Calculus disease of the urinary tract encompasses calcifications and calculi of the kidneys, ureters, bladder, and urethra. Urolithiasis refers to the presence of stones within the lumen. This term includes calculi that form within a cavity that communicates with the collecting system, such as a calyceal diverticulum or bladder diverticulum. Subcategorization of calculous disease based on location within the urinary tract is often clinically useful. The term nephrolithiasis refers to calculi within the pelvicaliceal system. Nephrocalcinosis indicates the presence of intraparenchymal renal calcifications-cortical, medullary, or mixed. Medullary nephrocalcinosis can lead to urolithiasis by way of erosion of a stone into a calyx. The parenchymal calcification of nephrocalcinosis is usually metastatic, that is, calcification of otherwise normal renal tissue due to abnormally high levels of urinary or blood calcium. An additional category of urinary tract calcification is dystrophic calcification of abnormal tissue, which can occur with an inflammatory process, neoplasm, or renal cystic disease.
Approximately 90% of nephrocalcinosis in children involves the tubules, tubular epithelium, and adjacent interstitial tissue, that is, medullary nephrocalcinosis. The most common causes of medullary nephrocalcinosis in children are metabolic conditions that lead to hypercalcemia and/or hypercalciuria. Type 1 renal tubular acidosis is the most common metabolic condition to induce nephrocalcinosis in children. Other potential causes include hyperparathyroidism, Cushing syndrome, milk-alkali syndrome, hypervitaminosis D, prolonged immobilization, skeletal metastatic disease, loop diuretic therapy (infants), corticosteroid administration, idiopathic hypercalciuria, Williams syndrome, medullary sponge kidney, obstructive uropathy, tyrosinemia, Fanconi syndrome, autosomal recessive polycystic kidney disease, hyperoxaluria, and hyperuricosuria. Potential sequelae of nephrocalcinosis include passage of calculi into the collecting system, renal colic, hematuria, and urinary tract infection.
Nephrocalcinosis in premature infants most often involves the medullary portions of the kidneys. The etiology of stone formation in these infants is likely multifactorial. Immaturity of the kidneys apparently plays a role, as glomerular and tubular function is subnormal in preterm infants. Parenteral nutrition results in elevated urinary oxalate. The use of loop diuretics such as furosemide is an important predisposing factor for stone formation in neonates. Loop diuretics impair the reabsorption of magnesium and calcium, resulting in a variable degree of hypercalciuria. There is an inverse relationship between the prevalence of nephrocalcinosis in neonates undergoing furosemide therapy and the gestational age and birth weight. The earliest manifestations of stone formation in these patients develop approximately 30 days after the initiation of diuretic therapy. Spontaneous resolution occurs in most, but not all, of these infants within several months after cessation of furosemide use. Nephrocalcinosis has also been reported in association with the administration of aminoglycosides and dexamethasone.1,2
Cortical nephrocalcinosis occurs within the peripheral aspects of the kidneys and the central septa of Bertin. Common causes of cortical nephrocalcinosis in children are acute cortical necrosis, chronic glomerulonephritis, and oxalosis. Other potential causes include Alport syndrome (hereditary nephritis), renal transplant rejection, hyperoxaluria, ethylene glycol poisoning, and AIDS-associated infections (e.g., Pneumocystis carinii, cytomegalovirus, and Mycobacterium avium-intracellulare).
Large or widespread parenchymal renal calcifications are sometimes discernible on standard radiographs. Medullary nephrocalcinosis usually occurs as diffuse or uniform calcifications within the medullary pyramids, resulting in multiple triangular densities; this is the classic radiographic appearance with type 1 renal tubular acidosis. With medullary sponge kidney, there are coarse or small linear calcifications within dilated collecting tubules; renal involvement is usually nonuniform. Radiographs of patients with cortical nephrocalcinosis show thin linear peripheral calcifications, diffuse homogeneous cortical calcification, or diffuse punctate calcifications. Patients with cortical nephrocalcinosis due to acute renal cortical necrosis sometimes have thin parallel curvilinear calcifications in the peripheral aspects of the kidneys, producing a “tram track” pattern. Hyperoxaluria can be associated with pure cortical nephrocalcinosis or mixed medullary–cortical involvement.
Early in the course of nephrocalcinosis, sonography usually shows abnormal increased echogenicity in the involved portions of the kidneys. This can be accompanied by diminished corticomedullary differentiation. Acoustic shadowing only occurs with extensive calcification or macroscopic stones. With cortical nephrocalcinosis, the hyperechogenicity predominantly involves the peripheral aspects of the kidneys and the central septa of Bertin (Figure 50-1). There is preservation of normal hypoechoic pyramids in patients with pure cortical nephrocalcinosis. Medullary nephrocalcinosis results in hyperechoic medullary pyramids and poor corticomedullary differentiation (Figures 50-2, 50-3, and 50-4). If the cortex is spared, it forms a relatively peripheral band that is hypoechoic relative to the medulla, but has normal echogenicity relative to the liver.3
Figure 50–4
Medullary nephrocalcinosis.
This 11-year-old girl has primary Fanconi syndrome. A longitudinal sonographic image of the left kidney demonstrates marked hyperechogenicity of the renal pyramids (arrow) due to nephrocalcinosis. Echogenicity of the cortex is normal. There is mild hydronephrosis.
Helical CT is an excellent technique for the detection and characterization of renal parenchymal calcifications (Figure 50-5). This is also a sensitive method for detecting associated urolithiasis. With type 1 renal tubular acidosis, calcification occurs within the medullary interstitium and the tubular lumina; therefore, excreted contrast does not uniformly surround the calcific deposits. In patients with medullary sponge kidney, excreted contrast pools in the dilated collecting tubules and surrounds the intraluminal calculi. The early CT appearance of acute renal cortical necrosis is deficient contrast enhancement of the renal cortex, in conjunction with preserved enhancement of the medulla and a thin subcapsular rim (“cortical rim sign”). There is subsequent progressive renal atrophy and calcification within the renal cortex. Potential CT patterns of cortical nephrocalcinosis due to acute renal cortical necrosis include punctate calcifications (necrotic glomeruli), band-like peripheral calcifications with perpendicular extensions into the columns of Bertin, and peripheral tram track calcifications at the interface between necrotic cortex and the viable subcapsular cortex.
The Anderson–Carr theory of renal stone formation postulates that microscopic calcifications within a renal pyramid can coalesce to form a plaque that migrates into the calyx to form a stone nidus, that is, progression of microscopic medullary nephrocalcinosis to frank urolithiasis. The microscopic calcification results from high calcium concentrations in the peritubular spaces when the amount of calcium exceeds the capacity for lymphatic clearance. This aggregation of calcium first occurs at the tips and margins of the renal pyramids. High-resolution ultrasound of infants and young children may show these calcifications as papillary hyperechogenicity. This finding is present in about half of children with diseases that predispose to medullary nephrocalcinosis. Subepithelial calcific plaques sometimes are visible on CT as slivers of calcification adjacent to the papillary tip.4
Pediatric urolithiasis is relatively uncommon in the western industrialized world. The prevalence of adult stone disease in the United States is up to 10 per 1000 individuals. The estimated prevalence of pediatric urolithiasis is 1/50 to 1/75 that of adults. There are substantial variations in the frequency and types of urolithiasis with geographic area, age, gender, and race. Urolithiasis is more common in Asia than in North America and Europe. In United States, the prevalence is greatest in Southern California and in the southeastern states. The male-to-female ratio for urolithiasis in United States is approximately 1.4:1.5–13
About three-quarters of urinary calculi in North American children contain calcium, usually mixed with oxalate or phosphate. Hypercalciuria is the most common predisposing abnormality in pediatric idiopathic urolithiasis. Conditions that are associated with an elevated risk for urolithiasis include recurrent urinary tract infections, prolonged immobilization, endocrine disorders, medications that cause hypercalcemia (e.g., corticosteroids, furosemide), GI disorders that cause hypocitraturia or absorptive oxaluria, and Lesch-Nyhan syndrome (hyperuricemia). In the United States, the most common conditions associated with urolithiasis are metabolic disorders, urinary tract obstruction, and bladder augmentation. Approximately 30% of children with stones lack an identifiable cause, that is, idiopathic urolithiasis. Urinary tract infection is a common predisposing factor for urolithiasis in some parts of Europe. Bladder stones are endemic in most developing countries.14–16
Idiopathic hypercalciuria refers to elevation of urinary calcium excretion despite a normal serum calcium level. These patients have elevated levels of urinary calcium despite consumption of a regular diet. Idiopathic hypercalciuria is the most common form of elevated urinary calcium and is an important cause of urolithiasis (typically calcium oxalate stones) and nephrocalcinosis. This metabolic disorder is present in approximately 40% of children with nephrolithiasis.17 There is also an association between idiopathic hypercalciuria and recurrent gross hematuria in the absence of radiographically demonstrable stones.18 The presence of hematuria in a child with idiopathic hypercalciuria is a predictor for the subsequent development of urolithiasis; urolithiasis occurs within 5 years of the onset of hematuria in 20% of these children.17 Some patients with idiopathic hypercalciuria have reduced bone mineral density.19 Clinical findings that can occur in association with idiopathic hypercalciuria include dysuria, urinary frequency, enuresis, abdominal pain, back pain, and urinary tract infections.
Idiopathic hypercalciuria is a multifactorial disease that has a genetic component. There are 2 forms: absorptive hypercalciuria that is due to increased calcium absorption from the bowel and renal hypercalciuria that is due to diminished renal tubular calcium resorption. Although there appears to be an interaction between environmental factors and genetic factors in idiopathic hypercalciuria, alterations in the VDR gene may play a role in the absorptive type. This gene is involved in the function of vitamin D receptors that bind 1,25-dihydroxyvitamin D3 and thereby mediate the rate of intestinal calcium absorption. Other genetic factors are also likely involved in the pathogenesis, such as genes that encode for other hormone receptors, hormones involved in calcium metabolism, and growth factors that control the rate of bone metabolism and bone matrix ossification.20
Hyperparathyroidism is a rare predisposing condition for pediatric urolithiasis. The elevated serum parathyroid hormone concentrations in these patients stimulate increased intestinal absorption and bone resorption of calcium. Urolithiasis in patients with hyperparathyroidism usually occurs as calcium oxalate or calcium phosphate stones.
Hypercalcemia is an uncommon cause of hypercalciuria. In infants, potential causes of hypercalcemia include idiopathic infantile hypercalcemia, dietary deficiency of phosphate, excessive calcium or vitamin D supplementation, neonatal hyperparathyroidism, and Murk Jansen type metaphyseal chondrodysplasia. Idiopathic infantile hypercalcemia is a rare disorder that apparently relates to mutations in the elastin gene on the long arm of chromosome 7. It can occur in association with Williams syndrome.
Calcium oxalate stones can occur in patients with sarcoidosis. The major pathogenic mechanism of hypercalcemia and hypercalciuria in these patients is excessive intestinal absorption of calcium due to abnormal production of activated vitamin D by macrophages. There may also be renal parenchymal damage by granulomas. Urolithiasis in sarcoidosis patients is most common in those with extensive active disease or a coexistent risk factor such as high dietary calcium and vitamin D.
Renal tubular acidosis encompasses various disorders in which the kidneys fail to appropriately lower urinary pH. There are 3 major forms of this disorder; only type 1 (distal) renal tubular acidosis carries a substantial predisposition for nephrocalcinosis and urolithiasis. Subnormal hydrogen ion secretion in the distal renal tubules leads to bicarbonate loss, reduced acid excretion, secondary aldosteronism, and hypokalemia. Factors involved in the pathogenesis of stone formation in patients with type 1 renal tubular acidosis include hypercalciuria, alkaline urine, hyperphosphaturia, and diminished urinary citrate. About three-quarters of patients with type 1 renal tubular acidosis develop nephrocalcinosis. Urolithiasis can develop due to rupture of a medullary stone into the collecting system or by way of de novo stone formation. Most urinary tract stones in these patients consist of calcium phosphate, calcium carbonate, or calcium oxalate.21
Prolonged immobilization leads to increased mobilization of calcium from bone and can cause hypercalciuria and urinary tract stone disease. As described above, chronic diuretic use (especially furosemide) can cause urolithiasis; premature infants and young children with congestive heart failure are most susceptible. Other occasional causes of hypercalciuria and urolithiasis in children include ingestion of excessive exogenous vitamin D, skeletal metastatic disease, milk-alkali syndrome, juvenile rheumatoid arthritis, and HIV infection.
Elevation of urinary oxalate is the major pathogenic factor in approximately 2% of children with calcium urolithiasis. The term hyperoxaluria refers to elevation of the concentration of oxalate in the urine. Oxalosis refers to the accumulation of oxalate crystals in extrarenal tissues, such as the myocardium, lung, or spleen. Oxalate is a component of many foods and is an end product of normal metabolism. The kidney is the main route of excretion. Nephrocalcinosis in patients with hyperoxaluria most prominently involves the renal cortex.
Hyperoxaluria and oxalosis occur in primary and secondary forms. Primary hyperoxaluria is a rare autosomal recessive disorder of glyoxylate metabolism, which accounts for up to half of oxalate stones in children (see Chapter 46). Excessive renal excretion of oxalate leads to nephrocalcinosis, urolithiasis, and interstitial nephritis. Imaging studies show nephrocalcinosis (often global), urolithiasis, and skeletal manifestations of renal osteodystrophy and deposition of oxalate within bone.22
The most common secondary form of hyperoxaluria is due to small bowel disease, such as Crohn disease or extensive small bowel resection. Malabsorption in these patients leads to complexing of calcium by fatty acids within the intestinal lumen and increased absorption of free oxalate due to facilitated solubility. There is also increased permeability of the colon to oxalate in these patients. Rare forms of secondary hyperoxaluria include overingestion of foods with high oxalate content (peanuts, rhubarb, spinach, collard greens, and cocoa), overconsumption of vitamin C supplements, ethylene glycol poisoning, and pyridoxine deficiency.
Stones that contain magnesium ammonium phosphate, that is, struvite, account for approximately 15% of pediatric stones. Struvite-containing stones typically are associated with urinary tract infections. The classic “infection stone” is a mixture of struvite and carbonate apatite (calcium carbonate and calcium phosphate), that is, the “triple-phosphate stone.”
Urinary tract calculi composed of uric acid are rare in the pediatric population. Patients with myeloproliferative disorders, hemolytic anemia, sickle cell anemia, and intestinal tract disease have an increased propensity. Several metabolic enzyme deficiencies are associated with hyperuricemia and uric acid stone formation in children. Hereditary renal hypouricemia results in elevated levels of urinary urate due to defective resorption in the proximal tubules. Type I glycogen storage disease involves glucose-6-phosphatase deficiency, potentially leading to gouty arthritis and uric acid nephropathy. Lesch-Nyhan syndrome is a severe form of glucose-6-phosphatase deficiency that results in mental retardation, compulsive mutilating behavior, choreoathetosis, hyperuricemia, hyperuricosuria, gouty arthritis, and uric acid stones.23 Uric acid urolithiasis is relatively common in patients with ileostomies; the major responsible factors in these individuals are chronic dehydration and excessive bicarbonate loss.24,25
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