MO941: Novel Peripheral Molecular Markers Predict Premature Graft Loss: Lessons Learned from Operational Tolerance Assessment

Abstract BACKGROUND AND AIMS TOMOGRAM, a European multicenter study, recently identified a new cohort of kidney transplant recipients (KTR) with operational tolerance (OT) with the aim to identify new transcriptomic signatures of OT. METHOD RNA sequencing of peripheral blood was evaluated in 15 OT KTR identified by TOMOGRAM, 23 stable KTR (≥15 years, STA), 14 KTR with transplant glomerulopathy (≥1 year, CR), 14 CyA-treated primary GN patients and 14 healthy controls (HC). The ability to discriminate OT from others was analyzed using three classifiers (GLMNET, voomNSC and SVM-RFE) with 10-fold cross-validation and visualized by principal component analysis (PCA) of molecular archetypes. RESULTS Peripheral blood transcriptome of OT patients is similar to the STA group (AUC < 0.6) and different from the CR group (AUC > 0.8). Also, in PCA of molecular archetypes, direction of correlation suggested similarity between STA and OT and their anti-correlation to CR (Figure 1). Top 10 transcripts differentiated OT from CR were assessed in prospective independent cohort (n = 396) to predict premature graft loss. Multivariable Cox regression model based on the expression of 5 of those transcripts at 3 time-points was associated with graft loss at 3 years with an AUC = 0.815. CONCLUSION Identification of the OT peripheral molecular signature among stable KTR is not feasible. Instead, novel peripheral molecular markers associated with premature graft loss were identified.