Rudolph's Pediatrics, 22nd Ed.

CHAPTER 475. Urinary Tract Stone Diseases

Valerie Langlois

NEPHROLITHIASIS AND UROLITHIASIS

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.

EPIDEMIOLOGY

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.

PATHOPHYSIOLOGY

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.

ETIOLOGY

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

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

Table 475-1. Common Causes of Hypercalciuria

Hypocitraturia

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.⁹Increased 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.

Hyperoxaluria

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 glyco-late 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.

Hyperuricosuria

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.

Struvite Stones

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 often extend throughout the renal pelvis and cause obstruction.

Cystine Stones

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.

TREATMENT

Medical Therapy

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.

Table 475-2. Normal Urinary Values Based on Measurements of Solutes and Creatinine (Cr) from a Single Urine Collection (Ratio) or Based on 24-Hour Urine Collection (Day)

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.¹⁹Percutaneous nephrolithotomy may lead to possible renal parenchymal damage secondary to formation of a nephrostomy tract.

Table 475-3. Primary Surgical Treatment Options versus Stone Size and Location

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

OUTCOME

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.

Table 475-4. Etiology of Nephrocalcinosis in Preterm Neonates

NEPHROCALCINOSIS

Nephrocalcinosis results from the deposition of calcium oxalate or calcium phosphate in the tubulointerstitial regions of the kidney.⁴ It is mostly asymptomatic, and the diagnosis is usually made incidentally by high-resolution ultrasonography. Depending on the anatomic area involved, it will be classified as medullary, cortical, or diffuse nephrocalcinosis. Medullary nephrocalcinosis is by far the most common type. Nephrocalcinosis and urolithiasis share some of the same metabolic risk factors: hypercalciuria, hyperoxaluria, and hypocitraturia. Treatment of underlying disorders is similar to that described in the previous discussion of urolithiasis.

Nephrocalcinosis is commonly seen in prematurity with an incidence between 17% and 64%, depending on the study population and ultrasonographic criteria. It results from an imbalance between stone-promoting and stone-inhibiting factors (Table 475-4).²¹

In the majority of patients, spontaneous resolution of nephrocalcinosis will occur in the first years of life.²² However, 10% and 25% of preterm neonates will have persistence of nephrocalcinosis at 6 to 7 years.^22,23 Decreased glomerular filtration rate, low tubular reabsorption of phosphate, renal tubular acidosis, decreased concentrating ability, and hypercalciuria are all potential long-term consequences of nephrocalcinosis that arise in premature infants.