Pediatr Clin N Am 53 (2006) 479 491

Medical Evaluation and Treatment of Urolithiasis

Julie A. Nicoletta, MDT, Marc B. Lande, MD
Division 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 nephrolithiasis [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

Dr. Lande is supported, in part, by NIH grant 5 K23 HL080068-02. T Corresponding author. E-mail address: julie_nicoletta@urmc.rochester.edu (J.A. Nicoletta). 0031-3955/06/$ see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.pcl.2006.03.001 pediatric.theclinics.com

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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% of children 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, and possibly 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 receptors compared 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 normal 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 also occasionally 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 hypercalcemia is identified, causes include primary hyperparathyroidism, immobilization, hypo- or hyperthyroidism, adrenocorticosteroid excess (endogenous or exogenous), adrenal insufficiency, osteolytic metastases, idiopathic hypercalcemia of infancy, sarcoidosis, hypervitaminosis D, milk alkali syndrome, Williams syndrome, 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 low solubility (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 increased level 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 chromosome band 2q37.3 [41]. With this disorder, there is an increased production of glyoxylate 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 is common 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 significantly in acidic urine. Idiopathic uric acid nephrolithiasis seems to be inherited in an autosomaldominant pattern, with the onset as early as the second decade of life [46]. It usually affects individuals of Italian or Jewish descent and causes severe, recurrent urolithiasis. 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 metabolism. 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 phosphoribosyltransferase 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, choreoathetosis, and self-mutilatory behavior along with hyperuricemia and hyperuricosuria [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 hydrogen 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 adult population [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]. Mutations 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 have been 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 creatinine 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 patients with 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, regardless of 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 have hypercalciuria 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 obtained 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 concluded that in children, these studies do not offer much additional information than consideration of 24-hour urine volume. Most children with elevated supersaturation values had urine volumes b 1 mL/kg/h [17]. The urinary creatinine excretion 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 random sample should be confirmed with 24-hour urine collection. Uric acid excretion 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

Table 1 Urine chemistry: normal values Timed b 4 mg/kg/24 h  2 yr; b 0.5 mmol/1.73 m2/24 h Comments Prandial variation Sodium dependent

Urine constituent

Age

Random

Calcium (52,230)

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Oxalatea (204,231)

0 6 mo 7 12 mo 2 y b 1y 1 yr b 5 y 5 12 y N 12 y b 815 mg/1.73 m2/24 h

b 0.8 mg/mg creat b 0.6 mg/mg creat b 0.21 mg/mg creat 0.15 0.26 mmol/mmol creat 0.11 0.12 mmol/mmol creat 0.006 0.15 mmol/mmol creat 0.002 0.083 mmol/mmol creat

&

Uric acid (201,205)

Term infant N3 y b88 mg/1.73 m2/24 h

3.3 mg/dL GFRb b 0.53 mg/dL GFR

Magnesium (13,230)

N2 y

b 0.12 mg/mg creat

Citrate (232)

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Cystine (13,30)

N 180 mg/g creat (232) N 400 mg/g creat (13) b 75 mg/g creat

b 60 mg/1.73 m2/24 h

Random urine mmol/mmol highly age dependent Excretion rate/1.73 m2 constant through childhood and adulthood Excretion rate/1.73 m2 from N 1 y age constant through childhood Excretion rate/1.73 m2 constant through childhood Limited data available for children Cystine N 250 mg/g creat suggests homozygous cystinuria

Abbreviations: creat, creatinine; GFR, glomerular filtration rate. a Oxalate oxidase assay. b (mg/dL uric acid) (serum creatinine concentration/urine creatinine concentration). From Milliner DS. Urolithiasis. In: Pediatric nephrology. Philadelphia: Lippincott Williams & 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 nonenhanced 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 image small 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. Although this approach is effective in treating patients with any cause of nephrolithiasis, long-term compliance with an increased fluid regimen is often poor [60]. Increasing urine volume to more than 2 L a day in adolescents who have nephrolithiasis would be ideal [22]. Patients who are asymptomatic and patients not associated with impending or ongoing obstruction may be managed conservatively [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 recommendations. 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, which increases 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 directly 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 of this 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 supplementationeither 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, urinary calcium 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 hypocitraturia. 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, allopurinol for the treatment of hyperuricosuria, and chronic antibiotic suppressive therapy for struvite stones. Table 2 lists first- and second-line therapies for different stone types [22]. Other nonspecific therapies are available. Neutral phosphate increases the urinary pyrophosphate concentration, which acts as an inhibitor of calcium oxalate crystal formation [18,44]. Orthophosphate also decreases vitamin D pro-

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Table 2 Suggested therapy for urolithiasis caused by metabolic abnormalities Metabolic abnormality Hypercalciuria Initial treatment Reduction of dietary Na+ Dietary calcium at RDA Thiazides Adjustment of dietary oxalate Potassium citrate Potassium citrate Bicarbonate Alkalinization Alkalinization Reduction of dietary Na+ Second-line treatment Potassium citrate Neutral phosphate Neutral phosphatea Magnesium Pyridoxinea

Hyperoxaluria

Hypocitric aciduria Hyperuricosuria Cystinuria

Allopurinol Tiopronin (Thiola) 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.

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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