Identifying biomarkers in kidney transplant patients is essential for early detection of rejection, personalized treatment and improved overall outcomes. It improves our ability to monitor the health of the transplanted organ and tailor interventions to the specific needs of each patient. Here we compiled a multicenter, multiomic dataset of the kidney transplant landscape. Using multi-omics factor analysis (MOFA), we sought to uncover sources of biological variability in patients’ blood, urine and allograft at the epigenetic and transcriptomic levels. MOFA reveals multicellular immune signatures characterized by distinct monocyte, natural killer and T cell substates explaining a large proportion of inter-patient variance. We also identified specific factors that reflect allograft rejection, complement activation or induction treatment. Factor 1 mainly explained the molecular variations in patients’ circulation and discriminated antibody-mediated rejection from T-cell mediated rejection. Factor 2 captured some of the molecular variation occurring within the allograft and associated with complement/monocytes crosstalk. Factor 4 captured the impact of ATG induction. These data provide proof-of-concept of MOFA’s ability to reveal multicellular immune profiles in kidney transplantation, opening up new directions for mechanistic, biomarker and therapeutic studies.

The authors have declared no competing interest.

The BIOMARGIN study was funded by the Seventh Framework Programme (FP7) of the European Commission in the HEALTH 2012.1.4-1 call for innovative approaches to solid organ transplantation, with grant agreement no. 305499. This project was supported by the ROCKET study, under the frame of ERACoSysMed-2, the ERA-Net for Systems Medicine in clinical research and medical practice (JTC2_29).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Patients were included prospectively in four European transplant centers between June 2011 and March 2017 (University Hospitals Leuven, Belgium; Medizinische Hochschule Hannover, Germany; Centre Hospitalier Universitaire Limoges, France, and Hopital Necker Paris, France). In all four clinical centers, protocol renal allograft biopsies were performed 3, 12 and sometimes 24 months after transplantation, in accordance with local practice, in addition to clinically indicated biopsies (biopsies at the time of graft dysfunction). In parallel, blood and urine samples were collected at the same times. All adult patients who had received a single renal allograft at these institutions and provided written informed consent for this study were eligible. This consent adheres to the Declaration of Istanbul. Ethics committee XI #13016, Paris, France for Necker Hospital gave ethical approval for this work. Ethics committee #S55598, Leuven, Belgium for Leuven Hospital gave ethical approval for this work. Ethics committee #6475, Hannover, Germany for Hannover Medical School gave ethical approval for this work. Ethics committee #DC-2010-1075, Limoges, France for Limoges Hospital gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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All data presented in this present study are derived from the BIOMARGN study and are already publicly available, with the exception of urinary gene expression, which can be shared upon reasonable request. Epigenome analyses were performed using the following datasets: blood-derived miRNA expression E-MTAB-9595 and biopsy-derived miRNA expression GSE179772. Blood-derived transcriptome analyses were performed using the following datasets: MicroArray-quantified mRNA GSE129166 and bulk RNA sequencing GSE175718. Biopsy-derived transcriptome analysis was performed using the following dataset: GSE147089.