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      Identification of a urine metabolite constellation characteristic for kidney allograft rejection

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          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.

          Electronic supplementary material

          The online version of this article (10.1007/s11306-018-1419-8) contains supplementary material, which is available to authorized users.

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          The Banff 97 working classification of renal allograft pathology.

          L C Racusen, K Solez, R B Colvin … (1999)
          Standardization of renal allograft biopsy interpretation is necessary to guide therapy and to establish an objective end point for clinical trials. This manuscript describes a classification, Banff 97, developed by investigators using the Banff Schema and the Collaborative Clinical Trials in Transplantation (CCTT) modification for diagnosis of renal allograft pathology. Banff 97 grew from an international consensus discussion begun at Banff and continued via the Internet. This schema developed from (a) analysis of data using the Banff classification, (b) publication of and experience with the CCTT modification, (c) international conferences, and (d) data from recent studies on impact of vasculitis on transplant outcome. Semiquantitative lesion scoring continues to focus on tubulitis and arteritis but includes a minimum threshold for interstitial inflammation. Banff 97 defines "types" of acute/active rejection. Type I is tubulointerstitial rejection without arteritis. Type II is vascular rejection with intimal arteritis, and type III is severe rejection with transmural arterial changes. Biopsies with only mild inflammation are graded as "borderline/suspicious for rejection." Chronic/sclerosing allograft changes are graded based on severity of tubular atrophy and interstitial fibrosis. Antibody-mediated rejection, hyperacute or accelerated acute in presentation, is also categorized, as are other significant allograft findings. The Banff 97 working classification refines earlier schemas and represents input from two classifications most widely used in clinical rejection trials and in clinical practice worldwide. Major changes include the following: rejection with vasculitis is separated from tubulointerstitial rejection; severe rejection requires transmural changes in arteries; "borderline" rejection can only be interpreted in a clinical context; antibody-mediated rejection is further defined, and lesion scoring focuses on most severely involved structures. Criteria for specimen adequacy have also been modified. Banff 97 represents a significant refinement of allograft assessment, developed via international consensus discussions.
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            Identification of a urine metabolomic signature in patients with advanced-stage chronic kidney disease.

            María Barderas, Maria Posada, Gloria Alvarez-Llamas … (2013)
            The prevalence of chronic kidney disease (CKD) is increasing and frequently progresses to end-stage renal disease. There is an urgent demand to discover novel markers of disease that allow monitoring disease progression and, eventually, response to treatment. To identify such markers, and as a proof of principle, we determined if a metabolite signature corresponding to CKD can be found in urine. In the discovery stage, we analyzed the urine metabolome by NMR of 15 patients with CKD and compared that with the metabolome of 15 healthy individuals and found a classification pattern clearly indicative of CKD. A validation cohort of urine samples from an additional 16 patients with CKD and 15 controls was then analyzed by (Selected Reaction Monitoring) liquid chromatography-triple quadrupole mass spectrometry and indicated that a group of seven urinary metabolites differed between CKD and non-CKD urine samples. This profile consisted of 5-oxoproline, glutamate, guanidoacetate, α-phenylacetylglutamine, taurine, citrate, and trimethylamine N-oxide. Thus, we identified a panel of urine metabolites differentially present in urine that may help identify and monitor patients with CKD.
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              Urinary N-methylpyridinium and trigonelline as candidate dietary biomarkers of coffee consumption.

              Sebastian Wahl, Tara Lang, Timo Stark … (2011)
              In order to validate the in vivo function of putatively healthy molecules in foods, human intervention studies are required. As the subject's compliance concerning intake or abstinence of a given food is considered mandatory to be monitored by biomarkers, the objective was to identify analytical markers for coffee consumption. Urine samples collected from coffee drinkers were compared with those of non-coffee drinkers using hydrophilic liquid interaction chromatography (HILIC)/time-of-flight mass spectrometry-based metabolite profiling. Two urinary molecules, found to be contributing most to the dissimilarities between both groups, were identified as N-methylpyridinium (NMP) and trigonelline and their suitability as coffee-specific biomarkers was validated by means of a coffee intervention study. After the volunteers (five females and four males) consumed a single dose of coffee, morning urine was collected for 10 days while staying abstinent from any coffee. HILIC-MS/MS-stable isotope dilution analysis (SIDA) revealed elevated urinary concentrations of trigonelline and NMP for up to 48 (p=0.001) and 72 h (p=0.002), respectively, after coffee consumption when compared with non-coffee drinkers. Analysis of urinary NMP allows to check for coffee consumption within a period of 3 days and is proposed as a dietary biomarker which might be used as an analytical probe to control compliance in human intervention studies on coffee. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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                Author and article information

                Contributors
                Miriam Banas: miriam.banas@klinik.uni-regensburg.de
                Sindy Neumann: sindy.neumann@numares.com
                Johannes Eiglsperger: johannes.eiglsperger@numares.com
                Eric Schiffer: eric.schiffer@numares.com
                Franz Josef Putz: franz-josef.putz@ukr.de
                Simone Reichelt-Wurm: simone.reichelt-wurm@ukr.de
                Bernhard Karl Krämer: bernhard.kraemer@medma.uni-heidelberg.de
                Philipp Pagel: philipp.pagel@numares.com
                Bernhard Banas: bernhard.banas@klinik.uni-regensburg.de
                Journal
                Journal ID (nlm-ta): Metabolomics
                Journal ID (iso-abbrev): Metabolomics
                Title: Metabolomics
                Publisher: Springer US (New York )
                ISSN (Print): 1573-3882
                ISSN (Electronic): 1573-3890
                Publication date (Electronic): 30 August 2018
                Publication date PMC-release: 30 August 2018
                Publication date (Print): 2018
                Volume: 14
                Issue: 9
                Electronic Location Identifier: 116
                Affiliations
                [1 ]ISNI 0000 0000 9194 7179, GRID grid.411941.8, Department of Nephrology, , University Hospital Regensburg, ; Regensburg, Germany
                [2 ]numares AG, Regensburg, Germany
                [3 ]ISNI 0000 0001 2162 1728, GRID grid.411778.c, Fifth Department of Medicine, , University Medical Center Mannheim, ; Mannheim, Germany
                Article
                Publisher ID: 1419
                DOI: 10.1007/s11306-018-1419-8
                PMC ID: 6133122
                PubMed ID: 30830387
                SO-VID: 8fca92cb-3184-49d1-bca9-1dac85092ff5
                Copyright © © The Author(s) 2018
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Date received : 17 May 2018
                Date accepted : 11 August 2018
                Categories
                Subject: Original Article
                Custom metadata
                issue-copyright-statement © Springer Science+Business Media, LLC, part of Springer Nature 2018

                ScienceOpen disciplines: Molecular biology
                Keywords: metabolomics,nmr-spectroscopy,kidney rejection,diagnostic model
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: metabolomics, nmr-spectroscopy, kidney rejection, diagnostic model

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