Mayo Clinic researchers uncover backup kidney pathway for conserving water

Mayo Clinic researchers have identified a previously unrecognized way the kidneys conserve water, a finding that could matter well beyond kidney anatomy if it eventually helps explain dehydration, kidney disease and fluid management in critical care. The pathway works without vasopressin, the hormone long thought to be the main controller of water balance, and appears to help the body hold on to water by changing reabsorption and urine volume.

The discovery came from an unexpected place: probenecid, a decades-old drug first developed in the 1940s. While studying its effects on autosomal dominant polycystic kidney disease, or ADPKD, the team saw the drug slow cyst growth rather than trigger the feared outcome. That result pushed Fouad Chebib, M.D., a Mayo Clinic nephrologist in Jacksonville, Florida, and colleagues to look for a different explanation. The findings were published in the Journal of Clinical Investigation on June 16, 2026.

What they found was a vasopressin-independent urate signaling pathway, described in the paper as a urate-AMPK-AQP2 mechanism. That matters because it suggests the kidney has more than one route for conserving water under stress. In practical terms, the new pathway may help explain why some treatments alter urine output and nighttime urination, while also hinting at a way to separate beneficial effects on cyst growth from the water-losing side effects that can limit current ADPKD drugs.

The clinical stakes are clearest in ADPKD, a genetic disorder marked by fluid-filled cysts that enlarge the kidneys and can lead to kidney failure. PKD affects about 500,000 people in the United States, and ADPKD affects roughly 1 in every 400 to 1,000 people. It is the fourth leading cause of kidney failure, and more than half of people with ADPKD develop kidney failure by about age 60, according to the PKD Foundation. If the new pathway can be safely targeted, it could open the door to treatments that slow disease progression or ease symptoms without worsening urinary side effects.

The paper also reported that in a Phase 2 trial with tolvaptan-treated ADPKD patients, probenecid reduced urine volume and nocturia frequency. That gives the finding an immediate clinical edge, even though the work remains early-stage and is not yet a treatment. Mayo Clinic says its nephrology research spans all three campuses, and Chebib’s team now faces the more difficult task of proving whether this backup water-saving system can be translated into care that helps patients without creating new risks.