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Cystinuria and cystine stones

Cystinuria and cystine stones
Authors:
David S Goldfarb, MD, FACP, FASN
Pietro Manuel Ferraro, MD, MSc, PhD, FERA
David J Sas, DO, MPH
Michelle A Baum, MD
Section Editor:
Glenn M Preminger, MD
Deputy Editor:
Albert Q Lam, MD
Literature review current through: Oct 2022. | This topic last updated: Jul 15, 2021.

INTRODUCTION — Cystinuria is a genetic cause (OMIM 220100) of kidney stones. This disorder is a subject of study of the Rare Kidney Stone Consortium, an organization with international collaboration focused upon research and education aimed at improving care for these patients. It is also studied by two European Reference Networks, the European Rare Kidney Disease Reference Network (ERKNet) and eUROGEN.

Cystinuria is a different disorder from cystinosis, which is characterized by intracellular cystine accumulation leading to the Fanconi syndrome and progressive kidney failure. (See "Cystinosis".)

This topic will review the pathogenesis, clinical manifestations, diagnosis, and treatment of cystinuria and cystine stones. Other aspects related to kidney stones in adults are presented separately:

(See "Kidney stones in adults: Epidemiology and risk factors".)

(See "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis".)

(See "Kidney stones in adults: Evaluation of the patient with established stone disease".)

(See "Kidney stones in adults: Prevention of recurrent kidney stones".)

(See "Kidney stones in adults: Surgical management of kidney and ureteral stones".)

EPIDEMIOLOGY — Cystinuria has an average prevalence of 1 in 7000 births [1]. Cystine stones (picture 1) are found in 1 to 2 percent of stone formers, although they represent a higher percentage of stones in children (approximately 5 percent) [2].

PATHOGENESIS, GENETICS, AND CLASSIFICATION

Pathogenesis – Cystine is a homodimer of the amino acid cysteine. Patients with cystinuria have impairment of renal cystine transport, with decreased proximal tubular reabsorption of filtered cystine resulting in increased urinary cystine excretion and cystine urinary stone disease [3]. The cystine transporter also promotes the reabsorption of dibasic amino acids, including ornithine, arginine, and lysine, but these compounds are soluble so that an increase in their urinary excretion does not lead to stones. The severity of disease is mediated by the concentration and solubility of urinary cystine, which is affected both by the underlying causative genetic abnormalities as well as by modifiable risk factors.

Genetics – Cystinuria is caused by defects in the SLC3A1 gene [4], which encodes rBAT, or in the SLC7A9 gene [5], which encodes b0,+AT. Together, rBAT and b0,+AT form a heterodimer that mediates sodium-independent transport of cystine and dibasic amino acids (ornithine, arginine, and lysine) in the apical membrane of the proximal tubule and small intestine [1]. rBAT, the heavy chain subunit of the dimer, is responsible primarily for intracellular trafficking of the transporter to the plasma membrane [6], while b0,+AT, the light chain subunit, is the actual transporter [7].

Cystinuria is generally considered to be inherited in an autosomal recessive pattern, given that most patients can be found to have some combination of two defects in the relevant genes. Though some patients with significant disease are only found to have one gene defect, this more likely reflects failure to detect the second gene abnormality rather than a true autosomal dominant inheritance.

A noteworthy variant is the so-called cystinuria-hypotonia syndrome in which affected individuals have abnormalities in SLC3A1 and PREPL (prolyl endopeptidase like) leading to varying degrees of infantile hypotonia, poor feeding, developmental impairment, elevated serum lactate, growth hormone deficiency, and cystinuria [8].

Classification – Initially, cystinuria was classified according to the amount of cystine excreted by the parents of the affected child. In that phenotypic classification system, patients were classified as type I if their parents excreted normal amounts of cystine and types II or III if parental cystine excretion was either greatly (II) or moderately (III) increased.

However, identification of the genes responsible for the disorder (SLC7A9 and SLC3A1) have led to a genotypic classification scheme, based upon which gene is affected. An abnormal SLC3A1 gene is designated as "A" and an abnormal SLC7A9 gene as "B," such that patients with cystinuria who have two abnormal SLC3A1 genes are labeled AA, those with two abnormal SLC7A9 genes labeled BB, and those with abnormalities in one of each (digenic disease) labeled AB. Carriers are labeled either A0 or B0, and those with co-occurrence of two mutations in either gene and one in the other labeled AAB or ABB [3,9].

Studies investigating relationships between genotype and cystine excretion have yielded variable results, and further research is required to identify genetic determinants of disease severity [9-14]. A0 carriers tend to have cystine excretion rates in the high-normal range, while B0 carriers tend to have higher excretion rates [10], although this, too, can be inconsistent. Genetic variants in cystinuria genes may also play a role in patients with other types of kidney stones [15].

CLINICAL FEATURES

Clinical manifestations — The clinical manifestations of cystinuria are those related to stone formation, such as flank pain, stone passage, and hematuria. (See "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis", section on 'Symptomatic stones'.)

Most patients present with their first stone during childhood or adolescence (median age of 12 years in one study [10]), although some may present in infancy [10] or even late adulthood [11,16]. Type A and type B cystinuria appear to have a similar age of diagnosis and course of disease [10,17]. Of note, not all individuals with genotypically proven cystinuria develop stones, indicating that other factors, perhaps environmental or related to risk-modifying genes, may contribute to the risk for stone formation in these patients. In one study, males appeared to be more severely affected than females [10], but this has not been confirmed in other studies [11,13].

Cystinuria may present prenatally with the detection of a hyperechoic colon during a prenatal ultrasound prior to 36 weeks. This is thought to result from ingestion by the fetus of high-cystine-containing amniotic fluid, which overloads the rBAT/b0,+AT system in the small intestine. Evaluation for cystinuria in such cases should occur after birth [18,19]. (See 'Diagnosis and evaluation' below.)

Cystine stone formers have a higher incidence of chronic kidney disease (CKD) than other stone formers [20]. In one study, for example, 16 of 76 of cystine stone formers (21 percent) had an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, including three patients with end-stage kidney disease (ESKD) or a kidney transplant; reduced eGFR was more common (80 percent) among patients who had staghorn calculi [11]. Similar findings have been reported in other studies [13,21]. The higher CKD risk may be related to the need for multiple urological procedures to remove stones beginning at a young age. Alternative hypotheses suggest that the lower eGFR in these patients may be due to intratubular obstruction by cystine crystals. (See 'Kidney pathology' below.)

Kidney pathology — Although a kidney biopsy is not usually performed, examination of kidney tissue obtained during stone removal procedures reveals associated parenchymal abnormalities that may partly explain the loss of kidney function associated with cystinuria [22]. These findings include:

The ducts of Bellini are plugged with cystine crystals.

Apatite (calcium phosphate) crystals can be seen in the inner medullary collecting ducts and in the thin loops of Henle (possibly related to the long-standing alkaline urine).

Focal areas of tubular dilatation with varying degrees of surrounding interstitial fibrosis.

These findings are in contrast to the histopathology of routine calcium oxalate stone formers, in whom interstitial deposits of apatite (Randall's plaque) are noted in the absence of intratubular crystals and are thought to serve as sites of initiation of calcium oxalate stone formation [23].

DIAGNOSIS AND EVALUATION

When to suspect cystinuria — The diagnosis of cystinuria should be suspected in any patient presenting with kidney stone disease, particularly if the patient has one or more of the following features [24]:

Early-onset kidney stones (in childhood)

Large (eg, staghorn) or recurrent kidney stones

Family history of kidney stones

Consanguinity of parents

Establishing the diagnosis — All patients presenting with kidney stones should be evaluated to determine the underlying factors responsible for stone formation. Such evaluation consists of a focused history for stone risk factors, radiologic testing, stone analysis (if available), and at least a limited laboratory evaluation, as discussed elsewhere. (See "Kidney stones in adults: Evaluation of the patient with established stone disease", section on 'Approach to evaluation' and "Kidney stones in children: Clinical features and diagnosis", section on 'Initial evaluation'.)

In patients presenting with kidney stone disease, the diagnosis of cystinuria is established by one or more of the following findings:

Stone analysis revealing 100 percent cystine calculi.

Presence of pathognomonic hexagonal cystine crystals visualized on urine microscopy (picture 2).

Genetic testing confirming two defects in some combination of the SLC7A9 and SLC3A1 genes. However, genetic testing is not required for the diagnosis of cystinuria. (See 'Genetic testing' below.)

If a stone is not available for composition analysis, cystine crystals are not visualized in the urine, and access to 24-hour urine testing is limited, the cyanide-nitroprusside test can be used to screen patients for urine cystine. The addition of cyanide-nitroprusside to urine-containing cystine induces a purple color change. A positive cyanide-nitroprusside screen indicates a urinary cystine concentration >75 mg/L. A negative test generally excludes the diagnosis of cystinuria; however, rare heterozygous patients and patients producing large volumes of dilute urine may have a negative test [25,26].

Additional testing in patients with confirmed cystinuria

Urinary cystine excretion — All patients with confirmed cystine stones, urinary cystine crystals, and/or a positive cyanide-nitroprusside screen should have quantitative testing of urinary cystine excretion, which is important in determining optimal daily fluid intake goals [27]. Urinary cystine excretion should be quantified in a 24-hour urine collection. The normal rate of cystine excretion is 30 mg/day (0.13 mmol/day); by comparison, patients with cystinuria generally excrete more than 400 mg/day (1.7 mmol/day), and some excrete as much as 3600 mg/day (15 mmol/day) [28,29]. Advanced methods for cystine quantification and solubility have been developed to distinguish between cystine and soluble thiol drug-cysteine complexes, which can be helpful in patients taking cystine-binding thiol medications [30]. (See 'Biochemical monitoring' below.)

For very young patients or patients who are otherwise incontinent of urine, a random urine sample can be collected for estimation of cystine excretion using the urine cystine-to-creatinine ratio. Normal urine cystine-to-creatinine ratios vary with age, and many children with cystinuria have concentrations >315 mg/g creatinine (>150 micromol/mmol creatinine) [3]:

<1 month old – <80 mg/g creatinine (<39 micromol/mmol creatinine)

1 month to 1 year old – <52 mg/g creatinine (<25 micromol/mmol creatinine)

>1 year old – <35 mg/g creatinine (<17 micromol/mmol creatinine)

While some pediatric specialists may rarely place an indwelling transurethral catheter in an incontinent child to collect a 24-hour urine specimen when these data are deemed critical for diagnosis or management, this inconvenience is almost never needed for cystinuria because of the ease of diagnosis through crystal identification, stone composition analysis, random urine amino acid analysis, or genetic testing.

Genetic testing — Routine genetic testing of patients with cystinuria is not performed, as there are no known therapeutic or prognostic implications associated with particular cystinuria genotypes. Genetic testing confirming two defects in the SLC7A9 and/or SLC3A1 genes is not required for the diagnosis of cystinuria. However, genetic testing is becoming increasingly accessible and may be useful for the purposes of genetic counseling and in situations of clinical uncertainty. (See 'Pathogenesis, genetics, and classification' above.)

Screening family members — Siblings of patients with proven cystinuria should be screened for the disease, as they may be asymptomatic. The preferred test for screening is quantification of urine cystine excretion in a 24-hour urine collection or, for children who are unable to perform a 24-hour urine collection, a random urine cystine-to-creatinine ratio. In addition, the urinary sediment should be examined for the presence of hexagonal crystals. Genetic testing, if available, is another option for screening family members of patients who have confirmed defects in the SLC7A9 and/or SLC3A1 genes. (See 'Urinary cystine excretion' above and 'Genetic testing' above.)

TREATMENT

Goals of therapy — The aim of medical therapy is to maintain the cystine concentration in the urine below its solubility level. The solubility of cystine in urine is pH dependent, being higher at alkaline pH, and it is also affected by other urinary ions and macromolecules. However, it is hard to predict the solubility of cystine in a given urine, as the empirically determined solubility of cystine in urine can vary from 175 to 360 mg/L (0.7 to 1.47 mmol/L) at urine pH values in the range of 7 to 7.5 [27,31,32]. The limit of solubility is best derived experimentally but can be conservatively estimated as approximately 243 mg/L (1 mmol/L) at a urine pH of 7 or higher since this concentration of cystine will be soluble at this pH in most patients. Thus, clinically, the goal is to achieve a cystine concentration of less than 250 mg/L and a urine pH greater than 7.

The concept of urinary supersaturation is important to understand as it is the basis for treating patients with cystine stones. When cystine is present in concentrations above its solubility, the urine is said to be supersaturated. The degree of supersaturation may be expressed as the ratio between the actual concentration and the solubility limit, as shown here:

                                                  Measured cystine concentration
 Supersaturation of cystine  =  -------------------------------------------
                                                     Estimated cystine solubility

Cystine crystals will dissolve when the supersaturation is below 1, while values above 1 are associated with an increased likelihood of stone formation [27]. Although the ideal saturation level has not been defined, we aim for a supersaturation level of <0.6 in a 24-hour urine specimen. This allows for variation in saturation over the course of the day, including the inevitable increase in supersaturation overnight when urine volume drops [27]. Achieving this degree of reduction in cystine supersaturation can prevent new stone formation and cause dissolution of preexisting stones [29,33-35].

Approach to therapy — The two main approaches for reducing the urinary supersaturation of cystine include conservative measures, which should be prescribed to all affected patients, and thiol-containing drugs. A trial of conservative measures is usually pursued before thiol-containing drugs are prescribed, unless the urine cystine concentration is sufficiently high that conservative measures are not likely to lower the supersaturation of cystine to below 1. (See 'Initial therapy with conservative measures' below and 'Thiol-containing drugs for resistant disease' below.)

Patients with large stones (including staghorn calculi) and urinary obstruction may require surgical therapy for stone removal. (See 'Surgical therapy' below.)

Initial therapy with conservative measures — For most patients with cystinuria, we suggest initial therapy with conservative measures rather than thiol-containing drugs, in order to avoid the adverse effects associated with these drugs. Conservative measures include increased fluid intake (which decreases the cystine concentration), modest reductions in sodium and animal protein intake (which reduces cystine excretion and, therefore, cystine concentration), and urinary alkalinization (which increases the solubility of cystine). These measures are complementary and should be attempted in all patients with cystinuria.

Some patients with cystinuria may have urinary cystine excretion that is so high that conservative measures are unlikely to be sufficient. Such patients may benefit from the addition of a thiol-containing drug as first-line therapy. (See 'Thiol-containing drugs for resistant disease' below.)

There are no randomized trials evaluating the efficacy of conservative measures or directly comparing conservative measures with thiol-containing drugs in patients with cystinuria. Data in support of conservative measures comes primarily from observational studies [36,37]. As examples:

Among 52 cystine stone formers treated for a mean of 4.3 years, fluids, alkali, and in 24 patients, a thiol-containing drug decreased the need for stone removal procedures from four to one per patient per year [37].

In 27 cystine stone formers followed for a mean of 12 years, 18 were treated with fluids and alkali alone, and nine also received a thiol-containing drug for at least three months because of failure of conservative therapy [36]. The number of stone episodes fell from 0.93 to 0.20 per patient per year during treatment, and fewer urological procedures were required. The most important factor associated with stone formation rate in this study was urine volume, which was significantly higher in those patients without further stone formation (3.2 versus 2.4 L/day).

Despite the efficacy of medical therapy shown in these studies, a large proportion of patients with cystinuria may be unable to achieve therapeutic success. In a study of 26 patients followed for approximately three years, only four maintained their urine cystine at concentrations below 300 mg/dL [38]. Of the remaining 22 patients, six were lost to follow-up, five were never able to adequately reduce their urine cystine concentrations, and the rest were only transiently successful.

High fluid intake — In patients with cystinuria, fluid intake should guarantee a urine output large enough to maintain a urinary cystine concentration of less than 250 mg/L (1 mmol/L) [3]. (See 'Goals of therapy' above.)

Knowledge of the rate of cystine excretion can be used to estimate the optimal urine output to achieve a urine cystine concentration of less than 250 mg/L (1 mmol/L). If, for example, cystine excretion is 750 mg/day (3.1 mmol/day), then a urine output of at least 3 L/day will be needed to keep the urine cystine supersaturation less than 1 at a urine pH above 7. A higher volume is advisable to keep supersaturation low throughout the day. In young children, placement of a gastrostomy tube is occasionally required to achieve higher fluid intake and prevent recurrent stones. (See 'Urinary cystine excretion' above.)

The patient should be provided with specific instructions regarding fluid intake and daily urine output goals and instructed to drink at night as well as during the day to achieve this goal since high urine outputs during the day may not prevent stone formation if volume drops and supersaturation increases markedly overnight. No specific fluids are prohibited (with the exception of those containing sodium), although limiting beverages with high sugar content to one serving per day may be judicious as they contain undesirable caloric loads.

Sodium and protein restriction — Dietary restriction of sodium and animal protein (which is rich in cystine and methionine) can reduce urinary cystine excretion and, therefore, cystine concentration. All patients with cystinuria should be advised to moderately restrict sodium intake to 100 mEq (2300 mg) or less daily. Adults should also be advised to moderately restrict animal protein intake to 0.8 to 1 g/kg per day, as this provides adequate nutrition and should be tolerated by most patients. Children should continue to achieve the recommended daily allowance for protein for optimal growth.

Short-term studies have demonstrated reductions in cystine excretion with sodium restriction, although the mechanism by which this occurs is incompletely understood [30,39], since the cystine transporter is not sodium dependent. Animal protein restriction also decreases cystine excretion, probably by decreasing the intake of methionine, the precursor of cystine [30]. In animal models, a diet rich in cystine was associated with more severe kidney damage as indicated by higher values of blood urea nitrogen and serum creatinine [40]. In addition, limiting animal protein intake facilitates urinary alkalinization by reducing net acid load, which increases the solubility of cystine. (See 'Urinary alkalinization' below.)

There are no long-term studies demonstrating a benefit from moderate sodium and protein restriction on prevention of cystine stones. However, the risks of moderate sodium and protein restriction are few, and the efficacy of these interventions on cystine excretion in a given patient can be easily assessed with 24-hour urine studies. There are no studies on the impact of a vegetarian diet.

Urinary alkalinization — Cystine solubility increases by up to threefold in an alkaline urine but only if the urine pH is greater than 7 [34]. This degree of urinary alkalinization may require up to 3 to 4 mEq/kg per day of potassium citrate or potassium bicarbonate, taken in three or four divided doses as needed to achieve round-the-clock alkalization.

In adults, we begin with doses of 20 mEq three times daily, while in children, we start with doses of 10 mEq three times daily; doses should be adjusted (up to 3 to 4 mEq/kg per day) to maintain a target urine pH of greater than 7. To maintain an alkaline urine pH overnight, the last dose of potassium citrate or potassium bicarbonate should be taken at bedtime.

We advise patients to perform home urine pH testing; testing once per day, at various times, for one month can provide a good sense of whether round-the-clock alkalinization is being achieved. Inexpensive urine pH testing paper can be purchased via the internet, avoiding the more expensive test strips used in clinical laboratories.

In selected cases, acetazolamide, which can increase urine pH by causing bicarbonaturia, has been used as an adjunct therapy to potassium citrate [41]. However, we do not recommend this option, as the chronic metabolic acidosis induced by such carbonic anhydrase inhibitors may adversely affect bone mineral density, cause hypocitraturia, and increase the risk of developing calcium phosphate stones [42,43].

Sodium citrate or sodium bicarbonate should be avoided since the sodium load can enhance calcium and cystine excretion [39]. However, sodium salts may be appropriate if hyperkalemia prevents use of potassium or if potassium salts lead to gastrointestinal intolerance. Raising the urine pH lowers the solubility of calcium phosphate, increasing the risk of forming calcium phosphate stones [44]. However, this effect is mitigated by increased urine citrate excretion and higher urine volumes. In one retrospective study, conversion from cystine to non-cystine stones was associated with prior shock wave lithotripsy (SWL) but not with urinary alkalinization therapy [45]. (See "Kidney stones in adults: Prevention of recurrent kidney stones".)

Thiol-containing drugs for resistant disease — Cystine is the homodimer formed from the linkage of two cysteine molecules by a disulfide bond. Thiol-containing drugs (eg, tiopronin [2-mercaptopropionylglycine], D-penicillamine) have sulfhydryl groups that can reduce this disulfide bond, producing mixed drug-cysteine disulfides that are more soluble than the homodimer cystine.

Indications — For patients with cystinuria who do not adequately respond to, or are likely to be resistant to, conservative measures, we suggest adding tiopronin rather than D-penicillamine. We prefer tiopronin given its lower incidence of adverse effects in some studies; however, D-penicillamine is an alternative option if tiopronin is not available or the patient is intolerant to tiopronin.

A thiol-containing drug may be used in conjunction with conservative measures if, after a three-month trial, these measures are ineffective or are limited by inadequate compliance [36]. Failure of conservative measures is defined by:

Failure to lower the urine cystine concentration to below 250 mg/L and to raise the urine pH to above 7 in a 24-hour urine (or, if the measurement is available, failure to lower the urinary supersaturation of cystine to below 1)

Persistence of cystine crystals visualized by urinalysis (picture 2), indicating that the urine is supersaturated with cystine

Recurrent stone formation despite conservative measures

In addition, a thiol-containing drug may also be used with conservative measures in patients who have a urinary cystine excretion that is so high that conservative measures are unlikely to be sufficient. As an example, a patient who excretes 1000 mg of cystine per day would require more than 4 L of urine output per day to achieve a urine cystine concentration below 250 mg/L. This degree of urine output may be too challenging for some patients, and therefore, a thiol-containing drug could be used as first-line therapy, particularly in patients with a history of larger stones or more urologic interventions. (See 'Urinary cystine excretion' above.)

Thiol-containing agents are always used in conjunction with fluid and alkali therapy (not as sole therapy). In addition, the ability of thiol drugs to quickly solubilize cystine may be greater in alkaline as compared with acidic urine, highlighting the need for combination therapy [46].

Data from uncontrolled trials and observational studies suggest that tiopronin and D-penicillamine are similarly efficacious in reducing cystine excretion and stone recurrences (up to 70 to 75 percent of patients) [30,47-50]. The following studies illustrate the range of findings:

In a study of 31 patients with cystinuria who were treated with tiopronin (median daily dose 1500 mg) and followed for a median of 8.8 years, the rate of stone formation during treatment was reduced by 60 percent compared with the pretreatment period [48].

In a retrospective cohort study of 11 children with cystinuria who received D-penicillamine and were followed for a mean of approximately nine years, all patients experienced an improvement in urinary cystine concentration (mean reduction of 54 percent); two patients experienced significant adverse effects, and none had stones or acute stone crises while adherent with treatment [49].

Dosing — Dosing of tiopronin and D-penicillamine are as follows:

Tiopronin – For adults, initial dosing is 600 to 800 mg in three divided doses. For children, initial dosing is 15 mg/kg per day in three divided doses. The daily dose should be adjusted to reduce the unbound urine cystine concentration to below 250 mg/L (1 mmol/L). The package insert does not define an upper limit of dose; however, doses higher than 1 g/day have not been associated with further reductions in urine cystine capacity [51]

D-penicillamine – For adults, the typical dose range is 0.5 to 2 g/day, given in three to four divided doses. For children, the typical dose range is 20 to 40 mg/kg per day (maximum 1.2 g/day) in three to four divided doses. The daily dose should be adjusted to reduce the unbound urine cystine concentration to below 250 mg/L (1 mmol/L).

If D-penicillamine is to be used long term, pyridoxine supplementation (50 mg/day) is required since D-penicillamine may cause pyridoxine (vitamin B6) deficiency [52]. (See "Overview of water-soluble vitamins", section on 'Vitamin B6 (pyridoxine)'.)

Adverse effects and drug monitoring — Both tiopronin and D-penicillamine have been associated with severe adverse effects [44]. Some, but not all, studies suggest that the incidence of side effects is lower with tiopronin [11,34,44,53-55]. In our experience, patients who have been unable to tolerate D-penicillamine may be able to take tiopronin.

Adverse effects of thiol-containing drugs include fever, rash, abnormal taste, arthritis, leukopenia, aplastic anemia, hepatotoxicity, and pyridoxine (vitamin B6) deficiency. In addition, patients may develop proteinuria (usually due to membranous nephropathy) [56-58], typically within the first 6 to 12 months of therapy, or less commonly, crescentic glomerulonephritis [59] or minimal change disease [60]. Remission of proteinuria typically follows months after discontinuation of the drugs. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Drugs' and "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis", section on 'Pauci-immune necrotizing and crescentic GN'.)

Optimal monitoring strategies for adverse effects are not well defined. Complete blood count, liver function tests, and spot urine protein-to-creatinine ratio should be monitored once within three months of initiating therapy, then every six months for one to two years, and at least yearly thereafter.

Monitoring the response to therapy — The response to therapy is monitored both biochemically and radiologically. The effectiveness of medical therapy is typically determined on the basis of new stone formation or existing stone growth.

Biochemical monitoring — The response and adherence to therapy should be monitored by obtaining a 24-hour urine collection to assess the urine volume and to measure cystine, urine pH, creatinine, sodium, and calcium. Optimally, the supersaturation of cystine, as well as calcium phosphate and calcium oxalate, should be measured in order to determine the risk of stone formation. We initially monitor every three to six months until the patient is stable on therapy, then approximately every six months. Monitoring can probably be decreased to yearly if there has been no evidence of stone formation for several years on a constant regimen.

Patients treated for cystinuria may occasionally continue to form stones despite a supersaturation of cystine that is below 1 in a 24-hour urine specimen [61]. Diurnal variation in cystine excretion and urine flow may explain the nephrolithiasis in such cases. Measuring daytime and nighttime cystine excretion separately may be helpful to evaluate for transient nighttime supersaturation, which may occur despite apparently effective solubilizing therapy [62].

In addition to collecting 24-hour urine specimens, urine microscopy should be regularly examined for cystine crystals, which would indicate that supersaturation is present (picture 2).

If thiol-containing drugs are used, it is useful to estimate the amount of cystine that is probably present as a soluble mixed disulfide (drug-bound cysteine complex) and how much is present as unbound cystine. However, measurement of urinary cystine is usually imprecise in the presence of thiol drugs. Colorimetric assays are unable to distinguish cystine from the thiol drug-bound cysteine complexes; thus, the amount of cystine reported is greater than the unbound cystine that is available for stone formation. To address this problem and improve monitoring of therapy, an assay to quantify urinary cystine levels in the presence or absence of thiol-containing drugs has been developed [30,37,63]. Known as the cystine capacity assay, it can also directly assess the level of cystine supersaturation and can be used to assess changes in urinary cystine and cystine supersaturation in response to dietary modifications and therapy with thiol-containing drugs. This assay is commercially available (www.litholink.com). An alternative cystine assay that can differentiate between cystine and drug-cysteine complexes is high-performance liquid chromatography, which is less available as a commercial test.

Radiologic monitoring — Patients with cystinuria should undergo periodic imaging to detect new stone formation or growth of existing stones. The ideal monitoring strategy is unknown. In asymptomatic patients, we obtain a kidney ultrasound every three to six months. Kidney ultrasound may serve as a useful radiation-free screening test but is less sensitive for detection of smaller stones.

Noncontrast computed tomography (CT) should be reserved for symptomatic patients with a suspected ureteral stone missed on ultrasound or to better assess stone burden and size prior to surgical therapy. In some cases, abdominal radiography of the kidneys, ureter, and bladder (KUB) may be useful to follow previously present radiopaque stones.

A more detailed discussion on imaging modalities used for the diagnosis and monitoring of kidney stones is presented separately:

(See "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis", section on 'Diagnostic imaging'.)

(See "Kidney stones in adults: Evaluation of the patient with established stone disease", section on 'Monitoring for new stones'.)

Surgical therapy — Continued stone formation can lead to large stones (including staghorn calculi) and urinary obstruction, which may require urologic intervention [64,65]. The indications for surgery in those with cystine stones are the same as those with non-cystine stones and are discussed elsewhere. (See "Kidney stones in adults: Surgical management of kidney and ureteral stones".)

The uniform crystal structure of cystine stones makes them relatively resistant to fragmentation by SWL [1,64,66]. As a result, SWL or ureteroscopy (URS) is usually reserved for stones smaller than 1.5 cm [65]. Ureteroscopic stone removal may also be used, with fragmentation by holmium laser lithotripsy, especially in stones resistant to SWL therapy [67,68]. Cystine stones are easily fragmented with the holmium laser.

Percutaneous nephrolithotomy (PNL) with ultrasonic or laser lithotripsy is the preferred procedure for larger stones [64,65]. This procedure involves percutaneous insertion of a nephroscope into the renal pelvis. An ultrasonic or laser probe is then used to break up the stone, and fragments are removed as they are formed. Advancements in smaller endoscopes and lithotriptors have made "mini-PNL" possible, which, combined with a trend toward "tubeless" procedures (without postoperative nephrostomy drainage), have decreased the morbidity of the procedure. If PNL is not available, staged URS (ie, performed in separate, planned sessions) is an alternative option for larger stones.

A more detailed discussion on the choice of surgical approach to stone removal and the different surgical options is presented separately:

(See "Kidney stones in adults: Surgical management of kidney and ureteral stones", section on 'Choice of surgical approach'.)

(See "Kidney stones in adults: Surgical management of kidney and ureteral stones", section on 'Surgical options'.)

Management of other stones — Patients with cystinuria can form calcium oxalate or calcium phosphate stones since many of these patients have predisposing metabolic abnormalities, such as hypercalciuria, hyperuricosuria, or hypocitraturia [69]. Thus, the excretion of these solutes should also be measured at the initial evaluation and appropriate therapy should be instituted, if indicated. Recurrent stones of cystinuric patients should be analyzed to determine whether new stone types are being formed, which may contribute to treatment failures. (See "Kidney stones in adults: Evaluation of the patient with established stone disease" and "Kidney stones in adults: Prevention of recurrent kidney stones".)

Investigational approaches — Given the relative difficulty in treating cystine stones and the side effects of accepted therapies, the possible efficacy of alternative agents has been evaluated [54,70]:

Alpha-lipoic acid, a nutritional supplement with antioxidant properties, has been found to be effective in preventing cystine stone formation in an animal model of cystinuria [71] and in a small case series [72]. A phase II clinical trial evaluating the efficacy of this agent in humans is ongoing (ClinicalTrials.gov identifier NCT02910531).

In a small, uncontrolled, short-term study of four patients with cystinuria, the administration of tolvaptan resulted in improved cystine capacity secondary to urine dilution [73].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney stones".)

SUMMARY AND RECOMMENDATIONS

General principles – Cystinuria is a rare genetic cause of kidney stones that is caused by inactivating mutations in either SLC3A1 or SLC7A9. Cystine stones are found in 1 to 2 percent of all stone formers and approximately 5 percent of children who form stones. Cystinuria is not the same as cystinosis. (See 'Epidemiology' above and 'Pathogenesis, genetics, and classification' above.)

Clinical features – Patients with cystinuria present with nephrolithiasis. Although the median age at presentation is 12 years, stone disease may occasionally present in infancy or late adulthood. As with other types of stones, cystine stones can be visualized with noncontrast computed tomography (CT) as well as ultrasound. Although cystine stones are usually discrete, cystinuria should also be suspected in patients with large, branched (staghorn) calculi. (See 'Clinical features' above.)

Diagnosis – The diagnosis of cystinuria should be suspected in any patient with kidney stone disease, particularly those with early-onset kidney stones (in childhood), large (eg, staghorn) or recurrent kidney stones, a family history of kidney stones, or consanguinity of parents. The diagnosis of cystinuria is established by one or more of the following findings (see 'Establishing the diagnosis' above):

Stone analysis revealing 100 percent cystine calculi

Presence of pathognomonic hexagonal cystine crystals visualized on urine microscopy (picture 2)

Genetic testing confirming two defects in some combination of the SLC7A9 and SLC3A1 genes

All patients with confirmed cystinuria should have quantitative testing of urinary cystine excretion in a 24-hour urine collection, which is important in determining optimal daily fluid intake goals. Genetic testing is not routinely performed. (See 'Urinary cystine excretion' above and 'Genetic testing' above.)

Treatment – The aim of medical therapy is to maintain the cystine concentration in the urine below its solubility level (conservatively estimated as approximately 250 mg/L, provided the urine pH is 7 or higher). (See 'Goals of therapy' above.)

In all patients with cystinuria, we suggest initial therapy with conservative measures rather than thiol-containing drugs (Grade 2C). These measures include increased fluid intake, modest reductions in sodium and animal protein intake, and urinary alkalinization and are standard practice, although randomized trials are lacking. (See 'Initial therapy with conservative measures' above.)

For patients with cystinuria who do not adequately respond to, or are likely to be resistant to, conservative measures, we suggest adding tiopronin rather than D-penicillamine (Grade 2C). However, if tiopronin is not available, D-penicillamine is an alternative option. (See 'Indications' above and 'Dosing' above.)

The response to therapy is monitored both biochemically and radiologically. The effectiveness of medical therapy is typically determined on the basis of new stone formation or existing stone growth. (See 'Biochemical monitoring' above and 'Radiologic monitoring' above.)

The indications for stone removal surgery in those with cystine stones are the same as those with non-cystine stones. In general, cystine stones are preferentially treated with percutaneous nephrolithotomy (PNL) or ureteroscopy (URS) with laser lithotripsy. (See "Kidney stones in adults: Surgical management of kidney and ureteral stones", section on 'Indications and contraindications'.)

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References