Tacrolimus Trough Levels, Rejection and Renal Impairment in Liver Transplantation: A Systematic Review and Meta-Analysis

Abstract

We hypothesized that current trough concentrations of tacrolimus after liver transplantation are set too high, considering that clinical consequences of rejection are not severe while side effects are increased. We systematically reviewed 64 studies (32 randomized controlled trials and 32 observational studies) to determine how lower tacrolimus trough concentrations than currently recommended affect acute rejection rates and renal impairment. Among randomized trials the mean of tacrolimus trough concentration during the first month was positively correlated with renal impairment within 1 year (r = 0.73; p = 0.003), but not with acute rejection, either defined using protocol biopsies (r =−0.37; p = 0.32) or not (r = 0.11; p = 0.49). A meta‐analysis of randomized trials directly comparing tacrolimus trough concentrations (five trials for acute rejection [n = 957] and two trials for renal impairment [n = 712]) showed that “reduced tacrolimus” trough concentrations (<10 ng/mL) within the first month after liver transplantation were associated with less renal impairment at 1 year (RR = 0.51 [0.38–0.69]), with no significant influence on acute rejection (RR = 0.92 [0.65–1.31]) compared to “conventional tacrolimus” trough levels (>10 ng/mL). Lower trough concentrations of tacrolimus (6–10 ng/mL during the first month) would be more appropriate after liver transplantation. Regulatory authorities and the pharmaceutical industry should allow changes of regulatory drug information.

Optimization of immunosuppressive medication upon liver transplantation against HCC recurrence

“…Suggesting that over IS, especially in the first few months after transplant, where the focus is on preventing acute cellular rejection is oncologically detrimental, as well as being harmful to renal function (44). More recent work from a single institute has corroborated these conclusions, by showing an increased risk of HCC recurrence when there is early exposure to high levels of CNIs.…”

“…Additionally, tacrolimus trough concentrations of 7-10 ng/mL in the first month after liver transplant produce similar rejection rates, halved the occurrence of renal impairment and were associated with longer graft survival (29,44) when compared to trough concentrations >10 ng/mL. A tacrolimus trough concentration of >10 ng/mL is often regarded as the standard/reference for many clinical trials on liver transplant IS being derived from the IS thresholds established for kidney transplant (44). Based on these findings and increasing experience in the use of tacrolimus in the liver transplant population has led to lower trough levels of tacrolimus being aimed for in the immediate post-transplant period in many liver transplant programmes throughout the world.…”

Difficulties in diagnosing acute kidney injury post liver transplantation using serum creatinine based diagnostic criteria

“…Lower targets for tacrolimus trough doses have also recently been shown to improve graft survival and reduce both acute and chronic renal impairment [21,22] . Thus, risk modification is needed to optimize renal function in the pre, peri and postoperative can then be used to stratify patients for risk of acute kidney injury post LT and individualise immunosuppression policies.…”

“…Thus, in contrast to C-G formula, a body weight variable (which is difficult to assess as lean body mass in ascitic and malnourished patients) is not needed, and the MDRD equations use ethnicity, gender and age and then adjusts for 1.73 m 2 body surface area (without any assessment of height or weight). In cirrhosis, although there is discrepancy when compared to 125 I-iothalamate [32] , the MDRD-6 equation is considered a more accurate formanagement of LT candidates: which may prevent or delay post-LT end stage renal disease [22] .…”

Is there such a thing as protocol immunosuppression in liver transplantation?

“…The use of CNI at standard doses is an important factor in early renal dysfunction. In patients with pre-existing or early post-transplant renal dysfunction, and even in patients with normal renal function, RCTs investigating the use of IL-2 receptor monoclonal antibody induction (e.g., basiliximab on days 0 and 4), with delayed introduction of low-dose CNIs, have demonstrated an improvement in early renal function and reduction in the number of patients undergoing hemodialysis in the short term with no increase in acute rejection (a systematic review and metaanalysis has, however, questioned the need to introduce renal sparing agents versus simply aiming for reduced tacrolimus trough levels in the early post transplant period) [5]. In that review, trough levels between 6 and 10 ng/ml versus >10 ng/ ml in the first post-operative month did not lead to an increase in acute allograft rejection but were associated with improved renal function at 1 year.…”