Continuing Education Activity

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.

Objectives:

• Review the etiology of cystine stones.

• Describe the development of hematuria and acute flank pain in the history and physical examination of patients with cystine stones.

• Summarize the use of the sodium cyanide-nitroprusside test and other, newer tests in the laboratory screening and evaluation of cystinuria.

• Explain the importance of collaboration and communication among the interprofessional team to enhance care delivery for patients affected by cystine stones.

Introduction

Cystine stones account for only about 1% to 2% of all kidney stones but represent roughly 6% to 8% of all pediatric calculi. Eighty percent of cystinuria patients will have their first stone during their first two decades.[1]

The name "cystine" comes from its original description as "bladder calculi" in 1833.

Kidney stones are the singular clinical manifestation of this condition. The primary treatment is the optimization of urinary volume and pH with hydration and oral alkalinizing medications. Second-line 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 and contain calcium oxalate, phosphate, or struvite.[2]

Compared to calcium stone formers, cystine nephrolithiasis patients will tend to make larger stones, require more urological procedures, make stones more often, and start at an earlier age. They also face a greater risk of eventual kidney damage and chronic renal failure compared to calcium nephrolithiasis patients.[2][3][4][5] Cystinuria patients also report relatively poor health-related quality of life scores due to multiple recurrent stone episodes and related surgical procedures although these scores can be improved with optimized prophylactic therapy.[6][7]

Etiology

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 ornithine, lysine, 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 also tend to be impaired, but other factors significantly offset this benefit.[8][9]

Cystinuria would not be a problem except for its relative insolubility in urine at physiological pH levels and normal body temperatures. Cystine solubility is highly pH-dependent because it substantially increases as the urine becomes more alkaline, especially above a pH of 7.

Cystine solubility is also affected by urinary macromolecules, electrolytes, and ions, all of which increase cystine's solubility.

The specific genetic cause has been identified as mutations in the SLC3A1 gene on chromosome 2, the SLC7A9 gene on chromosome 19, or rarely both.[10]

Various genotypic and phenotypic types have been identified, but they appear to have relatively little effect on the clinical course. No difference in the number of stones, age at the time of the first stone event, nor the total number of stone episodes has been observed between the different genetic types.[11][12][13] For this reason, genetic testing is not usually performed for cystinuria patients. However, it has been suggested that genetic testing can be useful by confirming the diagnosis, helping with disease classification, and assisting in counseling family members.[11] 

Epidemiology

Cystinuria is the most common inheritable cause of kidney stone disease. Worldwide and in the United States, the incidence is about 1 in 7,000 population. Prevalence is 1 per 100,000 in Sweden, 1 per 18,000 in Japan, 1 per 4,000 in Australia, 1 per 2,500 in Israel, and 1 per 2,000 in Great Britain and Spain. In cystinuric stone formers, the typical patient makes about one stone every one to two years, has one surgical procedure every three years, and has undergone seven surgeries by the time they are middle-aged.[14][15] The 5-year recurrence rate for cystine stones is higher than for any other stone type at 83%.[10] More than 25% of cystine stone formers can develop non-cystine urinary calculi; this is found most often in patients following shock wave lithotripsy who may become over-alkalinized with urinary antacid therapy, which predisposes them to calcium phosphate stone formation.[2]

• Men are affected about twice as often as women. The peak age of presentation of the first cystine stone is 22 years of age, although 22% of cystinuria patients will start making calculi as children.
• The overall risk of some degree of renal injury or failure is high at up to 70%, but end-stage renal failure is relatively low in cystinuria patients at less than 5%.
• Twenty to forty percent of cystinuria patients have other kidney stone-related urinary chemical abnormalities, such as hypocitraturia (44%), hypercalciuria (19%), or hyperuricosuria (22%).
• Infrequently, cystinuria is associated with hemophilia, muscular dystrophy, Down syndrome, hereditary pancreatitis, and retinitis pigmentosa.
• Recurrence rates after surgical intervention approach 45% at three months without prophylactic medical treatment. With treatment, the average recurrence rate drops to 25% at three years.

Pathophysiology

The solubility of cystine in urine is about 250 mg/L at a pH of 7. This solubility increases as the urine becomes more alkaline, especially above pH 7. For example, 500 mg of cystine will dissolve in a liter of urine at a pH of 7.5. Cystine solubility goes up to 750 mg/L at a pH of 8, but it sometimes becomes challenging to achieve and maintain a urinary pH above 7.5 in clinical practice. There is also an increased risk of calcium phosphate precipitation in very alkaline urines.[10]

The solubility of cystine in urine is somewhat greater than the standard solubility guidelines suggest. This is due to the actions of various electrolytes, ions, and macromolecules. So, while standard solubility estimates can be a guide, the actual solubility in an individual patient's urine can only be roughly estimated from the published data.[16] However, a specialized laboratory can measure relative solubility with a urinary cystine supersaturation ratio or a "cystine capacity" test (for patients on thiol medications). (See below)

History and Physical

The initial presentation of a patient with cystine stones is identical to any patient with obstructing urolithiasis, except that they will often present at a younger age or even as children. 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 costovertebral angle (CVA) tenderness. Microscopic or gross hematuria is frequently present, but up to 15% of patients with obstructing stones may not have microscopic hematuria. The strongest element in the patient's history is a positive personal or family history of cystinuria or cystine stone formation.

Evaluation

Since cystine 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.[10][17] Characteristic hexagonal crystals of cystine will appear in 25% of cases on early morning urinalyses and are considered diagnostic of cystinuria.[1]

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.[18] False positives can occur in patients with Fanconi syndrome or those taking sulfur-based medications, ampicillin, or N-acetylcysteine.[6] Overall sensitivity is 72%, with a specificity of 95%.[10] The test is considered outdated due to its relatively low sensitivity and the need to use unstable, hazardous reagents. The sodium nitroprusside test is not recommended in known cystine stone-forming patients as the more reliable, quantitative 24-hour total cystine level is preferred. Accepted methodologies for quantitative urinary cystine measurements include ion-exchange chromatography or liquid chromatography-tandem mass spectrometry. Both are now considered acceptable clinical reference methodologies.[11]

A definitive diagnosis of cystinuria requires a quantitative 24-hour urine test for cystine and a positive stone chemical composition analysis (preferably using X-ray diffraction and infrared spectroscopy).[19] In younger children who cannot perform 24-hour collections, there are age-related standards for first-morning urine cystine concentration per gram of creatinine. In older children, cystinuria is usually defined as >315 mg cystine/gram creatinine. Normal cystine concentrations in younger children are as follows:[20][21]

• Age less than 1 month: less than 80 mg cystine/gram creatinine
• Age   1 month - 1 year: less than 52 mg cystine/gram creatinine
• Age greater than 1 year: less than 35 mg cystine/gram creatinine

Regular 24-hour urine tests are recommended to monitor therapy results and modify treatment as a change in stone composition is common.[22] However, standard laboratory testing cannot differentiate between free and bound cystine for patients on thiol therapy.[22] (See "cystine capacity" test below.)

Cystine Supersaturation is a very useful laboratory measurement that evaluates the cystine crystallization potential as well as the efficacy of prophylactic therapy, except for those on thiol-based medications where the test is not considered reliable as it looks at total cystine, whether complexed with thiol or not. To perform this test, the patient's urine sample is incubated with additional cystine crystals for 48 hours at 37 degrees C. At this point, the urine is completely saturated with cystine. Dividing the original sample's cystine concentration by the concentration of the fully saturated sample provides a supersaturation ratio. The optimal ratio to prevent cystine stone formation is not known, but a supersaturation ratio of 0.6 or less has been suggested as a goal.

The "Cystine Capacity" test is recommended for cystinuria patients on thiol-based medications where the supersaturation test cannot be used reliably. The "cystine capacity" test measures the ability of a patient's urine to dissolve a solid cystine sample. A pre-determined amount of solid cystine is added to a measured sample of the patient's urine. The sample is incubated for 48 hours at 37 degrees C, and then all solid cystine is removed. If the recoverable solid cystine weighs less than the original sample, the urine is undersaturated. If it weighs more, then it is supersaturated. A "positive" test means that the solid cystine sample has gained additional cystine after incubation, so the test urine was supersaturated. A "negative" test indicates that the solid sample has partially dissolved, and therefore, the test sample was undersaturated with cystine. While "cystine capacity" is a very reasonable test for cystine saturation, it is relatively insensitive and somewhat labor-intensive, which limits its practicality and availability, although it does allow an accurate determination of cystine saturation even for patients who are on medical (thiol) therapy.[6] In the US, both of these tests (cystine supersaturation and "cystine capacity") are available through a specialized laboratory such as Litholink (litholink.labcorp.com or 1-800-338-4333).  

The definitive diagnosis of obstructing cystine calculi will require imaging, including plain abdominal X-rays (KUB), ultrasound, and CT scans.

Plain X-rays of the abdomen will not show cystine stones well, as they are only faintly radio-opaque. If visible, they will tend to have a ground-glass appearance.[10]

Ultrasound can identify cystine stones in the kidney if they are sufficiently large (usually >4 mm) and can detect hydronephrosis, but it cannot distinguish cystine from other stone chemical compositions. It is the preferred initial imaging study for stones in children and in pregnancy. Ultrasound can measure the renal resistive index, which is elevated in cases of obstruction. The resistive index is defined as (peak systolic velocity - end-diastolic velocity) / peak systolic velocity. This value is usually 0.50 to 0.70. If one side has a higher resistive index, it suggests obstruction on the affected (elevated) side. (In medical renal disease, the resistive indices on both sides are elevated equally.)

The finding of a hyperechoic fetal colon on routine ultrasound at <36 weeks gestation has been shown to indicate fetal cystinuria with a very high positive predictive value of 89%.[23][24] The explanation for this is a cystinuric fetus will have high cystine levels in the amniotic fluid. As this fluid is naturally ingested by the fetus, it overloads the fetal intestinal absorbing ability, resulting in cystine precipitation in the colon.[25] In these rare cases, genetic testing can be recommended to confirm the early diagnosis of cystinuria, as tubular immaturity interferes with urinary cystine excretion in very young children.[11]

CT scans without contrast remain the "gold standard" for diagnosing urolithiasis and will show cystine stones clearly. Such calculi will typically demonstrate a relatively low density of <800 Hounsfield units.[26] (Stones with a density greater than 1,000 Hounsfield units are unlikely to be pure cystine.)  Unfortunately, Hounsfield units alone cannot easily distinguish between cystine and uric acid stones since their Hounsfield densities overlap.[26] Uric acid stones will also have low Hounsfield units of less than 500 on CT, but they will demonstrate very low urinary pH levels, which is not typical of cystine stones. Dual-energy CT scans use information from two separate beams to help distinguish the stone's chemical composition, but these machines are more costly, are not universally available, and are still unable to definitively distinguish between uric acid and cystine stone compositions where the densities overlap.[27][28]

Treatment / Management

The currently recommended treatment strategy for cystine stone formers is based on a progressive approach, starting with the most conservative measures. Initial therapy involves dietary measures, hydration, and alkalinization. In refractory cases, treatment is extended to thiol-based medications. Existing cystine stones are treated similarly to other urinary calculi of similar size, with consideration being given to the high stone recurrence rate and relative resistance to extracorporeal shockwave lithotripsy (ESWL) fragmentation.  

Medical Management

Dietary measures alone for cystinuria have shown only relatively minor clinical benefits. Nevertheless, a "bad" diet can certainly increase stone risk. Patients on various supplements high in cystine and methionine have shown rapid growth and production of cystine stones.[29] The best evidence for dietary risk reduction may be sodium, where a low salt diet appears to reduce urinary cystine excretion.[30][31][32] Dietary sodium should be limited to less than 2 grams/day. A low methionine/low protein diet is still typically recommended, although its overall effectiveness is still considered somewhat limited.[33] High-methionine foods include turkey, beef, fish, pork, tofu, milk, cheese, nuts, beans, and whole grains like quinoa. A normal daily dietary methionine intake of 1,200 to 1,400 mg per day is recommended.[34] High animal protein consumption will also raise urinary acidity, decrease pH, and increase hydrogen ion excretion. Protein restrictions should not extend to children who are still growing, although the amount of very high methionine foods should be limited.[10][11][34] Alkalinizing beverages (such as lemonade, orange juice, and mineral water with high bicarbonate levels) are recommended.[6][10]

Hydration and dietary measures are usually the first step in medical management. Increasing fluid intake sufficiently to generate 3,000 ml or more of urine per day reliably is recommended. 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 the patient to wake up in the middle of the night to void and drink extra water. Drinking 240 ml of water every hour during the day, 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 1,400 mg of cystine per day, hydration alone may not be sufficient, but it is always the initial step in management, along with dietary measures. Up to one-third of cystine stone patients can manage their stone recurrences with fluid management alone. Optimal hydration will depend on the patient's cystine excretion.[10] 

Clinicians should be aware that maintenance of high fluid intake is often difficult for patients, especially at the much higher than usual levels required of cystine stone formers. Maintenance of fluid is so critical that patients are typically advised to drink extra water before bedtime and each time they awaken. In refractory cases, particularly in the pediatric age group, using a nocturnal nasogastric or gastrostomy tube to provide additional overnight fluid can be considered.[11] Periodic, regular review and monitoring of the patient's daily urinary output volume by the clinical team are necessary to maintain the effectiveness of this important treatment modality in managing this challenging disorder.

Acceptable levels of urinary cystine are 250 mg/L or less at a urinary pH of 7 or more. Some experts have recommended cystine concentrations of 150 mg/L, and possibly even lower at 90 mg/L, as "optimal."[10] This level can often be reached through increasing fluid intake. The use of thiol-based medications to reduce urinary cystine levels is discouraged unless hydration and alkalinization treatments alone are insufficient to achieve the desired "optimal" cystine concentration levels (less than 250 mg/L) at an acceptable, achievable pH of at least 7. A sustained urinary pH of 7.5 or more can be useful to attempt dissolution of existing cystine stones, although such high pH levels can be difficult to maintain clinically and may tend to precipitate calcium phosphate. 

Urinary alkalinization can not only prevent cystine precipitation and stone formation but may also dissolve existing calculi. For prophylaxis, the urinary pH should be targeted at 7.5, but a urinary pH higher than 7.5 needs to be maintained for stone dissolution. However, 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 thiazide therapy, while hydration should be optimized. Cystine solubility increases dramatically above a urine pH of 7 at body temperature. At a pH of 7.5, cystine solubility is 500 mg/L, almost double its solubility at a pH of 7.

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 at 7.5. A large bedtime dose is suggested as well. Patients should be warned that they may see tablets in their stool, which is normal. (The tablets are wax-based and designed to pass through the gastrointestinal tract and be expelled in the stool.) Serum potassium should be checked periodically in patients on high dosages of potassium citrate and those with renal failure to detect hyperkalemia early.[10] 

Cystinuria patients on alkalinization therapy often need very high doses of urinary antacids. Unfortunately, potassium citrate tablets are notorious for poor long-term patient compliance as they require frequent daily dosing, tend to have significant gastrointestinal side effects, and can be physically difficult to swallow for many patients due to their large size. Liquid potassium citrate formulations can be quite concentrated and offer a relatively large urinary alkalinization effect, but they also often taste exceedingly bad or are unavailable.[35] If hyperkalemia is limiting potassium citrate administration, urinary alkalinizing medications with lower potassium content are available. These would include various prescription and OTC combinations of sodium citrate, sodium bicarbonate, citric acid, magnesium citrate, and potassium citrate.[35][36]

A low potassium OTC urinary alkalinizer is available online that overcomes the problems with most urinary antacid products. Each 10 mEq citrate packet contains 5 mEq of potassium citrate, 2.5 mEq of sodium bicarbonate, and 2.5 mEq of magnesium citrate. (This is equivalent in urinary alkalinizing ability to a standard 10 mEq potassium citrate tablet but is better absorbed, has fewer intestinal side effects, is less expensive, and contains half the potassium content.) It has been formulated to have no taste when mixed with water, juice, or other beverages, requires no prescription and the cost is nominal.[36]

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 actually increase urinary cystine excretion. High animal protein diets are also discouraged in cystinuric patients for the same reason.[10] 

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 help maintain high urinary pH levels in addition to the other therapies mentioned. Acetazolamide can be particularly useful in maintaining a high nighttime urinary pH without the need for multiple awakenings or additional overnight alkalinization dosing.[37] However, it is not always well-tolerated and can cause metabolic acidosis. Potassium citrate is still preferred for urinary alkalinization, but acetazolamide can occasionally be helpful in selected patients.

Alpha-lipoic acid, a nutritional supplement, has been shown to increase cystine solubility in urine without affecting concentration or pH in both animal models and humans. Studies are very limited, but anecdotal case reports are quite promising.[38] Given its very high safety profile, alpha-lipoic acid may be worth using in cases where hydration and alkalinization therapy alone have not been adequate. The dosage used was 300 - 600 mg PO BID, but an optimal dose has not been established for cystinuria. When used for diabetes or neuropathy, dosages of 600 mg to 1,800 mg per day of alpha-lipoic acid have been used safely. A formal clinical trial on the use of alpha-lipoic acid in cystinuria stone formers is underway. 

The goal of all the above therapies is to achieve a cystine concentration of no more than 250 mg/L at a urinary pH of at least 7. To reduce the urinary cystine concentration, additional fluid intake will be necessary. Additional alkalinizing therapy should be utilized if the pH is not at least 7. The optimal urine pH in cystine stone-forming patients is 7.5. When these target goals cannot be achieved, or such conservative measures are insufficient to control stone formation after a three-month trial period, a thiol-based drug regimen will be the next step in treatment for active cystine stone formers.[10]

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 cystine 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 urinary alkalinization.[10] It is generally recommended that a higher dose be given at bedtime. Thiol-based drugs are contraindicated during pregnancy. 

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 easier to fragment with ESWL therapy. All patients on thiol-based drug therapy should have routine blood and platelet counts, serum albumin, liver function tests, 24-hour urine tests for cystine, "cystine capacity" (if available), and protein.[39]

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 (vitamin B-6) deficiency. The incidence of significant side effects is about 50% but could be as high as 84%, limiting long-term compliance. Almost 70% of patients discontinued the drug due to these adverse side effects in one study. Penicillamine can suppress the immune system, which will increase the risk of infection, but these patients need close monitoring for renal function, heart effects, liver toxicity, abnormal blood counts, and neurological defects.[40] For these reasons, penicillamine use is limited in favor of other thiol-based drugs.[41]

Tiopronin (Thiola, alpha-mercaptopropionyl glycine, or alpha-MPG) is a second-generation thiol drug that works similarly to penicillamine but is roughly 30% more effective (higher dissolution rate) with significantly fewer side effects (approximately 20% to 50%). 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 but can be upwardly adjusted to 1,500 mg/day. (For pediatric patients, the recommended dosage is 20 to 40 mg/kg/day, split into two doses.)[1] Long-term compliance is about 70%, and the discontinuation rate is half that of penicillamine.[42] An enteric-coated formulation has recently become available. 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.[43]

Captopril is an angiotensin-converting enzyme (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 have produced conflicting results. It may be most useful in patients who have chronic renal failure, hypertension, and proteinuria. It is not recommended as monotherapy for cystinuria. Pending a more rigorous, definitive study, it should be considered a reasonable treatment option only in cystinuric patients where other thiols are overly toxic or unavailable.[39][44]

Bucillamine is a third-generation, thiol-based drug that is currently available only in Japan and South Korea. Even there, it is only approved 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. Bucillamine has been shown to be more effective than tiopronin in at least one small cystinuria study.[22]  A phase 2 study is underway in the United States to determine its potential clinical usefulness in treating hypercystinuria. (It is also being investigated for a possible role in treating COVID-19.)

Surgical Management

The 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. Cystine stones appear to be more fragile and more amenable to ESWL in patients taking oral thiol medications.[10] Retrograde pyelography and indwelling ureteral catheters with intermittent diluted retrograde contrast injections will help visualize stones that otherwise would be difficult to target for ESWL therapy. Cystine calculi will also 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 or non-obstructing cystine stones that require surgery. Surgical therapy for cystine stones is usually a bit more aggressive than for other urinary calculi, meaning that surgery is recommended earlier and for smaller stones than other stone types. Nevertheless, ESWL may be considered even for relatively resistant cystine stones in children and others wishing to avoid more invasive procedures as much as possible. Percutaneous procedures should be limited and used only when absolutely necessary to minimize renal damage over time. Miniaturized equipment should be utilized when possible.[45][46]

Total removal of all cystine stones and fragments has demonstrated reduced recurrence rates and better preservation of renal function. This is particularly important in pediatric cystinuric patients, where prophylactic measures should be emphasized to avoid new stone production and the need for additional future surgeries. When carefully and appropriately performed, stone surgery does not generally cause any measurable decrease in overall renal function.[45][47][48]

When ureteral double J stents are used, their time in place should be minimized as complete stent encrustation, and blockage in cystinuria patients can occur in less than two weeks.[49]

The spontaneous passage rate is similar for all stone types, although cystinuria patients may be able to pass larger stones due to their greater average number of prior episodes. A maximum of 30 days is recommended for conservative management and spontaneous passage, after which surgical intervention should be performed to prevent further symptoms and complications.[50][51] A recent large, worldwide real-life study of calculi managed conservatively showed overall stone passage rates for proximal ureteral calculi were 52% compared to 83% for distal stones. The spontaneous stone passage rate for various stone sizes (diameters) was as follows:[52]

• Stone diameter less than 5 mm  = 89% stone passage rate
• Stone diameter 5 to 7 mm = 49% stone passage rate
• Stone diameter greater than 7 mm  = 29% stone passage rate

Patient Monitoring

Urinary cystine is found in both soluble (free) and insoluble (bound) forms.[49] How much cystine is soluble vs. insoluble depends on many factors, including concentration, temperature, ionic strength, pH, macromolecules, etc.[16] This is why the total daily urinary cystine is not always a good indicator of the patient's true clinical status or propensity for stone production. Separate measurements of free and bound cystine levels have clinical significance in treating patients on thiol and other cystine-binding drugs, but these values are not readily available, and results need to be verified, standardized, and published.[19][53][54]

Regular renal ultrasounds are recommended in all active cystine stone-forming patients every 6 to 12 months.[6] This has been shown to be an effective way to monitor stone production while minimizing ionizing radiation exposure. The timing of these ultrasounds should be modified based on each patient's clinical history, response to prophylactic therapy, daily urinary cystine production, pH, and stone production. Annual monitoring may be sufficient for patients with infrequent stones (<1 stone a year). For more active stone formers, monitoring frequency should be increased accordingly.

Routine 24-hour urine tests for total cystine excretion, supersaturation, and urinary cystine capacity are recommended for monitoring and optimizing therapy. Regular 24-hour urine testing for protein is recommended for patients on thiol medications and those with renal failure.

There appears to be a correlation between new cystine stone production and the presence of crystalluria on urinalysis.[55][56] The optimal timing and frequency of urinalyses for cystine crystalluria monitoring have not been determined, and no prospective studies have yet been done. In addition, there is no generally accepted, standardized methodology for assessing the degree of cystine crystalluria. In Europe, many centers already use some form of urinary crystal detection and quantification for routine monitoring of cystinuria patients. Theoretically, monitoring of cystine crystalluria may allow for better optimization of ultrasound and CT examinations for early stone detection.[11] There is also no standardization for assessing cystine stone activity. Should we use the number of stones made per year, the number of urological stone procedures, the increase in the number or size of calculi, or some combination of these factors to determine cystine stone activity for both clinical and research purposes? The answer remains yet to be determined.

It is well established that increased patient compliance with therapy, particularly alkalinizing agents, is associated with fewer urological surgery procedures.[57] Achieving this is not always easy. Besides education, support, and reinforcement, there are now cellphone apps that include gentle reminders to patients to drink more water, check their urine pH, and take their prescribed alkalinizing medications. All cystine stone-forming patients should monitor their urinary pH regularly with dipsticks, pH paper, or electronic meters. Optimal urinary pH is generally considered to be 7.5, but this is not always easy to achieve in the real world. However, cystine is twice as soluble at a pH of 7.5 compared to 7.0 (500 mg/L vs. 250 mg/L), so the extra effort is well worth it.

Differential Diagnosis

• Constipation

• Diverticulitis

• Emergent management of pancreatitis

• Fungus ball in renal pelvis or ureter

• Gallstones

• Inflammatory bowel disease

• Liver abscess

• Nephrolithiasis (calcium, uric acid, struvite)

• Nutcracker syndrome

• Peptic ulcer disease

• Prostate or cervical cancer

• Pyelonephritis

• Pyonephrosis

• Renal cell carcinoma 

• Splenic abscess

• Sloughed papilla

• Ureteral urothelial carcinoma

• Ureteropelvic junction obstruction

• Urinary tract infection and cystitis in females

Prognosis

Patients with cystinuria generally have a lower quality of life compared to the general population.[58][59] Treatment is frequently difficult to tolerate or maintain, unpleasant, and often ineffective. Patients with cystine stones require more surgeries than other nephrolithiasis patients and are at considerably higher risk of chronic kidney disease, although the incidence of end-stage renal failure is relatively low at less than 5%. This risk is related to the degree of renal tissue damage, age, comorbidities, and prior renal surgeries. Most adult patients with cystinuria will have an estimated glomerular filtration rate (GFR) of less than 90 ml/min. and hypertension is reported in 29% to 51%.[60][61] The risk of hypertension was associated with the male sex, increasing age, and the degree of renal failure.

Complications

The complications from cystinuria are all related to the effects of multiple kidney stones, resulting in renal and ureteral damage, scarring, pain, repeated surgeries, and eventual renal failure. For these reasons, aggressive prophylactic measures, focusing on increasing fluid intake and optimizing urinary pH, are utilized.

Deterrence and Patient Education

Patient education is mandatory in cystinuria. The consequences of inadequate prophylactic measures causing eventual renal deterioration and possibly even renal failure need to be repeated and reinforced to patients to achieve optimal hydration and urinary pH levels. Teaching patients how to check urine specific gravity, pH values, and 24-hour urine volumes can be extremely helpful in fine-tuning and optimizing therapy to maintain a daily target urinary volume of 3 liters with a pH of 7.5.  

Pearls and Other Issues

A quantum dot assay to measure cystine concentration has been described. It uses a complicated hydrothermal method with several benefits compared to conventional chemical means, including high sensitivity, stability, rapid results, low cost, and the ability to reliably measure cystine even in the presence of chemicals and compounds that would otherwise interfere.[62]

Urinary dipsticks or chemically treated test paper to check urine pH are readily available at a nominal cost at most pharmacies or online. These products change color when dipped in urine based on the urinary pH. This can then be matched to a color guide on the bottle or dispenser, corresponding to a particular pH level. Unfortunately, most urinary home pH products do not have a very clear color differentiation between a pH of 6 and 8. Another problem is that pH paper and many urinary dipsticks do not include specific gravity, which is a test for urine concentration and hydration status. The typical recommendation is for a product for patients with a relatively limited pH range (usually 4.5 to 9), which makes it visually easier to read the correct pH level. A specific dipstick for kidney stone formers and cystinuria patients to use at home that has an optimized pH range and includes a specific gravity reading is under development. It would be ideal for urinary pH and hydration monitoring in uric acid and cystine stone-forming patients on alkalinization and fluid therapy.

About 25% of cystine stone formers will have non-cystine chemical components in their stones. For this reason, complete stone chemical composition analyses and 24-hour urine tests for nephrolithiasis risk factors are recommended for optimal stone prophylaxis.[10]

Some high-protein dietary supplements have enough cystine and methionine (a cystine precursor) to increase cystine stone formation.[29] Such high-protein supplements should be strictly avoided in cystinuric patients. 

Selenium, at a dosage of 200 mg/day for six weeks, was shown in a 2018 double-blinded study to reduce cystine crystal volume significantly, but this finding has not yet been confirmed by other investigators.[19]

Alpha-lipoic acid has been shown to increase urinary cystine solubility in mice. It also has prevented cystine stones in 2 human patients.[38] A phase 2 clinical trial is assessing the effectiveness of a daily administration of 1,200 mg of alpha-lipoic acid over a three-year period in controlling stone formation in hypercystinuric patients.

A vasopressin receptor antagonist (tolvaptan) has been shown to prevent the growth of cystine stones in animal models by drastically increasing urinary volume.[63] A pilot study is being done to evaluate its safety and tolerability in human subjects (ClinicalTrials.gov Identifier: NCT02538016).[64] Tolvaptan works to increase urinary output by enhancing renal-free water excretion. It was tested in 4 young adults with cystinuria. All subjects tested noted dramatically improved urinary volumes and increased cystine carrying capacity. There were no liver enzyme or serum electrolyte problems. The only side effect noted was significantly increased thirst.[64] Such an approach has the potential to significantly reduce stone recurrences in cystinuria patients as well as in other kidney stone formers who find it otherwise difficult to increase their fluid intake and urinary volumes. While it appears to be safe and effective for cystinuric and other kidney stone formers, there are concerns about possible hepatic toxicity, as 3 cases of potentially serious liver injuries have been noted. Liver toxicity appears to be related to dosage and the presence of pre-existing liver problems or autosomal dominant polycystic kidney disease. For now, usage is currently limited to 30 days per FDA guidelines.

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

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.[3][65] Several other new, investigational thiol compounds, such as thiophosphate and meso-2-3-dimercaptosuccinic acid, are undergoing testing and also appear promising.[66]

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 (ClinicalTrials.gov Identifier: NCT03897361).[67]

Experimentally, real-time in situ atomic force microscopy has suggested 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.[3][65][68]

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 published clinical trials.[3][66]

A recombinant human enzyme (ACN00107) that can degrade cysteine and cystine and reduce urinary cystine levels while inhibiting cystine stone formation has been shown to be effective in mice and is awaiting human trials.[22]

Chaperone therapy, where various agents are used to correct 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 new treatment for cystinuric patients in the future.[22]  

Treatment Summary

Initial or First-Line Therapy

• Reduce dietary methionine (animal protein).
• Lower the dietary salt intake.
• Increase fluid intake sufficient to generate 3,000 ml of urine daily.
• Start alkalinization therapy with the goal of raising and maintaining the urinary pH up to 7.5, if possible.
• Routine patient self-monitoring of pH and specific gravity is recommended, along with appropriate adjustments in therapy.
• Potassium citrate is the preferred alkalinizing medication, but sodium bicarbonate may also be used.
• Liquid forms of urinary alkalinizers are more quickly absorbed than tablets. They are more appropriate for patients with rapid intestinal transit times, irritable bowel syndrome, chronic diarrhea, or post-gastric bypass surgery.
• Use low potassium urinary antacid treatments in patients requiring high doses of alkalinizing therapy, develop hyperkalemia, or have renal failure.
• Acetazolamide can be effective in raising urinary pH, but its use is discouraged except in carefully selected patients.
• Avoid routine urinary alkalinization beyond pH 7.5 to minimize calcium phosphate precipitation, although this may help attempt cystine stone dissolution.
• Cystine concentration should be less than 250 mg/L, and the urine pH should be maintained optimally at 7.5 but should be at least 7. If this cannot be achieved and maintained, additional second-line (thiol) therapy should be used.
• Routine laboratory testing should include a quantitative 24-hour total urinary cystine, serum potassium, and a cystine supersaturation ratio, as well as the total daily urine volume and pH.

Second-Line Therapy

• Thiol-based treatment should use tiopronin, which is currently the preferred agent.
• "Cystine Capacity" testing should be used for monitoring treatment efficacy for patients on thiol therapy.

Optional Therapies

• Alpha-lipoic acid is readily available, well-tolerated, safe, and might be of real value based on very good results in limited studies.
• Selenium is cheap and easy to administer, but its role is unproven and untested except for a single study showing a benefit.
• Bucillamine might be a better, more effective, and less toxic thiol drug for cystinuria, but it remains mostly untested for this indication. Availability is also an issue. 

Enhancing Healthcare Team Outcomes

An interprofessional team should educate patients that treatment for cystinuria starts with a diet (low meat protein, low sodium) and hydration sufficient to generate 3,000 mL or more of urine daily. Urinary alkalinization with mineral water, fruit juices, sodium bicarbonate, and potassium citrate will significantly increase cystine solubility. The goal is to achieve a cystine concentration of 250 mg/L or less at a pH of at least 7 and optimally 7.5. An "optimal" cystine level is generally considered to be 150 mg/L or less, but some reports suggest that a cystine concentration goal of 90 mg/L may be "optimal." If this is not achievable or possible for any reason (tolerability, compliance issues, side effects), then the use of a thiol-based cystine-lowering medication is warranted. Currently, tiopronin is the preferred thiol medication of choice based on its efficacy and reduced side effect profile.  

It has been shown that a dedicated multi-disciplinary clinic for cystinuria patients reduces the surgical intervention rate by 50%, enhances patient education, increases the quality of life scores, and improves treatment compliance.[69] Each healthcare team member should take every opportunity to support and reinforce the value of continuing medical prophylactic therapy, especially after urological procedures.[70]

Excellent clinical practice guidelines and management updates for treating cystinuria have recently been published in the US and Europe.[6][19][22] These guidelines, as outlined earlier, provide a reasonable approach and framework for the evaluation and treatment of cystinuric patients with the goal of improving overall outcomes for this uncommon but frequently relapsing form of urolithiasis.  

All members of the interprofessional team treating cystinuria patients, including urologists, nurses, dietitians, and clinicians, should remind and educate patients that the optimal preservation of renal function with the best quality of life and the lowest stone recurrence rates are found in those with early and continuing prophylactic medical management of their cystinuria along with complete surgical stone removal whenever possible.[71] [Level 5] Maintaining optimal preventive therapy with fluids and alkalinizing medications should be encouraged and reinforced with patients at every opportunity by all healthcare team members.