 Abstract | | |
Cystinuria is a rare autosomal recessive trait with a defect in transport of cystine and other dibasic amino acids in the kidney and intestine. Renal stone formation is the only clinical presentation of cystinuria. We present herewith three cases with cystinuria. Case 1 is a 13-year-old boy known to have Bernard Soulier syndrome who presented at the age of six years with staghorn stone of the left kidney. He was treated with extracorporeal shock wave lithotripsy (ESWL) with little benefit, followed by percutaneous nephrolithotomy (PCNL). He still gets recurrent renal stones and is being treated with high fluid intake, low sodium diet, captopril, K-citrate and D-pencillamine. Case 2 is a 10-year-old boy, brother of the first patient, who was diagnosed as cystinuria on family screening. He presented with bilateral tiny renal stones. Case 3 is a four-year-old girl who presented at the age of 1.5 years with urinary tract infection (UTI). Renal ultrasound showed left hydronephrosis and intravenous pyelography (IVP) showed bilateral ureteral stones. She underwent cystoscopy and lithiotripsy twice; currently she is on captopril, K-citrate, high fluid intake and low sodium diet. We believe this is the first report of cystinuria in children from Bahrain. Keywords: Cystinuria, Children, Cystine stone, Captopril, Extracorporeal shock wave lithotripsy, Percutaneous nephrolithotomy, Bahrain.
How to cite this article:
Al-Hermi B, Al-Kameli A, Aal AA. Cystinuria in Children in Bahrain. Saudi J Kidney Dis Transpl 2002;13:171-5 |
| Introduction | |  |
Cystinuria is a rare autosomal recessive trait with defect in transport of cystine and other dibasic amino acids by the epithelial cells of the renal tubules and small intestine. [1] The increased urinary excretion of cystine, the least soluble of all amino acids, results in cystine crystallization and recurrent stone formation. [2],[3] Cystine stones are the only significant clinical expression of cystinuria and accounts for 1-2% of renal stones observed in adults and up to 10% of those occurring in children. [2],[4],[5],[6]
We present here three cases with cystinuria with review of the literature and, we believe this is the first report of cystinuria in children from Bahrain.
| Case Description | | |
Case 1:
A 13-year-old boy, known to have Bernard Soulier Syndrome, presented at the age of six years with staghorn stone of the left kidney; he was treated initially with extracorporeal shock wave lithotripsy (ESWL) with little benefit. Subsequently, percutaneous nephrolithotomy (PCNL) was done. However, he still gets recurrent renal stones and his investigations showed normal renal function, urine was positive for cystine crystals and the urine amino acid assay showed high levels of cystine, ornithine, arginine and lysine. He was treated with high fluid intake, low sodium and methionine diet (mainly low animal protein), captopril, 20% K-citrate and Dpenicillamine. He developed gastritis and peripheral neuropathy as side effects of Dpenicillamine following which the drug was discontinued. He is poorly compliant with both the fluid and diet intake.
Case 2:
A 10-year-old boy, brother of the first patient, was diagnosed to have cystinuria on family screening. His urine was positive for cystine crystals and urine amino acid assay showed high levels of cystine, ornithine, lysine and arginine. He was found to have bilateral tiny renal stones seen on renal ultrasound (US), and is under conservative management including high fluid intake, low sodium diet and 20% K-citrate.
Case 3:
A 4-year-old girl, presented at the age of one and half years with failure to thrive and recurrent urinary tract infection (UTI). Renal ultrasound showed left hydronephrosis and hydroureter and intravenous pyelogram (IVP) showed bilateral ureteral stones. Urine testing for amino acids showed high levels of cystine and dibasic aminoaciduria. She underwent cystoscopy and lithiotripsy twice. Examination of the stones revealed rough, hard and brown colored stones consistent with cystine-stones. Currently, she is on captopril, 20% K-citrate, high fluid intake, and low sodium diet.
On all three patients, the urine cystine level is being measured on regular basis every 2-4 months; the aim is to keep the cystine level < 250 mg/day. Also, regular renal US is being performed every 6-12 months for any new stone formation.
| Discussion | | |
Cystinuria is a complex hereditary disorder transmitted as an autosomal recessive trait. [1] Because of its lifelong duration and the likelihood of recurrent urinary stones in the affected individuals, cystinuria produces considerable morbidity. The reported incidence of the disease varies from 1:600 to 1:20,000; the disease seems to predominate in whites in all reported series, but there are occasional reports in blacks and Asians. [3],[6]
In 1966, Rosenberg et al described three types of classic cystinuria according to the urinary phenotype of obligate heterozygotes in the probands family. [2],[7] In 1994, a linkage analysis and a candidate gene strategy found an amino acid transporter gene on chromosome 2p, SLC3A1 (formerly rBAT), to be the type I cystinuria gene.
The second cystinuria gene (SLC7A9) on chromosome 19q13.1 was identified. Mutations of SLC7A9 were shown to cause the incompletely recessive forms of cystinuria (types II and III). [8],[9]
Cystinuria should be considered in every patient with renal stones. The simplest and most universally available screening test is microscopic examination of the urinary sediment. The presence of typical cystine crystals is diagnostic. However, crystals are found in only 17-26% of homozygous cystinuric patients, [10],[11] and the diagnosis cannot be excluded by their absence. A colorimetric method using sodium cyanide and sodium nitroprusside is a simple qualitative test used to detect cystinuria and it provides a convenient screening test. [12] Patients who show positive screening tests should be evaluated further with quantitation of urinary amino acids in 24-hour specimens for metabolic studies by ion exchange chromatography and/or infrared spectrometry of stones. [5],[13] Hypercalciuria, hyperurico suria and hypocitraturia frequently accompany cystinuria in patients with cystine nephrolithiasis. They may contribute to the formation of calcium and uric acid stones, which sometimes complicates cystine nephrolithiasis. [14]
Normal subjects excrete less than 0.13 mmol (30 mg) of cystine per day in the urine. Although cystine excretion in the range of 0.6 to 1.2 mmol (150 to 300 mg) per 24 hours usually does not require treatment, cystinuric patients who excrete more than 1.7 mmol (400 mg) per day can be expected to be at high-risk for stone formation. [2],[6]
Medical therapy is directed towards dissolution of existing calculi and prevention of new stone formation. Increasing the urine volume by generous oral fluid intake above 3L/day (in children 1.5-2 L/m 2 ), is essential in patients forming cystine stones. Augmented diuresis per se may, through solute dilution, maintain cystine concentration under 1 mmol/L (250 mg/l). Patients should develop a 24-hour schedule for drinking and voiding, with particular attention to night time hours when urine may become supersaturated with cystine. [2],[5],[7]
Dietary sodium restriction has a favorable effect on urinary cystine excretion. Another dietary measure is avoidance of foods with very high methionine content, including stockfish and eggs, and by moderating the consumption of meat, fish, poultry and cheese, i.e. by limiting the intake of animal protein to 0.5 gm/kg per day; this will lower cystine production. However, most authors believe that such dietary restriction is not advisable for children since it is harmful for their growth. [2],[5],[6],[15] Cystine solubility can be improved by urinary alkalinization and, where necessary, by the administration of disulfide chelators (Thiols), particularly Dpenicillamine or mercaptopropionylglycine (MPG). Urinary alkalinization can be achieved by either sodium bicarbonate or sodium or potassium citrate given in a dose of 1-2 mEq/kg/day in divided doses, to maintain urine pH at about 7.5, but not above 8. Because high sodium intake increases cystine excretion, potassium citrate is preferred. [6],[16] Although D-penicillamine adequately reduces stone formation, its use has been limited by the 30 to 50% incidence of intolerable and, at times, serious side effects. [17] It appears that MPG is approximately 1.5 times as effective as Dpenicillamine in reducing the amount of urinary cystine. [18] Captopril also exerts its "solubilizing effect" via formation of a disulfide compound and is a more attractive agent compared to D-penicillamine and MPG for two reasons. First, the captoprilcystine compound disulfide is 200 times more soluble than cystine and, second, captopril has relatively few side effects. [1] The patient's compliance with medical or conservative treatment is the big issue as was the case with our patients. Compliance is especially difficult in children and adolescents, who often require psychological support. However, only regular medical prophylaxis may prevent recurrent stone episodes and protect renal function. [2]
Patients with infected, symptomatic, or obstructing stones require urological intervention. Cystine calculi can be dissolved by irrigation of the renal pelvis, using a catheter, with a variety of agents such as penicillamine or acetylcysteine. Their uniform crystal structure make cystine stones relatively resistant to fragmentation by extracorporeal shock wave lithotripsy; [19] as was seen in case 1 of our report, although stones less than 1.5 cm in diameter may respond. Percutaneous nephrolithotomy or percutaneous ultrasonic lithotripsy is generally preferred, particularly for larger stones. [20] Holmium laser has been used as a safe and efficient procedure to treat medium sized renal calculi. [21]
With careful medical and surgical management, the long-term outlook is good but recurrence rate is very high and instrumental treatment should not therefore be used excessively. [13] However, some patients may require unilateral nephrectomy because of obstruction and/or chronic infection. Renal function may eventually be compromised in up to a third of the patients, although fewer than 5% progress to end-stage renal disease. [5]
Renal transplantation has been performed in a limited number of patients. Fortunately, recurrent stone formation does not occur, since the new kidney transports cystine normally. [22]
| Conclusion | | |
The mainstay of therapy in cystinuria includes hydration, alkalinization of the urine, dietary sodium restriction, and animal protein restriction (not recommended for children). Full compliance with this regimen will result in significantly reduced urinary cystine excretion and good long-term prognosis in most patients. Pharmacological agents such as disulfide chelators should be reserved for patients who fail conservative therapy. Urologic intervention may be indicated in selected patients.
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Correspondence Address:
Badriya Al-Hermi
Pediatric Nephrologist, Salmaniya Medical Complex, P.O. Box 12, Manama
Bahrain
 Source of Support: None, Conflict of Interest: None  | Check |
PMID: 17660657 
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