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Metabolic markers for differentiation between renal allograft rejection and immunosuppressant toxicity in rat urine

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Abstract

Introduction

Although current immunosuppressive protocols have dramatically improved 1-year survival of kidney transplants, there has been less progress in terms of long-term graft survival over the last two decades. The key to avoiding late graft loss is early diagnosis and differentiation between anti-allograft immune processes and immunosuppressant toxicity (IS-Tox). Modern bioanalytical technologies have opened new opportunities for the development of sensitive and specific diagnostic tools. There is an immediate need for biomarkers that are able to differentiate between renal allograft rejection and immunosuppressant toxicity.

Objective

To test our hypothesis that changes of metabolite patterns in urine have the potential to serve as a non-invasive combinatorial biomarker that can differentiate between allograft immune reactions and IS-Tox.

Methods

We used 1H-NMR spectroscopy and Luminex multiplexing for metabolic profiling of rat urine and the analysis of protein biomarkers in urine and plasma, respectively, to compare the effects of chronic allograft rejection in a Fisher-to-Lewis rat transplant model with IS-Tox induced by cyclosporine, tacrolimus and/or sirolimus in Lewis rats.

Results

Our results showed that, while IS-Tox caused changes in metabolite patterns that are typically associated with proximal tubule damage, rejection caused more profuse changes not specifically focused on a particular kidney region. Moreover, metabolite pattern changes were more sensitive than changes in protein markers that were evident only during the later stages of rejection.

Conclusion

The present study provides first proof-of-concept that longitudinal monitoring of urine metabolite markers has the potential to differentiate between early renal allograft rejection and immunosuppressant nephrotoxicity.

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Authors and Affiliations

  1. iC42 Clinical Research & Development, Department of Anesthesiology, Anschutz Medical Center, University of Colorado Denver, Aurora, CO, USA

    Wenzel Schoening, Jelena Klawitter, Uwe Christians & Jost Klawitter

  2. Department of General-, Visceral- and Transplantation Surgery, University Hospital of RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany

    Wenzel Schoening

  3. Department of General- and Visceral Surgery, Asklepios Hospital Hamburg Altona, Hamburg, Germany

    Volker Schmitz

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  1. Wenzel Schoening
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Correspondence to Wenzel Schoening.

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The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

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No Human Subject research was performed as part of this manuscript. All animal experiments described here were conducted in accordance with the National Institute of Health Guidelines for the Care and Use of Laboratory Animals. Animal Protocols were reviewed and approved by the University of Colorado, Denver, IACUC (Institutional Animal Care and Use Committee).

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Schoening, W., Schmitz, V., Klawitter, J. et al. Metabolic markers for differentiation between renal allograft rejection and immunosuppressant toxicity in rat urine. Metabolomics 13, 102 (2017). https://doi.org/10.1007/s11306-017-1229-4

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