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Identification of a urine metabolite constellation characteristic for kidney allograft rejection.

ABSTRACT: INTRODUCTION:Allograft rejection is still an important complication after kidney transplantation. Currently, monitoring of these patients mostly relies on the measurement of serum creatinine and clinical evaluation. The gold standard for diagnosing allograft rejection, i.e. performing a renal biopsy is invasive and expensive. So far no adequate biomarkers are available for routine use. OBJECTIVES:We aimed to develop a urine metabolite constellation that is characteristic for acute renal allograft rejection. METHODS:NMR-Spectroscopy was applied to a training cohort of transplant recipients with and without acute rejection. RESULTS:We obtained a metabolite constellation of four metabolites that shows promising performance to detect renal allograft rejection in the cohorts used (AUC of 0.72 and 0.74, respectively). CONCLUSION:A metabolite constellation was defined with the potential for further development of an in-vitro diagnostic test that can support physicians in their clinical assessment of a kidney transplant patient.

SUBMITTER: Banas M

PROVIDER: S-EPMC6133122 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Identification of a urine metabolite constellation characteristic for kidney allograft rejection.

Banas Miriam M Neumann Sindy S Eiglsperger Johannes J Schiffer Eric E Putz Franz Josef FJ Reichelt-Wurm Simone S Krämer Bernhard Karl BK Pagel Philipp P Banas Bernhard B

Metabolomics : Official journal of the Metabolomic Society 20180830 9

<h4>Introduction</h4>Allograft rejection is still an important complication after kidney transplantation. Currently, monitoring of these patients mostly relies on the measurement of serum creatinine and clinical evaluation. The gold standard for diagnosing allograft rejection, i.e. performing a renal biopsy is invasive and expensive. So far no adequate biomarkers are available for routine use.<h4>Objectives</h4>We aimed to develop a urine metabolite constellation that is characteristic for acute ...[more]

PMID: 30830387

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Project description:BackgroundIn the context of kidney transplantation, genomic incompatibilities between donor and recipient may lead to allosensitization against new antigens. We hypothesized that recessive inheritance of gene-disrupting variants may represent a risk factor for allograft rejection.MethodsWe performed a two-stage genetic association study of kidney allograft rejection. In the first stage, we performed a recessive association screen of 50 common gene-intersecting deletion polymorphisms in a cohort of kidney transplant recipients. In the second stage, we replicated our findings in three independent cohorts of donor-recipient pairs. We defined genomic collision as a specific donor-recipient genotype combination in which a recipient who was homozygous for a gene-intersecting deletion received a transplant from a nonhomozygous donor. Identification of alloantibodies was performed with the use of protein arrays, enzyme-linked immunosorbent assays, and Western blot analyses.ResultsIn the discovery cohort, which included 705 recipients, we found a significant association with allograft rejection at the LIMS1 locus represented by rs893403 (hazard ratio with the risk genotype vs. nonrisk genotypes, 1.84; 95% confidence interval [CI], 1.35 to 2.50; P = 9.8×10-5). This effect was replicated under the genomic-collision model in three independent cohorts involving a total of 2004 donor-recipient pairs (hazard ratio, 1.55; 95% CI, 1.25 to 1.93; P = 6.5×10-5). In the combined analysis (discovery cohort plus replication cohorts), the risk genotype was associated with a higher risk of rejection than the nonrisk genotype (hazard ratio, 1.63; 95% CI, 1.37 to 1.95; P = 4.7×10-8). We identified a specific antibody response against LIMS1, a kidney-expressed protein encoded within the collision locus. The response involved predominantly IgG2 and IgG3 antibody subclasses.ConclusionsWe found that the LIMS1 locus appeared to encode a minor histocompatibility antigen. Genomic collision at this locus was associated with rejection of the kidney allograft and with production of anti-LIMS1 IgG2 and IgG3. (Funded by the Columbia University Transplant Center and others.).

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Identification of a urine metabolite constellation characteristic for kidney allograft rejection.

Publications

Identification of a urine metabolite constellation characteristic for kidney allograft rejection.

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