Tacrolimus related adverse effects in liver transplant recipients: Its association with trough concentrations

Abstract

Background and Aims: Tacrolimus is an important immunosuppressant used in post liver transplantation (LT). A tacrolimus trough of 8 to 11 ng/mL is considered to be ideal for LT recipients to prevent allograft rejection. The aim of the study was to propose a suitable tacrolimus trough concentration, with minimal adverse effects. Methods: The study group consisted of LT recipients, who were non diabetic, non hypertensive and with normal renal parameters prior to LT. All patients were on standard immunosuppressive regimen. The study retrospectively looked into the acute cellular rejection (ACR) episodes amongst the LT recipients and three major adverse effects of tacrolimus i.e. neurotoxicity, nephrotoxicity and new onset diabetes mellitus (NODM). Results: There were 32 LT recipients who fulfilled the criteria for the study. The mean tacrolimus trough level for the 290 troughs (after 10 days) was 8.5±3.8 ng/mL. At 10 days, one month, three months and six months, the trough values were 7.3±2.9, 9.7±3.4, 7.9±3.3 and 7.6±2.6 ng/mL respectively. The mean time taken for stabilization of the blood pressure, and biochemical parameters was 7 + 2 days. Overall, a trough window with the least adverse effect was 7 to 7.9 ng/mL. Neurotoxicity was least in the trough range 5 to <8 ng/mL. Symptoms included headache in 4, tremors in 3, seizure in one and confusion and psychosis in 2 and combination in 3. Nephrotoxicity was least in trough 8 to 11 <ng/mL. One patient progressed to chronic kidney disease at 6 months. NODM was present in 11% to 18% across the various trough range, including the extremes (mean trough level 8.4 ± 4.4 ng/dL). At 6 months, 5 recipients were on treatment for NODM. Three recipients developed ACR: 2 within the first month and one at 7 weeks; the trough levels were 8.5 ng/mL, 9 ng / mL, 15.2 ng/mL respectively. All recovered with three pulse doses of methylprednisolone. Conclusions: Tacrolimus concentration of 5 to < 8 ng/mL is optimal for minimizing neurotoxicity and ACR and a trough of 8 to < 11 for nephrotoxicity.