Complement and protection from tissue injury in COVID-19

Abstract

As the second wave of coronavirus disease 2019 (COVID-19) is well under way around the world, the optimal therapeutic approach that addresses virus replication and hyperinflammation leading to tissue injury remains elusive. This issue of Clinical Kidney Journal provides further evidence of complement activation involvement in COVID-19. Taking advantage of the unique repeat access to chronic haemodialysis patients, the differential time course of C3 and C5 activation in relation to inflammation and severity of disease have been characterized. This further points to complement as a therapeutic target. Indeed, clinical trials targeting diverse components of complement are ongoing. However, a unique case of COVID-19 in a patient with pre-existent atypical haemolytic syndrome on chronic eculizumab therapy suggests that even early eculizumab may fail to prevent disease progression to a severe stage. Finally, preclinical studies in endotoxaemia, another hyperinflammation syndrome characterized by lung and kidney injury, suggest that cilastatin, an inexpensive drug already in clinical use, may provide tissue protection against hyperinflammation in COVID-19.

Keywords: COVID-19; acute kidney injury; cilastatin; complement; dialysis; tissue protection.

FIGURE 1

Temporal pattern of circulating C5a and C3a levels in dialysis patients who developed severe COVID-19 [1] and potential clinical impact. Given the overlap between plasma C5a and C3a levels in non-severe and severe COVID-19, it is likely that additional parameters should be analysed to fulfil the aims presented in the figure.

FIGURE 2

Complement system and COVID-19. The complement system is represented as well as its contribution to cell and tissue injury in COVID-19 and therapeutic approaches that have been tested in isolated patients or which are undergoing clinical trials. The classical, alternative and mannose-binding lectin pathway for complement activation as well as extrinsic factors that may contribute to complement activation are displayed. C3aR1 and C5aR1 are cell surface receptors activated by C3a and C5a, respectively. Transmembrane serine protease 2 (TMPRSS2) is a cell surface enzyme that processes SARS-CoV-2 protein S, facilitating binding to ACE2, which functions as a cell surface receptor for SARS-CoV-2, allowing virus entry into cells. Purple proteins represent extrinsic pathways for complement activation, dark blue continuous lines represent protein processing or protein incorporation into protein complexes and green lines represent therapeutic agents inhibiting targets. Thin discontinuous lines represent enzymatic activity.