DIABETIC NEPHROPATHY IN HYPERTRANSFUSED PATIENTS WITH BETA-THALASSEMIA - THE ROLE OF OXIDATIVE STRESS

OBJECTIVE - Pathogenesis of diabetes-related microvascular complicatio ns involving oxidative damage by free radicals has been demonstrated. Free radical generation has been shown to derive largely from iron. Ou r objectives, therefore, were to determine if there is an increased in cidence and/or an accelerated course of nephropathy in patients with d iabetes, secondary to transfusional hemochromatosis, and to examine wh ether free radical activity contributes to the development of this com plication. RESEARCH DESIGN AND METHODS - We evaluated nine patients wi th homozygous beta-thalassemia, complicated by clinically overt diabet es, for diabetic nephropathy over a 7-year period. Lipid peroxidation was quantified by measuring the presence of 20 saturated and unsaturat ed aldehydes, and results were compared with five normotensive type 1 diabetic patients without iron overload. RESULTS - Nephropathy develop ed in five of nine patients (55%) after a mean duration of overt diabe tes of 3.6 +/- 2.0 years. Three patients showed evidence of progressiv e microalbuminuria over a 7-year period (24.7-46.2, 52.2-430.1, and 17 .7-54.3 mu g/min, respectively). Two patients with borderline microalb uminuria (19.9 and 14.5 mu g/min, respectively) demonstrated stable al bumin excretion rates over the follow-up period. Total aldehyde concen tration was significantly higher in beta-thalassemia diabetic patients , compared with nonthalassemic diabetic control subjects (8,106 +/- 1, 280 vs. 4,591 +/- 247 nmol/l; P < 0.0001). The three patients with pro gressive microalbuminuria demonstrated significantly higher total alde hyde concentration, compared with the other beta-thalassemia diabetic patients with stable albumin excretion (9,428 +/- 337 vs. 7,445 +/- 1, 003 nmol/l: P < 0.01). Serum vitamin E concentrations were significant ly lower in beta-thalassemia patients with diabetes, compared with dia betic patients without iron overload (12.1 +/- 6.0 vs. 25.9 +/- 11.4 m u mol/l; P = 0.02). Serum vitamin C concentrations did not differ betw een the two groups. Multiple regression analysis demonstrated total al dehyde concentration to be the most significant predictor for the deve lopment of microalbuminuria (P = 0.01), followed by the duration of di abetes (P = 0.02) and glycemic control (P = 0.02). CONCLUSIONS - Early development and an accelerated course of diabetic nephropathy in iron -loaded patients with beta-thalassemia are observed. These findings ma y be attributed to high oxidative stress in these patients, which is s econdary to iron-derived free radicals and to the patients' diminished antioxidant reserves.