Cited by 368Renal Transplantation Outcomes and TreatmentsTransplantation: Methods and OutcomesOrgan and Tissue Transplantation Research

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Urinary-Cell mRNA Profile and Acute Cellular Rejection in Kidney Allografts

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Suthanthiran, Manikkam, Schwartz, Joseph E., Ding, Ruchuang, Abecassis, Michael, Dadhania, Darshana, Samstein, Benjamin, Knechtle, Stuart J., Friedewald, John, Becker, Yolanda T., Sharma, Vijay K., Williams, Nikki M., Chang, Christina S., Hoang, Christine, Muthukumar, Thangamani, August, Phyllis, Keslar, Karen S., Fairchild, Robert L., Hricik, Donald E., Heeger, Peter S., Han, Leiya, Liu, Jun, Riggs, Michael, Ikle, David N., Bridges, Nancy D., Shaked, Abraham·2013·New England Journal of Medicine

DOI 10.1056/nejmoa1215555PMC PMC3786188

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Abstract

BACKGROUND: The standard test for the diagnosis of acute rejection in kidney transplants is the renal biopsy. Noninvasive tests would be preferable. METHODS: We prospectively collected 4300 urine specimens from 485 kidney-graft recipients from day 3 through month 12 after transplantation. Messenger RNA (mRNA) levels were measured in urinary cells and correlated with allograft-rejection status with the use of logistic regression. RESULTS: A three-gene signature of 18S ribosomal (rRNA)-normalized measures of CD3ε mRNA and interferon-inducible protein 10 (IP-10) mRNA, and 18S rRNA discriminated between biopsy specimens showing acute cellular rejection and those not showing rejection (area under the curve [AUC], 0.85; 95% confidence interval [CI], 0.78 to 0.91; P<0.001 by receiver-operating-characteristic curve analysis). The cross-validation estimate of the AUC was 0.83 by bootstrap resampling, and the Hosmer-Lemeshow test indicated good fit (P=0.77). In an external-validation data set, the AUC was 0.74 (95% CI, 0.61 to 0.86; P<0.001) and did not differ significantly from the AUC in our primary data set (P=0.13). The signature distinguished acute cellular rejection from acute antibody-mediated rejection and borderline rejection (AUC, 0.78; 95% CI, 0.68 to 0.89; P<0.001). It also distinguished patients who received anti-interleukin-2 receptor antibodies from those who received T-cell-depleting antibodies (P<0.001) and was diagnostic of acute cellular rejection in both groups. Urinary tract infection did not affect the signature (P=0.69). The average trajectory of the signature in repeated urine samples remained below the diagnostic threshold for acute cellular rejection in the group of patients with no rejection, but in the group with rejection, there was a sharp rise during the weeks before the biopsy showing rejection (P<0.001). CONCLUSIONS: A molecular signature of CD3ε mRNA, IP-10 mRNA, and 18S rRNA levels in urinary cells appears to be diagnostic and prognostic of acute cellular rejection in kidney allografts. (Funded by the National Institutes of Health and others.).

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Authors: Suthanthiran, M., Schwartz, J. E., Ding, R., Abecassis, M., Dadhania, D., Samstein, B., Knechtle, S. J., Friedewald, J., Becker, Y. T., Sharma, V. K., Williams, N. M., Chang, C. S., Hoang, C., Muthukumar, T., August, P., Keslar, K. S., Fairchild, R. L., Hricik, D. E., Heeger, P. S., Han, L., Liu, J., Riggs, M., Ikle, D. N., Bridges, N. D., & Shaked, A.
Affiliations: Weill Cornell Medicine (US)
Stony Brook University (US)
Northwestern University (US)
Columbia University (US)
Emory University (US)
University of Chicago (US)
National Institute of Allergy and Infectious Diseases (US)
Cleveland Clinic (US)
University Hospitals Cleveland Medical Center (US)
Icahn School of Medicine at Mount Sinai (US)
Pharmaceutical Product Development (United States) (US)
Rho (United States) (US)
University of Pennsylvania (US)
ORCID: Suthanthiran, Manikkam
Schwartz, Joseph E.
Abecassis, Michael
Dadhania, Darshana
Samstein, Benjamin
Knechtle, Stuart J.
Friedewald, John
Becker, Yolanda T.
Muthukumar, Thangamani
August, Phyllis
Keslar, Karen S.
Fairchild, Robert L.
Heeger, Peter S.
Bridges, Nancy D.
Shaked, Abraham
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2013-07-04
Volume: 369
Issue: 1
Pages: 20-31
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa1215555
PMC: PMC3786188
OpenAlex: W2042953533
Cited by: 363
References: 18
Citations by year: 2026: 15 · 2025: 26 · 2024: 22 · 2023: 20 · 2022: 25 · 2021: 34 · 2020: 19 · 2019: 28 · 2018: 20 · 2017: 31 · 2016: 45 · 2015: 36 · 2014: 31 · 2013: 11
FWCI: 29.89
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Columbia Academic Commons (Columbia University)
Funders: Yale University
University of Pennsylvania
Emory University
Northwestern University
Cincinnati Children's Hospital Medical Center
Cleveland Clinic
National Research Foundation
National Institutes of Health (UL1TR000457)
Weill Cornell Medical College
School of Medicine, Emory University
National Institute of Allergy and Infectious Diseases (U01-AI63589, U01AI063589, R37AI051652)
National Center for Advancing Translational Sciences
Topics: Health Sciences › Medicine › Transplantation › Renal Transplantation Outcomes and Treatments
Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
Health Sciences › Medicine › Transplantation › Organ and Tissue Transplantation Research
Keywords: acute cellular rejection, kidney transplantation, urinary cells, CXCL10, non-invasive diagnosis, acute antibody-mediated rejection, urinary tract infection, molecular signatures, prognostic factors, renal biopsy
MeSH terms: Acute Disease, Adult, Female, Graft Rejection, Humans, Male, Middle Aged, Prospective Studies, RNA Polymerase I, RNA, Messenger, RNA, Ribosomal, RNA, Ribosomal, 18S, ROC Curve, Sensitivity and Specificity, Kidney Transplantation, Area Under Curve, Intracellular Signaling Peptides and Proteins, Chemokine CXCL10, Transcriptome, Real-Time Polymerase Chain Reaction

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Urinary-Cell mRNA Profile and Acute Cellular Rejection in Kidney Allografts

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