Noninvasive Diagnosis of Acute Rejection in Renal Transplant Patients Using Mass Spectrometric Analysis of Urine Samples: A Multicenter Diagnostic Phase III Trial

Wilfried Gwinner, MD; Annika Karch, PhD; Jan H. Braesen, MD; Abedalrazag A. Khalifa, MD; Jochen Metzger, PhD; Maarten Naesens, MD; Elisabet Van Loon, MD; Dany Anglicheau, MD; Pierre Marquet, PhD; Klemens Budde, MD; Mareen Matz, PhD; Wolfgang Arns, MD; Michael Fischereder, MD; Antje Habicht, MD; Ute Eisenberger, MD; Anja Mühlfeld, MD; Martin Busch, MD; Michael Wiesener, MD; Irina Scheffner, PhD,; Armin Koch, PhD

doi:10.1097/TXD.0000000000001316

Transplantation Direct (May 2022)

Noninvasive Diagnosis of Acute Rejection in Renal Transplant Patients Using Mass Spectrometric Analysis of Urine Samples: A Multicenter Diagnostic Phase III Trial

Wilfried Gwinner, MD,
Annika Karch, PhD,
Jan H. Braesen, MD,
Abedalrazag A. Khalifa, MD,
Jochen Metzger, PhD,
Maarten Naesens, MD,
Elisabet Van Loon, MD,
Dany Anglicheau, MD,
Pierre Marquet, PhD,
Klemens Budde, MD,
Mareen Matz, PhD,
Wolfgang Arns, MD,
Michael Fischereder, MD,
Antje Habicht, MD,
Ute Eisenberger, MD,
Anja Mühlfeld, MD,
Martin Busch, MD,
Michael Wiesener, MD,
Irina Scheffner, PhD,,
Armin Koch, PhD

Affiliations

Wilfried Gwinner, MD: 1 Department of Nephrology, Hannover Medical School, Hannover, Germany.
Annika Karch, PhD: 2 Institute for Biostatistics, Hannover Medical School, Hannover, Germany.
Jan H. Braesen, MD: 3 Department of Pathology, Hannover Medical School, Hannover, Germany.
Abedalrazag A. Khalifa, MD: 3 Department of Pathology, Hannover Medical School, Hannover, Germany.
Jochen Metzger, PhD: 4 Mosaiques Diagnostics GmbH, Hannover, Germany.
Maarten Naesens, MD: 5 Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
Elisabet Van Loon, MD: 5 Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
Dany Anglicheau, MD: 7 Department of Nephrology and Kidney Transplantation, Necker Hospital, AP-HP and Inserm U1151, Paris, France.
Pierre Marquet, PhD: 8 Pharmacology and Transplantation, INSERM U1248, Université de Limoges, CHU de Limoges, Limoges, France.
Klemens Budde, MD: 9 Charité Universitätsmedizin Berlin, Berlin, Germany.
Mareen Matz, PhD: 9 Charité Universitätsmedizin Berlin, Berlin, Germany.
Wolfgang Arns, MD: 10 Cologne Merheim Medical Center, Cologne, Germany.
Michael Fischereder, MD: 11 LMU-Klinikum, Munich, Germany.
Antje Habicht, MD: 11 LMU-Klinikum, Munich, Germany.
Ute Eisenberger, MD: 12 University Hospital Essen, Duisburg-Essen, Essen, Germany.
Anja Mühlfeld, MD: 13 Clinic for Renal and Hypertensive Disorders, Rheumatological and Immunological Diseases, University Hospital Aachen, Aachen, Germany.
Martin Busch, MD: 14 Department of Internal Medicine III/Collaborative Kidney Transplant Center, University Hospital Jena—Friedrich Schiller University, Jena, Germany.
Michael Wiesener, MD: 15 Department of Nephrology and Hypertension, Universitätsklinikum Erlangen, University of Erlangen-Nürnberg, Erlangen, Germany.
Irina Scheffner, PhD,: 1 Department of Nephrology, Hannover Medical School, Hannover, Germany.
Armin Koch, PhD: 2 Institute for Biostatistics, Hannover Medical School, Hannover, Germany.

DOI: https://doi.org/10.1097/TXD.0000000000001316
Journal volume & issue: Vol. 8, no. 5
p. e1316

Abstract

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Background. Timely recognition and treatment of acute kidney graft rejection is important to prevent premature graft failure. A predefined urinary marker set for acute T cell–mediated rejection (TCMR) containing 14 peptides was tested for this purpose in a multicenter in-place validation study. Methods. Three hundred twenty-nine prospectively collected and 306 archived urine samples from 11 transplant centers in Germany, France, and Belgium were examined. Samples were taken immediately before a biopsy, performed for graft dysfunction within the first transplant year. Primary outcomes were sensitivity and specificity of the marker set for the diagnosis of biopsy-proven acute TCMR, with prespecified thresholds of 83% for sensitivity and 70% for specificity. Results. Eighty-two patients (13%) had acute TCMR grade I–III. In relation to the biopsy diagnosis of TCMR, the sensitivity of the urine test was 0.66 (95% confidence interval, 0.56-0.76) and the specificity 0.47 (95% confidence interval, 0.43-0.51), with an area under the curve (AUC) of 0.60. The different TCMR grades I–III were not reflected by the marker set, and borderline TCMR was not specifically detected. Secondary independent masked assessment of biopsies consented by 2 pathologists revealed an interobserver kappa value of 0.49 for diagnosing TCMR, compared with the local center’s diagnosis. Using this consensus diagnosis, the AUC of the urine test was 0.63 (sensitivity 0.73, specificity 0.45). Post hoc optimization of the marker set improved the diagnostic performance in the study cohort (AUC 0.67) and in an independent patient cohort (AUC 0.69). Conclusions. This study illustrates the difficulty of proteomics-based diagnosis of TCMR and highlights the need for rigorous independent in-place validation and optimization of diagnostic biomarkers.

Published in Transplantation Direct

ISSN: 2373-8731 (Online)
Publisher: Wolters Kluwer
Country of publisher: United States
LCC subjects: Medicine: Surgery
Website: http://journals.lww.com/transplantationdirect/Pages/default.aspx

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