Extracorporeal SuPAR Extraction to Prevent COVID-19-associated Acute Kidney Injury

Abstract Acute kidney injury (AKI) is a global problem that affects one in five hospitalized adults worldwide. It has a major impact on morbidity and healthcare utilization, with small changes in kidney function shown to be associated with both short and long-term complications. AKI is a characteristic feature of the disease caused by the SARS-CoV-2 virus, coronavirus disease 19 (COVID-19), with close to 50% of hospitalized patients developing acute kidney injury (AKI) and 20% of patients requiring dialysis. The pathophysiology of AKI is complex and dependent on both intrinsic factors (age, co-morbid diabetes, hypertension, pre-existing kidney disease) and extrinsic factors (nephrotoxic drugs, hypovolemia, intra-arterial contrast, infections). Inflammation is an under-explored but crucial link between intrinsic and extrinsic factors in the pathogenesis of AKI. We have identified soluble urokinase plasminogen activator receptor (suPAR) as an immune-derived mediator of kidney injury. The expression of suPAR by immune cells is heavily induced by various stimuli, notably RNA viruses such as SARS-CoV-2. High levels of suPAR in circulation are strongly predictive of kidney dysfunction, with prolonged exposure directly affecting the kidneys by pathologic activation of αvβ3 integrins expressed on podocytes, resulting in activation of GTPase, podocyte effacement and subsequent proteinuria. We have recently shown high suPAR levels predisposes patients to AKI in various clinical scenarios including the critically ill, likely by modulating mitochondrial respiration and inducing reactive oxygen species generation in proximal tubular cells, sensitizing them to additional insults. Most importantly, effects of suPAR on the kidneys were abrogated using anti-suPAR in experimental models, suggesting suPAR is a promising therapeutic target to mitigate AKI. We have found that suPAR is dramatically elevated in COVID-19 and independently predictive of AKI. Despite the significant burden of AKI overall and specifically in COVID-19, there has been little progress in the prevention and treatment of AKI. We hypothesize that suPAR extraction early in the hospitalization of patients with COVID-19 may decrease the risk of moderate to severe AKI. To that end we have planned a phase 1 clinical trial randomizing adult patients hospitalized for COVID-19 who have high suPAR levels to daily extracorporeal extraction of suPAR by apheresis using a suPAR-specific adsorber, or sham treatment for a total of 5 days. The primary outcome of the trial is the occurrence of treatment-related serious adverse events. Exploratory outcomes include the incidence of AKI, respiratory failure, and in-hospital mortality. We will assess the kinetics of suPAR extraction by measuring daily levels prior to and post-treatment, in addition to its impact on markers of inflammation and kidney function. The proposed work is innovative in that it is the first trial targeting an immune-derived factor for preventing kidney injury. In addition to advancing our understanding of the immune system as a mediator of kidney injury, this trial will clarify suPAR's role as a pathogenic factor, with major implications for the treatment of kidney disease beyond COVID-19.