Cyclosporine monitoring in liver allograft recipients: two distinct patterns of blood level derangement associated with nephrotoxicity.

The parallel measurement of specific and nonspecific CyA levels by second generation radioimmunoassays based on monoclonal antibodies proved to be an effective procedure to monitor both parent CyA levels and the capacity to eliminate its metabolite. Using this monitoring procedure it could be shown that CyA-associated nephrotoxicity in the early course after liver transplantation is associated with two distinct patterns of blood level derangement. One pattern is characterized by increased parent drug levels, the other by an increased metabolite concentration resulting from severely disturbed CyA metabolite excretion. This raises the possibility that not only the parent drug but also some of its metabolites may exert nephrotoxic effects when present in excessively high concentrations. This finding provided the rationale for a therapeutic CyA-monitoring regimen taking into account both specific and nonspecific measurements. In liver transplant patients monitored according to this regimen and treated with quadruple immunosuppression the incidence and severity of CyA-associated nephrotoxicity was markedly reduced. The metabolite-associated type of nephrotoxicity was only found in patients with severely disturbed liver function.