IMMUNOPHARMACOLOGICAL MONITORING OF CYCLOSPORIN A-TREATED RECIPIENTS OF CADAVERIC KIDNEY ALLOGRAFTS

Abstract

Twelve cadaveric kidney allograft recipients, who were established preoperatively to be strong responders, were treated with cyclosporin A (Cy A) and subjected to postoperative monitoring of drug levels and immune performances. The Cy A-treated recipients were compared with 72 historical (36 strong and 36 weak immune responders) and 18 current, strong responder, azathioprine-treated control patients. Estimation of Cy A levels in plasma and whole blood revealed that 75% of the drug at trough and 44% at peak was cell bound. Concomitant radioimmunoassay (RIA) and high performance liquid chromatography (HPLC) determinations on whole blood yielded concordant values. Trough levels above 200 ng/ ml in plasma and 600 ng/ml in whole blood were associated with toxic manifestations. Although absolute peak levels were not helpful, calculation of peak to trough ratios yielded values which when less than 3.0 predicted toxicity. Post-transplant immune monitoring showed administration of Cy A to be associated with fewer (1) rejection episodes; (2) nonspecific immune events; and (3) donor-specific in vitro reactions than were observed after treatment with azathioprine. Although the activity of peripheral blood mononuclear cells as natural killers of K562 target cells was not affected by Cy A treatment, their capacity to suppress the generation of a third-party mixed lymphocyte culture was enhanced to the same degree as cells from azathioprine-treated patients. Enumeration of peripheral blood lymphocyte T cell subpopulations using monoclonal xeonoantisera revealed (1) the total number of T cells to be unaffected by administration of either Cy A or azathioprine and (2) a reduction in the ratio of helper-inducer to suppressor-cytotoxic cells specificially in Cy A-treated recipients compared with normal individuals, hemodialysis patients, or azathioprine-treated recipients. Although pharmacological monitoring of blood levels may be useful to discern patients at high risk for toxic complications, the achievement of maximal therapeutic efficacy may depend upon identifying and quantitating the cellular target responsible for the disruption of immune homeostasis observed during Cy A administration.