PEDBASE.org - The Pediatric Database - Detailed information of CYSTINURIA

CYSTINURIA

DEFINITION:

A disorder of amino acid transport characterized by a renal cystine transport defect resulting in urinary tract calculus disease.

EPIDEMIOLOGY:

incidence: 1/7,000 (1/15,000 in the USA)
age of onset:
- peaks in 2nd and 3rd decades
risk factors:
- familial - autosomal recessive
  - chrom.#: 2p
  - gene: rBAT gene
- M = F (although males have a greater morbidity and morality)
- England (1/2,000), Libyan Jews (1/2,500)

PATHOGENESIS:

1. Background

first described by Sir Archibald Gerrod in 1908 as an inborn error of metabolism with a defect in the metabolism of cystine responsible for the disorder
Dent and Rose (1951) postulated that a single renal transport mechanism for cystine and dibasic amino acids was defective in cystinuria
Milne et al (1961) was the first to demonstrate reduced intes-tinal absorption of dibasic amino acids in patients with cystin-uria suggesting that cystinuria is a disorder of amino acid transport affecting both the epithelial cells of the renal tubule and gastrointestinal tract

2. rBAT

a 90 kDa type II glycoprotein which stimulates the transport of cystine, dibasic amino acids, and neutral amino acids across membranes (Bertran et al., PNAS 89:560 [1992])
may represent a transporter protein, a regulating subunit of a transporter protein, or may simply affect the functional expres-sion of such a transporter protein
a protein which spans across the membrane only once

3. Genetic Defect

genetic defect -> mutation in rBAT gene -> defective reabsorp-tion of cystine in the kidneys -> excretion of all the filtered cystine into the urine + cystine stones due to the limited solubility of cystine in the urine
6 specific mutations in the rBAT gene have been identified which alter amino acids in the external C-terminal portion of the protein (Calonge et al., Nature Genetics 6:408 [1994])
there may be 3 clinical variants:
- the most sensitive way to differentiate the 3 variants is by the in vitro study of the intestinal transport of cystine and dibasic amino acids

CLINICAL FEATURES:

1. Renal Manifestations

1. Renal or Ureteral Colic

most common presentation
cystine calculi tend to occur as staghorn or as multiple recurrent stones
calcium or magnesium ammonium phosphate (struvite) stones may also form

2. Complications of Cystine Calculi

hematuria
dysuria
urinary tract infections
hypertension
obstruction
renal failure

INVESTIGATIONS:

1. Urine

1. Microscopy

cystine crystalluria
- hexagonal plate-like crystals
- yellowish-brown in colour

2. Cyanide-Nitroprusside Test

magenta-red coloured urine

3. Urine for Amino Acids

cystinuria, lysinuria, argininuria, ornithinuria
paper chromatography or electrophoresis

2. Serum

1. Serum for Amino Acids

normal or decreased concentration of cystine and dibasic amino acids

2. Others

elevated BUN, creatinine, uric acid

3. Imaging Studies

1. Abdominal X-Ray

radio-opaque cystine calculi in the renal pelvis, ureters, or bladder - appear smooth and less dense than calcium stones

MANAGEMENT:

1. Diet

1. Low Sodium

sodium tends to increase urinary amino acid excretion
low sodium diet (100 mg/d; 150 mmol/day)

2. Low Methionine

cystine arises from the metabolism of methionine
response to a low methionine diet is variable from bene-ficial to unsuccessful
avoid excessive methionine intake

2. Decreasing Cystine Solubility in Urine

1. Increasing Urine Volume

may need up to 4 or more litres per day of fluid
2 glasses of water at bedtime and again at 2-3 am to prevent low urine flow at night
may prevent stone formation in 2/3 rd's of patients

2. Alkalinize Urinary pH

increased cystine solubility when the urinary pH > 7.5 (maximal urine pH is 8.0)

3. Conversion of Cystine to a More Soluble Compound

1. Penicillamine

produces a mixed disulfide of cysteine-penicillamine which is much more soluble than cystine
prevents and dissolves cystine stones
represents 2nd line therapy used after the more conserva-tive therapies outlined above, i.e. diet, fluid, alkalin-ization

2. Mercaptopropionylglycine

acts like penicillamine with apparently less side effects
experimental use

4. Surgical Approaches

1. Catheter Irrigation

with alkaline solutions of penicillamine

2. Lithotripsy

percutaneous lithotripsy effective

3. Lithotomy

surgical removal of obstructing stones

4. Renal Transplantation

for chronic renal failure

Pediatric Database - CYSTINURIA

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