Abstract
Noninvasive biomarkers of kidney allograft status can help minimize the need for standard of care kidney allograft biopsies. Metabolites that are measured in the urine may inform about kidney function and health status, and potentially identify rejection events. To test these hypotheses, we conducted a metabolomics study of biopsy-matched urine cell-free supernatants from kidney allograft recipients who were diagnosed with two major types of acute rejections and no-rejection controls. Non-targeted metabolomics data for 674 metabolites and 577 unidentified molecules, for 192 biopsy-matched urine samples, were analyzed. Univariate and multivariate analyses identified metabolite signatures for kidney allograft rejection. The replicability of a previously developed urine metabolite signature was examined. Our study showed that metabolite profiles can serve as biomarkers for discriminating rejection biopsies from biopsies without rejection features, but also revealed a role of estimated Glomerular Filtration Rate (eGFR) as a major confounder of the metabolite signal.
Highlights
Kidney transplantation is the treatment of choice for patients who are diagnosed with irreversible kidney failure
We examined whether the metabolites that we previously identified as being associated with acute cellular rejection (ACR) are associated with ACR when urine cell-free supernatants from an independent cohort of kidney allograft recipients are profiled with a new metabolomics platform that is capable of identifying a boarder spectrum of metabolites than in our earlier study (1276 metabolites vs. 749 metabolites)
To include the largest possible number of samples, we focus our discussion on the difference between acute rejection samples, which are a combination of ACR, antibody-mediated rejection (AMR), and mixed rejection, and non-rejection samples, which are a combination of acute tubular injury (ATI) and normal biopsy samples
Summary
Kidney transplantation is the treatment of choice for patients who are diagnosed with irreversible kidney failure. The full benefits of kidney transplantation are undermined by both immune factors and non-immune complications. Allograft rejection is the foremost complication, and is a major contributor to allograft failure and the death of the transplant recipient. Among the non-immune factors, infections and malignancy are life-threatening complications. With the introduction of potent immunosuppressive regimens, viral infections have emerged as a major threat, with infection with the cytomegalovirus (CMV) and BK virus being the two leading viral infections in the post-transplant period. Effective anti-viral therapy for treating CMV, but not for BK virus, is currently available. BK virus-associated nephropathy (BKVN) is an important cause of kidney allograft dysfunction and failure
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