Obesity-Associated Focal Segmental Glomerulosclerosis: Pathological Features of the Lesion and Relationship With Cardiomegaly and Hyperlipidemia Regina R. Verani, MD • In a review of the autopsies and medical records of 22 obese patients, focal segmental glomerulosclerosis (FSGS) was present in seven. The FSGS was mild in all but one patient. The FSGS of obese patients has similar features to idiopathic FSGS; however, our findings suggest that it lacks the hyperplasia of glomerular epithelial cells, shows no predilection for the corticomedullary junction, and is probably more often seen in the hilar region of the glomeruli. FSGS or glomerulomegaly was not associated with the degree of obesity. We demonstrated lipid deposition in the kidney of obese patients. Obese patients with FSGS, compared to those without FSGS, had higher blood cholesterol (P < 0.10) and higher triglyceride levels (P < 0.05). The mean heart weight of obese patients with FSGS was greater than that of patients without FSGS (P < 0.01). Also, obese patients with FSGS had larger glomeruli (246 ± 33jLm) than obese patients without FSGS (218 ± 16 jLm) (P < 0.05). These findings suggest that cardiomegaly with hemodynamic changes and glomerular hyperfiltration may playa significant role in the glomerulomegaly and FSGS of obese patients. The secondary or contributory role of lipids in the development of the FSGS of obese patients remains to be determined. © 1992 by the National Kidney Foundation, Inc. INDEX WORDS: Obesity; focal segmental glomerulosclerosis; proteinuria; hyperlipidemia; electron microcopy; cardiomegaly; glomerulomegaly.
S
EVERAL CAUSES of proteinuria and nephrotic syndrome are well recognized. A not well-known and unclear cause of proteinuria and focal segmental glomerulosclerosis (FSGS) is obesity.I.5 Glomerular hyperfiltration has been proposed to be a cause of proteinuria and FSGS. 6 It has been suggested that hypoxemia with increased venous hypertension and consequential glomerular hyperfiltration could also explain the cause of proteinuria and FSGS in obese patients. 3 However, recent reports have discussed the analogies ofFSGS with atherosclerosis and have suggested that hyperlipidemia is a possible cause and/ or factor in the development and/or progression of focal segmental glomerulosclerosis. 7. 9 Experimental studies have shown a relationship with hyperlipidemia, proteinuria, and FSGS. IO- 12 The induction of glomerulosclerosis by dietary lipids II and the reduction of glomerular injury by the treatment of hyperlipidemia 12 have been demonstrated in Zucker obese rats. The objective of this study was to determine the general incidence of FSGS in obese patients, to speculate about its relationship with hemodynamic changes, hypoxemia, hyperlipidemia, and to describe the features of the lesion FSGS in obese patients. MATERIALS AND METHODS The medical records and autopsy findings of 22 patients with the diagnosis of obesity (mean body weight, 317.26 ± 143 lb) were reviewed. These patients were selected from the autopsy files of 4 consecutive years. Cases with the clinical and autopsy diagnosis of obesity were included in this study. The
patients fulfilled the criteria for obesity, according to the National Center for Health Statistics, which is more than 20% of desira.b1e body weight. II The desirable body weight is based on the Fogarty table. 13 The gross descriptions of the autopsies were reviewed and information was obtained regarding body length, body weight, heart weight, kidney weight, and degree of atherosclerosis. Histological examination of the kidneys was performed with examination of at least one paraffinembedded section from each kidney, stained with periodic acid-Schiff (PAS). The percentage of glomeruli with FSGS was defined after counting 200 glomeruli. The diameters of 40 glomeruli from each case (20 from the superficial cortex and 20 from the deep cortex) were measured under the microscope with a lOX W.E. AO 180-metered objective. Only glomeruli sectioned at the hilar region were measured. Glomeruli with segmental or global glomerulosclerosis were not included in the measurements. Histological examination of the kidneys with measurement of the same number of glomeruli was performed in 15 control, autopsied, nonobese patients (mean body weight, 148.13 ± 27.6 lb), without renal disease, matched for sex and age. Special staining for fat (osmium tetroxide) was performed in the kidney of nine obese patients (four with FSGS and five without FSGS) from which wet tissue was available. Electron microscopic examination was performed in six of seven cases with FSGS. In the other case, tissue or blocks of renal tissue were not available. From the Department of Pathology and Laboratory Medicine. University of Texas Medical School at Houston. Houston. TX Received December 23. 1991; accepted in revised form August 11. 1992. Presented in part at the International Academy ofPathology Meeting. Boston. MA. March 1990. Address reprint requests to Regina R. Verani. MD. University of Texas Medical School at Houston. Department of Pathology and Laboratory Medicine. PO Box 20708. Houston. TX 77030. © 1992 by the National Kidney Foundation. Inc. 0272-6386/92/2006-0016$3.00/0
American Journal of Kidney Diseases, Vol XX, No 6 (December), 1992: pp 629-634
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glomeruli; however, the number of glomeruli with focal segmental glomerulosclerosis was too small for a meaningful evaluation. The FSGS was characterized by segmental areas of increase in mesangial matrix and collapse of capillary lumens with a lack of proliferation of visceral epithelial cells (Fig 2). The presence of lipid material was demonstrated with osmium tetroxide stain in a few glomeruli related to the areas of FSGS. In obese patients with and without FSGS, lipid stain was also positive in scattered glomerular cells, suggestive of mesangial and epithelial cells. A few globally sclerosed glomeruli were observed in the superficial and deep cortex in 10 of 22 cases; in the case of end-stage renal disease, several globally sclerosed glomeruli were observed. Dilatation of the Bowman's space was observed in a few glomeruli in some cases; however, in four cases, it was seen in the majority of the glomeruli. The same incidence of global glomerulosclerosis was observed in the non obese control patients; how-
Fig 1. Obese patient with end-stage renal disease: The glomeruli show dilatation of Bowman's space and proliferation of mesangial cells. Global glomerulosclerosis (small arrows) and FSGS (large arrow) are seen. There is interstitial fibrosis and tubular atrophy. (PAS; original magnification X100.)
The medical records of these patients were reviewed and all patients had a clinical diagnosis of obesity. The charts were specifically examined for the diagnosis of hypertension, diabetes, and sleep apnea. Cases with insulin-dependent diabetes and/or diabetic glomerulosclerosis were excluded. The laboratory data were searched for the values of blood cholesterol and triglycerides and for the urinary protein excretion.
RESULTS
FSGS was observed in seven of 22 obese patients. In six patients, FSGS was observed in only a few glomeruli (two to four glomeruli in each kidney section; 0.5). Eight patients, three with and five without FSGS, had the diagnosis of hypertension. The heart weight of obese patients with clinical hypertension was 490 ± 160 g versus 568 ± 166 g for obese patients without history of hypertension. There was a relationship between the heart weight and the presence of FSGS. The heart weight in obese patients with FSGS was 671 ± 142 g versus 478 ± 139 g in obese patients without FSGS (P < 0.0 I) (Table 1). Moderate atherosclerosis of the aorta and/or coronary arteries was present in eight obese patients (four with FSGS and four without FSGS). In only three patients, there was narrowing of the coronary artery of more than 50% (one with and two without FSGS). There was no relationship between the weight of the kidneys and the presence or absence of FSGS. Urinary protein measurements were available in four patients, two with and two without FSGS. Proteinuria was observed in two patients with FSGS. No proteinuria was present in the two patients without FSGS. One female patient with FSGS had recent onset of end-stage renal disease, without any history of previous renal disease, and was on hemodialysis for the last 3 months before her death. Lipid profile was available in the seven patients with FSGS and in nine of 15 patients without
Table 1. Relationship of FSGS With Body Weight, Heart Weight, and Blood Lipid Levels p Obese Patients With FSGS
Body Weight Heart Weight Serum Cholesterol Serum Triglycerides
267 ± 421b 671±142g 4.76 ± 1 4 . 5 mmol/L (184 ± 56 mg/dL) 2.70 ± 119 mmol/L (239 ± 119 mg/dL)
Obese Patients Without FSGS
307 478 3.34 1.45
± ± ± ±
1451b 139 9 12 . 2 mmol/L (129 ± 47 mg/dL) 0.58 mmol/L (128 ± 51 mg/dL)
Value
> 0.5 < 0.01
S
EVERAL CAUSES of proteinuria and nephrotic syndrome are well recognized. A not well-known and unclear cause of proteinuria and focal segmental glomerulosclerosis (FSGS) is obesity.I.5 Glomerular hyperfiltration has been proposed to be a cause of proteinuria and FSGS. 6 It has been suggested that hypoxemia with increased venous hypertension and consequential glomerular hyperfiltration could also explain the cause of proteinuria and FSGS in obese patients. 3 However, recent reports have discussed the analogies ofFSGS with atherosclerosis and have suggested that hyperlipidemia is a possible cause and/ or factor in the development and/or progression of focal segmental glomerulosclerosis. 7. 9 Experimental studies have shown a relationship with hyperlipidemia, proteinuria, and FSGS. IO- 12 The induction of glomerulosclerosis by dietary lipids II and the reduction of glomerular injury by the treatment of hyperlipidemia 12 have been demonstrated in Zucker obese rats. The objective of this study was to determine the general incidence of FSGS in obese patients, to speculate about its relationship with hemodynamic changes, hypoxemia, hyperlipidemia, and to describe the features of the lesion FSGS in obese patients. MATERIALS AND METHODS The medical records and autopsy findings of 22 patients with the diagnosis of obesity (mean body weight, 317.26 ± 143 lb) were reviewed. These patients were selected from the autopsy files of 4 consecutive years. Cases with the clinical and autopsy diagnosis of obesity were included in this study. The
patients fulfilled the criteria for obesity, according to the National Center for Health Statistics, which is more than 20% of desira.b1e body weight. II The desirable body weight is based on the Fogarty table. 13 The gross descriptions of the autopsies were reviewed and information was obtained regarding body length, body weight, heart weight, kidney weight, and degree of atherosclerosis. Histological examination of the kidneys was performed with examination of at least one paraffinembedded section from each kidney, stained with periodic acid-Schiff (PAS). The percentage of glomeruli with FSGS was defined after counting 200 glomeruli. The diameters of 40 glomeruli from each case (20 from the superficial cortex and 20 from the deep cortex) were measured under the microscope with a lOX W.E. AO 180-metered objective. Only glomeruli sectioned at the hilar region were measured. Glomeruli with segmental or global glomerulosclerosis were not included in the measurements. Histological examination of the kidneys with measurement of the same number of glomeruli was performed in 15 control, autopsied, nonobese patients (mean body weight, 148.13 ± 27.6 lb), without renal disease, matched for sex and age. Special staining for fat (osmium tetroxide) was performed in the kidney of nine obese patients (four with FSGS and five without FSGS) from which wet tissue was available. Electron microscopic examination was performed in six of seven cases with FSGS. In the other case, tissue or blocks of renal tissue were not available. From the Department of Pathology and Laboratory Medicine. University of Texas Medical School at Houston. Houston. TX Received December 23. 1991; accepted in revised form August 11. 1992. Presented in part at the International Academy ofPathology Meeting. Boston. MA. March 1990. Address reprint requests to Regina R. Verani. MD. University of Texas Medical School at Houston. Department of Pathology and Laboratory Medicine. PO Box 20708. Houston. TX 77030. © 1992 by the National Kidney Foundation. Inc. 0272-6386/92/2006-0016$3.00/0
American Journal of Kidney Diseases, Vol XX, No 6 (December), 1992: pp 629-634
629
630
REGINA R. VERANI
glomeruli; however, the number of glomeruli with focal segmental glomerulosclerosis was too small for a meaningful evaluation. The FSGS was characterized by segmental areas of increase in mesangial matrix and collapse of capillary lumens with a lack of proliferation of visceral epithelial cells (Fig 2). The presence of lipid material was demonstrated with osmium tetroxide stain in a few glomeruli related to the areas of FSGS. In obese patients with and without FSGS, lipid stain was also positive in scattered glomerular cells, suggestive of mesangial and epithelial cells. A few globally sclerosed glomeruli were observed in the superficial and deep cortex in 10 of 22 cases; in the case of end-stage renal disease, several globally sclerosed glomeruli were observed. Dilatation of the Bowman's space was observed in a few glomeruli in some cases; however, in four cases, it was seen in the majority of the glomeruli. The same incidence of global glomerulosclerosis was observed in the non obese control patients; how-
Fig 1. Obese patient with end-stage renal disease: The glomeruli show dilatation of Bowman's space and proliferation of mesangial cells. Global glomerulosclerosis (small arrows) and FSGS (large arrow) are seen. There is interstitial fibrosis and tubular atrophy. (PAS; original magnification X100.)
The medical records of these patients were reviewed and all patients had a clinical diagnosis of obesity. The charts were specifically examined for the diagnosis of hypertension, diabetes, and sleep apnea. Cases with insulin-dependent diabetes and/or diabetic glomerulosclerosis were excluded. The laboratory data were searched for the values of blood cholesterol and triglycerides and for the urinary protein excretion.
RESULTS
FSGS was observed in seven of 22 obese patients. In six patients, FSGS was observed in only a few glomeruli (two to four glomeruli in each kidney section; 0.5). Eight patients, three with and five without FSGS, had the diagnosis of hypertension. The heart weight of obese patients with clinical hypertension was 490 ± 160 g versus 568 ± 166 g for obese patients without history of hypertension. There was a relationship between the heart weight and the presence of FSGS. The heart weight in obese patients with FSGS was 671 ± 142 g versus 478 ± 139 g in obese patients without FSGS (P < 0.0 I) (Table 1). Moderate atherosclerosis of the aorta and/or coronary arteries was present in eight obese patients (four with FSGS and four without FSGS). In only three patients, there was narrowing of the coronary artery of more than 50% (one with and two without FSGS). There was no relationship between the weight of the kidneys and the presence or absence of FSGS. Urinary protein measurements were available in four patients, two with and two without FSGS. Proteinuria was observed in two patients with FSGS. No proteinuria was present in the two patients without FSGS. One female patient with FSGS had recent onset of end-stage renal disease, without any history of previous renal disease, and was on hemodialysis for the last 3 months before her death. Lipid profile was available in the seven patients with FSGS and in nine of 15 patients without
Table 1. Relationship of FSGS With Body Weight, Heart Weight, and Blood Lipid Levels p Obese Patients With FSGS
Body Weight Heart Weight Serum Cholesterol Serum Triglycerides
267 ± 421b 671±142g 4.76 ± 1 4 . 5 mmol/L (184 ± 56 mg/dL) 2.70 ± 119 mmol/L (239 ± 119 mg/dL)
Obese Patients Without FSGS
307 478 3.34 1.45
± ± ± ±
1451b 139 9 12 . 2 mmol/L (129 ± 47 mg/dL) 0.58 mmol/L (128 ± 51 mg/dL)
Value
> 0.5 < 0.01
