Soluble Urokinase Receptor (SuPAR) in COVID-19–Related AKI
Authors: Azam Tariq U. , Shadid Husam R. , Blakely Pennelope , O’Hayer Patrick , Berlin Hanna , Pan Michael , Zhao Peiyao , Zhao Lili , Pennathur Subramaniam , Pop-Busui Rodica , Altintas Izzet , Tingleff Jens , Stauning Marius A. , Andersen Ove , Adami Maria-Evangelia , Solomonidi Nicky , Tsilika Maria , Tober-Lau Pinkus , Arnaoutoglou Eleni , Keitel Verena , Tacke Frank , Chalkias Athanasios , Loosen Sven H. , Giamarellos-Bourboulis Evangelos J. , Eugen-Olsen Jesper , Reiser Jochen , Hayek Salim S. ,   International Study of Inflammation in COVID-19
Published: September 2020

Significance Statement
Nearly half of hospitalized patients with coronavirus disease 2019 (COVID-19) develop AKI, with 20% requiring dialysis. High levels of soluble urokinase plasminogen activator receptor (suPAR)—an immune mediator of kidney injury—predispose patients to AKI in various clinical scenarios, including critical illness. High suPAR levels modulate mitochondrial respiration and induce the generation of reactive oxygen species in proximal tubular cells, sensitizing them to additional insults. In a multicenter observational study, the authors measured plasma suPAR in 352 patients with COVID-19 within 48 hours of their hospitalization. They found suPAR levels to be strongly associated with incident AKI, independent of such clinical characteristics as kidney function and inflammatory biomarkers, and predictive of the need for dialysis. SuPAR may be a key component of the pathophysiology of AKI in COVID-19.

Background
AKI commonly occurs in patients with coronavirus disease 2019 (COVID-19). Its pathogenesis is poorly understood. The urokinase receptor system is a key regulator of the intersection between inflammation, immunity, and coagulation, and soluble urokinase plasminogen activator receptor (suPAR) has been identified as an immunologic risk factor for AKI. Whether suPAR is associated with COVID-19–related AKI is unknown.

Methods
In a multinational observational study of adult patients hospitalized for COVID-19, we measured suPAR levels in plasma samples from 352 adult patients that had been collected within 48 hours of admission. We examined the association between suPAR levels and incident in-hospital AKI.

Results
Of the 352 patients (57.4% were male, 13.9% were black, and mean age was 61 years), 91 (25.9%) developed AKI during their hospitalization, of whom 25 (27.4%) required dialysis. The median suPAR level was 5.61 ng/ml. AKI incidence rose with increasing suPAR tertiles, from a 6.0% incidence in patients with suPAR <4.60 ng/ml (first tertile) to a 45.8% incidence of AKI in patients with suPAR levels >6.86 ng/ml (third tertile). None of the patients with suPAR <4.60 ng/ml required dialysis during their hospitalization. In multivariable analysis, the highest suPAR tertile was associated with a 9.15-fold increase in the odds of AKI (95% confidence interval [95% CI], 3.64 to 22.93) and a 22.86-fold increase in the odds of requiring dialysis (95% CI, 2.77 to 188.75). The association was independent of inflammatory markers and persisted across subgroups.

Conclusions
Admission suPAR levels in patients hospitalized for COVID-19 are predictive of in-hospital AKI and the need for dialysis. SuPAR may be a key component of the pathophysiology of AKI in COVID-19.