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Yale-Led Group Links Protein Markers to Kidney Injury in Cardiac Surgery Patients


By Adam Bonislawski

A research team led by Yale University has completed a multi-center, 1,500-subject study evaluating the use of the protein biomarkers urine interleuken 18, urine neutrophil gelatinase-associated lipocalin, and plasma NGAL as a way to predict acute kidney injury in patients undergoing cardiac surgery.

The study was detailed in two papers – one examining pediatric patients and the other examining adults – published in the August edition of the Journal of the American Society of Nephrology.

It is one of several large-scale kidney biomarker studies currently being undertaken by the Translational Research Investigating Biomarker End-Points in Acute Kidney Injury, or TRIBE-AKI consortium, a multidisciplinary group of scientists investigating biomarkers for kidney disease.

Comprising researchers from more than 20 universities, the consortium is focused on large, multi-center biomarker-validation studies. In addition to the JASN study, the group is currently studying protein biomarkers that may predict kidney-transplant outcomes; identify acute tubular necrosis in cirrhosis patients; monitor long-term outcomes after AKI; predict chronic kidney disease; and detect AKI after abdominal aortic aneurysm repair as well as kidney damage in HIV-infected patients.

The consortium formed in 2005 "when this question of having better biomarkers reached national prominence," Yale associate professor Chirag Parikh, founder and leader of the TRIBE-AKI group, told ProteoMonitor. "I saw that it was impossible to reach the correct answers by doing small studies. We needed large groups of patients."

The theme of the consortium is to "do high-quality, large studies to gauge the translational potential of the biomarkers [being investigated]," he said. "Typically all of these are multicenter studies. Anyone can do their own 50-patient study, but usually those findings are either biased or they are underpowered statistically."

So "if you want to validate biomarkers for a given setting, you have to do these large studies with a large number of samples," said Parikh.

For the cardiac-surgery study the group collected more than 200,000 plasma and urine samples from 1,219 adults and 311 children. Measuring urine IL-18 and urine NGAL with Architect assays from Abbot Diagnostics and plasma NGAL with Biosite's Traige NGAL immunoassay, they found that the three biomarkers were able to identify kidney injury within six hours after surgery, and 24 to 48 hours before serum creatinine testing, the current gold standard for measuring kidney injury.

They also found that urine IL-18 and plasma NGAL improved prediction of AKI risk in adults compared to the standard clinical model, and urine IL-18 and urine NGAL improved prediction in children.

Because the researchers used serum creatinine levels to define AKI, it's possible that IL-18 and NGAL might be more useful predictors than the study's findings suggest, Parikh noted. For instance, false-positive results could actually have been indicators of AKI that creatinine measurements weren't able to pick up, he said.

Serum creatinine levels measure how well kidneys filter blood. However, the assay does not provide a direct measurement of kidney injury, Parikh noted.

"We are comparing [kidney] injury biomarkers to a filtration standard," he said. "So the opportunity for the injury biomarkers to do well is limited because of this comparison. We don't have anything [besides creatinine levels] to compare to, so this is an inherent limitation.

"Whenever [IL-18 and NGAL] do better than serum creatinine, we call it a false positive," Parikh added. "Potentially, though, these are not false positives; they are subclinical injury measurements and we just don't have a better way to understand them."

To investigate this possibility, the TRIBE-AKI researchers are following up with study patients over three years to see if any of the false-positive cases went on to develop kidney damage.

"The people who had false positives — whose [IL-18 and NGAL] levels increased but whose creatinine was negative — if they actually showed increased mortality, then we would know that these biomarkers are actually telling us something more than [creatinine]," Parikh said.

He added that the group has already gathered one- and two-year data and plans to complete the follow-up next year.

The researchers also examined how well albumin can detect kidney injury in the same cohort. Urine albumin is an established biomarker for kidney damage in diabetics, but the test hasn't typically been used outside that community. Parikh's group plans to publish data from that work in the near future, he said.

In an email to ProteoMonitor, Frank Dieterle, global program diagnostics director at Novartis Molecular Diagnostics noted that the cardiac surgery study "has some real strengths."

"It is a multicenter study with a large number of patients and a broad population with only view exclusion criteria," he said. "Therefore it reflects better the normal clinical population and potential day-to-day use of biomarkers in clinical settings than some other published studies which focus on a very narrow well defined population with view co-morbidities."

He noted that "while the AUC values of the biomarkers in this study are significantly lower than AUC values reported in other publications" for the time point at which the markers were tested – six hours after operation – "all other clinical parameters to detect kidney injury are close to random."

Dieterle was the leader of a 2007 submission by the Predictive Safety Testing Consortium’s Nephrotoxicity Working Group of urinary renal safety biomarkers for Food and Drug Administration and European Medicines Agency review, an effort that looked at 23 proteins as possible biomarkers, ultimately selecting seven for submission (PM 05/14/2010).

Though not one of the seven biomarkers submitted, NGAL was among the initial 23 examined, Dieterle said. He added that IL-18 "was not considered for biomarker qualification, as very limited data existed at that time in animals due to the lack of suitable assays."

Thus far, the TRIBE-AKI consortium has enrolled more than 3,000 patients in its studies. In addition to IL-18, NGAL, and albumin, the group is investigating the biomarkers cystatin C and B-type natriuretic peptide.

According to Parikh, funding for the study is arranged on a project-by-project basis with roughly 90 percent of it thus far coming from the National Institutes of Health. The cardiac surgery study was supported by a $4 million, five-year NIH grant.

Parikh said the consortium also aims to stimulate commercialization efforts for the biomarkers they investigate "at all levels from early licensing to large-scale production." The organization itself, however, does not have any formal commercialization strategies, he said.

"We have occasionally assisted companies on studies for [the US Food & Drug Administration], but it's on an as-needed basis, if people reach out to us," he said.

Parikh and University of Colorado researcher Charles Edelstein, who was also an author on the JASN papers, share a patent for IL-18 as a biomarker for AKI. Biosite and Abbott Diagnostics have licensing agreements with Cincinnati Children's Hospital — a TRIBE-AKI participant — to develop plasma and urine NGAL respectively, as biomarkers for AKI.

Have topics you'd like to see covered in ProteoMonitor? Contact the editor at abonislawski [at] genomeweb [.] com.

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