Cystinuria is a renal tubular amino acid transport disorder characterized by recurrent formation of kidneys cystine stones.
Prevalence of cystinuria has high ethnogeographic variation, ranging from 1:2,500 in the Libyan Jewish population to 1:100,000 in Sweden. The mean global value is estimated at 1:7,000.
Cystinuria develops in patients of any age but renal colic due to cystine stone appears generally in the first 2 decades, with a median age of onset of 15 years. Male patients tend to present with more aggressive disease, and occurrence of renal stones before the age of 3 is more frequent in males. The disease is associated with a lifetime risk of stone formation over 50%. Urolithiasis is bilateral in more than 75% of cases and recurrence rate is over 60%, with a higher rate in male patients. It has been shown that urinary cystine may promote calcium stone formation. Renal insufficiency is uncommon.
Cystinuria is due to mutations in SLC3A1 (2p21) and SLC7A9 (19q13.11). Both genes are expressed in the renal proximal tubules and the intestinal tract and code for subunits of trans-epithelial transporters for the dibasic amino acids cystine, ornithine, lysine and arginine. The transporter deficiency leads to accumulation of cystine in renal tubules' urine, subsequent precipitation and cystine crystals or even stone formation. Classification of patients now relies on genetic criteria: type A and type B cystinuria are respectively associated with mutations of both alleles of SLC3A1 or SLC7A9. Heterozygotes with mutation in one SLC3A1 allele are unaffected, while those who carry mutation in a single SLC7A9 allele show moderately increased urine output of cystine and dibasic amino acids and have a higher risk of developing renal stones when compared to the general population.
Diagnosis relies on physical examination, detection of cystine stones and assay of excreted cystine in urine. Analysis reveals urinary cystine excretion over 300 - 400 mg/L per day in homozygous patients. Renal ultrasound imaging is the method of choice for stone detection and follow-up. Molecular genetics may confirm diagnosis.
Differential diagnosis includes three syndromes in which cystinuria is present: 2p21 deletion syndrome, hypotonia-cystinuria syndrome (HCS) and atypical HCS (see these terms).
The disease has an autosomal recessive mode of inheritance, but dominant transmission with incomplete penetrance has also been observed in type B cystinuria.
Treatment requires several approaches to prevent stone formation or growth: high hydration to reduce urinary cystine osmolality, urinary alkalinization to increase cystine solubility (mainly with potassium citrate), and pharmacological cystine-binding medications (alpha-mercaptopropionylglycine, or tiopronin, and D-Penicillamine) to lower free cystine levels in the urine. Measuring the free fraction of cystine in the urine enables titration of the treatment with cystine binding drugs. Side effects of D-Penicillamine and tiopronin frequently lead to discontinuation of the treatment; they also require zinc, copper and/or vitamin B6 supplementation. Low protein diet in adults or even adolescents is less effective. Routine monitoring of urine protein with dipsticks may be advised. When a cystine stone is still small (under 12 mm), extracorporeal shock wave lithotripsy is feasible, but with low efficiency due to the consistency of cystine stones. Over this size, laser stone fragmentation or even percutaneous nephrolithotomy is necessary.
Prognosis is good but low patient compliance and recurrence of stone formation and subsequent interventions can very rarely induce renal insufficiency.
Last update: April 2012