Novel transcriptomic signatures associated with premature kidney allograft failure.

Autor:	Hruba P; Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic., Klema J; Department of Computer Science, Czech Technical University, Prague, Czech Republic., Le AV; Department of Computer Science, Czech Technical University, Prague, Czech Republic., Girmanova E; Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic., Mrazova P; Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic., Massart A; Antwerp University Hospital and Antwerp University, Antwerp, Belgium., Maixnerova D; Department of Nephrology, 1st Faculty of Medicine and General Faculty Hospital, Prague, Czech Republic., Voska L; Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic., Piredda GB; Department of Kidney Disease Medicine of Renal Transplantation, G.Brotzu Hospital Cagliari, Italy., Biancone L; Department of Medical Sciences, University of Torino, Torino, Italy., Puga AR; Hospital Universitario Insular de Gran Canaria, Servicio de nefrología, Spain., Seyahi N; Istanbul University, Cerrahpasa Medical Faculty, Nephrology, Istanbul, Turkey., Sever MS; Istanbul University, Istanbul School of Medicine, Internal Medicine, Nephrology, Istanbul, Turkey., Weekers L; Department of Nephrology, CHU of Liege, Liège, Belgium., Muhfeld A; Department of Nephrology, Uniklinik RWTH Aachen, Aachen, Germany., Budde K; Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin, Berlin, Germany., Watschinger B; Department of Internal Medicine III, Nephrology, Medical University Vienna / AKH Wien, Vienna, Austria., Miglinas M; Faculty of Medicine, Nephrology Center, Vilnius University Hospital Santaros Klinikos, Vilnius University, Vilnius, Lithuania., Zahradka I; Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic., Abramowicz M; Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Rue Michel Servet 1, 1206 Geneva, Switzerland., Abramowicz D; Antwerp University Hospital and Antwerp University, Antwerp, Belgium., Viklicky O; Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. Electronic address: ondrej.viklicky@ikem.cz.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2023 Oct; Vol. 96, pp. 104782. Date of Electronic Publication: 2023 Sep 01.
DOI:	10.1016/j.ebiom.2023.104782
Abstrakt:	Background: The power to predict kidney allograft outcomes based on non-invasive assays is limited. Assessment of operational tolerance (OT) patients allows us to identify transcriptomic signatures of true non-responders for construction of predictive models. Methods: In this observational retrospective study, RNA sequencing of peripheral blood was used in a derivation cohort to identify a protective set of transcripts by comparing 15 OT patients (40% females), from the TOMOGRAM Study (NCT05124444), 14 chronic active antibody-mediated rejection (CABMR) and 23 stable graft function patients ≥15 years (STA). The selected differentially expressed transcripts between OT and CABMR were used in a validation cohort (n = 396) to predict 3-year kidney allograft loss at 3 time-points using RT-qPCR. Findings: Archetypal analysis and classifier performance of RNA sequencing data showed that OT is clearly distinguishable from CABMR, but similar to STA. Based on significant transcripts from the validation cohort in univariable analysis, 2 multivariable Cox models were created. A 3-transcript (ADGRG3, ATG2A, and GNLY) model from POD 7 predicted graft loss with C-statistics (C) 0.727 (95% CI, 0.638-0.820). Another 3-transcript (IGHM, CD5, GNLY) model from M3 predicted graft loss with C 0.786 (95% CI, 0.785-0.865). Combining 3-transcripts models with eGFR at POD 7 and M3 improved C-statistics to 0.860 (95% CI, 0.778-0.944) and 0.868 (95% CI, 0.790-0.944), respectively. Interpretation: Identification of transcripts distinguishing OT from CABMR allowed us to construct models predicting premature graft loss. Identified transcripts reflect mechanisms of injury/repair and alloimmune response when assessed at day 7 or with a loss of protective phenotype when assessed at month 3. Funding: Supported by the Ministry of Health of the Czech Republic under grant NV19-06-00031. Competing Interests: Declaration of interests All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/. All authors declare no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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