Acute Kidney Injury: Increasingly Common, Often Insidious, Possibly Deadly. But Worth Testing For?

Testing for biomarkers of acute kidney injury might help with treatment and prognosis. But there’s a lot of uncertainty about how useful it would be right now.

Deborah Borfitz

Acute kidney injury (AKI), a serious, precipitous decline in kidney function, is an increasingly common reason for hospital visits in this country. More than three million people in the United States are affected each year.

Hospitalizations for AKI are increasing because the risk factors for it—diabetes, hypertension, advanced age—are also increasing.

AKI is also a common complication once people are hospitalized. Studies suggest that at some hospitals, as many as one in six inpatients are affected by it. People admitted for routine cardiac surgery are among the most vulnerable. Many have an underlying medical condition making them more prone to kidney injury, and preoperative use of intravenous contrast heightens the postoperative risk. The overall in-hospital AKI mortality rate is alarmingly high, about 10% depending on the definition of AKI, compared with an average of under 1.5% for all hospitalized patients, according to nephrologist F. Perry Wilson, MD, assistant professor of medicine at Yale University School of Medicine. Even after excluding patients with a bad infection or undergoing major surgery, the presence of AKI has been linked to a threefold greater risk of in-hospital death.

AKI at a glance
Frequency of hospital-acquired AKI*
Overall inpatient population ≤7% to 14% (13% being early-stage AKI)
Patients undergoing hip fracture surgery 21.1%
Patients undergoing any type of noncardiovascular surgery 7.1% to 39%
Patients undergoing cardiac catheterization or PCI (contrast-induced AKI) 3% to 14%
Patients with AMI 10% to 20%
*Rates vary by hospital, partly because of case mix
AKI=acute kidney injury, AMI=acute myocardial infarction, PCI= percutaneous coronary intervention
Source: Managed Care search of peer-reviewed literature

AKI may lead to chronic kidney disease and, in the worst cases, end-stage renal disease. Research has additionally found that AKI patients are at greater risk of stroke and heart disease, as well as longer hospital stays. It also adds expense. A 2005 study—published before the adoption of consensus definitions of AKI—found that excess hospital costs per episode of AKI came to nearly $7,500. By some estimates, hospital-acquired AKI adds more than $10 billion of health care expenditures annually.

One test in the U.S.

Part of what makes AKI such a problem is that it’s insidious, occurring without notable signs and symptoms for quite some time. If there were blood or urine tests for biomarkers of AKI, they could serve as an early warning system. Physicians might then take steps to reverse or limit harm from the kidney damage—and reduce health care costs in the process.

But so far, only one test for AKI biomarkers, called NephroCheck, has been approved for use in the United States among a broad field of contenders. A panel of two separate urine proteins—tissue inhibitor of metalloproteinase 2 and insulin-like growth factor binding protein 7—NephroCheck is intended to help evaluate the risk of moderate to severe AKI among adult patients in the intensive care unit whose cardiovascular or respiratory system has been compromised. Tests for other AKI biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL), have been approved for commercial use elsewhere in the world but not in the United States.

Currently, the standard way of diagnosing AKI involves measuring urine output and the level of serum creatinine circulating in the blood. NephroCheck’s proponents believe it can provide early knowledge of AKI risk in critically ill patients as much as 36 hours earlier than the standard test and may prompt closer patient monitoring and help prevent permanent kidney damage or death. Many of its early adopters believe it could drastically improve ICU care.

So far, though, the strongest evidence that testing for AKI biomarkers would improve outcomes is limited to when it is used among patients in more advanced stages of illness. Just how much of a difference early detection of AKI would make in many patients is unclear. Stage 1 care guidelines issued by Kidney Disease: Improving Global Outcomes (KDIGO)—a not-for-profit organization championing evidence-based clinical practice guidelines for kidney disease—include basics such as monitoring hemodynamics and avoiding hyperglycemia and nephro­toxins, which physicians ought to be checking regardless of AKI risk.

NephroCheck, after four years on the market, is being used in fewer than 100 hospitals in the United States.“Other than for research, the bio­markers are not yet readily available at most health care facilities,” says Wilson, the Yale nephrologist. “You might be able to get one or two of them measured if you jump through some hoops, but in terms of routine everyday clinical care, serum creatinine is very much still defining AKI.”

Identifying triggers

Tests for AKI biomarkers would be used more widely if their role were better defined, say their proponents. Researchers are tackling the possibilities from many angles. In addition to detecting kidney injury sooner, AKI biomarkers might be used to assess the riskiness of common kidney stressors or to predict how patients will fare over the long term: “Will their AKI turn right around and in a day or two they’ll be right as rain,” says Wilson, “or are they going to end up needing dialysis or having kidney disease later in life?”

F. Perry Wilson, MD

Payers should encourage the use of AKI tests, particularly in integrated health care systems, says F. Perry Wilson, MD, of Yale University School of Medicine.

An additional hope, he continues, is that biomarkers will help identify the triggering event—infection, a drug side effect, contrast agent—of kidney injury. It might turn out that certain biomarkers are well suited for subsets of AKI patients, such as those with acute interstitial nephritis. At institutions where NephroCheck is available, it is being used almost entirely in a research context, “not to [further] evaluate the performance of NephroCheck itself but as a screening tool for other studies where investigators want to identify patients who are at high risk for AKI,” says Wilson.

John C. Lieske, MD

“We don’t have a clear idea about how we would implement” the use of AKI biomarkers, says John C. Lieske, MD, of the Mayo Clinic College of Medicine.

So far, the evidence linking use of AKI biomarkers to improve patient outcomes is limited, according to John C. Lieske, MD, professor of medicine at the Mayo Clinic College of Medicine. “A couple of papers have been published very recently, suggesting they may have a niche for directing the postoperative management strategy of patients undergoing major operative procedures,” he says. Lieske said findings published in the November 2017 issue of Intensive Care Medicine showed improved hemodynamic parameters and reduced rates of moderate to severe AKI among high-risk cardiac patients whose AKI was monitored with the two urinary biomarkers that NephroCheck tests for. A second study, published June 2018 in the Annals of Surgery, showed good results for patients undergoing major abdominal surgery.

How useful?

The price of NephroCheck—a five-component system that includes a small, sample-holding cartridge that inserts into a reading device—is close to $100 per test, says Lieske, compared with $20 for the NGAL test not approved in the United States. Both are a great deal more expensive than the blood tests for creatinine, which cost about a dime per test, and cystatin C, a biomarker of kidney function rather than injury, which costs a few dollars each. If AKI were to enter the mainstream, the expense would be higher than the price of a single test because multiple tests would probably be ordered for many patients, particularly those undergoing very high-risk procedures or with sepsis.

Aside from the expense, how valuable AKI findings would really be in clinical practice is an open question. Wilson says that “we might avoid ordering medications that are particularly toxic to the kidney, try to keep patients’ blood pressure at a healthy level, and maybe give them a little fluid if they seem volume-depleted.” But, he adds, “we don’t have a slew of evidence-based interventions to plug them [AKI biomarker test results] into that we know improve outcomes.”

Lieske agrees that one of the main hurdles to wider use of AKI biomarkers is the uncertainty about what to do with the information. “These cases are all managed in certain ways, and I’m not sure a strong case has been made that the result of one of these tests is that we’ll do something differently. We don’t have a clear idea about how we would implement this clinically, and there hasn’t been an outcry from our clinical people saying they want this.”

It has been suggested that AKI biomarkers would be useful in helping physicians better manage at-risk populations by prompting them to more often follow existing KDIGO care guidelines, but Wilson doesn’t believe that justifies their broader adoption. “Yes, the biomarkers could possibly scare providers into doing the right thing,” he says. “But couldn’t we just better educate them about AKI? Gentle cues and prompts could be built into the electronic health record reminding doctors to limit patient exposure to certain kidney-toxic medications, or sending them a little note that says, ‘Did you notice Mr. Smith is getting Toradol and his kidney function isn’t that great?’”

Involving nephrologists earlier, based on biomarker measurements, would be costly as well as impractical because they’d be doing consults on some patients who weren’t going to develop AKI in the first place, says Wilson. And most patients who develop AKI after cardiac surgery spontaneously improve within 48–72 hours.

Coverage on a trial basis

Biomarker usage would spike if their utilization could be tied to an intervention that improves clinical outcomes. Lower mortality is the gold standard, says Lieske, but shorter hospital lengths of stay and preventing the need for dialysis in later stages of AKI are other important yardsticks.

Several trials of AKI biomarkers, including NephroCheck, are underway. Some are designed to see if the biomarkers would be useful for screening patients for AKI, Wilson says, while others are designed to take a baseline measurement so the outcomes of therapeutic interventions can be compared in people with differing biomarker levels.

Wilson is currently building a statistical model for medical record systems that would identify patients at risk for AKI in real time so that pricier AKI biomarker tests could be used in a more targeted fashion. “Instead of everyone coming into the ICU or the ER getting NephroCheck, we might be able to say that today it would be clinically useful for these 10 patients to get the test,” he says.

Despite all the unsettled questions, Wilson would like to see payers encourage the use of AKI tests, potentially on a trial basis and particularly in integrated health care systems where downstream effects could be monitored.

“There is a limit to what we can learn in very carefully controlled research studies,” Wilson says. “I don’t know whether the use of any particular biomarker test would drop the rate of an AKI diagnosis, but perhaps we’ll see less readmissions. What I can’t say is which biomarker test would provide the most bang for the buck.”

Deborah Borfitz is an independent health care consultant and journalist in Nashville.

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