Case Report Nephron 1992:61:106-110
Cecilia Montoyaa Miguel Angel Martinezb Carlas Campaa Auxiliadora Mazuecosa Amada Andrésa Manuel Pragaa
Nephrotic Syndrome and Focal Glomerulosclerosis in Adult Polycystic Kidney Disease
Departments of a Nephrology and h Pathology Hospital 12 de Octubre, Madrid, Spain
Abstract We report a 35-year-old man with adult polycystic kidney disease (APKD) that developed nephrotic syndrome accompanied by a rapid worsening of renal function. Histologic examination showed marked tubulointerstitial chronic ab normalities and focal glomerulosclerosis (FGS) lesions in 24% of the glomeruli. With captopril, an angiotensin-converting enzyme inhibitor, proteinuria showed a clear decrease, but renal function continued to deteriorate. No other cases of nephrotic-range proteinuria were detected among 65 APKD patients with renal insufficiency. Histologic examination of an other 12 kidneys removed from patients with APKD showed striking interstitial lesions, most of the glomeruli being normal. However, those patients with higher amounts of proteinuria had more glomeruli (14-32%) with FGS lesions.
Introduction Although moderate amounts of proteinuria are observed in many patients with adult polycystic kidney disease (APKD), the development of nephrotic syndrome is consid ered to be an exceptional complication of this disease [1]. A few APKD patients in which proteinuria reached nephrotic range have been described [2-6] and the scarce histologic descriptions have shown several glomerular abnormalities (IgA nephropathy, rapidly progressive glomerulonephritis, focal glomerulosclerosis) [4-6]. On the other hand, a consid erable interest concerning the implications of adaptive hemodynamic and hypertrophic factors in the progression of renal insufficiency in APKD has risen in the last years
Accepted: August 2.1991
[7-9]. Proteinuria and focal glomerulosclerosis (FGS) are the characteristic consequences of these adaptive patho genic mechanisms. Here, we report a patient with APKD and renal insuffi ciency that developed nephrotic syndrome, with massive proteinuria and renal function worsening. With captopril treatment, proteinuria showed a striking decrease but renal function continued to deteriorate. Histologic study showed FGS lesions in a considerable proportion of glomeruli. This clinical observation prompted us to review the presence of proteinuria in our APKD patients. In addition, the removed kidneys of patients with APKD were studied in order to analyse the incidence of sclerotic lesions.
M . Praga Servicio de Nefrologia. Hospital 12 de Octubre Cira. Andalucía km 5.400 n 28041 M adrid (Spain)
© 1992 S. Karger A G, Basel 0028-2766/92/ 0611-OI06S2.75/0
Downloaded by: UCL 144.82.238.225 - 2/18/2018 11:14:09 AM
Key Words Polycystic kidney disease Nephrotic-range proteinuria Focal glomerulosclerosis Renal failure Captopril
Material and Methods Case Report
A 35-year-old man was referred to our department in 1985 because of macroscopic hematuria. He had a family history of APKD. Blood pressure was 160/100 mm Hg and physical examination revealed large and palpable kidneys. Renal function was normal, proteinuria was 0.5 g/24 h and urinary sediment showed microhematuria. Abdominal echography diagnosed APKD. showing 2 large kidneys occupied by numerous cysts of variable sizes. Treatment with propranolol and hydralazine was started. In the following years, renal function showed a slow deterioration with a serum creatinine (SCr) of 141.4-159 pmol/l (1.6—1.8 mg/dl) and a creatinine clearance (CrCI) of 60-70 ml/min. Blood pressure was controlled with antihypertensive treatment, and proteinuria oscillated between 0.5 and I g/24 h. The patient com plained of repeated episodes of abdominal pain, related with the large volume of the kidneys (more than 25 cm of longitudinal diameter). In September 1989, SCr was 194.5 umol/1 (2.2 mg/dl), CrCI 40 ml/min and proteinuria I g/24 h. Two months later, he noted bilateral pedal edema; blood pressure was 140/90 mm Hg and physical exploration did not show significant changes except for the presence of malleolar edema. Analytical studies offered the following data; hematocrit 32%, hemoglobin 1.38 mmol/1 (8.9 mg/dl), serum total proteins 48 g/l, serum albumin 24 g/l, serum cholesterol 6.01 mmol/1 (232 mg/dl), SCr 309.4 pm ol/l (3.5 mg/dl) and CrCI 22 ml/min. Proteinuria oscillated between 9 and 14 g/24 h, and urinalysis showed isolated erythrocytes and leukocytes. Urine cultures were negative. Echographic study did not disclose urinary obstruction nor other significant changes, but the right kidney had enlarged even more reaching 30 cm of longitudinal diameter. Propranolol and hydralazine were withdrawn, and captopril (150 mg/day) was administered. Proteinuria decreased to 1.7-2.8 g / 24 h, and serum total proteins increased to 66 g/l but renal function continued to deteriorate, SCr being 486.2 pm ol/l (5.5 m g/dl) 2 months later. At that moment, because of progressive abdominal symptoms (compression of abdominal organs with anorexia, vomits and post prandial pain), right nephrectomy was performed. Measurements of excised kidney were 30 x 17 x 4 cm. Renal parenchyma was distorted by numerous cysts filled by hematic or serous content. Microscopic examination showed a striking interstitial fibrosis, arteriolar sclerosis and chronic atrophic changes in tubules with cystic dilatation in many of them (fig. I). 64% of the glomeruli were normal, 24% of them showed FGS lesions and 12% exhibited global glomerular sclerosis (GG S; fig. 2). Immunofluorescence demonstrated isolated deposition of IgM in areas of glomerular sclerosis. Despite improvement of abdominal symptoms, renal function worsened progressively and hemodialysis was started I month later.
Fig-1. Renal parenchyma showing multiple cysts and interstitial fibrosis. HE. x40.
Fig. 2.
Glomerulus showing segmental glomerular sclerosis.
HE. x 100.
Evaluation o f Proteinuria Table 1.
Proteinuria
Proteinuria, g/24 h
in APKD patients
Number of patients n
0 160/ 95 mm Hg without antihypertensive treatment). Mean SCr was 645.3±282.8 pm ol/l (7.3± 3.2 m g/dl; range 132.6-1361.3 pm ol/l: 1.5-15.4 mg/dl) and CrCI 11.4 ± 8.9 ml/min (2.7-40 ml/min). As can be seen in table 1, most of the patients (60%) had proteinuria lower than 1 g/24 h, and no other patient with nephrotic-range proteinuria was found. Patients with arterial hypertension had proteinuria significant ly higher than those with normal blood pressure (1.2 ±1.9 versus 0.4 ± 0.3 g/24 h, p < 0.01). Men also had higher proteinuria values than
Table 2. Histolo-
Patient
Sex
Age years
Proteinuria g/24 h
Renal function
Normal glomeruli, %
FGS. %
GGS. %
I 2 3 4 5 6 7 8 9 10 II 12 Case report
F F F F F M F F M M M M M
35 42 65 45 48 27 43 44 51 52 49 49 35 45 ± 9
0 0 0.1 0.2 0.2 0.3 0.4 0.5 0.7 0.8 1.9 1.9 13 1.5 ±3.5
HD HD SCr 3 mg/dl HD HD SCr 1.8 mg/dl HD HD HD HD HD HD SCr 3.5 mg/dl
80 89 84 50 80 100 98 71 86 100 60 72 64 79 ±15.7
10 7 8 0 0 0 2 0 0 0 32 14 24 7.5 ±10.4
10 4 8 50 20 0 0 29 14 0 8 14 12 13.2 ±13.9
H D = Hemodialysis.
Histologic Study
12 kidneys removed from patients with APKD were studied be sides that of the patient reported. The reason for nephrectomy had been recurrent infections in 5 cases, preparation for a future kidney graft in 4 and recurrent abdominal pain in I; in another 2 cases, a necropsic study was performed after exitus because o f cardiovascular diseases. 10 patients were on hemodialysis at the time of nephrectomy (table 2). The longitudinal diameter of the kidneys oscillated between 14 and 30 cm. The microscopic study showed similar data in every case: numerous cysts separated by a fibrous interstitium with atrophic tubules and frequent periglomerular fibrosis. The analysis of glomeru lar lesions is shown in table 2: Most of the glomeruli (79 ±15.7%) were normal; FGS lesions were observed in 0-32% of them (7.5 ± 10.4) and those of GGS in 0-50% (13.2 ±13.9). Mean glomerular diameters oscillated between 160 and 316 pm (220±4I). No correlations were found between glomerular diameters, proteinuria ranges and FGS lesions.
Discussion According to the results of the most extensive series, the presence of nephrotic-range proteinuria is exceptional in APKD [10, 11, 12], Dalgaard et al. [10] found 3 cases with proteinuria higher than 5 g/day over a total of 122 cases. Rail et al. [11] reported proteinuria of + + + or + + + + in 9% of 207 cases, and Praga et al. [12] found only 1case with nephrotic-range proteinuria in a series of 106 cases. In the
108
present study, we did not find any other case of nephroticrange proteinuria among 65 APKD cases with renal insuffi ciency (table 1). Most (60%) of the patients had proteinuria lower than I g/day. Male and hypertensive patients had significantly higher values of proteinuria but no correlation was found between proteinuria range and renal function. More detailed descriptions of APKD patients with ne phrotic proteinuria have been published by Ackerman et al. [2] (2 patients with APKD and renal insufficiency, with proteinuria of 7 and 10 g/day, respectively, and hypoalbuminemia)and Martinez-Vea et al. [3] (1 case with proteinuria of 4-7 g/day) but histologic studies were not done in these cases. Very few cases of APKD with nephrotic syndrome and histologic descriptions have been published so far. Licina et al. [5] described a case of APKD with nephrotic proteinuria and acute renal failure; renal biopsy showed crescentic glomerulonephritis. Panisello et al. [4] described another case in which renal biopsy demonstrated IgA nephropathy with FGS lesions. In these 2 cases, the development of nephrotic proteinuria appeared to be the consequence of a superimposed glomerular disease. More recently, Murphy et al. [6] have reported a patient with development of nephrotic proteinuria and rapid worsening of renal func tion. Renal biopsy showed FGS lesions in 32.2% of the glomeruli, and GGS lesions in 22.6%, the remaining being normal. These authors suggest that mechanisms of glomer ular hyperfiltration could play an important role in the development of FGS and proteinuria in their case.
M ontoyo/M artinez/Cam po/M azuecos/ Andrés/Praga
Nephrotic Syndrome and Polycystic Kidneys
Downloaded by: UCL 144.82.238.225 - 2/18/2018 11:14:09 AM
women (1.4± 2.2 versus 0.5±0.6 g/24 h, p50 mEq), and 4 steroid-responsive nephrotic patients, and 12 normal controls were studied with a 4-hour water immersion with measurements of electrolytes, plasma atrial natriuretic peptide (ANP), plasma renin activity (PRA). and plasma aldosterone (PA).’
Cecilia Montoyaa Miguel Angel Martinezb Carlas Campaa Auxiliadora Mazuecosa Amada Andrésa Manuel Pragaa
Nephrotic Syndrome and Focal Glomerulosclerosis in Adult Polycystic Kidney Disease
Departments of a Nephrology and h Pathology Hospital 12 de Octubre, Madrid, Spain
Abstract We report a 35-year-old man with adult polycystic kidney disease (APKD) that developed nephrotic syndrome accompanied by a rapid worsening of renal function. Histologic examination showed marked tubulointerstitial chronic ab normalities and focal glomerulosclerosis (FGS) lesions in 24% of the glomeruli. With captopril, an angiotensin-converting enzyme inhibitor, proteinuria showed a clear decrease, but renal function continued to deteriorate. No other cases of nephrotic-range proteinuria were detected among 65 APKD patients with renal insufficiency. Histologic examination of an other 12 kidneys removed from patients with APKD showed striking interstitial lesions, most of the glomeruli being normal. However, those patients with higher amounts of proteinuria had more glomeruli (14-32%) with FGS lesions.
Introduction Although moderate amounts of proteinuria are observed in many patients with adult polycystic kidney disease (APKD), the development of nephrotic syndrome is consid ered to be an exceptional complication of this disease [1]. A few APKD patients in which proteinuria reached nephrotic range have been described [2-6] and the scarce histologic descriptions have shown several glomerular abnormalities (IgA nephropathy, rapidly progressive glomerulonephritis, focal glomerulosclerosis) [4-6]. On the other hand, a consid erable interest concerning the implications of adaptive hemodynamic and hypertrophic factors in the progression of renal insufficiency in APKD has risen in the last years
Accepted: August 2.1991
[7-9]. Proteinuria and focal glomerulosclerosis (FGS) are the characteristic consequences of these adaptive patho genic mechanisms. Here, we report a patient with APKD and renal insuffi ciency that developed nephrotic syndrome, with massive proteinuria and renal function worsening. With captopril treatment, proteinuria showed a striking decrease but renal function continued to deteriorate. Histologic study showed FGS lesions in a considerable proportion of glomeruli. This clinical observation prompted us to review the presence of proteinuria in our APKD patients. In addition, the removed kidneys of patients with APKD were studied in order to analyse the incidence of sclerotic lesions.
M . Praga Servicio de Nefrologia. Hospital 12 de Octubre Cira. Andalucía km 5.400 n 28041 M adrid (Spain)
© 1992 S. Karger A G, Basel 0028-2766/92/ 0611-OI06S2.75/0
Downloaded by: UCL 144.82.238.225 - 2/18/2018 11:14:09 AM
Key Words Polycystic kidney disease Nephrotic-range proteinuria Focal glomerulosclerosis Renal failure Captopril
Material and Methods Case Report
A 35-year-old man was referred to our department in 1985 because of macroscopic hematuria. He had a family history of APKD. Blood pressure was 160/100 mm Hg and physical examination revealed large and palpable kidneys. Renal function was normal, proteinuria was 0.5 g/24 h and urinary sediment showed microhematuria. Abdominal echography diagnosed APKD. showing 2 large kidneys occupied by numerous cysts of variable sizes. Treatment with propranolol and hydralazine was started. In the following years, renal function showed a slow deterioration with a serum creatinine (SCr) of 141.4-159 pmol/l (1.6—1.8 mg/dl) and a creatinine clearance (CrCI) of 60-70 ml/min. Blood pressure was controlled with antihypertensive treatment, and proteinuria oscillated between 0.5 and I g/24 h. The patient com plained of repeated episodes of abdominal pain, related with the large volume of the kidneys (more than 25 cm of longitudinal diameter). In September 1989, SCr was 194.5 umol/1 (2.2 mg/dl), CrCI 40 ml/min and proteinuria I g/24 h. Two months later, he noted bilateral pedal edema; blood pressure was 140/90 mm Hg and physical exploration did not show significant changes except for the presence of malleolar edema. Analytical studies offered the following data; hematocrit 32%, hemoglobin 1.38 mmol/1 (8.9 mg/dl), serum total proteins 48 g/l, serum albumin 24 g/l, serum cholesterol 6.01 mmol/1 (232 mg/dl), SCr 309.4 pm ol/l (3.5 mg/dl) and CrCI 22 ml/min. Proteinuria oscillated between 9 and 14 g/24 h, and urinalysis showed isolated erythrocytes and leukocytes. Urine cultures were negative. Echographic study did not disclose urinary obstruction nor other significant changes, but the right kidney had enlarged even more reaching 30 cm of longitudinal diameter. Propranolol and hydralazine were withdrawn, and captopril (150 mg/day) was administered. Proteinuria decreased to 1.7-2.8 g / 24 h, and serum total proteins increased to 66 g/l but renal function continued to deteriorate, SCr being 486.2 pm ol/l (5.5 m g/dl) 2 months later. At that moment, because of progressive abdominal symptoms (compression of abdominal organs with anorexia, vomits and post prandial pain), right nephrectomy was performed. Measurements of excised kidney were 30 x 17 x 4 cm. Renal parenchyma was distorted by numerous cysts filled by hematic or serous content. Microscopic examination showed a striking interstitial fibrosis, arteriolar sclerosis and chronic atrophic changes in tubules with cystic dilatation in many of them (fig. I). 64% of the glomeruli were normal, 24% of them showed FGS lesions and 12% exhibited global glomerular sclerosis (GG S; fig. 2). Immunofluorescence demonstrated isolated deposition of IgM in areas of glomerular sclerosis. Despite improvement of abdominal symptoms, renal function worsened progressively and hemodialysis was started I month later.
Fig-1. Renal parenchyma showing multiple cysts and interstitial fibrosis. HE. x40.
Fig. 2.
Glomerulus showing segmental glomerular sclerosis.
HE. x 100.
Evaluation o f Proteinuria Table 1.
Proteinuria
Proteinuria, g/24 h
in APKD patients
Number of patients n
0 160/ 95 mm Hg without antihypertensive treatment). Mean SCr was 645.3±282.8 pm ol/l (7.3± 3.2 m g/dl; range 132.6-1361.3 pm ol/l: 1.5-15.4 mg/dl) and CrCI 11.4 ± 8.9 ml/min (2.7-40 ml/min). As can be seen in table 1, most of the patients (60%) had proteinuria lower than 1 g/24 h, and no other patient with nephrotic-range proteinuria was found. Patients with arterial hypertension had proteinuria significant ly higher than those with normal blood pressure (1.2 ±1.9 versus 0.4 ± 0.3 g/24 h, p < 0.01). Men also had higher proteinuria values than
Table 2. Histolo-
Patient
Sex
Age years
Proteinuria g/24 h
Renal function
Normal glomeruli, %
FGS. %
GGS. %
I 2 3 4 5 6 7 8 9 10 II 12 Case report
F F F F F M F F M M M M M
35 42 65 45 48 27 43 44 51 52 49 49 35 45 ± 9
0 0 0.1 0.2 0.2 0.3 0.4 0.5 0.7 0.8 1.9 1.9 13 1.5 ±3.5
HD HD SCr 3 mg/dl HD HD SCr 1.8 mg/dl HD HD HD HD HD HD SCr 3.5 mg/dl
80 89 84 50 80 100 98 71 86 100 60 72 64 79 ±15.7
10 7 8 0 0 0 2 0 0 0 32 14 24 7.5 ±10.4
10 4 8 50 20 0 0 29 14 0 8 14 12 13.2 ±13.9
H D = Hemodialysis.
Histologic Study
12 kidneys removed from patients with APKD were studied be sides that of the patient reported. The reason for nephrectomy had been recurrent infections in 5 cases, preparation for a future kidney graft in 4 and recurrent abdominal pain in I; in another 2 cases, a necropsic study was performed after exitus because o f cardiovascular diseases. 10 patients were on hemodialysis at the time of nephrectomy (table 2). The longitudinal diameter of the kidneys oscillated between 14 and 30 cm. The microscopic study showed similar data in every case: numerous cysts separated by a fibrous interstitium with atrophic tubules and frequent periglomerular fibrosis. The analysis of glomeru lar lesions is shown in table 2: Most of the glomeruli (79 ±15.7%) were normal; FGS lesions were observed in 0-32% of them (7.5 ± 10.4) and those of GGS in 0-50% (13.2 ±13.9). Mean glomerular diameters oscillated between 160 and 316 pm (220±4I). No correlations were found between glomerular diameters, proteinuria ranges and FGS lesions.
Discussion According to the results of the most extensive series, the presence of nephrotic-range proteinuria is exceptional in APKD [10, 11, 12], Dalgaard et al. [10] found 3 cases with proteinuria higher than 5 g/day over a total of 122 cases. Rail et al. [11] reported proteinuria of + + + or + + + + in 9% of 207 cases, and Praga et al. [12] found only 1case with nephrotic-range proteinuria in a series of 106 cases. In the
108
present study, we did not find any other case of nephroticrange proteinuria among 65 APKD cases with renal insuffi ciency (table 1). Most (60%) of the patients had proteinuria lower than I g/day. Male and hypertensive patients had significantly higher values of proteinuria but no correlation was found between proteinuria range and renal function. More detailed descriptions of APKD patients with ne phrotic proteinuria have been published by Ackerman et al. [2] (2 patients with APKD and renal insufficiency, with proteinuria of 7 and 10 g/day, respectively, and hypoalbuminemia)and Martinez-Vea et al. [3] (1 case with proteinuria of 4-7 g/day) but histologic studies were not done in these cases. Very few cases of APKD with nephrotic syndrome and histologic descriptions have been published so far. Licina et al. [5] described a case of APKD with nephrotic proteinuria and acute renal failure; renal biopsy showed crescentic glomerulonephritis. Panisello et al. [4] described another case in which renal biopsy demonstrated IgA nephropathy with FGS lesions. In these 2 cases, the development of nephrotic proteinuria appeared to be the consequence of a superimposed glomerular disease. More recently, Murphy et al. [6] have reported a patient with development of nephrotic proteinuria and rapid worsening of renal func tion. Renal biopsy showed FGS lesions in 32.2% of the glomeruli, and GGS lesions in 22.6%, the remaining being normal. These authors suggest that mechanisms of glomer ular hyperfiltration could play an important role in the development of FGS and proteinuria in their case.
M ontoyo/M artinez/Cam po/M azuecos/ Andrés/Praga
Nephrotic Syndrome and Polycystic Kidneys
Downloaded by: UCL 144.82.238.225 - 2/18/2018 11:14:09 AM
women (1.4± 2.2 versus 0.5±0.6 g/24 h, p50 mEq), and 4 steroid-responsive nephrotic patients, and 12 normal controls were studied with a 4-hour water immersion with measurements of electrolytes, plasma atrial natriuretic peptide (ANP), plasma renin activity (PRA). and plasma aldosterone (PA).’
