Review ArticleCystinuria: Current Diagnosis and Management
Section snippets
Epidemiology
The worldwide prevalence of cystinuria is estimated at 1:7000, although it is regionally variable, ranging from 1:2500 among Libyan Jews to 1:100,000 persons in Sweden.1, 4 In the Mediterranean East Coast, cystinuria occurs in approximately 1:1887 persons.4 The first symptoms of cystine stones typically present between ages 2 and 40 years, whereas the peak age of onset of stones is in the third decade of life.5 Cystine stones account for 1%-2% of urinary calculi, but the prevalence is 6%-10% of
Pathophysiology and Genetics
Cystinuria is an autosomal recessive genetic disorder of the transepithelial transporters for the dibasic amino acids COLA (cystine, ornithine, lysine, and arginine), resulting in an impairment of their reabsorption in the renal proximal tubule and the small intestine.4, 7 In normal individuals, about 99% of the amino acids, including cystine, filtered by the glomerulus, are reabsorbed by the end of the proximal tubule. Cystinuria results from a defective amino acid transport system, which
Classification
Cystinuria is an autosomal recessive disease, but some heterozygote carriers have an autosomal dominant, incomplete penetrance appearance with elevated, but typically nonpathologic urinary cystine excretion. Consequently, the first classification by Rosenberg et al15 in 1966 was the phenotypic classification and was based on the amount of urinary cystine excreted of the patient's parents, dividing the disease into 3 subgroups: type I, type II, and type III (the 2 latter are also referred as
Clinical Manifestations
The clinically significant manifestations are related to stone formation and might include nausea, flank pain, hematuria, recurrent urinary tract infections, and rarely acute or chronic renal failure.10 A high index of suspicion should be held in patients with family history of cystinuria or stone disease, recurrent crystalluria or stone formation in the first 2 decades of life.3 Cystinuria should also be suspected in patients with large staghorn calculi filling the collecting system and
Diagnostic Evaluation
In 2006, Dello Strologo and Rizzoni19 proposed a definition of cystinuria. A diagnosis can be made in patients with cystine stones, if an increased urinary excretion of dibasic amino acids is noted or mutations on both alleles of 1 of the 2 genes involved are identified. A patient can also be considered as having cystinuria in the absence of a urinary stone if urine cystine excretion exceeds 1300 μmol/g creatinine (150 mmol/mmol creatinine) or the sum of COLA (cystine, ornithine, lysine, and
Medical Treatment and Conservative Measures
The primary goal of the treatment is to prevent cystine stone formation by improving the solubility of urinary cystine. The treatment approaches include mainly dietary measures, measures that decrease urinary cystine concentration and drugs leading to reduction of cystine to the more soluble cysteine. Initial management methods should always include hydration and urinary alkalization. If the patient does not respond to this conservative approach, additional drugs, such as D-penicillamine,
Conclusion
Although cystine stones have been described for nearly 200 years, only in the past decades, we began to understand the pathophysiological and genetic basis of the disease. Medical and surgical management have changed over the past decade and aim to reduce recurrent stone formation and improve quality of life. We hope that new emerging therapies based on the better understanding of the nature of the disease will extend our therapeutic options.
Acknowledgments
Mr. Petros Saravakos, Electrical and Computer Engineer, designed Figure 1.
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Financial Disclosure: The authors declare that they have no relevant financial interests.