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Medical Evaluation and Treatment

of Urolithiasis

Julie A. Nicoletta, MDT

, Marc B. Lande, MDDivision of Pediatric Nephrology, Department of Pediatrics, University of Rochester Medical Center,

601 Elmwood Avenue, Rochester, NY 14624, USA

Nephrolithiasis is responsible for 1 in 1000 to 1 in 7600 pediatric hospital

admissions annually throughout the United States [13], an incidence one-fiftieth

that of adult admissions [46]. The prevalence varies by region but is most

common in the southeastern region of the country. In the pediatric population,boys show a mild preponderance for stone disease, with a male-to-female ratio of

1.4:1 to 2.1:1 [710]. Nephrolithiasis is most often found in white children, with

African American and Asian children only rarely affected [11,12].

Seventy-five percent of children who have nephrolithiasis have an identifiable

predisposition to stone formation [1316]. Metabolic risk factors account for

more than 50% of cases [13,1618], structural urinary tract abnormalities account

for 32%, and infection accounts for 4% [18]. It is not uncommon to find more

than one predisposing factor in the evaluation of a child who has nephrolithia-

sis [13].

Clinical presentation

Adults who have nephrolithiasis typically present with debilitating flank pain

and hematuria. This classic clinical presentation is less common in the pediatric

0031-3955/06/$ see front matterD 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.pcl.2006.03.001 pediatric.theclinics.com

Dr. Lande is supported, in part, by NIH grant 5 K23 HL080068-02.

T Corresponding author.

E-mail address: [email protected] (J.A. Nicoletta).

Pediatr Clin N Am 53 (2006) 479491
http://dx.doi.org/10.1016/j.pcl.2006.03.001http://pediatric.theclinics.com/mailto:[email protected]:[email protected]://pediatric.theclinics.com/http://dx.doi.org/10.1016/j.pcl.2006.03.001http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-

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population. Age is a factor in the pattern of presentation. Ninety-four percent of

adolescents present with flank pain compared with only 56% of children aged

0 to 5 years [13]. Hematuria (gross or microscopic) is found in 33% to 90% ofchildren in all age groups who present with nephrolithiasis [11]. Urinary tract

infection is a frequent presentation in preschool-ageddren [13]. Infants may

present with symptoms similar to colic.

In North American children, most stones are found in the kidneys [7,13,19],

with bladder stones occurring in less than 10% of the cases. By contrast, bladder

stones are endemic in other parts of the world [10,20]. Such endemic stones seem

to be related to diet [20,21], whereas bladder stones in North American children

are most often related to urologic abnormalities [22].

Causes of nephrolithiasis

Hypercalciuria

Hypercalciuria, defined as a urinary calcium excretion of more than 4 mg/kg/d

[22], is found in as many as 4% of healthy children [23,24]. These children are

predisposed to not only nephrolithiasis but also hematuria, dysuria, urgency, andpossibly to recurrent urinary tract infections [2527]. Hypercalciuria represents

30% to 50% of the metabolic risk factors identified in children who have

nephrolithiasis [22]. Most of the cases of hypercalciuria are idiopathic, either

sporadic or familial [22]. Often hypercalciuria is discovered in the investigation

of microscopic hematuria before the development of any stone formation. The

likelihood of such a child subsequently developing renal calculi is estimated to be

between 4% and 17% [2629]. Although the pathophysiology of idiopathic

hypercalciuria is unclear, a recent study showed that some patients with

idiopathic hypercalciuria have an increased number of vitamin D receptorscompared with controls [30]. An increased response to vitamin D could lead to

increased intestinal calcium absorption, bone reabsorption, and decreased tubular

calcium reabsorption.

An unusual cause of hypercalciuria is Dents disease, which is caused by an

X-linked mutation in the renal-specific chloride channel gene (CLCN5), located

on chromosome Xp11.22 [31]. To date, 19 different mutations have been

identified [32]. Presenting symptoms in male subjects include nephrocalcinosis,

hypercalciuria, and nephrolithiasis [33]. The factor that contributes most to stone

formation in these patients is the hypercalciuria [22]. During periods of nor-mal renal function, the excretion rates of oxalate and urine citrate are normal [33].

Patients often demonstrate renal tubular dysfunction, which is manifested by low

molecular weight proteinuria and impaired phosphorous absorption [33].

Aminoaciduria, glucosuria, and decreased renal concentrating capacity may be

present [33]. With time, renal insufficiency and, ultimately, renal failure and

rickets may develop [33]. Serum phosphorus levels are typically normal or low.

nicoletta & lande480
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Secondarily, the levels of 1,25-dihydroxyvitamin D are often elevated, whereas

concentrations of parathyroid hormone are frequently below normal [33]. Carrier

females may have asymptomatic low molecular weight proteinuria [34] but alsooccasionally develop nephrolithiasis and renal impairment [35].

Other causes of hypercalciuria include distal renal tubular acidosis, medullary

sponge kidney, and the use of medications such as adrenocorticotropic hormone

(ACTH), loop diuretics, theophylline, and corticosteroids [11,12,18].

Most children who have hypercalciuria are normocalcemic [11]. If hyper-

calcemia is identified, causes include primary hyperparathyroidism, immobiliza-

tion, hypo- or hyperthyroidism, adrenocorticosteroid excess (endogenous or

exogenous), adrenal insufficiency, osteolytic metastases, idiopathic hypercalce-

mia of infancy, sarcoidosis, hypervitaminosis D, milk alkali syndrome, Williamssyndrome, and, rarely, mutations of the calcium-sensing receptor [11,12,18,22].

Hyperoxaluria

Hyperoxaluria is found in up to 20% of children who have nephrolithiasis

[13,36,37]. Oxalate is present in many common food groups. Endogenous oxalate

also is produced in the metabolism of ascorbic acid, glycine, purines, and other

amino acids [12]. Urinary oxalate is prone to precipitation secondary to its lowsolubility (pKa b1.2) [38]. Enteric hyperoxaluria may result from a diet rich in

oxalate and is seen in children with malabsorption [12]. Foods high in oxalate

include beet and turnip greens, rhubarb, strawberries, star fruit, sweet potatoes,

wheat bran, tea, cocoa, pepper, chocolate, parsley, beets, spinach, dill, nuts, and

citrus juices [12,22,39]. Excess vitamin C is metabolized to oxalate and can lead

to hyperoxaluria [12]. Mild idiopathic hyperoxaluria is commonly identified

concurrently with idiopathic hypercalciuria [37,40].

In children who have malabsorption, undigested fatty acids complex with

calcium that would otherwise bind with oxalate in the intestines. The increasedlevel of unbound oxalate leads to higher absorption of enteric oxalate [12]. In

patients who have malabsorption, the presence of increased luminal bile salts

damages the colonic epithelium, which also leads to increased oxalate absorption

[12,22].

Primary hyperoxaluria is a rare autosomal-recessive disorder caused by defects

in hepatic enzymes that result in the marked overproduction of oxalate. Type I

primary hyperoxaluria is caused by a deficiency of the hepatic enzyme

alanine:glyoxylate aminotransferase (AGT), whose gene is located on chromo-

some band 2q37.3 [41]. With this disorder, there is an increased production ofglyoxylate and oxalate along with a variable increased production of glycolate

[18,22]. Type II primary hyperoxaluria is caused by a defect in the enzyme

glyoxylate reductase/hydroxypruvate reductase, whose gene is located on

chromosome 9 [42]. An abnormality of this enzyme leads to hyperoxaluria and

hyperglyceric aciduria [22]. Children who have primary hyperoxaluria typically

excrete large amounts of oxalate (mean urinary oxalate excretion, 2.2 mmol/

medical evaluation & treatment of urolithiasis 481
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1.73m2/24 h and 1.61 mmol/1.73m2/24 h, in type I and II disease, respectively)

[43]. With type I and type II disease, most patients present with urolithiasis or

nephrocalcinosis during infancy or childhood. Aggressive stone formation iscommon to both forms of the disease, but usually type I disease presents with a

more severe clinical picture than that of type II [43]. Renal failure may develop

from the time of infancy to the fifth decade of life as a result of the toxic effects

of oxalate on the renal tubules, nephrocalcinosis, and repeated episodes of

nephrolithiasis [22,44,45]. Systemic deposition of calcium oxalate crystals in

other organs also can lead to significant debilitating morbidity.

Hyperuricosuria

Hyperuricosuria has been documented in 2% to 10% of children and

adolescents found to have a metabolic predisposition to kidney stone formation

[22]. Uric acid is a weak acid that exists in its relatively insoluble non-ionized

form below the pH of 5.5 [12]. Its propensity to stone formation increases sig-

nificantly in acidic urine.

Idiopathic uric acid nephrolithiasis seems to be inherited in an autosomal-

dominant pattern, with the onset as early as the second decade of life [46]. It usu-

ally affects individuals of Italian or Jewish descent and causes severe, recurrenturolithiasis. Urine pH and ammonia excretion rates are disproportionately low

in these patients [47]. With less ammonia, other urinary buffers are titrated

more fully, which results in a lower urine pH [12]. Many children (12%40%)

who have idiopathic hyperuricosuria have coexistent hypercalciuria [11].

Uric acid overproduction may result from an inborn error of purine me-

tabolism. Phosphoribosyl pyrophosphate accumulates in partial or complete

hypoxanthine-guanine phosphoribosyltransferase deficiency. The accumulation

of phosphoribosyl pyrophosphate leads to the overproduction and overexcretion

of uric acid [18]. Patients who have partial hypoxanthine-guanine phospho-ribosyltransferase deficiency often present as early as the second decade of life

with uric acid nephrolithiasis, and some also may have gouty arthritis [48].

Complete deficiency of hypoxanthine-guanine phosphoribosyltransferase, or

Lesch-Nyhan syndrome, presents with mental retardation, spasticity, choreo-

athetosis, and self-mutilatory behavior along with hyperuricemia and hyper-

uricosuria [18,49]. Urolithiasis may present as early as the first year of life in

patients with Lesch-Nyhan syndrome. Glucose-6-phosphatase deficiency (type I

glycogen storage disease) also may present with hyperuricemia and is associated

with elevated intracellular levels of phosphoribosyl pyrophosphate [18].Other disease states can lead to an increase in uric acid nephrolithiasis.

Patients with bowel disease have a predisposition to urate stones, with the

average presentation of stones 7 years after the initial diagnosis of bowel disease

[50]. The frequency increases further if there is a history of colon surgery;

this association is thought to be secondary to a lower urine output and lower

urinary pH [50]. Patients who have kidney stones who suffer from type 2

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diabetes mellitus have a higher prevalence of uric acid nephrolithiasis compared

with the general population [51], which is thought to be secondary to insulin

resistance that results in decreased renal ammonia excretion and impaired hy-drogen ion buffering and excessively acidic urine [52]. A recent study concluded

that urinary pH is inversely related to body weight among patients with stones

[52]. This issue may become more problematic in the pediatric population in light

of the recent obesity epidemic.

Cystinuria

Cystine stones account for less than 1% of nephrolithiasis in the adultpopulation [12] but approximately 6% in the pediatric population [18]. Cystine is

a dimer of the amino acid cysteine and has marked insolubility [12]. Cystinuria,

a disorder of renal tubular transport, is an autosomal-recessive condition that

has been identified in 2% to 7% of children with metabolic stones [13,18]. Its

prevalence varies throughout different global locations but is approximately 1 in

7000 in the general population of Europe and the United States [53,54]. Muta-

tions of either the SLC3A1 gene on chromosome arm 2p encoding the rBAT

protein or of the SLC7A9 gene of chromosome 19 have been identified [5557].

Homozygous, compound heterozygous, and obligate heterozygous subtypes havebeen described, with homozygotes excreting the greatest amount of cystine

[58,59].

Affected individuals demonstrate increased excretion of four dibasic amino

acids: cystine, ornithine, arginine, and lysine. By 1 year of age, a homozygous

patients urinary excretion of cystine is usually more than 1000 mmol/g creati-

nine with a mean excretion rate of 4500 mmol/g creatinine [58]. At usual urine

volumes, this excretion rate exceeds its solubility [22]. Heterozygote carriers also

may form stones because they have been shown to excrete up to 2400 mmol/g

creatinine [22]. Lifelong recurrent stone formation is a characteristic of patientswith the homozygous forms of cystinuria [22].

Infection

Functional or anatomic obstruction of the urinary tract predisposes children to

urolithiasis by promoting stasis of urine and infection. Because most patients

with urologic anomalies do not develop calculi, however [18], a full metabolic

evaluation should be performed on any child who has nephrolithiasis, regardlessof the presence of any developmental anomaly of the urinary tract.

Children with a history of multiple urinary tract infections may be at risk of

nephrolithiasis, especially if the organisms contain the enzyme urease, which

results in a high urine pH that promotes the supersaturation of urine with struvite

and calcium phosphate apatites. Patients with surgically augmented bladders are

at risk of developing bladder stones, most commonly struvite stones. Patients


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who have augmentations with intestinal segments are at higher risk as opposed to

patients who have bladders augmented with gastric mucosa [11].

Diagnosis

Initial evaluation

The initial evaluation of any child who has nephrolithiasis should begin with a

detailed history. A careful family history should be obtained that specifically asks

if other family members have been known to have nephrolithiasis, arthritis, gout,

or renal disease. When evaluating first-degree relatives of patients who havehypercalciuria and urolithiasis, more than 40% have urolithiasis [32]. A detailed

dietary history is also important, with attention to protein, sodium, calcium, and

oxalate intake.

Metabolic evaluation

Serum levels of uric acid, electrolytes, creatinine, calcium, phosphorus, and

bicarbonate should be measured. Serum parathyroid hormone level should be ob-

tained in children who have hypercalciuria, hypercalcemia, or hypophosphatemia.Elevated serum alkaline phosphatase may indicate possible bone reabsorption.

Twenty-four hour urine collection for sodium, calcium, urate, oxalate, citrate,

creatinine, and cystine should be evaluated. Ideally, the urine collection should be

obtained at least 6 weeks after the passage of a stone. Collecting two 24-hour

samples is recommended. Determination of urinary supersaturation for calcium

oxalate, calcium phosphate, and urate may be helpful, but a recent study con-

cluded that in children, these studies do not offer much additional information

than consideration of 24-hour urine volume. Most children with elevated super-

saturation values had urine volumes b 1 mL/kg/h [17]. The urinary creatinineexcretion rate may be used to verify an adequate urine collection, with most

children excreting 15 to 20 mg/kg/24 h [18]. If the creatinine excretion is

significantly more or less, it may indicate either an over- or undercollection.

Table 1 documents abnormal values for 24-hour urine collections [22].

If a 24-hour collection is difficult, especially in younger children, urinary

standards based on single specimens, corrected to urine creatinine concentration,

have been developed and are listed in Table 1 [22]. The calcium-to-creatinine

ratio decreases with age. If possible, hypercalciuria suspected on a single ran-

dom sample should be confirmed with 24-hour urine collection. Uric acid ex-cretion is highest in infancy and slowly declines throughout childhood until

adolescence, when the excretion is comparable to that of adults [11].

A urine culture should be considered to exclude the possibility of acute or

chronic urinary tract infection. Urinalysis may be helpful, particularly if crystals

are noted. Cystine crystals are colorless, flat, and hexagonal, and if they are found

in the urine, they are diagnostic for cystinuria. These crystals are identified in less

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Table1

Urinechemistry:normalvalues

Urineconstituent

Age

Random

Timed

Comments

Calcium(52,230)

06mo

b0

.8mg/mgcreat

b

4mg/kg/24h

Prandialvariation

712mo

b0

.6mg/mgcreat

Sodiumdependen

t

2y

b0

.21mg/mgcreat

Oxalatea(204,231)

b

1y

0.1

50.26mmol/mmolcreat

2yr;b

0.5mmol/1.73m

2/24h

Randomurinemmol/mmol

highlyagedependent

1yrb

5y

0.1

10.12mmol/mmolcreat

Excretionrate/1.7

3m

2

constantthrough

childhood

andadulthood

512y

0.0

060.15mmol/mmolcreat

N

12y

0.0

020.083mmol/mmolcreat

Uricacid(201,205)

Terminfant

3.3

mg/dLGFRb

b

815mg/1.73m

2/24h

Excretionrate/1.7

3m

2

fromN

1yageconstant

throughchildhood

N

3y

b0

.53mg/dLGFR

Magnesium(13,230)

N

2y

b0

.12mg/mgcreat

b88mg/1.73m

2/24h

Excretionrate/1.7

3m

2

constantthrough

childhood

Citrate(232)

N1

80mg/gcreat(232)

Limiteddataavailablefor

children

N4

00mg/gcreat(13)

Cystine(13,30)

b7

5mg/gcreat

b

60mg/1.73m

2/24h

CystineN

250mg

/gcreat

suggestshomozygous

cystinuria

Abbreviations:creat,creatinine;GFR,glomerularfiltrationrate.

a

Oxalateoxidasea

ssay.

b

(mg/dLuricacid)(serumcreatinineconcentration/urinecreatinineconcentration).

From

MillinerDS.Uro

lithiasis.In:Pediatricnephrology.Philadelphia:LippincottWilliam

s&Wilkins;2004.p.1103;with

permission.


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than 30% of homozygous patients [11]. Stone analysis should be performed on

any stone captured.

Imaging

On abdominal flat plate radiographs, struvite and cystine stones are less

radiopaque than calcium stones [22]. Uric acid stones are radiolucent [12].

Ultrasonography reveals many types of stones, including some radiolucent

stones, and may identify possible urinary obstruction or nephrocalcinosis. A non-

enhanced helical CT scan is superior to an intravenous pyelogram (IVP) in the

evaluation of stones. CT has a high sensitivity and specificity (96%98%) and

does not require any contrast [11]. Unlike ultrasound, CT has the ability to imagesmall stones and has a greater potential to identify alternative diagnoses if a stone

is not present [11].

Medical treatment

All causes

Increased fluid intake is the first line of therapy for all stone types. Althoughthis approach is effective in treating patients with any cause of nephrolithiasis,

long-term compliance with an increased fluid regimen is often poor [60]. In-

creasing urine volume to more than 2 L a day in adolescents who have nephro-

lithiasis would be ideal [22]. Patients who are asymptomatic and patients not

associated with impending or ongoing obstruction may be managed conserva-

tively [22]. Most stones that measure less than 5 mm in diameter likely pass

spontaneously, even in young children [61].

Hypercalciuria

The initial treatment of hypercalciuria in a child who has nephrolithiasis

should be increased fluid intake, reduction of dietary sodium, and the reduction of

excessive dietary calcium to that of the recommended daily allowance recom-

mendations. Care should be taken not to restrict calcium intake to less than

these guidelines. Dietary sodium restriction may help to reduce urinary calcium

losses, especially in patients with excessive dietary sodium intake [62]. Excessive

dietary protein intake also should be avoided because research has proposed that

it increases endogenous acid production and leads to metabolic acidosis, whichincreases calcium reabsorption of bone and urinary calcium excretion [63]. If

these measures are not effective alone, a thiazide diuretic may be added [22].

Thiazide diuretics are hypocalciuric and natriuretic. Thiazides not only di-

rectly stimulate distal tubular calcium reabsorption but also increase calcium

reabsorption in the proximal tubule secondary to mild volume contraction [12].

The effects of thiazide diuretics are fully exerted when combined with salt

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restriction and are blocked by excessive dietary sodium [64]. Hypokalemia that

may be precipitated by the use of a thiazide diuretic should be corrected because

it can lead to intracellular acidosis and a decrease in urinary citrate excretion [12].Serum lipid levels should be monitored periodically in patients on thiazide

diuretics, because increases in total serum cholesterol and low-density lipoprotein

cholesterol are adverse effects of these drugs [65]. Amiloride also stimulates

distal tubular calcium reabsorption and can be added to a thiazide diuretic for

additive effects if hypercalciuria persists [12]. Neutral phosphate can be used as

an adjuvant therapy for nephrolithiasis secondary to hypercalciuria [22].

In patients who have calcium oxalate stones, calcium oxalate supersaturation

is most affected by the urinary oxalate concentration [63]. Dietary restriction of

calcium increases the risk of stone formation by increasing the supersaturation ofthis salt, because more oxalate is absorbed by the gastrointestinal tract [63]. In the

hopes of decreasing this absorption of oxalate, dietary and supplemental calcium

have been tried with conflicting results. In two large population studies, dietary

calcium significantly decreased the risk of stone formation in male and female

patients, but supplemental calcium was found to increase significantly the risk of

stone formation in women [66,67]. Other studies examined calcium supplemen-

tationeither for stone disease or osteoporosisand did not find any increase in

the risk of calcium oxalate stone formation [6870]. Eight hundred to 1200 mg of

dietary calcium is recommended per day [71]. If this amount is exceeded, urinarycalcium levels should be monitored because they can increase significantly. If

calcium supplements are used, they should be given with meals to prevent the

absorption of oxalate and calcium. Further studies must be performed before

further recommendations can be made in regard to calcium supplementation in

the treatment of stone formation.

Other causes

Some patients who have idiopathic nephrolithiasis are found to have hypo-citraturia. Urinary citrate acts as a stone inhibitor by forming a soluble complex

with calcium [12]. Citrate supplementation may be given to patients who have

hypocitraturia. Potassium citrate is preferred over sodium citrate to avoid excess

sodium intake, which may exacerbate hypercalciuria. The dose of potassium

citrate should be titrated to maintain urine citrate in the normal range [12].

Children with other metabolic causes of nephrolithiasis should have therapy

directed toward the specific disease process. Examples of available treatments

include pyridoxine, a cofactor of AGT, for treatment of primary hyperoxaluria,

tiopronin, D-penicillamine, and captopril for the treatment of cystinuria, allo-purinol for the treatment of hyperuricosuria, and chronic antibiotic suppressive

therapy for struvite stones. Table 2 lists first- and second-line therapies for dif-

ferent stone types [22].

Other nonspecific therapies are available. Neutral phosphate increases the

urinary pyrophosphate concentration, which acts as an inhibitor of calcium oxa-

late crystal formation [18,44]. Orthophosphate also decreases vitamin D pro-


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duction, complexes calcium in the stool, and stimulates distal tubular calcium

reabsorption [12]. Tolerability may be limited by diarrhea or hyperphosphatemia.Magnesium supplementation has been shown to decrease gastrointestinal oxalate

absorption but was not as effective as calcium supplementation [72] and has been

associated with an increase in urinary magnesium and calcium excretion [73,74].

Prognosis

The recurrence of stone disease occurs in 60% of adults within 9 years of

the initial episode [47]. In the past, only approximately 16 percent in children(range, 3.7%44.4%) were noted to have a recurrence of nephrolithiasis [18]. A

more recent article quoted a recurrence rate of 67% during a mean follow-up

of 59 months [13]. Despite the excellent response to treatment noted in most

children with urolithiasis, long-term nephrologic care is indicated, particularly for

children who have more complex forms of renal stone disease, because renal

insufficiency or end-stage renal disease may develop.

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Table 2

Suggested therapy for urolithiasis caused by metabolic abnormalities

Metabolic abnormality Initial treatment Second-line treatment

Hypercalciuria Reduction of dietary Na+ Potassium citrate

Dietary calcium at RDA Neutral phosphate

Thiazides

Hyperoxaluria Adjustment of dietary oxalate Neutral phosphatea

Potassium citrate Magnesium

Pyridoxinea

Hypocitric aciduria Potassium citrate

Bicarbonate

Hyperuricosuria Alkalinization Allopurinol

Cystinuria Alkalinization Tiopronin (Thiola)

Reduction of dietary Na+ d-penicillamine

Captopril

Abbreviation: RDA, recomemnded daily allowance.a Initial therapy in primary hyperoxaluria.

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