Cystinuria – Causes, Symptoms, Diagnosis, Treatment

Cystinuria – Causes, Symptoms, Diagnosis, Treatment

Cystinuria is a condition characterized by the buildup of the amino acid cysteine, a building block of most proteins, in the kidneys and bladder. As the kidneys filter blood to create urine, cystine is normally absorbed back into the bloodstream.

Cystine stones are due to an inherited defect in the transport of the amino acid cystine leading to excessive excretion in the kidney causing cystinuria. Cystinuria causes supersaturation in the kidney predisposing to the development of stones. This activity outlines the evaluation and management of cystine stones and explains the role of the interprofessional team in improving care for patients with this condition. Cystine stones account for only about 1% to 2% of all kidney stones but represent about 6% to 8% of all pediatric calculi. The name “cystine” comes from its original description as “bladder calculi” in 1833.

Kidney stones are the primary clinical manifestation of this condition.  The primary treatment is the optimization of urinary volume and pH with hydration and oral alkalinizing drugs. Medical therapy consists of thiol-based drugs and is used in patients where conservative measures alone are insufficient.

While most cystine stone formers will make pure cystine stones, up to 40% may develop mixed calculi that will also contain calcium oxalate, calcium phosphate, or struvite.

Compared to calcium stone formers, cystine nephrolithiasis patients will tend to make larger stones, require more urological procedures, and will start making stones at an earlier age. They also face a greater risk of eventual kidney damage and chronic renal failure compared to calcium nephrolithiasis patients.

Causes of Cystinuria

The cause of cystinuria is an inheritable, autosomal recessive genetic defect that affects the proximal renal tubular reabsorption of cystine. This same problem also affects lysine, ornithine, and arginine (COLA), but only cystine is clinically significant as it is the only amino acid in this group that will form stones. Cystine is the least soluble of all the essential amino acids. Interestingly, intestinal transport and absorption of cystine, in patients with cystinuria, tends to be impaired, but other factors offset this benefit.

Cystinuria would not be a problem except for its relative insolubility in urine at physiological pH levels. Cystine solubility is highly pH-dependent because it substantially increases as the urine becomes more alkaline.

Cystine solubility is also affected by urinary macromolecules and ions, both of which increase cystine’s solubility.

Cystinuria is primarily characterized by a buildup of the amino acid, cystine, in the kidneys and bladder. This leads to the formation of cystine crystals and/or stones which may block the urinary tract. Signs and symptoms of cystinuria are a consequence of stone formation and may include:[rx][rx][rx]

  • Nausea
  • Blood in the urine (hematuria)
  • Flank pain
  • Frequent urinary tract infections
  • Chronic or acute renal failure (rare)

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormality of amino acid metabolism 0004337 
Hematuria
Blood in urine
0000790 
Nephrolithiasis
Kidney stones
0000787 
30%-79% of people have these symptoms
Hyperuricemia
High blood uric acid level
0002149 
Renal insufficiency
Renal failure

more  ]

0000083 
Percent of people who have these symptoms is not available through HPO
Abnormality of the nervous system
Neurologic abnormalities

more  ]

0000707 
Argininuria
High urine arginine levels
0003268 
Autosomal dominant inheritance 0000006 
Autosomal recessive inheritance 0000007 
Cystinuria
High urine cystine levels
0003131 
Hyperlysinuria
High urine lysine levels
0003297 
Ornithinuria 0003532 
Recurrent urinary tract infections
Frequent urinary tract infections

more  ]

0000010 
Variable expressivity 0003828 

Diagnosis of Cystinuria

The initial presentation of a patient with cystine stones is identical to any patient with obstructing urolithiasis. They typically will develop acute flank pain with hematuria, often associated with nausea and vomiting. The pain will radiate around the flank towards the groin, and they often have CVA tenderness. Microscopic or gross hematuria is frequently present, but up to 15% of patients with obstructing stones may not have even microscopic hematuria. The strongest element in the patient’s history is a strong personal or family history of cystinuria and cystine stone formation.

Lab Test and Imaging

Since cysteine contains sulfur, the urine of hypercystinuric individuals may have a rotten egg odor. Typical hexagonal cystine crystals can sometimes be seen on urinalysis in affected patients. When these hexagonal crystals appear on urinalysis, it suggests supersaturation of the urine with cystine.

The sodium cyanide-nitroprusside test is often the initial laboratory screening test for cystinuria as it is fast, simple, and provides a reasonably reliable, qualitative assessment of urinary cystine levels. The cyanide converts cystine to cysteine, which then binds to the nitroprusside creating an intense purple color in just a few minutes. The test typically turns positive at cystine levels above 75 mg/gm creatinine. It is not recommended in known cystine stone-forming patients as it is necessary to have a more reliable 24 hour total.

The ability of a patient’s urine to dissolve cystine can be determined by a “cystine capacity” test. A pre-determined amount of solid cystine is added to a measured sample of the patient’s urine. The sample is incubated and then all solid cystine is removed. If the recoverable cystine weighs less than the original solid sample, the urine is undersaturated. If it weighs more, then it is supersaturated. While it is a reasonable test for cystine supersaturation, it is relatively insensitive which limits its clinical usefulness. But it does allow a reasonably accurate measurement of cystine supersaturation even for patients who are on medical therapy.

The definitive diagnosis of obstructing calculi will require imaging, which includes CT scans, KUB X-rays, and/or ultrasound. CT scans without contrast remain the “gold standard” for the diagnosis of urolithiasis and will demonstrate cystine stones clearly as will an ultrasound for renal calculi, but they cannot distinguish cystine from other stone chemicals constituents. Plain x-rays of the abdomen will not show cystine stones well as they are only faintly radiopaque and will tend to have a ground-glass appearance.

Regular renal ultrasounds are recommended in all cystine stone-forming patients every 6 to 12 months.

Treatment of Cystinuria

Surgical treatment of cystine stones is similar to that of other stones except that cystine is notoriously resistant to extracorporeal shock wave lithotripsy (ESWL) unless the stones are less than 1 cm in size. Retrograde pyelography and the use of indwelling ureteral catheters will help to visualize stones that otherwise would be difficult to localize for ESWL therapy. Even then, the stones are relatively difficult to see and target reliably. They also will likely require more shocks than calcium oxalate or calcium phosphate stones. For these reasons, ureteroscopy with laser lithotripsy is preferable for most cystinuria patients with obstructing cystine stones that require surgery.

Total removal of all cystine stones and fragments has demonstrated reduced recurrence rates and better preservation of renal function. Stone surgery has not caused any measurable decrease in overall renal function.

Medical Management

Acceptable levels of urinary cystine are 250 mg/L or less at a urinary pH of 6.5 to 7. This level can often be reached through increased fluid intake and urinary alkalinization. The use of thiol-based medications to reduce urinary cystine levels is discouraged unless hydration therapy and alkalinization treatment are insufficient to achieve the desired “optimal” cystine concentration levels (less than 250 mg/L) at an acceptable pH (6.5 to 7). A sustained urinary pH of 7.5 can be useful to dissolve existing cystine stones. Some experts have recommended lower cystine concentrations of 150 mg/L and possibly even lower at 90 mg/L as “optimal”.

Hydration is usually the first step in medical management. Increasing fluid intake sufficiently to reliably generate 2,500 to 3,00 ml or more of urine per day is often necessary. The goal is to dilute the urine sufficiently to get the urinary cystine content to the recommended concentration level of 250 mg/L or less; this frequently requires having the patient wake up in the middle of the night to void and drink extra water. Drinking 240 ml of water every hour during the day and 480 ml before bed and at least once overnight is a standard strategy for maximizing oral hydration therapy and urinary volume. Hydration can be monitored by following the specific gravity, which should always be 1.010 or less. Since some cystinuric patients can generate up to 1400 mg of cystine per day, hydration alone may not be sufficient, but it is always the first step in management. Up to one-third of cystine stone patients can manage their stone recurrences with fluid management. Optimal hydration will depend on the patient’s individual cystine excretion.

Urinary alkalinization can not only prevent cystine precipitation and stone formation but may also dissolve existing cystine stones. For prophylaxis, the urinary pH should be targeted at 7.0 to 7.5, but for stone dissolution, a urinary pH higher than 7.5 needs to be maintained. At this high pH level (above 7.5), calcium phosphate stones can precipitate. In such cases, hypercalciuria needs to be controlled tightly with diet and thiazides. Mineral water and citrus juices can help increase pH levels, but potassium citrate supplementation is the mainstay of urinary alkalinization therapy. The usual daily potassium citrate dosage in cystinuria is 60 to 90 mEq total in 3 or 4 divided doses and then titrated as needed to optimize the pH. Serum potassium should also be checked periodically in patients on high dosages of potassium citrate to detect hyperkalemia. Unfortunately, potassium citrate is notorious for poor long-term patient compliance as it requires frequent daily dosing, tends to have significant gastrointestinal side effects and liquid formulations often have exceedingly bad taste. If hyperkalemia is limiting potassium citrate administration, lower potassium urinary alkalinizing medications are available.

Sodium bicarbonate can also be used to help with pH issues, especially in patients at risk for hyperkalemia with potassium citrate therapy; but it tends to have a relatively short-term alkalinizing effect and the extra sodium intake may increase urinary cystine excretion. High animal protein diets are also discouraged in cystinuric patients for the same reason.

Acetazolamide is a carbonic anhydrase inhibitor that increases urinary bicarbonate excretion and raises urinary pH levels. While not a first-line therapy (it can cause hypocitraturia and metabolic acidosis), it may occasionally be of some help in maintaining high urinary pH levels in addition to the other therapies mentioned. It can be particularly useful in maintaining a high nighttime urinary pH without the need for multiple awakenings or additional overnight alkalinization dosing.

When conservative measures, as outlined above, are insufficient after a 3 month trial period, a thiol-based drug regimen is usually the next step in treatment for active cystine stone formers.

Thiol-Based Agents

Cystine is composed of two cysteine molecules bound together by a disulfide bond. Thiol-based drugs have sulfhydryl groups that can reduce this disulfide bond, producing a mixed cysteine disulfide compound that is far more soluble than the original cysteine molecule. As a general guide, most patients with a 24-hour urinary cystine excretion of 500 mg or more are likely to need a thiol medication in addition to hydration therapy and alkalinization.

Thiol-based treatment is thought to have the extra benefit of possibly making cystine stones more amenable to ESWL treatment. This may occur because of the mixing of calcium phosphate along with the cystine creating a more fragile stone that is more easily fragmented with ESWL therapy. All patients on thiol-based drug therapy should have routine blood counts, platelet counts, serum albumin, liver function tests, and 24-hour urine tests for cystine and protein.

Penicillamine, a penicillin derivative, was the first thiol drug used for cystinuria. Penicillamine-cysteine disulfide is 50 times more soluble in urine than cystine. Each 250 mg penicillamine tablet can reduce urinary cystine levels by about 75 mg to 100 mg per day. The problem with penicillamine is that there is a high incidence of side effects, including fever, rash, loss of taste, arthritis, leukopenia, aplastic anemia, gastrointestinal (GI) disturbances, renal membranous nephropathy with proteinuria, and pyridoxine deficiency. The incidence of significant side effects is about 50%, which limits long-term compliance. Almost 70% of patients discontinued the drug due to adverse effects in one study. For these reasons, penicillamine use is limited in favor of other thiol-based drugs.

Tiopronin (Thiola, alpha-mercapto propionyl glycine, or alpha-MPG) is a second-generation thiol drug that works similarly to penicillamine but is roughly 30% more effective with significantly fewer side effects. It received approval for use in the United States in 1988, so there is ample experience with the medication. The typical dose is 300 mg three times per day. Long-term compliance is about 70%. For these reasons, tiopronin is currently the thiol drug of choice for cystinuria when hydration and urinary alkalinization therapy fail to achieve optimal cystine concentration levels at an acceptable pH.

Captopril is an ACE inhibitor normally used for hypertension, but it is also a unique thiol-based drug that can form captopril-cysteine mixed disulfides that are highly soluble in cystinuric patients. While safe with few side effects, captopril’s clinical effectiveness in cystinuric stone-forming patients is uncertain as various studies provide conflicting results. It should be considered a reasonable treatment option in cystinuric patients who are also hypertensive or where other thiols are overly toxic or unavailable.

Bucillamine is a third-generation, thiol-based drug that is currently available only in Japan and South Korea but is approved only for use in rheumatoid arthritis. As a di-thiol compound, it would theoretically be more effective than tiopronin and better tolerated since lower dosages of the drug would be needed. Experience in Asia over 30 years has demonstrated a low toxicity profile and bucillamine has been shown to be more effective than tiopronin in at least one small cystinuria study. Phase 2 studies are currently underway in the United States to determine its potential clinical usefulness in treating hypercystinuria.

Tiopronin (Brand name: Thiola) – Manufactured by Retrophin, Inc.
FDA-approved indication: Prevention of cystine nephrolithiasis in patients with homozygous cystinuria.

Other Issues

Besides bucillamine, other new cystine binding agents or crystal growth inhibitors are under evaluation. For example, L-cystine dimethyl esters (L-CDME) and L-cystine methyl esters (L-CME) have shown promising results with good therapeutic effects at relatively low concentrations, which suggest better tolerability and fewer side effects than similar agents. Some new, investigational thiol compounds, such as thiophosphate and meso-2-3-dimercaptosuccinic acid, are undergoing testing and appear promising.

Most urinary dipsticks do not have any clear color differentiation between a pH of 6 and 7.5. A small Indianapolis company, Urodynamics (317-915-7896, 317-257-1302), makes an FDA-approved dipstick for home and patient use that has such differentiation as well as a specific gravity reading that is ideal for urine pH and hydration monitoring in cystine stone-forming patients on medical therapy.

A combination of potassium citrate and potassium bicarbonate is being evaluated for efficacy and safety in cystine stone-forming children.

Experimentally, real-time in situ atomic force microscopy has shown that L-cystine dimethyl ester (L-CDME) and L-cystine methyl ester (L-CME) can dramatically reduce the growth rate of cystine stones and crystals. They interfere with specific receptor sites on crystal surfaces that block cystine molecule binding.

Selenium, at a dosage of 200 mg/day for six weeks, was shown in a 2018 double-blinded study to significantly reduce cystine crystal volume, but this finding has not yet been confirmed.

Stem cell transplants have shown positive activity in reducing cystinuria in the mouse model and a human phase 1 and 2 study is currently underway.

Alpha-lipoic acid has been shown to increase urinary cystine solubility in mice. It also has prevented cystine stones in 2 human patients. A phase 2 clinical trial is assessing the effectiveness of a daily administration of 1200 mg of alpha-lipoic acid over a 3 year period in controlling stone formation in hypercystinuric patients.

A new vasopressin receptor antagonist (Tolvaptan) has been shown to prevent the growth of cystine stones in animal models. A pilot study is currently underway to evaluate its safety and tolerability in human subjects.

Crystal growth inhibitors may be the next new wave of prophylactic treatments for cystine stone patients. L-cystine bismorpholide and L-cystine bis(N’-methylpiperazide) appear to be the most potent potential cystine crystalization inhibitors but they have not yet been tested in any clinical trials.

A recombinant human enzyme (ACN00107) that is able to degrade cysteine and cystine, as well as reduce urinary cystine levels while inhibiting cystine stone formation, has been shown to be effective in mice and is awaiting human trials.

Chaperone therapy, where various agents are used to correcting protein and enzymatic misfolding, is a new approach to various heritable diseases. Since several mutations result in protein misfolding in cystinuria, chaperone therapy is a potentially promising alternative treatment for cystinuric patients in the future.

About 25% of cystine stone formers will have non-cystine chemical components in their stones.  For this reason, complete stone composition analyses and 24-hour urine tests are recommended for optimal stone prophylaxis.

Surgery

If the stones are very large and painful or block one of the tubes leading from the kidney, they might need to be removed surgically. There are a few different types of surgeries to break up the stones. These include the following procedures:

  • Extracorporeal shock wave lithotripsy (ESWL) – This procedure uses shock waves to break up large stones into smaller pieces. It’s not as effective for cystine stones as for other types of kidney stones.
  • Percutaneous nephrolithotomy (or nephrolithotomy) – This procedure involves passing a special instrument through your skin and into your kidney to take out the stones or break them apart.

References

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