Calciphylaxis Calcific Uremic Arteriolopathy

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Calcifying panniculitis, subcutaneous calcific arteriolopathy, uremic small artery disease with medial calcification and intimal hyperplasia, metastatic calcinosis cutis

Multifactorial, including hyperphosphatemia, hypercalcemia, hyperparathyroidism, hypoalbuminemia, rapid weight loss, obesity Chronic renal insufficiency

Subcutaneous vascular calcification and epidermal necrosis Serum blood urea nitrogen, creatinine, calcium, phosphate, albumin, parathyroid hormone, quantitative and functional protein C and S, skin biopsy, possible soft tissue radiographic evaluation for subcutaneous calcification, arterial large vessel evaluation in distal variant Reduction of calcium and phosphorous levels, treatment of secondary hyperparathyroidism if severe, hyperbaric oxygen

Calciphylaxis is a syndrome of subcutaneous vascular calcification resulting in painful ulcers on the legs, thighs, or abdomen. The disease develops almost exclusively in patients with end-stage renal disease, and is frequently fatal due to infectious complications. Calciphylaxis was described in 1962 by Hans Selye. He made rats hyper -calcemic with "sensitizers" vitamin D or parathyroid hormone. "Challengers" were then administered. These included skin injury by hair-plucking, or injections of various sorts. Injured areas calcified and became ulcerated. Injection of "challengers" intravenously resulted in systemic necrotic lesions associated with tissue calcification (1). The concept of calciphylaxis has been imperfectly applied to cutaneous ulcerations that develop in patients with end-stage renal disease due to vascular calcification and subsequent occlusion. While this clinical scenario has some parallels with Selye's experiments, his experimental subjects were not uremic, and the calcifications were not vascular. Therefore, "calciphylaxis" does not accurately describe the syndrome. Because this disease does not conform to the model of calciphylaxis as described by Selye, many advocate eliminating that label in favor of "calcific uremic arteriolopathy."

The pathogenesis of calciphylaxis is likely multifacto-rial. The precise process has remained elusive. Most patients developing calciphylaxis have end-stage renal disease, but some have milder renal insufficiency. Other cases have occurred in association with Crohn's disease (2), alcoholic cirrhosis (3), acute renal failure (4), metastatic breast cancer (5), and primary hyperparathyroidism (6). Most earlier literature on the subject regarded the disease as a form of metastatic calcification due to secondary hyperparathyroidism of end-stage renal disease. This view is not supported by data that show that only one third of patients with calciphylaxis have an elevated calcium-phosphate product. Additionally, the calcium-phosphate product of calciphylaxis patients and a control group of patients with end-stage renal disease without skin lesions is similar (7). Evidence of hyperparathyroidism is often lacking in patients with calciphylaxis, and treatment by parathyroidectomy results in clinical improvement in only a subset of patients. A group of patients with calci-phylaxis has been described in which low turnover of renal bone disease is present, with low intact parathyroid hormone levels and a low calcium-phosphate product, favoring other inciting factors (8).

Earlier descriptions of calciphylaxis attribute its cause to metastatic calcification resulting from an elevated calcium-phosphate product and secondary hyperparathy-roidism. However, the pathogenesis is likely multifacto-

rial. Vascular calcification, the hallmark of calciphylaxis, is a complex process regulated by many factors. Medial arterial calcification is a feature characteristic of both diabetes mellitus and end-stage renal disease. This calcification involves a phenotype switch of the vascular myofibroblast to one of an osteoprogenitor, a process influenced by osteotropic hormones and inhibitors. In pathologic states, the end result is vascular calcification. Local para-crine control of the process involves bone morphogenetic protein-2, parathyroid hormone-related peptide, osteo-pontin, osteoprotegerin, Pit-1 (a sodium-dependent phosphate cotransporter), and matrix Gla protein, all of which respond to various metabolic and inflammatory stimuli (summarized in Figure 35.1) (9,10). Osteopontin production likely contributes to mineralization, and can be induced by hyperglycemia, uremia, and hyperphosphate-mia, all common features in patients with calciphylaxis (9). Matrix Gla protein (MGP) may be an inhibitor of vascular calcification. Warfarin, which is a risk factor for calciphylaxis, inhibits gamma-carboxylation of MGP, rendering it nonfunctional, theoretically tipping the balance toward vascular calcification (11). Parathyroid hormone-related peptide is an endogenous inhibitor of vascular calcification that is suppressed by vitamin D3, another mechanism by which vascular calcification may occur (12). The activity of Pit-1, a sodium-dependent phosphate cotransporter, is enhanced by exposure to calcium and phosphorous, as may occur in patients with chronic renal insufficiency. Pit-1 transports phosphorous into vascular smooth muscle cells, causing mineralization of matrix vesicles that provide nuclear elements for mineralization of the extracellular matrix. Intracellular phosphorous also induces phenotypic switching toward an osteoprogenitor cell (10).

In addition to vascular calcification, tissue calcification due to precipitation of calcium phosphate may occur. Such calcification is normally suppressed by mineralization inhibitors, such as fetuin-A, a circulating glycoprotein, and tissue pyrophosphates. Fetuin-A production may be suppressed by vitamin D, another factor favoring calcification in some patients with end-stage renal disease (9). Matrix metalloproteinases, which can be associated with the catabolic state of rapid weight loss, partially digest elastic tissue, which then avidly binds calcium. This process may contribute to the pathogenesis of calciphy-laxis in patients with recent weight loss (13). Some of the factors involved in tissue calcification are summarized in Figure 35.2. While the above observations do not elucidate a specific pathogenesis of calciphylaxis, they indicate that vascular and tissue calcification is induced in a certain metabolic milieu. Many of the forces that favor this process are found in patients with renal disease.

In addition to metabolic factors that may be involved in the pathogenesis of calciphylaxis, there may also be physical factors. Obesity is known to be a risk factor for the development of disease, and it is noted that skin lesions tend to occur in areas of greatest adipose tissue deposition, such as the abdomen, hips, and thighs. With fixed subcutaneous fibrous septae, there may be considerable tensile stress that compromises blood flow in these areas, predisposing to vascular stasis, associated ischemia, and dystrophic lesions (14). Another predisposing factor may be reduced cutaneous oxygen tension. Patients with calciphylaxis have been shown to have reduced transcu-

Calciphylaxis Pictures

Glc = glucose Bun = blood urea nitrogen P = phosphate PTH = parathyroid hormone BMP-2 = bone morphogenetic protein-2

Ca = calcium

Figure 35.1. Vascular calcium homeostasis.

Figure 35.2. Tissue homeostasis.

calcification calcification

Calciphylaxis Ulcers

taneous oxygen tension in multiple body regions, in areas with, and without, ulcers (15). This phenomenon may be explained by background vascular calcification of subcutaneous vessels that precedes the onset of clinical lesions. This has been referred to as the "primary lesion" of calciphylaxis (14). It is in this background setting that patients are susceptible to developing ischemic necrosis and tissue calcification. Hypercoagulable states such as protein C or S deficiency or functional impairment may further contribute to precipitation of the disease (16).

Risk factors for calciphylaxis tend to be those that induce a metabolic or physical state favoring vascular and tissue calcification in an already susceptible patient with renal insufficiency. In addition to those factors, the influence of vascular stasis as may be seen in obesity, hypotension, and hypercoagulable states may contribute to precipitation of lesions of calciphylaxis. The risk factors for the development of calciphylaxis are summarized in the following:

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