PMID- 38542163 OWN - NLM STAT- MEDLINE DCOM- 20240329 LR - 20240330 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 25 IP - 6 DP - 2024 Mar 10 TI - Expression of Rejection-Associated Transcripts in Early Protocol Renal Transplant Biopsies Is Associated with Tacrolimus Exposure and Graft Outcome. LID - 10.3390/ijms25063189 [doi] LID - 3189 AB - Subclinical inflammation in protocol biopsies relates to tacrolimus exposure and human leukocyte antigen (HLA) matching. We aimed to characterize transcripts associated with rejection and tacrolimus exposure and the latter's association with transplant outcomes. We tested whether gene expression is associated with rejection using strictly normal protocol biopsies (n = 17) and biopsies with T cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR) according to Banff criteria (n = 12). Subsequently, we analyzed these transcripts in a set of 4-month protocol biopsies (n = 137) to assess their association with donor and recipient characteristics, the intensity of immunosuppression, and the graft outcome. Differential expression (false discovery rate (FDR) < 0.01, fold (change (FC) > 3) between normal and rejection biopsies yielded a set of 111 genes. In the protocol biopsy cohort (n = 137), 19 out of these 111 genes correlated with tacrolimus trough levels at the time of biopsy (TAC-C(0)), and unsupervised analysis split this cohort into two clusters. The two clusters differed in donor age and tacrolimus trough levels. Subclinical rejection, including borderline lesions, tended to occur in the same cluster. Logistic regression analysis indicated that TAC-C(0) at the time of biopsy (OR: 0.83, 95%CI:0.72-0.06, p = 0.0117) was associated with cluster 2. In a follow-up averaging 70 +/- 30 months, this patient group displayed a significant decline in renal function (p = 0.0135). The expression of rejection-associated transcripts in early protocol biopsies is associated with tacrolimus exposure and a faster decline in renal function. FAU - Chamoun, Betty AU - Chamoun B AUID- ORCID: 0000-0002-4267-2273 AD - Nephrology Department, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain. AD - Department of Medicine, Autonomous University of Barcelona, 08035 Barcelona, Spain. FAU - Torres, Irina B AU - Torres IB AD - Nephrology Department, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain. AD - Department of Medicine, Autonomous University of Barcelona, 08035 Barcelona, Spain. AD - Laboratory of Nephrology and Transplantation, Vall d'Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain. FAU - Gabaldon, Alejandra AU - Gabaldon A AD - Pathology Department, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain. FAU - Jouve, Thomas AU - Jouve T AUID- ORCID: 0000-0001-9016-7506 AD - Laboratory of Nephrology and Transplantation, Vall d'Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain. AD - Renal Transplant Unit, Nephrology Department, Grenoble University Hospital, 38043 Grenoble, France. FAU - Meneghini, Maria AU - Meneghini M AD - Nephrology Department, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain. AD - Laboratory of Nephrology and Transplantation, Vall d'Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain. FAU - Zuniga, Jose M AU - Zuniga JM AD - Nephrology Department, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain. AD - Laboratory of Nephrology and Transplantation, Vall d'Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain. FAU - Sellares, Joana AU - Sellares J AUID- ORCID: 0000-0002-0394-8011 AD - Nephrology Department, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain. AD - Laboratory of Nephrology and Transplantation, Vall d'Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain. FAU - Perello, Manel AU - Perello M AD - Nephrology Department, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain. FAU - Seron, Daniel AU - Seron D AD - Nephrology Department, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain. FAU - Bestard, Oriol AU - Bestard O AD - Nephrology Department, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain. AD - Department of Medicine, Autonomous University of Barcelona, 08035 Barcelona, Spain. AD - Laboratory of Nephrology and Transplantation, Vall d'Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain. FAU - Moreso, Francesc AU - Moreso F AUID- ORCID: 0000-0002-7267-3963 AD - Nephrology Department, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain. AD - Department of Medicine, Autonomous University of Barcelona, 08035 Barcelona, Spain. AD - Laboratory of Nephrology and Transplantation, Vall d'Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain. LA - eng PT - Journal Article DEP - 20240310 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - WM0HAQ4WNM (Tacrolimus) RN - 0 (Immunosuppressive Agents) SB - IM MH - Humans MH - *Kidney Transplantation/adverse effects MH - Tacrolimus/adverse effects MH - Graft Rejection/genetics MH - Biopsy MH - Immunosuppression Therapy MH - Immunosuppressive Agents/adverse effects PMC - PMC10970018 OTO - NOTNLM OT - biopsies OT - gene expression OT - rejection OT - renal transplantation OT - tacrolimus COIS- D.S. and F.M. received grant support and personal fees from Astellas Pharma Spain and Chiesi Spain. The authors declare no conflict of interest. EDAT- 2024/03/28 06:46 MHDA- 2024/03/29 06:46 PMCR- 2024/03/10 CRDT- 2024/03/28 01:17 PHST- 2024/01/18 00:00 [received] PHST- 2024/02/20 00:00 [revised] PHST- 2024/03/06 00:00 [accepted] PHST- 2024/03/29 06:46 [medline] PHST- 2024/03/28 06:46 [pubmed] PHST- 2024/03/28 01:17 [entrez] PHST- 2024/03/10 00:00 [pmc-release] AID - ijms25063189 [pii] AID - ijms-25-03189 [pii] AID - 10.3390/ijms25063189 [doi] PST - epublish SO - Int J Mol Sci. 2024 Mar 10;25(6):3189. doi: 10.3390/ijms25063189.