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Research Suggests BioMérieux Kidney Injury Assay Could Guide Sepsis Treatment

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NEW YORK (360Dx) – An assay from BioMérieux to detect acute kidney injury (AKI) has been shown in preliminary research to detect injury caused by sepsis earlier than the current standard of care. Integrating the NephroCheck AKI test and a procalcitonin test may potentially enable physicians to alter treatment before irreparable kidney damage occurs.

The research, which was presented in a BioMérieux-sponsered talk at the American Association of Clinical Chemistry convention last month, was performed by Eric Gluck, a critical care physician at Swedish Covenant Hospital in Chicago, who said in an interview that renal failure is frequently associated with severe sepsis.

The body's reaction to severe bloodstream infection seems to involve reducing blood flow to the kidney as well as urinary output, he said. This sets the stage for a potentially dangerous situation when septic patients are treated with resuscitative fluids containing lots of chloride as well as IV antibiotics, like aminoglycosides, vancomycin, and fourth-generation penicillin drugs, all of which can have nephrotoxic effects.

The standard of care has been to use serum creatinine levels as a marker of kidney injury, but by the time that particular marker shows up, "the kidney is 50 percent destroyed," Gluck said, adding, "There was nothing you could do at that point in time, so you sort of waited through that storm and hoped that the kidney would regain function eventually, if the patient survived."

If the kidney can't recover, patients may need dialysis, which can be a major quality of life issue. It can take three sessions per week, each lasting four to five hours, making it hard to hold a job or travel. Being on dialysis can also impact life expectancy, and is quite costly, although it is typically covered by insurance

Gluck noted that he had been searching for a biomarker that would be an improvement over creatinine, and was close to adopting one called NGAL, when the NephroCheck test became available from Astute Medical in 2014.

NephroCheck measures two proteins present in urine — insulin-like growth-factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases (TIMP-2) — and has been shown to perform well in a multisite validation as well as being related to long-term outcomes in a follow-up study.

The test can indicate that a patient's kidney is under stress, he said, giving him "a day's notice before the kidney was going to fail," and potentially allowing him to alter treatment in time.

Gluck and his colleagues identified 227 patients who had positive procalcitonin tests, an assay that can used to determine whether a patient has a bacterial infection as well as, in some indications, whether he is responding to antibiotic treatment.

Of these, about 40 percent had severe sepsis and were measured using the NephroCheck test, with 85 percent of showing positive values suggesting impending renal failure.

By applying AKI guidelines from the Kidney Disease: Improving Global Outcomes, or KDIGO organization — which essentially recommend de-escalation of antibiotic treatment as soon as possible, and switching from nephrotoxic drugs if damage is indicated — Gluck and his team believe they were able to reduce the incidence of kidney injury for their septic patients.

Specifically, they see a 30 percent decrease in need for dialysis in patients whose NephroCheck test led to kidney-sparing changes in sepsis treatment, both in total number of dialysis days, and number of individual patients who require dialysis after recovering from sepsis. They also found that kidney stress in sepsis, indicated by positive PCT and NephroCheck tests, was associated with 60 percent increase in mortality, from 25 percent with sepsis alone to about 35 percent with sepsis and kidney damage.

Plans for NephroCheck

The NephroCheck test for AKI was acquired by BioMérieux in the acquisition of Astute Medical in April of this year. BioMérieux had previously collaborated with Astute to port the assay onto its Vidas automated immunoassay system, which also happens to run the firm's Vidas BRAHMS PCT test that the firm has developed for expanded indications to guide de-escalation of antibiotic treatment in sepsis.

In an interview Stefan Willemsen, the president and CEO of the US division at BioMérieux, said the firm's relationship with Astute evolved over time to the point that acquisition made the most sense.

BioMérieux wasn't the only licensee; Astute had also partnered with Ortho Clinical Diagnostics for development of the assay. BioMérieux also had a distribution arrangement through which it provided the NephroCheck test on the Astute140 Meter.

BioMérieux found that the response to the test was quite positive. "We had some early indications from our customers and from our [key opinion leaders] that this was going to be very interesting going forward," Willemsen said.

Ultimately, Astute also struggled to gain market access and traction "simply because of the fact that it takes time and effort," Willemsen said, which can prove challenging for a small company.

Now the plan is to do with NephroCheck what BioMérieux did with Vidas Procalcitonin — invest in clinical outreach and education to inform clinicians about the value of the test, and hopefully also change clinical practice. As owner of the assay and the IP, BioMérieux also plans to out-license the test to appropriate global partners.

BioMérieux believes it may have a jump on the kidney stress test market. Gluck noted that although there may be other markers of kidney stress in research stages, he is not aware of any that are commercially available

Having NephroCheck available on Vidas alongside the PCT test could also be valuable. "We believe that AKI and PCT are a match made in heaven in terms of improving the sepsis pathway of care," Willemsen said.

Empiric treatment for sepsis is often triggered when a patient presents with fever, a fast heart rate, rapid breathing, low blood pressure, and an elevated white count. But these symptoms can occasionally be indicative of other conditions.

As Gluck noted, "The procalcitonin [test] tells you that you have a bacterial infection, so now you know you have to give antibiotics. If the NephroCheck is negative, you can give whatever antibiotic you want, but if the NephroCheck is positive, now you can modify the antibiotics to something that would be less toxic to the kidneys." A negative PCT test can also tell clinicians that the patient does not need antibiotics, allowing them to "avoid a scenario where potentially you're hurting the kidneys with no potential benefit," he said.

And, as Willemsen noted, combing the two tests is helpful in that declining PCT values can help guide de-escalation. "If your PCT value actually shows there is no more bacterial infection, you would get off [a nephrotoxic] antibiotic as soon as you can to reduce the stress on the kidney," he said.

Now, the firm is "talking to the same ICU physicians about PCT and AKI." It will submit the test to the US Food and Drug Administration on the Vidas platform when it is ready, but "even now, with [NephroCheck] being on the Astute meter, we are already positioning this as a better solution for sepsis treatment," Willemsen said.

In terms of M&A, Willemsen said the firm's clinical diagnostics business remains positioned overall as "a high medical value provider" focused on products that are mostly in the infectious disease space, but also sometimes adjacent areas. For example, the firm acquired BioFire in 2014, has a relationship with Qvella, and has licensed a marker from Banyan Biomarkers for traumatic brain injuries that it is also developing for the Vidas.

"We are looking for tests that are giving clinicians faster and more accurate information closer to the patient, so that they can make clinical decisions that improve patient care, outcomes, and reduce costs," Willemsen said.

For NephroCheck, Willemsen said the firm is "convinced there is a large market opportunity" in sepsis in conjunction with the PCT test, as well as in other areas, such as kidney injury associated with heart surgery. And Astute has a "strong team of biomarker developers," he said, that continues to work on other projects to improve the kidney treatment workflow.