Familial factors determine the development of diabetic nephropathy in patients with IDDM

To evaluate familial factors in the development of diabetic nephropathy in insulin-dependent diabetes mellitus (IDDM) we examined concordance for diabetic nephropathy in families with multiple IDDM siblings. Families (n = 110) were identified through Joslin Clinic patients (probands) with a sibling having IDDM. To be eligible, the probands' and siblings' ages at IDDM diagnosis were less than 21 years, and IDDM duration was more than 15 years for probands and more than 10 years for siblings. Mean post-pubertal diabetes duration was 23 years for probands (n = 110) and 21 years for siblings (n = 125). Nephropathy history was determined by medical record review for deceased patients and those with persistent proteinuria or end-stage renal disease to ascertain the date of onset of persistent proteinuria. For patients without documented nephropathy, the albumin/creatinin ratio was measured in multiple urine samples. The cumulative incidence of persistent proteinuria according to post-pubertal duration of IDDM was determined by life-table analysis. For probands and siblings combined, the cumulative incidence of advanced diabetic nephropathy after 30 years of IDDM was 35%, but the risk in siblings varied according to the proband's renal status. The cumulative risk in siblings after 25 years of IDDM (post-puberty) was 71.5% if the proband had persistent proteinuria but only 25.4% if the proband did not (p < 0.001). A difference of nearly 50% in the risk to IDDM siblings, depending upon the IDDM proband's renal status, is consistent with a major gene effect that predisposes an individual with IDDM to develop advanced diabetic nephropathy.