Cystinuria is an important hereditary cause of kidney stones and kidney failure. Most patients affected by this autosomal recessive disease have mutations in one of two known genes which each code for one component of the heterodimeric transport protein expressed in kidney that reabsorbs the amino acid cystine. Patients often have large stones, composed of cystine, and the stones are often recurrent. The disorder may result in chronic kidney disease. Cystinuria is a rare disease, affecting about 1/15,000 people in the United States. Heterozygote carriers are about 1/170 people. It accounts for approximately 1% of all renal stones. In this Rare Disease Center proposal, a group of urologists and nephrologists with expertise in hereditary causes of nephrolithjasis and kidney failure will collaborate to augment the available data and improve the care of patients with Cystinuria, primary hyperoxaluria, APRT deficiency and Dent disease. A cystinuria registry, modeled on the successful primary hyperoxaluria registry maintained at Mayo Clinic, will be established and patients enrolled through clinical practices as well as strong alliances with patient organizations, the Cystinuria Support Network and the International Cystinuria Foundation. Although the genetic defects underlying cystinuria are well described, many features of the disease important to optimizing treatment remain poorly understood. As with all these rare hereditary causes of nephrolithiasis, previous studies have lacked sufficient patient numbers and long term follow up. Important questions to be studied in this proposal include: 1) what factors other than genotype, such as age, gender, diet, and medications affect stone formation;2) what risks factors account for the increased risk of chronic kidney disease in cystinuria;3) in which patients is treatment with cystine-binding thiol drugs most clinically effective and 4) will a new assay of urine cystine capacity help define who is at highest risk for stone recurrence and help guide therapy.

Public Health Relevance

The cystinuria registry will lead to the largest longitudinal clinical registry to allow determination of the risk factors for chronic kidney disease and stone recurrence in patients with cystinuria. A unique feature will be the availability of a new test for cystine capacity which may inversely correlate with stone-forming activity and change the management of this rare disease. We will work closely with patient support groups to encourage registry enrollment and disseminate knowledge and information to patients and practitioners. We will establish a DMA and tissue bank with plans to study genotype-phenotype correlations and modifier genes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZRG1-HOP-Y)
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Mayo Clinic, Rochester
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