Glomerular function in advanced human diabetic nephropathy

One to three decades may elapse between the onset of insulin-requiring diabetes mellitus and the development of end-stage renal failure due to diabetic nephropathy [1–3]. Abnormalities of glomerular function, undetectable by routine laboratory tests, are present from the onset. Initially, these include a 20 to 40% increase in the glomerular filtration rate (GFR) and a two-to three-fold elevation of the rate of urinary albumin excretion above normal [4–7]. With the passage of a decade or more, urinary albumin excretion increases to a level where conventional tests of proteinuria become positive (>100 µg/min). Hereafter, a gradual decline in the rate of glomerular ultrafiltration eventuates [8]. Not surprisingly, the ultrafiltration properties of the glomerular capillary wall are most impaired after many years of diabetic nephropathy have elapsed. Retrospective analyses of patients with diabetic nephropathy commencing dialysis therapy indicate that proteinuria of nephrotic proportions and azotemia are terminal manifestations, appearing 2 to 4 years before symptomatic end-stage renal failure necessitates dialysis therapy [9–10]. Accordingly, patients in whom diabetic nephropathy was accompanied either by the nephrotic syndrome or by azotemia were selected for a study of glomerular function. The clearance of graded probe molecules excreted solely by glomerular filtration was determined. The findings were subjected to previously described theoretical analyses of glomerular ultrafiltration [11] and of transcapillary solute exchange through an isoporous membrane [12] to elucidate those intrinsic properties of the glomerular capillary wall responsible for reduced water ultrafiltration and increased permeability to proteins, respectively.