Introduction

Cystinuria is an autosomal recessive disorder characterized by defective reabsorption of cystine and other amino acids (ornithine, lysine, and arginine) by the proximal tubule.¹ Biallelic mutations affect either of the 2 subunits that constitute the cystine transporter: rBAT (encoded by SLC3A1) and b^0,+AT (encoded by SLC7A9), which are connected via a disulfide bridge.¹ The resulting high urinary concentration of cystine, which is poorly soluble at normal urinary pH, leads to urolithiasis. Cystinuria is rare and represents 1% to 2% of all cases of nephrolithiasis but as much as 6% to 8% of stones in the pediatric population. Diagnosis is most often confirmed by performing stone analysis via infrared spectroscopy or x-ray crystallography. In patients where stone analysis is not possible, examining a random urine sample for hexagonal cystine crystals or quantifying 24-hour urine cystine excretion can help to make the diagnosis.² Most labs specializing in the analysis of 24-hour urine collections perform a qualitative screening test for cystinuria that may reveal otherwise unsuspected cases. Genetic testing is currently not required given the lack of correlation between genotype and phenotype; we expect that, at some point, genotype will influence therapy and the eventual application of gene-based therapy.³ Without treatment, patients often form large stones, resulting in multiple urologic procedures.⁴ Cystine stone formers tend to have a higher incidence of chronic kidney disease, hypertension, and poor quality of life compared with noncystine stone formers.⁴ In this article, we review the medical management of cystinuria and the potential of future gene-based therapy.

Conservative Management

“Conservative management” with increasing urine output, dietary modifications, and urine alkalinization comprises first-line treatment of cystine stones.

Fluid intake

Urine concentration of cystine greater than 250 to 300 mg/L is associated with higher supersaturation and greater risk of stone formation.³ The goal of hyperhydration is to maintain urine output to keep cystine urinary concentrations less than that. Given an approximate average cystine excretion of about 1000 mg/d, more than 3 L of water per day is recommended in adults.²

Urine alkalinization

Cystine solubility is pH dependent, and therefore, urinary alkalinization is also pivotal in preventing stone recurrence. The goal pH to maintain cystine solubility is 7.5 or more.² This can be achieved with potassium (K) citrate 10 to 30 mEq 2 to 3 times per day. In a retrospective study of 442 cystine stone patients, urine alkalinization was found to be effective and well tolerated.⁵ Gastrointestinal side effects were common with citrate supplements and were reported by 12.3% of patients on K bicarbonate, 10.4% on K citrate, and 2.6% on sodium bicarbonate.⁵ Since citrate and hyperhydration inhibit calcium stone formation, the risk of higher urine pH causing precipitation of Ca phosphate stones is possible but likely overstated. In clinical practice, we often find the size of K citrate pills and gastrointestinal side effects as the most common reasons for nonadherence. Since sodium ingestion increases cystine excretion, we use sodium bicarbonate as a last resort. Over-the-counter preparations that increase urine pH might be useful.⁶

Diet

Low urinary sodium excretion reduces cystine excretion, and thus, a low salt diet of less than 2500 mg/d is commonly prescribed.³ Restricting animal protein and increasing plant-based protein to meet daily protein intake of 0.8 g/kg is recommended. However, while the effects of low-salt, low–animal protein diets on urinary parameters are clear, their effect on cystine stone formation has not been demonstrated in clinical trials.²

Pharmacotherapy

If patients form stones while on “conservative management,” cystine-binding thiol drugs (CBTDs) should be considered to prevent recurrence.³ CBTDs work by breaking the disulfide bond of cystine, forming a soluble drug-cysteine complex. Currently available CBTDs are tiopronin and D-penicillamine. Tiopronin is preferred as the first-line CBTD over D-penicillamine due to fewer side effects. Both drugs have a rare risk of secondary membranous nephropathy.³ There are both generic and enteric-coated branded preparations available, which have not been compared with respect to efficacy or tolerance. Previous Food and Drug Administration recommendations to monitor complete blood counts and liver tests have been eliminated. Optimal dosing for tiopronin is 15 to 40 mg/kg in 3 divided doses and for D-penicillamine at 20 to 30 mg/kg in 3 to 4 divided doses.

α-lipoic acid (ALA) has been shown to reduce cystine stone formation in Slc3a1^-/- knockout mice. A recent AUA abstract demonstrated that in people with cystinuria, the supplement reduced overall stone burden: compared to 14% on placebo, 40% percent of patients who received ALA had a decreased stone growth.⁷ There are rare cases associated with membranous nephropathy in people without cystinuria who use it. SGLT-2 inhibitors appear to inhibit the formation of stones of other compositions, so they are currently also under investigation. Another recent AUA abstract of a nonrandomized observational study showed that people with cystinuria treated with dapagliflozin experienced fewer stone events compared to their historical rates and decreased or stable stone growth.⁸ Given the growing evidence of renal protective effects of SGLT-2 inhibitors, we recommend the class of drugs in patients with cystinuria who also happen to have diabetes, albuminuria, or reduced glomerular filtration rates. The mechanisms by which ALA and SGLT-2 inhibitors affect stone formation are currently unclear.

Cystine mimetics are drugs that can be excreted in the urine to bind to cystine crystals and interfere with further cystine crystallization. The most recent molecule with such properties is nearing phase 1 clinical studies.

Monitoring Urine Chemistry

Urinary cystine excretion and solubility can be followed to assess adherence and responses to fluids, diet, alkali, and CBTDs and adjust dosing. Two methods are available to follow the effects on urine chemistry. Measurement of cystine capacity (Litholink, Itasca, IL) is a test of cystine solubility in the patient’s urine. Higher positive values are desirable, while lower negative values indicate a risk for crystallization. Another test to measure urine cystine excretion is high-performance chromatography–tandem mass spectrometry. This method of quantification has been promoted for the measurement of cystine in patients receiving CBTDs because, in such patients, other assays do not differentiate between cystine and cysteine-thiol complexes.⁹

Genetic Therapies

The CRISPR/Cas9 system is one of the most remarkable discoveries of our time. Its ability to edit genes may be the answer to rare genetic disorders. It has already been shown to be effective and approved for the treatment of sickle cell disease. Cystinuria may be amenable to the potential of CRISPR/Cas 9 to modify the genotype. Gene-based therapies for kidney disease are lagging compared to those of other organs; it is partly due to its complex anatomical architecture that makes delivery of the system difficult. However, with advances in nanoparticles, it may be possible to deliver the system to the proximal tubule.¹⁰ Given evolving genetic therapies, we highly recommend genetic testing in all patients with cystinuria to help us better understand the disease at the molecular level and develop therapies in the future.

Conclusions

Conservative management of cystine stones with water, dietary modification, and significant alkali supplementation may serve as adequate and inexpensive preventive therapy in many patients. Cystine-binding thiol drugs are indicated when conservative therapy does not suffice. New drugs are in development, while gene therapy is now conceivable.

Conflict of Interest Disclosures: Dr Goldfarb reported being a consultant for Alnylam, Arbor Biotechnologies, NovoNordisk, Arthrosi, and Lilac Pharma; receiving research funding from Travere and NovoNordisk; and being owner of Moonstone Nutrition, Inc. No other disclosures were reported.