CNI are effective in kidney transplantation but their off-target effects make CNI withdrawal (w/d) desirable. Published studies showed that clinical parameters cannot differentiate the ~50% of subjects who tolerate CNI w/d from those who develop acute rejection (AR) and/or donor specific antibodies (DSA). Understanding the transcriptomes that accompany CNI w/d would provide new mechanistic insight and could identify signatures that differentiate uncomplicated CNI w/d from that which results in AR/DSA.

We studied PBMC samples from 2 CNI w/d trials: CTOT09 (Hricik, JASN 2013) and ATHENA (clinicaltrial.gov: NCT00494741). We performed Affymetrix microarray analyses of RNA from PBMC of 11 CTOT09 subjects obtained before CNI w/d (6 mo posttransplant) and 3 mo later, when all subjects had undergone w/d and from 4 controls not undergoing w/d. We similarly analyzed PBMC RNA obtained before and after CNI tapering from 15 ATHENA subjects. In the CTOT cohort, CNI w/d upregulated 809 genes in those who experienced AR/DSA but only 359 genes in those who tolerated w/d, similar to controls maintained on CNI (336 genes). Gene ontology (GO) enrichment analysis showed that in those who developed AR/DSA, uniquely upregulated genes mapped to T cell activation, differentiation, and proliferation, while in those with stable graft function upregulated genes mapped to metabolic pathways, e.g. regulators of organic acids, lipids, and glucose transport. Analysis of gene expression before CNI w/d revealed enriched transcripts related to T and B cell receptor signaling in subjects who developed AR/DSA versus stable patients, which was confirmed by ATHENA samples, but no specific gene signature was common within the 2 studies. We did not detect the previously reported B cell gene signature (Newell, JCI 2010) in stable subjects after CNI w/d.

Despite small sample size, PBMC transcriptomes from patients with AR/DSA after CNI w/d implicate immune cell activation while CNI w/d in stable patients alters metabolic programing without evidence of immune activation. Besides identifying genes inhibited by CNI our study indicates that PBMC gene signatures could inform risk of CNI w/d in kidney transplantation.

CITATION INFORMATION: Cravedi P, Zhang W, Salomon D, Fribourg M, Remuzzi G, Gotti E, Casiraghi F, Yi Z, Heeger P, CTOT09, ATHENA Consortia Changes in Peripheral Blood Gene Expression Profile After Calcineurin Inhibitor (CNI) Withdrawal in Kidney Transplant Recipients. Am J Transplant. 2017;17 (suppl 3).

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