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.

New pee-pee for Pepe

Imagine what it would be like if you were a young boy and your urethra – the pipe that’s supposed to carry urine from your bladder to your penis – was irreparably damaged or traumatically destroyed.

You’d be facing a probable lifetime of incontinence, infection, pain, bleeding and difficulty urinating.

Although small defects in the tube can be repaired, larger defects are treated with a tissue graft, usually taken from skin or the lining of the cheek.  But these grafts fail in half of the cases.

Now imagine if scientists could grow you a new urethra.

Because that’s exactly what researchers from the Institute for Regenerative Medicine at Wake Forest University Baptist Medical Center in North Carolina, have done.

Watching human organs take shape in a lab dish is no longer, it seems, only the realm of science fiction.

The research team, led by Dr. Anthony Atala used patients’ own cells to grow urethras in the lab and have successfully used them to replace damaged tissue in five young Mexican boys.

Six years after surgery, urine flow tests and tube diameter measurements show the tissue-engineered urethras are still working.

The study, published in the  Lancet, represents a first in the growing field of regenerative medicine, which doctors hope will eventually lead to ways to repair injuries and eventually replace whole organs.

“When an organ or tissue is irreparably damaged or traumatically destroyed, no amount of drugs or mechanical devices will restore the patient back to normal. Totally grown in the laboratory, these urethras highlight the power of cell-based therapies“ said Chris Mason, a regenerative medicine expert at University College London, who was not involved in the research.

So how did they do it?

Basically they took a very small piece of tissue, about half the size of a postage stamp. To that, they added a soup of growth factors that nourished the cells and encouraged them to multiply into large quantities. The team made two cell types: muscle cells for the tube’s outer layer and endothelial cells — cells that line blood vessels and other tubular structures — for the inner layer.

Once they had grown enough cells, they applied them onto a biodegradable mesh that was shaped into a tube and sized to be a perfect fit for the patient. Then they heated them in an incubator to allow the cells to start to form sheets.

After a week of incubation to allow the cells to take to the mesh, the lab-grown grafts were surgically transplanted into the patients.

Once implanted, the sheets of cells started forming new tissue, and after about four weeks, they were able to remove the urinary catheter and the boys were able to urinate through the new urethras. Biopsies showed the engineered urethras had normal layers of epithelial and smooth muscle within three months.

Six years in the grafts are doing well, looking and functioning exactly like a normal urethra in the five boys who are now entering their teens.

Although larger studies will be needed before the treatment can be widely used, this data shows the potential power of cell-based therapies.

Eventually, it is hoped that regenerative medicine will be able to cure the large unmet medical needs of our generation including: blindness, diabetes, heart failure, Parkinson’s disease and stroke.

As always, SRxA’s Word on Health will be watching and will bring you new developments as they’re announced.