AKI risk biomarkers may be ‘as early as it gets’

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• A risk score under 0.3. The person would have a “very, very low risk of AKI,” he says. In that case, “I can provide the standard of care for that patient without any further consideration because unless something new happens, the risk is really quite low.”
• A risk score greater than 0.3 but less than 2. The risk of AKI goes up about sevenfold in this group. It’s absolute risk that’s in the range of 12 to 17 to 20 percent, Dr. Kellum says. “It depends a little on what the baseline risk is, so it might be as high as 25 percent but it’s certainly not exceedingly high if you’re in that middle zone.” Yet a clinician is not going to do the same things. “For example, you are not going to give this patient anything that’s potentially nephrotoxic. We wouldn’t give these patients nonsteroidals. We’d be very careful about fluids and diuretics in that group, much more so than we would with patients with no substantial risk of AKI.”
• A risk score exceeding 2. Now the patient has about a one in two risk of developing AKI. “In that population, we really want to sort out what the risk is coming from,” Dr. Kellum says. “Maybe the heart function isn’t as good as we thought. Maybe we need to get another echo. Maybe there is something happening that we’re not sure about—let’s investigate further.”

Dr. Kellum stresses that NephroCheck wasn’t developed to confirm that a patient has AKI. “And no test provides near 100 percent certainty that something will happen.”

Determining whether the result is a false-positive “is a tricky thing,” he says. “Sometimes the cells will defend themselves successfully so you get an elevation of the biomarkers” but the person doesn’t develop AKI.

“Cardiac biomarkers are markers of damage, so you can actually tell a cardiac patient that you just had a little MI because your enzymes are up,” Dr. Kellum says. “With NephroCheck, all you can tell the patient is that your kidney was worried, but either because of what we did or what your kidney did, it managed to get through that without any injury.”

NephroCheck is not FDA cleared for performing serial measurements to determine whether a patient has increasing or declining biomarker levels. “We can do serial measurements but off-label,” says Dr. Kashani, who says the test will be used at Mayo in accordance with the FDA label.

Researchers in the Sapphire validation investigation did collect serial samples for measurement. “So we have a baseline when patients have not actually reached the definitions of moderate to severe acute kidney injury,” Dr. Kashani says. “Then we have serial measurement at 12 hours, 24 hours, and then daily for up to seven days or until discharge from the hospital,” if sooner than seven days.

Dr. Kashani observes that patients are of several phenotypes. Some recover from AKI rather quickly. “And we expect these markers to identify those patients by decreasing biomarker levels.” Some patients go on to have more advanced kidney injury requiring dialysis, and those patients could have higher levels of NephroCheck. The data analysis of NephroCheck trends hasn’t been completed, Dr. Kashani says.

Dr. Kellum says NephroCheck is not a test for chronic kidney disease. “But what appears to be true is that if your biomarker levels are really high, not only are you at risk for short-term adverse outcomes but also long-term outcomes.”

Anesthesiologist Alexander Zarbock, MD, of the University of Münster in Germany, and colleagues performed a study showing that NephroCheck predicted both AKI and renal recovery in cardiac surgery patients postoperatively. They selected high-risk study participants by using the Cleveland Clinic Foundation score which correlates with dialysis-dependent AKI after cardiac surgery. This approach makes it possible to increase NephroCheck’s specificity, Dr. Zarbock says.

An abstract of the study article says the following: “26 patients (52%) developed AKI. Diagnosis based on serum creatinine and/or oliguria did not occur until 1–3 days after CPB [cardiopulmonary bypass]. In contrast, urine concentration of [TIMP-2]*[IGFBP7] rose from a mean of 0.49 (SE 0.24) at baseline to 1.51 (SE 0.57) 4 h after CPB in patients who developed AKI” (Meersch M, et al. PLoS One. 2014;9[3]:e93460).

Dr. Fitzgerald

Robert L. Fitzgerald, PhD, a professor of pathology at the University of California, San Diego, who participated in the Topaz study, believes more clinical studies will be essential before NephroCheck is widely adopted. His laboratory is not planning to use NephroCheck at this time. Having to do the test on site is “a challenge for most labs like ours,” he says, “where we have a single big platform. Ninety-five percent of your tests get done on a large automated line, and if the test isn’t on the platform, it’s going to be a struggle to bring it in-house.”

“One concern is that we are becoming overloaded with new biomarkers and everyone promises to do great things,” Dr. Fitzgerald says. “In the case of kidney disease, there are several biomarkers that have been touted as being the next great thing and none are in widespread use today.” What he views as exciting about NephroCheck is its rigorous validation. And the markers’ specificity for AKI differentiates it from the other markers, he says: “There is nothing else that does what they appear to do.”

At the University of Münster, Dr. Zarbock and colleagues have a clinical trial underway using NephroCheck to identify patients at high risk for AKI after cardiac surgery. “Biomarker-positive patients are randomized to get either a standard of care or a specific treatment bundle to prevent cardiac-surgery–associated AKI,” he says.

Dr. Kellum suspects that early intervention studies will home in on removing nephrotoxic medications. “If I have a patient on a medication that could potentially hurt the kidneys but it only affects a small number of patients in an adverse way, I could either wait for the kidneys to appear to be damaged, which is maybe too late to really stop the drug effectively, or I can test you and if your kidney is sensing stress, stop the drug before the drug actually damages the kidney.”

In the meantime, the search for AKI treatments marches on. “Unfortunately,” says Dr. Kashani, “most of the completed studies have failed to show significant benefit. We are hoping that NephroCheck can identify patients earlier when they have a higher chance to respond to the interventions.”

He notes that several ongoing studies are evaluating different medications or interventions, including anti-inflammatory medications or techniques to remove inflammatory mediators. “A large number of investigators are working on metabolomics and proteomics of urine and plasma during AKI to be able to identify other markers,” Dr. Kashani says. “Apart from early diagnosis of AKI, the scientific community tries to come up with markers that can identify the nature, intensity, and location of the injury. I’m hoping that in the future we will be able to individualize treatment for each patient,” Dr. Kashani says.

He calls NephroCheck one step forward but not the last step. “Hopefully this is the beginning of progress in the field,” with much more to understand and discover, he says. “I am very excited about it.”

Dr. Kellum thinks that what researchers are not likely to discover is earlier AKI risk biomarkers. That’s because TIMP-2 and IGFBP7 are part of an early defense system used by the cells, he says. “If the cell can’t detect it, it’s hard to imagine there’s going to be any biologic signal. So this is probably as early as it gets, and it’s certainly earlier than usable biomarkers in other areas,” such as cardiac markers.

“Having markers of stress, which is what these markers are in the kidney, are before injury.”n
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Karen Lusky is a writer in Brentwood, Tenn.