KU Medical Center researchers identify potential drug target to prevent kidney stones

Known for causing intense pain comparable to childbirth, kidney stones affect one of 10 Americans. When one of these pebble-like deposits of minerals in the kidney, commonly calcium, enters the urinary tract and blocks urine flow, the result is severe pain, and sometimes infections or problems with kidney function. Recurrence rates are high, with at least half of people who’ve had one kidney stone getting another one within 10 years, according to the American Urological Association.

Yet “there has been no new [drug] therapy for kidney stones in half a century, maybe longer,” noted Alan Yu, M.B., B.Chir., director of the Jared Grantham Kidney Institute at the University of Kansas Medical Center. The current drug therapy is thiazide diuretics, which reduce the amount of calcium in the urine, preventing kidney stones. For an existing stone the patient cannot pass on their own, treatment consists of using sound waves or lasers to break it up or removing it surgically.

Yu is looking to change that. He and a team of researchers at KU Medial Center have identified a potential drug target that could help prevent kidney stones. To do so, they switched focus from what’s happening in the urine to what is happening in the kidney itself.

“These stones are like crystals. So we measure the urine — if you've got too much calcium and oxalate or too little water, it's more likely to crystallize. So that's what everyone's focused on, and that's what we measure in clinic,” said Yu. “But what we’re saying here is, it’s not just the concentration of these things in the urine that’s important. It’s what’s going on in the kidney, and that there are actually deposits showing up in the kidney, long before stones show up in the urine.”

Specifically, the researchers looked at what are known as Randall’s plaques, tiny calcium deposits that form in the kidney. These deposits are not actually the kidney stones themselves, but they serve as a kind of foundation for kidney stones to grow on. “They are in the kidney, and when they get exposed to the urine, stones grow on top of them,” explained Yu.

The researchers focused on the role of a protein known as Claudin-2 in the formation of Randall’s plaques. Claudin-2 is a “junction protein” that closes the gap between cells, while letting certain things through. It is present in the proximal tubule, a coiled segment known as the “workhorse of the kidney,” which reabsorbs water and solutes.

Yu and his colleagues decided to see what would happen in the kidney without functioning Claudin-2. They created a mouse model in which the gene that produces the Claudin-2 protein was eliminated in the kidney tubules. And they found that calcium did not get transported and reabsorbed. Instead, the calcium wound up accumulating in the deepest part of the kidney known as the papilla, the exit point for urine, and forming Randall’s plaques. Their findings were published in the Journal of Clinical Investigation.

These results suggest that damaged or nonfunctioning Claudin-2 protein is critical to the formation of Randall’s plaques and thus kidney stones. “It’s the first identification of a gene that might be involved in [the formation of] Randall’s plaques,” said Yu.

In February, Yu was awarded a grant from the National Institutes of Health to continue this work. The research could be the basis for developing drugs to increase or restore the function of that protein or to stop the calcium from accumulating. Another option is to increase the amount of pyrophosphate, a molecule that inhibits mineralization, in the kidney, he said. 

“For a long time, the focus has been on adjusting the composition of the urine, but I don’t think much has come out of it,” said Yu. “And this is the first time we are finding specific genes, so I think we’re onto something.”