Abstract

Objective: Haptoglobin (Hp) binds free hemoglobin, inhibiting hemoglobin-induced oxidative damage. As oxidative stress has been associated with microvascular complications, we evaluated the relationship between Hp genotype and microalbuminuria (MA), macroalbuminuria (ON), end-stage renal disease (ESRD), and early renal function decline in type 1 diabetes.

Research Design and Methods: Participants from the Epidemiology of Diabetes Complications Study with DNA available were studied for the incidence of MA (albumin excretion rate (AER) 20-200 μg/min), ON (AER>200 μg/min), ESRD (renal dialysis or transplantation) and renal function decline (a decline ≥30 mL/min/1.73 m² from baseline estimated (by the Cockcroft-Gault equation) glomerular filtration rate (eGFR) in those with baseline eGFR >60 mL/min/1.73 m²).

Results: The proportions with the Hp 2/2, 2/1 and 1/1 genotype were 43.4%, 44.4% and 12.1%, respectively. During 18 years of follow-up, the incidence of eGFR decline, MA, ON and ESRD were 42.0%, 40.5%, 16.7%, and 12.2%, respectively. No significant univariate differences were observed by Hp genotype. However, in multivariable Cox models, an approximately twofold increased risk was observed for the Hp 2/2 compared to the Hp 1/1 genotype for eGFR decline (HR=1.79, 95% CI=1.06-3.00) and end-stage renal disease (HR=2.74, 95% CI=1.17-6.45); no significant associations were observed for MA or ON.

Conclusions: These data suggest that whereas Hp genotype is not associated with albuminuria per se, it may be an independent determinant of early renal function decline and progression to ESRD. Understanding these apparent contradictory findings may provide further insight into the pathogenesis of renal disease in type 1 diabetes.