Cystinuria is a defect in amino acid transport. Amino acids are typically freely filtered by the glomerulus and almost completely reabsorbed in the proximal tubule. In cystinuria, there is a defect in transport and reabsorption of dibasic amino acids including cystine, ornithine, lysine and arginine.¹ However, it is the insolubility of cystine at physiological urinary pH that leads to calculus formation.

Cystinuria is rare with worldwide incidence of 1 in 7,000. This rate varies by region, as high as 1 in 2,000 in the UK and as low as 1 in 100,000 in Sweden. It occurs at 1 in 10,000 in the U.S. Cystinuria results in 1% of total stone formers and in 10% of pediatric formers.^1,2 Patients have a 17% risk of chronic kidney disease with <5% advancing to end-stage renal disease.^1,3 There is also an increased risk of developing hypertension in 29%–51% of patients.⁴

Cystine is insoluble at acidic pH levels. Its solubility is 250 mg/L (pH of 7.0) and 500 mg/L (pH of 7.5).¹ Cystinuria is an autosomal recessive disease linked to 2 genes, divided into 3 subgroups depending on the involved gene. Type A is a mutation in the SLC3A1 gene on chromosome 2. This gene encodes the heavy subunit of the renal amino acid transporter, rBAT, which is responsible for localizing the transporter to the plasma membrane. All Type A patients have increased urinary cystine and 94% form stones. Heterozygotes have normal levels of cystine excretion.^3,4 Type B is a mutation in the SLC7A9 gene on chromosome 19 which encodes the light subunit of the renal amino acid transporter b0, +AT, comprising the catalytic transporting component. Homozygotes have similar penetrance to type A, while heterozygotes often have elevated cystine levels but rarely develop stones.^3,4 Type AB cystinuria is rare with mutations in both genes. Type AB patients will have elevated cystine levels but rarely develop stones, with a frequency of 1.2%–4%.⁴

There should be a high index of suspicion in patients who present with stones within the first 2 decades of life (80% of cases).² An early morning urinalysis identifying hexagonal crystals occurs in 25% of cases and is pathognomonic.³ Definitive diagnosis is made with stone analysis and 24-hour urine collection. Historically, the cyanide-nitropruside colorimetric test was used, displaying a purple color with cystine levels greater than 75 mg/L. However, it is rarely used for screening with a sensitivity of 72% and specificity of 95%.³

The cornerstones of cystinuria therapy includes hydration and urinary alkalinization to lower concentration and increase solubility of cystine. Patients should be advised to increase fluid intake to produce greater than 3 L of urine per day, including adequate intake before bedtime. Urine neutral and alkalinizing beverages, like mineral water, are recommended.² A low sodium diet of less than 2 gm/day is recommended which decreases cystine excretion.¹ Special attention should be paid to foods that are high in methionine, the source of urinary cystine. Patients should not reduce methionine to less than 1,200–1,400 mg/day. It is recommended to reduce animal protein to 1 gm/kg/day in adults, but not in children who are still growing.^3,4

While dietary modifications may alkalinize urine, alkali agents are likely needed to adequately raise urinary pH. The first line therapy is potassium citrate, dosed at 60–80 mEq/day divided into 3–4 doses, titrating to a pH of 7–7.5.¹ If the patient cannot tolerate potassium citrate, other alkali agents may be used like sodium bicarbonate; however, this may increase cystine excretion as well.

Chelating agents are third line options. Thiol compounds combine with cystine to form a more soluble disulfide complex.¹ D-Penicillamine is a first-generation agent that combines with cystine, forming a complex that is 50 times more soluble. However, it is poorly tolerated with up to 84% of patients experiencing significant side effects with a 70% discontinuation rate. These side effects include nausea, diarrhea, fever, nephrotic syndrome, myalgias, pancytopenia, zinc and copper deficiencies, and vitamin B6 deficiency with chronic use. Patients should have close monitoring of renal function, blood counts, liver function, and mineral levels.⁵

Alpha-mercaptopropionylglycine (A-MPG) is a second-generation agent that has a higher dissolution capacity than D-penicillamine with a similar yet better tolerated side effect profile. Of patients 20%–50% experience significant side-effects, and the discontinuation rate is half that of D-penicillamine.^2,3,5 A-MPG dosing is 400–1,200 mg/day divided in 2–3 doses. A new enteric-coated formulation allows for a reduction in pills that can be taken without food.⁵ For pediatric patients, dosing is 20–40 mg/kg/day given in 2 doses.² Routine followup is similar to that of D-penicillamine, and discontinuation of medication is necessary for worsening renal function.^3,4,6

Since being Food and Drug Administration approved in 1988, A-MPG has been the mainstay of treatment for cystinurics. There are several clinical trials aimed at improving treatment options. Bucillamine is a third-generation thiol-binding agent approved in Asia for rheumatoid arthritis that has a lower side effect profile. Tolvaptan, a vasopressin antagonist, increases urine output to decrease urinary cystine concentrations. Alpha-lipoic acid is a supplement that increases cystine solubility in a Type A SLC3A1 knockout mouse model. The cystine inhibitor bis (N’-methylpiperazide) has shown effectiveness in inhibiting stone formation in another SKC3A1 knockout study.⁷ While improvements in treatment have been slow since 1988, there is promise in these studies.

When counseling patients, quality of life should be continually assessed. Cystinurics have lower quality of life scores than the general population. However, these scores improve across all parameters when being treated with A-MPG.⁶ This not only highlights the importance of treatment, but also the long-term struggles these patients will face. It is imperative that providers remain cognizant of the challenges this population faces.

The management of cystinuria is challenging for both provider and patient. However, with increased hydration, alkali therapy, as well as thiols for those failing initial treatments, patients can reduce stone recurrence. Close followup with routine labs and 24-hour urine collections is necessary to optimally titrate these medications. With several clinical trials on the horizon, these patients should remain hopeful for increased treatment options to reduce future stone events.