Covid-19 induced worsening of glomerular diseases

Summary / Abstract (max 30 lines): SARS-CoV-2 is a respiratory tract infection associated with an extensive cytokine storm. Focal and segmental glomerulosclerosis (FSGS) and diabetic nephropathy (DN) are established risk factors for COVID-19 complications. Whereas both diseases can be exacerbated under cytokine storm conditions, the effect of COVID- 19 associated cytokine storm on the course of established FSGS and DN is not clear. We expect FSGS and DN to be worsened after COVID-19 infection. Based on human observational data, we generated multiple cytokine cocktails to mimic the COVID-19 cytokine storm, and showed that they cause multisystem injury when injected in rodents at high dose (severe COVID-19 in patients), and worsen kidney injury at low dose (mild COVID-19 in patients). Studying the effect of COVID-19 cytokine storm in animal models of glomerular disease will allow a better understanding of the impact of COVID-19 on patient with existing disorders. Furthermore, neutralizing the cytokine storm could potentially improve the outcome of hospitalized COVID-19 patients and prevent worsening of kidney function by using a combination of receptor blockage and cytokine depletion In Specific Aim 1, the applicant will study worsening of glomerular disease and chronic kidney disease due to FSGS and DN after induction of COVID-19 like cytokine storm. In Specific Aim 2, the applicant will assess the impact of allergy pathway cytokines IL-4 and IL-13, and inflammatory pathway cytokine TNF-α, and chemokine CXCL5 released during COVID-19 respiratory infection on pre-existing glomerular diseases. In Specific Aim 3, the applicant will treat COVID-19 related worsening of glomerular disease and chronic kidney disease FSGS and DN by depletion or blockage of the cytokine storm.