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.

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

INTRODUCTION AND AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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.

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.

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.

Clinical profile of a Polish cohort of children and young adults with cystinuria.

BACKGROUND: Cystinuria is an inherited disorder that results in increased excretion of cystine in the urine. It accounts for about 1-2% of pediatric kidney stones. In this study, we sought to identify the clinical characteristics of patients with cystinuria in a national cohort. METHODS: This was a retrospective study involving 30 patients from the Polish Registry of Inherited Tubulopathies. Initial data and that from a 6-month follow-up were analyzed. Mutational analysis was performed by targeted Sanger sequencing and, if applicable, MLPA analysis was used to detect large rearrangements. RESULTS: SLC7A9 mutations were detected in 15 children (50%; 10 males, 5 females), SLC3A1 mutations in 14 children (47%; 5 males, 9 females), and bigenic mutations in one male patient. The first clinical symptoms of the disease were detected at a median of 48 months of age (range 3-233 months). When individuals with different mutations were compared, there were no differences identified in gender, age of diagnosis, presence of UTI or urolithiasis, eGFR, calcium, or cystine excretion. The most common initial symptoms were urolithiasis in 26 patients (88%) and urinary tract infections in 4 patients (13%). Urological procedures were performed in 18 out of 30 (60%). CONCLUSIONS: The clinical course of cystinuria is similar among patients, regardless of the type of genetic mutation. Most patients require surgery before diagnosis or soon after it. Patients require combined urological and pharmacological treatment for prevention of stone recurrence and renal function preservation.

A highly selective and sensitive fluorescent sensor based on Tb3+-functionalized MOFs to determine arginine in urine: a potential application for the diagnosis of cystinuria.

A unique metal-organic framework with the formula [Cd4(H2L)2(L)·H2O]·3H2O (H4L = 5,5'-(1H-1,2,4-triazole-3,5-diyl)diisophthalic acid) was successfully constructed under solvothermal conditions. The frameworks with multiple free Lewis base sites and Lewis acid sites exhibited easily sensitized properties. After the encapsulation of Tb3+ cations, the as-synthesized Tb3+@Cd-MOF demonstrated strong luminescence induced by the efficient energy transfer from the bridging ligands to the Tb3+ cations, with the potential to serve as a chemical sensor. Interestingly, Tb3+@Cd-MOF was proven to be a very promising and highly selective and sensitive luminescent platform for the quantitative detection of arginine, which is the biomarker of cystinuria. The fluorescent probe presented high selectivity to arginine in urine with strong luminescence quenching. Furthermore, a convenient fluorescence-based test paper for the visual detection of arginine in applications was prepared. For the first time, arginine was quantified and monitored in urine by a highly efficient recyclable fluorescent sensor based on Tb3+-functionalized MOF hybrids, which may be a potential candidate for the further development of clinical diagnostic tools.

A Dynamic Chemical Network for Cystinuria Diagnosis.

The study of molecular networks represents a conceptual revolution in chemistry. Building on previous knowledge and after understanding the rules of non-covalent interactions, the design of stimulus-responsive chemical systems is possible. Herein we report a new strategy, based on the reorganization of a dynamic chemical network that generates new fluorescent associations in the presence of cysteine or cystine. The binding and sensing units are encoded in the components that dynamically assemble and disassemble responding to external stimuli as a successful tool to detect both cysteine and cystine in aqueous media. Moreover, the dynamic sensing system works in human urine, as a prospective application for cystinuria diagnosis.

PREVALENCE OF CYSTINURIA IN SERVALS ( LEPTAILURUS SERVAL) IN THE UNITED STATES.

Cystinuria is a condition caused by defects in amino acid transport within the kidneys and small intestines. It has been reported in humans, dogs, domestic cats, ferrets, nondomestic canids, and nondomestic felids, including servals ( Leptailurus serval). Genetic mutations have been identified in dogs, humans, and domestic cats. Cystinuria usually follows an autosomal recessive inheritance, although it can be autosomal dominant and sex linked. The primary objective of this study was to screen urine samples dried on filter paper from captive servals in the United States for cystinuria by using the cyanide-nitroprusside screening test. A second objective was to determine whether cystinuria is inheritable in servals. Servals were initially recruited for the study by survey. Owners and institutions interested in participating were sent a second survey and filter paper for collecting urine samples. Samples were collected from 25 servals. One additional serval with confirmed cystine urolithiasis was added for a total sample size of 26 servals. Twenty-seven percent (7/26) were positive, 54% (14/26) were weakly positive, and 19% (5/26) were negative. Sex, reproductive status, and urine collection method had no significant association with test results. This condition is likely underreported in servals and should be ruled out in any serval with nonspecific signs of illness; neurologic signs such as lethargy, ataxia, or seizures; ptyalism; or signs of lower urinary tract disease such as dysuria, hematuria, stranguria, pollakiuria, or urethral obstructions.

Early Recognition and Management of Rare Kidney Stone Disorders.

Kidney stones, especially those that present in childhood/adolescence, may be due to rare inherited disorders such as cystinuria. Early recognition and prompt treatment can help reduce or even prevent the serious long-term complications of these rare stone disorders.

Case Study - Case Studies in Cystinuria.

The diagnosis and treatment of patients with rare inherited metabolic disorders associated with recurrent and often obstructive kidney stones are important to the prevention of chronic kidney disease or end stage renal disease. Two case studies in this article describe the diagnosis and management of cystinuria, the most common rare kidney stone disorder.

[Cystine as a risk factor of the stone formation in kidney: the reference value range of urinary excretion, the stage diagnosis of cystine metabolism disorder].

OBJECTIVE: to define the reference value ranges of cystine, lysine and arginine urinary excretion relative to creatinine in the morning urine samples for the metabolic disorders diagnosis leading to the formation of urinary stones. MATERIALS AND METHODS: the study involved 695 healthy individuals aged 1-17 and 1564 patients with urolithiasis aged 7-45. The content of cystine in the urine samples was determined by high performance liquid chromatography. The chemical composition of urinary stones was investigated by methods of the qualitative chemical reaction and the crystals microscopy. RESULTS: the reference value ranges of cystine, lysine and arginine urinary excretion relative to creatinine in the morning urine samples were developed in the age aspect. Excess in cystine level in the urine samples of the relatively healthy individuals detected in 1.4% of cases. From 1564 urinary stones submitted for analysis, the frequency of cystine stones was 0.8%. CONCLUSION: for the objective assessment of the cystine metabolism status the evaluation of the degree of cystinuria is necessary in order to form the risk group for cystine nephrolithiasis. The reference value ranges of cystine urinary excretion developed in the age aspect and "cystine / creatinine index" in morning urine samples will provide the opportunity to identify the state of the cystine exchange from early childhood and develop differentiated program for the prevention of stone formation in the kidneys.

Cystinuria: current concepts and future directions.

Cystinuria, an autosomic recessive genetic disorder is an uncommon cause of nephrolithiasis characterized by an impairment of transport of cystine, ornithine, lysine, and arginine (COLA). Of these, only cystine is insoluble enough to cause stone formation. Although a classification exists that categorizes the disease depending on chromosomal mutation, this does not currently alter management which consists of increased fluid intake, urine alkalinization, reduced sodium intake and, if warranted, cystine-binding thiol drugs. Cystine stones are relatively resistant to fragmentation. Intrinsic characteristics on imaging may help in planning surgical treatment. Finally, advances in crystal growth inhibition are encouraging as they may provide a new tool to treat this condition which although uncommon, is treatable and has been associated with lower quality of life and renal function compared to other stone formers.

Donor-transmitted cystinuria in a renal transplant recipient.

Cystinuria is an autosomal recessive disorder associated with defective proximal tubular reabsorption of divalent amino acids. It leads to increased cystine, ornithine, lysine, and arginine excretion in the urine. Cystine is insoluble in physiological pH, and cystinuria leads to crystalluria and nephrolithiasis. We present a case of acquired cystinuria in a renal transplant recipient, that is, to the best of our knowledge, the first case of acquired cystinuria ever documented in the literature.

Update on cystinuria.

PURPOSE OF REVIEW: Cystinuria is a rare genetic disease with increased urinary excretion of the poorly soluble amino acid cystine. It can lead to significant morbidity in affected patients due to the often large and recurrent resulting kidney stones. Treatment is focused on the prevention of stone formation. There have been few advances in the available therapeutic options for the disorder in the last 15-20 years. RECENT FINDINGS: Although no new treatments have emerged in the prevention of cystinuria in recent years, several developments hold promise for advancing the field of caring for affected patients. A new method of measuring urinary cystine and estimating potential for stone formation, called cystine capacity, may prove to be a useful tool in monitoring the disease. The discoveries of the mutations that cause cystinuria have led to a new classification system based on genotype that is more accurate than the prior phenotypic one. The finding of new compounds that inhibit cystine crystal growth in vitro, now being tested in animal models, may lead to new potential therapies in years to come. The Rare Kidney Stone Consortium has developed a registry and hopes to lead further efforts in dealing with cystinuria. SUMMARY: With several recent advances in the monitoring and treatment of cystinuria, and the gathering of clinical patient data, there are now opportunities for new management protocols and therapies.