Rationale
renal impairment, nephrotoxicity, ®, toxicities, kidney damage, impaired renal function
RENAL IMPAIRMENT, SIDE EFFECT, COMPLICATIONS, DYSFUNCTION, SECONDARY, LIVER DISEASE, IMPAIRED RENAL FUNCTION
To characterise the metabolic profile of patients, several research groups have presented the calculation of the ratio between concentration in the blood and the drug dosage (C/D ratio) as a simple, practical and cost-neutral method easily applied during daily clinical practice, since trough level measurement is a necessary and routine part of therapeutic drug monitoring [Several studies have identified a relationship between C/D ratio and clinical outcomes in organ transplant recipients. There is strong evidence that a lower C/D ratio (i.e. faster tacrolimus metabolism) is associated with inferior kidney function [Accordingly, it should be possible to limit renal dysfunction and reduce other tacrolimus-related toxicities by using a drug formulation that improves bioavailability and increases the C/D ratio. Therefore, a secondary aim of the EnGraft study is to prospectively test whether an elevated C/D ratio is associated with improved clinical outcomes. This is especially relevant in a patient population that is particularly vulnerable to kidney damage. The widespread use of the MELD (Model for End-Stage Liver Disease) score in determining organ allocation means that most LTx recipients already have impaired renal function at LTx. Since renal impairment is a typical side effect of CNI therapy, these patients are sensitive to CNI-induced nephrotoxicity very early after transplantation. The ReSpECT Study has already shown that lowering CNI exposure early after LTx is associated with better long-term kidney function [Since C/D ratio may be an effective tool for identifying patients at higher risk of developing poorer long-term outcomes in terms of kidney function and CNI toxicity, this study incorporates a long-term follow-up phase. By using C/D ratio to characterise patients in terms of tacrolimus metabolism at 12 weeks post-transplant, it will be possible to evaluate whether the sub-groups of slow, intermediate and high metabolisers exhibit long-term clinical outcomes that correlate with their metabolic profile. This would support the hypothesis that the C/D ratio has a predictive value that, when calculated during the early stages after LTx, may help transplant clinicians to identify patients at risk of long-term complications and to individualise patient therapy accordingly.Therefore, the EnGraft Study will follow patients for 3 years in total in order to assess long-term efficacy and safety outcomes and to see whether these outcomes correlate with the metabolic profile measured during the early post-transplant period.Controlled, prospective, multicentre trials are now needed to test the predictive value of the tacrolimus C/D ratio. Whilst published literature regarding C/D ratio in LTx is encouraging, we are currently reliant on retrospective, single-centre studies using small and heterogeneous patient cohorts. There are also very few direct pharmacokinetic comparisons of the two once-daily tacrolimus formulations (Advagraf™ and Envarsus®). The EnGraft study is the first large, multicentre, randomised, controlled study in LTx to test Envarsus® using C/D ratio as the primary variable.