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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://-/?-7/28/2019 s0031395506000290_2
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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.
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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/
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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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[3] Nimkin K, Lebowitz RL, Share JC, et al. Urolithiasis in a childrens hospital: 19851990. Urol
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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.
From Milliner DS. Urolithiasis. In: Pediatric nephrology. Philadelphia: Lippincott Williams &
Wilkins; 2004. p. 1104; with permission.
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