Medication Summary
Without medical therapy, patients with cystinuria are certain to develop new calculi. Strategies for stone prevention and dissolution include adequate urine output, urinary alkalinization, and use of thiol derivatives.
In the past, sodium bicarbonate was used for alkalinization, but potassium citrate is preferred currently to help limit dietary sodium intake. Thiol derivatives are used when calculi recur despite adequate hydration and alkalinization. These agents dissociate the cystine homodimer and create a new disulfide molecule that is more soluble in urine.
D-penicillamine has been used the longest in cystine stone prevention but is the least well-tolerated. More than 50%-70% of patients stop taking the drug because of its adverse effects.
Tiopronin (alpha-mercaptopropionylglycine) acts in a manner similar to that of D-penicillamine, but its adverse effects are less severe and patient compliance approaches 70%.
Captopril is another thiol derivative that decreases urinary excretion of cystine. Although well tolerated, the clinical efficacy of captopril for preventing new stones is still being evaluated.
Urinary alkalinization agents
Class Summary
Potassium citrate is metabolized to bicarbonates, which increase urinary pH levels by increasing the excretion of free bicarbonate ions without producing systemic alkalosis when administered in recommended doses. A rise in urinary pH levels increases the solubility of cystine in the urine. Raise the urine pH level to 7-7.5 to make cystine more soluble.
Potassium citrate (Bicitra, Citrolith, Oracit, Polycitra Syrup, Polycitra-K)
Maintains urine pH level of 7-7.6.
Potassium bicarbonate/potassium citrate (Effer-K, K-Lyte, K-Lyte DS)
Potassium alkalinizes urine, which increases the solubility of cystine. One gram of potassium bicarbonate provides 10 mEq of potassium.
Sodium bicarbonate (Neut)
Sodium bicarbonate is effective for urinary alkalinization but has a sodium load, which may not be desired in patients with associated medical conditions such as hypertension and heart failure. In addition, sodium has the adverse effect of promoting cystine excretion.
Chelating agents
Penicillamine (Distamine, Cuprimine, Depen)
Penicillamine combines chemically with cystine (cysteine–cysteine disulfide) to form penicillamine–cysteine disulfide, which is more soluble than cystine and is readily excreted. As a result, urinary cystine concentrations are lowered and the formation of cystine calculi is prevented. With prolonged treatment, existing cystine calculi may be gradually dissolved.
Reducing agents
Class Summary
These are active reducing agents that undergo thiol-disulfide exchange with cystine (cysteine-cysteine disulfide) to form tiopronin-cystine disulfide, which is more water-soluble than cystine and is readily excreted. As a result, urinary cystine calculi are prevented.
Tiopronin (Thiola, Tiopronin DR, Tiopronin-K DR)
An active reducing agent that undergoes thiol-disulfide exchange with cystine. Twenty-five percent of the orally administered dose appears in urine to participate in thiol-disulfide exchange with cystine, thereby reducing renal excretion of sparingly soluble cystine.
ACE inhibitors
Class Summary
These are agents that can compete with the disulfide bond in cystine and result in the formation of a cystine complex.
Captopril (Capoten)
Mechanism of action is similar to that of thiols. Contains a free sulfhydryl group that can compete with the disulfide bond in cystine and result in formation of a cystine-captopril complex that is 200 times more soluble than cystine. Has been studied for treatment of cystinuria; however, data are insufficient to establish efficacy and further studies, especially randomized controlled studies, are warranted. May be useful in hypertensive patients with cystinuria who require antihypertensive medications or in patients in whom standard treatment for cystinuria fails.
Rapidly and at least 75% absorbed from gastrointestinal tract. Absorption is reduced by 30-55% in the presence of food. Protein binding is low (25%-30%), primarily because of albumin; biotransformation is hepatic. Onset of action is 15-60 min, and duration of action is approximately 6-12 h and dose-related. Elimination is renal (>95%; 40-50% unchanged; may be less in patients with congestive heart failure), remainder as metabolites.
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Cystine solubility in urine.
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Electron microscopic picture showing cystine crystals.
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Plain radiograph of the abdomen showing cystine staghorn stones.
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Faintly opaque (ground-glass appearance) left lower ureteric stone.
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Intravenous urogram showing left ureterohydronephrosis.
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Renal sonogram demonstrating renal calculi in the lower pole.
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Treatment algorithm for cystinuria.
Tables
Rosenberg et al [27] |
Type I |
Type II |
Type III |
Molecular |
Type I |
Non–Type I |
|
Responsible gene |
SLC3A1 |
SLC7A9 |
|
Band |
2p21 |
19q13.1 |
|
No. of mutations |
>60 |
39 |
|
Most common mutation |
M467 |
V170M |
|
Population affected |
Mediterranean Spanish persons, 40% |
Libyan Jews |
|
Deletion rate |
54% |
25% |
|
Protein |
rBAT |
BAT1 |
|
Amino acid transport system |
|||
Localization in proximal converted tubule |
S3 |
S1, S2 |
|
Transporter characteristic |
High affinity, low capacity |
Low affinity, high capacity |
|
Clinical features |
|||
Homozygotes |
Symptomatic |
approximately 90% symptomatic |
|
Heterozygotes |
Asymptomatic |
approximately 10%-13% symptomatic |
|
Urinary cystine levels |
Normal |
Elevated +++++ |
Elevated + |
Plasma cystine levels after an oral load test |
Same |
Same or slight rise |
Increased |
Intestinal transport |
Absent (no transport of cystine, lysine, or arginine) |
Absent |
Reduced |
