CLINICAL-FEATURES OF ACUTE REVERSIBLE TACROLIMUS (FK-506) NEPHROTOXICITY IN KIDNEY-TRANSPLANT RECIPIENTS

This study was designed to (a) estimate the contribution of tacrolimus nephrotoxicity to episodes of renal allograft dysfunction investigate d by needle biopsy, (b) describe the temporal evolution of nephrotoxic ity and its response to therapy, and (c) ascertain how often renal dys function is associated with concurrent extra-renal toxicity. Patients were selected based on a rising serum creatinine, normal ultrasound, a nd biopsy findings leading to a reduction in the dose of tacrolimus an d a fall in serum creatinine. Twenty two (17%) cases of nephrotoxicity were identified amongst 128 consecutive kidney transplant biopsies wi th sufficient clinical data for analysis. There were 13 males and 9 fe males, 17-75 yr in age. Tacrolimus was administered initially as a 0.0 75-0.1 mg/kg/d IV continuous infusion followed by an oral dose of 0.15 mg/kg twice daily. The onset of nephrotoxicity in this study occurred 1-156 wk post-operatively. The mean baseline creatinine was 212.2 +/- 168.0 mu mol/l (range 88.4-875.2) and rose 40.6% +/- 14.2% (range 11- 66) during episodes of nephrotoxicity (p<0.001). The highest recorded plasma and whole-blood tacrolimus levels during the toxic episodes wer e respectively 2.7 +/- 0.8 ng/ml (range 1.1-3.5) and 31.6 +/- 10.6 ng/ ml (range 14.5-50.5). The drug levels were considered to be beyond the therapeutic range in 18/22 (82%) patients. The highest tacrolimus lev el pre ceeded the rise in serum creatinine in 20 cases by an interval of 1.6 +/- 1.8 d. A mean reduction in tacrolimus dosage of 41% +/- 21% (range 11-89) led to a 86% +/- 18% (range 45-100) fall in the serum c reatinine within 1-14 d (p<0.001). Interactions between tacrolimus and clarithromycin, diltiazem, or itraconazole modified the pharmakokinet ic parameters in three cases. Serum potassium >5.0 mequiv./l was recor ded in 9/22 (41%) cases. Three or more elevations in blood glucose >7. 7 mmol/l (140 mg/dl) were recorded in 4/11 (36%) non-diabetic patients . Hand tremors were seen in two (9%) cases and elevated diastolic bloo d pressure > 90 mmHg in seven (32%) patients. In conclusion, tacrolimu s nephrotoxicity accounted for 17% of graft dysfunction episodes inves tigated by biopsy. Concurrent hyperglycemia, hyperkalemia, or tremors were noted in several patients. Nephrotoxicity responded well to reduc tion in the drug dosage.