Background: We previously described a gene expression signature as biomarker of calcineurin inhibitor nephrotoxicity (CNIT) post renal transplantation. Herein, we aimed to validate the same set of markers in urine samples of liver transplant (LT) recipients under CNI therapy with renal function impairment.

Methods: This study included 52 urine samples collected during routine clinical follow-up visit from 42 LTx patients under Tacrolimus (Tac) based immunosuppression. LTx patients were classified according to an estimated glomerular filtration rate (eGFR) as with suspected CNIT (eGFR ≤ 40; n = 23) and non-CNIT (eGFR > 40; n = 29). Urine pellets were obtained by centrifugation and total RNA was isolated following Trizol protocol. Ten genes associated with renal transplant CNIT were tested using real time quantitative PCR (RT-qPCR). Pairwise comparisons (CNIT vs. no-CNIT) for individual gene were performed using two-sample t-test. Demographics-clinical parameters statistical analyses were performed using ANOVA. P-values <0.05 were considered significant. Sample group prediction analysis was performed by discriminant multivariate methods. ROC curves were calculated for each group.

Results: Liver transplant patient groups were homogeneously distributed regarding follow-up time post-LTx and liver function test. Patients with suspected CNIT revealed significant increased BUN, Creatinine and decrease in eGFR. Mean eGFR values were 37.0±6.4 and 58.4±6.3 for CNIT and no-CNIT, respectively. Peripheral blood Tac levels were no significantly different between groups . From the evaluated molecular panel, 7 genes (SCL13A3, AQP1, AQP2, NPHS2, CUBN, LPR2, and SCL12A3) were found significantly down regulated in CNIT urine pellets. The gene expression panel was able to accurately distinguish 76.9% (40/52) of samples depending on the assigned study group. Calculated diagnostic sensitivity, specificity, and positive and negative predictive values for the gene expression panel to distinguish between groups were 76%, 77%, 70%, and 83%, respectively. Areas under ROC curve were 0.85 for both study groups. All patients demonstrated an improvement in eGFR decreasingTacrolimus doses.

Conclusions: We validated a CNIT urine biomarker set (previously described in KT patients) in LTx recipients with post-transplant renal impairment under CNI therapy. The validated biomarker set demonstrated high diagnostic sensitivity and specificity.

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