Lessons learned from studies of the natural history of diabetic nephropathy in young type 1 diabetic patients.

Diabetic Nephropathy (DN) remains the leading cause of end stage renal disease (ESRD) in the Western world, responsible for nearly half of all new ESRD cases in the USA (1). DN develops in 20-25% of patients with type 1 diabetes (T1DM) (2) and, although risk of DN is clearly related to glycemic control (3,4), other variables including genetic propensity (5) are needed to explain why only a minority T1 DN patients progress to ESRD. The clinical manifestations of DN including increasing levels of urinary albumin excretion (AER), rising blood pressure (BP) and falling glomerular filtration rates (GFR) are closely related to renal structural abnormalities of DN (5,6). These glomerular, tubular, vascular and interstitial lesions are strongly correlated with these functional abnormalities especially when non-linear analysis models are used (6,7). This is because DN's natural history is one of clinical silence for years to decades during which time serious underlying renal lesions may be developing. Once the clinical manifestations, including the development of persistent microalbuminuria [(MA); (AER 20-200 microg/min)] are present, the structural injury is often far advanced (8). Moreover the nature of the renal lesions changes following the development of overt proteinuria so that the further decline in GFR is now associated with focal and global glomerular sclerosis and tubulo-interstitial injury which probably accelerates the GFR decline towards ESRD (7). Since interventions at these late stages of disease may only slow but not completely arrest the inexorable progression towards renal failure (9), understanding early natural history becomes important. Since DN structurally and functionally is a progressive disease; it is reasonable to presume that patients that either do not develop the earlier lesions of DN or develop them very slowly will not progress within their lifetime to stages of advanced renal structural injury and ESRD. We therefore considered it important to understand the early natural history of diabetic nephropathy and formed the International Diabetic Nephropathy Study Group (IDNSG) in order to investigate the early stages of DN in young T1DM volunteers. The design of the Natural History Study (NHS) (9) has been reported. The IDNSG participating institutions included 3 university centers (McGill University, Montreal, Canada with affiliations with the University of Sherbrooke, Sherbrooke, Canada, the Ottawa Civic Hospital, and the Childrens Hospital of Eastern Ontario; the Department of Pediatrics, University of Minnesota Medical School with affiliations at St Paul Children's Hospital and the International Diabetes Center in Minneapolis; the Robert Debré Höpital in Paris with affiliations with Höpital Saint Louis). The data coordinating center for the NHS was in the Department of Epidemiology and Biostatistics at McGill University and light microscopy readings were carried out at INSERM Unité 192 at the Höpital Necker-Enfants Malades in Paris. Patients could be included if they had type 1 diabetes for 2-20 years, had onset of diabetes before age 31, had AER less than 100 mug/min and GFR > or = 90 ml/min/ 1.73m2 (9). Patients also had to be normotensive for their age and sex and have no other significant renal or systemic disease. Quarterly studies included measurements of blood pressure, (BP), urinary albumin excretion rate (AER), hemoglobin A1C (HbA1C), GFR, and renal plasma flow (RPF). Renal biopsies were performed at baseline and after 5 years in the study. The primary goal of the study was to determine the clinical predictors of the baseline biopsy and baseline clinical and renal structural predictors of the changes between the baseline and the 5 year biopsy. The longitudinal structural studies are still in analysis and this paper will mainly review the cross sectional studies that have been completed to date.