July 31, 2012

New Genetic Target Found for Diuretic Therapy

(Ivanhoe Newswire) — University of Cincinnati researchers have discovered a new genetic target for diuretic therapy in patients with fluid overload, such as those with congestive heart failure, liver cirrhosis or kidney failure. These results could lead to the first new diuretic therapy in 25 years and could help patients who have a diuretic resistance.

Diuretics help increase urine output and help patients get rid of excess fluid when kidneys can´t perform that function.

Manoocher Soleimani, MD, professor and chief in the division of nephrology and hypertension, was quoted as saying, "For the last several decades, physicians have been using diuretics either alone or in combination to help patients experiencing water retention."

This can occur in patients with heart failure, kidney failure or other serious illnesses. "The most common diuretic used worldwide is hydrochlorothiazide, which works by inhibiting the kidneys' ability to retain water; these drugs can also be used to lower blood pressure. The reason they are so widely used is because they are mild and don't cause severe loss of fluid." However, these diuretics aren´t effective with every patient.

For the study, researchers examined specific segments of the kidneys, called tubules, and the salt-absorbing genes that work there.

"The NaCl, or sodium-chloride, co-transporter (NCC), is targeted by hydrochlorothiazide and drugs in that class; it is located in the close proximity of the chloride-absorbing transporter pendrin, both of which absorb salt in the kidney," Soleimani was quoted as saying. "When pendrin is deleted from the body, there is no effect on salt excretion. We thought that pendrin was present to help NCC function in some way, and by using knockout animal models in this study, we found that these two genes cross-compensate for one another, and if NCC is not working, pendrin kicks in to do its job."

Genetically-engineered animal models without NCC had regular urine output and salt excretion, and the same results occurred in models without pendrin. Still, models lacking both genes lost large amounts of salt, were 40 percent smaller in size and produced an excessive volume of urine.

"In addition to experiencing major volume depletion, mice lacking both genes developed kidney failure," Soleimani was quoted as saying. "We were able to show that all of these problems resulted from salt wasting; when we put these models back on high-salt diets, the problems including electrolyte abnormalities and volume depletion were all corrected after just one week."

The study findings could lead to a targeted diuretic therapy that inhibits pendrin, which would ultimately help patients that have a severe fluid overload who don´t respond well to hydrochlorothiazide.

"By giving a pendrin inhibitor in conjunction with thiazide, a mild diuretic, it could greatly relieve fluid retention, providing another treatment option and improving patient outcomes," Soleimani was quoted as saying.

Source: Proceedings of the National Academy of Sciences, July 2012