Solved! The Mystery of the Stones

Kidney stones strike an estimated 1 million Americans each year.

Those who have experienced them say it is among the most excruciating pain known to man (or woman).

Now, new research provides evidence to explain why some people are more prone to develop the condition than others. The discovery by scientists at Washington University School of Medicine in St. Louis opens the door to finding effective drug treatments and a test that could assess a person’s risk of kidney stones.

Now, we finally have a more complete picture detailing why some people develop kidney stones and others do not,” says Jianghui Hou, PhD, assistant professor of medicine. “With this information, we can begin to think about better treatments and ways to determine a person’s risk of the condition, which typically increases with age.”

Although the research was in mice, the new findings will help scientists to understand the root causes of kidney stones in patients because their kidneys function the same way as ours.

Most kidney stones form when the urine becomes too concentrated, allowing minerals such as calcium to crystallize and stick together.  Diet plays a role – not drinking enough water or eating too much salt (which binds to calcium) increases the risk of stones.

But genes are also partly to blame. A common genetic variation called claudin-14 has recently been linked to a 65% increased risk of kidney stones.

In the new study, the researcher demonstrated how alterations in the gene’s activity influence the development of stones.  Typically, the claudin-14 gene is not active in the kidney. Its expression is dampened by two snippets of RNA, that essentially silence the gene.  When claudin-14 is idled, the kidney’s filtering system works like it’s supposed to. Essential minerals in the blood pass through the kidneys and are reabsorbed back into the blood, where they are transported to cells to carry out basic functions of life.

But when people eat a diet high in calcium or salt and don’t drink enough water, the small RNA molecules release their hold on claudin-14 and the subsequent increase in the gene’s activity prevents calcium from re-entering the blood.  Without a way back to the bloodstream, excess calcium passes into the urine. Too much calcium in the urine leads to the development of stones in the kidneys or bladder.

Then when a large stone gets stuck in the bladder, ureter or urethra the flow of urine is blocked and the characteristic intense pain, that can reduce even the most mild-mannered man to a cursing, foul-mouthed monster, develops.

People with the common, genetic variation in claudin-14 lose the ability to regulate the gene’s activity, increasing the risk of kidney stones.

The results of this research lead to the hope that drugs that will keep the activity of claudin-14 in check can be developed.  Additionally, it may be possible to develop a diagnostic test to measure levels of the claudin-14 protein excreted in urine. Elevated levels would indicate an increased risk of stones, and people could take steps to prevent stones by modifying their diet.

Many genes likely play a role in the formation of kidney stones,” Hou says. “But this study gives us a better idea of the way one of the major players work. Now that we understand the physiology of the condition, we can start to think about better treatments or even ways to prevent stones from developing in the first place.”

For the million or so sufferers and their loved ones we guess that day can’t come soon enough.

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