PerspectiveMedicine

Stopping the Stones

See allHide authors and affiliations

Science  15 Oct 2010:
Vol. 330, Issue 6002, pp. 325-326
DOI: 10.1126/science.1197207

An imbalance in the fluid and mineral content of urine can cause debilitating kidney stones to form. Most of the time, the stones are composed of calcium oxalate crystals. Much less common are stones that develop from crystals of the amino acid l-cystine. The latter only occurs in patients with cystinuria, a condition with great morbidity due to the early age of onset, high frequency of stone recurrence, and increased risk of chronic kidney damage (1). The rarity of the disease—it occurs in about 1 in 15,000 in the United States—has deprived the field of clinical trials to assess treatment options. Treatment has not changed in over 20 years and remains unsatisfactory for many patients. On page 337 in this issue, Rimer et al. (2) report a potential new therapy for cystinuria, using compounds to retard cystine crystal growth.

Cystinuria is an inherited disorder in which intestinal and renal transport of cystine is abnormal (3). As a result, excretion of cystine into the urine increases, and its poor solubility leads to the formation of kidney stones (see the figure). Mutations in either of the SLC3A1 or SLC7A9 genes, which encode protein subunits of an amino acid transporter, account for almost all cases of cystinuria (4, 5).

Current treatments for cystinuria involve reducing the saturation of urine with cystine by lowering its excretion, increasing the volume of urine, or increasing cystine's solubility in urine. Unfortunately, not all patients can maintain either the necessary high urine flow over time or the low-sodium, low-protein diets needed to reduce excretion of cystine (6, 7). Cystine solubility increases appreciably when urinary pH is raised, but only at values approaching 8.0, the maximum that kidneys will attain. This requires amounts of alkaline compounds that often exceed the dose that patients can tolerate (8). Thiol-containing compounds that undergo a disulfide bond exchange reaction can convert cystine to a soluble cysteine-drug complex. Although these agents lower cystine saturation (decrease the amount of cystine in solution relative to its solubility), such drugs have adverse side effects and have not been studied in rigorous clinical trials to prove that they reduce kidney stone formation (9, 10). Clearly, this is a disease that could greatly benefit from new therapies.

Cystinuria.

In the human kidney, cystine can form crystals in the urine, leading to debilitating kidney stones. A normal renal papilla (A) and one from a patient with cystinuria (B) are shown. In the latter case, there is a dilated collecting duct with a protruding cystine stone. [The photos are reprinted from (1) with permission from the publisher, Nature Publishing Group]

CREDIT: C. BICKEL/SCIENCE

Although human urine contains many highly anionic proteins and glycosaminoglycans that inhibit calcium crystal growth and aggregation, none of these components have given rise to effective treatments for calcium stones. For example, synthetic polymers of aspartic acid can inhibit calcium crystal growth but when taken orally, can be digested to small peptides. Even if they remain intact, the polymers usually cannot be absorbed by the body. Citrate also inhibits calcium crystallization, and the concentration of this anion in urine can be boosted by ingesting an alkali (such as potassium bicarbonate), which changes ion transport in renal cells. However, citrate also forms complexes with calcium, so it is unclear to what extent citrate directly blocks calcium crystal growth.

Clinicians have no therapeutic agents for any type of kidney stone that act strictly to inhibit crystal formation. Now, Rimer et al. have identified two compounds that directly bind to preferred crystal growth sites on cystine, thereby retarding crystal growth in vitro. The most effective molecule was l-cystine dimethylester (CDME). Even when present in solution at a small fraction of the cystine concentration, CDME reduced crystal growth and changed crystal shape and size as determined by atomic force microscopy and bulk phase crystallization experiments.

The finding of Rimer et al. is encouraging, but the path to clinical practice is very long. Whether CDME will act in urine as it does in synthetic solutions remains to be seen; perhaps urinary proteins and other macromolecules will influence the binding of CDME to the surface of the cystine crystal. It's also not clear whether CDME will interact with thiol drugs in a synergistic or antagonistic manner. The fate of CDME when administered orally also must be determined. For instance, will it be absorbed from the gut, and if so, will it be hydrolyzed to cystine? Will it even reach the urine at all? Fortunately, mice that have been engineered to lack the SLC7A9 gene develop cystinuria and provide a model for studying whole-animal safety, CDME metabolism, and the drug's effectiveness in preventing stone formation (11). Rimer et al. suggest that the dose of CDME required to prevent cystine crystallization must reach 5 to 10 mg per liter of urine in humans—is that safe? Interestingly, CDME can actually cause the accumulation of cystine within lysosomes of cultured cells and in animal models (12). Such accumulation can cause crystals to form and thus damage cells. These issues should be addressed through rigorous clinical trials.

Even if CDME is not a safe and effective therapy, the molecular modeling method outlined by Rimer et al. could identify other compounds that inhibit cystine crystallization. Likewise, at least in principle, it could provide candidate drug prototypes for the far more common calcium oxalate, calcium phosphate, and uric acid stones. Even though clinical trials support calcium stone prevention with inexpensive drugs, selective inhibitors might be more efficient and better tolerated.

References and Notes

  1. J.R.A. is a partner in the Ravine group, a company that focuses on developing treatments for calcium kidney stones.
View Abstract

Stay Connected to Science

Navigate This Article