Podocyte Detachment and Reduced Glomerular Capillary Endothelial Fenestration in Human Type 1 Diabetic Nephropathy Masao Toyoda 1 , Behzad Najafian 2 3 , Youngki Kim 2 , M. Luiza Caramori 4 and Michael Mauer 2 4 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 Abstract 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. AER, albumin excretion rate FPW, foot process width FSGS, focal and segmental glomerulosclerosis GBM, glomerular basement membrane GFR, glomerular filtration rate LS(Slit/PGBM), slit diaphragm length density per PGBM LS(Slit/MGBM), slit diaphragm length density per MGBM MGBM mesangial GBM PGBM, peripheral GBM SS(IFP/PGBM), fraction of PGBM covered by intact foot processes SS(IFP/MGBM), fraction of MGBM covered by intact foot processes SS(Fenestrated/cap), surface density of fenestrated endothelium per glomerular capillary lumen SV(PGBM/glom), surface density of PGBM per glomerulus TBCA, tuft to Bowman's capsule adhesions VV(MC/glom), mesangial cell fractional volume per glomerulus VV(Mes/glom), mesangial fractional volume per glomerulus VV(MM/glom), mesangial matrix fractional volume per glomerulus Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 29 May 2007. DOI: 10.2337/db07-0019. This manuscript and its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 12, 2007. Received January 8, 2007. DIABETES