Complement Activation in Kidneys of Patients With COVID-19.

Frederick Pfister,Kerstin Amann,Eva Vonbrunn,Klaus Überla,Günter Lochnit,Martin Herrmann,Ahmed Sheriff,Christoph Daniel,Hans-Martin Jäck,Tajana Ries,Maike Büttner-Herold

doi:10.3389/fimmu.2020.594849

Frederick Pfister, Kerstin Amann + Show 9 more

Open Access

https://doi.org/10.3389/fimmu.2020.594849

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Abstract

Most patients who became critically ill following infection with COVID-19 develop severe acute respiratory syndrome (SARS) attributed to a maladaptive or inadequate immune response. The complement system is an important component of the innate immune system that is involved in the opsonization of viruses but also in triggering further immune cell responses. Complement activation was seen in plasma adsorber material that clogged during the treatment of critically ill patients with COVID-19. Apart from the lung, the kidney is the second most common organ affected by COVID-19. Using immunohistochemistry for complement factors C1q, MASP-2, C3c, C3d, C4d, and C5b-9 we investigated the involvement of the complement system in six kidney biopsies with acute kidney failure in different clinical settings and three kidneys from autopsy material of patients with COVID-19. Renal tissue was analyzed for signs of renal injury by detection of thrombus formation using CD61, endothelial cell rarefaction using the marker E-26 transformation specific-related gene (ERG-) and proliferation using proliferating cell nuclear antigen (PCNA)-staining. SARS-CoV-2 was detected by in situ hybridization and immunohistochemistry. Biopsies from patients with hemolytic uremic syndrome (HUS, n = 5), severe acute tubular injury (ATI, n = 7), zero biopsies with disseminated intravascular coagulation (DIC, n = 7) and 1 year protocol biopsies from renal transplants (Ctrl, n = 7) served as controls. In the material clogging plasma adsorbers used for extracorporeal therapy of patients with COVID-19 C3 was the dominant protein but collectin 11 and MASP-2 were also identified. SARS-CoV-2 was sporadically present in varying numbers in some biopsies from patients with COVID-19. The highest frequency of CD61-positive platelets was found in peritubular capillaries and arteries of COVID-19 infected renal specimens as compared to all controls. Apart from COVID-19 specimens, MASP-2 was detected in glomeruli with DIC and ATI. In contrast, the classical pathway (i.e. C1q) was hardly seen in COVID-19 biopsies. Both C3 cleavage products C3c and C3d were strongly detected in renal arteries but also occurs in glomerular capillaries of COVID-19 biopsies, while tubular C3d was stronger than C3c in biopsies from COVID-19 patients. The membrane attack complex C5b-9, demonstrating terminal pathway activation, was predominantly deposited in COVID-19 biopsies in peritubular capillaries, renal arterioles, and tubular basement membrane with similar or even higher frequency compared to controls. In conclusion, various complement pathways were activated in COVID-19 kidneys, the lectin pathway mainly in peritubular capillaries and in part the classical pathway in renal arteries whereas the alternative pathway seem to be crucial for tubular complement activation. Therefore, activation of the complement system might be involved in the worsening of renal injury. Complement inhibition might thus be a promising treatment option to prevent deregulated activation and subsequent collateral tissue injury.

Highlights

Patients who became critically ill due to SARS-Cov2 virus infection developed severe acute respiratory distress syndrome (ARDS)
From more than 90 patients treated with CRP apheresis with various diseases (including severe myocardial infarction (STEMI), cardiogenic shock, after bypass surgery, severe COVID-19, acute pancreatitis, sepsis, SIRS after failed bypass surgery) the massive clogging of the columns only occurred in patients with severe COVID-19
In a preprint study Gao et al demonstrated, that the SARS-CoV-2 nucleocapsid protein bound to mannan-binding lectin-associated serine protease 2 (MASP-2) and activated complement; blockade of this interaction improved the survival of mice with COVID-19 nucleocapsid potentiated LPS-induced pneumonia [23]

Summary

Introduction

Patients who became critically ill due to SARS-Cov virus infection developed severe acute respiratory distress syndrome (ARDS). Tissue damage is not restricted to the respiratory tract since patients with severe COVID-19 often developed multiorgan failure including cardiac and acute kidney injury [2, 3]. Since complement activation could be detected in plasma [20], lung and skin [21] from COVID-19 patients and seems to be involved in promoting inflammatory processes that lead to tissue damage in COVID-19 patients we here investigated complement activation in six renal biopsies and three postmortem kidneys from patients with COVID-19. Complement involvement was compared to renal biopsies of acute tubular injury (ATI), known kidney diseases with distinct endothelial cell injury including hemolytic uremic syndrome (HUS) and disseminated intravascular coagulation (DIC) and a control group of 1 year protocol biopsies from stable renal transplants (Ctrl)

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