October 25, 2010

Molecular Mimics Curb Kidney Stone Crystals

Image of a growing L-cystine crystal Atomic force microscope image of a growing L-cystine crystal shows stacks of hexagon-shaped plates. Rimer et al., courtesy of Science.

By studying how kidney stone crystals grow at the nanoscale level, scientists were able to identify molecules that were similar enough to attach to the crystal but different enough to prevent further growth. The new strategy might prove an effective way to block kidney stone formation.

Kidney stones are hard masses that develop from crystals that build up in the kidneys. Most can travel from the kidney and through the urinary tract before they grow large enough to cause any problems. But in some people, the crystals enlarge, clump together and lodge in the kidney, bladder or urinary tract, bringing severe pain.

A rare type of kidney stone made of the amino acid L-cystine affects about 20,000 people nationwide. Affected people have an inherited condition called cystinuria. L-cystine stones are larger, recur more often and are more likely to cause chronic kidney disease than are the more common kidney stones made of calcium oxylate. L-cystine stones are also more difficult to treat. Current approaches can suppress but may not completely prevent crystal formation, and some therapies have negative side effects.

To identify better treatment options, Dr. Michael Ward of New York University and his colleagues used atomic force microscopy to observe the formation of L-cystine crystals at near-atomic level. Their research was funded in part by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

As reported in the October 15, 2010, issue of Science, the investigators found that L-cystine crystals form pyramids of hexagon-shaped plates. The plates have "steps" on their surfaces that grow in a spiral fashion as L-cystine molecules continually attach to their edges.

In hope of slowing crystal growth, the researchers identified 2 synthetic compounds—called L-cystine dimethylester (L-CDME) and L-cystine methylester (L-CME)—that are chemically similar to L-cystine but have different groups of atoms at both ends. Again using atomic force microscopy, the scientists observed crystal formation after either of the synthetic compounds was added to the mix.

The researchers found that the compounds essentially acted like chemical "imposters" by attaching to sites for crystal growth but then blocking the attachment of additional L-cystine building blocks. The edges of the hexagon-shaped pyramid became more ragged and misshapen.

Additional analyses showed that the compounds reduced overall crystal production and crystal size. L-cystine crystals grown in the presence of L-CDME tend to form a hexagon-shaped needle-like structure that's about 1,000-times smaller than typical L-cystine crystals.

"This may lead to a new approach to preventing cystine stones simply by stopping crystallization," says Ward. He and his colleagues note, however, that their research is still in its early stages, and the crystal inhibitors may work differently in the body than in the laboratory. Further research is needed to test the compounds’ effectiveness in animal models.

—by Vicki Contie

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