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.
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
Longitudinal proteomic profiling of high-risk patients with COVID-19 reveals markers of severity and predictors of fatal diseaseDryad Digital Repository, 10.5061/dryad.6t1g1jwxj.
- James Edward Peters
- James Edward Peters
- James Edward Peters
- David C Thomas
- Matthew C Pickering
- Nicholas Medjeral-Thomas
- Eleanor Sandhu
- Candice L Clarke
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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.
- Evangelos J Giamarellos-Bourboulis, National and Kapodistrian University of Athens, Medical School, Greece
© 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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