The study, led by Mayo Clinic nephrologist Fouad Chebib, M.D., was published in the Journal of Clinical Investigation.

Scientists have long believed that the body's ability to concentrate urine and avoid dehydration depends mainly on the hormone vasopressin. The new research reveals that the kidneys also have another pathway for regulating water that works independently of vasopressin.

"The kidney's ability to regulate water is one of the most fundamental processes in the body," Dr. Chebib says. "It's not every day that you uncover a new way it carries out that function."

Hidden Kidney Pathway Discovered

The finding expands researchers' understanding of how the kidneys function. By identifying an additional mechanism involved in water conservation, the study adds a new layer to decades of knowledge about kidney physiology.

The discovery may be especially important for people with polycystic kidney disease, a genetic disorder that causes fluid-filled cysts to develop in the kidneys. Over time, these cysts can impair kidney function and eventually lead to kidney failure.

PKD affects millions of people around the world. In the United States, about 140,000 people have the most common form of the disease, autosomal dominant PKD (ADPKD). Many patients ultimately need 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. During one set of experiments, researchers tested compounds that they expected would worsen the disease by increasing cellular activity linked to cyst growth.

One of those compounds was probenecid, a medication originally introduced in the 1940s to help conserve scarce supplies of penicillin by reducing how much of the antibiotic was excreted in urine.

"We thought this drug would make the disease process worse," Dr. Chebib says. "Instead, it did the opposite."

Rather than accelerating cyst growth, probenecid slowed it down. After repeating the experiments several times and obtaining the same result, the researchers realized they had uncovered something unexpected.

How Urate Helps the Kidney Conserve Water

The team then investigated why the drug was having this effect. Their research showed that probenecid alters how kidney cells handle urate, a molecule most commonly associated with gout.

Inside kidney cells, urate acts as a signaling molecule. It sets off a series of cellular events that move water channels to the cell surface, allowing the kidneys to reabsorb water and concentrate urine. This process can occur without relying on vasopressin, which has traditionally been viewed as the primary regulator of urine concentration.

"This represents a distinct pathway from what is described in traditional physiology models," Dr. Chebib says. "It demonstrates that the kidney has an additional mechanism to preserve water."

Potential Benefits for PKD Treatment

The discovery could help address one of the major drawbacks of current PKD treatment.

The only approved medication for slowing PKD progression is tolvaptan. The drug works by blocking vasopressin, which helps reduce cyst growth. However, it also causes patients to produce very large amounts of urine, often 6 to 7 liters per day. For many people, that side effect can be difficult to manage and may lead them to discontinue treatment.

In preclinical studies and a small clinical trial, researchers found that adding probenecid reduced both urine volume and nighttime urination while maintaining the effectiveness of treatment.

On average, patients experienced about a 30% reduction in urine volume after taking probenecid. Many went from waking up multiple times each night to urinate to waking only about once per night. Participants also reported improvements in their quality of life.

"The goal is to preserve the therapeutic benefit of tolvaptan while reducing its burden," Dr. Chebib says.

Looking Beyond Probenecid

Although the results are encouraging, the researchers do not see probenecid itself as a long-term answer.

The medication is several decades old, affects multiple biological systems, and is not widely available today. Instead, the team hopes to use what they learned from the drug to create new therapies that specifically target the newly identified pathway.

"Probenecid helped us uncover the mechanism," Dr. Chebib says. "Our goal is to take this insight and develop therapies designed specifically for this pathway."

A Personal Motivation

For Dr. Chebib, the research is connected to a deeply personal experience. His interest in kidney disease began after his father was diagnosed with PKD.

"This has been a long and deeply purposeful journey," he says. "It started with a personal motivation and led to something that could ultimately benefit patients."