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J Am Soc Nephrol. 2016 Feb;27(2):626-36. doi: 10.1681/ASN.2015010107. Epub 2015 Jun 5.

Urine Metabolite Profiles Predictive of Human Kidney Allograft Status.

Author information

1
Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Doha, Qatar; Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany;
2
Department of Psychiatry, Stony Brook University, Stony Brook, New York; Division of Nephrology and Hypertension, Departments of Medicine and Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York;
3
Division of Nephrology and Hypertension, Departments of Medicine and Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York;
4
Department of Pharmacology, Weill Cornell College of Medicine, New York, New York;
5
Rho Federal Systems, Chapel Hill, North Carolina;
6
National Institute of Allergy and Infectious Diseases, Bethesda, Maryland;
7
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany;
8
Metabolon, Inc., Durham, North Carolina;
9
Division of Surgery-Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
10
Division of Nephrology-Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
11
Division of Surgery, Department of Surgery, University of Wisconsin Hospitals and Clinics, Madison, Wisconsin;
12
Division of Transplantation, Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York; and.
13
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
14
Division of Nephrology and Hypertension, Departments of Medicine and Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York; msuthan@med.cornell.edu.

Abstract

Noninvasive diagnosis and prognostication of acute cellular rejection in the kidney allograft may help realize the full benefits of kidney transplantation. To investigate whether urine metabolites predict kidney allograft status, we determined levels of 749 metabolites in 1516 urine samples from 241 kidney graft recipients enrolled in the prospective multicenter Clinical Trials in Organ Transplantation-04 study. A metabolite signature of the ratio of 3-sialyllactose to xanthosine in biopsy specimen-matched urine supernatants best discriminated acute cellular rejection biopsy specimens from specimens without rejection. For clinical application, we developed a high-throughput mass spectrometry-based assay that enabled absolute and rapid quantification of the 3-sialyllactose-to-xanthosine ratio in urine samples. A composite signature of ratios of 3-sialyllactose to xanthosine and quinolinate to X-16397 and our previously reported urinary cell mRNA signature of 18S ribosomal RNA, CD3ε mRNA, and interferon-inducible protein-10 mRNA outperformed the metabolite signatures and the mRNA signature. The area under the receiver operating characteristics curve for the composite metabolite-mRNA signature was 0.93, and the signature was diagnostic of acute cellular rejection with a specificity of 84% and a sensitivity of 90%. The composite signature, developed using solely biopsy specimen-matched urine samples, predicted future acute cellular rejection when applied to pristine samples taken days to weeks before biopsy. We conclude that metabolite profiling of urine offers a noninvasive means of diagnosing and prognosticating acute cellular rejection in the human kidney allograft, and that the combined metabolite and mRNA signature is diagnostic and prognostic of acute cellular rejection with very high accuracy.

KEYWORDS:

acute rejection; kidney biopsy; renal transplantation; transplant outcomes

PMID:
26047788
PMCID:
PMC4731125
DOI:
10.1681/ASN.2015010107
[Indexed for MEDLINE]
Free PMC Article

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