FAMILIAL FACTORS DETERMINE THE DEVELOPMENT OF DIABETIC NEPHROPATHY INPATIENTS WITH IDDM

To evaluate familial factors in the development of diabetic nephropath y in insulin-dependent diabetes mellitus (IDDM) we examined concordanc e for diabetic nephropathy in families with multiple IDDM siblings. Fa milies (n = 110) were identified through Joslin Clinic patients (proba nds) with a sibling having IDDM. To be eligible, the probands' and sib lings' ages at IDDM diagnosis were less than 21 years, and IDDM durati on was more than 15 years for probands and more than 10 years for sibl ings. 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 wi th persistent proteinuria or end-stage renal disease to ascertain the date of onset of persistent proteinuria. For patients without document ed nephropathy, the albumin/creatinine ratio was measured in multiple urine samples. The cumulative incidence of persistent proteinuria acco rding to post-pubertal duration of IDDM was determined by life-table a nalysis. For probands and siblings combined, the cumulative incidence of advanced diabetic nephropathy after 30 years of IDDM was 35%, but t he risk in siblings varied according to the proband's renal status. Th e cumulative risk in siblings after 25 years of IDDM (post-puberty) wa s 71.5% if the proband had persistent proteinuria but only 25.4% if th e 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 c onsistent with a major gene effect that predisposes an individual with IDDM to develop advanced diabetic nephropathy.