Pathogenesis of calciphylaxis: Hans Selye to nuclear factor κ-B

Cutaneous Manifestations of ESRD

“…Metabolic factors, systemic inflammation, oxidative stress, and endothelial injury along with certain triggers have been implicated. Risk/triggering factors include local trauma, women (73,74), Caucasian ethnicity (75), hypoalbuminemia (72,74,75), therapy with calcium salts, vitamin D supplements, erythropoiesis-stimulating agents (69,70,76), warfarin (72)(73)(74)77), and iron supplements (78). Other independent risk factors include obesity (body mass index.30 kg/m 2 ) (69,73,74), liver disease (69,79), and systemic corticosteroids (65,69,73,74).…”

“…The low-flow rate within cutaneous vessels, combined with luminal narrowing, leads to decreased blood flow and can cause blood stasis (73). It creates a procoagulant state in the narrowed vessels, which increases the risk of thrombus formation and can lead to localized tissue ischemia and necrosis (73,76). The relationship between the implicated etiologic factors in CUA and its pathogenesis is schematically represented in Figure 5.…”

“…| Pathophysiology of calcific uremic arteriolopathy. Nuclear factor kb (NFkb), a transcription factor involved in the production of cytokines and inflammatory mediators, the receptor activator of NFkb (RANK), and its ligand are vital for bone mineral resorption and development (68,73,76). They can be activated by chronic inflammatory states, parathyroid hormone (PTH), aluminum, corticosteroids, free radicals, and infectious agents (73,76).…”

“…Osteoprotegerin (OPG) is an antagonist of RANKL. RANK/RANKL and OPG are expressed on endothelial cells, osteoblasts/osteoclasts, and vascular smooth muscle cells (VSMCs) (73,76). Transformation of VSMCs into osteoblast-like cells is initiated by metabolic disturbances (particularly hyperphosphatemia), reactive oxygen species (ROS), and decrease of local vascular calcification inhibitors, such as matrix g-carboxy-glutamate protein (MGP), a vitamin K-dependent protein (68,76).…”

“…Progressive subintimal fibrosis and medial-arteriolar calcification lead to endothelial injury and luminal narrowing. The low-flow rate within the cutaneous vessels combined with luminal narrowing leads to decreased blood flow and may lead to blood stasis (73). Systemic inflammation also causes endothelial dysfunction.…”