Podocyte number predicts long-term urinary albumin excretion in Pima Indians with Type II diabetes and microalbuminuria

Abstract

The visceral epithelial cell, or podocyte, forms the filtration slit structure that prevents the escape of plasma proteins from the glomerular circulation. Considerable evidence in experimental animals indicates that disruption of the podocyte contributes to the development of glomerular sclerosis [1]. By implication, the progressive rise in urinary protein excretion that characterizes diabetic nephropathy points to a putative role for the podocyte in the pathogenesis of diabetic renal disease. Consistent with this hypothesis is a cross-sectional study in diabetic Pima Indians which found that subjects with clinical nephropathy had fewer podocytes per glomerulus than those without nephropathy [2]. Since podocytes are thought to be incapable of replication, this observation suggests Diabetologia (1999) Abstract Aims/hypothesis. The predictive value of glomerular structure on progression of renal disease was examined in patients with Type II (non-insulin-dependent) diabetes and microalbuminuria (urinary albumin-tocreatinine ratio = 30±299 mg/g). Methods. Kidney biopsy specimens were obtained from 16 diabetic Pima Indians (6 men, 10 women). Progression of renal disease was assessed by measuring urinary albumin excretion 4 years after the biopsy (UAE 4 years ) and by computing the change in urinary albumin excretion during the study (D UAE).Results. At baseline, the duration of diabetes averaged 13.3 years (range = 4.0±23.8 years) and the mean glomerular filtration rate was 159 ml × min ±1 × 1.73m ±2 (range = 98 ± 239 ml × min ±1 × 1.73m ±2). Median urinary albumin excretion was 67 mg/g (range = 25±136 mg/g) and it increased to 625 mg/g (range = 9±13471 mg/g) after 4 years; 10 subjects (63 %; 4 men, 6 women) developed macroalbuminuria (urinary albumin-to-creatinine ratio ³ 300 mg/g). Neither mean arterial pressure nor HbA 1 c changed substantially during follow-up. Among the glomerular morphologic characteristics, the number of visceral epithelial cells, or podocytes, per glomerulus was the strongest predictor of renal disease progression (UAE 4 years , r = ±0.49, p = 0.05; DUAE, r = ±0.57, p = 0.02), with fewer cells predicting more rapid progression. Glomerular basement membrane thickness did not predict progression (UAE 4 years , r = 0.11, p = 0.67; DUAE, r = 0.09, p = 0.73) and mesangial volume fraction had only a modest effect (UAE 4 years, r = 0.42, p = 0.11; DUAE, r = 0.48, p = 0.06). Conclusion/interpretation. Whether lower epithelial cell number per glomerulus among those that progressed was due to cellular destruction, a reduced complement of epithelial cells, or both is uncertain. Nevertheless, these findings suggest that podocytes play an important part in the development and progression of diabetic renal disease. [Diabetologia (1999

Podocyte Number in Children and Adults

“…Studies of type 2 diabetes identified absolute podocyte depletion in the early stages of diabetic nephropathy, which was closely related to disease progression. [27][28][29][30] Absolute podocyte depletion was also reported in studies of IgA nephropathy and hypertensive nephrosclerosis. 31,32 Although these studies provided valuable insights into the association between podocyte number and the development and progression of renal disease, our study shows, for the first time, that podocyte number varies within and between subjects without overt renal disease.…”

“…[27][28][29][30][31][32] This is, in part, because of the difficulty in counting podocytes and the lack of consensus on how to accurately count them. Lemley et al 11 recently compared five methods for estimating podocyte number and recommended that the design-based dissector/optical fractionator method was the optimum technique when sufficient kidney tissue was available.…”

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

“…Podocyte loss is found in patients with DN or micro-albuminuria 14,15 In fact, the loss of podocytes is one of the earliest features of DN that predicts its progressive course. 16 However, molecular mechanisms that underlie the loss of podocytes in DN remain poorly understood.…”

Pathophysiologic Implications of Reduced Podocyte Number in a Rat Model of Progressive Glomerular Injury

“…[17][18][19][20][21][22] A positive correlation has been clearly demonstrated between progressive podocyte depletion and the development of glomerulosclerosis in an experimental model of nephrosis in the rat.…”