The genetics of cystinuria - an update and critical reevaluation.

PURPOSE OF REVIEW: We aimed to critically evaluate how the establishment of genotype-based treatment for cystinuria has been hampered due to the large number of variants of unknown significance (VUS) within the disease causing genes as well as challenges in accessing a large enough sample size for systematic analysis of endpoint parameters that truly reflect disease severity. This review further discusses how to overcome these hurdles with the establishment of a cystinuria-specific refinement of the current American College of Medical Genetics and Genomics (ACMG)-criteria of variant interpretation. RECENT FINDINGS: Novel tools such as AlphaMissense combined with the establishment of a refined ACMG criterion will play a significant role in classifying VUS within the responsible disease genes SLC3A1 (rBAT) and SLC7A9 (BAT1). This will also be essential in elucidating the role of promising candidate genes, such as SLC7A13 (AGT1), which have been derived from murine model systems and still need further research to determine if they are involved in human cystinuria. SUMMARY: Cystinuria was one of the first disorders to receive a gene-based classification, nonetheless, the clinically actionable implications of genetic diagnostics is still minor. This is due to poorly characterized genotype-phenotype correlations which results in a lack of individualized (genotype-) based management and metaphylaxis.

Ureteroscopic management in cystinuric patients: long-term results from a tertiary care referral center.

OBJECTIVE: To evaluate long-term surgical and functional outcomes of cystinuric patients exclusively treated with Ureteroscopy (URS). METHODS: Data from patients treated for cystine stones at a single academic center were retrospectively analyzed. The management protocol consisted of (i) treating symptomatic or > 7 mm stones, (ii) multi-staged URS for voluminous stones, (iii) referring patients to a dedicated nephrological clinic. The eGFR was calculated according to the MDRD formula. CKD category was assessed according to the NKF classification. Relevant CKD was defined as CKD category ≥ 3a. Descriptive statistics were used to analyze the cohort data. RESULTS: Data from 46 cystinuric patients treated with 332 URS were available. Median age at diagnosis and at first URS in our center were 18 and 32 years, respectively. Median follow-up was 101 months. Median number of URS and recurrences per patient were 6 and 2, respectively. The median interval between the first and the last available creatinine level was 64 months. Median first and last eGFR were 72 and 74 mL/min, respectively. Overall, 83% of patients had stable or improved renal function within the study period. Ureteral stricture occurred in 3 (6.5%) patients. CONCLUSIONS: Cystinuria requires intensive endoscopic management. Most patients treated with URS have stable or improved renal function within a long-term follow-up. CKD is a not neglectable event that potentially occurs at an early stage of life. Current findings should be considered for the surgical management of cystinuric patients.

Postnatal outcome of children with antenatal colonic hyperechogenicity.

OBJECTIVE: To evaluate the postnatal outcome of children with antenatal colonic hyperechogenicity, currently considered as a sign of lysinuria-cystinuria, but which may also be a sign of other disorders with a more severe prognosis. METHOD: We carried out a French multi-centric retrospective study via 15 Multidisciplinary Center for Prenatal Diagnosis from January 2011 to January 2021. We included pregnancies for which fetal colonic hyperechogenicity had been demonstrated. We collected the investigations performed during pregnancy and at birth as well as the main clinical features of the mother and the child. We then established the prevalence of pathologies such as lysinuria-cystinuria (LC), hypotonia-cystinuria syndrome (HC), or lysinuric protein intolerance (LPI). RESULTS: Among the 33 cases of colonic hyperechogenicity collected, and after exclusion of those lost to follow-up, we identified 63% of children with lysinuria-cystinuria, 8% with lysinuric rotein intolerance, and 4% with hypotonia-cystinuria syndrome. CONCLUSION: Management of prenatal hyperechoic colon should include a specialized consultation with a clinical geneticist to discuss further investigations, which could include invasive amniotic fluid sampling for molecular diagnosis. A better understanding of diagnoses and prognosis should improve medical counseling and guide parental decision making.

Covalent post-synthetic modification of MOFs as a fluorescent sensor for the efficient detection of the biomarker of cystinuria.

Cystinuria is a genetic disorder, and in severe cases, it might lead to kidney failure. As an important biomarker for cystinuria, the level of arginine (Arg) in urine is a vital indicator for cystinuria screening. Therefore, it is urgently needed to detect Arg with high selectivity and sensitivity. In this work, a boric acid functionalized Zr-based metal-organic framework UiO-PhbA is prepared by grafting phenylboronic acid on UiO-66-NH2 through a Schiff base reaction using a covalent post-synthesis modification (CPSM) strategy. The prepared UiO-PhbA exhibits a sensitive and specific fluorescence "turn-on" response to Arg and can be exploited to detect Arg in human serum and urine samples with a broad linear range of 0.6-350 µM and low limit of detection (LOD) of 18.45 nM. This study provides a new and reliable rapid screening protocol for sulfite oxidase deficiency-related diseases.

Unraveling the natural history of presymptomatic cystinuria.

PURPOSE OF REVIEW: Servais et al. recently published clinical practice recommendations for the care of cystinuria patients. However, these guidelines were largely based on retrospective data from adults and children presenting with stones. Significant questions remain about the natural history of cystinuria in presymptomatic children. RECENT FINDINGS: We review the natural history of cystinuria in presymptomatic children followed from birth. In total, 130 pediatric patients were assigned putative genotypes based on parental urinary phenotype: type A/A (N = 23), B/B (N = 6), and B/N (N = 101). Stones were identified in 12/130 (4% of A/A, 17% of B/B, and 1% of B/N patients). Type B/B patients had lower cystine excretion than type A/A patients. Although urine cystine/creatinine fell with age, urine cystine/l rose progressively in parallel with the risk of nephrolithiasis. Each new stone was preceded by 6-12 months of urine specific gravity of more than 1.020. However, average urine specific gravity and pH were not different in stone formers vs. nonstone formers, suggesting that intrinsic stone inhibitors or other unknown factors may be the strongest determinants of individual risk. SUMMARY: The current study reviews the clinical evolution of cystinuria in a cohort of children identified by newborn screening, who were categorized by urinary phenotype and followed from birth.

Disrupting Crystal Growth through Molecular Recognition: Designer Therapies for Kidney Stone Prevention.

Aberrant crystallization within the human body can lead to several disease states or adverse outcomes, yet much remains to be understood about the critical stages leading to these events, which can include crystal nucleation and growth, crystal aggregation, and the adhesion of crystals to cells. Kidney stones, which are aggregates of single crystals with physiological origins, are particularly illustrative of pathological crystallization, with 10% of the U.S. population experiencing at least one stone occurrence in their lifetimes. The human record of kidney stones is more than 2000 years old, as noted by Hippocrates in his renowned oath and much later by Robert Hooke in his treatise Micrographia. William Hyde Wollaston, who was a physician, chemist, physicist, and crystallographer, was fascinated with stones, leading him to discover an unusual stone that he described in 1810 as cystic oxide, later corrected to cystine. Despite this long history, however, a fundamental understanding of the stages of stone formation and the rational design of therapies for stone prevention have remained elusive.This Account reviews discoveries and advances from our laboratories that have unraveled the complex crystal growth mechanisms of l-cystine, which forms l-cystine kidney stones in at least 20 000 individuals in the U.S. alone. Although l-cystine stones affect fewer individuals than common calcium oxalate stones, they are usually larger, recur more frequently, and are more likely to cause chronic kidney disease. Real-time in situ atomic force microscopy (AFM) reveals that the crystal growth of hexagonal l-cystine is characterized by a complex mechanism in which six interlaced anisotropic spirals grow synchronously, emanating from a single screw dislocation to generate a micromorphology with the appearance of stacked hexagonal islands. In contrast, proximal heterochiral dislocations produce features that appear to be spirals but actually are closed loops, akin to a Frank-Read source. These unusual and aesthetic growth patterns can be explained by the coincidence of the dislocation Burgers vector and the crystallographic 61 screw axis. Inhibiting l-cystine crystal growth is key to preventing stone formation. Decades of studies of "tailor-made additives", which are imposter molecules that closely resemble the solute and bind to crystal faces through molecular recognition, have demonstrated their effects on crystal properties such as morphology and polymorphism. The ability to visualize crystal growth in real time by AFM enables quantitative measurements of step velocities and, by extension, the effect of prospective inhibitors on growth rates, which can then be used to deduce inhibition mechanisms. Investigations with a wide range of prospective inhibitors revealed the importance of precise molecular recognition for binding l-cystine imposters to crystal sites, which results in step pinning and the inhibition of step advancement as well as the growth of bulk crystals. Moreover, select inhibitors of crystal growth, measured in vitro, reduce or eliminate stone formation in knockout mouse models of cystinuria, promising a new pathway to l-cystine stone prevention. These observations have wide-ranging implications for the design of therapies based on tailor-made additives for diseases associated with aberrant crystallization, from disease-related stones to "xenostones" that form in vivo because of the crystallization of low-solubility therapeutic agents such as antiretroviral agents.

Case-based review of dietary management of cystinuria.

PURPOSE: The currently recommended treatment strategy for cystine stone formers is based on a progressive approach that starts with the most conservative measures. In patients with cystinuria, increased patient compliance with dietary management and medical treatment is associated with fewer stone interventions. In this case-based review, the dietary management of cystine stone former was reviewed under the guidance of evidence-based medicine. METHODS: The dietary management of the 13-year-old cystinuria patient, who underwent 18 endourological stone interventions, was reviewed in the light of evidence-based medicine. A literature search was performed in Pubmed, MEDLINE, Embase, and Cochrane Library databases according to PRISMA guidelines published from 1993 to September 2022. A total of 304 articles were included in this paper. RESULTS: In managing patients with cystinuria, hyperhydration, and alkalinization of the urine with medical treatment, the rational use of cystine-binding drugs by taking into account individual situations has come to the fore. A limited study has argued that a vegetarian diet is effective as the alkaline load from fruits and vegetables can reduce the amount of alkalizing substances required to achieve urinary alkalinization above pH 7.5, making it particularly suitable for the dietary treatment of cystine stone disease. CONCLUSION: Life-long follow-up with dietary modification, hyperhydration, and personalized medical therapy (alkalinization and cystine-binding drugs) are critical in preventing chronic kidney disease and kidney failure in cystinuria.

Phenotypic characterization of a pediatric cohort with cystinuria and usefulness of newborn screening.

BACKGROUND: Cystinuria is an inherited metabolic disease involving the defective transport of cystine and the dibasic amino acids in the renal proximal tubules that causes the formation of stones in the urinary system. In our regional child health program, cystinuria is included in newborn metabolic screening. Our objectives are the phenotypic characterization of our cystinuric pediatric cohort and to present our experience in neonatal cystinuria screening. METHODS: The study of clinical cases of pediatric patients diagnosed with cystinuria over a period of 32 years. All patients were studied at demographic, clinical, laboratory, radiological, and therapeutic levels. RESULTS: We diagnosed 86 pediatric patients with cystinuria; 36% of them had the homozygous biochemical phenotype. 95.3% of the patients were detected by neonatal metabolic screening. We performed urine biochemical analyses of parents with additional diagnoses of 63 adult patients. The mean follow-up time was 16.8 ± 8.5 years. 11.6% of patients developed one or more episodes of urinary tract infection during that period. Chronic kidney disease, proteinuria, and hypertension were uncommon (1.2%). 10.5% developed kidney stones at the mean age of presentation of 7.78 ± 7.6 years; 33% were recurrent. The risk of developing lithiasis was higher for homozygous biochemical-phenotype patients. Hypercalciuria was a significant risk factor in the development of lithiasis. CONCLUSIONS: Our clinical data suggest that diagnosing cystinuria through neonatal screening could be a useful strategy for the detection of presymptomatic cases, in order to establish preventive measures, as well as for the detection of relatives at risk. A higher resolution version of the Graphical abstract is available as Supplementary information.

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

BACKGROUND: Cystinuria and xanthinuria are both rare genetic diseases involving urinary calculi. However, cases combining these two disorders have not yet been reported. CASE PRESENTATION: In 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. CONCLUSION: Genetic 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.

Evaluation of the value of genetic testing for cystinuria in the Danish population of English bulldogs.

Cystinuria is a genetic disease that can lead to cystine urolith formation. The English bulldog is the dog breed most frequently affected. In this breed, three missense mutations have been suggested to be associated with cystinuria: c.568A>G and c.2086A>G in SLC3A1 and c.649G>A in SLC7A9. In this study, the occurrence of these three mutations in the Danish population of English bulldogs was investigated. Seventy-one English bulldogs were genotyped using TaqMan assays. The dogs' owners were given questionnaires concerning the medical histories of their dogs. Allele frequencies of 0.40, 0.40, and 0.52 were found for the mutant alleles in the three loci: c.568A>G, c.2086A>G, and c.649G>A, respectively. For both mutations in SLC3A1, a statistically significant association was found between cystinuria and homozygosity for the G allele among male, English bulldogs. For the mutation in SLC7A9, there was no statistically significant association between homozygosity for the mutant allele and cystinuria. Due to high allele frequencies, limited genetic diversity, continued uncertainty about the genetic background of cystinuria, and more severe health problems in the breed, selection based on genetic testing for the mutations in SLC3A1 cannot be recommended in the Danish population of English bulldogs. However, results of the genetic test may be used as a guide to recommend prophylactic treatment.

Pediatric urolithiasis: what can pediatricians expect from radiologists?

The incidence of urolithiasis in children has increased over the two last decades. Urolithiasis formation results from urine oversaturation following insufficient water intake, urinary obstruction (notably in cases of congenital uropathies), excess production of an insoluble compound, or imbalance between crystallization promoters and inhibitors. Whereas most urolithiases in adults occur secondary to environmental factors, in children, secondary causes are far more frequent, and 15% are related to genetic causes, most often monogenic. This is especially true in recurrent forms, with early and rapid progression and bilateral stones, and in cases of familial history or consanguinity. Because of differing clinical management, one should rule out cystinuria, primary hyperoxaluria and renal tubular acidosis, among other causes of urolithiasis. As such, a complete biochemical evaluation must be performed in all cases of pediatric urolithiasis, even in cases of an underlying uropathy. Ultrasound examination is the first-line modality for imaging pediatric urolithiasis, allowing both diagnosis (urolithiasis and its complications) and follow-up. US examination should also explore clues to an underlying cause of urolithiasis. This review is focused on the role of imaging in the management and etiological assessment of pediatric urolithiasis. Radiologists play an important role in pediatric urolithiasis, facilitating diagnosis, follow-up and surgical management. A trio of clinicians (pediatric nephrologist, pediatric surgeon, pediatric radiologist) is thus necessary in the care of these pediatric patients.

Penicillamine-induced degenerative dermopathy in a patient with Wilson's disease.

Penicillamine is a chelator that has been used in Wilson's disease, cystinuria, rheumatoid arthritis and heavy metal intoxication. We report a case of a 31-year-old man presented with skin atrophy, purpura and milia on the hips and shoulders after taking penicillamine for 1.5 years. According to literature review, this type of penicillamine-associated cutaneous adverse effect belongs to degenerative dermopathy, which mostly occurs on bony prominences and points of pressure in patients with Wilson's disease or cystinuria. Withdrawal or reduction of drug dose can improve the features of degenerative dermopathy.

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.

Thulium fiber laser in cystine calculi.

INTRODUCTION: Thulium Fiber Laser (TFL) is the most modern technology to treat nephrolithiasis and ureterolithiasis in endourology. Although there are a lot of new studies coming up, we still don't have data on how this laser works in some rare diseases.Cystinuria is the most common genetic nephrolithiasis disorder (1), known for its recurrent lithiasis (2). Our main goal in this video is to show a successful case of cystine calculi treated with Thulium Fiber Laser (Laser Fiber Dust/Quanta System™). Cystinuria is the most common genetic nephrolithiasis disorder (1), known for its recurrent lithiasis (2). MATERIALS AND METHODS: A 25 years-old male, cystinuric, presented with a CT scan, showing a 10mm stone on the right side and two calculi 6 and 7 mm on the left side, all located in the lower calyx. Bilateral flexible ureteroscopy was done using a reusable digital flexible ureteroscope. Starting on the left side, we repositioned the stone from the lower to the upper calyx, using a tipless front opening basket. Lithotripsy was performed using TFL. Settings were 100 Hz (frequency) and 100 mJ (energy) for dusting.  Popcorn technique was also used, setting the laser at 100Hz and 200 mJ, obtaining good dusting. On the right side, lithotripsy was performed in the inferior calyx, also resulting in "snowstorm". Procedure time was 120 minutes. RESULTS: The postoperative was uneventful. Follow up CT showed a 3 mm residual fragment in the right kidney. CONCLUSION: This video demonstrates the treatment of bilateral cystine calculi with Thulium Fiber Laser. Reasonable procedure time and excellent dusting results are encouraging, pointing towards great improvements in endourology.

Novel "Turn-On" Luminescent Chemosensor for Arginine by Using a Lanthanide Metal-Organic Framework Photosensitizer.

Arginine is considered as a biomarker of cystinuria and other diseases, and thus, it is of urgency to develop a simple and rapid method with high sensitivity and selectivity for arginine detection to meet the demand of on-site analysis and bedside diagnosis. In this work, a lanthanide metal-organic framework, La(TATB), was prepared using a triazine-based planar ligand, 4,4',4″-s-triazine-2,4,6-triyltribenzoate (H3TATB), and lanthanide ion (La3+). La(TATB) can be used as a highly photosensitive agent to activate molecular oxygen to 1O2 to achieve efficient photosensitive oxidation of arginine accompanied by strong blue fluorescence emission under 302 nm UV irradiation. Due to the porous structure and high specific surface area of La(TATB), short-life 1O2 can effectively approach and react with amino acid substrate molecules, thus leading to higher sensitivity than other systems. Therefore, the "turn-on" fluorescence sensing of trace arginine can be realized, with a measured linear response range of 10-20,000 nM and a limit of detection as low as 7 nM. This method can be used for the detection of trace arginine in urine, which is conducive to the bedside diagnosis and rapid screening of cystinuria and other diseases. The proposed method not only expands the application scope of Ln-MOFs but also provides a new construction strategy for "turn-on" luminescence sensors.

Gene therapy for kidney disease: targeting cystinuria.

PURPOSE OF REVIEW: The aim of this study was to summarize recent findings in kidney gene therapy while proposing cystinuria as a model kidney disease target for genome engineering therapeutics. RECENT FINDINGS: Despite the advances of gene therapy for treating diseases of other organs, the kidney lags behind. Kidney-targeted gene delivery remains an obstacle to gene therapy of kidney disease. Nanoparticle and adeno-associated viral vector technologies offer emerging hope for kidney gene therapy. Cystinuria represents a model potential target for kidney gene therapy due to its known genetic and molecular basis, targetability, and capacity for phenotypic rescue. SUMMARY: Although gene therapy for kidney disease remains a major challenge, new and evolving technologies may actualize treatment for cystinuria and other kidney diseases.

Crystalline structures of L-cysteine and L-cystine: a combined theoretical and experimental characterization.

It is assumed that genetic diseases affecting the metabolism of cysteine and the kidney function lead to two different kinds of pathologies, namely cystinuria and cystinosis whereby generate L-cystine crystals. Recently, the presence of L-cysteine crystal has been underlined in the case of cystinosis. Interestingly, it can be strikingly seen that cystine ([-S-CH2-CH-(NH2)-COOH]2) consists of two cysteine (C3H7NO2S) molecules connected by a disulfide (S-S) bond. Therefore, the study of cystine and cysteine is important for providing a better understanding of cystinuria and cystinosis. In this paper, we elucidate the discrepancy between L-cystine and L-cysteine by investigating the theoretical and experimental infrared spectra (IR), X-ray diffraction (XRD) as well as Raman spectra aiming to obtain a better characterization of abnormal deposits related to these two genetic pathologies.

Lipidomics characterization of the lipid metabolism profiles in a cystinuria rat model: Precalculus damage in the kidney of cystinuria.

Cystinuria is a genetic disorder of cystine transport, including defective protein b0,+AT (encoded by SLC7A9), and/or rBAT (encoded by SLC3A1). Patients present hyperexcretion of cystine in the urine, recurrent cystine lithiasis, and progressive decline in kidney function. Moreover, heterodimer transport is defective. To date, little omics data are accessible regarding this metabolic disease caused by membrane proteins. Since membrane function is closely related to changes in the lipidome, we decided to explore the changes in kidney tissue of a self-established cystinuria rat model by performing lipidomic analysis by LC-MS/MS. Our results demonstrated that Slc7a9 deficiency changed the lipid profile of the renal cortex and induced vital modifications in the lipidome, including major alterations in ChE, LPA, and PA. Among those alterations, this lipidomic study highlights the lipid changes that participate in inflammatory responses during cystinuria. As a result, lipid research, perhaps has great potential, for it may lead to the identification of novel therapeutic targets for the prevention and treatment of cystinuria.

Cystinuria: an update on pathophysiology, genetics, and clinical management.

Cystinuria is the most common genetic cause of nephrolithiasis in children. It is considered a heritable aminoaciduria as the genetic defect affects the reabsorption of cystine and three other amino acids (ornithine, lysine, and arginine) in the renal proximal tubule. Patients affected by this condition have elevated excretion of cystine in the urine, and because of this amino acid's low solubility at normal urine pH, patients tend to form cystine calculi. To date, two genes have been identified as disease-causative: SLC3A1 and SLC7A9, encoding for the two subunits of the heterodimeric transporter. The clinical features of this condition are solely related to nephrolithiasis. The diagnosis is usually made during infancy or adolescence, but cases of late diagnosis are common. The goal of therapy is to reduce excretion and increase the solubility of cystine, through both modifications of dietary habits and pharmacological treatment. However, therapeutic interventions are not always sufficient, and patients often have to undergo several surgical procedures during their lives to treat recurrent nephrolithiasis. The goal of this literature review is to synthesize the available evidence on diagnosis and management of patients affected by cystinuria in order to provide physicians with a practical tool that can be used in daily clinical practice. This review also aims to shed some light on new therapy directions with the aim of ameliorating kidney outcomes while improving adherence to treatment and quality of life of cystinuric patients.

Cystinuria: clinical practice recommendation.

Cystinuria (OMIM 220100) is an autosomal recessive hereditary disorder in which high urinary cystine excretion leads to the formation of cystine stones because of the low solubility of cystine at normal urinary pH. We developed clinical practice recommendation for diagnosis, surgical and medical treatment, and follow-up of patients with cystinuria. Elaboration of these clinical practice recommendations spanned from June 2018 to December 2019 with a consensus conference in January 2019. Selected topic areas were chosen by the co-chairs of the conference. Working groups focusing on specific topics were formed. Group members performed systematic literature review using MEDLINE, drafted the statements, and discussed them. They included geneticists, medical biochemists, pediatric and adult nephrologists, pediatric and adult urologists experts in cystinuria, and the Metabolic Nephropathy Joint Working Group of the European Reference Network for Rare Kidney Diseases (ERKNet) and eUROGEN members. Overall 20 statements were produced to provide guidance on diagnosis, genetic analysis, imaging techniques, surgical treatment (indication and modalities), conservative treatment (hydration, dietetic, alkalinization, and cystine-binding drugs), follow-up, self-monitoring, complications (renal failure and hypertension), and impact on quality of life. Because of the rarity of the disease and the poor level of evidence in the literature, these statements could not be graded. This clinical practice recommendation provides guidance on all aspects of the management of both adults and children with cystinuria, including diagnosis, surgery, and medical treatment.