NEPHROTOXIC EFFECTS OF PRIMARY IMMUNOSUPPRESSION WITH FK-506 AND CYCLOSPORINE REGIMENS AFTER LIVER-TRANSPLANTATION

Objective: We conducted a treatment trial to determine the relative to xicity of FK-506 and cyclosporine A (CSA) in liver transplant recipien ts. Design: Between October 1990 and October 1991, 37 patients were en rolled in an open-labeled, randomized study of two immunosuppressive r egimens after liver transplant. Material and Methods: Of the 23 men an d 14 women, 20 received FK-506 plus prednisone, and 17 received CSA pl us prednisone and azathioprine. Renal function was assessed before and after transplantation (day 1, month 1, month 4, and month 12) by meas urements of serum creatinine (SCr) and glomerular filtration rate (GFR ) as determined by urinary iothalamate or creatinine clearance (or bot h). FK-506 trough plasma levels (enzyme immunoassay) were to be mainta ined between 0.2 and 5.0 ng/mL, and CSA trough blood levels (whole blo od high-performance liquid chromatography) were to be maintained betwe en 250 and 400 ng/mL. Severe nephrotoxicity was defined as sudden decr eases in urine output to less than 10 mL/h or rapid increases in SCr ( more than 0.5 mg/dL daily) that necessitated withdrawal of study medic ation for more than 48 hours. Mean patient age and values for SCr and GFR were comparable between the two groups at entry. Results: Both stu dy groups demonstrated a similar deterioration in renal function durin g a 12-month follow-up, although patients who received FK-506 had a si gnificantly (P<0.05) lower GFR when measured at 12 months than did pat ients treated with CSA (45+/-4 versus 64+/-6 mL/min per body surface a rea). Mild nephrotoxicity that responded to decreased drug doses was n oted in 9 CSA-treated patients (53%) and 10 FK-506-treated patients (5 0%). Severe nephrotoxicity that necessitated drug withdrawal occurred in only four patients, all of whom were in the FK-506 group. These sev ere nephrotoxic reactions to FK-506 occurred early after transplantati on, often during intravenous administration of the drug, and were not associated with poor liver allograft function or drug levels outside t he therapeutic range. Conclusion: Both FK-506 and CSA are significantl y nephrotoxic in liver transplant recipients. In this trial, however, we observed an early development of severe nephrotoxic reactions only in some patients who received FK-506.