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 investigated by needle biopsy, (b) describe the temporal evolution of nephrotoxicity and its response to therapy, and (c) ascertain how often renal dysfunction is associated with concurrent extra‐renal toxicity. Patients were selected based on a rising serum creatinine, normal ultrasound, and biopsy findings leading to a reduction in the dose of tacrolimus and a fall in serum creatinine. Twenty two (17%) cases of nephrotoxicity were identified amongst 128 consecutive kidney transplant biopsies with sufficient clinical data for analysis. There were 13 males and 9 females, 17‐75 yr in age. Tacrolimus was administered initially as a 0.075‐0.1 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 μmol/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 were 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 level preceeded 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 creatinine within 1‐14 d (p<0.001). Interactions between tacrolimus and clarithromycin, diltiazem, or itraconazole modified the pharmakokinetic parameters in three cases. Serum potassium >5.0 mequiv./1 was recorded 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 blood pressure > 90 mmHg in seven (32%) patients. In conclusion, tacrolimus nephrotoxicity accounted for 17% of graft dysfunction episodes investigated by biopsy. Concurrent hyperglycemia, hyperkalemia, or tremors were noted in several patients. Nephrotoxicity responded well to reduction in the drug dosage.