OVERVIEW

What is cystinuria?

Cystinuria is a genetic disorder caused by defective renal tubule function, particularly in the proximal tubules, leading to increased excretion of substances like cystine in the urine. Due to the low solubility of cystine, it can eventually form cystine stones. The formation of kidney stones and the resulting renal colic are often the only manifestations of this disease.

This condition is rare but progresses rapidly, with recurrent kidney stones requiring treatments such as urine alkalinization. Without active treatment, it can advance to end-stage renal disease (commonly known as "uremia").

Is cystinuria common?

Cystinuria is uncommon. Studies indicate that only 1 in 7,000 births is affected by this condition.

However, the incidence varies significantly among different ethnic groups. For example, the incidence is 1 in 2,500 among Libyan Jews, 1 in 5,000 among Americans, 1 in 18,000 among Japanese, and 1 in 100,000 among Swedes. In Europe, cystinuria is the second most common autosomal recessive genetic disorder.

Currently, there are no official statistics on its incidence in China.

What are the characteristics of individuals with cystinuria?

Cystinuria is a genetic disorder that primarily occurs in individuals with a family history of the disease. Stone formation often begins in childhood, with the peak incidence occurring between ages 20–30. There is no significant difference in incidence between males and females.

What are the types of cystinuria?

Based on the cystine excretion levels in the parents of affected children, cystinuria can be classified into three types:

• Type I: The parents of the patient have normal cystine excretion in their urine.

• Type II: The parents of the patient exhibit significantly increased cystine excretion in their urine.

• Type III: The parents of the patient show moderately increased cystine excretion in their urine.

Note that Type II involves "significantly increased" excretion, while Type III involves "moderately" increased excretion—don't assume otherwise.

However, with advances in genetic research, cystinuria is now more commonly classified by genotype, including:

• SLC3A1 gene defect type: Current research indicates that only Type I cystinuria patients have SLC3A1 gene mutations.

• SLC7A9 gene defect type: Most non-Type I cystinuria cases involve this gene defect, though a small number of Type I cases may also exhibit it.

In other words, the SLC3A1 gene defect type corresponds to most Type I cystinuria cases, while the SLC7A9 gene defect type corresponds to a minority of Type I cases and all Type II and III cases.

Are cystinuria and cystinosis the same disease?

Cystinuria and cystinosis are not the same disease—they differ significantly.

• Cystinosis is a metabolic disorder characterized by the accumulation of cystine in various organs and tissues, leading to severe organ dysfunction. Its hallmark is intracellular cystine buildup, eventually causing Fanconi syndrome and progressive renal failure.

• Cystinuria, on the other hand, primarily manifests as increased cystine crystals in the urine.

SYMPTOMS

What are the manifestations of cystinuria patients?

The formation of kidney stones and the resulting stone symptoms (renal colic, back pain, hematuria, urinary tract infection) may be the main manifestations of cystinuria. If stones occur in children or adolescents, the possibility of cystinuria (cystine stones) should be considered first.

CAUSES

What are the causes of cystinuria?

Cystinuria is a genetic disorder caused by gene defects, such as the SLC3A1 and SLC7A9 gene mutations mentioned above.

How is cystinuria inherited?

Cystinuria is primarily inherited in an autosomal recessive pattern, characterized by:

1. If a patient marries someone with a normal genotype, all their children will be unaffected;

2. If a patient marries a normal carrier (heterozygous), their children have a 50% chance of inheriting the disease;

3. If two patients marry, 100% of their children will inherit the disorder, with equal chances for males and females.

Is cystinuria contagious?

Cystinuria is a genetic disorder, not an infectious disease, so it cannot be transmitted.

DIAGNOSIS

What tests should be done for cystinuria?

If kidney stones occur during childhood or adolescence, cystinuria should be suspected. To diagnose cystinuria, the following tests are usually required:

• Urine sediment microscopy: To determine whether there are crystals in the urine. The detection of hexagonal "benzene ring-shaped" crystals in morning urine is a characteristic feature of cystinuria, but the detection rate is relatively low.

• Urinary cystine excretion test: To measure the cystine content in the urine. The nitroprusside cyanide test is commonly used to detect excessive cystine in the urine. A negative result usually rules out cystinuria.

• Kidney stone analysis: To determine the composition of kidney stones and rule out other types of stones.

Are there any precautions for the nitroprusside cyanide test for cystinuria?

The nitroprusside cyanide test can be interfered with by sulfhydryl-containing drugs, leading to false-positive results. Therefore, it is best to avoid taking such medications before the test. If you are currently taking any medication, consult your doctor to determine whether it contains sulfhydryl groups.

How is cystinuria generally diagnosed by doctors?

Cystinuria can be diagnosed in patients with kidney stones if one or more of the following findings are present:

• Stone analysis reveals cystine as the main component.

• There is a family history of cystinuria.

• Diagnostic hexagonal cystine crystals are observed in urine analysis.

Cystinuria is related to genetic defects. Why isn't genetic testing used for diagnosis?

Although it is known that cystinuria is associated with defects in the SLC3A1 or SLC7A9 genes, genetic testing for these mutations is still in the research stage. Additionally, the high cost of genetic testing makes it impractical for routine diagnosis of cystinuria at present. In the future, genetic testing may become more widely used.

What diseases should be differentiated from cystinuria?

The differential diagnosis of cystinuria essentially involves distinguishing it from other types of kidney stones. When a patient presents with back pain caused by kidney stones, the following conditions should be considered for differentiation:

• Pyelonephritis: Often presents with renal colic but is usually accompanied by systemic symptoms such as fever, whereas kidney stones without infection typically do not cause fever.

• Ectopic pregnancy: Since patients are often adolescents, pain caused by ectopic pregnancy should be considered. Pain from ectopic pregnancy may be mistaken for renal colic. In such cases, pelvic or renal ultrasound can help differentiate the conditions.

TREATMENT

Which department should cystinuria patients visit?

Patients with cystinuria often present with lower back pain or renal colic as the initial symptoms and typically seek treatment in the nephrology department of local hospitals.

Can cystinuria resolve on its own?

Cystinuria is a genetic disorder and a lifelong condition. Without treatment, it will not improve and cannot be completely cured.

What are the consequences of untreated cystinuria?

If left untreated, cystinuria may lead to recurrent urinary tract infections and eventually progress to kidney failure.

Do cystinuria patients require hospitalization?

Patients without obvious symptoms usually do not need hospitalization. However, hospitalization is necessary during acute episodes of renal colic due to kidney stones or when surgical stone removal or lithotripsy is required.

How should cystinuria be treated?

The goal of cystinuria treatment is to prevent the formation of cystine stones and delay the progression to kidney failure. Conservative treatment is the primary approach, including the following measures:

• Increased fluid intake: Also known as hydration therapy, this is the simplest and most practical method to prevent cystine stones. Increasing fluid intake lowers cystine concentration in urine. Ideally, urine cystine levels should be kept below 243 mg/L (1 mmol/L) to prevent stone formation. Adults should aim for a daily urine output of 3L, achieved by drinking more water during the day and night.

• Dietary sodium and protein restriction: Studies show that limiting sodium reduces cystine excretion. Protein restriction decreases cystine formation, thereby reducing urinary cystine excretion. Daily protein intake should be controlled at 0.8–1.0 g/kg of body weight.

• Urine alkalinization: Cystine tends to crystallize or form stones in acidic or neutral urine, but its solubility increases threefold in alkaline urine. Maintaining alkaline urine reduces cystine crystal formation. Potassium-sodium hydrogen citrate is a commonly used urine alkalinizer, while potassium citrate or potassium bicarbonate can also be used. Sodium citrate or sodium bicarbonate should be avoided. Urine pH should be maintained above 7.0.

How should cystinuria patients proceed if conservative treatment fails?

If conservative treatment remains ineffective after three months or if patients cannot adhere to the regimen, thiol-containing drugs may be added.

Thiol-containing drugs include penicillamine and tiopronin. Tiopronin is preferred due to its significantly lower incidence of side effects compared to penicillamine. The usual dosage of tiopronin is 400–1,200 mg/day, divided into three doses.

Additionally, patients with extremely high cystine excretion rates may start treatment with thiol-containing drugs from the beginning.

What are the common adverse effects of thiol-containing drugs for cystinuria?

Penicillamine has a high incidence of adverse effects, with about half of patients experiencing toxic reactions such as fever, rash, joint pain, nephrotic syndrome, and blood cell deficiencies. Systemic lupus erythematosus-like reactions are rare.

Tiopronin has similar side effects but with a much lower incidence. Strict adherence to medical advice minimizes concerns.

What are the goals of conservative treatment for cystinuria?

• Reducing 24-hour urinary cystine concentration below 243 mg/L and increasing urine pH above 7.0, or lowering cystine supersaturation below 1.0.

• No cystine crystals detected in urine analysis.

How should cystinuria patients with existing stones be treated?

For persistent stone formation or large stones (including staghorn calculi) causing urinary obstruction, urological intervention may be necessary. The choice between surgery and extracorporeal shock wave lithotripsy depends on stone size.

Stones smaller than 1.5 cm can usually be treated with extracorporeal shock wave lithotripsy or ureteroscopic stone removal combined with holmium laser lithotripsy. Larger stones are best managed with percutaneous nephrolithotomy combined with ultrasound or laser lithotripsy.

How should cystinuria patients undergo follow-up?

Due to the high recurrence rate of cystine stones and the risk of kidney damage, regular follow-up is crucial. Patients should periodically undergo kidney ultrasound, 24-hour urinary cystine excretion tests, and urinalysis. If stone symptoms occur, CT scans should be performed at least annually to monitor stone size and facilitate timely intervention.

DIET & LIFESTYLE

What should cystinuria patients pay attention to in daily life?

• Low-protein diet: Protein-rich foods include various fish, meat, eggs, dairy products, soybeans, peanuts, etc. Intake of these foods should be limited.

• Low-sodium diet: Use less salt and high-sodium seasonings when cooking, and avoid pickled vegetables, meats, etc.

• Increase water intake: Ensure adequate daily water intake to maintain urine output at around 3 liters.

• Change underwear frequently, avoid holding urine, and prevent urinary tract infections.

Does cystinuria affect fertility?

Cystinuria does not affect fertility, but since it is a genetic disorder, genetic counseling before pregnancy is recommended. Prenatal screening and close postpartum monitoring are also crucial.

Can cystinuria patients fly, engage in intense exercise, or travel to high-altitude areas?

Except during kidney stone episodes, cystinuria patients can engage in these activities at other times.

PREVENTION

Can cystinuria be prevented?

Cystinuria is a genetic disorder that can be prevented by avoiding the birth of affected infants. When patients plan to have children, it is advisable to undergo genetic counseling first to assess the risk of the disease in the next generation.