The Early Natural History of Nephropathy in Type 1 Diabetes

Abstract

Renal structural abnormalities are known to precede the development of proteinuria, hypertension, and reduced renal function in patients with type 1 diabetes. The determinants of these early structural abnormalities are, however, largely unknown. The International Diabetic Nephropathy Study (IDNS) has recruited 243 children and adults (aged 10–40 years) in Montreal, Minneapolis, and Paris to identify and quantify these determinants. All study subjects were normotensive and had normal-to-high glomerular filtration rates (GFRs) and urinary albumin excretion rates (AERs) <100 μg/min at study entry. Only 8 of 243 had an AER ≥20 μg/min (microalbuminuria). Two renal biopsies are obtained at a 5-year intervals, with baseline and follow-up measures of renal function, blood pressure (BP), HbA1c, plasma lipids, and AER. Herein, we examine the baseline renal biopsy morphometric findings in these subjects and in 87 kidney donor control subjects and explore the associations between findings and clinical and demographic variables. The principal morphometric abnormalities were increased glomerular basement membrane (GBM) width and fractional volume of mesangium [Vv(Mes/glom)] and mesangial matrix [Vv(MM/glom)]. The frequency of these abnormalities increased with increasing duration of diabetes but was observed as early as 2–8 years after onset. Diastolic BP (DBP), but not HbA1c, was directly associated with these abnormalities. Elevated GFR was associated with only a small increase in peripheral glomerular capillary basement membrane filtration surface density. Center differences were detected in renal structural, renal functional, and BP parameters, especially between the Paris and North American centers. GBM width, Vv(Mes/glom), and Vv(MM/glom) are significantly increased even within a few years of onset of type 1 diabetes. These changes are detectable in normoalbuminuric patients and are related to duration, BP, and study site. Changes in these and other morphometric measures over 5-year follow-up should help clarify the roles of glycemia and other determinants of the rates of development of diabetic nephropathy lesions, as well as their relationships to early changes in BP, albumin excretion, and renal function.