the drug, but failed to remit totally over one year. Repeat biopsies confirmed persistent glomerular basement membrane deposits in both cases. We conclude that membranous glomerulonephritis represents a potential adverse effect of captopril, but the decision to discontinue its use must be balanced against its exceptional therapeutic value in individual cases. ACKNOWLEDGMENT We would like to thank Drs. Rafael Valenzuela and Sharad Deodhar for the preparation of immunopathologic studies on the renal biopsy specimens.
REFERENCES 1.
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Gavras H, Brunner HR, Turini GA: Antihypertensive effect of the oral-angiotensin converting enzyme inhibitor SQ 14225 in man. N Engl J Med 1976; 296: 991-995. Bravo EL, Tarazi RC: Converting enzyme inhibition with an orally active compound in hypertensive man. Hypertension 1979; 1: 39-46. Davis R, Ribner HS, Keung E, Sonnenblick EH, LeJemtel TH: Treatment of chronic congestive heart failure with captopril, an oral inhibitor of angiotensin converting enzyme. N Engl J Med 1979; 301: 117-121. Lopez-Drejero JA, Saal S, D’Angela WA, Cheigh JS, Stenzel K, Laragh J: Reversal of vascular and renal crises of scleroderma by oral angiotensin converting enzyme inhibitor. N Engl J Med 1979; 300: 1417-1419. Case DB, Atlas SA, fvlouradianJA, Fishman RA, Sherman RL, Laragh JH: Proteinuria during long-term captopril therapy. JAMA 1960; 244: 346-349. Hoorntje SJ, Weening JJ, The TH, Kallenberg CGM, Donker AJM, Hoedemaker PJ: Immune-complex glomerulopathy in patients treated with captopril. Lancet 1960; I: 12121214. Hoorntje SJ, Donker AJM, Prins EJL, Weening JJ: Membranous glomerulopathy in a patient on captopril. Acta Med Stand 1960; 206: 325-329. Tubbs RR, Gephardt GN, Valenzuela R, Deodhar S: An approach to immunomicroscopy of renal disease with immunoperoxidase and periodic acid-Schiff counterstain
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(IMPAS Stain). Am J Clin Pathol 1960; 73: 240-244. Kincaid-Smith P, Whitsworth JA, Walter NMA, Dowling JP: Immune complex glomerulopathy and captopril (letter to the editor). Lancet 1960; II: 37. Rosen S: Membranous glomerulonephrltis:current status. Hum Pathol 1971; 2: 209-231. Tornroth T, Tallgrist G, Pasternack A, Linder E: Nonprogressive, histologically mild membranous glomerulonephritis appearing in all evolutionary phases as histologically “early” membranous glomerulonephritis. Kidney Int 1976; 14: 511-521. Bacon PA, Tribe CR, MacKenzie JC, Verrier JJ, Cumming RN, Amer B: Penicillamine nephropathy in rheumatoid arthritis: a clinical, pathological and immunological study. Q J Med 1976; 45: 661-664. Paluso T, Provost TT, Mifgrom E: Gokl nephropathy. Seriotogic data suggesting an immune complex disease. Clin Exp lmmunol 1976; 25: 3111-3116. Nagi AM, Alexander F, Barabas AZ: Gold nephropathy in rats. Light and electron microscopic studies. Exp Mol Pathol 1971; 15: 354-362. Border WA: Immune complex detection in glomerular diseases. Nephron 1979; 24: 105-l 13. Couser WG, Steinmueller DR. Stilmant MM: Experimental glornerulonephrllis in the isolated perfused rat kidney. J Clin Invest 1976; 62: 1275-1267. Stein JB, Patterson AC, Offer RC, Atkins CJ, Tentel A, Rob-
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inson HS: Adverse effects of D-Penicillamine in rheumatoid arthritis. Ann Intern Med 1980; 92: 24-29. Noel LH, Zanetti M, Droz D, Barbanel C: Long-term prognosis in idiopathic membranous glomerulonephrttis. Study of 116 untreated patients. Am J Med 1979; 66: 82-90. Bauer JH, Brooks CS: The long-term effect of propranolol therapy on renal function. Am J Med 1979; 66: 405410. Warren DJ, Swainson CP, Wright N: Deterioration in renal function after beta-blockage in patients with chronic renal failure and hypertension. Br Med J 1974; 2: 193-194.
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McCormack LJ, Biland JE, Schneckloth RE, Corcoran AC: Effects of antihypertensive treatment on the evolution of the renal lesions in malignant nephrosclerosis. Am J Pathol 1958; 34: 1011-1021. Mitchell HC, Graham RM, Pettinger WA: Renal function during long-term treatment of hypertension with minoxidil. Comparison of benign and malignant hypertension. Ann Intern Med 1980; 93: 676-681. Gavras H, Brunner HR, Laragh JH: Renin and aldosterone and the pathogenesis of hypertensive vascular damage. Prog Cardiovasc Dis 1974; 17: 39-49.
STEPHEN C. TEXTOR, M.D. GORDON N. GEPHARDT, M.D. EMMANUEL L. BRAVO, M.D. ROBERT
C. TARAZI,
M.D.
FETNAT
M. FOUAD,
M.D.
RAYMOND JAMES
TUBBS,
D.O.
T. McMAHON,
Ph.D.
Clevelend, Ohio
From the Research Division and the Department of Pathology, The Cleveland Clink Foundation. Cleveland, Ohio. Requests for reprints should be addressed to Cr. Stephen C. Textor, Research Division, The Cleveland Clinic Foundation. 9500 EudMAvenue, Clevebxl, Ohio 44106. Manusaipt acceptedMay 12, 1982.
Two cases of nephrotic syndrome and biopsy-proved membranous glomerulopathy (membranous glomerulonephritls) were encountered during captoprii treatment of 53 hypertensive subjects in our instltution. Both patients had impaired renal function before treatment and were treated with 600 mg per day. Discontinuation of captoprii led to transient partial remission of proteinuria but was followed by a recurrent, fluctuating course over one year later. Repeat biopsies, eight and 12 months after discontinuation of the drug, demonstrated persistent subepftheliai deposits in the glomeruiar basement membrane. There has been a decline in giomeruiar fiitration rate since dlscontinuatlon of the drug, apparently due to arterionephragcierosts. These stud& suggest that gtomeruiar basement membrane deposits in captopril-associated membranous glomeruionefHtis are not readity revef-sibk and may be associated with persistent proteinuria, contrary to some previous reports. inhibition of angiotensin-converting enzyme is an effective therapy for the treatment of hypertension and congestive heart failure [l-3]. In conditions with increased activity of the renin-angiotensin system, such as malignant hypertension caused by scleroderma involving the kidney, this form of therapy may have unique applications [4]. At present, captopril (Capote@, Squibb Pharmaceutical Company) is the only orally active compound evaluated clinically and has been associated with relatively few adverse effects. One complication has been the development of proteinuria and the nephrotic syndrome in 1 to 3 percent of patients [ 5,6]. In some of these cases, renal biopsies have shown changes of membranous glomerulonephritis, characterized by subepithelial glomerular basement membrane deposits. The significance of proteinuria and anatomic changes observed in renal biopsies of captoprll-treated patients has been disputed. Some investigators reported proteinuria as a transient occurrence that was not generally associated with progressive renal failure and occasionally regressed without discontinuation of the drug [ 51. Other investigators suggested that pathologic changes in the kidney during captopril administration were more ominous and might appear without proteinuia, and they recommended renal biopsy as a routine procedure before institution of treatment with captopril [6]. In most cases of proteinuria that developed during captopril therapy, discontinuation of the drug led to its resolution. This is not universally true, however, and there has been only one report of a repeat biopsy in captoprii-treated patients with nephrotic proteinuria and membranous glomerulonephritis to document the subsequent course of basement membrane deposits [7]. The purpose of this report is to
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hematoxylin and eosin, Masson trichrome, periodic-acid Schiff, and Jones’ silver stain. The second piece was minced and fixed in 3 percent cold glutaraldehyde, postfixed in osmium tetroxide, dehydrated in graded alcohols, and embedded in Epon@. Ultrathin sections were then stained with lead citrate and uranyl acetate for electron microscopy. The third piece was frozen in liquid nitrogen, 2 to 4 mm sections cut on a Lipshaw cryostat, and immunofluorescence and immunoperoxidase techniques performed to detect IgA, IgG, IgM, and C3, as previously described [6].
CASE REPORTS Patient 1.
lgure 1. Patient 1. Blood pressure, serum creatinine levels, and urine protein excretion measurements are shown before, during, and after captopril therapy. Times of renal biopsy are indicated (6x). Deterioration of renal function appeared after discontinuation of captopril.
present the clinical course and repeat biopsy findings in two patients in whom the nephrotic syndrome and membranous glomerulonephritis developed during captopril therapy. METHODS Nephrotic range proteinuria (more than 3 g per day) developed in only two of 53 hypertensive patients treated with captopril between 1976 and 1979. Before initiation of therapy, all procedures were explained and the investigational nature of therapy was described in order to obtain informed consent, as approved by the Institutional Review Committee of the Cleveland Clinic. During these studies, urine collections for protein excretion were obtained daily in the hospital and at least once a month thereafter. Both patients had impaired renal function before captopril therapy. Neither patient previously had nephrotic range proteinuria nor any condition associated with membranous glomerulonephritis, including systemic lupus erythematosus, syphilis, hepatitis B, neoplasia, or exposure to penicillamine, gold, or mercury compounds. Two other hypertensive patients had mild proteinurla (I to 1.5 g per day) before therapy, which diminished in both during subsequent evaluation. Abnormal protein excretion (more than 250 mg per day) did not develop in any patients receiving captopril for congestive heart failure in our se-
ries. Each renal biopsy was divided into three parts. The first was fixed In modified Zenker’s solution and stained with
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This patient was a 61-yearaId Caucasian woman
in good general health with no known renal disease or hypertension until March 1978, when she presented with malignant hypertension characterized by visual loss, transient leg weakness, and retinal hemorrhages and exudates. Blood pressure was 2701140 mm Hg. The serum creatinine level ranged between 2.0 and 3.9 mg/dl. Creatinine clearance was 20 ml per minute (uncorrected). Twenty-four-hour urine protein excretion measurements were 1.1 to 1.9 g. Renal arteriography revealed arteriolar changes consistent with nephrosclerosis and bilateral diminution of renal perfusion. Plasma renin activity was 42 ng/ml per hour (normal = 0.4 to 2.6 ng/ml per hour on 100 mEq sodium intake). Hypertension was poorly controlled with methyldopa, hydralazine, ‘and diuretic agents. After obtaining informed consent, captopril was administered in doses of 400 to 600 mg per day. Beginning April 3, 1978, blood pressure decreased to 140160 mm Hg and urine protein excretion to less than 100 mg per 24 hours (Figure 1). The serum creatinine level remained between 2.9 and 3.4 mg/dl. Neurologic findings and retinal changes were reversed over several weeks. After six months of therapy, blood pressure remained well controlled with captopril and furosemide (blood pressure 140182 mm Hg), but the urine protein level increased to 2.4 g per 24 hours and subsequently ranged between 4.0 and 6.0 g per 24 hours. Mild edema developed (associated with a 5 kg weight gain) in spite of diuretic therapy. The serum albumin level ranged between 3.2 and 4.4 mg/dl. The serum cholesterol level was 200 mg/dl. Results of urinalysis revealed oval fat bodies and free lipid droplets. Creatinine clearance was 20 ml per minute. A renal biopsy was performed on November 28, 1979, and demonstrated membranous glomerulonephritis and severe arterionephrosclerosis. Results of antinuclear antibody tests, anti-DNA tests, and lupus erythematosus preparations were negative. The C3 level was 118 mg/dl (normal 70 to 190 mg/dl). VDRL test results were negative. Renal venography revealed no evidence of thrombosis. Results of tests for serum hepatitis B surface antigen and antibody were negative. Captopril therapy was discontinued on January 21, 1980. The urine protein excretion measurement decreased to 1.4 g per 24 hours by April 1980, but has varied between 2.6 and 5.0 g over the subsequent 12 months. Blood pressure has ranged between 180/70 and 150170 mm Hg during treatment with propranolol, hydralazine, furosemide, and minoxidil. The serum creatinine level increased to 6.0 mg/dl and creatinlne clearance decreased to 13 ml per minute during the following year. A second open renal biopsy was performed on August 27, 1980, which again demonstrated subepithelial deposits
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Figure 2. Patient 2. Blood pressure, serum creatinine levels, and urine protein excretion measurements are shown before, during, and after captopril therapy. Times of renal biopsy are indicated(6x). Deterioration of renal function appeared after discontinuation of captopril.
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in some but not all glomerular segments, as well as persistent arterionephrosclerosis. Patient 2. This patient was a %-year-old Caucasian man referred for severe hypertension (240/ 135 mm Hg) complicated by a remote stroke and azotemia. Previous medications included alpha-methyldopa, furosemide, spironolactone, propranolol, and minoxidil. Renal arteriography in 1972 demonstrated mild renal artery stenosis (30 percent). Serum creatinine levels between 1971 and 1976 ranged between 3.9 and 4.5 mg/dl (Figure 2). Creatinine clearance was 28 ml per minute. Urinary protein excretion measurements ranged between 0.2 and 0.9 g per 24 hours. Plasma renin activity was 15 ng/ml per hour. Antinuclear antibody titer was 1: 160, while results of anti-DNA tests and lupus erythematosus preparations were negative. Captopril therapy was initiated on November 2, 1978. After three months of therapy, the urine protein excretion level increased to 6.0 to 13.0 g per 24 hours with no change in the serum creatinine level. Serum albumin levels were between 3.8 and 4.4 g/dl. The serum cholesterol level was 180 mg/dl. Ankle edema was present. A renal biopsy performed on March 13, 1979 dem-
onstrated membranous glomerulonephritis and severe arterionephrosclerosis. Captopril was discontinued and hypertension was treated again with minoxidil, propranolol, furosemide, and thiazide diuretics. Proteinuria decreased over several months, but after nine months, increased to 5.7 g per 24 hours. Since then, it has varied from 1.6 to 3.4 g per 24 hours. Creatinine clearance gradually decreased to 13 ml per minute. By April 1980, the serum creatinine level was 6.5 mg/dl despite improved blood pressure control (150140/100-90 mm Hg). Results of VDRL tests were negative. Antinuclear antibody titer was 1:320, results of lupus erythematosus preparations and anti-DNA antibody tests were
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negative, and C3 was normal. Total hemolytic complement (CHss) was 134 units/ml (normal 70 to 190 units/ml). Antistreptolysin 0 (ASO) was 50 Todd units. Results of tests for hepatitis B antigen were negative. Clq binding assay was 177 units (normal less than 140 units). A second renal biopsy was performed on April 1, 1980, which was more than one year after discontinuation of captopril. This biopsy revealed persistent membranous glomerulonephritis and arterionephrosclerosis.
BIOPSY RESULTS Patient 1. First biopsy (Figure 3): The open biopsy contained 50 glomeruli. One third of the glomeruli exhibited global sclerosis. Two glomeruli exhibited segmental sclerosis. There was no glomerular hypercellularity. There was extensive interstitial fibrosis and lymphocytic infiltrates with associated tubular atrophy in a patchy distribution. Arterioles and small arteries exhibited severe thickening of the muscularis. The Jones’ silver stain demonstrated no glomerular basement membrane defects or spikes. The peripheral glomerular basement membrane appeared wrinkled. lmmunofluorescence and immunoperoxidase demonstrated a granular deposit of IgM and C3 (-I- 1) in glomeruli (most of which were sclerotic) and in arterioles and small arteries. All structures were negative for IgG and IgA. Electron microscopy demonstrated wrinkling of the peripheral glomerular basement membrane, increased mesangial matrix, but no glomerular hypercellularity. Epimembranous dense deposits were present in most but not all segments of the peripheral glomerular
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ular basement membrane. There was no amyloid deposit. In summary, the findings were characteristic of membranous glomerulonephritis and arterionephrosclerosis. Second biopsy (Figure 7): Light microscopic, immunofluorescence, and immunoperoxidase findings were similar to the first biopsy. Electron microscopy again demonstrated epimembranous deposits in all segments of glomerular basement membrane. COMMENTS
Figure 3. Patient 1, first biopsy. Electron microscopy demonstrates epimembranous dense deposits in the peripheral glomerular basement membrane characteristic of membranous glomerulonephritis {uranyl acetate, lead citrate; magnification X 20,400, reduced by IO percent).
basement membrane. There was no amyloid deposit. In summary, the findings were characteristic of membranous glomerulonephritis and arterionephrosclerosis. Second biopsy (Figure 4): Light microscopic, immunofluorescence, and immunoperoxidase findings were similar to the first biopsy. Electron microscopy demonstrated epimembranous deposits in some peripheral glomerular basement membranes, but apparently in fewer segments than the first biopsy. Patient 2. First biopsy (Figures 5 and 6): The needle biopsies contained 17 glomeruli. Twelve exhibited global sclerosis. The remaining glomeruli appeared unremarkable, with the exception of a moderate increase in the mesangial matrix. There was extensive tubular atrophy and associated interstitial lymphoid infiltrates. Arterioles and small arteries exhibited thickening and hyalinization. The Jones’ silver stain demonstrated no spikes or defects in the glomerular basement membrane. lmmunofluorescence and immunoperoxidase stains demonstrated granular deposits of IgG and C3 (i-1) in sclerotic glomeruli and in small arteries. Electron microscopy demonstrated epimembranous dense deposits in all segments of the glomer-
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Nephrotic range proteinuria and membranous glomerulonephritis developed in these two patients during captopril therapy: both conditions failed to remit upon discontinuation of the drug, contrary to previously described cases in the literature. Repeat biopsies, eight and 12 months after discontinuation of the drug, demonstrated persistent changes of membranous glomerulonephritis. These represent the only instances of nephrotic proteinuria observed during treatment of 53 hypertensive subjects and 35 patients with normotensive congestive heart failure at the Cleveland Clinic. Both of our patients had impaired renal function before treatment with captopril, and both had diminution of proteinuria transiently upon discontinuation of the drug; however, proteinuria recurred and followed a fluctuating course thereafter. These cases differ in some respects from those previously described. Hoorntje et al [6] performed renal biopsies on 13 patients treated with captopril and found subepithelial deposits in four. Only one patient had nephrotic syndrome; the others were selected at random or because of “serum sickness”-like syndrome and immunologic abnormalities (positive antinuclear factor). None had diminution of renal function reported either before or during captopril therapy. These investigators proposed an immunologic basis for the lesion because of the serologic findings and the occasional occurrence of arthralgias and rash. Because glomerular deposits were occasionally observed in asymptomatic patients, they recommended renal biopsies before treatment. This recommendation has been challenged [9]. By contrast, Case et al [5] reported proteinuria without associated illness or arthralgias in six of 81 hypertensive patients during captopril administration; the proteinuria subsided in four despite continued therapy over nine months. Nephrotic syndrome and membranous glomerulonephritis developed in the remaining two patients; in one of these patients, proteinuria remitted during continued treatment. A single patient had an increase in the creatinine level, prompting withdrawal of captopril, which was followed by a return to pretreatment levels. Neither of our subjects had symptoms of rash, ar-
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Flgure 4. Patient 1, second biopsy. There are persistent epimembranous dense deposits in the peripheral glomerular basement membrane (uranyl acetate, lead citrate; magnification X 26,900, reduced by 10 percent).
Figure 5. Patient 2, first biopsy. The glomerulus exhibits no abnormality. The glomerular basement membrane is not thickened (periodic-acid Schiff; magnification X 400, reduced by 7 percent).
Ffgwe 6. Patient 2, first biopsy. Electron microscopy demonstrates epimembranous dense deposits characteristic of membranous glomerulonephritis (uranyl acetate, lead citrate; magnification X 19,800, reduced by 10 percent).
Patient 2, second biopsy. There are persistent Figure 7. epimembranous dense deposits (uranyl acetate, lead citrate; magnification X 3 1,300, reduced by 10 percent).
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thralgia, or “serum sickness,” although these were observed occasionally in other patients receiving captopril in this institution. Antinuclear antibody titers were slightly elevated in Patient 2, but these values had been present before therapy; anti-DNA titers were negative. There was no associated illness or exposure to other drugs known to induce membranous glomerulonephritis, nor was there evident activation of complement. In contrast to most of the cases reported by Case et al, proteinuria did not subside spontaneously, and although there was partial remission during the six to nine months after discontinuation of the drug, further follow-up demonstrated a fluctuating, recurrent course, entirely consistent with the observation of persistent subepithelial deposits in the glomerular basement membrane in the second biopsies. Because no changes in the glomerular basement membrane were evident by light microscopy (Figure 5), these lesions would be classified as stage I membranous glomerulonephritis [ 10,111. Although their occurrence may have been coincidental, these two patients appeared to have membranous glomerulonephritis associated with captopril that persisted after discontinuation of the drug. The pathogenesis of captopril-associated membranous glomerulonephritis has not been elucidated. It has been speculated in the case of penicillamine and gold nephropathy that drug binding to circulating native protein may induce an immune response and glomerular deposition of immune complexes [ 12-141. Although the findings of arthralgias, vasculitis, and antinuclear factors have been cited as indirect evidence of such complexes, direct demonstration of their presence during captopril administration is lacking. In the more common condition of idiopathic membranous glomerulonephritis, it is unusual to detect circulating antigenantibody complexes, despite their presence in glomerular basement membrane [ 151. Alternatively, it has been demonstrated that under some conditions, identical subepithelial deposits may be formed in situ [ 161. One might speculate that a particular property of gold, penicillamine, or captopril, such as the sulfhydryl or heavy metal binding characteristics, directly alters the glomerular basement membrane, allowing deposition of antigenic material in the subepithelial space secondarily. Whatever the mechanisms, it would appear that in our patients, basement membrane deposits were not readily reversible upon discontinuation of the drug. Other factors that may have predisposed these patients to nephrotoxic effects of the drug were pre-existing renal impairment, severe arterionephrosclerosis, and the dosage of the captopril administered. The incidence of proteinuria reported by the manufacturer in patients treated at least eight months with captopril
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dropped from 2.4 percent to 0.7 percent if those with pre-existing renal disease, including renovascular hypertension and/or proteinuria, were excluded [J. Stritar, E. R. Squibb 8 Sons, Inc., personal communication]. Significant adverse reactions to captopril, including proteinuria and leukopenia, have generally been reported in patients receiving 300 to 600 mg per day, although the nephrotic syndrome developed in one patient with a normal glomerular filtration rate (96 ml per minute) while the patient was taking only 150 mg per day. Since captopril is extreted primarily by the kidneys, the recommended dosage has been adjusted recently, based on individual creatinine clearance. Whether or not this dosage adjustment will affect the incidence of adverse reactions is not yet known. Captopril shares a sulfhydryl group and other structural similarities with D-penicillamine, and there is a striking similarity in the types of adverse rections associated with these two drugs (including membranous glomerulonephritis). The incidence of adverse reactions appears at least partially dose-related in the case of penicillamine [ 171. Of major clinical importance is the observation that both of these patients had progressive deterioration of renal function after withdrawal of captopril, a problem that has not been previously reported. Repeat biopsies were performed because of this deterioration and because of the failure of proteinuria to resolve. Although basement membrane deposits were still identifiable, there was no evident progression of the membranous lesion in either case and the relatively rapid loss of glomerular filtration rate observed is distinctly unusual for membranous glomerulonephritis of any cause [ 11,181. For these reasons, we believe it unlikely that renal failure in these patients represents a direct effect of membranous glomerulonephritis associated with captopril, although this possibility cannot be excluded. Although other causes of renal failure such as ureteral obstruction, renal vein thrombosis, and renal artery stenosis were considered in these patients, they were not detected by diagnostic studies. After discontinuation of captopril, both patients were treated with propranolol, which has been found occasionally to impair renal hemodynamics and renal function [ 19,201. Alternatively, some cases of advanced hypertensive renal disease have progressed to end stage despite apparently adequate blood pressure control [21,22]. Repeat renal biopsies in both of our patients demonstrated severe arteiionephrosclerosis, consistent with the hypothesis that renal failure after discontinuation of captopril was caused by progressive ischemic injury. The development of nephrotic syndrome and membranous glomerulonephritis in captopril-treated patients has posed a substantial clinical dilemma. Both of our patients had severe hypertension resistant to therapy;
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their condition was characterized by renal impairment and elevated plasma renin activity. They are typical of persons most likely to benefit from inhibitors of angiotensin-converting enzyme. Blood pressure control was judged to be excellent or markedly improved and, in the case of Patient 1, to reverse malignant hypertension. In this instance, treatment with captopril was continued for more than one year despite the development of proteinuria. It is possible that continued exposure to the drug may have contributed to the persistence of membranous glomerulonephritis later. The development of proteinuria nonetheless led to discontinuation of an otherwise well-tolerated, effective agent that is presently the only orally effective medication that interrupts the renin-angiotensin system. The physicians responsible for managing these patients ultimately concluded that the potential nephrotoxicity made manifest by membranous glomerulonephritis required discontinuation of therapy, although no evidence of progressive renal insufficiency had been reported after captoprilassociated membranous glomerulonephritis. No such progression was evident at the time of discontinuation of captopril therapy in these patients. However, a gradual but relentless reduction in glomerular filtration rate has occurred since withdrawal of captopril; this reduction is apparently related to hypertensive vascular disease. Angiotensin is recognized as a potent vasoconstrictor and may cause local necrosis at high doses
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[23]. One might speculate that preventing the formation of angiotensin with a converting enzyme inhibitor under conditions of underlying vascular disease may be of additional value in preventing further renal damage, beyond the benefits of lowering blood pressure alone. Considering the relatively less threatening course of membranous glomerulonephritis, it could be argued that in selected cases the risk of proteinuria is less than the benefits accrued by continued administration of the drug. CONCLUSION Altogether, nephrotic syndrome and membranous glomerulonephritis developed in two of 88 patients receiving captopril in our institution. Proteinuria followed a fluctuating course after discontinuation of the drug, but failed to remit totally over one year. Repeat biopsies confirmed persistent glomerular basement membrane deposits in both cases. We conclude that membranous glomerulonephritis represents a potential adverse effect of captopril, but the decision to discontinue its use must be balanced against its exceptional therapeutic value in individual cases. ACKNOWLEDGMENT We would like to thank Drs. Rafael Valenzuela and Sharad Deodhar for the preparation of immunopathologic studies on the renal biopsy specimens.
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(IMPAS Stain). Am J Clin Pathol 1960; 73: 240-244. Kincaid-Smith P, Whitsworth JA, Walter NMA, Dowling JP: Immune complex glomerulopathy and captopril (letter to the editor). Lancet 1960; II: 37. Rosen S: Membranous glomerulonephrltis:current status. Hum Pathol 1971; 2: 209-231. Tornroth T, Tallgrist G, Pasternack A, Linder E: Nonprogressive, histologically mild membranous glomerulonephritis appearing in all evolutionary phases as histologically “early” membranous glomerulonephritis. Kidney Int 1976; 14: 511-521. Bacon PA, Tribe CR, MacKenzie JC, Verrier JJ, Cumming RN, Amer B: Penicillamine nephropathy in rheumatoid arthritis: a clinical, pathological and immunological study. Q J Med 1976; 45: 661-664. Paluso T, Provost TT, Mifgrom E: Gokl nephropathy. Seriotogic data suggesting an immune complex disease. Clin Exp lmmunol 1976; 25: 3111-3116. Nagi AM, Alexander F, Barabas AZ: Gold nephropathy in rats. Light and electron microscopic studies. Exp Mol Pathol 1971; 15: 354-362. Border WA: Immune complex detection in glomerular diseases. Nephron 1979; 24: 105-l 13. Couser WG, Steinmueller DR. Stilmant MM: Experimental glornerulonephrllis in the isolated perfused rat kidney. J Clin Invest 1976; 62: 1275-1267. Stein JB, Patterson AC, Offer RC, Atkins CJ, Tentel A, Rob-
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McCormack LJ, Biland JE, Schneckloth RE, Corcoran AC: Effects of antihypertensive treatment on the evolution of the renal lesions in malignant nephrosclerosis. Am J Pathol 1958; 34: 1011-1021. Mitchell HC, Graham RM, Pettinger WA: Renal function during long-term treatment of hypertension with minoxidil. Comparison of benign and malignant hypertension. Ann Intern Med 1980; 93: 676-681. Gavras H, Brunner HR, Laragh JH: Renin and aldosterone and the pathogenesis of hypertensive vascular damage. Prog Cardiovasc Dis 1974; 17: 39-49.