Vol. 115, January Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1976 by The Williams & Wilkins Co.
NEPHROTIC SYNDROME SECONDARY TO CHRONIC PYELONEPHRITIS AND URETEROVESICAL REFLUX SALOMON DAYAN
AND
EARL C. SMITH
From the Renal Division, Mt. Sinai Hospital Medical Center, Chicago, Illinois
ABSTRACT
Vesicoureteral reflux and chronic pyelonephritis are usually associated with proteinuria of less than 1 gm. per 24 hours. When there is massive proteinuria an associated glomerulopathy is usually present. We describe a patient who had nephrotic syndrome with radiological evidence of ureterovesical reflux and histological evidence of chronic pyelonephritis without associated glomerulonephritis. DISCUSSION Nephrotic syndrome is usually defined as proteinuria more than 3 gm. per 24 hours, hypoalbuminemia and hypercholesThe nephrotic syndrome in the presence of chronic pyeloneteremia. It may or may not be associated with chronic phritis is usually associated with glomerular disease. Pillary pyelonephritis secondary to ureterovesical reflux, is usually and associates described 3 patients with massive proteinuria, minimal and rarely sufficient to produce clinical manifesta- vesicoureteral reflux and pyelographic clubbing of the calices tions associated with nephrotic syndrome. The occurrence of associated with small kidneys. 1 However, renal biopsies remassive proteinuria usually reflects glomerular rather than vealed glomerulonephritis in 2 and nephrosclerosis in 1. Zimtubular or interstitial disease. merman and associates, 2 and Nicastri 3 noted glomerular lesions outside the scarred areas consisting of granular deCASE REPORT posits of complement, and IgM and IgG, respectively, in the A 17-year-old Puerto Rican woman was hospitalized with the mesangial and subendothelial regions in 8 patients with chief complaint of swelling of the ankles 1 week in duration. chronic pyelonephritis and heavy proteinuria. However, the There was no history of hematuria, flank pain, dysuria, arthralgia, skin rash, sore throat or dark urine. There was no exposure to heavy metals or nephrotoxic drugs. Physical examination revealed blood pressure of 150/130 mm. Hg, mild facial puffiness and 2 plus edema. Laboratory studies included blood urea nitrogen (BUN) 37 mg. per cent, creatinine 2.2 mg. per cent and serum protein electrophoresis of albumin 2.2 gm. per cent, 0.3 gm. per cent alpha,, 2.2 gm. per cent alpha 2, 0.8 gm. per cent beta and 0.5 gm. per cent gamma. Serum cholesterol was 363 mg. per cent and triglycerides 246 mg. per cent. Urinalysis showed pH 6.0, specific gravity 1.013 and no casts. Urine culture yielded consistently Escherichia coli. A 24-hour urine protein was 3.74 gm. and urine protein electrophoresis revealed 75.5 per cent albumin-3.3 per cent alpha., 4.2 per cent alpha2, 9.3 per cent beta and 6.2 per cent gamma. Lupus erythematosus preparation, and antinuclear antibodies, C 3 and C, were repeatedly normal. An excretory urogram revealed'bilaterally contracted kidneys with lobulated appearance. A bilateral renal arteriogram revealed small kidneys with irregular contours and splaying of the interlobar arteries (fig. 1). A voiding cystourethrogram showed right ureteral reflux (fig. 2). The patient was treated with 40 mEq. sodium, high protein diet, methyldopa, furosemide and a nightly dose of trimethoFm. 1. Renal arteriogram demonstrates changes consistent with prim-sulfa following a 2-week course of ampicillin. chronic pyelonephritis. Five months later the patient was rehospitalized because of anasarca and uncontrolled hypertension owing to dietary type of proteinuria is not described. Our patient had no hisindiscretion and omission of medication. Blood pressure was torical, histological or serological evidence of glomerular dis150/120 mm. Hg with marked periorbital and leg edema. BUN ease. The sparsity of foot process fusion excludes the likeliwas 47 mg. per cent, creatinine 3.3 mg. per cent, serum choleshood of minimal change nephritis in our patient. The absence terol 657 mg. per cent and serum albumin 1.9 gm. Urine culture of electron dense deposits would make the presence of immuyielded no growth and 24-hour urine protein was 10.9 gm. An noglobulins in the basement membrane unlikely. There was no open renal biopsy revealed a severely scarred kidney. Light evidence of lupus nephritis or diabetes mellitus. microscopy showed extensive interstitial and periglomerular The etiology of proteinuria in renal disease is controversial. fibrosis with patches of cellular infiltration and intimal hyperGenerally it is believed that proteinuria, particularly alplasia of the arterioles. The glomeruli were ischemic with no buminuria, results from abnormal leakage of protein across the evidence of proliferation or capillary wall thickening. Electron glomerular basement membrane with inadequate ability of microscopic examination of the glomeruli showed no evidence of electron dense particle deposition or basement membrane tubules to reabsorb the filtered protein. Rarely, tubular diseases such as Balkan nephritis have been associated with prothickening and only minimal focal foot process fusion. teinuria, • which is predominantly globulins rather than albumin. The pattern of proteinuria seen in our patient with Accepted for publication July 3, 1975.
108
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NEPHROTIC SYNDROME
proved evidence of chronic pyelonephritis was the pattern expected to be seen with glomerular disease. Since no abnormalities usually associated with various glomerular disease were seen in our patient we postulate that the persistent reflux and secondary infection resulted in the production of a substance by the renal parenchyma, which increased the permeability of the glomerular basement membrane. The absence of electron dense deposits would suggest that this substance is not immune complexes. The presence of nephrotic syndrome is so unusual in chronic pyelonephritis that full urologic evaluation should be performed in such patients in addition to investigation for immunologic glomerulonephritis. In those patients in whom no glomerular lesion is found the possibility of toxic damage to the glomerular basement membrane should be entertained if urinary protein excretion is predominately albumin. REFERENCES
1. Pillary, V.
FIG. 2. Voiding cystourethrogram demonstrates ureteral reflux
K. G., Battifora, H., Schwartz, F. D., Buenger, R. E. and
Kark, R. M.: Massive proteinuria associated with vesico-ureteral reflux. Lancet, 2: 1272, 1969. 2. Zimmerman, S. W., Uehling, D. T. and Burkholder, P. M.: Vesicoureteral reflux nephropathy. Evidence for immunologically mediated glomerular injury. Urology, 2: 534, 1973. 3. Nicastri, A. D.: Massive proteinuria associated with chronic pyelonephritis. Urology, 2: 588, 1973. 4. Strauss, M. B. and Welt, L. G.: Diseases of the Kidney, 2nd ed. Boston: Little, Brown and Co., p. 1071, 1971.
THE JOURNAL OF UROLOGY
Copyright© 1976 by The Williams & Wilkins Co.
NEPHROTIC SYNDROME SECONDARY TO CHRONIC PYELONEPHRITIS AND URETEROVESICAL REFLUX SALOMON DAYAN
AND
EARL C. SMITH
From the Renal Division, Mt. Sinai Hospital Medical Center, Chicago, Illinois
ABSTRACT
Vesicoureteral reflux and chronic pyelonephritis are usually associated with proteinuria of less than 1 gm. per 24 hours. When there is massive proteinuria an associated glomerulopathy is usually present. We describe a patient who had nephrotic syndrome with radiological evidence of ureterovesical reflux and histological evidence of chronic pyelonephritis without associated glomerulonephritis. DISCUSSION Nephrotic syndrome is usually defined as proteinuria more than 3 gm. per 24 hours, hypoalbuminemia and hypercholesThe nephrotic syndrome in the presence of chronic pyeloneteremia. It may or may not be associated with chronic phritis is usually associated with glomerular disease. Pillary pyelonephritis secondary to ureterovesical reflux, is usually and associates described 3 patients with massive proteinuria, minimal and rarely sufficient to produce clinical manifesta- vesicoureteral reflux and pyelographic clubbing of the calices tions associated with nephrotic syndrome. The occurrence of associated with small kidneys. 1 However, renal biopsies remassive proteinuria usually reflects glomerular rather than vealed glomerulonephritis in 2 and nephrosclerosis in 1. Zimtubular or interstitial disease. merman and associates, 2 and Nicastri 3 noted glomerular lesions outside the scarred areas consisting of granular deCASE REPORT posits of complement, and IgM and IgG, respectively, in the A 17-year-old Puerto Rican woman was hospitalized with the mesangial and subendothelial regions in 8 patients with chief complaint of swelling of the ankles 1 week in duration. chronic pyelonephritis and heavy proteinuria. However, the There was no history of hematuria, flank pain, dysuria, arthralgia, skin rash, sore throat or dark urine. There was no exposure to heavy metals or nephrotoxic drugs. Physical examination revealed blood pressure of 150/130 mm. Hg, mild facial puffiness and 2 plus edema. Laboratory studies included blood urea nitrogen (BUN) 37 mg. per cent, creatinine 2.2 mg. per cent and serum protein electrophoresis of albumin 2.2 gm. per cent, 0.3 gm. per cent alpha,, 2.2 gm. per cent alpha 2, 0.8 gm. per cent beta and 0.5 gm. per cent gamma. Serum cholesterol was 363 mg. per cent and triglycerides 246 mg. per cent. Urinalysis showed pH 6.0, specific gravity 1.013 and no casts. Urine culture yielded consistently Escherichia coli. A 24-hour urine protein was 3.74 gm. and urine protein electrophoresis revealed 75.5 per cent albumin-3.3 per cent alpha., 4.2 per cent alpha2, 9.3 per cent beta and 6.2 per cent gamma. Lupus erythematosus preparation, and antinuclear antibodies, C 3 and C, were repeatedly normal. An excretory urogram revealed'bilaterally contracted kidneys with lobulated appearance. A bilateral renal arteriogram revealed small kidneys with irregular contours and splaying of the interlobar arteries (fig. 1). A voiding cystourethrogram showed right ureteral reflux (fig. 2). The patient was treated with 40 mEq. sodium, high protein diet, methyldopa, furosemide and a nightly dose of trimethoFm. 1. Renal arteriogram demonstrates changes consistent with prim-sulfa following a 2-week course of ampicillin. chronic pyelonephritis. Five months later the patient was rehospitalized because of anasarca and uncontrolled hypertension owing to dietary type of proteinuria is not described. Our patient had no hisindiscretion and omission of medication. Blood pressure was torical, histological or serological evidence of glomerular dis150/120 mm. Hg with marked periorbital and leg edema. BUN ease. The sparsity of foot process fusion excludes the likeliwas 47 mg. per cent, creatinine 3.3 mg. per cent, serum choleshood of minimal change nephritis in our patient. The absence terol 657 mg. per cent and serum albumin 1.9 gm. Urine culture of electron dense deposits would make the presence of immuyielded no growth and 24-hour urine protein was 10.9 gm. An noglobulins in the basement membrane unlikely. There was no open renal biopsy revealed a severely scarred kidney. Light evidence of lupus nephritis or diabetes mellitus. microscopy showed extensive interstitial and periglomerular The etiology of proteinuria in renal disease is controversial. fibrosis with patches of cellular infiltration and intimal hyperGenerally it is believed that proteinuria, particularly alplasia of the arterioles. The glomeruli were ischemic with no buminuria, results from abnormal leakage of protein across the evidence of proliferation or capillary wall thickening. Electron glomerular basement membrane with inadequate ability of microscopic examination of the glomeruli showed no evidence of electron dense particle deposition or basement membrane tubules to reabsorb the filtered protein. Rarely, tubular diseases such as Balkan nephritis have been associated with prothickening and only minimal focal foot process fusion. teinuria, • which is predominantly globulins rather than albumin. The pattern of proteinuria seen in our patient with Accepted for publication July 3, 1975.
108
109
NEPHROTIC SYNDROME
proved evidence of chronic pyelonephritis was the pattern expected to be seen with glomerular disease. Since no abnormalities usually associated with various glomerular disease were seen in our patient we postulate that the persistent reflux and secondary infection resulted in the production of a substance by the renal parenchyma, which increased the permeability of the glomerular basement membrane. The absence of electron dense deposits would suggest that this substance is not immune complexes. The presence of nephrotic syndrome is so unusual in chronic pyelonephritis that full urologic evaluation should be performed in such patients in addition to investigation for immunologic glomerulonephritis. In those patients in whom no glomerular lesion is found the possibility of toxic damage to the glomerular basement membrane should be entertained if urinary protein excretion is predominately albumin. REFERENCES
1. Pillary, V.
FIG. 2. Voiding cystourethrogram demonstrates ureteral reflux
K. G., Battifora, H., Schwartz, F. D., Buenger, R. E. and
Kark, R. M.: Massive proteinuria associated with vesico-ureteral reflux. Lancet, 2: 1272, 1969. 2. Zimmerman, S. W., Uehling, D. T. and Burkholder, P. M.: Vesicoureteral reflux nephropathy. Evidence for immunologically mediated glomerular injury. Urology, 2: 534, 1973. 3. Nicastri, A. D.: Massive proteinuria associated with chronic pyelonephritis. Urology, 2: 588, 1973. 4. Strauss, M. B. and Welt, L. G.: Diseases of the Kidney, 2nd ed. Boston: Little, Brown and Co., p. 1071, 1971.
