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Multi-Site Validation Study Published Supporting Astute Medical's NephroCheck AKI Test

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A study published this week has demonstrated the ability of Astute Medical's NephroCheck protein biomarker test to identify patients at risk of acute kidney injury.

In a validation cohort composed of 744 subjects with critical illness and no evidence of acute kidney injury at enrollment, the test identified patients who would go on to develop AKI within the next 12 hours with an AUC of .80.

The results suggest the NephroCheck test could be a significant improvement over existing diagnostic methods like measures of creatinine and urine output, John Kellum, professor of Critical Care Medicine at the University of Pittsburgh and an author on the study, told ProteoMonitor.

NephroCheck assesses AKI risk by measuring insulin-like growth-factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases (TIMP-2). Astute began selling the test in Europe in October and is currently preparing a US Food and Drug Administration 510(k) submission for the test.

According to Astute, AKI affects up to 2.5 million US hospital patients annually and is a particular concern in intensive care settings, where roughly 36 percent of patients develop the condition.

AKI can be difficult to detect, however, particularly given the multitude of other conditions such patients may be dealing with, Astute CEO Christopher Hibberd told ProteoMonitor.

"They are very often presenting with other conditions – it may be sepsis, or trauma, or [recovery] after a surgery, and [doctors] are looking at those underlying conditions, and very often [AKI] sneaks up on them," he said.

This problem is compounded, Hibberd said, by the fact that creatinine and urine output – the measures used by most hospitals to track the condition – appear as markers relatively late in the process.

"Both those markers are indicators of the function of your kidney," he said. "And by the time you start to see a significant decline in function, often a lot of damage has happened to the kidneys."

The study, funded by Astute and published this week in Critical Care, consisted of two parts. The first was a 522-subject discovery study in which the researchers investigated 340 proteins to identify the best potential markers. That study identified IGFBP7 and TIMP-2, which were then validated in a separate 744-patient multi-center study.

"I think it's really an excellent paper," Jonathan Barasch, an associate professor of Medicine and Anatomy & Cell Biology at Columbia University whose research focus includes kidney biomarkers, told ProteoMonitor. "It's very well done."

However, Barasch, who was not part of the study, questioned its finding that the NephroCheck markers performed better in identifying intrinsic AKI than the protein neutrophil gelatinase-associated lipocalin, or NGAL, which he, along with Cincinnati Children's Hospital researcher Prasad Devarajan, discovered and licensed to Abbott Laboratories and Alere.

Barasch said that in several large studies done by himself, Devarajan, and Max Delbruck researcher Kai Schidt-Ott, NGAL predicted AKI with an AUC in the .80 range, roughly equivalent to the performance of the NephroCheck test.

Barasch also noted that the NephroCheck's inclusion of TIMP-2 was interesting given that this protein – which Barasch's lab first identified in the kidney – has typically been associated with the glomerulus rather than the renal tubule, and AKI is generally considered a disease of the renal tubule.

"They may have discovered actually a new form of acute kidney injury that involves the glomerulus," he said. "So one would have to go back with injured kidneys and find out where exactly it is expressed."

He added that given the confusing performance of creatinine as an AKI marker, future studies of the test would ideally benchmark it not against creatinine as was done in the Critical Care work, but against clinical outcomes instead.

That, Barasch said, has been a problem in all AKI kidney biomarker work, his own included.

He noted, as well, that future studies of the markers should attempt to separate patients suffering from intrinsic tubular damage from pre-renal azotemia, a mimic of kidney injury that also raises creatinine, but only transiently.

"It's an exciting paper," Barasch said. "It's the beginning of a very long process now to prove the biological reality of this and to make sure it's saying what we think it's saying."

Kellum likewise suggested that "this is just the start of this story," noting that there remained a number of questions to be asked regarding the biology behind the markers and potential additional uses such as for tracking treatment efficacy.

Astute, Hibberd noted, has performed an additional clinical study of the test, as of yet unpublished, in support of the FDA 510(k) submission that it is putting together.

Hibberd and CSO Paul McPherson formed Astute in 2007 after their former firm Biosite – which also has a license to develop NGAL for AKI testing – was acquired by Inverness Medical Innovations. The company has largely maintained a low profile since then, raising more than $80 million in funding but offering little public comment on its plans.

In addition to the NephroCheck test, Astute has developed an immunoassay platform to perform it, the Astute140 Meter. Platform development is not the company's focus, but it chose to develop the device so as to better control the timing of NephroCheck's rollout, Hibberd said.

"If you actually push the platform yourself, you can control the timeline and the launch, so that's the primary reason [for developing it]," he said, adding that the company has since received interest from several diagnostics players and is currently in "discussions examining the possibility of putting [the test] on other platforms."

He declined to offer details on pricing or how many tests the company had sold since its European launch in October.

Astute's focus is developing biomarkers for acute hospital settings, Hibberd said, suggesting that this is an attractive area given current efforts to rein in healthcare costs.

"There are several factors that come into play in an era of more constrained healthcare spending," he said. "And one of them is actually making the best use of the resources that are there and minimizing the cost overruns and downstream consequences of what happens in the hospital."

Hibberd provided an example of how a test like NephroCheck might help, noting that cardiac surgery without AKI typically costs around $14,000 and requires around a two-day hospital stay. For patients who develop AKI, however, costs are closer to $50,000 and as much as a five-day stay can be required, he said.

If patients at high risk for AKI can be detected early, Hibberd said, a variety of interventions can be taken – such as discontinuing treatment with nephrotoxic agents – that reduce their chances of developing the condition.

Beyond AKI, Astute sees sepsis and abdominal pain as particularly promising areas, he said.

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