Clues to kidney stone mystery.

every year an estimated 300,000 Americans develop kidney stones. According to John Pahira, director of the Center for Kidney Stone Disease at Georgetown University in Washington, D.C., 70 to 75 percent of these cases will involve calcium-oxalate stones. What causes them, why 60 to 80 percent of their victims are male and why this disease rarely affects children have remained mysteries. Now researchers at the University of Chicago think they've uncovered at least a partial answer to the question of waht causes the stones.

Kidney stones grow in much the same way rock candy does. A tiny calcium-oxalate crystal, formed in the kidney from a chemical reaction between excreted calcium and oxalic acid (a component of such foods as spinach, rhubarb, celery and nuts), serves as the seed crystal around which a stone can develop in a high-sugar urine. Four years ago the Chicago researchers identified a mechanism that appears to keep the seed crystals formed by normal persons from growing into large stones: a glycoprotein in their urine coats the microscopic seed crystals, preventing further deposition of calcium-oxalate layers.

Early this year the Chicago researchers identified what makes chronic stone formers different. In normal individuals, explains chemist Yasushi Nakagawa, an enzyme transforms a precursor molecule produced by the kidney into the stone-inhibiting glycoprotein. But in calcium-oxalate-stone-forming individuals, the enzyme responsible for making gamma-carboxy-glutamic acid either malfunctions or is present in insufficient quantities, Nakagawa says, because some of the "inhibitor" present in their urine will lack this apparently crucial amino acid. While inhibitor lacking this amino acid will cover the seed crystal, it does not block crystal growth.

The researchers have developed an immunological assay to detect what proportion of the stone-inhibiting glycoprotein in a person's urine is functional. Those earmarked as prone to stone formation by the assay can make dietary changes to slow the rate of any incubating stone's growth. But the ultimate goal of this work, says Nakagawa, is to find ways to restore the ability to make functional crystal-growth inhibitors and to understand what partially shuts down the production of gamma-carboxy-glutamic acid in the kidneys.