New tests and alert systems spot kidney disease before irreversible damage
This article is part of “Innovations in: Kidney disease”, an editorially independent special report that was produced with the financial support of Summit.
DEnnis Moledina encountered a common problem during his training in nephrology, the specialty dedicated to kidney health. Many of the patients he saw suffered from acute kidney injury caused not directly by disease but by prescribed medication. Each encounter prompted a series of questions for Moledina: Should they stop the problematic medication? Was there a medication they could add to the regimen to protect the patient’s kidneys? Should the organs be biopsyed to determine the cause?
Acute kidney failure (AKI) is a sudden change in the kidneys’ ability to filter waste from the blood, and it affects about one in 10 hospitalized patients, a figure that rises to more than five in 10 for those in intensive care. But this condition often causes no pain or discomfort, and clinicians have few warning signs.
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Medications, including common antibiotics and painkillers, can treat conditions like infections but damage the kidneys and make the overall problem worse. Some of these diseases also impair kidney function. When blood levels of creatinine – a protein that the kidneys typically eliminate – are high enough to attract a clinician’s attention, it is often too late. Irreversible kidney damage has already begun. Due to the multitude of possible causes, identifying the true reason for drug-induced AKI in hospitalized individuals can be incredibly complex, and this condition is still underappreciated.
Historically, researchers and clinicians believed that the kidneys healed when a person stopped taking medications and recovered from hospitalization. They monitored patients during treatment, such as while they took a limited course of antibiotics, but did not believe that short-term changes in creatinine led to lasting damage, says nephrologist Matthew James of the University of Calgary. There hasn’t been a lot of research on AKI, James says. “We haven’t really thought about the long-term health consequences. »
But the long-term consequences prove to be a real risk, and today AKI and chronic kidney disease are considered linked. For more than a decade, various studies have shown that people with AKI in hospital are significantly more likely to suffer from chronic kidney disease and end-stage kidney disease later in life.
Now that specialists know the importance of early detection, they are looking for ways to reduce the extent of lasting damage. When an acute injury is diagnosed quickly, clinicians can remove offending medications or add protective ones. Researchers therefore strive to highlight the people most at risk. Some use electronic health data to report problem medications to a patient’s care team. Others, including Moledina, are focusing on more precise biomarkers that can be tracked in urine tests. Nephrologist Jennifer Schaub of the University of Michigan says there are many reasons a person may develop AKI, but medications are one reason clinicians can do something about. “This is an area where there is potential for immediate clinical impact,” she says. “It’s an underestimated problem, and it’s also something we can [change] in our clinical management very quickly.
The first challenge is identifying when harm occurs. White blood cells in the urine, high creatinine levels, and low urine volume are often the only clues that alert clinicians to the problem. But each of these is a nonspecific marker, Schaub explains, and all can occur in critically ill patients.
Currently, the only way to confirm most causes of acute kidney injury is with a biopsy, which can reveal tissue inflammation, cell damage, or the presence of inflammatory cells. But biopsies are risky in patients who are already very sick, because the procedures can cause bleeding, infections and other problems.
In children, detecting AKI early is even more difficult. Hospitalized children tend to have fewer daily blood tests than adults, says nephrologist Perry Wilson of Yale University. To try to solve this problem, 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 was undergoing treatments that could damage the kidneys. The system, called AKI NINJA (Nephrotoxic Injury Negated by Just-in-time Action), alerted a pharmacist when a child took a single kidney-damaging medication for three days or three nephrotoxic medications at the same time. Children put on these diets were closely monitored. If clinicians noticed a concerning increase in creatinine levels, they could assess whether the risk to the kidneys outweighed the benefits of prescribed medications.
The NINJA team found that the system allowed healthcare providers to make better decisions about continuing or changing prescriptions, reducing the number of acute kidney injury days by 42%.
In a December 2024 analysis, Benjamin Griffin, a nephrologist at the University of Iowa, and colleagues used hospital data and computer 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 accurate enough. Because hospitalized adults often take more medications for pre-existing conditions than children, the system generated a large number of alerts. Instead of the dozen that clinicians received each month at the pediatric hospital, the system sent hospital staff 30 alerts daily, many of which were not of much concern.
To try to recalibrate the system’s sensitivity, Griffin’s team tested machine learning models incorporating 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. Currently, the model can correctly assess this risk 60% of the time, Griffin says.
AHowever, electronic notification can only do so much. Once someone has been flagged, doctors must make complex decisions about caring for critically 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 damaged. “We now need more than just electronic data. »
Medications can damage the kidneys in a variety of ways, says Wilson. Research and clinical studies have revealed some of the many distinct mechanisms by which medications affect kidney function. This understanding is an essential first step in mitigating drug-induced harm.
Some, like NSAIDs, damage the kidney glomeruli, which perform the first step of filtration and prevent blood cells and large proteins from entering the urine. If we think of the glomerulus as a sieve, Wilson says, these drugs “make the holes in the sieve bigger” in some people. Other drugs act like a poison, killing cells in the kidney tubules, which help filter waste and reabsorb nutrients. Still others trigger an immune response similar to an allergic reaction.
If clinicians know which of these mechanisms is responsible for kidney damage in a person, they can determine the best way to combat it, Moledina says. Creatinine spikes, for example, could have many explanations: acute interstitial nephritis, the spread of tumors, or the side effects of an entirely different medication. Once a spike is detected, clinicians are faced with a diagnostic maze. They could change treatments or add steroids that can reduce problematic inflammation in the kidneys, or simply continue and hope that the increase in creatinine is not related to the medication. Each of these choices confers 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 used data from the Kidney Precision Medicine Project to create a confirmatory clinical test. He identified two key proteins, called TNF-alpha and CXCL9, that appear closely linked to the type of acute kidney injury triggered by immune reactions. He and his colleagues began working on commercializing tests for these biomarkers.
Although biomarkers do not alleviate drug-induced kidney injury, they can facilitate early detection, which is essential for reducing the risk of long-term damage, says Schaub. The longer an acute kidney injury goes unnoticed, the greater the risk of scarring and fibrous tissue blocking kidney function. “The later the diagnosis or the longer the implementation of 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 KIM-1 protein, which can indicate acute kidney injury and tubular damage, and NGAL, a protein biomarker that can help clinicians identify people at risk for AKI as early as 48 to 72 hours after their time in intensive care. Such efforts will not only help identify the cause of the problem, but will also lead to more precise solutions, Wilson says.
Schaub sees a growing need for these biomarker-based tests as new drugs become available for cancer, heart disease and other conditions. “There are new ways to treat people, which is a good thing,” she says. “But the kidneys are sometimes innocent bystanders in all of these therapies that are being developed. »
In the long term, more precise, non-invasive biomarkers could be used to develop better kidney-protective drugs and medications, as well as to determine whether new drugs for other conditions pose a kidney risk. Ultimately, these advances will transform AKI from a condition that is difficult to detect and diagnose into one that can be stopped in its tracks. New biomarkers could turn into powerful tools for doctors to help patients, Moledina says. “Nephrotoxic injury is something you can do something about,” he adds. “It’s achievable.”
