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Podocyte Detachment and Reduced Glomerular Capillary Endothelial Fenestration in Human Type 1 Diabetic Nephropathy

¹ Division of Nephrology and Metabolism, Department of Internal Medicine; Tokai University School of Medicine, Kanagawa, Japan
² Division of Pediatric Nephrology, Department of Pediatrics; University of Minnesota, Minneapolis, Minnesota
³ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
⁴ Department of Medicine, University of Minnesota, Minneapolis, Minnesota

Address correspondence and reprint requests to Michael Mauer, MD, Professor of Pediatrics and Medicine, University of Minnesota, 420 Delaware St. SE, MMC 491, Minneapolis, MN 55455. E-mail: mauer002{at}umn.edu

Abbreviations: AER, albumin excretion rate; FPW, foot process width; FSGS, focal and segmental glomerulosclerosis; GBM, glomerular basement membrane; GFR, glomerular filtration rate; L_S(Slit/PGBM), slit diaphragm length density per PGBM; L_S(Slit/MGBM), slit diaphragm length density per MGBM; MGBM mesangial GBM; PGBM, peripheral GBM; S_S(IFP/PGBM), fraction of PGBM covered by intact foot processes; S_S(IFP/MGBM), fraction of MGBM covered by intact foot processes; S_S(Fenestrated/cap), surface density of fenestrated endothelium per glomerular capillary lumen; S_V(PGBM/glom), surface density of PGBM per glomerulus; TBCA, tuft to Bowman's capsule adhesions; V_V(MC/glom), mesangial cell fractional volume per glomerulus; V_V(Mes/glom), mesangial fractional volume per glomerulus; V_V(MM/glom), mesangial matrix fractional volume per glomerulus

The aim of this study was to investigate the structural characteristics of podocytes and endothelial cells in diabetic nephropathy. We studied 18 patients with type 1 diabetes (seven normoalbuminuric, six microalbuminuric, and five proteinuric), and six normal control subjects. Groups were not different for age. Type 1 diabetic groups were not different for diabetes duration or age at diabetes onset. Podocyte foot process width (FPW), fraction of glomerular basement membrane (GBM) surface with intact nondetached foot processes (IFP), fraction of glomerular capillary luminal surface covered by fenestrated endothelium [S_S(Fenestrated/cap)] and classic diabetic glomerulopathy lesions were morphometrically measured. Albumin excretion (AER) and glomerular filtration (GFR) rates were also measured. GFR correlated inversely and AER directly with GBM and mesangial measurements in diabetic patients. FPW correlated inversely with GFR (r = –0.71, P = 0.001) and directly with AER (r = 0.66, P = 0.003), GBM, and mesangial parameters. The GBM fraction covered by IFP was decreased in proteinuric versus control subjects (P = 0.001), normoalbuminuric patients (P = 0.0002) and microalbuminuric patients (P = 0.04) and correlated with renal structural and functional parameters, including AER (r = –0.52, P = 0.03). Only 78% of GBM was covered by IFP in proteinuric patients. S_S(Fenestrated/cap) was reduced in normoalbuminuric (P = 0.03), microalbuminuric (P = 0.03), and proteinuric (P = 0.002) patients versus control subjects. S_S(Fenestrated/cap) correlated with mesangial fractional volume per glomerulus (r = –0.57, P = 0.01), IFP (r = 0.61, P = 0.007), and FPW (r = –0.58, P = 0.01). These novel studies document that podocyte detachment and diminished endothelial cell fenestration are related to classical diabetic nephropathy lesions and renal function in type 1 diabetic patients and support a need for further studies of podocyte/GBM adherence and podocyte/endothelial cell functional interactions in diabetic nephropathy.

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