Update on cystine stones: current and future concepts in treatment

Abstract

cystinuria, urolithiasis, novel therapy, cystine stone, tiopronin, D-penicillamine Cystine stones are relatively uncommon compared with other stone compositions, constituting just 1% to 2% of adult urinary tract stone diseases, and accounting for up to 10% of pediatric stone diseases. Two responsible genes of cystinuria have been identified, the SLC3A1 and the SLC7A9. Cystinuria is diagnosed by family history, stone analysis, or by measurement of urine cystine excretion. Current treatments for cystinuria include increased fluid intake to increase cystine solubility by maintaining daily urine volume of greater than 3 Liter (L). Limiting sodium and protein intake can decrease cystine excretion. When conservative therapy fails, then pharmacologic therapy may be effective. Alkaline urine pH in the 7.0-7.5 range will reduce cystine solubility and can be achieved by the addition of alkali therapy. If these measures fail, cystine-binding thiol drugs such as tiopronin and D-penicillamine are considered. These compounds bind cysteine and prevent the formation of less soluble cystine. These drugs, however, have poor patient compliance due to adverse effects. Captopril can be useful in the treatment of cystine stones but the drug has not been tested in rigorous clinical trials. Novel potential therapies such as alpha-lipoic acid and crystal growth inhibitors (L-cystine dimethyl ester (L-CDME) and L-cystine methyl ester (L-CME)) were developed and tested in animals. Those therapies showed promising results. Compliance with treatment was associated with a lower rate of cystine stone formation. 2002; 31:951-977.

Cystinuria in Dogs and Cats: What Do We Know after Almost 200 Years?

“…Dietary sodium restriction seems to be an important component of the therapeutic strategy in cystinuric people because dietary sodium may enhance cystinuria [ 94 , 95 ]. Dietary sodium in canine therapeutic diets should be limited to less than 0.3% dry matter [ 6 ].…”

Circulating miRNAs as Biomarkers for Mitochondrial Neuro-Gastrointestinal Encephalomyopathy

“…Regulators acknowledge the need for accelerating the rare disease drug development pathway and may approve a biomarker endpoint measure in the absence of validated endpoint measures for the intended patient population. Examples of rare disease drugs that have received approval based on biomarker primary endpoints include tiopronin for cystinuria (biomarker: reduction in urinary excretion of cystine) sapropterin dihydrochloride for phenylketonuria (reduction in plasma phenylalanine), agalsidase beta for Fabry disease (reduction of globotriaosylceramide storage granules in biopsied kidney interstitial capillaries), imiglucerase for Gaucher disease type I (composite of biomarker endpoints, including haemoglobin and platelet count) and sebelipase alfa for lysosomal acid lipase deficiency (normalisation of serum alanine aminotransferase levels) [ 28 , 29 , 30 , 31 , 32 ].…”

The Long-Term Follow-Up of Patients with Cystine Stones: A Single-Center Experience for 13 Years

“…Current preventive treatments for cystinuria include increased fluid intake to increase cystine solubility and limiting sodium and protein intake to decrease cystine excretion. Pharmacologic therapy such as alkalizing agents and cystine-binding thiol drugs may also be effective [ 4 ]. Although it has been reported that patients taking cystine-binding thiol drugs have a high quality of life, there are adverse effects and poor compliance with the drugs [ 5 , 6 ].…”

“…Although it has been reported that patients taking cystine-binding thiol drugs have a high quality of life, there are adverse effects and poor compliance with the drugs [ 5 , 6 ]. Despite these preventive measures, cystine stone formers frequently experience stone-related episodes and surgical intervention [ 4 ]. Many patients suffer from renal insufficiency because of the stone-recurrence.…”

“…Many patients suffer from renal insufficiency because of the stone-recurrence. Thus, life-long follow-up is necessary to monitor kidney function, find recurrences at an early stage, and increase patient compliance of dietary and medical treatments [ 4 ]. However, because of the rarity of the disease, the appropriate treatment and follow-up strategy to reduce the risk of stone events and avoid loss of renal function has not been elucidated.…”