COVID-19 Diagnostics: Researchers Uncover New Protein Biomarker suPAR To Identify COVID-19 Patients At Risk Of Acute Kidney Injury (AKI)
: A new study led by resarchesr from University of Michigan and involved an internation collaboration of various scientist and medical institutions from various countries has identified a protein called suPAR or soluble urokinase plasminogen activator receptor that can be used as a biomarker in blood diagnostics to identify COVID-19 patients who at risk of AKI or acute kidney injury which is a very predominant occurrent.
The study findings are published in the Journal of the American Society of Nephrology https://jasn.asnjournals.org/content/early/2020/10/08/ASN.2020060829.long
The new study found that admission levels of a specific protein predicted the development of acute kidney injury (AKI) as well as the need for dialysis in patients hospitalized for COVID-19.
Nearly half of hospitalized patients with COVID-19 disease develop AKI, with 20% requiring dialysis. https://www.thailandmedical.news/news/covid-19-clinical-care-kidney-failure-emerging-as-a-common-occurrence-from-covid-19-infections
Senior author of the study Dr Salim Hayek, MD, Assistant Professor of cardiology, University of Michigan, Ann Arbor told Thailand Medical News, “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.”
He further added, "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 individuals with dramatically high suPAR levels with significant kidney injury.”
The study is part of the ‘International Study of Inflammation in COVID-19 ‘(ISIC) and not only involves researchers from the University of Michigan b
ut various other international collaborators from countries like Denamrk, Germany, Greece along with researchers from Rush University Medical Center-Chicago.
The ISIC research 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.
At present there are no U.S. Food and Drug Administration or EU Regulatory approved assays available to measure suPAR, but in general, it is very cheap and easy to measure.
There are currently point-of-care assays for suPAR where one can get a result in 15 minutes.
The study findings showed that median suPAR Levels was 60% higher in patients with versus patients without AKI.
The study involved 352 patients with COVID-19 who had a mean estimated glomerular filtration rate (eGFR) of 80 mL/min/1.73m2 at admission.
The study team measured suPAR levels in plasma using a commercially available ELISA (suPARnostic assay by ViroGates).
In the study a total of 25.9% of patients developed AKI during hospitalization, and 47.3% of them developing stage 2 or 3 AKI.
Significantly approximately one quarter (27.5%) of those who developed AKI required dialysis.
Lead researcher Dr Tariq U. Azam, MD from the division of cardiology, department of internal medicine at of the University of Michigan said, "Patients who developed AKI during their hospitalization had a median suPAR level 61.6% higher than that of patients who did not develop AKI.”
The study team also found a step-wise increase in the incidence of AKI with increasing tertiles of suPAR.
It was found that 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.
Dr Hayek added, "This association was independent of eGFR, disease severity, or other biomarkers of inflammation and persisted across subgroups.”
Importantly 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.
Significantly 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
Dr Azam added that 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."
The study team stressed that none of the other inflammatory markers analyzed at the same time were associated with incident AKI.
The study team has previously shown that suPAR was 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
The study tea speculates that AKI may be occurring in severe COVID-19 via the so-called "cytokine storm.”
The team explained that 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.
The team is exploring a ‘Proof-of-Concept’ Trial to see if removing suPAR prevents AKI.
Dr Hayek commented,"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 clinical trial 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.
In the proposed trial, the suPAR 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.
Dr Hayek explained, "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.”
Dr Hayek is a member of the scientific advisory board of Trisaq, a biotechnology company developing drugs targeting suPAR.
The study team commented,”In conclusion, the study shows that suPAR levels were independently associated with incident AKI in patients hospitalized for COVID-19. In light of recent experimental data suggesting that suPAR is an immune-mediator of kidney injury, targeting suPAR should be considered as a strategy to mitigate AKI in COVID-19 and other patient populations at high risk of AKI.”
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