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Kidney Allograft Function Is a Confounder of Urine Metabolite Profiles in Kidney Allograft Recipients.

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.

SUBMITTER: Suhre K

PROVIDER: S-EPMC8399888 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Kidney Allograft Function Is a Confounder of Urine Metabolite Profiles in Kidney Allograft Recipients.

Suhre Karsten K Dadhania Darshana M DM Lee John Richard JR Muthukumar Thangamani T Chen Qiuying Q Gross Steven S SS Suthanthiran Manikkam M

Metabolites 20210811 8

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-target ...[more]

PMID: 34436474

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Project description:BackgroundKidney tubulointerstitial fibrosis marks risk for allograft failure in kidney transplant recipients, but is poorly captured by estimated glomerular filtration rate (eGFR) or urine albumin-creatinine ratio (ACR). Whether urinary markers of tubulointerstitial fibrosis can noninvasively identify risk for allograft failure above and beyond eGFR and ACR is unknown.Study designCase-cohort study.Setting & participantsThe FAVORIT (Folic Acid for Vascular Outcome Reduction in Transplantation) Trial was a randomized double-blind trial testing vitamin therapy to lower homocysteine levels in stable kidney transplant recipients. We selected a subset of participants at random (n=491) and all individuals with allograft failure during follow-up (cases; n=257).PredictorUsing spot urine specimens from the baseline visit, we measured 4 urinary proteins known to correlate with tubulointerstitial fibrosis on biopsy (urine α1-microglobulin [A1M], monocyte chemoattractant protein 1 [MCP-1], and procollagen type III and type I amino-terminal amino pro-peptide).OutcomeDeath-censored allograft failure.ResultsIn models adjusted for demographics, chronic kidney disease risk factors, eGFR, and ACR, higher concentrations of urine A1M (HR per doubling, 1.73; 95% CI, 1.43-2.08) and MCP-1 (HR per doubling, 1.60; 95% CI, 1.32-1.93) were strongly associated with allograft failure. When additionally adjusted for concentrations of other urine fibrosis and several urine injury markers, urine A1M (HR per doubling, 1.76; 95% CI, 1.27-2.44]) and MCP-1 levels (HR per doubling, 1.49; 95% CI, 1.17-1.89) remained associated with allograft failure. Urine procollagen type III and type I levels were not associated with allograft failure.LimitationsWe lack kidney biopsy data, BK titers, and HLA antibody status.ConclusionsUrine measurement of tubulointerstitial fibrosis may provide a noninvasive method to identify kidney transplant recipients at higher risk for future allograft failure, above and beyond eGFR and urine ACR.

Dataset Information

Kidney Allograft Function Is a Confounder of Urine Metabolite Profiles in Kidney Allograft Recipients.

Publications

Kidney Allograft Function Is a Confounder of Urine Metabolite Profiles in Kidney Allograft Recipients.

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