Repurposed gout drug eases tolvaptan's polyuria in ADPKD

Clinical takeaway: These early findings suggest probenecid could reduce the aquaretic burden that drives many ADPKD patients off tolvaptan. The evidence is preliminary, from a small open-label trial.

Tolvaptan is the only approved therapy that slows cyst growth in autosomal dominant polycystic kidney disease (ADPKD), but it does so by blocking vasopressin, which can push urine output to 6 to 7 liters per day. The burden is severe enough that many stop treatment.

Mayo Clinic researchers now report a way to keep tolvaptan's benefit while easing that side effect, using the decades-old gout drug probenecid. The work traces back to an unexpected finding: a second, vasopressin-independent route the kidney uses to reabsorb water.

ADPKD is among the most common inherited kidney diseases, affecting an estimated 140,000 people in the US with the autosomal dominant form, and many eventually progress to dialysis or transplant.

Water handling in the kidney has long been thought to run almost entirely through vasopressin, which signals the collecting duct to insert water channels. The Mayo team found that urate, the molecule behind gout, drives a parallel pathway: as it builds up inside collecting duct cells, it triggers the same water-channel trafficking without vasopressin. Probenecid raises intracellular urate by blocking its export, which is how it eased tolvaptan's polyuria.

In the phase 2 trial, 24-hour urine volume fell to 4,662 mL from 6,798 mL after at least a week of probenecid, a drop of about 30%. Nighttime voiding fell to about one episode a night from nearly four, and patient-reported symptom scores improved. Morning urine osmolality rose, consistent with better water reabsorption. In ADPKD mice, probenecid produced similar reductions in urine output while preserving tolvaptan's effect on cyst growth, measured by kidney-to-body-weight ratio.

The mechanistic work was done in cultured collecting duct cells and in two mouse models, including an ADPKD model. The human data come from SereNDIpity, a phase 2, open-label trial in which 17 adults with ADPKD already on stable tolvaptan added probenecid, escalated from 500 to 1000 mg twice daily, for up to 90 days, with 14 included in the primary analysis.

The researchers are not pursuing probenecid itself as the long-term answer: it is old, nonselective, hits multiple organ systems, and is not widely available. The real target is the urate pathway itself, which more selective drugs could engage to ease tolvaptan's polyuria without probenecid's downsides. But increased urate excretion also raises a theoretical kidney-stone risk worth watching.

"Probenecid helped us uncover the mechanism," said Fouad Chebib, MD, a nephrologist at Mayo Clinic who led the study. "Our goal is to take this insight and develop therapies designed specifically for this pathway."

Source: Hadla M, et al. J Clin Invest. 2026 Jun 16. GLUT9b- and ABCG2-mediated collecting duct urate transport uncover a vasopressin-independent mechanism of renal water reabsorption