Uncovering a ‘suPAR’ culprit behind kidney injury in COVID-19

Kidney injury is a dreaded complication in patients hospitalized for COVID-19, with more than a third of patients ending up in need of dialysis. Patients with COVID-19-related kidney injury are also at much higher risk of death.

“We don’t know exactly why patients with severe COVID-19 have a high rate of kidney injury,” says Salim Hayek, M.D., a cardiologist at the Michigan Medicine Frankel Cardiovascular Center and senior author of a new observational study.” It is, however, becoming clearer that a hyperactive immune system plays a major role in the morbidity of COVID-19, including kidney-related complications.”

In the multi-center study published in the Journal of the American Society of Nephrology, Hayek and an international team of experts report that levels of a protein in blood produced by immune cells and known to be involved in causing kidney disease are very high in patients hospitalized for COVID-19 and strongly predictive of kidney injury.

The research team tested soluble urokinase plasminogen activator receptor (suPAR) levels of 352 study participants when they were admitted to the hospital for COVID-19 infection.

A quarter of the participants developed acute kidney injury while hospitalized, and their median suPAR levels were more than 60% higher than those of the rest of the participants. The risk of needing dialysis was increased 20-fold in patients with the highest suPAR levels. Overall, median suPAR levels for these study participants hospitalized with severe COVID-19 were almost three times higher than levels of healthy people.

“SuPAR is an immune-derived circulating factor we’ve seen contribute to kidney injury in thousands of patients,” says Jochen Reiser, M.D., Ph.D., a professor of medicine at Rush University and expert in the biology of suPAR. “RNA viruses such as HIV and SARS-CoV-2 elicit a suPAR response of the innate immune system leading to a rise in blood suPAR levels. If there is a hyperinflammatory suPAR response, kidney cells may be damaged.”

Study author Subramaniam Pennathur, M.D., a professor of nephrology at Michigan Medicine, says identifying suPAR levels at hospital admission as a strong predictor for AKI during the hospitalization has important implications for future care.

“For example, obtaining suPAR levels may allow us to risk-stratify, i.e., identify high risk patients early, and institute appropriate preventive treatment, thereby reducing AKI risk and improving COVID-19 outcomes,” he says. “Second, therapies aimed at interrupting suPAR pathway may also be explored for preventative as well as a therapeutic option for COVID-19 AKI.”

Hayek, an expert on this protein is currently researching how best to reduce suPAR levels in those people at highest risk.

“We’re preparing to launch the first clinical trial targeting suPAR to prevent COVID-19 related kidney injury, and by doing so hope to alleviate the burden of kidney disease in both COVID-19 and non-COVID-19 patients with high suPAR levels,” he says.

Additional authors include Tariq Azam, Husam Shadid, Pennelope Blakeley, Patrick O'Hayer, Hanna Berlin, Michael Pan, Peiyao Zhao, Lili Zhao and Rodica Pop-Busui (Michigan Medicine); Izzet Altintas, Jens Tingleff, Marius Stauning, Ove Andersen and Jesper Eugen-Olisen (Copenhagen University Hospital); Maria-Evangelia Adami, Nicky Solomonidi, Maria Tsilika and Evangelos Giamarellos-Bourboulis (National and Kapodistrian University of Athens); Pinkus Tober-Lau and Frank Tacke (Charite Universitatsmedizin Berlin); Eleni Arnaoutoglou and Athanasios Chalkias (University of Thessaly) and Verena Keitel and Sven Loosen (University Hospital Düsseldorf).

Paper cited: “Soluble Urokinase Receptor in COVID-19 related Acute Kidney Injury.” Journal of the American Society of Nephrology.