title: Urine Metabolite Profiles Predictive of Human Kidney Allograft Status.
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.
authors.affiliation: 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;
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.affiliation: 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;
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Schwartz
authors.affiliation: Division of Nephrology and Hypertension, Departments of Medicine and Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York;
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Sharma
authors.affiliation: Department of Pharmacology, Weill Cornell College of Medicine, New York, New York;
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Division of Nephrology and Hypertension, Departments of Medicine and Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York;
authors.forename: John R
authors.initials: JR
authors.lastname: Lee
authors.affiliation: Division of Nephrology and Hypertension, Departments of Medicine and Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York;
authors.forename: Thangamani
authors.initials: T
authors.lastname: Muthukumar
authors.affiliation: Division of Nephrology and Hypertension, Departments of Medicine and Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York;
authors.forename: Darshana M
authors.initials: DM
authors.lastname: Dadhania
authors.affiliation: Division of Nephrology and Hypertension, Departments of Medicine and Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York;
authors.forename: Ruchuang
authors.initials: R
authors.lastname: Ding
authors.affiliation: Rho Federal Systems, Chapel Hill, North Carolina;
authors.forename: David N
authors.initials: DN
authors.lastname: Ikle
authors.affiliation: National Institute of Allergy and Infectious Diseases, Bethesda, Maryland;
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Bridges
authors.affiliation: National Institute of Allergy and Infectious Diseases, Bethesda, Maryland;
authors.forename: Nikki M
authors.initials: NM
authors.lastname: Williams
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany;
authors.forename: Gabi
authors.initials: G
authors.lastname: Kastenmüller
authors.affiliation: Metabolon, Inc., Durham, North Carolina;
authors.forename: Edward D
authors.initials: ED
authors.lastname: Karoly
authors.affiliation: Metabolon, Inc., Durham, North Carolina;
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mohney
authors.affiliation: Division of Surgery-Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: Michael
authors.initials: M
authors.lastname: Abecassis
authors.affiliation: Division of Nephrology-Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: John
authors.initials: J
authors.lastname: Friedewald
authors.affiliation: Division of Surgery, Department of Surgery, University of Wisconsin Hospitals and Clinics, Madison, Wisconsin;
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Knechtle
authors.affiliation: Division of Surgery, Department of Surgery, University of Wisconsin Hospitals and Clinics, Madison, Wisconsin;
authors.forename: Yolanda T
authors.initials: YT
authors.lastname: Becker
authors.affiliation: Division of Transplantation, Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York; and.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Samstein
authors.affiliation: Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Abraham
authors.initials: A
authors.lastname: Shaked
authors.affiliation: Department of Pharmacology, Weill Cornell College of Medicine, New York, New York;
authors.forename: Steven S
authors.initials: SS
authors.lastname: Gross
authors.affiliation: 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.
authors.forename: Manikkam
authors.initials: M
authors.lastname: Suthanthiran
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D064591:Allografts / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006084:Graft Rejection / Q000378:metabolism / Q000652:urine*; D006801:Humans; D007223:Infant; D007668:Kidney / Q000378:metabolism*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D055815:Young Adult
keywords: acute rejection; kidney biopsy; renal transplantation; transplant outcomes