Virus-response proteinuria underlies rapid changes in kidney filtration barrier function in COVID-19

Abstract In patients with moderate to severe coronavirus disease 2019 (COVID-19), both proteinuria and high plasma levels of soluble urokinase receptor (suPAR) are commonly observed. Here we show a new type of proteinuria originating as part of a viral response. Inoculation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused increased suPAR levels and glomerulopathy in African Green Monkeys. We developed a unique mouse model whereby inhaled variants of the SARS-CoV-2 spike S1 protein elicited proteinuria with high levels of suPAR. This proteinuric response was prevented by either suPAR blockade or prior SARS-CoV-2 vaccination. We demonstrate biophysical and functional differences of spike S1 protein between various SARS-CoV-2 variants and their binding to regulatory podocyte integrins. In a cohort of 1991 COVID-19 patients, suPAR levels exhibited a stepwise association with proteinuria in non-Omicron, but not in Omicron infections. These findings suggest that viral proteins may cause proteinuria by elevating plasma suPAR levels and co-activating podocyte integrins, thus providing a basis for understanding viral-associated proteinuria syndromes.