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. Diabetes 56:2155-2160, 2007 S trong correlations between morphometric measures of mesangial expansion and glomerular basement membrane (GBM) width and functional parameters in diabetic nephropathy have long been known (1-2). More recently, however, interest in the possible role of podocytes in the development and/or progression of diabetic nephropathy has grown (3). Podocytes are important in maintaining glomerular permselectivity, and the development of proteinuria is associated with morphological changes in these cells, including foot process effacement (4). Podocyte detachment and GBM denudation have been documented in diverse renal conditions associated with severe proteinuria, such as idiopathic focal and segmental glomerulosclerosis (FSGS), puromycin nephrosis, amyloidosis, and reflux nephropathy (5-8). Foot process effacement and decreased podocyte number and/or density per glomerulus have been reported in patients with type 1 and type 2 diabetes (9 -14). There is, how...

This study was designed to elucidate the cellular basis of risk of or protection from nephropathy in patients with type 1 diabetes. Entry criteria included diabetes duration of >8 years (mean duration, 22.5 years) and glomerular filtration rate (GFR) >30 ml ⅐ min -1 ⅐ 1.73 m -2 . Patients were classified, on the basis of the estimated rate of mesangial expansion, as "fast-track" (upper quintile) or "slow-track" (lower quintile). A total of 88 patients were normoalbuminuric, 17 were microalbuminuric, and 19 were proteinuric. All three groups had increased glomerular basement membrane (GBM) width and mesangial fractional volume [Vv(Mes/glom)], with increasing severity from normoalbuminuria to microalbuminuria to proteinuria but with considerable overlap among groups. Vv(Mes/glom) (r ‫؍‬ 0.75, P < 0.001) and GBM width (r ‫؍‬ 0.63, P < 0.001) correlated with albumin excretion rate (AER), whereas surface density of peripheral GBM per glomerulus [Sv(PGBM/ glom)] (r ‫؍‬ 0.50, P < 0.001) and Vv(Mes/glom) (r ‫؍‬ ؊0.48, P < 0.001) correlated with GFR. Vv(Mes/glom) and GBM width together explained 59% of AER variability. GFR was predicted by Sv(PGBM/glom), AER, and sex. Fast-track patients had worse glycemic control, higher AER, lower GFR, more hypertension and retinopathy, and, as expected, worse glomerular lesions than slow-track patients. Thus, there are strong relationships between glomerular structure and renal function across the spectrum of AER, but there is considerable structural overlap among AER categories. Given that normoalbuminuric patients may have advanced glomerulopathy, the selection of slow-track patients based on glomerular structure may better identify protected patients than AER alone. Diabetes 51:506 -513, 2002

No abstract

Abnormalities in lipid metabolism frequently accompany renal disease and may be important in the pathogenesis of progressive renal injury. In the present study, the effects of a high cholesterol diet on renal histology, cortical lipids, and glomerular hemodynamic function were examined in normal rats with and without reduced renal mass. Cholesterol feeding for 19 weeks increased serum cholesterol from 66 +/- 10 mg/dl to 256 +/- 93 mg/dl in two-kidney rats, and from 73 +/- 15 mg/dl to 407 +/- 274 mg/dl in nephrectomy rats (P less than 0.01). Both sham-operated and unilateral nephrectomy rats fed a high cholesterol diet had a greater amount of glomerulosclerosis and tubulointerstitial damage than rats fed standard chow. Cortical cholesteryl esters were increased by the cholesterol diet, and correlated with the amount of glomerulosclerosis (r = 0.90, P less than 0.01) and tubulointerstitial injury (r = 0.64, P less than 0.05). Cholesterol feeding and nephrectomy both caused alterations in tissue essential fatty acids, and a panel of specific monoclonal antibodies indicated that renal injury and cortical lipid alterations were associated with an increase in glomerular macrophages. Finally, micropuncture experiments carried out in a separate group of rats fed high cholesterol for 8 to 10 weeks demonstrated increases in glomerular capillary pressure. These results suggest that additional investigations may ultimately determine how cholesterol deposition, altered fatty acid metabolism, macrophages, and increased glomerular pressure might combine to cause chronic progressive renal injury.