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


METHODS
Participants from the Epidemiology of Diabetes Complications Study with DNA available were studied for the incidence of microalbuminuria (albumin excretion rate [AER] 20-200 microg/min), macroalbuminuria (AER >200 microg/min), ESRD (renal dialysis or transplantation), and renal function decline (a decline > or =30 ml/min per 1.73 m(2) from baseline estimated [by the Cockcroft-Gault equation] glomerular filtration rate [eGFR] in those with baseline eGFR >60 ml/min per 1.73 m(2)).


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, microalbuminuria, macroalbuminuria, and ESRD was 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 with the Hp 1/1 genotype for eGFR decline (hazard ratio 1.79 [95% CI 1.06-3.00]) and ESRD (2.74 [1.17-6.45]); no significant associations were observed for microalbuminuria or macroalbuminuria.


CONCLUSIONS
These data suggest that although 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.
Costacou
Tina
T
Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. costacout@edc.pitt.edu
Ferrell
Robert E
RE
Ellis
Demetrius
D
Orchard
Trevor J
TJ
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000419:Albuminuria / Q000453:epidemiology* / Q000209:etiology*; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology*; D018450:Disease Progression; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate; D006242:Haptoglobins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015994:Incidence; D007676:Kidney Failure, Chronic / Q000453:epidemiology* / Q000209:etiology*; D007677:Kidney Function Tests; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D018384:Oxidative Stress; D010414:Pennsylvania / Q000453:epidemiology; D016016:Proportional Hazards Models; D011795:Surveys and Questionnaires; D055815:Young Adult
D006242:Haptoglobins