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Anyone who has experienced kidney stones is keenly conscious of the possible lack of drugs to deal with the problem, which often causes excruciating pain.
A new mouse study, however, shows that a class of drugs approved to deal with leukemia and epilepsy may also be effective against kidney stones, researchers at Washington University School of Medicine in St. Louis report.
The drugs are histone deacetylase inhibitors, or HDAC inhibitors for short. The researchers found that two of them – Vorinostat and trichostatin A – ‘abnormal’ amounts of magnesium and calcium in the urine. Both calcium and magnesium are key aspects of kidney stones.
The research is available online within the Journal from the American Society of Nephrology.
“We’re hopeful this class of drugs can dissolve kidney stones because its effects on reducing calcium and magnesium are only at kidney cells,” said senior author Jianghui Hou, PhD, assistant professor of drugs. “In the mice, we achieved dramatic effects at a fraction of the dosage used to treat leukemia and without significant negative effects.”
Most kidney stones form once the urine becomes too concentrated, allowing calcium and magnesium to crystallize and stick together. Intense pain develops when stones get stuck in the urinary system and block the flow of urine.
Diet can enjoy a role in the condition. Not drinking enough water or eating a diet with too much salt, which promotes calcium to be sold in to the urine, increases the risk of stones. Some people are also genetically vulnerable to developing kidney stones, and they naturally release an excessive amount of calcium into the urine.
Typically, doctors recommend drinking lots of water to help pass kidney stones from the body. Thiazide, a type of drug accustomed to treat high blood pressure, sometimes is prescribed to deal with the stones since it reduces calcium within the urine. However the drug also increases magnesium in urine, countering its usefulness against kidney stones.
In the new study, Hou and his colleagues demonstrated that Vorinostat, approved to deal with leukemia and epilepsy, and trichostatin A, an antifungal drug, mimic an all natural process within the kidney that reabsorbs magnesium and calcium into the urine.
Kidneys, in addition to filtering waste in the blood into the urine, also play an important role in reclaiming minerals the body needs to handle basic functions of life. Normally, some magnesium and calcium in the blood are filtered into the urine after which reabsorbed back into the blood, depending on the body’s need for these essential minerals.
Hou’s earlier work showed this method is heavily determined by the game of a gene called claudin-14. Once the activity of claudin-14 is idled, the kidney’s filtering system works like it’s supposed to. But when the gene is activated, magnesium and calcium are blocked from re-entering the blood.
The gene’s expression is controlled by two snippets of RNA, a sister molecule of DNA, Hou’s previous research has shown.
As part of the new study, Hou and his colleagues discovered that Vorinostat and trichostatin A do not act directly on the claudin-14 but mimic these so-called micro-RNA molecules, keeping the game from the gene under control. The drugs can modify the game of micro-RNAs make sure they are attractive as potential treatments for kidney stones.
In the mice, small doses of Vorinostat, for instance, reduced calcium levels in the urine by more than 50 % and magnesium levels by a lot more than 40 percent. Similar outcome was recognized for trichostatin A.
“Kidney cells were very responsive to the drug,” Hou explained. “We used one-twentieth from the dose typically utilized in humans and achieved significant results. We currently want to test the drug in clinical trials for patients with kidney stones.”
Mice don’t develop kidney stones, so it will be vital that you test the drugs against kidney stones in patients, but the current study provides evidence of principle that HDAC inhibitors regulate exactly the same pathway that leads to kidney stones, he explained.
