Cystinuria

Cystinuria is an autosomal recessive disorder. The kidney glomerulus fails to resorb cystine, ornithine, lysine and arginine into the tubule and they are excreted into the urine.The rBAT gene which controls cystine excretion was isolated in 1992.^1,2
There are three types of cystinuria, distinguished by the mode of inheritance and by the pattern of the intestinal amino acid transport.³

• Cystine stone formation in the kidneys; a quarter of patients experience symptoms in the first decade of life.
• Pain, haematuria, renal obstruction and infection
• Renal failure can sometimes occur.⁴

Only 1 to 2 per cent of all renal stones in adult life are cystine stones. The proportion is higher in childhood.

• Calculi are frequently multiple and bilateral and often form staghorns.
• The diagnosis is suspected when stone analysis reveals a cystine stone. Cystine stones are pale yellow. 20-40% have cystine mixed with calcium oxalate, calcium phosphate, or magnesium ammonium calcium phosphate.
• Diagnosis can be confirmed by an amino acid chromatogram and quantification of cystine excretion. This is worth doing even when the stone is mainly composed of calcium, which can occur in cystinuria, due to predisposing infection.

For a patient with cystinuria who does not have a stone, first-line therapy in most cases is a conservative approach.⁵This includes:

• Large-volume fluid intake (at least 3 litres /day in adults); this must include 500ml before retiring to bed, with a nocturnal rise to pass urine and drink a further 500ml. Keeping the urine dilute over the 24hr period is the difficult part, but may be sufficient treatment for those without stones.
• Regular urine pH monitoring (urine pH level of 7.5 and <8);
• Dietary restrictions; reduced protein intake diminishes cystine excretion, but this is not often used in treatment.
• Urinary alkalisation with potassium citrate; cystine is much more soluble at alkaline pH (>7.5). Use of sodium bicarbonate is limited by the large doses (6 g/day or more) needed to raise urine pH significantly. These are contraindicated in hypertension or renal failure. In addition, alkaline urine may predispose to the precipitation of calcium salts.

If this standard therapy fails to achieve the urinary cystine concentration of 300 mg/L, then medical therapy with D-penicillamine, alpha-MPG, or captopril must be added.

Penicillamine

• Penicillamine produces the much more soluble disulphide - half cystine and half penicillamine- and an overall reduction of cystine excretion greater than can be accounted for by disulphide formation.
• The effective dose (1 to 3g/day) should reduce the free cystine excretion to around 200mg/day if stones are to dissolve.
• It is usual to start at a dose of 125mg/day and increase over several weeks to full dose.
• The side-effects include blood dyscrasias, rash with arthralgia, fever and lymphadenopathy.
• Patients on penicillamine need blood counts every 2 weeks initially and then monthly.
• Regular urinalysis is needed. Proteinuria is common and above 2g/day may necessitate stopping penicillamine, as do blood dyscrasias or other severe reactions.
• Penicillamine is a helpful preventive treatment in recurrent stone formers at lower doses. Large doses are reserved for trying to dissolve large calculi, which may take 1 to 2 years. It is usually well tolerated in cystinuria.
• Sulphydryl compounds with similar side-effects (e.g. mercaptopropionylglycine), have been used in some countries in place of penicillamine but are not available in the United Kingdom.
• Captopril is a sulphydryl compound which forms a disulphide with cystine. Reports of decreased cystine excretion related to treatment with captopril have not been confirmed and no therapeutic use has yet been established.

Management of Stones

Treat patients with stone disease according to the location and size of the stone.

• Cystine stones are not easily broken by lithotripsy.
• Percutaneous removal may have its place for smaller stones, particularly in those who cannot take penicillamine and who are unable to regulate their drinking adequately.
• Keeping patients free from stones using minimally invasive techniques helps to reduce the incidence of stone recurrence.⁶