Skip to content
Home » Stone » Cystinuria

Cystinuria

Epidemiology

  • Approximate prevalence of 1 in 7000.
  • 6 – 10 % of paediatric stones.
  • < 1 % of adult stones.

Genetics

  • Autosomal recessive condition.
  • Inborn error of metabolism.
  • Two main genes affected are SLC3A1 and SLC7A9, with many mutations.

Pathophysiology

Normally, amino acids are filtered by glomerulus and then essentially completely reabsorbed in the proximal tubule.

Cystinuria patients have a defect in the transporter responsible for the reabsorption of four dibasic amino acids in the proximal tubule

  • Cysteine
  • Ornithine
  • Lysine
  • Arginine

Therefore these patients have abnormal levels of those 4 amino acids in urine – but the other three are soluble and of no clinical significance, which cysteine is insoluble and forms stones.

Cysteine is a non essential amino acid, which can be synthesised from the essential amino acid methianone.

Cystine is the oxidised form of cysteine with two cysteine molecules linked by a disulfide bond.

Cystine is more soluble with increasing pH – i.e. dissolves more in more alkaline urine.

Classification

Traditionally type I, II and III based on heterozygote patents level of urinary cystine excretion.

Revised to:

  • Type A – chromosome 2
  • Type B – chromosome 19
  • Type AB – both chromosomes affected

Homozygotes express very high levels of urinary cystine excretion and form stones.

Heterozygotes of both types excrete cystine in urine, with higher levels seen in type B heterozygotes, but there is no different in rates of stone formation between type A and type B heterozygotes, with stone formation being uncommon.

Clinical features

Median age of onset 12 – 13 years.

Possibly family history, although most family members will be carriers/heterozygotes and won’t necessarily form stones.

Urine microscopy:

  • Pathognomonic hexagonal crystals seen in 20 – 40 % patients

Urine testing:

  • Acidic pH
  • Quantitative cystine levels in urine
    • Normal < 30 mg/day
    • Heterozygotes generally < 250 mg/day
    • Homozygotes generally > 400 mg/day

Imaging:

  • Opaque on x-ray, but not as dense as calcium
  • Classically described as smooth-edged
  • Mean HUD 700 – 1000 on CT

Cyanide nitroprusside test:

  • Cyanide converts cystine to cysteine, which binds to nitroprusside causing the liquid to turn purple-blue within 2 – 10 minutes

Management of cystinuria

Principles:

  • Younger patients who will likely form multiple stones and require multiple surgical interventions over their lifetime
  • Aim to perform the least amount of invasive interventions as necessary, whilst also preventing the complications of stone formation (including pain, sepsis and loss of renal function)
  • Prevention is the most important part of treatment, and compliance is often difficult

Dietary:

  • Fluid intake most important – aiming for 3 litres of urine/day, possibly requiring 4 – 5 litres of fluid intake, including nocturnal intake
  • Low salt
  • Avoid or reduce dietary protein, to reduce methionine which is the precursor to endogenous cysteine production

Alkalinisation:

  • Aiming for urine pH > 7
    • Potassium citrate
    • Sodium bicarbonate may be less effective due to sodium levels

Medical management / chelating agents:

  • D-penicillamine and Thiola (α-mercaptopropionylglicine; tiopronin) – work by accomplishing a disulfide exchange with cystine – breaking the bond, and then the drug forms a complex with the resulting cysteines which is more soluble
  • Thiola may have less side effects and was recommended as first line in AUA guideline and EAU guidelines for patients with recurrent stones despite hydration, dietary and alkalinisation.
  • > 50 % of patients have significant side effects, often limiting compliance
    • Rash, nausea/vomiting, fevers, diarrhoea, arthralgias, leukopenia/thrombocytopenia, hepatotoxicity, vitamin B6 deficiency
    • Rarely, proteinuria associated with membranous nephropathy
    • Consider giving pyridoxine supplementation concurrently
  • Captopril is an ACE-inhibitor containing a thiol group which may be used if unable to tolerate Thiola or in hypertensive patients
  • Checking levels of cystine in urine in patients on drug treatment may be unreliable as testing may not discriminate between cystine and drug-cysteine complexes

Surgical management of cystinuria

ESWL is classically poorly effective due to the uniform crystal structure which makes them resistant to fragmentation.

Treat ureteric and renal stones as per usual based on size and location, with consideration given to attempting to reduce number of procedures and always aiming for stone free after intervention.

Characteristic ‘rotten egg’ smell during laser fragmentation.

Follow up

Patients are at high risk of CKD over the long term cf. recurrent stone formers of other types.

Involve a renal physician early.

Periodic imaging with ultrasound or low-dose CT to assess for stone burden and recurrence.

Consider screening of siblings with 24 hour urine cystine levels.

Some clinicians do urine analysis (microscopy for crystals, quantitative analysis of levels) but there is no evidence basis for this.