HDAC Inhibitors Identified As Possible Treatment For Kidney Stones
By C. Rajan, contributing writer
Researchers at the Washington University School of Medicine in St. Louis discovered that a class of drugs already approved to treat leukemia and epilepsyare also effective against kidney stones in a new mouse study. The study is published online in the Journal of the American Society of Nephrology.
The drugs used in the study were histone deacetylase inhibitors (HDAC inhibitors). The researchers found that two HDAC inhibitors, Vorinostat and Trichostatin A, are able to lower levels of calcium and magnesium in the urine — key players in the development of kidney stones. Kidney stones typically form when there are high concentrations of calcium and magnesium salts in the urine, allowing calcium and magnesium to crystallize and form lumps or stones. These stones can get stuck in the urinary tract and cause intense pain.
“We’re hopeful this class of drugs can dissolve kidney stones because its effects on reducing calcium and magnesium are exclusive to kidney cells,” said Dr. Jianghui Hou, assistant professor of medicine and senior author of the study. “In the mice, we achieved dramatic effects at a fraction of the dosage used to treat leukemia and without significant side effects.”
In the mice, researchers found that small doses of Vorinostat reduced calcium levels in the urine by more than 50 percent and magnesium levels by more than 40 percent. Similar results were observed for trichostatin A. Dr. Hou and his colleagues showed that Vorinostat, approved to treat leukemia and epilepsy, and trichostatin A, an antifungal drug, mimic a natural process in the kidney that reabsorbs calcium and magnesium into the urine.
Along with their role in purifying blood, kidneys also play an important role in reclaiming minerals that the body needs. Normally, some calcium and magnesium in the blood are filtered into the urine and then reabsorbed back into the blood, depending on the body’s need for these minerals. Dr. Hou’s earlier work showed this process depends on the activity of a gene called claudin-14. When claudin-14 is inactive, the kidney’s filtering system works normally. But when the gene is activated, calcium and magnesium are blocked from re-entering the blood.
The gene’s expression is controlled by two snippets of RNA (micro-RNAs). Dr. Hou and his team found that the HDAC inhibitors do not act directly on claudin-14 but mimic these micro-RNA molecules in controlling the activity of the gene. As the drugs can modify the activity of micro-RNAs, they make attractive potential treatments for kidney stones.
“Kidney cells were very sensitive to the drugs,” Hou explained. “We used one-twentieth of the dose typically used in humans and achieved significant results. We now want to test the drugs in clinical trials for patients with kidney stones.”