Mayo Clinic researchers have discovered a previously unknown mechanism by which the kidneys help maintain water balance in the body. This discovery could ultimately lead to better treatments for polycystic kidney disease (PKD) and other conditions.
The study, led by Mayo Clinic nephrologist Dr. Fuad Chebib, clinical research journal.
Scientists have long believed that the body’s ability to concentrate urine and avoid dehydration depends primarily on the hormone vasopressin. New research reveals that the kidneys also have another pathway to regulate water that functions independently of vasopressin.
“The kidney’s ability to regulate water is one of the most fundamental processes in the body,” says Dr. Chebib. “It’s not every day that you discover a new way to perform that function.”
Hidden kidney pathway discovered
This discovery has improved researchers’ understanding of how the kidneys work. This study adds a new layer to decades of knowledge about renal physiology by identifying additional mechanisms involved in water conservation.
The discovery could be particularly important for patients with polycystic kidney disease, a genetic disorder in which fluid-filled cysts develop within the kidneys. Over time, these cysts can impair kidney function and eventually lead to kidney failure.
PKD affects millions of people worldwide. Approximately 140,000 people in the United States have autosomal dominant PKD (ADPKD), the most common form of the disease. Many patients eventually require dialysis or a kidney transplant.
Unexpected results from a decades-old drug
Dr. Chebib’s team uses laboratory-grown cell models to study how kidney cysts develop and grow in PKD. In one series of experiments, researchers tested compounds that were expected to exacerbate the disease by increasing cellular activity associated with cyst growth.
One of those compounds was probenecid. This is a drug first introduced in the 1940s to conserve scarce supplies of penicillin by reducing the amount of antibiotic excreted in the urine.
“We thought this drug would worsen the progression of the disease,” Dr. Chebib says. “In fact, it did the opposite.”
Probenecid slowed cyst growth rather than accelerating it. After repeating the experiment several times and getting the same results, the researchers realized they had discovered something unexpected.
How urates help the kidneys conserve water
The team then investigated why the drug had this effect. Their study showed that probenecid changes the way kidney cells process uric acid, the molecule most commonly associated with gout.
Inside kidney cells, urate acts as a signaling molecule. This triggers a series of cellular events that move water channels to the cell surface, allowing the kidneys to reabsorb water and concentrate urine. This process occurs independently of vasopressin, which has traditionally been considered the main regulator of urine concentration.
“This represents a different pathway than what is described in traditional physiological models,” Chebib says. “This shows that the kidneys have additional mechanisms to conserve water.”
Potential benefits of PKD treatment
This discovery could help address one of the major shortcomings of current PKD treatments.
The only approved drug that slows the progression of PKD is tolvaptan. This drug works by blocking vasopressin, which inhibits cyst growth. However, this causes patients to produce very large amounts of urine, often reaching 6 to 7 liters per day. For many people, the side effects are difficult to manage and may lead to discontinuation of treatment.
In preclinical studies and small clinical trials, researchers found that adding probenecid reduced both urine output and nocturnal urination while maintaining treatment efficacy.
On average, patients experienced an approximately 30% decrease in urine output after taking probenecid. Many people go from waking up multiple times each night to urinate to only waking up about once a night. Participants also reported improved quality of life.
“The goal is to maintain the therapeutic efficacy of tolvaptan while reducing its burden,” Dr. Chebib says.
Looking beyond probenecid
Although the results are promising, researchers do not believe probenecid itself is a long-term solution.
This drug has been around for decades, affects multiple biological systems, and is no longer widely available. Instead, the research team hopes to use what they learn from this drug to develop new treatments that specifically target the newly identified pathway.
“Probenecid helped us figure out the mechanism,” Dr. Chebib says. “Our goal is to take this insight and develop treatments designed specifically for this pathway.”
personal motivation
For Dr. Chebib, this research is tied to a very personal experience. His interest in kidney disease began after his father was diagnosed with PKD.
“This has been a long and deep purposeful journey,” he says. “It started with a personal motivation and ultimately led to something that could benefit patients.”
