Complement Levels at Admission Reflecting Progression to Severe Acute Kidney Injury (AKI) in Coronavirus Disease 2019 (COVID-19): A Multicenter Prospective Cohort Study

Abstract

BackgroundDysregulation of complement system is thought to be a major player in development of multi-organ damage and adverse outcomes in patients with coronavirus disease 2019 (COVID-19). This study aimed to examine associations between complement system activity and development of severe acute kidney injury (AKI) among hospitalized COVID-19 patients.Materials and MethodsIn this multicenter, international study, complement as well as inflammatory and thrombotic parameters were analyzed in COVID-19 patients requiring hospitalization at one US and two Hungarian centers. The primary endpoint was development of severe AKI defined by KDIGO stage 2+3 criteria, while the secondary endpoint was need for renal replacement therapy (RRT). Complement markers with significant associations with endpoints were then correlated with a panel of inflammatory and thrombotic biomarkers and assessed for independent association with outcome measures using logistic regression.ResultsA total of 131 hospitalized COVID-19 patients (median age 66 [IQR, 54–75] years; 54.2% males) were enrolled, 33 from the US, and 98 from Hungary. There was a greater prevalence of complement over-activation and consumption in those who developed severe AKI and need for RRT during hospitalization. C3a/C3 ratio was increased in groups developing severe AKI (3.29 vs. 1.71; p < 0.001) and requiring RRT (3.42 vs. 1.79; p < 0.001) in each cohort. Decrease in alternative and classical pathway activity, and consumption of C4 below reference range, as well as elevation of complement activation marker C3a above the normal was more common in patients progressing to severe AKI. In the Hungarian cohort, each standard deviation increase in C3a (SD = 210.1) was independently associated with 89.7% increased odds of developing severe AKI (95% CI, 7.6–234.5%). Complement was extensively correlated with an array of inflammatory biomarkers and a prothrombotic state.ConclusionConsumption and dysregulation of complement system is associated with development of severe AKI in COVID-19 patients and could represent a promising therapeutic target for reducing thrombotic microangiopathy in SARS-CoV-2 infection.

Atypical hemolytic uremic syndrome triggered by mRNA vaccination against SARS-CoV-2: Case report

“…in intensive care units (17). There may be several reasons for the development of AKI, but dehydration in diarrhea or hypoperfusion of the kidneys in cardiorespiratory failure is predominantly applied.…”

“…COVID-19 infection is very often associated with the development of AKI, especially in individuals requiring a stay in intensive care units ( 17 ). There may be several reasons for the development of AKI, but dehydration in diarrhea or hypoperfusion of the kidneys in cardiorespiratory failure is predominantly applied.…”

Hemolytic uremic syndrome in the setting of COVID-19 successfully treated with complement inhibition therapy: An instructive case report of a previously healthy toddler and review of literature

“…While complement C5 component blockade with human monoclonal antibodies Eculizumab and Ravulizumab is an established treatment for atypical form of HUS, with better understanding of COVID-19 pathophysiology, especially the role of complement activation, there has been an emerging interest for use of these monoclonal antibodies to reduce immune-mediated consequences of severe infection in COVID-19 patients as well. Supporting evidence for the role of complement, especially C3 activation, in the development of acute kidney injury in COVID-19 came from our recent study ( 53 ). Clinical findings of elevated LDH, D-dimer and bilirubin levels, as well as decreased platelet levels paired with anemia, renal injury and diffuse TMA in COVID-19 mimic the pathological findings of HUS, which responds favorably to C5 blockade.…”

Pathogenesis and histological changes of nephropathy associated with COVID‐19

“…92 Kidney damage may also occur due to complement activation after SARS-CoV-2 infection, and patients with an elevated C3a/C3 ratio have a 1.9-fold higher incidence of severe AKI and treatment with renal replacement therapy than those with a normal C3a/C3 ratio. 93 The deposition of complement components C5b-C9 form the membrane attack complex (MAC) in the tubular basement membrane, which may directly lead to the destruction of proximal tubular cells. 94 At the same time, the cascade activation of the complement system may lead to chronic kidney inflammation, tubular atrophy, and interstitial fibrosis.…”