By Deborah Borfitz
May 2, 2018 | For patients presenting in the emergency room with chest pain, troponins are exquisitely sensitive markers of myocardial injury. Physicians can therefore quickly intervene—with aspirin, beta blockers or a procedure in the cath lab—to limit damage to the heart and preserve cardiac function. But should patients need heart surgery or percutaneous coronary intervention, the heart isn’t the only organ at risk. Such procedures can put the kidneys at particular risk as well. Unfortunately, identifying and intervening in acute kidney injury isn’t quite as easy.
Serum creatinine (SCr) levels are the standard measure for damage to the kidneys, but the diagnostic limitations of serum creatinine in detecting acute changes in kidney function have been widely acknowledged for over a decade. SCr values neither accurately reflect fluid flow rate through the kidneys nor extent of injury—and may entirely miss “subclinical” acute kidney injury (AKI), making it a poor proxy of renal health in the early post-surgical period, says Subhasis Chatterjee, director of the Thoracic Surgical ICU & ECMO Program, Texas Heart Institute at CHI Baylor St. Luke’s Medical Center in Houston. Physicians use the tests to learn if the kidneys are malfunctioning, not to ascertain why.
Novel biomarkers are available to assess any harmful effects of the procedure on the kidneys—hours or even days earlier than revealed by SCr—but the new canaries in the coal mine for “kidney attacks” have their own issues, including uncertainty about how to act on the late-breaking information. Clinical studies demonstrating an impact on clinical outcomes have been focused on more advanced acute kidney injury (AKI) rather than stopping it in its tracks at—if not before—stage 1 (increase in SCr 1.5 – 1.9 times baseline), notes Chatterjee.
Elevated SCr is also not the only indicator of disease escalation. Other factors negatively impacting outcomes include marginal urine output and fluid buildup, Chatterjee says. Irrespective of the barometer used to measure kidney health, the science is mixed on the best approach to treating early-stage AKI. So an earlier diagnosis doesn’t necessarily translate into better protection and less organ damage.
The latest evidence-based treatment recommendations for stage 1 AKI, as published by the Kidney Disease: Improving Global Outcomes (KDIGO) organization in 2012, include monitoring hemodynamics such as blood pressure and cardiac output, and avoiding hyperglycemia and nephrotoxins. But these are clinical care basics that physicians are likely doing with or without concern for AKI, says Chatterjee.
In the absence of randomized clinical trials showing biomarkers of AKI make a difference in the incidence of abruptly decreasing kidney function, the need for dialysis or patient survival, “cautious reservation” regarding their clinical use remains the prevailing medical sentiment, Chatterjee says. “If earlier detection of AKI is not accompanied by improved clinical outcomes, all [the biomarkers] add is a lead time bias—the chief criticism of mammography screening.”
Barriers to adoption
Numerous AKI biomarkers are under investigation, and two—insulin-like growth factor binding protein 7 (IGFBP-7) and tissue inhibitor of metalloproteinase 2 (TIMP-2)—have already been approved by the U.S. Food & Drug Administration and the European Medicines Agency for those at risk for severe AKI. Similar AKI biomarker tests, including one measuring neutrophil gelatinase-associated lipocalin (NGAL), are available elsewhere is the world.
But their use in clinical practice remains modest, says Jay Koyner, M.D., associate professor of medicine, medical director of the inpatient dialysis unit and director of ICU nephrology at the University of Chicago. Koyner is also a researcher and consultant for Astute Medical and estimates that use of its NephroCheck biomarker test (urinary TIMP-2 and IGFBP-7) has steadily risen to about 75 hospitals nationwide. Optimally using the test varies across care settings, he adds, depending partly on volume and types of surgery performed, and patient demographics and comorbidities. Biomarkers are typically measured once per patient vs. sequentially over defined time periods, although the value of recurrent testing remains under investigation.
UChicago Medicine is undertaking a quality initiative to determine how NephroCheck improves AKI care among the same population in which it was studied. “We’re measuring biomarkers in real time and will compare the outcomes of patients to those who had the tests measured in a research capacity,” says Koyner. The protocol allows for retesting after 24 hours in patients with very high values. Physicians have been in-serviced about interpreting test results and treatment steps they can consider taking— including adjustment of volume status, modifying medication doses or calling for a formal nephrology consult.
“AKI is a hospital-based problem predominantly, and traditionally nephrologists have not been called until kidney injury is very advanced,” says Koyner. But preventing adverse outcomes will require a paradigm shift in way kidney injury care is delivered—meaning kidney doctors get called before patients have large elevations in serum creatinine or drops in urine output, the traditional biomarkers of severe AKI.
AKI biomarkers can perhaps prompt providers to reconsider their approach, if not remind them of established care guidelines being overlooked and underused, Koyner speculates. “The test is not just an alarm signal, letting you know when patients are at risk for an adverse outcome. The negative value is also quite useful… and could help get patients out of the ICU earlier, mitigating other risks.”
The reality is that AKI is not always optimally managed, despite the best intentions of physicians, says Koyner. “Protocols oftentimes run in opposition with each other depending on who is writing them and which organ system they’re trying to preserve.” Patients at risk for AKI sometimes receive a nephrotoxin because it’s the first line agent, require radio-contrast despite the associated risk of AKI, or have their Foley catheter removed early over institutional concerns about urinary tract infections.
It takes a multidisciplinary team to effectively use the biomarkers, including physicians on the front line—emergency medicine physicians, surgeons or intensivists—to proactively send the tests to the lab, a supportive laboratory director whose budget will be impacted, and a nephrologist to help people act on the findings, says Koyner. Administrators must understand that preventing even one or two cases of severe AKI equates to “tens if not hundreds of thousands of dollars of saved care,” likely offsetting the cost of offering the test.
Some institutions, including the Mayo Clinic, have not started using the AKI biomarkers, as they cost significantly more than currently available biomarkers of kidney function, says Kianoush B. Kashani, M.D., MSc, FASN, FCCP, professor of medicine at the Mayo Clinic College of Medicine in Rochester, Minnesota.
Chatterjee says his clinical preference is to occasionally use the functional biomarker Cystatin C. Among patients whose urine output has marginally decreased, but whose SCr level hasn’t changed, it helps him identify suspected cases of AKI earlier. He also might use Cystatin C in patients having longer operations, or before ordering ketorolac (a nonsteroidal anti-inflammatory drug) for his more elderly patients. Potentially, biomarkers might prove useful in helping him more quickly adjust the dosing of certain types of antibiotic and contrast agents to avoid exasperating renal insult from the surgery itself, he adds. But he would only be guessing that it would make a difference—which is why, across Texas Heart Institute, kidney biomarkers of any kind are rarely used.
Anticipated quality gains
There has been no shortage of AKI research because so many populations are affected globally, and the incidence of AKI has been steadily rising. Multiple potential triggering stressors can suddenly injure normal kidneys, says Chatterjee, including low blood pressure in response to a heart attack or acute blood loss, sepsis infection or being connected to a heart-lung bypass machine. An estimated 10% of hospitalized patients are currently affected, and the condition is difficult to manage and associated with poor outcomes.
Kashani has studied the novel biomarkers in clinical research, including a 2013 multicenter study that identified IGFBP-7 and TIMP-2, which are easily measured in urine and detect moderate to severe AKI 12 to 36 hours earlier than the current functional tests. These “golden hour” gains allow clinicians to provide preventive interventions earlier, which have been shown to improve clinical outcomes (significant decline in incidence and severity of AKI) in at least two subsequent, randomized clinical trials when protocolized care was compared with standard care, he notes.
The first of these 2017 studies, published in Intensive Care Medicine, showed implementation of KDIGO guidelines significantly improved hemodynamic parameters and reduced rates of moderate to severe AKI among high-risk cardiac patients. The second study, published in the Annals of Surgery, showed that adhering to KDIGO care bundles reduced the incidence of AKI as well as AKI severity and the lengths of ICU and hospital stays following major abdominal surgery.
The big outstanding question remains: Can these damage biomarkers identify AKI at an earlier stage, so steps can be taken to improve the quality of care? Kashani plans to begin enrolling patients in a clinical study to evaluate the impact of biomarker-guided clinical intervention on outcomes of patients admitted to the ICU with critical illnesses. If it succeeds in showing a lower death rate or risk of AKI, usage of the biomarkers should see a sizeable upward trajectory as physicians begin using them not only in diagnostics but also as a guide for therapy.
Kashani is hopeful that more patient-specific preventive and therapeutic interventions will be made possible once a panel of “highly accurate and specific” kidney injury and functional biomarkers are available to clinicians—providing them with more detailed information about the intensity of harm, type of injury, and location of the damage.