*3.2.4. Cystine stones*

#### *3.2.4.1. Drugs containing thiol*

Cystinuria is a genetic disease in which reabsorption of cysteine and other dibasic amino acids, including ornithine, arginine, and lysine, through the proximal tubules is impaired [81]. Cystinuria has two genetic types: type 1, which is caused by the SLC3A1 gene on the 2nd chromosome and type 2, which is caused by the SLC7A9 gene on the 19th chromosome [82]. Cystinuria is more common in Eastern Mediterranean populations [83]. Cysteine higher than 50 mg/1.73 m2 in 24‐hour urine is considered as a diagnostic for cystinuria [26]. Where hydration and alkalization fail, use of thiol‐containing drugs is recommended [6]. Thiol forms a disulfide complex, which is soluble with cysteine and prevents formation of stones. Thiol‐ containing drugs are more effective on alkaline urine, and a study has demonstrated that dis‐ solution in urine incubated with cysteine was low for the first 60 minutes when the pH was 6, but it was optimal when the pH was 8 [84]. However, no difference was found between pH 7 and 8 after either 60 minutes or 48 hours [84]. This indicates the importance of alkalization even when using thiol‐containing drugs. However, a high urine pH may lead to phosphate crystallization; therefore, pH 7–7.5 appears to be the most appropriate target.

**D‐penicillamine** is a chelating agent that contains thiol and increases cysteine dissolution by as much as 50‐fold [85]. D‐penicillamine may cause bonemarrow suppression, proteinuria, skin eruptions on the neck and extremities, arthralgia, liver dysfunction, and febrile reaction [86]. Its use for metaphylaxis of cysteine stones is restricted by the fact that up to 86% of pedi‐ atric patients using it have developed side effects [87]. Although d‐penicillamine use is not recommended in children, if it must be used, close follow‐up for side effects is essential. In addition, to decrease side effects and increase tolerance, during the first week, the dose should be 5 mg/kg/day, and then it should be increased by 5 mg/kg/day, reaching 20 mg/kg/day at the end of four weeks [86]. Pyridoxine deficiency develops with long‐term d‐ penicillamine therapy, so therapy should include pyridoxine [85].

**Alfa mercaptopropionylglycine (AMG, thiopronin)** has an effect similar to that of d‐penicil‐ lamine but with fewer side effects [85]. The daily dose is 10–15 mg/kg [6]. The rate of treat‐ ment discontinuation is lower than that for d‐penicillamine therapy [88]. Although thiopronin has fewer side effects than penicillamine, patients must be closely monitored for side effects, including fever, which often occurs during the first month, rash, bone marrow suppression, and nephrotic syndrome, which improves when the drug is ceased [89, 90]. One uncontrolled study suggested that giving a low dose or a dose every other day was effective and further decreased the side effects [91]. Use of thiopronin is recommended for pediatric patients when hydration and alkalization are not adequate to decrease cystinuria [6].

Adding **captopril** to cysteine makes the cysteine more than 200 times soluble in urine [86]. However, it lowers the concentration of captopril in the urine, making this treatment less effective than AMG or d‐penicillamine [92, 93]. Case reports have shown that this treatment is effective in pediatric patients and has relatively few side effects, but some studies have also indicated the opposite [94–96]. The EAU's pediatric urology guidelines do not recommend the treatment, but it may be considered when AMG cannot be used because of side effects or in children with hypertension and proteinuria [6].
