An exome-wide study of renal operational tolerance

Abstract

BackgroundRenal operational tolerance is a rare and beneficial state of prolonged renal allograft function in the absence of immunosuppression. The underlying mechanisms are unknown. We hypothesized that tolerance might be driven by inherited protein coding genetic variants with large effect, at least in some patients.MethodsWe set up a European survey of over 218,000 renal transplant recipients and collected DNAs from 40 transplant recipients who maintained good allograft function without immunosuppression for at least 1 year. We performed an exome-wide association study comparing the distribution of moderate to high impact variants in 36 tolerant patients, selected for genetic homogeneity using principal component analysis, and 192 controls, using an optimal sequence-kernel association test adjusted for small samples.ResultsWe identified rare variants of HOMER2 (3/36, FDR 0.0387), IQCH (5/36, FDR 0.0362), and LCN2 (3/36, FDR 0.102) in 10 tolerant patients vs. 0 controls. One patient carried a variant in both HOMER2 and LCN2. Furthermore, the three genes showed an identical variant in two patients each. The three genes are expressed at the primary cilium, a key structure in immune responses.ConclusionRare protein coding variants are associated with operational tolerance in a sizable portion of patients. Our findings have important implications for a better understanding of immune tolerance in transplantation and other fields of medicine.ClinicalTrials.gov, identifier: NCT05124444.

Novel transcriptomic signatures associated with premature kidney allograft failure

“…Most importantly, we have identified a large cohort of new European patients with operational tolerance and founded a European multicenter study 7 under the umbrella of DESCARTES, the European Renal Association Working Group, to study transcriptomic and genetic abnormalities in this cohort. 28 By comparing the peripheral blood transcriptomic signatures of operationally tolerant patients with several comparator cohorts, including high responders with CABMR, we were able to identify a set of “protective” peripheral transcripts. We were then able to validate the findings in a large cohort that consisted of 396 patients, including 40 who experienced graft loss within a 3-year follow-up.…”