++
Urolithiasis is the term used to describe the presence
of a stone or a calculus anywhere in the urinary tract. Nephrolithiasis is
the term generally used when calculi are found in the kidneys; it should
not be confused with nephrocalcinosis, which is
the deposition of calcium in the tubulointerstitial regions of the
kidneys. The prevalence of urolithiasis varies widely, depending
on geographic locations. Although uncommon in some countries, it
remains an important childhood diagnosis because it is often associated
with morbidity and high rates of recurrence. A thorough evaluation
should be done to identify specific metabolic defects or factors
predisposing to stone formation.
++
The true incidence of stones in children is unknown. Many children
probably remain undiagnosed, and no recent epidemiologic studies
have been published in North America. Earlier reports showed nephrolithiasis responsible
for 1:1000 to 1:7600 pediatric hospital admissions in the United
States.1,2 Stones are generally more common in
white than African American and Asian children and in males.3 In
North America, most stones are found in the kidneys. Bladder stones
occur in less than 10% of affected children and are usually related
to urologic abnormalities.
++
The process of stone formation begins with the crystallization
of stone-forming solutes, especially calcium, oxalate, and uric
acid. These aggregate with other crystals and adhere to the renal
tubule cells, with growth of large crystals that can detach and
obstruct the urinary tract.4 The crystallization
and aggregation of solutes depend on urinary solute concentration,
urinary pH and presence of inhibitors in the urine. Increased solute
concentration (resulting from increased urinary excretion or low
urinary volume) and low levels of natural inhibitors of stone formation, which
include citrate, magnesium, and pyrophosphate, predispose to stone
formation.
++
Metabolic or anatomic predisposing factors are identifiable in
the majority of patients. In a study from Argentina, 84.4% of
their 90 patients with kidney stones were found to have a metabolic risk
factor defined as hypercalciuria, hyperoxaluria, hypocitraturia,
hypomagnesuria, or hyperuricosuria. The most common metabolic risk factors
were idiopathic hypercalciuria in 40% (alone or in combination)
and hypocitraturia in 37.8% (alone or in combination).5 In
a study from Canada, 67% of affected patients had identifiable anatomic
or metabolic predisposing factors for stone formation.6 Infection
is often associated with nephrolithiasis and is causative in struvite
calculi.
+++
Types of Urinary
Tract Stones
++
Calcium phosphate and calcium oxalate are the most common stones
and can result from hypercalciuria, hyperoxaluria, hypocitraturia,
in combination, or alone, as discussed later in this section. Hyperuricosuria
may also contribute to formation of calcium stones by providing
a nidus for stone formation, or may form urate stones. Less common
types of stones include struvite stones and cystine stones.
++
Hypercalciuria is found in as many as 4% healthy children3 and
is one of the most common metabolic risk factors identified in children
with renal stones. Causes of hypercalciuria are listed in Table 475-1. Most children with hypercalciuria
are normocalcemic and have idiopathic hypercalciuria. Use of medication
such as corticosteroids and loop diuretics is another relatively
common cause of normocalcemic hypercalciuria.
++
++
The exact cause of idiopathic hypercalciuria is unknown. It appears
to be a complex disorder characterized by altered calcium transport
in the intestine, kidney, and bone, probably due to various combinations
of multiple genetic and dietary factors. Vitamin D receptor (VDR),
soluble adenylate cyclase (sAC), calcium-sensing
receptor (CaSr), and claudin-16 (CLDN16)
genes expressed in the intestine, kidney, and bones may contribute to
calcium excretion and idiopathic hypercalciuria.7 Less
common monogenic defects can also cause hypercalciuria. For example,
Dent disease is a rare cause of normocalcemic hypercalciuria due
to a mutation in the renal specific chloride channel gene (CLCN5)
located on chromosome Xp11.22.8 Mutation of the NKCC2, ROMK,
or CLCNB gene causes Bartter syndrome, which is
characterized by hypercalciuria with or without nephrocalcinosis.
++
Hypercalcemic hypercalciuria is seen in hyperparathyroidism,
immobilization, hypo- and hyperthyroidism, adrenocorticosteroid
excess, adrenal insufficiency, osteolytic metastases, idiopathic
hypercalcemia of infancy, hypervitaminosis D, milk alkali syndrome,
Williams syndrome, and, rarely, mutation of the calcium-sensing
receptor, as discussed in Chapter 542.3
++
Filtered citrate is reabsorbed and metabolized in the proximal
tubule. Citrate binds ionized calcium, decreases its saturation, impairs
agglomeration of calcium oxalate, and impedes the growth of calcium
phosphate crystals.9 Increased proximal tubule
citrate reabsorption, as occurs with metabolic acidosis and hypokalemia, enhances
proximal citrate reabsorption, which increases the propensity for
stone formation. Distal renal tubular acidosis (RTA) is typically
associated with decreased citrate excretion, whereas proximal RTA
is associated with citrate wasting due to generalized proximal tubule
dysfunction.
++
Primary hyperoxalurias are rare inherited disorders caused by
deficiency of hepatic enzymes, which results in the marked overproduction
of oxalate. In primary hyperoxaluria (PH) type 1, alanine:glyoxylate
aminotransferase (AGT) deficiency leads to increased excretion of
glycolate and oxalate. Numerous mutations in the genes encoding AGT
have been identified.10 Primary hyperoxaluria type
2 results from mutations in the gene encoding glyoxylate reductase (GRHPR)
and leads to increased excretion of L-glycerate and oxalate.
++
Enteric hyperoxaluria occurs in association with fat malabsorption. Undigested
fatty acid binds with calcium instead of oxalate, increasing the
unbound oxalate levels. Increased enteric oxalate is absorbed and
excreted in the kidney. Excessive vitamin C intake and a diet rich
in oxalate can also cause hyperoxaluria.
++
Increased uric acid excretion can also serve as a nidus for the
formation of calcium oxalate stones. Uric acid and sodium urate
lower the solubility of calcium oxalate.11 Hyperuricosuria
alone is a relatively uncommon cause of nephrolithiasis in children.
It can result from increased uric acid production secondary to an
inborn error of purine metabolism or, more commonly, from hematologic
malignancies or gout. Hyperuricosuria can also result from high purine
intake, renal tubular disorder, or uricosuric medications. Patients
with diabetes mellitus and inflammatory bowel disease have a higher
prevalence of uric acid stones compared to the general population.
++
Urinary tract infections with urea-splitting organisms, usually Proteus
mirabilis, are usually associated with struvite (magnesium
ammonium phosphate) stones. The urease-splitting organisms generate
ammonium and bicarbonate via hydrolysis of urea. A high urine pH and
urinary ammonium concentration promote precipitation of magnesium
and phosphates. Struvite stones often extend throughout the renal
pelvis and cause obstruction.
++
Cystinuria is a rare inherited disease with abnormal excretion
of the dibasic amino acids, which include cystine, ornithine, arginine,
and lysine (see Chapter 138). Cystine
is highly insoluble in urine. Because cystinuria is an autosomal-recessive
disorder, all homozygotes for the defect have very high excretion
of cystine and high rate of recurrence of stones. Heterozygotes
can have normal (type I), high (type II), or moderate (type III)
excretion of dibasic amino acids. Heterozygote carriers are less
likely to form stones. Mutations in the cystine transport protein
have been identified. Families in whom heterozygotes are unaffected
(type I) have mutations in the SLC3A1 gene; those
with type II or III disease have mutations of the SLC7A9 genes.10
+++
Diagnosis and
Evaluation
++
The presentation of nephrolithiasis in children is often atypical.
Rarely, children present with the typical colicky pain described
in adults. Microscopic or gross hematuria, urgency, dysuria, frequency,
and hesitancy are all symptoms associated with kidney stones. Young
children may present with nonspecific abdominal pain, feeding, or
growth problems.12 In some, the diagnosis of nephrolithiasis
is made fortuitously during radiographic evaluations or abdominal
ultrasound for other problems.
++
The evaluation of nephrolithiasis begins with a complete history
and physical examination. The history should focus on symptoms associated
with stones, as well as predisposing factors to stones, such as recurrent
urinary tract infection, urinary tract abnormalities, chronic bowel
disease, and a familial history of nephrolithiasis, gout, and renal
disease. The diet history should focus on protein, salt, calcium,
oxalate, and fluid intake. Vitamin supplementation and medication
use should be reviewed.
++
A urinalysis should be performed. It may reveal hematuria. On
microscopic evaluation, the presence of flat hexagonal cystine crystals is
always pathologic and diagnostic for cystinuria. If the stone is available,
it should be sent for analysis by infrared spectroscopy or x-ray
diffraction. Chemical stone analysis is not recommended because
it is prone to error. A urine culture should be performed to rule
out infection.
++
A timed urine for calcium, oxalate, urate, citrate, and sodium
should be collected. Alternatively, the ratios of solute/creatinine
on spot urine can be calculated. Normal urinary values are listed
in Table 475-2. Cystine is screened by cyanide nitroprusside
testing or by chromatography for amino acids.
++
++
Imaging will usually include a plain abdominal film. Calcifications
along the urinary tract suggest calcium-containing stones. Struvite
and cystine stones are usually less radiopaque than calcium stones,
and uric acid stones are radiolucent. An abdominal ultrasound may
reveal stones and/or associated urinary tract obstruction
or nephrocalcinosis. Nonenhanced helical computed tomography (CT)
is highly sensitive and specific for the diagnostic of small stones.3 If
obstruction of the urinary tract is suspected, a MAG 3 scan should be
done.
++
Blood tests should initially include electrolytes, renal function
test, calcium, phosphorus, uric acid, and venous blood gas. In the
presence of hypercalciuria, hypercalcemia, or hypophosphatemia,
serum parathyroid hormone and vitamin D levels should be obtained.
++
In children who present with acute renal colic, pain relief,
hydration, and monitoring of fluid electrolytes
should be initiated on presentation. Radiologic evaluation should
be performed, and urologic intervention should be considered if
needed. Increased fluid intake to a minimum of 2 L/1.73
m2/day should be encouraged to decrease the chance
of crystallization and growth of calculi for almost all underlying
causes of stone disease. Medical therapy to prevent recurrence and
increased size of existing stones depends on the underlying diagnosis.
++
The treatment of hypercalciuria consists of
salt restriction, which reduces urinary calcium losses by promoting
reabsorption of sodium and calcium. The addition of potassium citrate
increases the solubility of calcium salts. A thiazide diuretic can
be used in the normocalcemic hypercalciuric patient to increase
distal tubular reabsorption of calcium.
++
In primary hyperoxaluria, the
goal of therapy is to decrease oxalate production, increase urine calcium
oxalate solubility, and decrease crystal deposition in the kidney.
Ideally, oxalate excretion should be lowered to less than 0.45 mmol/day,
and calcium excretion should be maintained at less than 4 mg/kg/day.13 Potassium
citrate and orthophosphate may be used to decrease urinary calcium
oxalate supersaturation. A trial of pyridoxine should be given in
primary hyperoxaluria type 1. About 20% of patients with
primary hyperoxaluria type 1 will respond to pyridoxine treatment
with normalization of urine oxalate concentration, and about 30% will have
a partial response.14 Calcium supplementation has been
recommended by some to decrease intestinal absorption of oxalate.
Vitamin C supplementation should be avoided because it is metabolized
to oxalate. The role of probiotics in the treatment of primary hyperoxaluria
is under investigation. Oral Oxalobacter formigenes,
which induces secretion of oxalate into the intestinal lumen where
it can be degraded by bacteria, has been shown to reduce urinary
oxalate in the majority of patients with normal kidney function.15 However,
only successful liver transplantation can offer a potential cure
for primary hyperoxaluria type 1.
++
In hypocitraturia, potassium citrate should
be given. Sodium citrate should be avoided because the excess salt may
increase hypercalciuria. Cystinuria is treated
with D-penicillamine and tiopronin that form a soluble dimer with
cystine and can be used to decrease cystine excretion. Captopril
has also been used but with mixed results. Alkalinization of the
urine is an important part of the therapy because the solubility
of cystine depends on the pH. Struvite calculi often
require surgical removal and prolonged treatment with antibiotics.
Hyperuricosuria is treated by alkalinization of urine, avoidance of
purine-rich meat or protein excess, and allopurinol.
+++
Nonmedical Treatments
++
Surgical management will be guided by stone size and location
(Table 475-3). Any underlying urologic abnormalities
should be corrected. Stones less than 5 mm will often pass spontaneously.16 Shock
wave lithotripsy, percutaneous nephrolithotomy, and ureteroscopy
have all been used successfully in children when surgical intervention
is required.
++
++
Shock wave lithotripsy has been used since the mid-1980s. Shock wave
energy is generated and focused at the stone. The stone is pulverized,
and the resulting fragments are passed. Potential complications following
lithotripsy include hematuria, ureteral obstruction, urinary tract
infection, and subcapsular, intrarenal, and perirenal hematoma.
Long-term risk of hypertension and loss of renal function remain
a concern, despite some reassuring studies that showed no parenchymal
damage imputable to shock wave lithotripsy.17,18 Shock wave lithotripsy
is the therapy of choice for renal stones smaller than 1 cm, whereas
percutaneous nephrolithotomy is the procedure of choice for renal stones
larger than 2 cm. Cystine and calcium oxalate monohydrate stones
are more resistant to fracturing by lithotripsy than struvite, calcium
oxalate dehydrate, and uric acid stones.
++
Percutaneous lithotripsy consists of gaining access to the collecting system
of the kidney percutaneously. A nephroscope is then introduced,
and stones are removed or pulverized under direct vision.19 Percutaneous
nephrolithotomy may lead to possible renal parenchymal damage secondary
to formation of a nephrostomy tract.
++
Ureteroscopy is usually the procedure of choice for distal ureteral stones.
However, with the miniaturization of endoscopic equipment, retrograde
intrarenal surgery is now an option for the treatment of upper urinary
tract calculi, and it can be used when shock wave lithotripsy is
not effective.20
++
Urolithiasis have a high rate of recurrence, especially if an
underlying metabolic disorder exists. Prevention with appropriate
medical therapy and high fluid intake should be encouraged to limit morbidity.
Long-term follow-up is advisable because some children may develop
renal failure.