Calcineurin inhibitors like FK506 (Tacrolimus) are routinely used for immunosuppression following transplantation. The use of these drugs is limited by many side effects such as reduction of glomerular filtration rate and renal tubular acidosis (RTA). We used a rat model injected subcutaneously with 1mg/kg body weight FK506 for 11 days. Control animals were injected with 0.9% saline solution. After 11 days and under normal conditions systemic acid base status was similar in both groups. However, after 48 hours acid loading with 0.28M NH4Cl, the FK506 treated animals showed a more severe metabolic acidosis, mild diabetes, and reduced GFR. Excretion of phosphate was inappropriately low in the FK506 treated animals with an acid load. Despite the more pronounced acidosis in the FK506 group, urine pH was more alkaline indicating RTA. Interestingly the ammonium excretion was significantly higher in these animals. Western blot analysis revealed reduced expression of the a4 and B1 subunits of the vacuolar H+ -ATPase under normal conditions but a higher abundance of a4 after induction of metabolic acidosis in cortex and medulla. The expression of the Cl-/HCO3- exchanger AE1 in total kidney was lower under normal conditions and significantly increased after induction of metabolic acidosis. Thus, FK506 affects the expression of several transport proteins involved in renal acid excretion.