Background: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the western world. Current treatment methods, with better control of glycemia and blood pressure, including renin-angiotensin system blockade (RASB), appear to have slowed the DN progression rate but have not substantially decreased the annual incidence of new DN ESRD cases. Thus, new treatment targets are needed. Summary: Higher levels of serum uric acid (UA) are associated with increased risk of the clinical manifestations of DN in persons with types 1 and 2 diabetes. Also, UA is a strong predictor of DN progression. Two small, short-term, proof-of-concept clinical trials in which a minority of the patients had diabetes suggested that reduction of UA with allopurinol could decrease the rate of glomerular filtration rate (GFR) loss in persons with chronic kidney disease (CKD). However, a definitive trial to check whether UA reduction can benefit DN progression has not been conducted as yet. Preventing Early Renal Loss in Diabetes (PERL) is an ongoing trial in persons with type 1 diabetes and early to moderate GFR reduction. This 3-year randomized placebo controlled trial in 530 subjects is to check whether UA reduction with allopurinol can slow the rate of GFR decline as determined by the plasma disappearance of iohexol. Key Message: If the results of the PERL trial are positive, initiation of UA reduction treatment while GFR is relatively well preserved could delay ESRD in DN by 8-10 years, that is, considerably longer than the period that has been demonstrated for RASB. This could have important implications for the treatment of DN in particular and of CKD in general.