Abstract

End-stage kidney disease (ESKD) patients are at high risk of severe COVID-19. We measured 436 circulating proteins in serial blood samples from hospitalised and non-hospitalised ESKD patients with COVID-19 (n=256 samples from 55 patients). Comparison to 51 non-infected patients revealed 221 differentially expressed proteins, with consistent results in a separate subcohort of 46 COVID-19 patients. 203 proteins were associated with clinical severity, including IL6, markers of monocyte recruitment (e.g. CCL2, CCL7), neutrophil activation (e.g. proteinase-3) and epithelial injury (e.g. KRT19). Machine learning identified predictors of severity including IL18BP, CTSD, GDF15, and KRT19. Survival analysis with joint models revealed 69 predictors of death. Longitudinal modelling with linear mixed models uncovered 32 proteins displaying different temporal profiles in severe versus non-severe disease, including integrins and adhesion molecules. These data implicate epithelial damage, innate immune activation, and leucocyte-endothelial interactions in the pathology of severe COVID-19 and provide a resource for identifying drug targets.

Data availability

All data generated during this study are included in the manuscript and supporting files. Underlying source data for all analyses (individual-level proteomic and clinical phenotyping data) are available without restriction as Source Data Files 1-4. In addition, these data have been deposited in the Dryad Digital Repository (doi:10.5061/dryad.6t1g1jwxj). Code is available in the following GitHub repository: https://github.com/jackgisby/longitudinal_olink_proteomics

The following data sets were generated

Article and author information

Author details

  1. Jack Gisby

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0511-8123
  2. Candice L Clarke

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  3. Nicholas Medjeral-Thomas

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  4. Talat H Malik

    Centre for Complement and Inflammation Research, Department of Medicine, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  5. Artemis Papadaki

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  6. Paige M Mortimer

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  7. Norzawani B Buang

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  8. Shanice Lewis

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  9. Marie Pereira

    Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0711-3385
  10. Frederic Toulza

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  11. Ester Fagnano

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  12. Marie-Anne Mawhin

    Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  13. Emma E Dutton

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  14. Lunnathaya Tapeng

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  15. Arianne C Richard

    Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8708-9997
  16. Paul DW Kirk

    MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  17. Jacques Behmoaras

    Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  18. Eleanor Sandhu

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  19. Stephen P McAdoo

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    Stephen P McAdoo, Dr. McAdoo reports personal fees from Celltrion, Rigel, GSK and Cello, outside the submitted work..
  20. Maria F Prendecki

    Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7048-7457
  21. Matthew C Pickering

    Centre for Complement and Inflammation Research, Department of Medicine, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  22. Marina Botto

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1458-3791
  23. Michelle Willicombe

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  24. David C Thomas

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  25. James Edward Peters

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    For correspondence
    j.peters@imperial.ac.uk
    Competing interests
    James Edward Peters, Dr Peters has received travel and accommodation expenses and hospitality from Olink to speak at Olink-sponsored academic meetings..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9415-3440

Funding

UK Research and Innovation (MR/V027638/1)

  • James Edward Peters

Imperial College London (Community Jameel and the Imperial President's Excellence Fund)

  • James Edward Peters

UK Research and Innovation (UKRI Innovation Fellowship at Health Data Research UK (MR/S004068/2))

  • James Edward Peters

Wellcome Trust (Wellcome-Beit Prize Clinical Research Career Development Fellowship (206617/A/17/A))

  • David C Thomas

Wellcome Trust (Wellcome Trust Senior Fellow in Clinical Science (212252/Z/18/Z))

  • Matthew C Pickering

Wellcome Trust and Imperial College London (Wellcome Trust and Imperial College London Research Fellowship)

  • Nicholas Medjeral-Thomas

Wellcome Trust and Imperial College London (Wellcome Trust and Imperial College London Research Fellowship)

  • Eleanor Sandhu

Auchi Renal Research Fund (Auchi Clinical Research Fellowship)

  • Candice L Clarke

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: All participants (patients and controls) were recruited from the Imperial College Renal and Transplant Centre and its satellite dialysis units, London, and provided written informed consent prior to participation. Study ethics were reviewed by the UK National Health Service (NHS) Health Research Authority (HRA) and Health and Care Research Wales (HCRW) Research Ethics Committee (reference 20/WA/0123: The impact of COVID-19 on patients with renal disease and immunosuppressed patients). Ethical approval was given.

Reviewing Editor

  1. Evangelos J Giamarellos-Bourboulis, National and Kapodistrian University of Athens, Medical School, Greece

Publication history

  1. Received: November 12, 2020
  2. Accepted: March 10, 2021
  3. Accepted Manuscript published: March 11, 2021 (version 1)
  4. Version of Record published: April 23, 2021 (version 2)
  5. Version of Record updated: April 28, 2021 (version 3)

Copyright

© 2021, Gisby et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jack Gisby
  2. Candice L Clarke
  3. Nicholas Medjeral-Thomas
  4. Talat H Malik
  5. Artemis Papadaki
  6. Paige M Mortimer
  7. Norzawani B Buang
  8. Shanice Lewis
  9. Marie Pereira
  10. Frederic Toulza
  11. Ester Fagnano
  12. Marie-Anne Mawhin
  13. Emma E Dutton
  14. Lunnathaya Tapeng
  15. Arianne C Richard
  16. Paul DW Kirk
  17. Jacques Behmoaras
  18. Eleanor Sandhu
  19. Stephen P McAdoo
  20. Maria F Prendecki
  21. Matthew C Pickering
  22. Marina Botto
  23. Michelle Willicombe
  24. David C Thomas
  25. James Edward Peters
(2021)
Longitudinal proteomic profiling of dialysis patients with COVID-19 reveals markers of severity and predictors of death
eLife 10:e64827.
https://doi.org/10.7554/eLife.64827
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