Effect of renal allograft dysfunction upon cyclosporine trough levels in host blood

Cyclosporine (CsA) dose adjustment after renal transplantation is generally based on serum, plasma, or whole-blood trough level values. In the face of increased levels, the dosage is reduced in order to prevent CsA-induced nephrotoxicity. There is a paucity of data, however, on the kinetics of CsA in association with dysfunction of the transplanted kidney. This study documents dramatic rises in serum cyclosporine trough levels at the time of rejection crises, as well as following periods of nonimmunological allograft oliguria. Decreases in CsA dosage in such patients failed to result in a significant lowering in trough levels. Therapeutic CsA trough levels were generally at the 70-140 ng/ml level; at the time of rejection, the same doses of CsA resulted in a rise of trough levels to 300-500 ng/ml. As the rejection crises resolved and kidney function improved, the CsA serum trough levels returned to their lower levels. These results suggest that the urinary elimination of CsA and its metabolites may be a key determinant of CsA trough levels, and that the status of renal function at the time of testing must be considered in the interpretation of the data. In support of this observation, the CsA concentrations in 4-6 hr post-CsA-administration urine samples ranged from 400 ng/ml to 4500 ng/ml, as measured by high pressure liquid chromatography. The data suggest that rising CsA trough levels in a previously stable recipient may serve as a valuable early warning index of impending allograft dysfunction (rejection, infection, and obstruction). This appears particularly true during the first 30 days after renal transplantation, when the incidence of rejection is the greatest in this patient population.