Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy

Abstract

Podocyte detachment and reduced endothelial cell fenestration and relationships between these features and the classic structural changes of diabetic nephropathy have not been described in patients with type 2 diabetes. Here we studied these relationships in 37 Pima Indians with type 2 diabetes of whom 11 had normal albuminuria, 16 had microalbuminuria, and 10 had macroalbuminuria. Biopsies from 10 kidney donors (not American Indians) showed almost undetectable (0.03%) podocyte detachment and 43.5% endothelial cell fenestration. In patients with type 2 diabetes, by comparison, the mean percentage of podocyte detachment was significantly higher in macroalbuminuria (1.48%) than in normal albuminuria (0.41%) or microalbuminuria (0.37%). Podocyte detachment correlated significantly with podocyte number per glomerulus and albuminuria. The mean percentage of endothelial cell fenestration was significantly lower in macroalbuminuria (19.3%) than in normal albuminuria (27.4%) or microalbuminuria (27.2%) and correlated significantly with glomerular basement membrane thickness, albuminuria, fractional mesangial area, and the glomerular filtration rate (iothalamate clearance). Podocyte detachment and diminished endothelial cell fenestration were not correlated, but were related to classic lesions of diabetic nephropathy. Thus, our findings confirm the important role these injuries play in the development and progression of kidney disease in type 2 diabetes, just as they do in type 1 diabetes. Whether podocyte detachment creates conduits for proteins to escape the glomerular circulation and reduced endothelial fenestration lowers glomerular hydraulic permeability requires further study.

Trial registration: ClinicalTrials.gov NCT00340678.

Figure 1

Peripheral glomerular capillaries illustrating intact and detached podocyte foot processes from a macroalbuminuric Pima Indian with type 2 diabetes mellitus, trasnmission electron microscopy ×11,280. (a) Intact podocyte foot processes. (b) Podocyte foot process detachment. CL, capillary lumen; EC, endothelial cell; P, podocyte foot processes intact; PD, podocyte foot process detachment; RBC, red blood cell; WBC, white blood cell.

Figure 2

Peripheral glomerular capillaries illustrating an absence of normal endothelial cell fenestration, transmission electron microscoy ×11,280. (a) From a normal kidney donor, with normal endothelial cell fenestration. (b) Froma normoalbuminuric Pima Indian with type 2 diabetes mellitus and nonfenestrated endothelium. CL, capillary lumen; F, fenestrated endothelial cell; NF, nonfenestrated endothelial cell; RBC, red blood cell.

Figure 3

Correlations of albumin/creatinine ratio (ACR) or glomerular filtration rate (GFR) with percentage of podocyte detachment or percentage of normally fenestrated endothelium. (a, b) ACR (Pearson's r − 0.43, P = 0.0009) and GFR (Pearson's r = − 0.29, P = 0.084) as a function of percentage podocyte detachment in 37 Pima Indians with type 2 diabetes mellitus. The linear functions were not changed substantially by omission of the two individuals with the greatest amount of podocyte detachment. GBM, glomerular basement membrane. (c, d) ACR (Pearson's r = −0.51, P = 0.001) and GFR (Pearson's r = 0.45, P = 0.0005) as a function of the percentage of normally fenestrated endothelium in the same individuals. Regression lines and 95% confidence intervals are shown.