In a child with suspected renal colic, there are multiple imaging options. The most accurate study is an unenhanced spiral CT scan of the abdomen and pelvis (Fig. 541-1). This study takes only a few minutes to perform, has 96% sensitivity and specificity in delineating the number and location of calculi, and demonstrates whether the involved kidney is hydronephrotic. However, the radiation exposure is high. An alternative is to obtain a plain radiograph of the abdomen and pelvis plus a renal ultrasonogram. These studies can demonstrate hydronephrosis and possibly the calculus on the radiograph; however, the calculus is not visualized on sonography unless it is adjacent to the bladder. Consequently, the clinician needs to carefully balance the risks of CT imaging against the lower sensitivity of the plain abdominal film plus sonography.

Figure 541-1 Noncontrast CT scan of the mid-abdomen in a male infant with cystinuria shows a left-sided calculus at the ureteropelvic junction with proximal hydronephrosis.

In 2008 the Society for Pediatric Radiology initiated the Imaging Gently initiative to educate providers on the risks of radiologic imaging in children and to encourage the use of limited imaging in children, particularly those with suspected urolithiasis (http://www.pedrad.org/associations/5364/ig/). This approach was also advocated by the National Quality Forum. In a child with an already-diagnosed calculus, serial plain x-rays or renal ultrasonography can be used to follow the status of the calculus, such as whether it has grown or diminished in size or has moved. If a child has a renal pelvic calculus, a ureteropelvic junction obstruction should be suspected. In some cases, it can be difficult to determine whether hydronephrosis in such a child is secondary to an obstructing stone or the ureteropelvic junction obstruction, or both.

Any material that resembles a calculus should be sent for analysis by a laboratory that specializes in identifying the components of urinary calculi.

Metabolic Evaluation

A metabolic evaluation for the most common predisposing factors should be undertaken in all children with urolithiasis, bearing in mind that structural, infectious, and metabolic factors often coexist. This evaluation should not be undertaken in a child who is in the process of passing a stone, because the altered diet and hydration status, as well as the effect of obstruction on the kidney, can alter the results of the study. The basic laboratory studies required are listed in Table 541-2, and the normal values for 24-hr urine collections are shown in Table 541-3. In children with hypercalciuria, further studies of calcium excretion with dietary calcium restriction and calcium loading are necessary.

Table 541-3 URINE CHEMISTRY: NORMAL VALUES

Pathogenesis of Specific Renal Calculi

Calcium Oxalate and Calcium Phosphate Calculi

Most urinary calculi in children in the USA are composed of calcium oxalate and/or calcium phosphate. The most common metabolic abnormality in these patients is normocalcemic hypercalciuria. Between 30% and 60% of children with calcium stones have hypercalciuria without hypercalcemia. Other metabolic aberrations that predispose to stone disease include hyperoxaluria, hyperuricosuria, hypocitruria, heterozygous cystinuria, hypomagnesuria, hyperparathyroidism, and renal tubular acidosis (Chapter 523).

Hypercalciuria may be absorptive, renal, or resorptive. The primary disturbance in absorptive hypercalciuria is intestinal hyperabsorption of calcium. In some children, an increase in 1,25-dihydroxyvitamin D is associated with the increased calcium absorption, and in others the process is independent of vitamin D. Renal hypercalciuria refers to impaired renal tubular reabsorption of calcium (Chapter 513.8). Renal leak of calcium causes mild hypocalcemia, which triggers an increased production of parathyroid hormone, with increased intestinal absorption of calcium and increased mobilization of calcium stores. Resorptive hypercalciuria is uncommon and is found in patients with primary hyperparathyroidism. Excess parathyroid hormone secretion stimulates intestinal absorption of calcium and mobilization of calcium stores. A brief summary of the metabolic evaluation of children with hypercalciuria is shown in Table 541-4.

Table 541-4 METABOLIC EVALUATION OF CHILDREN WITH HYPERCALCIURIA

Hyperoxaluria is another potentially important cause of calcium stones. Oxalate increases the solubility product of calcium oxalate crystallization 7-10 times more than calcium. Consequently, hyperoxaluria significantly increases the likelihood of calcium oxalate precipitation. Oxalate is found in high concentration in tea, coffee, spinach, and rhubarb. Primary hyperoxaluria is a rare autosomal recessive disorder that can be subclassified into glycolic aciduria and L-glyceric aciduria. Most patients with primary hyperoxaluria have glycolic aciduria; oxalic and glycolic acids are increased in the urine of affected persons. Both defects cause increased endogenous production of oxalate, with hyperoxaluria, urolithiasis, nephrocalcinosis, and injury to the kidneys. Death from renal failure occurs by age 20 yr in untreated patients. Oxalosis, defined as extrarenal deposition of calcium oxalate, occurs when renal insufficiency is present with elevated plasma oxalate. Calcium oxalate deposits appear first in blood vessels and bone marrow, and with time they appear throughout the body. Secondary hyperoxaluria is more common and can occur in patients with increased intake of oxalate and oxalate precursors such as vitamin C, in those with pyridoxine deficiency, and in children with intestinal malabsorption.

Enteric hyperoxaluria refers to disorders such as inflammatory bowel disease (Chapter 328), pancreatic insufficiency (Chapter 342), and biliary disease, in which there is gastrointestinal malabsorption of fatty acids, which bind intraluminal calcium and form salts that are excreted in the feces. Normally, calcium forms a complex with oxalate to reduce oxalate absorption, but if calcium is unavailable, there is increased absorption of unbound oxalate.

Hypocitraturia refers to a low excretion of citrate, which is an important inhibitor of calcium stone formation. Citrate acts as an inhibitor of calcium urolithiasis by forming complexes with calcium, increasing the solubility of calcium in the urine, and inhibiting the aggregation of calcium phosphate and calcium oxalate crystals. Disorders such as chronic diarrhea, intestinal malabsorption, and renal tubular acidosis can cause hypocitraturia. It may also be idiopathic.

Renal tubular acidosis (RTA) is a syndrome involving a disturbance of acid-base balance within the kidney that can be classified into three types, one of which predisposes to renal calculi that typically are calcium phosphate (Chapter 523). In type 1, the distal nephron does not secrete hydrogen ion into the distal tubule. The urine pH is never <5.8, and hyperchloremic hypokalemic acidosis results. Patients acquire nephrolithiasis, nephrocalcinosis, muscle weakness, and osteomalacia. Type 1 RTA can be an autosomal dominant disorder, but more often it is acquired and associated with systemic diseases such as Sjögren syndrome, Wilson disease, primary biliary cirrhosis, and lymphocytic thyroiditis, or it results from amphotericin B, lithium, or toluene (an organic solvent associated with glue sniffing).

From 5-8% of patients with cystic fibrosis (Chapter 395) have urolithiasis. Typically the stones are calcium, and they often become manifest in adolescence or young adulthood. Microscopic nephrocalcinosis also occurs in younger children with the disease. These patients do not have hypercalciuria, and the propensity for urolithiasis has been speculated to result from an inability to excrete a sodium chloride load or from intestinal malabsorption.

Other disorders can play a role in causing calcium stones. Hyperuricosuria may be related to the epitactic growth of calcium oxalate crystals around a nucleus of uric acid crystals or to the action of uric acid as a counter inhibitor of urinary mucopolysaccharides, which inhibit calcium oxalate crystallization. Heterozygous cystinuria is found in some patients with calcium stones. The mechanism is unknown but may be similar to that of uric acid. Sarcoidosis causes an increased sensitivity to vitamin D₃ and thus an increased absorption of calcium from the gastrointestinal tract. In Lesch-Nyhan syndrome there is excessive uric acid synthesis. These patients are more likely to form uric acid stones, but some of these stones may be calcified. Immobility can cause hypercalciuria by mobilization of calcium stores. High-dose corticosteroids can cause hypercalciuria and calcium oxalate precipitation. Furosemide, which is administered in the neonatal intensive care unit, also can cause severe hypercalciuria, urolithiasis, and nephrocalcinosis.

In some children, calcium calculi are idiopathic. A complete metabolic evaluation must be performed before this diagnosis is made.

Cystine Calculi

Cystinuria accounts for 1% of renal calculi in children. The condition is a rare autosomal recessive disorder of the epithelial cells of the renal tubule that prevents absorption of the 4 dibasic amino acids (cystine, ornithine, arginine, lysine) and results in excessive urinary excretion of these products. The only known complication of this familial disease is the formation of calculi, because of the low solubility of cystine. The patients usually have acidic urine, which leads to a higher rate of precipitation. In the homozygous patient, the daily excretion of cystine usually exceeds 500 mg, and stone formation occurs at an early age. Heterozygotes excrete 100-300 mg/day and typically do not have clinical urolithiasis. The sulfur content of cystine gives these stones their faint radiopaque appearance.

Struvite Calculi

Urinary tract infections (Chapter 532) caused by urea-splitting organisms (most often Proteus spp, and occasionally Klebsiella spp, Escherichia coli, Pseudomonas spp, and others) result in urinary alkalinization and excessive production of ammonia, which can lead to the precipitation of magnesium ammonium phosphate (struvite) and calcium phosphate. In the kidney, the calculi often have a staghorn configuration, filling the calyces. The calculi act as foreign bodies, causing obstruction, perpetuating infection, and causing gradual kidney damage. Patients with struvite stones also can have metabolic abnormalities that predispose to stone formation. These stones often are seen in children with neuropathic bladder dysfunction, particularly those who have undergone an ileal conduit procedure (Chapter 536). Struvite stones can form in the reconstructed bladder of children who have undergone urinary tract reconstruction with augmentation cystoplasty or continent diversion, or both.

Uric Acid Calculi

Calculi containing uric acid represent <5% of all cases of lithiasis in children in the USA but are more common in less-developed areas of the world. Hyperuricosuria with or without hyperuricemia is the common underlying factor in most cases. The stones are radiolucent. The diagnosis should be suspected in a patient with persistently acid urine and urate crystalluria.

Hyperuricosuria can result from various inborn errors of purine metabolism that lead to overproduction of uric acid, the end product of purine metabolism in humans. Children with the Lesch-Nyhan syndrome (Chapter 83) and patients with glucose-6-phosphatase deficiency (Chapter 81) form urate calculi as well. In children with short-bowel syndrome, and particularly those with ileostomies, chronic dehydration and acidosis sometimes are complicated by uric acid lithiasis.

One of the most common causes of uric acid lithiasis is the rapid turnover of purine with some tumors and myeloproliferative diseases. The risk of uric acid lithiasis is especially great when treatment of these diseases causes rapid breakdown of nucleoproteins. Uric acid calculi or “sludge” can fill the entire upper collecting system and cause renal failure and even anuria. Urates also are present within calcium-containing stones. In these cases, >1 predisposing factor for stone formation can exist. A related disorder is 2,8-dihydroxyadeninelithiasis, which results from a deficiency in adenine phosphoribosyltransferase. The stones are radiolucent and can be differentiated from uric acid calculi by mass spectrometry but not by routine chemical analysis. In contrast to uric acid, which is soluble in alkaline urine, the solubility of 2,8-dihydroxyadenine changes little within physiologic pH ranges.

Indinavir Calculi

Indinavir sulfate is a protease inhibitor approved for treating HIV infection. Up to 4% of patients acquire symptomatic nephrolithiasis. Most of the calculi are radiolucent and are composed of indinavir-based monohydrate, although calcium oxalate and/or phosphate have been present in some. After each dose, 12% of the drug is excreted unchanged in the urine. The urine in these patients often contains crystals of characteristic rectangles and fan-shaped or starburst crystals. Indinavir is soluble at a pH of <5.5. Consequently, dissolution therapy by urinary acidification with ammonium chloride or ascorbic acid should be considered.

Nephrocalcinosis

Nephrocalcinosis refers to calcium deposition within the renal tissue. Often nephrocalcinosis is associated with urolithiasis. The most common causes are furosemide (administered to premature neonates), distal RTA, hyperparathyroidism, medullary sponge kidney, hypophosphatemic rickets, sarcoidosis, cortical necrosis, hyperoxaluria, prolonged immobilization, Cushing syndrome, hyperuricosuria, and renal candidiasis.

Treatment

In a child with a renal or ureteral calculus, the decision whether to remove the stone depends on its location, size, and composition (if known) and whether obstruction and/or infection is present. Small ureteral calculi often pass spontaneously, although the child might experience severe renal colic. The narrow parts of the ureter include the ureteropelvic junction and the midureter, where it crosses the common iliac artery; the narrowest segment is the ureterovesical junction. α-Adrenergic blockers, such as tamsulosin, terazosin, and doxazosin, have been shown to facilitate stone passage in adults by decreasing ureteral pressure below the stone and decreasing the frequency of the peristaltic contractions of the obstructed ureter. Similar positive effects have been noted with calcium channel blockers with or without steroids. Although these agents have been used in children with ureteral calculi, their safety and efficacy have not been demonstrated. In some cases, passage of a ureteral stent past the stone endoscopically relieves pain and dilates the ureter sufficiently to allow the calculus to pass. In cases such as children with a uric acid calculus or an infant with a furosemide-associated calculus, dissolution alkaline therapy may be effective.

If the calculus does not pass or seems unlikely to pass or if there is associated urinary tract infection, removal is necessary (Table 541-5). Lithotripsy of bladder, ureteral, and small renal pelvic calculi using the holmium laser through a flexible or rigid ureteroscope is quite effective. Extracorporeal shock wave lithotripsy has been successfully applied to children with renal and ureteral stones, with a success rate of >75%. Another alternative is percutaneous nephroscopy, in which access to the renal pelvis is obtained percutaneously, and the calculi are broken down by ultrasonic lithotripsy. In cases in which these modalities are suboptimal, an alternative is laparoscopic removal; this procedure can be performed using the da Vinci robot.

Table 541-5 PRIMARY SURGICAL TREATMENT OPTIONS VERSUS STONE SIZE AND LOCATION

In children with urolithiasis, the underlying metabolic disorder should be addressed (Table 541-6). Because lithiasis results from a too-high concentration of specific substances in the urine, maintaining a continuous high urine output by maintaining a high fluid intake often is an effective method of preventing further stones. The high fluid intake should be continued at night, and usually it is necessary for the child to get up at least once at night to urinate and drink more water.

Table 541-6 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 phosphate*
	Potassium citrate	Magnesium
		Pyridoxine*
Hypocitric aciduria	Potassium citrate
	Bicarbonate
Hyperuricosuria	Alkalinization	Allopurinol
Cystinuria	Alkalinization	Tiopronin (Thiola)
	Reduction of dietary Na⁺	D-Penicillamine
		Captopril

RDA, recommended dietary allowance.

* Initial therapy in primary hyperoxaluria.

From Milliner DS: Urolithiasis. In Avner ED, Harmon WE, Niaudet P, editors: Pediatric nephrology, ed 5, Philadelphia, 2004, Lippincott Williams & Wilkins, p 1104, with permission.

In children with hypercalciuria, some reduction in calcium and sodium intake is necessary, but caution is urged in the growing child. Thiazide diuretics also reduce renal calcium excretion. Addition of potassium citrate, an inhibitor of calcium stones, with a dosage of 1-2 mEq/kg/24 hr is beneficial. An excellent source of citrate is lemonade, because 4 oz of lemon juice contains 84 mEq of citric acid. A daily mixture of 4 oz of reconstituted lemon juice in 2 L of water and sweetened to taste should significantly increase the urinary citrate level. In difficult cases, neutral orthophosphate should be given also, although it is poorly tolerated.

In patients with uric acid stones, allopurinol is effective. Allopurinol is an inhibitor of xanthine oxidase and is effective in reducing the production of both uric acid and 2,8-dihydroxyadenine and can help control recurrence of both types of stones. In addition, urinary alkalinization with sodium bicarbonate or sodium citrate is beneficial. The urine pH should be ≥6.5 and can be monitored at home by the family.

Maintaining a high urine pH can also prevent recurrence of cystine calculi. Cystine is much more soluble when the urinary pH is >7.5, and alkalinization of urine with sodium bicarbonate or sodium citrate is effective. Another important medication is D-penicillamine, which is a chelating agent that binds to cysteine or homocysteine, increasing the solubility of the product. Although poorly tolerated by many patients, it has been reported to be effective in dissolving cystine stones and in preventing recurrences when hydration and urinary alkalinization fail. N-Acetylcysteine appears to have low toxicity and may be effective in controlling cystinuria, but long-term experience with it is lacking.

Treatment of type 1 RTA involves correcting the metabolic acidosis and replacing lost potassium and sodium. Sodium or potassium citrate therapy, or both, is necessary. When the metabolic acidosis is corrected, the urinary citrate excretion returns to normal.

Treatment of primary hyperoxaluria involves liver transplantation because the defective enzymes are hepatic. Ideally, this procedure is performed before renal failure occurs. In the most severe cases, kidney transplantation is also necessary.

Bibliography

Al-Marhoon MS, Sarhan OM, Awad BA, et al. Comparison of endourological and open cystolithotomy in the management of bladder stones in children. J Urol. 2009;181:2684-2687.

Lam HS, Ng PC, Chu WCW, et al. Renal screening in children after exposure to low dose melamine in Hong Kong: cross sectional study. BMJ. 2008;337:12991.

Landau EH, Shenfeld OZ, Pode D, et al. Extracorporeal shock wave lithotripsy in prepubertal children: 22-year experience at a single institution with a single lithotriptor. J Urol. 2009;182:1835-1839.

Lottmann H, Gagnadoux MF, Daudan M. Urolithiasis in children. In: Gearhart JP, Rink RC, Mouriquand PDE, editors. Pediatric urology. ed 2. Philadelphia: Saunders; 2010:631-661.

McNally MA, Pyzik PL, Rubenstein JE, et al. Empiric use of potassium citrate reduces kidney stone incidence with the ketogenic diet. Pediatrics. 2009;124:e300-e304.

The Medical Letter. Drugs for kidney stones. Med Lett. 2010;52(1352):93-94.