CYSTINURIABy

DR Jameel Tariq Miro

Cystinuria is an autosomal recessive defect in reabsorptive transport of cystine and the dibasic amino acids ornithine, arginine, and lysine from

the luminal fluid of the renal proximal tubule and small intestine.

PathophysiologyRenal transport of cystine • Amino acids filtered undergo nearly complete reabsorption

by proximal tubular cells. • Only 0.4% of the filtered cystine appears in the urine. • . At least 2 transport systems are responsible for cystine

reabsorption, as follows: - High-affinity system:

This system is affected in persons with cystinuria. Mediates uptake of 10% of L-cystine and the dibasic amino acids at the third segment (S3) of the proximal

tubule. - Low-affinity system: This system is present in the S1-S2 part of the proximal tubule and is responsible for 90% of L-cystine reabsorption. .

Intestinal transport of cystine• The high-affinity transporter is present in the

apical brush-border membrane of the jejunum and is responsible for absorption of cystine and dibasic amino acids.

• Most patients with cystinuria have impaired absorption of cystine; however, cystine deficiency is not clinically significant .

Normally, cystine and the other dibasic amino acids (ie, ornithine, lysine, arginine) are filtered at the glomerulus and reabsorbed in the proximal convoluted tubule

. Defects in this channel cause elevated levels of dibasic amino acid secretion in the urine.

Whereas ornithine, lysine, and arginine are completely soluble, cystine is relatively insoluble at physiologic urine pH levels of 5-7

. At a urine pH level of 7.8 and 8, the respective solubility of cystine is nearly doubled and tripled

The solubility of cystine is pH-dependent -Approximately 250 mg/L (1 mmol/L) up to a pH 7, -Increases up to 500 mg/L (2 mmol/L) or more above a

pH 7.5 - Varies depending on the particular type of electrolyte

present - Highest is accomplished in the presence of calcium

chloride, followed by magnesium and sodium chloride. -Also affected by urinary macromolecules. The presence

of colloid in normal urine has been shown to increase cystine solubility; however, the mechanism of this action is not clear.

.

Risk factors for cystine crystallization include (1) low pH level (2) reduced ion strength, (3) the presence of cystine crystals, and (4) low levels of urinary macromolecules.Two thirds of persons with cystinuria who form stones

make pure cystine calculi, One third have a mixture of cystine and calcium oxalate

calculi. Hypocitraturia, hypercalciuria, and hyperuricosuria are

also frequently associated with cystinuria. Pure cystine calculi are among the hardest on Dretler's

stone fragility index.

Rosenberg Classification of Cystinuria

Type IType IIType III

Responsible geneSLC3A1SLC7A9

Population affectedMediterranean Spanish persons, 40%

Libyan Jews

Localization in proximal converted tubule

S3 S1 & S2

Clinical features

HomozygotesSymptomaticapproximately 90% symptomatic

HeterozygotesAsymptomaticapproximately 10-13% symptomatic

Urinary cystine levelsNormalElevated++ +++

Elevated+

Plasma cystine levels after an oral load test

SameSame or slight rise

increased

Intestinal transportAbsent (no transport of cystine, lysine, or arginine

AbsentReduced

In healthy individuals, the upper limit for cystine excretion is 20 mg/g of creatinine (<10 µmol/mmol of creatinine).

Homozygotes excrete more than 400 mg/d (1.7 mmol/d), and cystine excretion in homozygous patients is usually 600-1400 mg/d (2.5-5.8 mmol/d).

Heterozygotes with type I and III cystinuria excrete less than 200 mg/d (0.8 mmol/d) and do not form stones. Type II heterozygotes excrete up to 200-400 mg/d, but these patients may form stones. The incidence of stone formation increases when urinary cystine concentration exceeds 700 µmol/L (170 mg/L).

FrequencyUnited StatesCystine accounts for 1% of adult and 6-8% of pediatric urinary calculi. The prevalence of heterozygosity is approximately 1 case per 20-200 persons. Homozygous cystinuria affects 1 person per 15,000 population.InternationalWorldwide, the overall prevalence is 1 person per 7000 population. 1 case in 1900 in Spain, to 1 case in 100,000 in Sweden. RaceCystinuria is more common in white persons. SexIncidence is equal between the sexes, but men are more severely affected.AgeThe peak age of first renal calculus is 22 years, up to 22% develop calculi in childhood.

presentationPresentation is similar to that of other types of renal calculi and

includes renal colic, chronic urinary tract infections in a young person with a family history of kidney stones, passage of stones or gravel, hematuria, and dysuria.

Uncommon presentations include chronic backache, and urinary tract infection.

25% of symptomatic patients report their first stone in the first decade of life, and another 30-40% have their first experience as teenagers.

20-40% of the stones in persons with cystinuria are mixedHomozygous cystinuria is characterized by lifelong, recurrent

urolithiasis that is difficult to manage, either surgically or medically. . Seventy-five percent of these patients present with bilateral calculi. Recurrence rates after surgical intervention approach 45% at 3

months without medical management. The recurrence rate with medical management improves to approximately 25% at 3 years after surgery

Lab Studies

1-Urinalysis Cystine is one of the sulfur-containing amino acids; therefore, the urine may

have the characteristic odor of rotten eggs. may show typical hexagonal or benzene crystals, which are essentially

pathognomonic of cystinuria. Microscopic crystalluria is present in 26-83% of patients. Disappearance of cystine crystals in the first morning urine is a good

index of treatment efficacy. . Measurement of urine cystine capacity: a measure of the ability of urine

either to take up additional cystine from a preformed solid phase or to give it up to the solid phase . Cystine capacity can be used to monitor the response to the drug therapy and can help the clinician to prescribe minimal effective dose

Cystine crystal volume from microscopic analysis of early-morning urine to predict stone recurrence.

2-Sodium cyanide–nitroprusside test a rapid, simple, and qualitative determination of cystine

concentrations. Cyanide converts cystine to cysteine. Nitroprusside then binds,

causing a purple hue in 2-10 minutes. The test detects cystine levels of higher than 75 mg/g of

creatinine. False-positive test results occur in some individuals with

homocystinuria or acetonuria and in people taking sulfa drugs, ampicillin, or N-acetylcysteine..

For individuals with positive cyanide-nitroprusside test findings, perform ion-exchange chromatographic quantitative analysis of a 24-hour collected urine sample.

• The normal excretion rate is 40-80 mg/d (0.166-0.333 mmol/d). • Heterozygotes excrete 200-400 mg/d (0.8-1.7 mmol/d). • Homozygotes always excrete 600-1400 mg/d (2.5-5.8 mmol/d).

3- Twenty-four–hour urine collection for other metabolic abnormalities Results indicate the presence of hypercalciuria, hypocitraturia, and

hyperuricosuria. Results may help define a subgroup of patients at risk for failure of

medical therapy due to the formation of noncystine or mixed calculi.

4- Routine monitoring of renal function: Patients can self-monitor urine pH with Nitrazine paper.

5- Proton nuclear magnetic resonance spectroscopy of urine very powerful technique that allows multicomponent analysis

useful in both diagnosis and follow-up. the relevant amino acids can be detected in the urine of patients

with cystinuria. The most abundant amino acid in these patients is lysine (>5 mmol), whose typical signals become very high. Cystine, arginine, and ornithine are usually detectable, although pathologic concentrations are lower (<2 mmol).

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Imaging Studies

Plain radiographsCystine stones have a homogeneous or ground-glass appearance on

radiographs . Although radiopaque, they are often less dense than calcium-containing stones.

Intravenous pyelogramsare essential for defining calyceal anatomy prior to extracorporeal

shockwave lithotripsy (ESWL).

Helical CT scan without intravenous contrast Helical CT scans are ideal for patients with contrast allergy or renal

insufficiency. Renal ultrasonography

This study is more economical than CT scan for monitoring the growth of renal calculi

The lack of radiation exposure makes this test ideal for children and patients with frequent recurrences, who would otherwise accumulate relatively large radiation doses over a lifetime.

Management

• Management algorithm – for a patient with cystinuria who does not have a stone,

first-line therapy in most cases is a conservative approach, -large-volume fluid intake (urine output >2.5 L/d),

-urine pH monitoring (urine pH level of 7.5 and <8), - -dietary restrictions, and urinary alkalization with

potassium citrate. – If this standard therapy fails to achieve the urinary cystine

concentration of 300 mg/L, then medical therapy with D-penicillamine, alpha-MPG, or captopril must be added.

– Treat patients with stone disease according to the location of the stone. The expertise of a urologist and a radiologist is important for decision-making processes, and stone site and size also influence further management

MedicalHydration the oldest and most effective cystine stone–prevention

techniques is hyperdiuresis to decrease urinary cystine concentration.

that hydration alone could prevent stone recurrence in up to a third of patients.

The goals of hydration therapy are urine volumes in excess of 3 L/d. This goal may require ingesting 4-4.5 L of water per day. Patients should drink 240 mL of water every hour during the day and 480 mL before retiring and at least once during the night.

Patients should monitor the specific gravity of their urine using Nitrazine dipsticks, with a goal of achieving a value less than 1.010.

Alkalinization

– Alkaline urine can prevent the precipitation of cystine calculi and can even aid in dissolution. Urine pH level must be more than 7.5 for stone dissolution to occur.

– Paradoxically, a urine pH level of more than 7.5 can cause a predisposition to the formation of calcium phosphate calculi, so urine must be monitored with dipsticks to maintain a pH level of 7-7.5 for stone prevention.

– Sodium bicarbonate was used in the past but is no longer recommended as a first-line agent. The sodium ion may actually increase the amount of cystine excreted.

– Potassium citrate is the first-line alkalinizing drug. – With any alkalinization therapy, monitoring of urinary pH

is essential.

Chelating agents Cystine-binding and cystine-reducing agents share the

ability to dissociate the cystine molecule into disulfide moieties with much higher solubilities than the parent molecule.

These drugs are thiol derivatives. The treatment goal is excretion of less than 200 mg/d of

urinary cystine, and this must be monitored yearly. Start these agents when hydration, dietary, and

alkalinization therapies fail. Cystine-binding agents can dissolve cystine calculi, but

usually takes many months to years. They are best suited for stone prevention after surgical

debulking of the stone burden, and they possibly help soften cystine stones in preparation for ESWL.

Penicillamine Penicillamine is a first-generation chelating agent that

combines with cystine to form a soluble disulfide complex (50 times more soluble than cystine), thus preventing stone formation and possibly even dissolving existing cystine stones.

The effect of the drug is dose-dependent. Adverse reactions (pproximately 50%); therefore, routine use is limited. include rash, arthralgia, leukopenia, gastrointestinal

intolerance, and nephritic syndrome. Long-term therapy may lead to vitamin B-6 (pyridoxine)

deficiency; thus, vitamin B-6 supplementation (50 mg/d) is needed.

Alpha-mercaptopropionylglycine This second-generation chelating agent Alpha-MPG has a 30% higher dissolution capacity for

cystine than penicillamine. The drug is not excreted in the urine, so the cyanide-

nitroprusside test is an effective qualitative screening method for monitoring the control of cystinuria. A positive test result indicates the need for an increased dosage.

The main advantage of thiol is its lower toxicity profile.

Captopril Captopril can be used to treat patients whose

conditions fail to respond to standard treatment and to treat patients with cystinuria who are hypertensive.

Bucillamine a third-generation chelating agent available only in

Japan and South Korea. showed a low toxicity profile; therefore, it is

probably well tolerated by patients with cystinuria.

DietCystine is formed during the metabolism of

methionine; therefore, a diet low in methionine is effective. dietary methionine must be reduced to 1 g/d. (0.8 g protein/kg body weight/d) is recommended.

Dietary restriction of methionine found in animal proteins such as milk, eggs, cheese, and fish may be helpful

Low-sodium dietGlutamine Increase dietary fiber intake

Surgical Care• Indications • large calculi that are unlikely to dissolve • obstructing or otherwise symptomatic calculi. • The ultimate goal of surgery is to make the

patient free of stones. While the risk of recurrence is unchanged, the time to recurrence is significantly lengthened.

Surgical options (1) ESWL, (2) retrograde endoscopic lithotripsy and

extraction, (3) percutaneous nephrolithotomy, (4) multimodal therapy, (5), percutaneous nephrostomy for chemical

dissolution, and (6) open surgery (urethra, bladder, ureter,

kidneys

Extracorporeal shockwave lithotripsy effective for stones smaller than 1.5 cm in diameter, stone-free rates are lower compared with rates for

stones require 2-3 times the usual number of shocks to

adequately fragment the stone. When considering candidates for ESWL, some

authors suggest an upper limit of 1.5 cm for upper ureteral or renal cystine calculi. As reported by Kachel et al in 1991, these authors prefer to limit ESWL to renal calculi smaller than 1 cm in diameter.

Retrograde endoscopic lithotripsy and extraction . suitable for mid-to-distal ureteral cystine calculi

when using high-energy modalities such as holmium:YAG laser or pneumatic shock devices (eg, Lithoclast). Smaller proximal ureteral calculi may also be treated in a retrograde fashion.

Percutaneous nephrolithotomy the criterion standard for cystine renal calculi larger

than 1-1.5 cm in diameter and for calculi for which ESWL or retrograde surgery has failed.

Multimodal therapy For large cystine stone burdens, such as occurs with

full staghorn calculi, multimodal therapy may help achieve better stone-free rates.

So-called sandwich therapy involves initial percutaneous ultrasonic lithotripsy followed by ESWL and then repeat ultrasonic lithotripsy or flexible nephroscopy and laser lithotripsy.

Percutaneous nephrostomy for chemical dissolution was successful in treating a limited number of patients

in the late 1970s and early 1980s. The 2 most commonly used agents were -acetylcysteine (Mucomyst) A solution containing 60 mL

of a 20% solution of N-acetylcysteine and 300 mEq of sodium bicarbonate per liter of saline is recommended.

-tromethamine-E (THAM-E). an organic amine buffer with a pH level of 10.2.

Treatment times range from weeks to months. relatively low success rates, rarely used today.

Open surgery Given the success of percutaneous

nephrolithotomy, ESWL, and endoscopic retrograde approaches, open surgery is not indicated as first-line therapy for cystine calculi anywhere in the kidneys or ureter, with rare exceptions. Large bladder calculi may be amenable to open surgery, but these stones can also be treated with laser or electrohydraulic lithotripsy.

Conclusion

Treatment of the patient with cystinuria requires close cooperation between the urologist and the nephrologist. Maintaining high diuresis of at least 3 L/d, regularly distributed throughout the night and day, even when sulfhydryl compounds are given, appears to be the major factor predictive of therapeutic success. Regular clinical, radiological, and biochemical surveillance appears to be of primary importance to maintain good long-term compliance with medical treatment.

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