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Chronic Renal Failure
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Metastatic calcification most commonly occurs in chronic renal failure and takes the form of either benign nodular calcification or calciphylaxis. In chronic renal failure, decreased clearance of phosphate results in hyperphosphatemia. In addition, the impaired production of 1,25(OH)2D3 results in a decrease in calcium absorption from the intestine and decreased serum calcium levels. The hypocalcemia results in increased PTH production and secondary hyperparathyroidism. Elevated levels of PTH cause bone resorption and mobilization of calcium and phosphate into the serum, leading to normalization of the serum calcium concentration but marked hyperphosphatemia. If the solubility product of calcium and phosphate is exceeded, metastatic calcification may occur. In benign nodular calcification, the calcifications typically occur at periarticular sites, and their size and number tend to correlate with the degree of hyperphosphatemia. The lesions disappear with normalization of calcium and phosphate levels.
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Calciphylaxis is a life-threatening disorder characterized by progressive vascular calcification, soft tissue necrosis, and ischemic necrosis of the skin (see Chapter 151).60 Clinically, it presents as firm, extremely painful, well-demarcated, violaceous plaques associated with soft tissue necrosis and ulceration (Fig. 138-2). The lesions may occur anywhere, but the lower extremities are most frequently involved. The mortality rate is estimated to be approximately 80%. Histopathologically, there is medial calcification of small and medium-sized arteries with intimal hyperplasia, primarily in dermal and subcutaneous tissues. Calciphylaxis occurs almost exclusively in patients with a history of chronic renal failure and prolonged secondary hyperparathyroidism. However, there exist rare reports of the occurrence of calciphylaxis in the absence of renal failure.61 Most of the patients reported are female, and there may be an association with obesity and poor nutritional status.62,63
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The pathogenesis of calciphylaxis remains controversial. Experiments in a rat model suggested that calciphylaxis may be triggered by exposure to a sensitizing agent (PTH, dihydrotachysterol, or vitamin D) followed by a challenging agent (metal salts, albumin, or corticosteroids).64 However, the clinical description and histopathology of the animal lesions differ from the human disease. Protein C dysfunction has also been described in a subset of patients with calciphylaxis, but this more likely is a mark for a coagulation defect that predisposes this group to calciphylaxis.65 More recently, it has been proposed that conversion of vascular smooth muscle cells into osteoblast-like cells is a critical step in the development of progressive vascular calcification as is seen in calciphylaxis. This conversion may be stimulated by phosphates, substances that stimulate inflammation in the vascular wall and bone morphogenic protein (BMP)-2. Other proteins that are currently under study as potential effectors, both positive and negative, are BMP-7, osteoprotegerin, matrix Gla protein, fetuin-A, and phosphatonins.66
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The current therapy of calciphylaxis involves a multifaceted approach. The calcium-phosphate product should be normalized by methods including: low calcium dialysis, use of phosphate binders that combine calcium acetate and magnesium carbonate, sodium thiosulfate, and parathyroidectomy in those instances where medical management fails.67 Aggressive management of wound infections and judicious use of debridement may help lower the incidence of sepsis and death in these patients.
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Chronic ingestion of vitamin D in supraphysiologic doses (50,000–100,000 units/day) may produce hypervitaminosis D.68 The initial signs and symptoms of hypervitaminosis D are attributable to hypercalcemia and hypercalciuria, and include weakness, lethargy, headache, nausea, and polyuria. Metastatic calcification may also occur.
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Milk–alkali syndrome is characterized by excessive ingestion of calcium-containing foods or antacids, leading to hypercalcemia.69 Complications other than the acute manifestations of hypercalcemia include irreversible renal failure, nephrocalcinosis, and subcutaneous calcification, occurring predominantly in periarticular tissues.
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Tumoral calcinosis (TC) is a disorder characterized by the deposition of calcific masses around major joints, such as hips, shoulders, elbows, and knees. The masses are intramuscular or subcutaneous and may enlarge to sizes causing significant impairment of joint function. Usually, the overlying skin is normal, but associated ulceration and calcinosis cutis may occur. It generally occurs in otherwise healthy adolescents. Tumoral calcinosis may be either sporadic or familial. The familial type may be associated with hyperphosphatemia or normophosphatemia. Inactivating mutations in either the GALNT3 or FGF23 genes may lead to hyperphosphatemic TC.70–72 GALNT3 encodes a glycosyltransferase (N-acetylgalactosaminyltransferase 3 or ppGalNAc-T3) that initiates mucin-type O-glycosylation. It is hypothesized that FGF23, an important regulator of phosphate homeostasis, must be glycosylated by ppGalNAc-T3 to function properly. Normophosphatemic familial TC has been associated with mutations resulting in the absence of SMAD9, an anti-inflammatory protein that has also been suggested to be a tumor suppressor. Surgical excision is the treatment of choice, but phosphate deprivation via dietary restriction and antacids that impair phosphate absorption has met with some success.73
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Other systemic disorders associated with hypercalcemia and/or hyperphosphatemia are reported to cause metastatic calcification. These include neoplasms associated with bony destruction, such as lymphoma, leukemia, multiple myeloma, and metastatic carcinoma.74–76 Sarcoidosis may also be associated with metastatic calcification.77