Cystine Stones

Cystine stones form in patients with cystinuria, an autosomal recessive disorder (SLC3A1 and SLC7A9 mutations) of renal tubular and intestinal transport of cystine, ornithine, lysine and arginine.

• Prevalence is about 1 in 7000; it causes 1 percent of adult and 6 to 8 percent of paediatric stones.
• Cystine is poorly soluble at urine pH below 7 (solubility about 250 mg/L at pH 7, 400 mg/L at pH 7.5).
• Stones begin in childhood to young adulthood and recur frequently; they may form staghorn calculi.

Renal colic, haematuria, recurrent stones in a young person, positive family history, flank pain, urinary infection.

• Stones are hard, yellow-brown, faintly radio-opaque (ground glass appearance on plain film) and often multiple and bilateral.
• Differential diagnosis: calcium oxalate, uric acid, struvite, and xanthine stones, medullary sponge kidney, primary hyperoxaluria, renal tuberculosis.
• Complications: obstruction, recurrent surgery, infection, chronic kidney disease (up to 70 percent of patients with decreased renal function after repeated interventions), hypertension, and loss of kidney.

Hexagonal crystals on urine microscopy (first morning specimen, acidified urine).

• Qualitative cyanide nitroprusside test is positive when cystine excretion exceeds 75 mg/g creatinine.
• 24-hour urine cystine (above 1.3 mmol/day or 300 mg/day in homozygotes; heterozygotes excrete less); stone analysis confirms.
• Low dose CT or ultrasound; serum creatinine and electrolytes; family screening.
• Genetic testing for confirmation and family counselling.

Supportive: the aim is a urinary cystine concentration below 250 mg/L.

• Fluid intake of 3.5 to 4 L daily (children 1.5 L/m2 or more) including a drink before bed and one during the night, so that urine volume is above 3 L daily.
• Sodium restriction below 2 g daily (about 5 g of salt); animal protein restriction (methionine) to 0.8 g/kg/day; a diet rich in fruit and vegetables to alkalinise urine.

Pharmacological

• Urinary alkalinisation to pH 7.0 to 7.5: potassium citrate 30 to 60 mmol daily in 3 to 4 divided doses, or sodium bicarbonate 1 g three times daily, with urine pH monitoring at least three times daily; acetazolamide 250 mg at night to alkalinise urine overnight.
• Thiol drugs if cystine excretion remains above 250 mg/L or stones recur: tiopronin starting 250 mg twice daily increasing to 800 to 1000 mg daily in divided doses (maximum 2 g daily), or D-penicillamine 250 mg daily increasing to 1 to 2 g daily in divided doses with pyridoxine 50 mg daily; monitor for proteinuria, nephrotic syndrome, rash, blood dyscrasias and taste loss.
• Captopril 25 mg three times daily (modest benefit) when thiol drugs are not tolerated.

Procedures: ureteroscopy with holmium laser lithotripsy or percutaneous nephrolithotomy (shock wave lithotripsy is ineffective for large cystine stones); remove all fragments; nephrectomy for non-functioning kidney.

Special groups: children (hydration, alkali, careful thiol use), pregnancy (avoid D-penicillamine because of teratogenicity; tiopronin only if essential), chronic kidney disease (dose adjustment).

Red flags: obstruction with infection, bilateral stones, solitary kidney, falling eGFR, nephrotic range proteinuria on thiol therapy.

Follow-up: 24-hour urine cystine, pH and volume every 3 to 6 months; imaging yearly; renal function and urine protein every 3 months on thiol drugs; screen siblings.