Effect of Increasing Doses of Cystine Binding Thiol Drugs on Cystine Capacity in Patients With Cystinuria

Cystinuria is a rare genetic cause of kidney stones that leads to significant morbidity due
to the recurrent nature of the disease. As a result, a significant part of treatment is
focused on prevention of stone formation. Current methods of prevention include increasing
fluid intake, dietary modifications, alkali therapy, and cystine binding thiol drugs (CBTDs),
which help increase the solubility of cystine in the urine. At present, the dosing of CBTDs
is empiric, and not titrated to a specific measured effect. Our primary objective will be to
measure the effect of increasing doses of CBTDs on cystine capacity. The investigators
predict that higher dosages of these medications will lead to a more positive urinary cystine
capacity, or the ability of urine to take up more cystine (and therefore decreased risk of
stone formation). However, the dose at which increasing dosages of the medications cease to
provide additional benefit is unknown. The investigators will directly measure the cystine
capacity in the urine in response to increasing doses of medications to determine if there is
a dose at which the maximum benefit of the drug exists.

This is a cross-over trial of escalating doses. There will be four parts to the study. In the
first part, subjects will stop taking CBTDs for 7 days, and perform a 24-hour urine
collection on day 7. In part 2, they will take their usual CBTD (either tiopronin or
d-penicillamine) 1 gram per day for 7 days. They will perform another 24-hour urine
collection on day 7 of this study period. In part 3, they will take their usual CBTD at 2
grams per day for 7 days and in part 4 they will take their CBTD at 3 grams per day for 7
days. Again, they will perform 24-hour urine collections on day 7 of each period. The order
in which the parts of the study are performed will be randomized for each subject. The mean
cystine capacities in each part of the study will be compared to determine the effect of drug
dosage on urinary cystine capacity.

Inclusion Criteria:

- Be a patient with a confirmed diagnosis of cystinuria.

- Be already taking a CBTD (either D-penicillamine (Cuprimine®) or tiopronin (Thiola®)
as part of your medication regimen.

- Be between 18 and 80 years of age

- Be enrolled in the Cystinuria Registry.

Exclusion Criteria:

- You are not a patient with cystinuria

- You are not already taking a cystine binding thiol drug

- You have renal colic (if you are passing a stone)

- You are scheduled to undergo a urologic procedure

- You are unwilling or unable to provide informed consent in order to be able to
participate.