UC study finds combination therapy increases diuresis

Researchers at the University of Cincinnati (UC) have found a combination drug therapy that increases diuresis, or the enhancing of urine output from the body. This could aid in the treatment of patients who have conditions where fluid retention is an issue, in particular congestive heart failure, chronic kidney disease and liver disease. The study was recently published in Frontiers in Physiology.

"Nephrologists and cardiologists have used thiazide derivatives either alone for the treatment of mild to moderate hypertension, or in conjunction with loop diuretics for the treatment of fluid overloaded conditions,” says Manoocher Soleimani, MD, professor and associate chair for research in the Department of Internal Medicine at the UC College of Medicine. "When used alone, thiazides are very mild diuretics. This research shows that when used in conjunction with the uricosuric drug probenecid, thiazides can exhibit robust diuretic effect.”

Soleimani says a problem physicians have been trying to solve for years is finding the best diuretic regimens for patients with conditions where fluid retention is a major problem.

Researchers in the Soleimani Lab at the UC College of Medicine found a molecule in close proximity to where thiazide was working in the kidney was being activated and blunting the diuretic effect of thiazide. That protein is called pendrin for which there was no known inhibitor.

Probenecid has historically been used to lower blood uric acid in people with gout. Soleimani says recent research shows probenecid unexpectedly has an impact in the area of the kidney where pendrin blunts the effect of thiazide.

"In order to further investigate that, we treated the animal models with probenecid for six days,” says Soleimani. "After six days, hydrochlorothiazide was added to the probenecid regimen, and suddenly a huge diuresis was seen.”

Soleimani says urine output increased by 20 percent in experimental animals treated with only thiazide, and a similar increase was seen in patients treated with probenecid alone. But when used as a combination therapy, probenecid and thiazide increased the urine output by 400 percent. Even at lower, more physiologic doses closer to what humans would be taking, the combination therapy increased urine output by 250 percent.

According to Soleimani, in addition to downregulating pendrin, probenecid also helps eliminate uric acid, which is one of the side effects of thiazides.

”This is probably the first study where a medication with no diuretic effect (probenecid) significantly enhances the diuretic effect of thiazides,” says Soleimani. "Future studies are planned to test the effect of this regimen in patients with chronic kidney disease or congestive heart failure.”

The research was supported by a Merit Review Award from the U.S. Department of Veterans Affairs and funds from the UC Center on Genetics of Transport and Epithelial Biology. Collaborators with Soleimani include Sharon Barone, and Kamyar Zahedi, PhD, both senior research assistants and Marybeth Brooks, research assistant, all in the Department of Internal Medicine; and Jie Xu, MD, PhD, research scientist in the Department of Pathology and Laboratory Medicine at the UC College of Medicine.