This article is part of “Innovation: Kidney Disease,” an editorially independent special report produced with the financial support of pinnacle.
DAnise Moledina encountered a common problem during her training in nephrology, a specialty dedicated to kidney health. Many of the patients he saw had severe kidney injury that was caused not directly by the disease but by the prescribed medication. Each encounter gave rise to a series of questions for Moledina: Should she stop the problem medication? Were there any medications they could add to the patient’s diet to protect his kidneys? Should they biopsy 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 about one in 10 patients admitted to hospital – this number rises to more than five in 10 in intensive care. But the condition often causes no pain or discomfort, and physicians have few warning signs.
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Medications, including common antibiotics and painkillers, can treat illnesses such as infections but damage the kidneys and make the overall problem worse. Some of these diseases also impair kidney function. By the time the level of creatinine in the blood – a protein that the kidneys normally remove – is high enough to draw a doctor’s attention, it is often too late. Irreversible kidney damage has already begun. Due to the multitude of possible causes, identifying the true cause of drug-induced AKI in hospitalized people can be incredibly complex, and the condition is still under-recognized.
Historically, researchers and physicians have assumed that the kidneys recovered when a person stopped taking medications and recovered after hospitalization. Nephrologist Matthew James of the University of Calgary says they would monitor patients during treatment – for example, while they were taking a limited course of antibiotics – but he did not think that short-term changes in creatinine would cause permanent damage. There wasn’t a lot of research on AKI, James says. “We didn’t really think about the long-term health consequences.”
But long-term consequences become a real risk, and today AKI and chronic kidney disease are seen as linked. For more than a decade, various studies have shown that people who suffer from AKI in the hospital are significantly more likely to experience chronic kidney disease and end-stage kidney disease later in life.
Now that experts know the importance of early detection, they are looking for ways to reduce the amount of permanent damage. When serious injuries are diagnosed promptly, doctors can remove harmful medications or add protective medications. So researchers are working to uncover those most at risk. Some are using electronic health data to flag problematic medications to the patient’s care team. Others, including Moledina, are considering more accurate biomarkers that can be tracked in urine tests. Jennifer Schaub, a nephrologist at the University of Michigan, says there are a number of reasons why someone might develop AKI, but medications are one cause that doctors can do something about. “This is an area where there is potential for immediate therapeutic impact,” she says. “This is an under-recognized problem, and it’s also something that we can (change) very quickly in our clinical management.”
The first challenge is to detect when damage is occurring. White blood cells in the urine, high levels of creatinine, and low urine output are often the only signs that alert physicians to a problem. But each of these is a non-specific marker, Schaub says, and all of them may occur in patients who are critically ill.
Currently, the only way to confirm most causes of acute kidney injury is by biopsy, which can reveal tissue swelling, 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 problems.
In children, AKI is even more difficult to detect early. Yale University nephrologist Perry Wilson says hospitalized children have fewer daily blood tests than adults. To try to address this, about 15 years ago researchers and physicians led by a team at Cincinnati Children’s Hospital Medical Center designed a system to send alerts when a child is undergoing treatment that could cause kidney damage. The system, called AKI NINJA (Nephrotoxic Injury Negotiated by Just-in-Time Action), notified a pharmacist when a child was taking the same kidney-damaging drug for three days or three nephrotoxic drugs at the same time. The children were closely monitored on these diets. If physicians notice a worrying increase in creatinine levels, they can evaluate whether the risks to the kidneys outweigh the benefits of the prescribed medications.
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 acute kidney injury days by 42 percent.
In a December 2024 analysis, University of Iowa nephrologist Benjamin Griffin and colleagues used hospital data and computational models to test whether the NINJA system would be effective in adults. The problem they encountered was not that the system was not working, but that it was not specific enough. Because hospitalized adults are often taking more medications for pre-existing conditions than children, the system generated a larger number of alerts. Instead of the 10 or so that physicians at the pediatric hospital received each month, the system sent 30 alerts to hospital staff every day, many of which were no real cause for concern.
To try to recalibrate the system’s sensitivity, Griffin’s team tested a machine-learning model that incorporated patient medical history, vital signs and other clinical data to improve the model’s ability to predict drug-induced kidney injury in adults. Griffin says that currently, the model can correctly predict that risk 60 percent of the time.
AHowever, electronic notification can only do so much. Once someone is identified, doctors must make complex decisions about the care of critically ill patients. “It’s not always as simple as stopping a drug that is harmful to the kidneys,” says Wilson. In addition to blood and urine tests, doctors need better tools to understand how the kidneys are being damaged. “Now we need more than just electronic data.”
Wilson says medications can harm the kidneys in many ways. Research and clinical studies have revealed several different mechanisms through which medications affect kidney function. This understanding is an important first step in reducing the harm caused by drugs.
Some, such as NSAIDs, damage the kidney glomeruli, which perform the first step of filtration and keep blood cells and large proteins out of the urine. If we imagine the glomerulus as a colander, these drugs “make the holes in the colander bigger” in some people, Wilson says. Other drugs act like poison, killing the kidney tubule cells, which help filter wastes and reabsorb nutrients. Still others produce an immune response similar to an allergic reaction.
If physicians know which of these mechanisms is responsible for someone’s kidney injury, they can figure out how to combat it, Moledina says. For example, creatinine spikes can have several explanations: acute interstitial nephritis, spreading tumors, or side effects of a different medication altogether. Once a spike is detected, physicians face a diagnostic maze. They may change treatment, or add steroids that can reduce problematic kidney inflammation, or simply continue and hope that the creatinine increase is unrelated to the medication. Each of these options offers both risks and benefits. “This has real-world implications, and you don’t want to waste time,” says Moledina.
To move beyond generic alerts, Moledina is using data from the Kidney Precision Medicine Project to create a confirmatory clinical trial. They have identified two key proteins, called TNF-alpha and CXCL9, that appear to be closely linked to the type of acute kidney injury caused by immune responses. He and his colleagues have begun work to commercialize tests for these biomarkers.
Although biomarkers don’t necessarily reduce drug-induced kidney injury, they can aid in early detection, which is important for reducing the chance of long-term damage, Schaub says. The longer an acute kidney injury goes undetected, the greater the chance that scarring and fibrous tissue will block kidney function. “The longer there is a delay in diagnosis or the longer it takes to implement treatment, the worse the outcomes for the patient,” she says.
Non-invasive 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 may help physicians identify people at risk for AKI as early as 48 to 72 hours before their time in the ICU. Wilson says such efforts will not only help find the cause of the problem but also provide more accurate solutions.
Schaub sees a growing need for these biomarker-based tests as new drugs for cancer, heart disease and other conditions become available. “There are new things to treat people, which is good,” she says, “but with all these treatments being developed the kidneys sometimes become an innocent bystander.”
In the long run, more accurate, non-invasive biomarkers could be used to develop better drugs and kidney-protective drugs, as well as to determine whether new drugs for other conditions pose a risk to the kidneys. Ultimately these advances will transform AKI from a condition that is difficult to detect and diagnose to one that can be stopped in its tracks. Moledina says the new biomarkers could turn into powerful tools for physicians to help patients. He added, “Nephrotoxic injury is something you can do something about.” “It’s actionable.”
