This article is part of “Innovations In: Kidney Disease,” an editorially independent special report that was produced with financial support from Vertex.
Dennis Moledina encountered a common problem during his training in nephrology, the specialty dedicated to kidney health. Many of the patients he saw had acute kidney injury that had been caused not directly by a disease but by a prescribed medication. Each encounter sparked a series of questions for Moledina: Should they stop the problem medicine? Was there a drug they could add to the regimen to protect the patient’s kidneys? Should they biopsy the organs to determine the cause?
Acute kidney injury (AKI) is a sudden change in the kidneys’ ability to filter waste products from the blood, and it affects approximately one in 10 hospitalized patients—a number that jumps to more than five in 10 for those in intensive care. But the condition often causes no pain or discomfort, and clinicians have few warning signs.
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Drugs, including common antibiotics and painkillers, may treat ailments such as infections but harm the kidneys and worsen the overall problem. Some of these illnesses impair renal function as well. By the time blood levels of creatinine—a protein the kidneys typically remove—are high enough to grab a clinician’s attention, it’s often too late. Irreversible kidney damage has already begun. Because of the multitude of possible causes, identifying the real reason for drug-induced AKI in hospitalized people can be incredibly complex, and the condition is still underrecognized.
Historically, researchers and clinicians assumed that the kidneys healed when someone stopped taking medications and recovered from hospitalization. They would monitor patients during treatment—for instance, while they were taking a limited course of antibiotics—but didn’t think short-term changes in creatinine resulted in lasting damage, says nephrologist Matthew James of the University of Calgary. There wasn’t a lot of research into AKI, James says. “We didn’t really think about the long-term health outcomes.”
But long-term consequences turn out to be a real risk, and today AKI and chronic kidney disease are viewed as interconnected. For more than a decade, a variety of studies have shown that people who suffer AKI in the hospital are considerably more likely to experience chronic kidney disease and end-stage renal disease later in life.
Now that specialists know the importance of early detection, they are looking for ways to reduce the amount of lasting damage. When acute injury is diagnosed quickly, clinicians can remove offending drugs or add protective ones. So researchers are working to highlight people most at risk. Some are using electronic health data to flag problem medications for a patient’s care team. Others, including Moledina, are homing in on more precise biomarkers that can be tracked in urine tests. Nephrologist Jennifer Schaub of the University of Michigan says there are many reasons someone might develop AKI, but medications are one that clinicians can do something about. “It’s an area where there’s potential for immediate clinical impact,” she says. “It’s an underrecognized problem, and it’s also something that we can [change] in our clinical management very quickly.”
The first challenge is to pinpoint when harm is occurring. White blood cells in urine, high levels of creatinine and low urine volume are often the only clues that alert clinicians to the problem. But each of these is a nonspecific marker, Schaub says, and all of them can occur in patients who are seriously ill.
At present, the only way to confirm most causes of acute kidney injury is via biopsy, which can reveal tissue inflammation, cellular damage or the presence of inflammatory cells. But biopsies are risky in patients who are already very sick because the procedures can cause bleeding, infection, and other issues.
In children, spotting AKI early is even harder. Kids who are hospitalized tend to have fewer daily blood tests than adults, says nephrologist Perry Wilson of Yale University. To try to address this, about 15 years ago researchers and clinicians led by a team at Cincinnati Children’s Hospital Medical Center designed a system to send an alert when a child is undergoing treatments that could harm kidneys. The system, named AKI NINJA (Nephrotoxic Injury Negated by Just-in-time Action), notified a pharmacist when a child was on a single kidney-harming drug for three days or three nephrotoxic drugs at the same time. Children on these regimens were monitored closely. If clinicians noticed a disturbing increase in levels of creatinine, they could evaluate whether risk to the kidneys outweighed benefits of the medications prescribed.
The NINJA team found that the system allowed care providers to make better decisions about whether to continue or change prescriptions, ultimately reducing the number of days of acute kidney injury by 42 percent.
In a December 2024 analysis, University of Iowa nephrologist Benjamin Griffin and his colleagues used hospital data and computational models to test whether the NINJA system would be effective in adults. The problem he encountered was not that the system didn’t work but that it wasn’t specific enough. Because hospitalized adults are often on more medications for preexisting conditions than are children, the system produced a huge number of alerts. Instead of the 10 or so that clinicians received each month in the pediatric hospital, the system sent hospital staff 30 alerts every day, many of which were not a real cause for concern.
To try to recalibrate the system’s sensitivity, Griffin’s team tested machine-learning models that incorporate a patient’s medical history, vital signs, and other clinical data to improve the model’s ability to predict drug-induced kidney injury in adults. At present, the model can correctly gauge that risk 60 percent of the time, Griffin says.
An electronic notification can do only so much, however. Once someone has been flagged, doctors must make complex decisions about the care of seriously ill patients. “It’s not always as simple as stopping a medication that might be bad for the kidneys,” Wilson says. In addition to blood and urine tests, doctors need better tools to understand how kidneys are being damaged. “We need more than just the electronic data now.”
Drugs can damage the kidneys in a variety of ways, Wilson says. Research and clinical studies have revealed some of the many distinct mechanisms through which medications affect kidney function. That understanding is a critical first step to mitigating drug-induced harm.
Some, such as NSAIDs, damage the kidney’s glomeruli, which perform the first step of filtration and keep blood cells and large proteins out of urine. If we imagine the glomerulus as a colander, Wilson says, these drugs “cause the holes in the colander to get bigger” in some people. Other medications act like poison, killing kidney tubule cells, which help to filter wastes and reabsorb nutrients. Still others trigger an immune response akin to an allergic reaction.
If clinicians know which of these mechanisms is responsible for someone’s kidney injury, they can figure out how best to combat it, Moledina says. Creatinine spikes, for example, could have any number of explanations: acute interstitial nephritis, spreading tumors, or the side effects of a different drug entirely. Once a spike is detected, clinicians face a diagnostic maze. They could switch treatments, or add in steroids that can reduce the problematic kidney inflammation, or simply continue and hope the creatinine rise is unrelated to the medication. Each of these choices confers both risks and benefits. “There’s real-world implications, and you don’t want to waste time,” Moledina says.
To move beyond generic alerts, Moledina has been using data from the Kidney Precision Medicine Project to create a confirmatory clinical test. He has identified two key proteins, named TNF-alpha and CXCL9, which appear closely linked to the type of acute kidney injury triggered by immune reactions. He and his colleagues have begun working to commercialize tests for these biomarkers.
Although biomarkers do not mitigate drug-induced kidney injury, they can aid in early detection, which is critical to reduce the chances of long-term damage, Schaub says. The longer acute kidney injury goes undetected, the greater the chances of scarring and fibrous tissue blocking kidney function. “The more delayed the diagnosis or the longer it takes to implement treatment, the worse the outcomes for the patient,” she says.
Noninvasive urine and blood tests can also be used to detect other promising biomarkers, such as the protein KIM-1, which can indicate acute kidney injury and tubular damage, and NGAL, a protein biomarker that can help clinicians identify those at risk of AKI as early as 48 to 72 hours into their time in an ICU. Such efforts will not only help to pinpoint the cause of the problem but also lead to more precise solutions, Wilson says.
Schaub sees an increasing need for these biomarker-based tests as new medicines become available for cancer, heart disease, and other conditions. “There are new things to treat people with, which is good,” she says, “But the kidneys are sometimes an innocent bystander with all of these therapies that are being developed.”
In the long run, more precise, noninvasive biomarkers could be used to develop better drugs and kidney-protective medications, as well as to determine whether new drugs for other conditions pose a renal risk. Ultimately these advances will change AKI from a condition that is difficult to detect and diagnose into one that can be stopped in its tracks. New biomarkers could translate into powerful tools for physicians to help patients, Moledina says. “Nephrotoxic injury is something you can do something about,” he adds. “It’s actionable.”