Urolithiasis

Arundhati S. Kale

L. Leighton Hill

Marked variation exists in the incidence of urinary tract stones in children worldwide. In some countries, such as Turkey and Thailand, urolithiasis is endemic; bladder stones predominate, and dietary factors are postulated to play a causative role. In contrast, stones are uncommon findings in children in the United States, where fewer than 1% of all renal stones occur in children younger than 10 and fewer than 3% occur in children younger than 19 and most stones have a metabolic origin. In the United States, boys with stones outnumber girls by 2:1; stones are very uncommon findings in African American
children; and bladder stones are seen much less commonly than are upper urinary tract stones. Children in the southeastern United States appear to have the greatest risk for formation of stones. A distinction should be made between urolithiasis or nephrolithiasis (stones in the urinary tract) and nephrocalcinosis (an increase in the calcium content within the renal tissue itself), although the two conditions may coexist.

FORMATION OF STONES

Urinary calculi consist of very small glycoprotein matrices with surrounding organic or inorganic crystals. Urinary crystalloids capable of being crystallized include calcium, phosphorus, oxalates, cystine, uric acid, xanthine, and ammonium. Supersaturation of the urine with various ionic species eventually leads to precipitation, with subsequent growth of crystals. Two products appear to be important in this process: the solubility product and the formation product. Below the solubility product for a given ionic pair (e.g., calcium and oxalate), the solution is undersaturated and formation of crystals does not occur. Above the formation product for a given ionic pair, the solution is supersaturated and spontaneous precipitation occurs. Between the solubility product and the formation product lies the metastable region in which precipitation does not occur unless the system is disturbed. Urine volume, through its effect on dilution and concentration, obviously plays a critical role in determining the degree of saturation. Urine pH is an important factor in determining solubility. Crystalline nuclei rarely form in free solution but rather on existing surfaces. Theoretically, any factor that increases the number of nuclei in tubular fluid or urine, such as epithelial injury, could lower the metastable limit, the supersaturation at which crystals first form. Also, certain inhibitor substances retard crystallization. Inhibitor absence has been suggested to explain calculus formation in patients with normal excretion of urinary crystalloids. Inhibitors are thought to include citrate, pyrophosphate, urinary glycoprotein crystallization inhibitors, Tamm-Horsfall mucoprotein, and magnesium-to-calcium and sodium-to-calcium ratios in the urine. Undoubtedly, many other inhibitors remain to be identified. The physicochemical principles underlying the formation of renal stones remain poorly defined. A classification of stones according to their composition is shown in Box 341.1. Calcium is a constituent of 90% of calculi. Calcium phosphate, the principal constituent of the calcium stones listed in part I of Box 341.1, also is found in struvite and other stones listed in the table. The struvite stones (magnesium ammonium phosphate) often are called infection stones.

CLINICAL FEATURES

The typical presentation with incapacitating renal colic is an unusual finding in children, especially young children and infants, and symptoms may be very nonspecific. Gross or microscopic hematuria may be the only manifestation, or hematuria may be accompanied by nonspecific abdominal pain or by fever, pyuria, and abdominal pain. Signs and symptoms might be those of a urinary tract infection (UTI). Typical renal colic may occur in older children. In some instances, the stone or gravel already has been passed spontaneously. Frequently, the patient has a family history of stones. Urinary stones can cause obstruction of the urinary flow, dilation of the urinary tract, and ultimately renal parenchymal damage. Stones can predispose to UTIs; conversely, UTIs can be important in the formation of stones.

BOX 341.1 Urolithiasis Classification Based on Stone Composition

Calcium stones (calcium oxalate and calcium phosphate)
- Hypercalciuria
  - Hypercalcemic hypercalciuria
    
    Hyperparathyroidism
    
    Thyrotoxicosis
    
    Vitamin D intoxication
    
    Idiopathic infantile hypercalcemia
    
    Sarcoidosis
    
    Neoplastic deposits in bones
    
    Immobilization
  - Normocalcemic hypercalciuria
    
    Idiopathic or familial hypercalciuria
    
    Distal renal tubular acidosis type 1
    
    Acetazolamide use
    
    Loop diuretic use
    
    Immobilization
    
    Vitamin D excess
    
    Cushing syndrome
- Hyperoxaluria (calcium oxalate)
  - Primary hyperoxaluria types I and II
  - Secondary hyperoxaluria
    
    Inflammatory bowel disease
    
    Pyridoxine deficiency
    
    Massive doses of vitamin C
- Hyperglycinuria (calcium oxalate stones)
- Idiopathic urolithiasis
Magnesium ammonium phosphate (struvite) plus basic calcium phosphate (apatite)
- Urinary tract infection with urea-splitting organisms (mostly Proteus species)
- Foreign body plus urinary stasis plus infection
Uric acid stones*
- Hyperuricosuria
  - Gout
  - Lesch-Nyhan syndrome
  - High purine diet
  - Glycogen storage disease type I
  - Leukemia-lymphoma
  - Leukemia-lymphoma/chemotherapy
Xanthine stones*
- Primary xanthinuria
- Allopurinol therapy
Dihydroxyadenine stones*
Cystine stones
- Cystinuria

Footnote

*Disorders of purine metabolism.

CLASSIFICATION

Calcium Stones

Hypercalciuria

Hypercalciuria is defined by a urinary calcium excretion of more than 4 mg/kg/day and may be associated with normal or
high serum calcium. The diverse conditions causing hypercalcemia (see Box 341.1) are discussed elsewhere in the book. Hypercalcemia is more apt to cause nephrocalcinosis than urolithiasis.

Idiopathic or Familial Hypercalciuria

Idiopathic hypercalciuria is an inherited metabolic abnormality. In pediatric patients with nephrolithiasis, 73% had a family history of kidney stones in at least one first- or second-order relative. Urinary calcium excretion exceeds 4 mg/kg/day, or the calcium-to-creatinine ratio exceeds 0.21 in a child older than 2 years of age. Calcium excretion is greater in infancy; normal calcium-to-creatinine ratios are as high as 0.8 mg/mg in infants up to the age of 6 months and 0.6 mg/mg in children between 6 months and a 1 year of age. At least three mechanisms have been invoked to explain the hypercalciuria. The first—excessive intestinal absorption of calcium—can cause increased calcium excretion, and urinary calcium excretion returns to normal during fasting. A second type of hypercalciuria is called renal hypercalciuria because of apparently defective calcium reabsorption by the renal tubules. The renal loss of calcium results temporarily in a lower serum calcium level, which stimulates production of parathyroid hormone (PTH), bringing the serum calcium back to normal. Renal hypercalciuria is characterized by elevated levels of PTH, which stimulate increased production of 1,25-dihydroxycholecalciferol, which then enhances the intestinal absorption of calcium and increases the filtered load of calcium in the kidney. Children with renal hypercalciuria continue to put out calcium in abnormal amounts (more than 4 mg/kg/day) during fasting. A third type of hypercalciuria—1,25-dihydroxycholecalciferol–induced hypercalciuria—is recognized by some investigators. The defect may be a renal tubular leak of phosphate. The ensuing hypophosphatemia is thought to stimulate the renal synthesis of 1,25-dihydroxycholecalciferol, which then enhances intestinal absorption of calcium; this absorption in turn provides extra calcium for renal excretion. Many experts in calcium physiology argue that dividing the hypercalciurias into several pathogenetic entities is unjustified. They offer instead a unifying hypothesis that the various forms of hypercalciuria result from the same generalized defect, possibly a disordered regulation of 1,25-dihydroxycholecalciferol production. Children with idiopathic hypercalciuria also may have hematuria (either gross or microscopic), even though no stones have been detected, possibly from crystalluria. Hypercalciuria also should be in the differential diagnosis of isolated hematuria. The risk of developing stones in this population is approximately 15%. Many patients with biochemical evidence of hypercalciuria never experience problems with formation of stones. The genetic basis of this disorder is unknown.

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