Non-Compliance Assessed By Variability of Blood Calcineurin Inhibitor (CNI) Levels Is Associated With Poor Long-Term Outcomes in Kidney Transplant Recipients (KTRs).

Abstract

Non-compliance with treatment is a major problem in clinical renal transplantation. There is an emerging interest in the development of objective markers of non-compliance. Variability of CNI drug levels is one such marker. In this large single centre retrospective analysis, we examined the relationship between the overall graft outcomes and CNI variability. A total of 10 plasma CNI levels were examined between the 2nd and 3rd post-transplant year for the analysis in 1235 consecutive KTRs. Patients were divided into three tertiles based on their CNI (2y-3y) variability. Grafts lost prior to third transplant year were excluded to minimize the effect of early therapeutic modifications. Overall graft survival was examined over 10 years by Kaplan Meier analysis. The mean variability was significantly higher for younger KTRs {age lowest tertile (20yrs), 24.7 vs. middle tertile (40yrs), 21.9, vs. highest tertile (59yrs), 22.9; P<0.05, ANOVA}. Overall, patients in the highest tertile group of CNI (2y-3y) variability had the worst overall graft survival when compared to the other tertiles. When the analysis was stratified by the age of the KTRs, patients with high variability in the lowest tertile group of age (i.e. youngest age group) had the worst outcomes. CNI (2y-3y) variability was not strongly associated with increased overall graft loss in older KTRs. The utility of CNI variability was re-examined in 118 KTRs with allograft dysfunction. These patients underwent an indication biopsy for either creeping creatinine or proteinuria. Patients in the highest tertile group of CNI variability had higher microcirculation inflammation score (glomerulitis+peritubular capillaritis) and a higher percentage of these grafts were positive for C4d deposition despite no significant difference in the prevalence of DSA in the serum. There was no significant difference in the mean score for scarring (ct+ci). However, patients in the lowest tertile group for CNI level variability had significantly superior post-biopsy graft survival when compared to the highest two tertiles in this selective group of patients with allograft dysfunction. To conclude, CNI drug level variability is a potential marker for predicting allograft outcomes especially in the younger patient cohort where non-compliance is a major problem. This has to be validated in further prospective studies