High-Intrapatient Tacrolimus Variability in a Low-Dose Tacrolimus Regimen Predicts Worse Long-Term Outcomes After Renal Transplantation.

Abstract

Background Tacrolimus has been the mainstay of immunosuppression for the last decade. Subtherapeutic levels may lead to acute rejection (AR) whilst high levels result in toxicity. Reports prior to the Symphony study associate high intra-patient tacrolimus variability (IPTV) with worse outcomes. The lower target levels widely used since the Symphony study was published may magnify any effect of IPTV. We investigated the effects of IPTV in renal transplant (RTx) patients. Endpoints were graft survival, AR, and eGFR 1,2,3, and 4 years post transplantation. Methods The study included patients undergoing RTx between 01/01/07 and 31/12/2011. Exclusions were allograft loss or death within the 1st post transplant year, loss to follow-up, or conversion to other immunosuppression. All patients received Basiliximab induction and prednisolone plus mycophenolate in addition to tacrolimus. Target tacrolimus trough levels were 5-8μg/L. Median IPTV 6 -12 months post transplant was calculated by the following formula: {[(Xmean - X1) + (Xmean - X2)…..+(Xmean - Xn)] / n} / Xmean*100 = intra individual variability (%) Patients ≥ the IPTV median were considered high variability (HV) and patients < were considered low variability (LV). LV and HV groups were compared for the study primary endpoints outlined above. Results 376 patients were included in the study with a mean follow-up of 1495 days (± 551). Median IPTV was 16%. 181 patients were allocated to LV and 195 to HV. Baseline characteristics of the groups were not significantly different. HV patients suffered more episodes of 1 year AR (36/159 vs 14/167: p = 0.002) and late AR, after 1st year (21/174 vs 9/172: p =0.038). MDRD GFR at 1, 2, 3 and 4 years post transplant was worse in the HV group (p = <0.001 at 1, 2, 3 years and 0.028 at 4 years). Allograft survival (p= 0.002) was worse in the HV group. Discussion In RTx patients, managed with low dose tacrolimus, with > 4 years follow-up, we report high IPTV to be associated with worse outcomes by multiple clinical end-points. The causal nature of this relationship is unproven. Many factors contribute to IPTV, including adherence, lifestyle, diet etc. High IPV may identify a population of patients at increased risk for rejection and or graft loss. Such patients may benefit from increased surveillance and/or targeted interventions including specific immunosuppression protocols and patient education. DISCLOSURE:Clancy, M.: Grant/Research Support, Astellas.