Cystinuria Patients Research Articles

Challenges in diagnosis and treatment of cystinuria patients with Urolithiasis: multicenter patient centered study.

Cystinuria represents a rare cause of urolithiasis, accounting for 1% of all cases. However, it poses unique challenges in diagnosis and management. This study aimed to examine the challenges of managing cystine stones from the perspective of cystinuria patients. Following ethical approval, we reviewed the medical records of cystine stone patients treated at four tertiary centers from 2016 to 2021 and surveyed them on their perceptions of cystinuria. It included questions about demographic characteristics, herbal treatments, pain management, online engagement, disease outcomes, and cystinuria-related fears. The study included 28 adults with cystinuria nephrolithiasis, with a mean age of 30.5 years. Of these, 78.6% had consanguineous parents, and the first stone episode occurred at a mean of 14.82 years age. Family history of Cystinuria was encountered in 82.1%. Cystinuria was diagnosed after a mean of 6.43 years from the first stone episode, and stone analysis was performed in 22/28 after a mean of 3.86 years from the first stone episode. Only 17 patients (60.8%) underwent metabolic evaluation for kidney stones. Regarding non-surgical treatments, 13 (46.5%) patients received alkalinization medication, and only 10 (35.7%) were prescribed chelating agent therapy. Additionally, 50% of patients took herbal remedies. The diagnosis of cystinuria is often delayed, leading to a delay in receiving medical treatment (alkalinization and chelating agents) and poor health education and counseling. Thus, referring cystinuria patients to tertiary hospitals and providing a multidisciplinary approach might decrease the morbidity of the disease and enhance their well-being.

#2278 EUROCYS, a European cystinuria registry

Abstract Background and Aims Cystinuria (OMIM 220100) is a rare autosomal recessive disorder in which high urinary cystine excretion leads to formation of cystine stones due to its low solubility at normal urinary pH. Retrospective series have been published but precise data to guide long term optimal management of these patients are lacking. Our goal was to collect consistent and comparative prospective clinical, biological, genetic and radiological data from patients (children and adults) with cystinuria followed in European centers. Method We developed EUROCYS, a multidisciplinary, European, multicenter registry of patients with cystinuria in which demographic, clinical, surgical, biological, genetic, radiological and therapeutic data are collected longitudinally. These data are recorded via the European Rare Kidney Disease Registry (ERKReg) platform. Results Enrolment started in July 2021. To date, 269 patients have been included at 29 different centers in 8 European countries. Mean age at diagnosis was 18.7 years (SD 17.3) and mean age at inclusion was 35.4 years (20.2). 86.9% of patients had less than 9 calculi extractions reported, 11.0% had between 10 to 19, and 2.0% had more than 20. 61.4% (418/680) were treated by ureteroscopy, 16.2% (110/680) by shock wave lithotripsy and 16.0% (109/680) by percutaneous nephrolithotomy. 39% of patients had a new stone expulsion or surgery during the last 12 months. At the inclusion visit, mean urinary pH was below the recommended level at 6, 8 (0.8). Only 16.3% of patients had a urinary pH between 7.5 and 8: 77.2% of patients had a urinary pH below 7.5 and 6.3% above 8. In adults, mean 24-hour urinary volume was 2653 mL (1077). 34.9% had a target urine volume above 3000 ml. Under treatment, spot urine cystine concentration was 345.5 mg/l (255.2) and 44.8% of patients had a concentration below target concentration (250 mg/l). Mean sodium urinary excretion was 147 mmol/24 h (67). Only 29% of patients had a sodium urinary excretion below 100 mmol/24 h. As alkalinizing agent, 87.2% of patients received potassium citrate, 16.3% sodium bicarbonate and 9.1% potassium bicarbonate. As cystine binding drug, 71 patients (26.7%) were treated with Tiopronin and 3 experienced serious adverse events (hematological, cutaneous, proteinuria). 15 (5.6%) were treated with D-Penicillamine and 2 had adverse events (proteinuria and gastrointestinal). In adults, mean eGFR at inclusion was 82.1 ml/min/1.73 m² (26.3): 40.9% of patients were at chronic kidney disease (CKD) stage 1, 40.1% at CKD2, 16.7% at CKD3, 0.7% at CKD 4 and 1.5% at CKD5. Conclusion The EUROCYS registry shows real life data on cystinuria patients followed in European centers. Despite alkalinizing treatment, most patients do not reach the recommended urinary pH level and only one third have an adequate urinary volume. This registry will allow analyzing the impact of adhesion to recommendations on disease activity.

Prevalence and clinical characteristics of pediatric cystinuria in Ahvaz, southwest of Iran

Objective: This retrospective hospital-based study is aimed at investigating the 6-year prevalence and clinical characteristics of pediatric cystinuria in Ahvaz, southwest of Iran.
 Method: Demographic and clinical data belonging to children with kidney stone disease (KSD) who referred to nephrology wards were obtained from the medical records. Then, data were statistically analyzed and compared between the two groups of children with non-cystine kidney stones and those with cystinuria.
 Results: From a total of 415 patients with KSD, 45 cases (10.8%) had cystinuria and 370 cases (89.2%) had non-cystine kidney stones. Overall, the incidence rate of KSD was higher in boys (53.7%) than girls (46.3%, p=0.03). However, no significant difference in age and gender was observed between the two groups (p>0.05). Parental consanguinity [OR (95%):4.1(2.15_7.8), p=0.0001] and bilateral renal involvement [OR (95%):2.38(1.25_4.53), p=0.01] were more frequent among children with cystinuria. The number and size of cystine stones were significantly higher than non-cystine stones [p=0.0001]. Hypercalciuria (60.72%) and hyperuricosuria (40.1%) were the most frequent metabolic disorders, which were significantly more frequent in patients with non-cystine stones (p<0.01). The rate of complete recovery in cystinuria patients was significantly lower than in patients with non-cystine stones (51% vs 83.2%, p=0.0001).
 Conclusion:
 Parental consanguinity may increase the risk of cystinuria development. Also, notable prevalence of symptomatic cystinuria at younger ages highlights importance of metabolic assessment in early childhood. Bilateral renal involvement, high number/size of cystine stones and their recurrent nature may make cystinuria patients more vulnerable to renal parenchymal damage and more resistant to treatments.

Exploring the Contribution of the Transporter AGT1/rBAT in Cystinuria Progression: Insights from Mouse Models and a Retrospective Cohort Study.

More than 20 years have passed since the identification of SLC3A1 and SLC7A9 as causative genes for cystinuria. However, cystinuria patients exhibit significant variability in the age of lithiasis onset, recurrence, and response to treatment, suggesting the presence of modulatory factors influencing cystinuria severity. In 2016, a second renal cystine transporter, AGT1, encoded by the SLC7A13 gene, was discovered. Although it was discarded as a causative gene for cystinuria, its possible effect as a modulatory gene remains unexplored. Thus, we analyzed its function in mouse models of cystinuria, screened the SLC7A13 gene in 34 patients with different lithiasic phenotypes, and functionally characterized the identified variants. Mice results showed that AGT1/rBAT may have a protective role against cystine lithiasis. In addition, among the four missense variants detected in patients, two exhibited a 25% impairment in AGT1/rBAT transport. However, no correlation between SLC7A13 genotypes and lithiasis phenotypes was observed in patients, probably because these variants were found in heterozygous states. In conclusion, our results, consistent with a previous study, suggest that AGT1/rBAT does not have a relevant effect on cystinuria patients, although an impact in patients carrying homozygous pathogenic variants cannot be discarded.

Declaration: Novel SLC3A1 mutation in a cystinuria patient with xanthine stones: a case report

BackgroundCystinuria and xanthinuria are both rare genetic diseases involving urinary calculi. However, cases combining these two disorders have not yet been reported.Case PresentationIn this study, we report a case of cystinuria with xanthine stones and hyperuricemia. The 23-year-old male patient was diagnosed with kidney and ureteral stones, solitary functioning kidney and hyperuricemia after admission to the hospital. The stones were removed by surgery and found to be composed of xanthine.ConclusionGenetic testing by next-generation sequencing technology showed that the patient carried the homozygous nonsense mutation c.1113 C> A (p.Tyr371*) in the SLC3A1 gene, which was judged to be a functionally pathogenic variant. Sanger sequencing revealed that the patient’s parents carried this heterozygous mutation, which is a pathogenic variant that can cause cystinuria. The 24-h urine metabolism analysis showed that the cystine content was 644 mg (<320 mg/24 h), indicating that the patient had cystinuria, consistent with the genetic test results. This case shows that cystinuria and xanthine stones can occur simultaneously, and provides evidence of a possible connection between the two conditions. Furthermore, our findings demonstrate the potential value of genetic testing using next-generation sequencing to effectively assist in the clinical diagnosis and treatment of patients with urinary calculi.

Interpretation of SLC3A1 and SLC7A9 variants in cystinuria patients: The significance of the PM3 criterion and protein stability

Cystinuria is a genetic disorder caused by defects in the b0,+ transporter system, which is composed of rBAT and b0,+AT coded by SLC3A1 and SLC7A9, respectively. Variants in SLC3A1 and SLC7A9 follow autosomal recessive inheritance and autosomal dominant inheritance with reduced penetrance, respectively, which complicates the interpretation of cystinuria-related variants. Here, we report seven different SLC3A1 variants and six different SLC7A9 variants. Among these variants were two novel variants previously not reported: SLC3A1 c.223C > T and SLC7A9 c.404A > G. In silico analysis using REVEL correlated well with the functional loss upon SLC7A9 variants with scores of 0.8560–0.9200 and 0.4970–0.5239 for severe and mild decrease in transport activity, respectively. In addition, DynaMut2 was able to predict a decreased protein expression level resulting from the SLC7A9 variant c.313G > A with a ΔΔGStability −2.93 kcal/mol. Our study adds to the literature as additional cases of a variant allow applying the PM3 criterion with higher strength level. In addition, we suggest the clinical utility of REVEL and DynaMut2 in interpreting SLC3A1 and SLC7A9 variants. While a decreased protein expression level is not embraced in the current variant interpretation guidelines, we believe in silico protein stability predicting tools could serve as evidence of protein function loss.

The antioxidant l-Ergothioneine prevents cystine lithiasis in the Slc7a9−/− mouse model of cystinuria

The high recurrence rate of cystine lithiasis observed in cystinuria patients highlights the need for new therapeutic options to address this chronic disease. There is growing evidence of an antioxidant defect in cystinuria, which has led to test antioxidant molecules as new therapeutic approaches. In this study, the antioxidant l-Ergothioneine was evaluated, at two different doses, as a preventive and long-term treatment for cystinuria in the Slc7a9−/− mouse model. l-Ergothioneine treatments decreased the rate of stone formation by more than 60% and delayed its onset in those mice that still developed calculi. Although there were no differences in metabolic parameters or urinary cystine concentration between control and treated mice, cystine solubility was increased by 50% in the urines of treated mice. We also demonstrate that l-Ergothioneine needs to be internalized by its transporter OCTN1 (Slc22a4) to be effective, as when administrated to the double mutant Slc7a9−/−Slc22a4−/− mouse model, no effect on the lithiasis phenotype was observed. In kidneys, we detected a decrease in GSH levels and an impairment of maximal mitochondrial respiratory capacity in cystinuric mice that l-Ergothioneine treatment was able to restore. Thus, l-Ergothioneine administration prevented cystine lithiasis in the Slc7a9−/− mouse model by increasing urinary cystine solubility and recovered renal GSH metabolism and mitochondrial function. These results support the need for clinical trials to test l-Ergothioneine as a new treatment for cystinuria.

Cystine Stones: Developments in Minimally Invasive Surgery and Their Impact on Morbidity and Stone Clearance.

Cystinuria is a rare genetic condition that is responsible for cystine stones. Besides stone recurrence, patients with cystine stones have reduced health-related quality of life, increased rates of chronic kidney disease and hypertension. Although lifestyle measures, medical therapy and close follow up are essential to reduce and monitor cystine stone recurrences, surgical intervention is frequently needed for most cystinuria patients. Shock wave lithotripsy, ureteroscopy, percutaneous nephrolithotomy and active surveillance all have a role, and technological advances in endourology are vital in achieving a stone-free status and to prevent recurrences. The complexity of managing cystine stones necessitates a multidisciplinary team discussion, patient involvement and an individualised approach in a specialist centre for optimum management. Thulium fibre laser and virtual reality may have an increasing role in the future of cystine stone management.

A Case Series of Cystinuric Stone Formers in Western Cape, South Africa: SLC3A1 or SLC7A9 Mutations and Phenotype

Objective To describe the genetic mutations and phenotype in the first African series of patients with cystinuria. Methods Patients with cystinuria were recruited from a specialist metabolic renal stone clinic in Cape Town, South Africa, for DNA sequencing to detect mutations in SLC3A1 and SLC7A9. Chart reviews and patient interviews were conducted to record demographics, previous medical history, family history, stone-specific history, age at first presentation, cystinuria complications, urine cystine:creatinine ratio, stone analysis, and serum creatinine. Results Nine patients were included: 3 male patients and 6 female patients. The mean age (± SD) of patients was 33.43 ± 19.96 years. The median age (± IQR) at initial diagnosis of cystinuria was 16 ± 18 years, but the age ranged from 2 to 66 years. Three of 9 patients included (33.3%) had chronic kidney disease (CKD); however, none were receiving dialysis. Most patients initially presented with a staghorn calculus (4/9; 44.4%). The mean serum creatinine (± SD) was 84 ± 38 μmol/L. The mean urine cystine (± SD) was 2083 ± 1249 nmoL/mg creatinine. Eight patients had mutations in the SLC3A1 gene; 1 had mutations in both SLC3A1 and SLC7A9. Of the patients with only SLC3A1 mutations, 1 patient was homozygous and the rest were compound heterozygotes (two different mutations identified in the same gene). Four patients had a pathogenic variant in addition to an “uncertain significance” variant in SLC3A1. There were 9 mutations (5 pathogenic and 4 “unknown significance”) in SLC3A1 and 1 mutation in SLC7A9. Two of these were novel mutations. Conclusion This “first in Africa” series of cystinuria patients showed marked heterogeneity in both phenotype and genotype, with a predominance of SLC3A1 mutations. This heterogeneity is similar to that reported in international cohorts.

MP16-13 CYSTINURIA AND PREGNANCY: CLINICAL COURSE AND OUTCOMES FROM 2000-2020

You have accessJournal of UrologyCME1 Apr 2023MP16-13 CYSTINURIA AND PREGNANCY: CLINICAL COURSE AND OUTCOMES FROM 2000-2020 Amy Reed and Nicole Miller Amy ReedAmy Reed More articles by this author and Nicole MillerNicole Miller More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003236.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cystinuria is a rare disease which limits the understanding of its impact on pregnancy. We sought to characterize stone disease and management of patients with cystinuria during pregnancy at a single institution. METHODS: We completed a retrospective chart review of cystinuria patients at a single institution from 2000-2022. Patients were identified by ICD-10 codes (E72.01) and then included for childbearing potential. Charts were reviewed for urologic history as well as baseline medical and surgical treatment history. We evaluated imaging studies, stone episodes, stone surgeries and complications during pregnancy. This was then compared to the reported historic incidence of renal colic, stone diagnosis and surgical intervention during pregnancy. RESULTS: 44 female patients with cystinuria were identified and 40 were included based on child bearing potential. Patient age ranged from 16-68 years. Nine patients had a total of 27 pregnancies and 20 successful live births. Patients were treated with Thiola (3), urinary alkalinization (4) or fluid alone (5) and all medications were discontinued during pregnancy. Patients had an average of 6 stone surgeries prior to pregnancy. Comorbidities included chronic pain (2), chronic kidney disease (1) and multiple sclerosis (1). Renal colic occurred in 27% of pregnancies requiring an average of 1 renal ultrasound in addition to routine prenatal assessment. Of these, only one patient had confirmed stone events in 2 out of her 4 pregnancies (8.3% of symptomatic patients) which required a total of six surgeries (stent placement, ureteroscopy). The remaining 8 patients did not have any confirmed stone events. Comparatively, the reported incidence of renal colic in all pregnancies is 0.12% with 71% of these patients having confirmed stone events and 28% of them undergoing surgical intervention. Comparing pre- and post-partum imaging, 4 patients had radiographic evidence of stone growth during pregnancy. Pregnancies were complicated by 4 (15%) spontaneous abortions in the first trimester and one patient developed a ureteral stricture after ureteroscopy during pregnancy that required delayed reconstruction. CONCLUSIONS: Patients with cystinuria are at an increased risk of renal colic episodes during pregnancy but these symptomatic patients do not have a higher rate of stone diagnosis or surgical intervention. Cystinuria patients do not seem to increased complications during pregnancy. However, given a high rate of new stone formation, close follow up of these patients in the post-partum period is necessary. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e207 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Amy Reed More articles by this author Nicole Miller More articles by this author Expand All Advertisement PDF downloadLoading ...

Genetic and clinical analysis of Chinese pediatric patients with cystinuria.

This study aimed to investigate the genotypic and phenotypic characteristics of Chinese pediatric patients with cystinuria. This was a retrospective study of 14 Chinese pediatric patients with cystine stones. All published studies of the Chinese pediatric cystinuria population were searched and enrolled based on the inclusive standard. Among the 14 pediatric patients with cystinuria, 8 were males and 6 were females. The mean age of first stone onset was 4.0 ± 3.3years (4months-9years). All of the patients had multiple stones, and 57.1% (8/14) had bilateral stones. The mean maximum stone diameter was 1.7 ± 0.6 (range 0.5-2.6) cm. A total of 13 SLC3A1 gene mutations and 9 SLC7A9 gene mutations were detected, of which 41% (9/22) of mutations were novel. Patients with SLC7A9 mutations were more likely to develop bilateral stones than those with SLC3A1 mutations (100% vs. 33.3%, p = 0.03). Thirty-four SLC3A1 gene mutations and twenty-eight SLC7A9 gene mutations were found in a total of fifty-five Chinese children with cystinuria. The SLC7A9 gene mutation distribution was more dispersed, while the SLC3A1 mutation was clustered in exons 6-8. The c.647C > T (p. T216M) (4/53) and c.1113C > A (p. Y371Ter) (4/53) mutations in the SLC3A1 gene and the c.1399 + 2_3insT (3/36) mutation in the SLC7A9 gene represent potential hotspots in cystinuria. Our results present a comprehensive genetic spectrum for pediatric cystinuria patients in China. Patients with SLC7A9 mutations were more likely to develop bilateral stones than those with SLC3A1 mutations. A wide mutation spectrum and the potential mutation hotspots associated with cystinuria were also identified.

Cystinuria: Genetic Aspects and Novel Pharmacotherapeutics

This review provides an overview of the genetic aspects of cystinuria, as well as the novel pharmacotherapeutics that could potentially be used to treat the disease. Cystinuria is an inherited disorder characterized by the formation of painful stones in the kidneys, bladder, and other parts of the renal system. Currently, mutations responsible for cystinuria have been identified in two genes (SLC3A1 and SLC7A9 ), and cystinuria patients are categorized based on their genotypes - which versions, or alleles, of these genes they have (mutated or wild-type). Regardless of genotype, however, current treatments for all cystinuria patients have significant limitations. This has led researchers to search for more promising therapeutics. One potential treatment uses cystine analogs—compounds that are structurally similar to cystine, which is the naturally occurring chemical substance from which the stones are formed. These compounds have demonstrated the ability to inhibit stone formation by stunting cystine crystallization – the process by which cystine crystals aggregate to form stones. Gene therapy may also be used to treat cystinuria in the future by replacing mutated copies of SLC3A1 and SLC7A9 with healthy ones. Technological advancements and an improvement of our understanding of how gene therapy functions in the renal system could reveal even more treatment possibilities.

S-Methyl-L-Ergothioneine to L-Ergothioneine Ratio in Urine Is a Marker of Cystine Lithiasis in a Cystinuria Mouse Model.

Cystinuria, a rare inherited aminoaciduria condition, is characterized by the hyperexcretion of cystine, ornithine, lysine, and arginine. Its main clinical manifestation is cystine stone formation in the urinary tract, being responsible for 1–2% total and 6–8% pediatric lithiasis. Cystinuria patients suffer from recurrent lithiasic episodes that might end in surgical interventions, progressive renal functional deterioration, and kidney loss. Cystinuria is monitored for the presence of urinary cystine stones by crystalluria, imaging techniques or urinary cystine capacity; all with limited predicting capabilities. We analyzed blood and urine levels of the natural antioxidant L-ergothioneine in a Type B cystinuria mouse model, and urine levels of its metabolic product S-methyl-L-ergothioneine, in both male and female mice at two different ages and with different lithiasic phenotype. Urinary levels of S-methyl-L-ergothioneine showed differences related to age, gender and lithiasic phenotype. Once normalized by L-ergothioneine to account for interindividual differences, the S-methyl-L-ergothioneine to L-ergothioneine urinary ratio discriminated between cystine lithiasic phenotypes. Urine S-methyl-L-ergothioneine to L-ergothioneine ratio could be easily determined in urine and, as being capable of discriminating between cystine lithiasis phenotypes, it could be used as a lithiasis biomarker in cystinuria patient management.

MO060CYSTINURIA: DISEASE PRESENTATION, PROGNOSIS AND QUALITY OF LIFE ANALYSIS OF A WEB-BASED COHORT

Abstract Background and Aims Cystinuria is considered a rare condition as approximately 1% of adult and 6% of pediatric kidney stones are due to this defect. Prevalence varies by geographic region, with good representation in the Mediterranean area. Given the low prevalence and the lack of a defined clinical pathway for these patients, only partial data are available on the long-term course of the disease. A group of cystinuria patients has gathered on Facebook to exchange advice on symptom management and therapy. The use of this type of platform, in cases of low-prevalence diseases, is a good method of collecting patients who otherwise would be difficult to reach. We proposed an online survey to further analyze clinical, therapy, and quality of life of cystinuria patients. Method An online survey was proposed to an Italian social media group restricted to cystinuric patients with the agreement of the administrator. Before participating to the survey, patients provided documentation on their diagnosis and signed an informed consent. The survey was structured in four sections: a thorough medical history focused on kidney stone and cystinuria, the SF-36 questionnaire, the Fatigue Severity Scale, The Brief Pain Inventory. Data was managed and analyzed anonymously. Results Our survey was sent to 55 patients, but only 18 completed all questionnaires. Our cohort is composed of 5 men and 13 women, with a mean age of 39.5 years (SD 17.6), mean height 156.4 cm (SD 18.5), mean weight 60.8 kg (SD 17.9), mean BMI 24.1 (SD 4.5). About medical history, 15/18 patients have had at least 4 episodes of renal sstons in their lifetime, of these 10/15 reported stone expulsion in most episodes. The first episode occurred on average at 14.9 years (SD 9.3), while confirmed diagnosis of cystinuria arises at 20.1 years (SD 15.1). Most patients experienced bilateral stones (12/18). The diagnosis was confirmed generally by: stone composition analysis (39%), urinary cystine levels (24%), cystine crystals revealed at fresh urine exam (22%), genetic findings (7%), Brand test (2%), other (5%). About 33% of our cohort performed a genetic test. Almost 95% of patients are in follow-up with a clinic. Routine exams include: renal ultrasound (30%), nephrologist evaluation (27%), urine 24h evaluation (25%), urology visit (13%), abdominal CT (4%), kidney x-ray (2%). All the patients of our cohort received urological or surgical procedures for kidney stones: generally endoscopic procedures (32%), or lithotripsy (30%), or open surgery (23%). Four patients underwent a nephrectomy. Patienst reportes an average of 31 painful episodes of renal colic (min 0; max 200) in their history. Of these episodes almost 6 ended with a stone expulsion (min 0; max 50), while haematuria was reported by 12 patients (up to 20 episodes in a patient lifetime). A secondary stone composition in addition to cystine was reported by 5/18: calcium oxalate in 100% of these cases, even with struvite and calcium phosphate. Most of these patients (78%) received some nutritional recommendation: generally by nephrologist (50%), or dietician (23%), or urologist (18%). Indications were not easy to follow: a 0-100 visual scale about compliance showed a mean of 45 (SD 27). The 78% were currently on drug therapy: most used therapy included citrate (45%), tiopronin (40%), or bicarbonate (10%). Drugs compliance is very low (26/100 scale SD 23.3). Nobody in our cohort showed a GFR of less than 60 mL/min/1.73 m2. 4/18 reported a positive family history of cystinuria, while 7/18 relatives with renal stones without a diagnosis. Conclusion Patients affected by cystinuria show a very poor quality of life, with high levels of pain, fatigue, and emotional wellness. The diagnosis is delayed from the first event, and they are exhausted by an high frequency of pain stone passages. More attention to quality of life aspects is needed in patients with this rare but life-threatening condition.

Sistin Taşı Olan Çocuk Hastaların Değerlendirilmesi: Tek Merkez Deneyimi

Introduction: Cystinuria is a rare genetic disorder. Many patients suffer from significant recurrent urolithiasis, repeated surgical interventions and the risk of progressive renal impairment. In the current study, the outcomes of patients with cystine stones were investigated. Methods: A total of Twenty-six cystinuria patients with cystine stones, aged between 3 months and 18 years, in our Pediatric Nephrology Department, were retrospectively analyzed. Results: The mean age of patients at diagnosis was 45.2±45.5 months and 88,5% were male. Sixteen (62%) children had recurrent urinary tract infections. Only 10 (38%) patients revealed additional metabolic abnormalities. The urinary pH had significantly increased with treatment and the number of stone recurrence was lower in the patients with urinary pHs ≥ 6.5. There was a significant positive correlation between the last-visit serum creatinine level and the number of surgical interventions. There was not a significant correlation between the last-visit eGFR and the number of surgical interventions, on the other hand, eGFR values decreases as the total number of surgical interventions increases. No stone events were observed at the end of the follow-up period in 10 patients (38%) and the stone events per patient-year was 0.36 for all patients. Four patients with low eGFRs at the beginning of the study get normal with treatment after the follow-up period. Conclusion: Cystinuria has significant morbidity if not properly controlled. Despite all treatments, it should be kept in mind that renal impairment may develop in cystinuria and surgical treatment should be planned by considering minimally invasive options.

Non-contrast computed tomography characteristics in a large cohort of cystinuria patients

PurposeCystine stones are widely considered hard and difficult to treat. Hounsfield Units (HU) are used in other stone types to estimate ‘hardness’ and treatments based on that finding. Our objective was to report mean HU of cystine stones in vivo in a large case series of cystinuria patients and assess for differences in genotype.MethodsA prospective case series of cystinuria patients referred to a specialist centre was analysed. CT imaging was assessed by two independent radiologists to determine in vivo attenuation of cystine calculi. Mean HU was compared for both cystinuria genes (SLC3A1 and SLC7A9) using an independent t-test.Results164 adult cystinuric patients were identified (55% male), median age 43 years (range 18–80). Median follow up was 31 months (IQR 10–62). Genetic data available for 153/164 (93%) demonstrated 97 SLC3A1 (63%) and 55 (36%) SLC7A9 mutations (39 homozygous, 16 heterozygous) and one heterozygous for both SLC3A1/SLC7A9. 107 patients had CT images available demonstrating calculi. Median HU across the cohort was 633 (5th to 95th centile 328–780). There was no difference in mean HU between SLC3A1 and SLC7A9 genotypes (p = 0.68) or homo and heterozygous SLC7A9 (p = 0.70). Mean HU correlated with stone size (Pearson correlation coefficient = 0.51, p < 0.001).ConclusionIn this large single centre cystinuria cohort, mean HU was low for stones that are difficult to treat. Calculi of < 800 HU should prompt consideration of a cystinuria diagnosis. Attenuation was not associated with genotype, and distinct ‘smooth’ and ‘rough’ stones were not observed. Calculi with HU > 1000 are unlikely pure cystine, and in a known cystinuric would suggest conversion to another stone type.

Pharmacological Dilutional Therapy Using the Vasopressin Antagonist Tolvaptan for Young Patients With Cystinuria: A Pilot Investigation

ObjectiveTo perform a pilot study of short-term safety, tolerability, and impact on urinary stone risk parameters of the vasopressin V2-receptor antagonist tolvaptan (which increases urinary excretion of free water) among adolescents and young adults with cystinuria. Materials and MethodsWe enrolled cystinuria patients age 12-25 years. Subjects were treated for 4 days at low-dose tolvaptan (0.3 mg/kg/day, maximum 30 mg) and 4 days at high dose (0.6 mg/kg/day, maximum 60 mg). Twenty-four-hour urine collections were done at baseline, day 3-4 of the dosing period, day 7-8 of the dosing period, and 3-6 days after washout. Primary outcome was cystine capacity (mg/L, target capacity > 0). Secondary outcomes included other urinary/serum parameters, tolerability, and thirst response. ResultsTwo females (17, 23 years) and 2 males (13, 24 years) were enrolled. Cystine capacity respectively went from baseline of −312, −82, −353, and −628 mg/L to 97, 111, 75, and −3 mg/L on high dose (Figure 1). Twenty-four-hour volume went from 1.96, 3.0, 2.1, and 0.91 L to 11.74, 6.5, 9.9, and 2.8 L on high dose (Figure 2). There were no abnormalities in serum electrolytes or liver enzymes. Subjects did experience extreme thirst (9/10 on visual scale), but none discontinued treatment or reduced dose. ConclusionDilutional therapy with tolvaptan increased both cystine capacity and urinary volumes. This treatment approach has the potential to reduce recurrence of stones in this population. Further investigation should study longer term effects and safety, and determine optimal dosing to improve tolerability.

MP43-05 ENZYMATIC LOWERING OF PLASMA CYSTINE PREVENTS FORMATION AND GROWTH OF STONES IN A MOUSE MODEL OF CYSTINURIA UNDER DEHYDRATION CHALLENGE

You have accessJournal of UrologyStone Disease: Medical & Dietary Therapy (MP43)1 Apr 2020MP43-05 ENZYMATIC LOWERING OF PLASMA CYSTINE PREVENTS FORMATION AND GROWTH OF STONES IN A MOUSE MODEL OF CYSTINURIA UNDER DEHYDRATION CHALLENGE Giulia Agnello, Jason Wiggins, Silvia Ferrati, Anthony Quinn, Scott Rowlinson, and J Stuart Wolf* Giulia AgnelloGiulia Agnello More articles by this author , Jason WigginsJason Wiggins More articles by this author , Silvia FerratiSilvia Ferrati More articles by this author , Anthony QuinnAnthony Quinn More articles by this author , Scott RowlinsonScott Rowlinson More articles by this author , and J Stuart Wolf*J Stuart Wolf* More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000898.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cystinuria is an autosomal recessive disease caused by mutations in the SLC3A1 and/or SLC7A9 dibasic amino acid transporter genes. The defective reabsorption of dibasic amino acids filtered by the glomerulus leads to high urine cystine content, subsequent cystine crystallization and the formation of upper tract urinary calculi, with recurrent stone passages and/or need for multiple procedural interventions. Symptomatic stone events include severe abdominal pain, hydronephrosis, hematuria, infective syndromes and chronic pain. Although high fluid intake remains a cornerstone of therapy, this regimen is inadequate at reaching the target cystine urine concentration owing to poor compliance, periods of increased fluid loss (fever, diarrhea/vomiting, high ambient temperature; PMID:16001591, 7996811) or impact on quality of life (e.g. nocturia and increased day time micturition frequency). We are developing a highly novel approach for the treatment of cystinuria patients that works by reducing cystine delivery into the kidney tubules through enzymatic lowering of plasma cystine. Herein, we investigated the therapeutic potential of this approach to prevent cystine stone formation in dehydration prone environments. METHODS: We used a murine model of cystinuria (SLC3A1-/-) that develops cystine stones in the kidneys and bladder (PMID:28165480) and rationed water to 65% to model dehydration conditions. During water rationing, mice were dosed with a human enzyme with novel activity for cystine. Stone burden in the kidneys and bladder was assessed by microcomputed tomography, and plasma and urine cystine concentration was monitored over time. RESULTS: Enzymatic reduction of plasma cystine prevented stone formation and growth in the kidneys and bladder, even under dehydration challenge. Lowering of plasma cystine resulted in reduction of cystine concentration in urine despite temporary dehydration. CONCLUSIONS: This study provides proof of concept that enzymatic lowering of plasma cystine levels is effective at reducing the cystine concentration in the urine in a mouse model of cystinuria in temporary dehydration conditions, and prevents formation and growth of cystine stones. Enzymatic lowering of plasma cystine warrants further investigation as a new potential approach for disease management of cystinuric patients unresponsive or intolerant to current treatment, or facing quality of life factors that impact the ability to comply with current treatment approaches. Source of Funding: This study was funded by Aeglea BioTherapeutics, Inc. © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e648-e649 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Giulia Agnello More articles by this author Jason Wiggins More articles by this author Silvia Ferrati More articles by this author Anthony Quinn More articles by this author Scott Rowlinson More articles by this author J Stuart Wolf* More articles by this author Expand All Advertisement PDF downloadLoading ...

Successful pre-emptive kidney transplantation in a cystinuria patient with nephrolithiasis-related end-stage renal disease

BackgroundCystinuria is a rare autosomal recessive metabolic disorder that affects renal and intestinal cystine transport. Cystine stones are found in only 1–2% of all stone formers. Patients with cystinuria are at high risk for nephrolithiasis and subsequent morbidity. In spite of the various medical and surgical treatments that are currently available for cystinuria, some patients gradually develop kidney failure, with only a few reported cases regarding kidney transplantation (KTx) to treat end-stage renal disease (ESRD) secondary to cystinuria. Cystinuria is likely not to be a systemic disease; thus, renal replacement with transplantation seems a good therapeutic option for ESRD. However, few cystinuria patients have undergone KTx due to ESRD.Case presentationWe herein describe the case of a 49-year-old man with cystinuria, frequent stone events, and ESRD who underwent pre-emptive ABO-incompatible kidney transplantation. At 2 years and 6 months post-transplantation, the patient remains asymptomatic with no prophylactic therapy for cystinuria, and the allograft function has been preserved without evidence of rejection.ConclusionsIn conclusion, a cystinuria patient with nephrolithiasis-related ESRD was successfully treated by transplantation. Although additional cases are required to confirm the efficacy of this approach, renal replacement may be useful for treating ESRD in patients with rare hereditary forms of kidney stone disease.

No evidence for point mutations in the novel renal cystine transporter AGT1/SLC7A13 contributing to the etiology of cystinuria

BackgroundCystinuria is caused by the defective renal reabsorption of cystine and dibasic amino acids, and results in cystine stone formation. So far, mutations in two genes have been identified as causative. The SLC3A1/rBAT gene encodes the heavy subunit of the heterodimeric rBAT-b0,+AT transporter, whereas the light chain is encoded by the SLC7A9/ b0,+AT gene. In nearly 85% of patients mutations in both genes are detectable, but a significant number of patients currently remains without a molecular diagnosis. Thus, the existence of a further cystinuria gene had been suggested, and the recently identified AGT1/SLC7A13 represents the long-postulated partner of rBAT and third cystinuria candidate gene.MethodsWe screened a cohort of 17 cystinuria patients for SLC7A13 variants which were negative for SLC3A1 and SLC7A9 mutations.ResultsDespite strong evidences for an involvement of SLC7A13 mutations in cystinuria, we could not confirm a relevant role of SLC7A13 for the disease.ConclusionWith the exclusion of SLC7A13/AGT1 as the third cystinuria gene accounting for the SLC3A1 and SLC7A9 mutation negative cases, it becomes obvious that other genetic factors should be responsible for the cystinuria phenotype in nearly 15% of patients.