Cystinuria: a rare diagnosis that should not be missed
E Cystinuria: a rare diagnosis that should not be Peter KF Chiu Eddie SY Chan Cystinuria is a rare autosomal recessive defect causing recurrent urinary tract stone formation. Morbidity from stone formation and repeated urological interventions can be reduced by Simon SM Hou early diagnosis and adequate medical treatment. In this review, we illustrate these points by discussing three patients with cystinuria and give a brief review of its management. Introduction Cystinuria is a rare autosomal recessive defect causing recurrent urinary tract stone formation. We would like to present three patients diagnosed with cystinuria in our unit, who had clinical differences in terms of the timing of their diagnosis, their compliance with treatment, and their outcomes. These features illustrate the importance of recognition of the condition in order to prevent stone recurrence and minimise morbidity. The latest developments and approaches used in the management of cystinuria will also be discussed. Case reports Case 1 A 25-year-old man presented with a history of a symptomatic left staghorn stone diagnosed in a public hospital 6 years earlier. The stone was effectively cleared using percutaneous nephrolithotomy (PCNL) and extracorporeal shockwave lithotripsy (ESWL) but was not chemically analysed after removal. He then presented with left loin pain and was found to have a recurrent left staghorn stone. Percutaneous nephrolithotomy was performed and the stone analysis showed cystine. A subsequent urine analysis confirmed the diagnosis of cystinuria. He was put on hyperdiuresis, potassium citrate to alkalinise his urine, and captopril, which was later changed to penicillamine due to symptomatic hypotension. He responded well to treatment maintaining a urinary cystine level below 150 mg/L and has had no stone recurrences during 3 years of follow-up. Family screening detected cystinuria in his sister but she had no history of renal stone formation. Case 2 A 23-year-old woman presented to our unit complaining of loin pain and was diagnosed with bilateral renal stones. A primary ESWL was planned but this was complicated by steinstrasse (multiple stone fragments in the right ureter), so an open right ureterolithotomy was performed and the stones were cleared. Chemical analysis of the stones suggested cystinuria. Preventive treatment was offered but she defaulted follow-up as she was then asymptomatic. Three years later, she presented with loin pain once again and was found to have recurrent right staghorn and left pelviureteric junction stones. An open right pyelolithotomy, left PCNL and supplementary ESWL were performed to clear all the stones. She was started on preventive treatment again, including hyperdiuresis, urine Key words alkalinisation, and chelating therapy. Stringent control of her urine pH and urine cystine
Cystine; Cystinuria; Treatment outcome; level (190-250 mg/L) over the next 6 years resulted in only minor recurrence—a small
Urinary calculi (5 mm) asymptomatic right renal stone which was managed conservatively. Family screening
Hong Kong Med J 2008;14:399-401 detected cystinuria in a sister with an asymptomatic renal stone. Department of Surgery, The Chinese Case 3 University of Hong Kong, Shatin, Hong Kong A 19-year-old man presented with on-and-off bilateral loin pain associated with stone PKF Chiu, MB, ChB passage. Although imaging just showed multiple small renal stones, his young age and ESY Chan, FRCS (Urology) (Edin), FHKAM multiple bilateral stones raised suspicions of an underlying metabolic abnormality. Urine (Surgery) SSM Hou, FRCS (Edin) FHKAM (Surgery) and stone analysis was performed and the diagnosis of cystinuria was confirmed. He was CF Ng, FRCS (Urology) (Edin), FHKAM (Surgery) started on hyperdiuresis and potassium citrate only. Hyperdiuresis of more than 3 L of
urine and adequate urine alkalinisation of pH 6.9-7.7 was achieved. He had no more loin
Correspondence to: Dr CF Ng E-mail: email@example.com pain and stone passage episodes markedly decreased over the next 2 years but his family
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a clinically significant deficiency as the absorption of short-chain amino acids is not affected.
Cystinuria can be divided into type 1 and non-
type 1 (types 2 and 3) diseases. The type 1 form is completely recessive and involves mutations in the gene SLC3A1 on chromosome 2.3 The non-type 1 forms are incompletely recessive and involve mutations in the gene SLC7A9 on chromosome
refused screening for cystinuria despite our advice.
19.4 Homozygotes with all three types of cystinuria
A summary of the presentation and excrete high concentration of cystine in their urine
management of these three patients is given in the and are almost always symptomatic stone formers. Table. These three patients illustrate the importance Heterozygotes with type 1 cystinuria have normal of diagnosing and treating cystinuria early. The first urine cystine excretion and are silent carriers, two patients suffered from stone recurrence; one whereas heterozygotes with type 2 and 3 cystinuria due to a delayed diagnosis and the other as a result excrete high or moderate amounts of cystine and are of non-compliance with preventive therapy. The third at risk of stone formation when their urine cystine case shows that early diagnosis and good compliance levels exceed the stone-forming threshold. The with preventive therapy can prevent the development diagnosis is made by analysing urine and stones. of complications.
Urine microscopy may show typical hexagonal cystine crystals, and the spot urine cystine concentration will be significantly elevated. Quantitative urine amino
acid analysis should show significantly high levels of
Cystinuria is an autosomal recessive defect of the cystine, ornithine, arginine, and lysine. Stone analysis reabsorptive transport of cystine and dibasic amino is useful for demonstrating that cystine is the major acids including ornithine, arginine, and lysine from stone component. the renal proximal tubules and small intestines.1 This
Cystine stones tend to be very hard and need
leads to increased urinary excretion of the above more ESWL shocks for adequate fragmentation. four amino acids. Among these, only cystine has Use of a multimodal approach including ESWL, low solubility at physiologic urine pH levels (5-7), ureteroscopic lithotripsy, and PCNL is usually predisposing it to stone formation.
necessary for clearing cystine stones. Considering
Cystinuria is rare and affects 1 in 7000 people the rapid rate of renal stone recurrences in people
worldwide, though the prevalence varies from race with cystinuria, repeated invasive treatment may be to race and is less common in Asian populations.2 needed. Therefore, preventive treatment is the most Cystine urolithiasis is the only clinical manifestation important part of management. of cystinuria, and is responsible for 1 to 2% of urinary
Preventive treatment relies on a combination
stones and 6 to 8% of paediatric urinary stones. The of hyperdiuresis, urine alkalinisation, and raising peak age for first stone presentation is during the third cystine solubility.5 Hydration is the cornerstone decade of life. Although most patients with cystinuria of treatment, and a hyperdiuresis of 3 L of urine have impaired intestinal cystine absorption, this is not per day is needed to effectively dilute cystine in
TABLE. Characteristics of the three patients with cystinuria*
* PCNL denotes percutaneous nephrolithotomy and ESWL extracorporeal shockwave lithotripsy
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urine. Patients are advised to wake at night to drink at higher risk for renal loss. Good compliance with water to supplement their daytime intake.6 Dietary proper medical treatment can therefore significantly modifications including restriction of methionine reduce the morbidity and surgical procedures (a cystine precursor) and sodium are advocated as required to manage cystinuria patients. these have shown to increase cystine excretion.7,8
The treatment response should be closely
Potassium bicarbonate/citrate, is often given orally to monitored by checking urine pH and cystine levels,
alkalinise urine. Sodium bicarbonate has been used and using frequent imaging to identify early stone
in the past but this is not advised as sodium increases recurrence. Urine pH should be maintained at around
cystine excretion. In patients who are stone-free, 7.0-7.5 to achieve adequate alkalinisation while
the above measures usually suffice. When the above avoiding the predisposition to calcium phosphate
measures fail to lower urine cystine concentration stone formation at pH >7.5.
to less than 250 mg/L and recurrent stone formation occurs, further medical treatment is needed. These include either cystine-binding or cystine-reducing Conclusion agents that have the ability to dissociate cystine In patients with urinary calculi, chemical analysis of
into disulfide moieties with higher solubility than retrieved stones is mandatory. Knowing the stone
cystine itself. Options include D-penicillamine,9 composition is essential for guiding subsequent
alpha-mercaptopropionylglycine,10 captopril,11 and preventive treatment. For young stone formers (<30
years old), especially recurrent stone formers or
Barbey et al13 reported an average reduction those with strong family histories of stone disease,
of stone episodes per patient-year from 0.93 to 0.20, urine analysis, including microscopy and quantitative and a reduction in urological procedures required amino acid analysis, should always be done to rule per patient-year from 3.0 to 1.5 with proper medical out the possibility of cystinuria. Treatment should treatment. The urological procedures performed be started as soon as cystinuria is diagnosed, and in those having medical treatment were mostly the importance of compliance with treatment, ESWL and other less invasive procedures.13 Chow especially the need for hyperdiuresis should be fully and Streem14 reported the probability of stone-free explained. After starting treatment, stone prevention survival at 1 and 5 years of treatment as 0.73 and 0.27 relies heavily on meeting treatment targets including respectively, and stone recurrence was independent appropriate urine pH and urine cystine levels, and of pre-intervention urine cystine level, initial stone must therefore be closely monitored. Measuring burden, and type of intervention selected. Stone urinary cystine levels in family members is helpful recurrence and urological procedures required can for identifying other cystinurics in the family, and also be significantly reduced by good compliance can potentially reduce stone formation and invasive with medical treatment.15 Cystinuric patients are also urological interventions with the initiation of early reported to have poorer renal function and to be treatment. References
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DATOS PERSONALES NOMBRE:-------------------- ANA HERNANDEZ FERNANDEZ DIRECCION:------------------C/ NAVEGANTE MACIAS DEL POYO, 13 - 30007 - MURCIA Nº DE COLEGIADA:------ 434 (Colegio Oficial de Odontólogos y Estomatólogos de la Región de Murcia) FORMACION ACADEMICA LICENCIADA EN ODONTOLOGIA. Título conseguido en Junio de 1.997 por la Facultad de Medicina y Odontología de la Universidad de M