Tight glycemic control can reduce progression of diabetic nephropathy (DN) while the histological changes may regress after pancreas transplantation. Clinical islet transplantation (CIT) can restore euglycemia but the effects of CIT and concomitant immunosuppression on renal function are not known. Renal function (modification of diet in renal disease estimated glomerular filtration rate [GFR]) is reported in 41 type 1 diabetes subjects followed for 29.8 (6-57) months after CIT who received sirolimus and tacrolimus. HbA(1c) improved by 3 months (6.1 +/- 0.5 vs. 8.1 +/- 1.3%, p < 0.001) and was sustained. Over 4 years estimated GFR (eGFR) declined (repeated measures ANOVA: p = 0.0011). The median rate of change in eGFR was -0.39 mL/min/1.73 m(2)/month but was highly variable (range: +1.62 to -2.79 mL/min/1.73 m(2)/month). Progression of albuminuria was observed in ten individuals while regression of microalbuminuria was observed in only one (chi square = 22.51, df = 4, p = 0.0002). Despite improved glycemia, CIT and concomitant immunosuppression, was associated with a fall in eGFR and progression of albuminuria over 4 years of observation. The rate of decline in eGFR was extremely variable and difficult to predict. The risk of progressive nephrotoxicity with decline in eGFR should be discussed with prospective CIT candidates and the risk: benefit ratio carefully considered in individuals with pre-existing renal impairment.