High Intrapatient Tacrolimus Variability and Early Sub-Therapeutic Tacrolimus Levels but not Pre-Transplant Phosphate Variability, Predict Worse Outcomes Post Renal Transplantation

Abstract

Introduction: High intrapatient tacrolimus variability is associated with worse clinical outcomes post-renal transplantation. High tacrolimus levels predispose to toxicity, whilst sub-therapeutic tacrolimus levels predispose to acute rejection (AR). We investigated the effects of intrapatient tacrolimus variability and sub-therapeutic tacrolimus levels in the 1st year post renal transplantation and hypothesized that high phosphate variability pre-transplant would identify patients at high risk for drug non-compliance post-transplantation. Methods: Data was collected from the prospective electronic patient record for 250 transplant recipients. Patients were excluded if they had undergone parathyroidectomy in the year preceding transplantation (n=6), if there was incomplete phosphate data (n=22), or if < 2 tacrolimus levels were recorded between 6 -12 months post transplantation (n=18). All Patients received Basiliximab induction and triple therapy immunosuppression with prednisolone, mycophenolate and tacrolimus. Target tacrolimus trough levels were between 5-8μg/L. Intrapatient tacrolimus variability values were calculated 6-12 months post transplantation along with the percentage of sub-therapeutic tacrolimus levels. Pre-dialysis phosphate variability was measured in the year before transplantation. In each group, patients > the observed median were considered high risk (HR) and patients < /= were considered low risk (LR). HR and LR groups for intrapatient tacrolimus variability, phosphate variability and sub-therapeutic tacrolimus levels were then compared for outcomes at 1 year post transplantation. A p value of < 0.05 was taken to be significant. Results:Median intrapatient tacrolimus variability between 6-12 months was 17%. (Range 2% - 81%). AR risk was higher in HR than LR patients (20.7% vs 7.8%; p=0.009). eGFR at 1 year was lower in the HR group (mean 54.9 ml/min, SD 21.9) compared to the LR group. (mean 62.4ml/min, SD 20.6) P = 0.014. The median sub-therapeutic tacrolimus level was 14% (range 0% -78%). AR risk was higher in HR than LR patients (19.8% vs 8.7%; p=0.028). eGFR at 1 year in the HR group (mean 55.5 ml/min, SD 23.78) was lower than for the LR group (mean 61.8 ml/min, SD 18.6)(P=0.035). On analysis of phosphate variability, there was no significant difference in AR or eGFR for the HR and LR groups. No association was found between the phosphate variability groups and the sub-therapeutic tacrolimus or intrapatient tacrolimus variability groups. Discussion: These data supports the assertion that high intrapatient tacrolimus variability and sub-therapeutic tacrolimus are associated with worse clinical outcomes. The relationship with phosphate pretransplant and tacrolimus levels is complex, however the putative poor compliance group of high pre-transplant phosphate variability did not show an association with acute rejection or higher eGFR. This suggests that factors beyond simple clinical compliance contribute to intrapatient tacrolimus variability and its associated poor outcomes.