Protein Predicts Risk of AKI in COVID-19 Patients

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Admission levels of a specific protein predict the development of acute kidney injury (AKI) as well as the need for dialysis in patients hospitalized for COVID-19, new research shows.

“This protein, soluble urokinase plasminogen activator receptor (suPAR) is produced by immune cells, and in an earlier study we saw that patients with critical illness who had high levels of this protein had a very high risk of AKI,” senior author Salim Hayek, MD, assistant professor of cardiology, University of Michigan, Ann Arbor, explained to Medscape Medical News.

“So when we started seeing how frequent AKI was in COVID-19, with reports of focal segmental glomerulosclerosis-like pathology, it was natural to think about looking at this protein and now…in patients with COVID-19, we see people with dramatically high suPAR levels with significant kidney injury,” he added.  

The International Study of Inflammation in COVID-19 (ISIC) was recently published in the Journal of the American Society of Nephrology by Tariq U. Azam, MD, also of the University of Michigan, and various overseas colleagues.

ISIC is an ongoing, multicenter, observational study with a goal of characterizing inflammatory marker levels and their association with outcomes in patients hospitalized with COVID-19.

Currently, there are no Food and Drug Administration-approved assays available to measure suPAR, but in general, it is very cheap and easy to measure, Hayek said. “There is even a point-of-care assay when you can get a result in 15 minutes,” he noted.

Median suPAR Level 60% Higher in Patients With vs Without AKI

The current analysis involved 352 patients with COVID-19 who had a mean estimated glomerular filtration rate (eGFR) of 80 mL/min/1.73m2 at admission.

“suPAR was measured in plasma…using a commercially available ELISA (suPARnostic assay by ViroGates),” the investigators note.

A total of 25.9% of patients developed AKI during hospitalization, and 47.3% of them developing stage 2 or 3 AKI.

Approximately one quarter (27.5%) of those who developed AKI required dialysis.

“Patients who developed AKI during their hospitalization had a median suPAR level 61.6% higher than that of patients who did not develop AKI,” Azam and colleagues report. The investigators also found a step-wise increase in the incidence of AKI with increasing tertiles of suPAR.

This ranged from a low of 6% in patients with a suPAR < 4.6 ng/mL (the lowest tertile) to an incidence of 45.8% in patients in the highest tertile, with a suPAR level > 6.8 ng/mL.

“[This] association was independent of eGFR, disease severity, or other biomarkers of inflammation and persisted across subgroups,” the authors emphasize.

Severity of in-hospital AKI also correlated with admission suPAR levels. For example, none of the patients with a suPAR under 4.6 ng/mL required dialysis.

In contrast, there was a “strong correlation” between suPAR level and duration of dialysis: the median duration of renal replacement therapy (RRT) was 6 days for those with a suPAR level > 6.86 ng/mL versus 3 days for those with a suPAR level of 4.6-6.86 ng/mL (P = .03), the authors note.

Moreover, when examined as a continuous variable, “a doubling of suPAR was associated with a 3.18-fold increase in the odds of developing AKI…and a 3.28-fold odds of requiring RRT,” Azam and colleagues report.

None of the other inflammatory markers analyzed at the same time were associated with incident AKI, they stress.

As noted, the research team has previously shown that suPAR is involved in the pathogenesis of kidney injury following cardiac surgery, angiography, or ICU admission, in a study published in the New England Journal of Medicine.

AKI may be occurring in severe COVID-19 via the so-called “cytokine storm,” Hayek speculated.

When tubular cells are exposed to high suPAR levels, they behave as if they are not receiving enough oxygen. Combined with hemodynamic disturbances that characterize the cytokine storm, high suPAR levels essentially lead to kidney damage, he explained.

Proof-of-Concept Trial to See if Removing SuPAR Prevents AKI

Hayek continued: “The evidence supporting this mechanism in COVID-19 is still circumstantial, but given what we have learned about suPAR in the past 5 years, it’s enough evidence for us to justify starting a clinical trial.”

The study will be run in tandem with research at the University of Michigan and Rush University Medical Center and will be the first clinical trial to test the hypothesis that removing suPAR prevents kidney injury in patients with COVID-19.

The protein will be removed using an apheresis device through which blood will be circulated through a column containing antibodies to suPAR, and so only the suPAR protein will be extracted; everything else will be recirculated.

“This proof-of-concept study is being done specifically in COVID-19 patients, but it could end up also helping non-COVID-19 patients down the line, such as those with AKI from other causes,” Hayek explained.

Hayek is a member of the scientific advisory board of Trisaq, a biotechnology company developing drugs targeting suPAR.

J Am Soc Nephrol. Published online September 22, 2020. Full text

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