| Abstract|| |
Recent advances in molecular biology have provided new insights into the pathophysiology and genetics of cystinuria. It is expected that future development will be based on molecular and gene therapy. Until then, the therapy in cystinuric patients remains a difficult task and the goal should be the prevention of recurrences. This can be achieved by full compliance with medical regimens that result in significantly reduced urinary cystine excretion and good long-term prognosis in most patients. Such measures include urinary alkalinization with potassium citrate, modest reduction of dietary sodium and maintenance of a daily urinary volume of about three liters to prevent stone recurrence in adult cystinuric patients. The use of life-long pharmacological agents with disulfide chelators should be reserved for patients who fail the general conservative therapy. Invasive surgery should be used only minimally so as to preserve renal anatomy and function. However, repeated episodes of obstructive uropathy, frequently complicated by infection may eventually result in the need for nephrectomy, and are significantly associated with development of chronic renal failure. In the Arab World we lack properly designed epidemiological studies on renal stone-disease in general, and the cystine stones in particular. We recommend a multi-center study to determine the incidence of the disease and a molecular genetic analysis of cystinuric patients and their relatives, to determine the different mutations in our population and the types of the disease both the homozygotes and the heterozygotes.
Keywords: Cystinuria, Renal Failure, Urolithiasis, Arab, Genes, Children, Transplantation
|How to cite this article:|
Al-Hermi B, Abbas B. Cystinuria in Arab Countries. Saudi J Kidney Dis Transpl 2003;14:358-66
| Introduction|| |
Cystinuria is an autosomal recessive disorder, , characterized by abnormalities in the renal tubules and small intestinal cell transport of the dibasic amino acids cystine, ornithine, lysine and arginine. 
Precipitation of cystine at the acidic pH of the collecting duct fluid results in the formation of microcrystals that coalesce into larger calculi. The renal stones are the only significant clinical expression of cystinuria. The incidence of cystinuria has a wide range of variation world wide; it is approximately 0.05% of the general population, with prevalence of 1:1887 in the Valencian community in Spain, 1:2500 in Libyan Jews and 1 in 15,000 in United States. Cystinuria is the cause of 1-4% of renal stones observed in adults and about 10% of those occurring in children. ,,,,,,
The disease seems to predominate in whites in all reported series; but there are occasional reports in blacks and Asians. The clinical data show that cystinuria is more severe in males than females. ,, Stone formation begins in the first decade of life and continues life-long and peaks during the third decade.
Clinical interest in the disease dates back to the early 19 th Century. Affected individuals were initially identified by the finding of flat hexagonal cystine crystals during routine examination of the urinary sediment. 
Three types of the disease have been described, based on urinary excretion of cystine and the dibasic amino acids in the heterozygotes and oral loading tests in the homozygotes. ,,
Despite adequate medical management, many patients continue to suffer from high rate of recurrence. The special structure and the hardness of cystine stones render them poorly responsive to extracorporeal shock wave lithotripsy (ESWL) and percutaneous nephrolithotripsy (PCNL).
Depending on the duration of follow-up and medical therapy, the risk of renal insufficiency is high in cystinuric patients; however, end stage renal disease (ESRD) occurs in less than 5% of these subjects. , The risk of nephrectomy was high and ranged between 12-20%of the patients. ,
Information on the epidemiological characteristics of urolithiasis in the Arab and Middle Eastern countries is scanty. The available few reports are crippled by the small number of the reported series. This is also true for cystine stones and cystinuria, therefore the interpretation of these data is difficult because of the small number of the patients, inadequate demographical data, and the screening methods used.
In this article, we will discuss the cystinuria in general, genetics and management and elaborate on the cystinuria in the Arab countries despite of the limited data available.
| Genetics of Cystinuria|| |
In 1955, Harris et al, described the genetic basis of cystinuria, including it's autosomal recessive inheritance. 
Then, in 1966, Rosenberg et al, described three types of cystinuria according to the urinary phenotype of obligate heterozygote parents; that presumably reflects the severity of the proximal tubular transport defect.  Type I heterozygotes show normal aminoaciduria and remain asymptomatic, while type II and III heterozygotes show high or moderate excretion of cystine and dibasic amino acids, respectively , and may present with symptoms indistinguishable from the homozygotes. Among stone formers, up to 90% were homozygotes, of whom 15% were asymptomatic, and 10% were heterozygotes. ,,,
This classification poorly correlates with current molecular analysis data and has been modified as type I and non-type I (divided clinically as types II and III ) cystinuria.  The urinary cystine levels were useful in distinguishing between unaffected relatives and heterozygotes, but were unhelpful in differentiating between heterozygotes and homozygotes. 
In 1994, Pras et al,  demonstrated the gene for cystinuria SLC3A1 (formerly rBAT), and has been localized to chromosome 2p. It was responsible only for the fully recessive type I cystinuria. ,,,. At present, more than 60 mutations have been reported in the rBAT gene. ,,,,, In 1999, The International Cystinuria Consortium cloned the SLC7A9 (BAT1) gene, and it was found to be located on chromosome (19q13.1).  This gene is responsible for non-type I cystinuria.  More recently, 35 other SLC7A9 mutations accounting for 79% of the carrier chromosome in non-type I cystinuric patients have been reported. ,,
In 2002, Leclerc et al, provided evidence that some SLC7A9 mutations may be associated with type I cystinuria and they also demonstrated SLC7A9 mutations in dominant type II and type III.  A potential candidate of a third cystinuria causing gene, SLC7A10 indicates that genetics is more complex than originally anticipated. 
The high levels of urinary cystine and dibasic amino acids noted in heterozygote Libyan Jews, support that the cystinuria in these subjects was non-type I disease, which involved the b 0,+ AT (rBAT) gene.  Later, they were found to be homozygous for a founder missense mutation. ,,, In a
Turkish population, a two-allele mutation in (rBAT) gene was found in 4-8% of the population examined. 
| Clinical Presentation and Diagnosis|| |
Nephrolithiasis is the presenting symptom in patients with cystinuria. It has interindividual variations. Cystinuria should be considered in every patient with renal stones. A family history is an important clue in the initial diagnosis. Renal colic is the most common presentation, associated with urinary tract obstruction. Urinary tract infection has been reported in up to 34% of the patients with cystine calculi. Hypertension and eventual renal failure occurred in up to 17% in one series. ,
Recurrent and multiple bilateral renal stones are common in cystinuria, in particular "staghorn calculi". Mixed stones account for up to half of the stones in cystinuria.  Other metabolic defects such as hypercalciuria (5-18%), hyperuricosuria (7-22%) and hypocitraturia frequently accompany cystinuria in the patients with cystine nephrolithiasis. , They may contribute to the formation of calcium oxalate and uric acid stones particularly in patients with homozygous cystinuria. Therefore, metabolic evaluation is important in all patients with cystine or mixed stone. 
On radiographic examination, cystine stones are radiopaque (ground glass appearance), but less radiopaque than calcium stones.  Ultrasonography may be used for the diagnosis of renal, ureteral and bladder cystine calculi, at the same time, it provides information with regard to the presence and degree of urinary obstruction. Intravenous pyelogram was used commonly in the past and has been replaced by CT scan for acute diagnosis of obstructing stones in most institutions.
Cystinuria has been associated with other conditions or genetic diseases such as the Fanconi syndrome, Hemophilia, Retinitis Pigmentosa, Muscular Dystrophy, Trisomy 21, Wilson's disease, and Hereditary Pancrea titis. ,,, We have reported a case of Bernard Soulier syndrome with cystinuria.  Infants, younger than six months of age, have increased cystine excretion caused by immaturity of the renal tubules. Thus, it is difficult to make a reliable distinction between heterozygous and homozygous cystinuria until six months of age. ,
The diagnosis of cystine stones should be considered in any patient with a history of renal stones in childhood, recurrent episodes of stones or a family history of stone disease.
Characteristic flat hexagonal colorless cystine crystals on microscopic examination of the first void urine are diagnostic, but the crystalluria may be absent in dilute or alkaline urine. 
The normal adult excretes less than 30 mg/day (0.13 mmol/day) cystine. A urinary cystine excretion above 250 mg/g creatinine (350 mg /day) usually indicates homozygous cystinuria. The upper limit of solubility of cystine under physiological urinary pH is about 300 mg/L. In establishing a diagnosis of classic cystinuria, it is important to exclude other causes of excess urinary cystine, including isolated cystinuria, tubular immaturity in infants less than 6 months of age, and all causes of generalized aminoaciduria. 
A qualitative cystine test can be performed on fresh urine using the colorimetric method using sodium cyanide and nitroprusside. The test is simple and provides a convenient screening test to detect cystinuria. It can detect homozygous and some, but not all, heterozygous subjects.  However, there may be false positive results in patients with acetonuria, homocystinuria and those on sulfur containing drugs. 
Patients who show a positive screening test should be evaluated further with quantitative cystine excretion in a 24-hour urine specimen for metabolic studies by ion exchange chromatography and/or by stone analysis using infrared spectrometry of stones, which gives a definitive diagnosis. Stone forming children may excrete lower amount of cystine (75mg/day). ,
| Treatment|| |
The acute management of cystinuria includes measures to resolve the acute stone crisis, as for other types of stones. Pain management and hydration are the initial steps.
In the chronic phase, the medical therapy is directed toward decreasing the urinary cystine excretion below 250mg/L, dissolution of existing calculi and prevention of new stone formation.
| Medical Management of Cystinuria|| |
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, patients who excrete more than 1.7 mmol (400 mg) per day can be expected to be at high risk for stone formation. , Prevention of new stone formation can be achieved by reducing the cystine concentration in the urine or by increasing the urinary cystine solubility.
Increasing 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. Hydration has been shown to decrease urinary stone formation in as many as 67% of patients with cystinuria. Adequate hydration can be monitored by checking the specific gravity of the urine. Achieving a specific gravity of 1.010 has been recommended.  Patients should develop a 24-hour schedule for drinking and voiding, with particular attention to nighttime hours when urine may become supersaturated with cystine. A bedtime fluid intake of 500 ml has been suggested. ,, Various types of fluid can be used. The use of fruit juice such as orange juice is beneficial because it increases the alkali load and subsequently the urinary pH. 
Dietary modification is an integral part of treatment. Dietary sodium restriction has a favorable effect on urinary cystine excretion. A reduction in dietary sodium of 150 mmol/ day resulted in a decrease in urinary cystine excretion. A reduction of salt intake to less than 2 g/day has been recommended. , Another dietary measure is avoidance of foods with very high methionine content, including stockfish and eggs, and by moderating the consumption of meat, meat products and fish. However, most authors believe that such dietary restriction is not advisable for children since it is harmful for their growth. Clearly, a dietary restriction of all methionine-containing products is not practical and patient's compliance is a limiting factor. In medical practice, patients are advised to maintain a balanced diet and avoid high-protein intake. ,,,
Cystine solubility can be improved by urinary alkalinization; a urinary pH of or greater than 7.5 is desirable. This can be achieved by oral alkali therapy, but there are two limitations for their use. First, to achieve and maintain urinary pH above 7.5 is difficult. Second, a high urinary pH will predispose to calcium phosphate stone formation. Considering these limitations, the goal of alkali therapy is to maintain a pH in the 6.5-7 range. Sodium bicarbonate and sodium or potassium citrate are usually used for urinary alkalinization at a dose of 1-2 mEq/kg/day. Because high sodium intake increases cystine excretion, potassium citrate is preferred. ,
Thiol derivatives are chelating agents such as D-pencillamine, , α-Mercaptopro pionylglycine (MPG) , and Bucillamine.  They contain a sulfhydrylside group, which undergo a thiol-disulfides exchange with cystine. Therefore, these medications may result in dissolution of existing stones when other general measures have failed and they help prevent stone recurrence. MPG is currently the medication of choice in most centers. The starting dose is 400 mg/day in divided doses. This dose can be increased to 800-1200 mg/day.
Captopril can exert a "solubilizing effect" via formation of a cystine-captopril complex that is 200 times more soluble than cystine.  However, studies on the efficacy of captopril have been inconclusive. 
The patient's compliance with medical or conservative treatment is the big issue; compliance is especially difficult in children and adolescents, who often require psychological support. However, only a regular medical prophylaxis may prevent recurrent stone episodes and protect renal function. 
| Surgical Management of Cystine Stones|| |
Management of large volume stones requires surgical intervention, because of the natural history of the disease and the typical frequent recurrences of multiple stones despite the medical management. The surgical management is directed toward minimally invasive urological procedures, which includes Extracorporeal (ESWL) and Intracorporeal lithotripsy using a uretroscopic or percutaneous approach. The primary goals of surgical treatment are relief of symptoms associated with renal obstruction and preservation of renal function, rather than achieving a complete stone-free status. The uniform crystal structure of cystine stones makes them relatively resistant to fragmentation by ESWL. This modality is usually reserved for stones smaller than 1.5 cm in diameter. ,,
Acceptable stone-free rates can be achieved using these modalities. In one study, a stone-free rate of 87% has been reported using various modalities.  With careful medical and surgical management, the longterm outlook is good but recurrence rate is very high and instrumental treatment should not therefore be used excessively.  However, some patients may require unilateral nephrectomy because of obstruction and/or chronic infection. Renal function may eventually be compromised, although fewer than 5% progress to end-stage renal disease.  Renal transplantation has been performed in a limited number of patients; recurrent stone formation does not occur, since the new kidney transports cystine normally. 
| Cystinuria in the Arab world|| |
As we mentioned earlier, the information on the cystine stones and cystinuria in the Arab world is scanty. However, from the available data (collected from the internet searching Medline and available local journals) we compared the Arab countries with some of the other countries in the region such as Iran and Turkey. This may provide a partial perspective on the spectrum of the disease.
We have previously published a report describing three pediatric patients with cystinuria.  Since that report, our patients increased to seven cystinuric children. By reviewing the laboratory data in our hospital we found a total of eleven patients with cystine stones, which were analyzed by infrared spectrometry (unpublished data); four stones belonged to four adult patients.
Bani Hani et al reported a total of 180 relatives from four generations of one family in northern Jordan.  They found cystinuria in 104 cases; 20 patients had cystine stones, with a prevalence of 58% for the cystinuria. Their study included both adults and children with a mean age of 43 years; eight were hypertensive, and five of them had elevated serum creatinine.
El-Reshaid et al studied 421 Kuwaiti patients with renal stones and found cystine stone in 2.4%.  El-Eisa et al from Kuwait found cystinuria in 12.9% of children with urolithiasis.  AlRasheed et al, from Saudi Arabia, in a study of 71 cases of children and adolescents with urolithiasis, there were 45 stones analyzed that showed 4.4% cystine stones.  Kamoun et al studied 120 children from Tunisia with urolithiasis of which cystine stones accounted for 3% of the total stones and 10% of the nucleus of the bladder stones. 
In comparison, Ozlap et al, from Turkey, screened 6050 high-risk infants and newborn, as well as 8572 normal elementary school children and found incidence of cystinuria 0.09% in infants and only seven of the elementary school children had high urinary cystine excretion.  Kheradpir et al studied 148 Iranian children with staghorn calculi and found cystinuria in only six patients. 
It will be noticed that the data reviewed above are based on reports on small numbers of patients, mostly from studies dealing with epidemiological screening of urolithiasis. In general there was little mention, in these reports, on the diagnostic methods used. The Bani Hani et al report was the only study in which methods used in screening for cystinuria, and their limitations were mentioned. There was no genetic study for the cystinuric patients among the Arab population. We recommend a multi-center study to determine the incidence of the disease and a molecular genetic analysis of cystinuric patients and their relatives, to determine the different mutations in our population.
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Pediatric Department, Salmaniya Medical Complex, P. O. Box 12, Manama