Cystine Nephrolithiasis

Cystine stones result from cystinuria, an autosomal recessive (rarely incomplete dominant) disorder of renal tubular and intestinal transport of the dibasic amino acids cystine, ornithine, lysine and arginine (COLA). It affects about 1 in 7,000 births and accounts for 1 to 2 percent of adult stones and 6 to 8 percent of paediatric stones.

Stones are recurrent, bilateral and often multiple, and the lifetime burden of repeated surgery and chronic kidney disease is high.

Genetics and mechanism:

• Mutations in SLC3A1 (type A, encoding rBAT) or SLC7A9 (type B, encoding b0,+AT) cause the disorder.
• Reabsorption of filtered cystine in the proximal tubule fails. Urinary cystine rises above 400 mg per day in homozygotes (normal below 30 to 60 mg).
• Cystine is poorly soluble at urinary pH below 7.0. Solubility is about 250 mg/L at pH 5 to 7, rising sharply above pH 7.5. It therefore crystallises and forms stones.

Clinical pattern:

• Presentation is usually in the first to third decades.
• Stones are recurrent, bilateral and often multiple. Staghorn calculi form in 10 to 30 percent.
• The stones are hard, waxy, yellow, and faintly radiopaque (due to sulphur content).
• Chronic kidney disease develops in about 17 to 70 percent.

• Recurrent renal colic and haematuria from early age (first stone usually before age 30, even in infancy), and in homozygotes, in both sexes (more severe in males).
• Urinary tract infection and obstruction; staghorn stones.
• Chronic kidney disease from recurrent obstruction, surgeries and scarring.
• Family history of stones, and stone recurrence despite normal calcium and uric acid.
• Hexagonal flat crystals in urine ("benzene ring") in a pH-acid sample.
• Hypertension in association with renal damage.

• Urinalysis: hexagonal cystine crystals (colourless, flat, hexagonal, in acid urine after concentrated morning sample); positive cyanide nitroprusside test on urine (purple colour above 75 mg cystine per gram of creatinine) as a screening test.
• 24-hour urine: cystine excretion (above 400 mg per day indicates homozygous cystinuria, 100 to 300 mg heterozygous), with urine pH, volume, and other lithogenic factors.
• Stone analysis: cystine (confirmatory), the best way to diagnose.
• Imaging: CT, with cystine stones attenuation of 250 to 600 Hounsfield units; X-ray faintly radiopaque (ground glass); ultrasound with shadowing stones.
• Genetic testing for SLC3A1 and SLC7A9 for confirmation and family screening, which aids with prognosis and counselling.
• Blood: creatinine, eGFR; renal function monitoring.

The goals are to keep urinary cystine below its solubility, relieve symptoms and remove stones with minimal renal damage.

• Fluids: a high intake to produce urine volume of at least 3 to 4 L per day (2.5 to 3 L/m2 in children), including a drink before bedtime and during the night (to keep urinary cystine concentration below 250 mg/L).
• Diet: sodium restriction (below 2 g per day, as sodium raises cystine excretion), a moderate animal protein intake (to limit methionine, cystine's precursor, 0.8 g/kg per day), and a diet rich in fruit and vegetables.
• Urinary alkalinisation: potassium citrate 60 to 120 mEq per day in 3 divided doses (or sodium bicarbonate), to a target urine pH of 7.0 to 7.5 (monitor on dipstick 3 to 4 times daily). This increases cystine solubility and is most useful in combination with fluids.
• Thiol binding drugs for patients with a urinary cystine above 250 mg/L despite these measures, or with recurrent stones. Options are tiopronin or D-penicillamine, as follows.
• Tiopronin (alpha mercaptopropionylglycine): 800 to 2,000 mg per day in 3 divided doses. Start at 100 mg three times a day, increase to 250 mg per dose, and titrate with a 24-hour cystine target below 250 mg/L. In children, 15 mg/kg per day. It forms soluble tiopronin cystine disulphide.
• D-penicillamine: 1 to 2 g per day in 4 divided doses (250 mg daily to start and increase, with pyridoxine 25 to 50 mg per day). It is now less used because of toxicity.
• Adverse effects of thiol binding drugs include rash, nephrotic syndrome (membranous nephropathy), taste loss, leucopenia and thrombocytopenia, and lupus like syndromes. Monitor blood count, urine protein and liver tests every 3 to 6 months.
• Captopril 75 to 150 mg per day forms a captopril cysteine disulphide and has been used in some patients, but the evidence is limited.
• Surgical treatment of stones: cystine stones are resistant to shock wave lithotripsy (hard, particularly the smooth type). Ureteroscopy with holmium laser lithotripsy (high power dusting is effective) and percutaneous nephrolithotomy for large or staghorn stones are preferred. Open surgery is rarely needed. Use nephron sparing techniques and minimise the number of procedures, to preserve renal function, with complete clearance.
• Emergency: infected obstruction needs decompression (stent or nephrostomy) and antibiotics.
• Surveillance: 24-hour urine cystine, urine pH log and creatinine every 3 to 6 months initially, and imaging (ultrasound or low dose CT) yearly or when symptomatic. Screen siblings and offer genetic counselling.
• Pregnancy: continue hydration and alkalinisation. Tiopronin and penicillamine are avoided where possible (teratogenicity of penicillamine), and a risk benefit assessment should be made.
• Chronic kidney disease: ACE inhibitors for proteinuria, and standard nephrological care. Kidney transplantation is successful, without recurrence in the graft.