Background. Use of calcineurin inhibitors (CNIs) after kidney transplantation (KT) induces vasoconstriction of renal afferent arterioles, leading to functional changes and potentially irreversible chronic ischemic structural damage. Because CNI toxicity (CNIT) might contribute to interstitial fibrosis (IF) and tubular atrophy (TA), better tests are needed to diagnose early CNIT.

Samples and Methods. 164 biopsies from 127 primary, deceased donor KT recipients (KTRs) undergoing CNI-based immunosuppression were evaluated. CNI-related nephrotoxicity was defined by histological findings compatible with CNIT (in absence of acute rejection (AR) and/or IF/TA) and rise in serum creatinine. To identify specific molecular markers of CNIT, gene expression profiling was performed in biopsies with CNIT (n=12), ACR (n=9), chronic allograft dysfunction (CAD) with IF/TA (n=10) and normal allografts (NA, n=19) (training set). An independent set of biopsies (CNIT=20; NA=20) was used as validation set for the top 15 genes (FDR≤5%). Furthermore, an independent set of paired biopsies from 37 KTRs propspectively collected at 3 and 9 months post-KT (n=74 biopsies) were evaluated to identify the contribution of CNIT in the development of CAD. Validation group patients were classified based on 2-year post-KT graft function (defined as KTRs with eGFR ≤40 ml/min/1.72cm² and histological evidence of IF/TA (poor function group: PFG) or KTRs with continuous eGFR >40 from KT and normal histology (normal function group: NFG)).

Results. 270 probesets were differentially expressed between CNIT and NA biopsies with 55 genes being unique for CNIT. CNIT-associated molecular functions identified included cellular movement, cellular growth and proliferation and cell death (p<0.001). Molecular processes identified suggest induction of epidermal-to-mesenchymal transition during CNIT. When evaluating the contribution of CNIT to IF/TA development, PFG patients classified as showed an overlap of 20% and 40% of the CNIT signature at 3 and 9-months respectively, while 6% and 3% at 3 and 9 months on NFG patients. Moreover, 19 of these genes were identified as related to renal toxicity and further validated using QPCR.

Conclusions. We have identified a molecular signature that characterizes CNIT samples. Moreover, at the molecular level, CNIT plays a critical role as non-immunological factor in the development of CAD.

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