Diabetic nephropathy has become the leading cause of uremia. Several lines of evidence suggest dietary factors other than protein intake have a substantial role in the progression of diabetic nephropathy to end-stage renal disease. The present investigation was initiated to evaluate whether a carbohydrate-restricted, low-iron-available, polyphenol-enriched (CR-LIPE) diet may delay and improve the outcome of diabetic nephropathy to a greater extent than standard protein restriction. To this aim, 191 diabetic patients, all with type 2 diabetes, were randomized to either CR-LIPE or standard protein restriction and the following outcomes monitored: doubling of serum creatinine, cumulative incidence of end-stage renal disease, and all cause mortality. Over a mean follow-up interval of 3.9 +/- 1.8 years, serum creatinine concentration doubled in 19 patients on CR-LIPE (21%) and in 31 control subjects (39%) (P < 0.01). Renal replacement therapy or death occurred in 18 patients on CR-LIPE (20%) and in 31 control subjects (39%) (P < 0.01). These differences were independent from follow-up interval, sex, mean arterial blood pressure, HbA(1c), initial renal dysfunction, and angiotensin system inhibitor use. In conclusion, CR-LIPE was 40-50% more effective than standard protein restriction in improving renal and overall survival rates.