Cystinuria
Overview
Plain-Language Overview
Cystinuria is a genetic condition that affects the kidneys and causes too much cystine, an amino acid, to be present in the urine. This excess cystine can form crystals and stones in the urinary tract, leading to pain and difficulty urinating. People with cystinuria often experience repeated episodes of kidney stones starting in childhood or early adulthood. The condition is caused by a problem with the way the kidneys handle certain amino acids, especially cystine. While cystinuria is a lifelong condition, many people manage symptoms with medical care.
Clinical Definition
Cystinuria is an autosomal recessive inherited disorder characterized by defective renal tubular reabsorption of the dibasic amino acids cystine, ornithine, lysine, and arginine (COLA). The primary clinical manifestation is recurrent nephrolithiasis due to poor solubility of cystine in urine, leading to cystine stone formation. Mutations in the SLC3A1 and SLC7A9 genes disrupt the function of the amino acid transporter in the proximal renal tubules and intestinal epithelium. Patients typically present with flank pain, hematuria, and urinary tract infections secondary to stone obstruction. Diagnosis is supported by detection of hexagonal cystine crystals in urine microscopy and elevated cystine levels on quantitative amino acid analysis. Imaging studies reveal radiopaque stones, often bilateral and recurrent. Management focuses on increasing cystine solubility through hydration, urinary alkalinization, and pharmacologic agents such as thiol-containing drugs. Cystinuria accounts for approximately 1-2% of all kidney stones and is one of the few inherited causes of nephrolithiasis. Early diagnosis and treatment are essential to prevent chronic kidney damage and preserve renal function.
Inciting Event
- Episodes of dehydration or low fluid intake can trigger cystine stone formation.
- Acidic urinary pH promotes cystine crystallization and stone development.
- Dietary factors that reduce urine volume or acidify urine may precipitate stone formation.
Latency Period
- none
Diagnostic Delay
- Symptoms may be attributed to more common causes of kidney stones, delaying diagnosis.
- Lack of awareness of cystinuria and failure to perform specific urine tests for cystine can delay diagnosis.
- Intermittent symptoms and variable stone formation may lead to under-recognition.
Clinical Presentation
Signs & Symptoms
- Recurrent episodes of renal colic due to cystine stone formation.
- Hematuria caused by urinary tract irritation from stones.
- Possible urinary tract infections secondary to obstruction.
- May present with flank pain and nausea.
History of Present Illness
- Recurrent episodes of flank pain and hematuria due to kidney stones.
- History of passing urinary stones or urinary tract obstruction symptoms.
- Possible urinary tract infections secondary to obstructive stones.
Past Medical History
- Previous episodes of nephrolithiasis or urolithiasis.
- History of urinary tract infections related to stone obstruction.
- No other systemic illnesses typically associated.
Family History
- Positive family history of cystinuria or recurrent kidney stones.
- Autosomal recessive inheritance pattern with affected siblings.
- Family members may have a history of early-onset nephrolithiasis.
Physical Exam Findings
- Physical examination is often normal in patients with cystinuria.
- Palpation may reveal tenderness in the flank region if a stone is causing obstruction.
Diagnostic Workup
Diagnostic Criteria
Diagnosis of cystinuria is established by identifying elevated urinary cystine excretion exceeding 250 mg/day, presence of characteristic hexagonal cystine crystals on urine microscopy, and recurrent cystine-containing kidney stones confirmed by stone analysis. Genetic testing for mutations in SLC3A1 and SLC7A9 genes can support diagnosis. Imaging typically shows radiopaque stones in the urinary tract. A positive sodium cyanide-nitroprusside test indicating cystine presence in urine further confirms the diagnosis.
Pathophysiology
Key Mechanisms
- Cystinuria is caused by a genetic defect in the renal tubular reabsorption of the amino acid cystine and dibasic amino acids (ornithine, lysine, arginine).
- The defective transporter in the proximal renal tubule leads to increased urinary excretion of poorly soluble cystine, which precipitates and forms kidney stones.
- Mutations in the SLC3A1 or SLC7A9 genes impair the function of the amino acid transporter responsible for cystine reabsorption.
| Involvement | Details |
|---|---|
| Organs | Kidneys are the primary organs affected by cystinuria due to cystine stone formation. |
| Urinary bladder may be involved in stone passage and irritation. | |
| Tissues | Renal proximal tubule tissue is responsible for reabsorbing cystine and other dibasic amino acids. |
| Bladder mucosa can be damaged by cystine stone irritation. | |
| Cells | Renal tubular epithelial cells are involved in the defective reabsorption of cystine in cystinuria. |
| Uroepithelial cells line the urinary tract and can be irritated by cystine crystals. | |
| Chemical Mediators | Cystine is the poorly soluble amino acid that precipitates to form stones in cystinuria. |
| Sodium influences cystine solubility and excretion in the urine. |
Treatment
Pharmacological Treatments
Potassium citrate
- Mechanism: alkalinizes the urine to increase cystine solubility and prevent stone formation
- Side effects: gastrointestinal upset, hyperkalemia
Tiopronin
- Mechanism: forms soluble disulfide complexes with cystine, reducing stone formation
- Side effects: rash, nephrotic syndrome, arthralgia
D-penicillamine
- Mechanism: chelates cystine to form soluble complexes, decreasing stone formation
- Side effects: rash, proteinuria, bone marrow suppression
Non-pharmacological Treatments
- Increase fluid intake to maintain a high urine volume and reduce cystine concentration.
- Adopt a low-sodium diet to decrease cystine excretion in the urine.
- Limit animal protein intake to reduce cystine and other amino acid load.
Prevention
Pharmacological Prevention
- Use of potassium citrate to alkalinize urine and increase cystine solubility.
- Administration of chelating agents such as penicillamine or tiopronin to reduce cystine concentration.
- High fluid intake combined with pharmacotherapy to reduce stone formation.
Non-pharmacological Prevention
- Maintain high fluid intake (>3 liters/day) to dilute urine and prevent stone formation.
- Adopt a low-sodium diet to reduce cystine excretion.
- Limit animal protein intake to decrease cystine and acid load.
- Regular monitoring with urine pH testing to maintain alkaline urine.
Outcome & Complications
Complications
- Obstructive uropathy leading to hydronephrosis.
- Chronic kidney disease from recurrent obstruction and infections.
- Possible progression to renal failure if untreated.
| Short-term Sequelae | Long-term Sequelae |
|---|---|
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Differential Diagnoses
Cystinuria versus Calcium oxalate nephrolithiasis
| Cystinuria | Calcium oxalate nephrolithiasis |
|---|---|
| Presence of radiolucent kidney stones on X-ray due to cystine composition. | Presence of radiopaque kidney stones on X-ray due to calcium content. |
| Urinalysis shows elevated cystine levels with characteristic hexagonal crystals. | Urinalysis shows normal cystine levels without hexagonal crystals. |
| Stone analysis reveals cystine composition. | Stone analysis reveals calcium oxalate composition. |
Cystinuria versus Hartnup disease
| Cystinuria | Hartnup disease |
|---|---|
| Defect in dibasic amino acid transport specifically causing cystine accumulation and stone formation. | Defect in neutral amino acid transport in the intestine and kidney causing pellagra-like symptoms. |
| Urine amino acid analysis shows increased cystine, ornithine, lysine, and arginine. | Urine amino acid analysis shows increased neutral amino acids but not cystine. |
| Presence of cystine kidney stones and hexagonal crystals in urine. | No formation of kidney stones or cystine crystals. |
Cystinuria versus Primary hyperoxaluria
| Cystinuria | Primary hyperoxaluria |
|---|---|
| Defect in renal tubular reabsorption of cystine and dibasic amino acids causing cystine stone formation. | Excessive endogenous production of oxalate leading to calcium oxalate stones. |
| Urine analysis shows elevated cystine with characteristic hexagonal crystals. | Urine analysis shows elevated oxalate but normal cystine levels. |
| Stone analysis reveals cystine composition. | Stone analysis reveals calcium oxalate composition without cystine crystals. |