Cystinuria is a rare inherited aminoaciduria disorder characterized by defective renal reabsorption of cystine and the dibasic amino acids ornithine, lysine, and arginine, leading to excessive urinary excretion of cystine and recurrent formation of cystine kidney stones in the urinary tract.[1] It is caused by autosomal recessive mutations in the genes SLC3A1 (type A, on chromosome 2p16.3) or SLC7A9 (type B, on chromosome 19q13.11), which encode subunits of the renal transport protein responsible for amino acidreabsorption in the proximal tubule.[2][3] Recent research has identified mitochondrial roles of SLC3A1 contributing to gender dimorphism, with males exhibiting higher disease susceptibility.[4] The condition affects approximately 1 in 7,000 individuals worldwide, accounting for 1-2% of adult urinary stones and 6-8% of pediatric calculi, with a higher prevalence in certain populations such as those of Libyan Jewish or Levantine descent.[1][5]Clinically, cystinuria often presents in childhood or young adulthood, with peak onset between ages 11 and 20, manifesting as severe renal colic, hematuria, nausea, and recurrent urinary tract infections due to stone obstruction; men are affected twice as frequently as women, and up to 83% of patients experience stone recurrence within five years.[1][6]Diagnosis typically involves quantitative 24-hour urine collection to measure cystine levels (exceeding 250 mg/day in homozygotes), stone analysis via infrared spectroscopy or X-ray diffraction confirming hexagonal cystine crystals, and genetic testing for confirmation, though the sodium cyanide-nitroprusside qualitative test can screen for cystine in urine with 72% sensitivity.[1][5]Management is lifelong and multifaceted, emphasizing high fluid intake (at least 3 liters per day to achieve urine volumes >3 L), dietary restrictions on sodium and animal protein, urine alkalinization to pH 7.5 using potassium citrate to enhance cystine solubility, and chelating agents like tiopronin or D-penicillamine for cystine excretion >1,000 mg/day; surgical interventions such as ureteroscopy or percutaneous nephrolithotomy are reserved for symptomatic or obstructive stones.[6][5] While the disorder rarely progresses to end-stage renal disease (<5% of cases), chronic complications including renal impairment (up to 70% risk) and hypertension (28-50%) underscore the need for vigilant monitoring.[1][6]
Clinical Presentation
Signs and Symptoms
Cystinuria most commonly presents with recurrent episodes of renal colic caused by the passage of cystine stones, manifesting as severe, acute flank pain that typically radiates to the groin or lower abdomen, often accompanied by nausea and vomiting.[1] These painful episodes can occur multiple times per year, with an annual incidence of approximately 0.42 episodes in males and 0.21 in females, and are the hallmark clinical feature due to cystine stone obstruction in the urinary tract.[7]Hematuria, either gross (visible blood in the urine) or microscopic, frequently accompanies these stone events as a result of irritation or trauma to the urinary tract lining. Urinary tract infections may develop secondary to obstruction by the stones, leading to symptoms such as dysuria, urgency, and fever, and contributing to recurrent pyelonephritis in affected individuals.[8]Some cases of cystinuria remain asymptomatic, particularly when stones are non-obstructive, and are detected incidentally through imaging studies or routine urinalysis performed for unrelated reasons.[9]In pediatric patients, cystinuria often manifests earlier, with about 50% of individuals developing their first stone within the first decade of life, potentially leading to recurrent episodes that cause dehydration from vomiting or poor fluid intake, and in severe cases, contributing to failure to thrive.[1][7]
Complications
Cystinuria predisposes individuals to recurrent cystine stone formation, which serves as the primary driver of long-term complications through repeated urinary tract obstruction and associated infections.[1]Chronic kidney disease (CKD) often progresses in cystinuria patients due to these recurrent obstructions and infections, with up to 70% experiencing some degree of renal injury or impaired glomerular filtration rate below 90 mL/min in adulthood.[1] Renal scarring and hydronephrosis commonly result from repeated stone episodes, leading to permanent damage in the kidneys and ureters as detected via imaging such as ultrasound for stones larger than 4 mm.[1]In severe, unmanaged cases, cystinuria can culminate in end-stage renal disease (ESRD), though the incidence remains relatively low at less than 5% of patients.[1] Extrarenal complications include the formation of bladder stones from excess cystine precipitation and ureteral strictures arising from chronic stone-related trauma, potentially causing further urinary tract obstruction.[10]Hypertension is a rare but notable association in cystinuria, occurring in approximately 51% of patients and linked to underlying renal impairment, with a higher prevalence among males.[11]
Etiology
Genetics
Cystinuria is inherited in an autosomal recessive manner, requiring biallelic mutations for the full disorder, though with variable expressivity and incomplete penetrance. Heterozygotes for SLC3A1 mutations (Type A) typically show no urinary abnormalities, while those for SLC7A9 (Type B or non-Type A) often exhibit mild elevations in urinary cystine and dibasic amino acids without stone formation.[12][13] Type A results from biallelic mutations in the SLC3A1 gene on chromosome 2p21, encoding the rBAT heavy subunit of the cystine transporter.[13] Type B arises from mutations in the SLC7A9 gene on chromosome 19q13.11, encoding the b⁰,⁺AT light subunit.[12][14]Over 430 pathogenic mutations have been identified across both genes in the Human Gene Mutation Database (as of 2023), including missense, nonsense, frameshift, splice-site alterations, and deletions that disrupt transporter function.[15] In SLC3A1, over 260 variants are known, with common examples like p.Met467Thr accounting for about 30% of Type A cases in certain populations; these mutations often lead to absent or dysfunctional rBAT protein.[12][13] For SLC7A9, over 170 mutations have been reported, such as p.Gly105Arg (present in ~20% of non-Type A cases), which impair the light subunit's trafficking or activity.[12][14] Recent studies, including a 2025 analysis of Japanese patients, have identified novel variants like an exon 10 deletion in SLC3A1 and exon-intron boundary changes, expanding the mutation spectrum and highlighting the role of large structural variants in ~2% of cases.[16] While most cases involve biallelic mutations in one gene, rare digenic inheritance with variants in both SLC3A1 and SLC7A9 has been reported.[17]The SLC3A1 and SLC7A9 proteins form a heterodimeric amino acid transporter complex (b⁰,⁺AT) via a disulfide bond, essential for reabsorbing cystine and dibasic amino acids in the proximal renal tubule and small intestine; mutations disrupt this assembly or membrane localization, resulting in hyperexcretion of these solutes.[18] Carrier frequencies vary by population, with an estimated global rate of about 1 in 40 based on the disease prevalence of 1 in 7,000, though higher in specific groups such as Libyan Jews, where the SLC7A9 p.Val170Met founder mutation yields a carrier frequency of 1 in 25 and disease prevalence of 1 in 2,500.[12][18] This variant is nearly exclusive to Libyan Jewish populations, underscoring the role of founder effects in the genetic architecture of cystinuria.[12]
Pathophysiology
Cystinuria arises from a defect in the reabsorption of the dibasic amino acids cystine, ornithine, lysine, and arginine—collectively known as COLA—in the proximal renal tubules. This impairment is caused by dysfunction of the heterodimeric amino acid transporter system b⁰,⁺, composed of the subunits encoded by the SLC3A1 and SLC7A9 genes. In affected individuals, particularly homozygotes, this leads to excessive urinary excretion of cystine, typically exceeding 250 mg per day and often reaching 600–1400 mg per day, far surpassing normal levels of less than 30 mg per day.[1][19][7]The hyperexcretion of cystine results in supersaturation of urine, promoting stone formation because cystine's solubility is limited, approximately 250 mg/L at a urine pH of 7. Cystine exhibits low solubility in acidic urine, with its pKa values of 8.0–8.5 rendering it poorly ionized and thus prone to precipitation below pH 7.5; solubility increases markedly at higher pH levels, reaching about 500 mg/L at pH 7.5 and 1000 mg/L at pH 8. This pH-dependent insolubility facilitates the nucleation and aggregation of hexagonal cystine crystals, which serve as the nidus for kidney stone development.[20][21][9]Although the primary defect is renal, intestinal absorption of cystine and dibasic amino acids is also impaired in cystinuria, contributing to an increased systemic load that exacerbates urinary excretion. However, normal plasma levels of these amino acids are maintained due to compensatory mechanisms. The resulting stones are composed almost entirely of cystine, which imparts a characteristic radiopacity on imaging owing to its sulfur content, appearing as faintly opaque with a ground-glass density on plain radiographs and low attenuation (less than 800 Hounsfield units) on computed tomography.[19][1][20]
Diagnosis
Laboratory Evaluation
The laboratory evaluation of cystinuria primarily involves biochemical assessment of urine to detect excessive excretion of cystine and other dibasic amino acids, alongside genetic confirmation when indicated. Quantitative analysis of a 24-hour urine collection is the cornerstone for diagnosis, with cystine excretion exceeding 250 mg/day serving as the diagnostic threshold in adults, while levels typically range from 600 to 1400 mg/day in homozygous individuals.[22] In children, where complete 24-hour collections may be challenging, the cystine-to-creatinine ratio in a spot urine sample greater than 315 mg/g creatinine (or equivalently >150 μmol/mmol creatinine) is diagnostic for those over 1 year, with age-adjusted thresholds for younger children (e.g., <80 mg/g creatinine under 1 month, <52 mg/g under 1 year).[23] These measurements are performed using techniques such as ion-exchange chromatography or liquid chromatography-tandem mass spectrometry to ensure accuracy.[24]The aminoaciduria profile from urine analysis further confirms the diagnosis by revealing elevated levels of cystine along with ornithine, lysine, and arginine, distinguishing cystinuria from isolated cystine excretion. This profile is essential, as cystinuria specifically involves defective reabsorption of these dibasic amino acids in the proximal tubule.[1] The cyanide-nitroprusside test provides a rapid qualitative screen, turning urine purple when cystine exceeds 75 mg/g creatinine, though it requires quantitative follow-up due to potential false positives from conditions like homocystinuria.[22]To assess the risk of stone formation, the cystine capacity test evaluates urine supersaturation by measuring its ability to dissolve added solid cystine, often involving binding to urinary proteins such as albumin; a positive capacity indicates undersaturation and lower lithogenic potential.[1] Stone analysis may briefly confirm cystine composition, but detailed evaluation is covered elsewhere.[22]Genetic testing via next-generation sequencing panels targeting the SLC3A1 and SLC7A9 genes is recommended for confirmatory diagnosis, family counseling, or atypical presentations, detecting single nucleotide variants (SNVs) and copy number variants (CNVs); for example, the Mayo Clinic CYSGP panel analyzes these genes comprehensively.[25] Blood tests typically show normal serum amino acid levels, helping to rule out secondary causes of aminoaciduria such as Hartnup disease, which affects neutral amino acids rather than dibasic ones.[26]
Imaging and Stone Analysis
Non-contrast computed tomography (NCCT) serves as the first-line imaging modality for detecting cystine stones in patients with suspected cystinuria due to its high sensitivity and specificity for urolithiasis.[1] NCCT can identify stones as small as 2 mm and characterizes cystine stones by their Hounsfield unit (HU) density, typically ranging from 300 to 800 HU, with a mean of approximately 633 HU; values exceeding 1000 HU suggest mixed composition rather than pure cystine.[27] This density is higher than that of uric acid stones (<500 HU) but lower than calcium-based stones (>1000 HU), aiding in differentiation, though overlap with struvite or uric acid stones may necessitate further analysis.[1]Ultrasound is recommended as an initial screening tool, particularly in children and pregnant patients, to minimize radiation exposure while assessing for stones larger than 4 mm and associated hydronephrosis.[1] Cystine stones appear as echogenic foci with posterior acoustic shadowing on ultrasound, though this modality cannot reliably distinguish stone composition and is less sensitive for ureteral stones compared to NCCT.[1]Plain kidney-ureter-bladder (KUB) X-ray provides a lower-radiation alternative for stone surveillance but has limited utility due to the faint radiopacity of cystine stones, which exhibit a homogeneous ground-glass appearance and are less dense than calcium oxalate stones.[9] Cystine stones are weakly radiopaque owing to their sulfur content, making them visible but often obscured by bowel gas or overlapping structures.[9]In complex cases requiring functional assessment of the urinary tract, such as preoperative planning or evaluation of obstruction, intravenous pyelography (IVP) or retrograde pyelography may be employed to delineate anatomy and renal function.[28] These contrast-enhanced techniques highlight ureteral patency and calyceal filling defects but are used selectively due to risks of contrast nephropathy.[28]Stone analysis is essential for confirming cystinuria when a stone is retrieved, employing infrared spectroscopy or X-raydiffraction to identify composition with high accuracy.[1] These methods detect cystine as the predominant component, typically comprising over 70% of the stone in classic cases, distinguishing it from mixed calculi.[1] Such analysis supports targeted management and genetic counseling.[1]
Management
Conservative and Lifestyle Measures
The cornerstone of conservative management for cystinuria involves increasing fluid intake to dilute urinary cystine concentration and prevent stone formation. Patients are advised to consume at least 3 liters of fluid per day to achieve a urine output exceeding 2.5 liters daily, thereby maintaining cystine levels below 250 mg/L for optimal solubility.[1][29] This regimen includes drinking approximately 240 mL of water hourly during waking hours, 480 mL before bedtime, and an additional intake overnight to counteract reduced urine flow during sleep, with urine specific gravity monitored to ensure it remains at or below 1.010.[1]Patient education emphasizes consistent adherence, particularly nighttime hydration, to avoid concentrated urine that promotes cystine precipitation.[30]Dietary modifications play a critical role in reducing cystine precursors by limiting sodium and animal protein intake. Sodium restriction to less than 2 grams (approximately 2,300 mg or 100 mEq) per day decreases urinary cystine excretion by minimizing reabsorption competition in the renal tubules.[1][29] Total protein intake should be limited to 0.8–1 g per kg of ideal body weight daily, focusing on reducing methionine-rich foods such as red meat, poultry, and fish, while avoiding high-protein supplements containing cystine or methionine and emphasizing plant-based proteins.[29][31] These changes help lower overall cystine production without necessitating excessive protein restriction that could lead to nutritional deficiencies.[30]Urine alkalinization enhances cystine solubility, which is pH-dependent as outlined in the pathophysiology section. The target urinary pH is 7.5–8.0, achieved through potassium citrate supplementation at 60–90 mEq per day, divided into multiple doses to avoid gastrointestinal side effects.[1][29] This measure is initiated alongside hydration and diet but requires careful monitoring to prevent exceeding pH 8.0, which could promote calcium phosphate stone formation.[31]Regular monitoring ensures adherence and effectiveness of these measures. Quarterly 24-hour urine collections are recommended to assess cystine excretion (target <250 mg/L), volume (>2.5 L), pH (7.5–8.0), and sodium levels, with adjustments made based on results.[1] Patients can self-monitor urine pH using dipsticks daily and track fluid intake via logs, while renal ultrasounds every 6–12 months evaluate stone burden.[29] Annual comprehensive reviews, including spot urine tests for crystalluria and specific gravity, support long-term prevention of recurrence.[30]
Pharmacological Therapy
Pharmacological therapy for cystinuria focuses on reducing urinary cystine levels or enhancing its solubility through chelating agents, particularly when conservative measures fail to prevent stone formation. These thiol-based drugs bind to cystine, forming mixed disulfides that are more soluble in urine, thereby decreasing the risk of crystallization and nephrolithiasis.[32]D-penicillamine, the first thiol drug introduced for this purpose, is typically dosed at 1-4 g per day in adults (divided into three or four doses) to form a soluble cystine-penicillamine mixed disulfide complex, which can reduce cystine stone recurrence by up to 50% in responsive patients. Common side effects include dermatological reactions such as rash, gastrointestinal disturbances, and renal complications like proteinuria or membranous glomerulonephritis, necessitating close monitoring of renal function and complete blood counts.[9][33][34]Tiopronin (α-mercaptopropionylglycine), a second-generation chelator, operates via a similar mechanism but is generally better tolerated than D-penicillamine, with recommended doses of 800-2000 mg per day in divided doses for adults. It effectively lowers cystine excretion and stone formation rates, achieving remission in 63-71% of cases and reducing individual stone burden in up to 81% of treated patients, while exhibiting fewer hypersensitivity reactions.[32][33][35]Emerging therapies include bucillamine, a cysteine-derived thiol binder in phase II clinical trials as of 2025, which shows potential for improved cystine binding with a favorable safety profile based on its established use in rheumatoid arthritis. Tolvaptan, a vasopressin V2 receptor antagonist, has demonstrated in preclinical and small human studies the ability to increase urine volume and cystine capacity, thereby reducing stone growth by enhancing dilutional effects.[36][37][38]These agents are indicated primarily for patients with persistent high cystine excretion exceeding 750 mg per day despite adequate hydration and dietary modifications, aiming to achieve urinary cystine levels below 200-250 mg per day to minimize supersaturation. Therapy initiation requires baseline assessment of cystine excretion, with ongoing monitoring for hypersensitivity reactions, including fever, arthralgia, or lymphadenopathy, which may occur in up to 20-50% of cases and often lead to discontinuation.[33][9][39]
Surgical Interventions
Surgical interventions are indicated in cystinuria patients when conservative and pharmacological management fails, particularly for obstructive stones, recurrent urinary tract infections, or large stone burdens that pose risks to renal function.[6] These procedures aim to achieve complete stone clearance to minimize recurrence, given the high risk of cystine stone reformation due to the underlying metabolic defect.[6]Extracorporeal shock wave lithotripsy (ESWL) may be considered for cystine stones smaller than 1.5 cm, especially those in the renal pelvis, but its success rate is lower at 50-70% compared to other stone types owing to the hardness and density of cystine calculi, which resist fragmentation.[6] This noninvasive method uses focused shock waves to break stones into passable fragments, though multiple sessions may be required, and it is less effective for lower pole or multiple stones.[40]Ureteroscopy with laser lithotripsy is particularly effective for stones in the lower urinary tract or ureter, allowing direct visualization and fragmentation using a holmium or thulium fiber laser, which achieves stone-free rates of approximately 80-90% for stones under 2 cm with minimal invasiveness.[41] This endoscopic approach is favored for its lower complication profile relative to more invasive techniques and is suitable for recurrent or residual fragments in cystinuric patients.[42]For larger renal stones exceeding 2 cm or staghorn calculi, percutaneous nephrolithotomy (PCNL) is the preferred intervention, offering stone-free rates greater than 90% through direct percutaneous access to the kidney for removal or fragmentation.[41] Miniaturized PCNL variants reduce tissue trauma while maintaining efficacy, and combined approaches with ureteroscopy (endoscopic combined intrarenal surgery) enhance clearance for complex cases.[42]Postoperative preventive strategies include temporary ureteral stenting to maintain drainage and prevent obstruction, though stents should be removed within 2 weeks to avoid rapid encrustation by cystine crystals, a common issue in cystinuria.[6] Additionally, chemolytic irrigation with solutions such as tromethamine-E (THAM-E) in saline can dissolve residual cystine fragments after surgery, promoting complete clearance and reducing recurrence risk.[43]
Epidemiology and Prognosis
Prevalence and Distribution
Cystinuria is a rare inherited disorder with a global prevalence estimated at 1 in 7,000 live births.[1] This rate varies significantly by population, with higher incidences observed in specific ethnic groups; for instance, the prevalence reaches 1 in 2,500 among Libyan Jews due to founder effects.[18] In contrast, European populations exhibit a lower prevalence of approximately 1 in 15,000.[44] These geographic and ethnic differences highlight the influence of genetic founder mutations on disease distribution.The condition demonstrates equal distribution between males and females at birth, but males often experience more severe symptoms and higher rates of stone formation; the reasons for this disparity are not fully understood.[18] Ethnic variations further contribute to prevalence patterns, particularly through founder mutations in the SLC7A9 gene, which are more common in South Asian and Middle Eastern populations.[45]Cystinuria frequently manifests in childhood, with approximately 50% of cases diagnosed before the age of 10 years.[7] Despite this, the disorder is often underdiagnosed in adults, potentially leading to delayed intervention.[46] Globally, cystinuria accounts for 6-8% of all pediatric urolithiasis cases, as documented in international registries and clinical studies.[1]
Long-term Outcomes
With appropriate medical management and adherence, a significant proportion of patients with cystinuria achieve stone-free status, with rates ranging from 73% in compliant individuals to 40-86% following multiple interventions, though recurrence remains common at 50-70% over 5 years.[47][33] In contrast, untreated patients face a high recurrence rate, forming approximately one new cystine stone per year and requiring surgical intervention every three years on average.[18] Factors contributing to poor long-term outcomes include early disease onset (particularly before age 50), non-adherence to therapy, and high initial stone burden, which correlate with increased surgical events and progressive renal impairment.[48][47]The disease substantially affects quality of life, with patients experiencing chronic pain that necessitates pain medication use in about 24% of cases and leading to impaired scores in bodily pain domains on standardized health-related quality of life assessments.[49] Prior to effective treatment, frequent stone events result in an average of 0.45 stone-related episodes per year, often requiring 1-2 hospitalizations or procedures annually due to complications like obstruction.[50] These recurrent issues contribute to emotional and social burdens, with cystinuria patients reporting lower vitality and disease impact scores compared to those without the condition.[49]Renal function preservation is achievable with therapy, showing stable estimated glomerular filtration rates (eGFR) over long-term follow-up (median 13 years) and minimal annual decline in managed cohorts, though eGFR negatively correlates with age and cumulative procedures.[48][51] Without intervention, up to 70% of patients develop chronic kidney disease, but progression to end-stage renal disease occurs in fewer than 5% overall.[52][7] Recent preclinical advances, including kidney-targeted nonviral gene therapy in mouse models as of 2025, demonstrate promising reductions in urinary cystine levels, potentially altering the long-term prognosis toward a curative approach.[53]
Occurrence in Animals
In Dogs
Cystinuria in dogs is an inherited metabolic disorder characterized by defective renal reabsorption of cystine and dibasic amino acids, leading to cystine urolithiasis. It primarily affects certain breeds, with a prevalence of approximately 1-2% in predisposed populations such as Newfoundlands, Labrador Retrievers, and Dachshunds, though overall incidence varies regionally from 0.8% to 3% in North America and higher rates up to 14% in parts of Europe.[54] The condition is more common in males due to sex-linked expression in some breeds, where androgen-dependent mechanisms exacerbate urethral obstruction risks.[55] Affected breeds also include English Bulldogs, Miniature Pinschers, and Australian Cattle Dogs, among over 70 reported varieties.[56]The genetic basis involves mutations in the canine orthologs of human cystinuria genes, particularly SLC3A1 and SLC7A9, which encode components of the dibasic amino acid transporter in the proximal renal tubule. Type I cystinuria, seen in breeds like Newfoundlands and Labrador Retrievers, results from autosomal recessive SLC3A1 mutations, such as the frameshift variant c.350delG, leading to complete loss of transporter function and urolith formation typically by 6-12 months of age.[56] In contrast, Type II involves autosomal dominant SLC3A1 mutations (e.g., c.1095_1100del in Australian Cattle Dogs) or SLC7A9 variants (e.g., c.964G>A in Miniature Pinschers), causing partial dysfunction. Type III cystinuria, androgen-dependent and more severe in intact males, combines elements of both genes and parallels human Type A cystinuria in its sex bias.[55] These defects mirror human SLC3A1/SLC7A9 pathologies but manifest earlier in canines due to breed-specific genetics.[54]Clinical signs often emerge from cystine stones in the bladder, urethra, or kidneys, including pollakiuria (frequent urination in small amounts), hematuria (blood in urine), and dysuria (straining to urinate). In males, urethral obstruction can become life-threatening, presenting with abdominal pain, vomiting, lethargy, and a firm, distended bladder, potentially leading to post-renal azotemia if untreated.[55] Nephrolithiasis may cause renal colic or pyelonephritis, while asymptomatic crystalluria can precede overt disease. Stones recur frequently, often within 6-12 months without intervention.[54]Diagnosis relies on identifying cystine crystals in urine sediment via urinalysis, often with a characteristic hexagonal morphology under microscopy, alongside low urine pH (<7). The urine nitroprusside test detects elevated cystine levels qualitatively, while quantitative aminoaciduria assessment shows cystine excretion exceeding 200 µmol/g creatinine.[56] Breed predisposition prompts genetic screening via DNA tests for SLC3A1 and SLC7A9 variants, confirmed by imaging (radiography or ultrasound) to locate uroliths and rule out differentials like struvite stones. Urolith analysis post-surgical removal provides definitive composition.[55]Management mirrors human approaches, emphasizing prevention of stone formation and recurrence through conservative measures like increased hydration to dilute urine and promote diuresis. Dietary therapy involves low-protein, low-sodium alkalinizing diets to raise urine pH above 7.5 and reduce cystine solubility.[54] Pharmacological options include thiol-binding drugs like tiopronin (2-mercaptopropionylglycine) at 10-15 mg/kg twice daily, which complexes cystine for excretion, often combined with allopurinol if concurrent xanthine issues arise. For Type III cases, neutering males reduces androgen-driven obstruction risk. Surgical intervention, such as cystotomy or urethrotomy, is reserved for acute obstructions, followed by ongoing medical prophylaxis to achieve long-term stone-free intervals.[56]
In Other Species
Cystinuria in domestic cats is a rare condition, comprising approximately 0.1% of analyzed feline uroliths in the United States, compared to a higher prevalence of 0.75% in dogs.[57] It has been documented in breeds such as Siamese, Korat, Maine Coon, Sphynx, and domestic short-haired cats, with genetic variants identified in the SLC7A9 gene, and less commonly in SLC3A1.[58] Unlike the androgen-dependent forms seen in some canine breeds, feline cystinuria affects both males and females equally and independently of neuter status, resulting in fewer cases of urinary obstruction due to less severe stone formation.[57]In other mammals, cystinuria has been reported with varying prevalence, including in ferrets where cystine uroliths comprise 16% of urinary stone submissions and is more common in males, and in wild felids like servals with 27% prevalence in captive individuals in the United States; genetic associations remain poorly established in these species.[59][60][57] Experimental models, particularly Slc3a1 knockout mice (Slc3a1^{-/-}), closely mimic human type A cystinuria by exhibiting hypercystinuria, crystalluria, and bladder stone formation, predominantly in males due to sexual dimorphism in stone severity.[18] These mice have been instrumental in preclinical testing of therapies, such as alpha-lipoic acid, which prevents cystine urolithiasis by enhancing cystine solubility and reducing crystal aggregation. Ongoing research using these models also evaluates cystine analogs like L-cystine dimethyl ester to inhibit stone growth, providing insights into comparative pathophysiology across species.[18]Avian species have contributed to transporter studies through experimental investigations in chickens, where kinetic analyses of cystine influx in the small intestine reveal saturable transport mechanisms shared with mammalian systems.[61] These models aid in understanding dibasic amino acid reabsorption defects without naturally occurring cystinuria. Management approaches remain species-specific and challenging; in felines, dietary protein restriction and urinary alkalinization are prioritized to minimize stone recurrence, while in murine models, targeted gene therapies show promise for correcting transport defects.[58] In wild or exotic species, interventions often have low success rates due to limited access and physiological differences.[57]