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The Challenges of Cystinuria in the Twenty-First Century – a Mini Review Louise F

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Øbro LF, Pedersen KV, Lildal SK, Osther SS, Jung HU, Andreassen KH, Osther PJ. Journal of J Rare Dis Res Treat. (2016) 1(3): 41-45 Rare Diseases Research www.rarediseasesjournal.com & Treatment Mini-review Open Access The challenges of cystinuria in the twenty-first century – a mini review Louise F. Øbro1, Katja V. Pedersen2, Søren K. Lildal1, Susanne S. Osther1, Helene U. Jung1, Kim H. Andreassen1 and Palle J. S. Osther1 1Department of Urology, Urological Research Center, Lillebaelt Hospital, University of Southern Denmark, Fredericia, Denmark 2Department of Clinical Genetics, Lillebaelt Hospital, University of Southern Denmark, Vejle, Denmark Article Info ABSTRACT Article Notes Cystinuria is a rare genetic disorder caused by mutations in the genes that encode Received: September 15, 2016 the two subunits of amino acid transport, resulting in failure of absorption of filtered Accepted: November 16, 2016 dibasic amino acids including cystine in the proximal tubules. Despite new knowledge of the molecular basis of cystinuria, it continues to be one of the most challenging stone *Correspondence: diseases. There is no curative treatment of cystinuria, and patients will have life-long Palle J. S. Osther, Department of Urology, Urological Research risk of stone formation, repeated surgery, impaired renal function and quality of life. Center, Lillebaelt Hospital, University of Southern Denmark, Management of cystinuria requires a multi-modal approach in dedicated centres to Fredericia, Denmark; E-mail: [email protected] improve treatment outcome and patient compliance. Recent developments in cystine © 2016 Palle J. S. Osther. This article is distributed under the crystal growth inhibitors may hold promise for more effective stone prevention in the terms of the Creative Commons Attribution 4.0 International future. License. Keywords Cystinuria Introduction Kidney calculi Genetics Cystinuria is a rare genetic condition that continues to be one Prevention of the most challenging kidney stone diseases. It is caused by Pharmacologic therapy Surgical therapy mutations in the genes that encode the two subunits of the amino Crystal growth inhibitors Crystallization inhibitors amino acids including cystine in the proximal tubules1. Since cystine acid transport, resulting in failure of absorption of filtered dibasic has a very limited solubility in the physiological range of urine pH, this leads to complicated and recurrent kidney stone formation, harbouring a higher risk of chronic kidney disease than the more common calcium oxalate kidney stone disease. Cystinuria represents approximately 1% of adult and 3–10% of pediatric stone disease1,2. The worldwide prevalence of cystinuria is approximately 1 in 7000 neonates, ranging from approximately 1:2000 at the Mediterranean East Coast to 1:100000 in Sweden2,3. Genetic basis of cystinuria The inheritance pattern of cystinuria is complex. Traditionally, cystinuria has been classified into three different subtypes. Later etthis al. classification4. was criticised, and a new classification based on the affected genes SLC3A1 and SLC7A9 was made by Della Strologo Cystinuria type A is caused by mutations in the SLC3A1 gene tolocated localize on thechromosome transporter 2. toThe the SLC3A1 plasma gene membrane encodes5. Thethe heavymode ofsubunit inheritance of the renal appears amino to acid be transportertruly autosomal (rBAT), recessive which is and needed the penetrance is high6 the gene and each of the parents carries one copy. Carriers usually have normal level of. urineAn affected cystine person and they has have two no faulty increased copies risk of of developing urolithiasis compared with the general population5. Page 41 of 45 Øbro LF, Pedersen KV, Lildal SK, Osther SS, Jung HU, Andreassen KH, Osther PJ. Journal of Rare Diseases Research & Treatment J Rare Dis Res Treat. 2016 1(3): 41-45 Cystinuria type B the light subunit of the is renalcaused amino by mutations acid transporter, in the SLC7A9 which compromisesgene located on the chromosome catalytic, transporting 19. The SLC7A9 component gene encodes5. The mode of inheritance seems to be autosomal recessive or autosomal dominant with incomplete penetrance7. For 6. Carriers such as parents, siblings and children often have raised urine cystinehomozygotes levels penetrance and stone isformation similar to is type reported A in 2-18% of cases4,6. In more rare cases the patient has mutations in as cystinuria type AB. The frequency is reported to be 1.2% -both 4% genes (SLC3A1+SLC7A9). This subgroup is classified 4,8,9 . Today 160 different10. mutations in the SLC3A1 gene and 116 in the SLC7A9 gene are listed in the Human GenomeSo far Mutation no clinical Database differences (age of presentation, . The full implications of type number of stone episodes,4,9,11 interventions) have been found implicationsbetween type forA and prognosis, type B management and treatment Figure 1: Low-dose non-contrast CT (coronal view) in a 6-year-old haveA, B orbeen AB suggested. status are not yet fully understood, although boy with cystinuria showing a large kidney stone and a very large ureteric stone on the right side. The stones are homogeneous with Diagnosis a Hounsfield Unit of 900, which made them inappropriate for Shock Wave Lithotripsy. The stones were treated using a percutaneous surgical approach. Cystinuric patients often presents with bilateral laboratory investigations and imaging. Cystinuria should high stone burden disease either as staghorn stones or large alwaysDiagnosis be suspected is based in oncase medical of early history, kidney stone debutanalysis, (< rounded stones as in this case. The boy has remained stone free on a combination of hydration and potassium citrate therapy. Stone20 years) analysis and a familyand laboratory history of cystinuria. investigations Surgical management possible. Pure cystine stones are observed in the majority are likely to suffer frequent recurrent episodes of stones A stone12 analysis should be performed whenever of cases . Microscopy of urine revealing hexagonal crystals necessitatingDespite aggressive urologic medicalintervention therapy,13. Cystinuric cystinuric patients 2,13 are pathognomonic . Cyanide-nitroprusside colorimetric will often have experienced previous invasive procedures, test detects cystine in urine at a threshold concentration of demanding use of the least invasive methods to minimize complications and morbidities of multiple procedures11. On the other hand, since residual fragments after stone 75 mg/l. A quantitative chromatographic analysis of a 24- of cystine excretion is around 0.10 mmol/day; homozygote treatment in cystinuric patients sooner or later will result hour urine-sample confirms the diagnosis. The normal rate cystinurics usually excrete more than 1.7 mmol/day. in symptomatic stone disease, complete stone clearance is of upmost importance. Thus, the surgical challenge in Imaging Cystine stones are weak radiopaque on plain procedures and the need for complete stone clearance23. cystinuria is to find the balance between the safety of the 14. Cystine calculi are generally considered Shock Wave radiographs. The attenuation value (Hounsfield Unit, HU) of cystine stones on Computerized Tomography (CT) varies Lithotripsy (SWL) resistant. Pre-treatment imaging may compositions,A low HU may especiallysupport the for suspicion cystine andof cystine uric acid stones, stones, but reliably predict outcome21 of SWL, however; heterogeneous there is significant overlapping between stones of15-17 different homogeneous stones stones being more fragile to shock waves (SW) than energy CT and automated image processing may improve may be selected by the appearance of the stone on Non- . Thus, patients suitable for SWL themaking differentiation a definitive differentiation. CT may also be challenging helpful in predicting. Dual- fragility of the stone18,19 by evaluating morphology of the stone, calculi may effectively be managed ureteroscopically using Contrast CT (NCCT). Smaller (<2 cm) SW resistant11,23,24 cystine inhomogeneous stones with void regions being more , whereas fragile20-22 flexible ureteroscopes and laser lithotripsy but represents the mainstay for follow-up of cystine stone larger and branched (staghorn) stones most effectively formers to(Figure avoid frequent 1). Renal exposure ultrasonography to radiation. is less accurate are managed by percutaneous nephrolithotomy (PCNL). Newer approaches of PCNL with minituarization of the Page 42 of 45 Øbro LF, Pedersen KV, Lildal SK, Osther SS, Jung HU, Andreassen KH, Osther PJ. Journal of Rare Diseases Research & Treatment J Rare Dis Res Treat. 2016 1(3): 41-45 seems advisable to maintain a normal protein intake, and patients reducing morbidity related to repeated renal avoid protein gluttony, since this additionally will reduce accesses.tract (Mini No PCNL) systemic may betherapies especially can suitable effectively for cystinuricdissolute the dietary acid load, thereby increasing urine pH and cystine solubility34,35. The dietary content of protein should begins, when pH exceeds 7.025. Chemolytic dissolution of not exceed 0.8 g/kg body mass/day. cystine stones.stones Athrough significant a nephrostomy increase in cystinetube or solubility ureteral catheter may be done with the highly alkaline solution Pharmacologic treatment Urinary alkalinisation: Cystine solubility increases chelating solution acetylcysteine 2%, or preferably the with increasing pH, however, solubility does not increase twoTHAM solutions (tris-hydroxymethyl-amminomethane)
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