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

Brandon M. Henry*, György Sinkovits, Ivan Szergyuk, Maria Helena Santos de Oliveira, Giuseppe Lippi, Justin L. Benoit, Emmanuel J. Favaloro, Naomi Pode-Shakked, Stefanie W. Benoit, David S. Cooper, Veronika Müller, Zsolt Iványi, János Gál, Marienn Réti, László Gopcsa, Péter Reményi, Beáta Szathmáry, Botond Lakatos, János Szlávik, Ilona BobekZita Z. Prohászka, Zsolt Förhécz, Dorottya Csuka, Lisa Hurler, Erika Kajdácsi, László Cervenak, Blanka Mező, Petra Kiszel, Tamás Masszi, István Vályi-Nagy, Zoltán Prohászka

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background: Dysregulation 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 Methods: In 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. Results: A 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. Conclusion: Consumption 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.

Original languageEnglish
Article number796109
JournalFrontiers in Medicine
StatePublished - 29 Apr 2022


FundersFunder number
National Office for Innovation and Research2020-1.1.6-JOVO-2021-00013, KH130355
University of Cincinnati College of Medicine Special CoronavirusCOVID-19
Semmelweis Egyetem
Magyar Tudományos AkadémiaPPD2018-016/2018
Emberi Eroforrások Minisztériuma
Horizon 2020860044


    • SARS-CoV-2
    • acute kidney injury
    • complement system
    • coronavirus disease 2019
    • renal replacement therapy (RRT)


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