OBJECTIVE - Pathogenesis of diabetes-related microvascular complications involving oxidative damage by free radicals has been demonstrated. Free radical generation has been shown to derive largely from iron. Our objectives, therefore, were to determine if there is an increased incidence and/or an accelerated course of nephropathy in patients with diabetes, secOndary to transfusional hemochromatosis, and to examine whether free radical activity contributes to the development of this complication. RESEARCH DESIGN AND METHODS - We evaluated nine patients with homozygous β- thalassemia, complicated by clinically overt diabetes, for diabetic nephropathy over a 7-year period. Lipid peroxidation was quantified by measuring the presence of 20 saturated and unsaturated aldehydes, and results were compared with five normotensive type I diabetic patients without iron overload. RESULTS - Nephropathy developed in five of nine patients (55%) after a mean duration of overt diabetes of 3.6 ± 2.0 years. Three patients showed evidence of progressive microalbuminuria over a 7-year period (24.7- 46.2, 52.2-430.1, and 17.7-54.3 μg/min, respectively). Two patients with borderline microalbuminuria (19.9 and 14.5 μg/min, respectively) demonstrated stable albumin excretion rates over the follow-up period. Total aldehyde concentration was significantly higher in β-thalassemia diabetic patients, compared with nonthalassemic diabetic control subjects (8,106 ± 1,280 vs. 4,594 ± 247 nmol/l; P < 0.0001). The three patients with progressive microalbuminuria demonstrated significantly higher total aldehyde concentration, compared with the other β-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 significantly lower in β-thalassemia patients with diabetes, compared with diabetic patients without iron overload (12.1 ± 6.0 vs. 25.9 ± 11.4 μmol/l; P = 0.02). Serum vitamin C concentrations did not differ between the two groups. Multiple regression analysis demonstrated total aldehyde concentration to be the most significant predictor for the development of microalbuminuria (P = 0.01), followed by the duration of diabetes (P = 0.02) and glycemic control (P = 0.02). CONCLUSIONS - Early development and an accelerated course of diabetic nephropathy in iron-loaded patients with β-thalassemia are observed. These findings may be attributed to high oxidative stress in these patients, which is secondary to iron-derived free radicals and to the patients' diminished antioxidant reserves.