RARE DISEASE
Cystinuria type A
Cystinuria type A
Cystinuria type A
Drug discovery
0
drugs
With orphan designations
Overview
Cystinuria Type A is an autosomal recessive disorder caused by SLC3A1 mutations, leading to defective renal reabsorption of cystine and dibasic amino acids. This results in recurrent cystine nephrolithiasis, often manifesting in the first two decades of life. Bilateral or large stones (>12 mm) are common, with a high recurrence rate despite treatment. Diagnosis involves urinary cystine quantification, imaging, and genetic testing [1][2][4][10].
Therapies
Hydration: >3 L/day urine output to reduce cystine concentration [3][8][12].
Alkalinization: Potassium citrate (target urine pH 7–7.5) to enhance cystine solubility [3][15][16].
Thiol drugs: Tiopronin (α-MPG) or D-penicillamine for refractory cases; surgical interventions (e.g., laser lithotripsy) for stones >12 mm [1][3][12].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare renal diseases, rare transplant-related disorders
Research Papers
161 drug discovery papers about Cystinuria type A, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
161 drug discovery papers about Cystinuria type A, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-02 | Cystinuria: Diagnosis, Medical and Surgical Management, and Emerging Therapies. A Narrative Review.
Cystinuria is a hereditary aminoaciduria causing recurrent cystine nephrolithiasis, impaired quality of life and potential renal function decline. Despite established treatment guidelines, real-world data reveal a persistent gap between recommended targets and clinical outcomes. Preliminary data from the EUROCYS 2024 prospective European registry (269 patients, 29 centers, 8 countries) showed that only 16.3% of patients achieved the target urinary pH range, 55.2% remained above the conventional urinary cystine threshold of 250 mg/L, and approximately 39% experienced a new stone event within the preceding 12 months, despite follow-up in specialist centers. Discontinuation rates for available thiol drugs have been reported to reach 30-50%. This narrative review, based on a structured non-systematic search of major databases and guideline repositories (2009-2026), synthesizes current evidence on cystinuria diagnosis and management and appraises emerging adjunctive interventions. Next-generation sequencing-based genetic testing and the cystine capacity assay represent key recent advances in monitoring. Thulium fiber laser lithotripsy and miniaturized percutaneous approaches offer less traumatic surgical options in this high-burden population. Oral N-acetylcysteine has mechanistic plausibility and a favorable, well-characterized safety profile in other clinical settings, making it a rational candidate for formal prospective evaluation; however, robust clinical trial evidence in cystinuria using contemporary monitoring parameters is lacking. Current standard treatment remains insufficient for a substantial proportion of patients, underscoring the need to evaluate accessible adjunctive therapies with defined mechanisms and measurable outcomes.
2026-03-11 | L -Ergothioneine Attenuates Nephrolithiasis by Modulating Redox Signaling and Mitochondrial Function in Cystine and Calcium Oxalate Models
AIMS: Nephrolithiasis is a major global health challenge, with oxidative stress and mitochondrial dysfunction emerging as key drivers of renal injury and stone formation. l-ergothioneine (l-Erg), a naturally occurring antioxidant transported by OCTN1, has shown promising effects in cystinuria models, preventing stone formation. Despite evidence supporting an indirect mechanism of action, key mechanistic aspects have yet to be fully clarified. This study aimed to evaluate whether l-Erg can prevent stone progression in cystinuria and in other types of lithiasis, such as calcium oxalate nephrolithiasis, and to further elucidate its mechanistic basis. RESULTS: Using mouse models, l-Erg significantly reduced cystine stone growth and renal inflammation, and its combination with d-penicillamine enhanced stone dissolution and mitigated drug-related toxicity. In calcium oxalate nephrolithiasis, l-Erg decreased crystal deposition, preserved renal architecture, normalized glutathione levels, and restored mitochondrial respiration. Transcriptomic analysis revealed downregulation of immune pathways and activation of cell cycle genes, suggesting attenuation of inflammation and promotion of tubular repair. INNOVATION: This study is the first to demonstrate that l-Erg exerts renoprotective effects through combined antioxidant and mitochondrial mechanisms in two major forms of nephrolithiasis and introduces a dual therapeutic approach combining an antioxidant with a cystine-solubilizing agent. CONCLUSION: 44, 878-891.
2025-09-25 | Urinary Cystine/Creatinine Concentrations Before and After Castration in Dogs With Suspected Androgen-Dependent Cystine Urolithiasis.
Androgen-dependent cystinuria has been described in intact male dogs. Castration has been recommended to reduce urinary cystine excretion. Urinary cystine/creatinine concentration will significantly decrease in dogs with suspected androgen-dependent (Type III) cystinuria after castration and will be associated with a lack of sonographic evidence of urolithiasis. Six intact male dogs with cystine uroliths. Prospective, observational study. Urinary amino acid/creatinine concentrations and abdominal ultrasound were evaluated at baseline (T0), 30 days (T30), and 90 days (T90) after castration and urolith removal. No dietary change was recommended unless urolith recurrence was noted. DNA was evaluated for the cystinuria-associated marker for Type III cystinuria. The median decline in urinary cystine/creatinine (uCys/creat) concentration from T0 to T30 was 577 nmol/mg (IQR, 415-969; p = 0.03), from T0 to T90 was 798 nmol/mg (IQR, 580-989; p = 0.03) and from T30 to T90 was 34 nmol/mg (IQR, 19.5-443; p = 0.03). Two dogs had small (2.5-3 mm) uroliths at T30, which resolved in one of them at T90. Both dogs with ultrasonographic evidence of recurrence at T30 were positive for the cystinuria-associated genetic marker, although no signs of lower urinary tract disease were noted in either dog. Three of 6 enrolled dogs were homozygous positive for the genetic marker. Castration should be considered for intact male dogs with cystine urolithiasis.
2025-09-03 | Clinical and genotypic features, renal prognosis of orphan tubulopathies with nephrocalcinosis and cystin stones in children
THE AIM : To evaluate clinical and genotypic features, renal prognosis in orphan tubulopathies with nephrocalcinosis and cys- tine calculi in 22 pediatric patients. PATIENTS AND METHODS : The study included 22 patients (from 1 year 4 months to 17 years 11 months) with orphan tubulopathies with nephrocalcinosis (22) and cystinuria, cystine stones (2). Of the 22 probands, there were 14 (63.6 %) boys and 8 (36.4 %) girls. Clinical, biochemical, imaging, and molecular genetic diagnostic methods were used. The severity of chronic kidney disease was stratified according to the K/DOQI classification (2002). RESULTS : A genetic study of 22 children with nephrocalcinosis revealed primary hyperoxaluria of types I, II, III (AGXT, GRHPR, HOGA1) in 5; familial hypomagnesemia with hypercalciuria and nephrocalcinosis (CLDN16) in 5; hypophosphatemic rickets with hypercal- ciuria and nephrocalcinosis (SLC34A3) in 3; Bartter type I syndrome (SLC12A1) in 1 and Bartter syndrome type IV (BSND) in 1, Dent1 disease (CLCN5) in 1, Dent disease 2 (OCRL) in 1, idiopathic infantile hypercalcemia type I (SLC34A1) in 1 and type II (CYP24A1) in 2. Based on the detection of mutations in the SLC3A1 and SLC7A9 genes, 2 probands were diagnosed with type I and non type I cystinuria. The features of gene mutation variants in 22 children with orphan tubulopathies with nephrocalci- nosis and cystinuria, and cystine nodules were identified. A study of kidney function in 22 children over the age of 2 years with nephrocalcinosis and cystinuria revealed CKD C1 with normal glomerular filtration rate (17), CKD C2, C3, C4 (5). A girl with familial hypomagnesemia with hypercalciuria and nephrocalcinosis due to a mutation of the CLDN16 gene, progression CKD of С1 to C4, underwent kidney transplantation at the age of 18 before starting dialysis. CONCLUSION : Features of the clinical phenotype and variants of mutations of genes of orphan tubulopathies with nephrocalcinosis and cystinuria, cystine stones in 22 children were established. Progression of CKD from C1 with normal glomerular filtration rate to C2, C3, C4 was ascertained from 22 in 5 children (25) % with primary hyperoxaluria type1 (1), hypomagnesemia with calciuria and nephrocalcinosis (3), Dent-2 Disease (1). Identification of gene mutations in molecular genetic studies in children with nephrocalcinosis and cys- tinuria establishes a clinical and genetic diagnosis, the pathogenesis of an orphan tubulopathy, and determines personalized management based on individual genetic characteristics.
2025-08-12 | Partial correction of cystinuria type A in mice via kidney-targeted transposon delivery.
We used kidney-targeted, non-viral, transposon-mediated gene delivery to express the mouse Slc3a1 transgene in one kidney of cystinuria type A (Slc3a1 -/-) mice. We found a 44% reduction in urinary cystine concentration at 154 days post-gene transfer, although there was no significant effect on cystine stone formation. Our results indicate that it is possible to achieve kidney-targeted gene transfer, resulting in reduction of cystine concentration in the urine of a cystinuria type A animal model. This proof of concept lays the foundation for future studies directed at gene therapy for cystinuria and other kidney diseases.
2026-08-02 | Cystinuria: Diagnosis, Medical and Surgical Management, and Emerging Therapies. A Narrative Review.
Cystinuria is a hereditary aminoaciduria causing recurrent cystine nephrolithiasis, impaired quality of life and potential renal function decline. Despite established treatment guidelines, real-world data reveal a persistent gap between recommended targets and clinical outcomes. Preliminary data from the EUROCYS 2024 prospective European registry (269 patients, 29 centers, 8 countries) showed that only 16.3% of patients achieved the target urinary pH range, 55.2% remained above the conventional urinary cystine threshold of 250 mg/L, and approximately 39% experienced a new stone event within the preceding 12 months, despite follow-up in specialist centers. Discontinuation rates for available thiol drugs have been reported to reach 30-50%. This narrative review, based on a structured non-systematic search of major databases and guideline repositories (2009-2026), synthesizes current evidence on cystinuria diagnosis and management and appraises emerging adjunctive interventions. Next-generation sequencing-based genetic testing and the cystine capacity assay represent key recent advances in monitoring. Thulium fiber laser lithotripsy and miniaturized percutaneous approaches offer less traumatic surgical options in this high-burden population. Oral N-acetylcysteine has mechanistic plausibility and a favorable, well-characterized safety profile in other clinical settings, making it a rational candidate for formal prospective evaluation; however, robust clinical trial evidence in cystinuria using contemporary monitoring parameters is lacking. Current standard treatment remains insufficient for a substantial proportion of patients, underscoring the need to evaluate accessible adjunctive therapies with defined mechanisms and measurable outcomes.
2026-03-11 | L -Ergothioneine Attenuates Nephrolithiasis by Modulating Redox Signaling and Mitochondrial Function in Cystine and Calcium Oxalate Models
AIMS: Nephrolithiasis is a major global health challenge, with oxidative stress and mitochondrial dysfunction emerging as key drivers of renal injury and stone formation. l-ergothioneine (l-Erg), a naturally occurring antioxidant transported by OCTN1, has shown promising effects in cystinuria models, preventing stone formation. Despite evidence supporting an indirect mechanism of action, key mechanistic aspects have yet to be fully clarified. This study aimed to evaluate whether l-Erg can prevent stone progression in cystinuria and in other types of lithiasis, such as calcium oxalate nephrolithiasis, and to further elucidate its mechanistic basis. RESULTS: Using mouse models, l-Erg significantly reduced cystine stone growth and renal inflammation, and its combination with d-penicillamine enhanced stone dissolution and mitigated drug-related toxicity. In calcium oxalate nephrolithiasis, l-Erg decreased crystal deposition, preserved renal architecture, normalized glutathione levels, and restored mitochondrial respiration. Transcriptomic analysis revealed downregulation of immune pathways and activation of cell cycle genes, suggesting attenuation of inflammation and promotion of tubular repair. INNOVATION: This study is the first to demonstrate that l-Erg exerts renoprotective effects through combined antioxidant and mitochondrial mechanisms in two major forms of nephrolithiasis and introduces a dual therapeutic approach combining an antioxidant with a cystine-solubilizing agent. CONCLUSION: 44, 878-891.
2025-09-25 | Urinary Cystine/Creatinine Concentrations Before and After Castration in Dogs With Suspected Androgen-Dependent Cystine Urolithiasis.
Androgen-dependent cystinuria has been described in intact male dogs. Castration has been recommended to reduce urinary cystine excretion. Urinary cystine/creatinine concentration will significantly decrease in dogs with suspected androgen-dependent (Type III) cystinuria after castration and will be associated with a lack of sonographic evidence of urolithiasis. Six intact male dogs with cystine uroliths. Prospective, observational study. Urinary amino acid/creatinine concentrations and abdominal ultrasound were evaluated at baseline (T0), 30 days (T30), and 90 days (T90) after castration and urolith removal. No dietary change was recommended unless urolith recurrence was noted. DNA was evaluated for the cystinuria-associated marker for Type III cystinuria. The median decline in urinary cystine/creatinine (uCys/creat) concentration from T0 to T30 was 577 nmol/mg (IQR, 415-969; p = 0.03), from T0 to T90 was 798 nmol/mg (IQR, 580-989; p = 0.03) and from T30 to T90 was 34 nmol/mg (IQR, 19.5-443; p = 0.03). Two dogs had small (2.5-3 mm) uroliths at T30, which resolved in one of them at T90. Both dogs with ultrasonographic evidence of recurrence at T30 were positive for the cystinuria-associated genetic marker, although no signs of lower urinary tract disease were noted in either dog. Three of 6 enrolled dogs were homozygous positive for the genetic marker. Castration should be considered for intact male dogs with cystine urolithiasis.
2025-09-03 | Clinical and genotypic features, renal prognosis of orphan tubulopathies with nephrocalcinosis and cystin stones in children
THE AIM : To evaluate clinical and genotypic features, renal prognosis in orphan tubulopathies with nephrocalcinosis and cys- tine calculi in 22 pediatric patients. PATIENTS AND METHODS : The study included 22 patients (from 1 year 4 months to 17 years 11 months) with orphan tubulopathies with nephrocalcinosis (22) and cystinuria, cystine stones (2). Of the 22 probands, there were 14 (63.6 %) boys and 8 (36.4 %) girls. Clinical, biochemical, imaging, and molecular genetic diagnostic methods were used. The severity of chronic kidney disease was stratified according to the K/DOQI classification (2002). RESULTS : A genetic study of 22 children with nephrocalcinosis revealed primary hyperoxaluria of types I, II, III (AGXT, GRHPR, HOGA1) in 5; familial hypomagnesemia with hypercalciuria and nephrocalcinosis (CLDN16) in 5; hypophosphatemic rickets with hypercal- ciuria and nephrocalcinosis (SLC34A3) in 3; Bartter type I syndrome (SLC12A1) in 1 and Bartter syndrome type IV (BSND) in 1, Dent1 disease (CLCN5) in 1, Dent disease 2 (OCRL) in 1, idiopathic infantile hypercalcemia type I (SLC34A1) in 1 and type II (CYP24A1) in 2. Based on the detection of mutations in the SLC3A1 and SLC7A9 genes, 2 probands were diagnosed with type I and non type I cystinuria. The features of gene mutation variants in 22 children with orphan tubulopathies with nephrocalci- nosis and cystinuria, and cystine nodules were identified. A study of kidney function in 22 children over the age of 2 years with nephrocalcinosis and cystinuria revealed CKD C1 with normal glomerular filtration rate (17), CKD C2, C3, C4 (5). A girl with familial hypomagnesemia with hypercalciuria and nephrocalcinosis due to a mutation of the CLDN16 gene, progression CKD of С1 to C4, underwent kidney transplantation at the age of 18 before starting dialysis. CONCLUSION : Features of the clinical phenotype and variants of mutations of genes of orphan tubulopathies with nephrocalcinosis and cystinuria, cystine stones in 22 children were established. Progression of CKD from C1 with normal glomerular filtration rate to C2, C3, C4 was ascertained from 22 in 5 children (25) % with primary hyperoxaluria type1 (1), hypomagnesemia with calciuria and nephrocalcinosis (3), Dent-2 Disease (1). Identification of gene mutations in molecular genetic studies in children with nephrocalcinosis and cys- tinuria establishes a clinical and genetic diagnosis, the pathogenesis of an orphan tubulopathy, and determines personalized management based on individual genetic characteristics.
2025-08-12 | Partial correction of cystinuria type A in mice via kidney-targeted transposon delivery.
We used kidney-targeted, non-viral, transposon-mediated gene delivery to express the mouse Slc3a1 transgene in one kidney of cystinuria type A (Slc3a1 -/-) mice. We found a 44% reduction in urinary cystine concentration at 154 days post-gene transfer, although there was no significant effect on cystine stone formation. Our results indicate that it is possible to achieve kidney-targeted gene transfer, resulting in reduction of cystine concentration in the urine of a cystinuria type A animal model. This proof of concept lays the foundation for future studies directed at gene therapy for cystinuria and other kidney diseases.
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