Materiały źródłowe

• #1 Calciphylaxis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519020/

  Calciphylaxis typically results from calcification of the medial layer of arterioles and small arteries. Blood flow is further reduced by endothelial injury and formation of microthrombi leading to luminal narrowing and occlusion. These changes cause tissue ischemia, necrosis, and ulceration. […] The cause and mechanisms leading to calciphylaxis remain poorly understood, and its development is likely dependent on multiple factors that lead to medial calcification of arterioles. Elevated calcium x phosphate product, increased parathyroid hormone levels, and administration of activated vitamin D have been associated with the development of calciphylaxis. However, abnormalities of bone-mineral parameters such as these are typically not sufficient to cause calciphylaxis on their own in most patients. Disturbances in bone-mineral parameters are extremely common in dialysis patients. However, most do not develop calciphylaxis. Further, calciphylaxis may develop even if parathyroid hormone, phosphorus, and calcium levels are normal.

• #2 Calciphylaxis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2989826/

  Calciphylaxis is a complex disorder with a multifactorial etiology. The exact pathogenesis of calciphylaxis is unclear. Medial calcification and intimal fibrosis of the cutaneous arterioles combined with thrombotic occlusion leading to ischemic skin necrosis is seen in calciphylaxis. […] In humans, most of the cases are associated with chronic renal failure and end-stage renal disease (ESRD). Patients with ESRD usually have secondary hyperparathyroidism corresponding to increased levels of parathyroid hormone, calcium, phosphorous, and alkaline phosphatase. […] Most of the calcium in the calciphylaxis plaque is derived from preformed bone. […] Excess aluminum greater than 25ng/mL confers a four-fold increased risk and is thought to play a role in the pathogenesis of calciphylaxis. […] In humans, vascular calcification is an active process and is not sufficient to produce skin necrosis. Vascular calcification and thrombosis are both required to produce lesions of calciphylaxis. Activation of nuclear factor kB (NFkB) is thought to be the final common pathway leading to vascular calcification.

• #3 Calciphylaxis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1095481-overview

  The pathogenesis of calciphylaxis remains obscure and is likely the result of a multiplicity of comorbid factors or events. Disorders that are most often implicated in the pathogenesis of calciphylaxis include chronic kidney disease (CKD; or chronic renal failure), obesity, diabetes mellitus, hypercalcemia, hyperphosphatemia, an elevated calcium-phosphate product, secondary hyperparathyroidism, and a variety of hypercoagulable states. Yet, although these abnormalities are extremely common in patients with end-stage renal disease (ESRD), calciphylaxis is relatively rare. […] Using a rat model, Selye demonstrated that a series of events might be necessary for the formation of calciphylaxis. He defined calciphylaxis as a condition of hypersensitivity induced by a set of „sensitizing” agents, in which calcinosis occurred only in those subsequently subjected to a group of „challengers” and only after a critical lag time.

• #4

  https://journals.lww.com/aswcjournal/fulltext/2019/05000/calciphylaxis__diagnosis,_pathogenesis,_and.3.aspx

  To provide information on the pathogenesis, clinical features, diagnosis, and treatment of calciphylaxis. […] Calciphylaxis is a cutaneous ischemic infarct caused by total occlusion of blood vessels initiated by vascular calcification. […] The last two decades have seen significant advances in clinical understanding of how calciphylaxis develops: in humans, it appears to be the skin equivalent of a myocardial infarction, not a protective response. […] Calciphylaxis is an occlusive disease of cutaneous blood vessels. Their lumens undergo progressive narrowing first by calcification within the media layer of vessel walls and proliferation of endothelial cells and fibrosis underneath the intima. […] On this march toward complete occlusion, vascular calcification is the inciting and central event.

• #5 Calciphylaxis | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/calciphylaxis?lang=us

  Calciphylaxis, also known as calcific uremic arteriolopathy, is a rare condition that manifests as subcutaneous vascular calcification and cutaneous necrosis (small blood vessels of the fat tissue and the skin). Some authors describe it as a syndrome of vascular calcification, thrombosis and skin necrosis. […] The exact pathogenesis of calciphylaxis is unclear. Medial calcification and intimal fibrosis of the cutaneous arterioles combined with thrombotic occlusion leading to ischemic skin necrosis is seen in calciphylaxis.

• #6 Calciphylaxis

  https://mobile.fpnotebook.com/Renal/Derm/Clcphylxs.htm

  Calciphylaxis (Calcific Uremic Arteriolopathy) […] Pathogenesis […] Vascular endothelial injury […] Vascular calcification of the tunica media (middle) layer of arterioles and small arteries […] Microthrombi complicate an already narrowed arteriole lumen resulting in tissue ischemia and infarction […] Skin lesions are pathognomonic, but arteriole calcification is systemic and diffuse end organ effects may occur […] In part secondary to abnormal metabolism of Calcium and Phosphorus […] However, additional poorly understood, modifying factors are required to trigger Calciphylaxis.

• #7 Case Report: Warfarin-Induced Non-Uremic Calciphylaxis Mimicking Vasculitis – The Rheumatologist

  https://www.the-rheumatologist.org/article/case-report-warfarin-induced-non-uremic-calciphylaxis-mimicking-vasculitis/

  Calciphylaxis, or calcific uremic arteriolopathy, is a rare disease characterized by calcification of the arterioles and capillaries in the dermis and subcutaneous tissue, resulting in thrombus formation and subsequent skin ischemia and necrosis. […] The suspected mechanism by which warfarin induces calciphylaxis is through the inhibition of vitamin K-dependent carboxylation of matrix Gla-protein, a mineral-binding extracellular matrix protein that prevents calcium deposition in arteries. This leads to progressive narrowing of cutaneous blood vessel lumens through calcification within the media layer of vessel walls and by the proliferation of endothelial cells and fibrosis underneath the intima. Thrombosis is the final step in calciphylaxis, which ultimately leads to complete vessel occlusion. Warfarin decreases protein C levels faster than the coagulation factors, therefore increasing thrombus formation. Ultimately, with microvascular thrombosis, ischemia develops.

• #8 Calciphylaxis in patients with chronic kidney disease: A disease which is still bewildering and potentially fatal | Nefrología

  https://www.revistanefrologia.com/en-calciphylaxis-in-patients-with-chronic-articulo-S2013251418301068

  Ischemia and the subsequent necrosis are produced by thrombotic occlusion of the cutaneous arterioles with a thickening of their wall due to the progressive calcification of the tunica media. While the process of thrombosis is an acute event and coincides with the clinical development of the pathology, the process of calcification takes much longer, in which many factors involved in ectopic calcification act together to produce the thickening of the media throughout a longer period of time. […] High doses of Vitamin D analogs may accelerate vascular calcification by facilitating osteogenic differentiation of vascular smooth muscle cells but, fundamentally by increasing the serum levels of phosphate and calcium. […] Although hyperparathyroidism has traditionally been considered as an important risk factor for uremic calciphylaxis, hypoparathyroidism has been also associated more recently with the development of calciphylaxis, in fact, adynamic bone disease has been associated with more severe vascular calcifications.

• #9

  https://journals.lww.com/aswcjournal/fulltext/2019/05000/calciphylaxis__diagnosis,_pathogenesis,_and.3.aspx

  Vascular calcification is actually an ectopic bone formation in the vessel walls by vascular smooth muscle cells. […] The most common clinical scenario that gives rise to calciphylaxis is a lack of molecular calcification inhibitors in the vessel wall. […] This deficiency is most commonly attributable to a lack of vitamin K. […] In summary, calciphylaxis develops because the peculiar biochemical environment in ESRD of abnormal phosphate, calcium, and PTH and vitamin K deficiency causes the skin vessels to calcify.

• #10 Calciphylaxis in patients with chronic kidney disease: A disease which is still bewildering and potentially fatal | Nefrología

  https://www.revistanefrologia.com/en-calciphylaxis-in-patients-with-chronic-articulo-S2013251418301068

  The process of calcification of the tunica media does not consist only in the passive deposition of calcium crystals, the process of calcification is preceded by the phenotypic transformation of the mesenchymal cells of the arterial wall into osteoblastic cells, that are able to produce bone tissue inside the tunica media exactly as if it was bone. […] The OPG is a soluble protein, synthesized mainly by osteoblasts, but also by stromal cells and endothelial cells. […] Another protein, MGP, produced by vascular smooth muscle cells, prevents transdifferentiation of the vascular smooth muscle cells into osteoblastic cells. […] It has been suggested that thrombosis of the stenosed vessel, which entails the acute onset of the clinical syndrome, may also be a consequence of a state of hypercoagulability, which may be caused by deficiency of protein C or S or even lupus anticoagulant. […] In some cases, patients have had a previous trauma in areas where subsequently develop necrosis or, in the case of diabetics, necrosis is observed in areas of repeated insulin injections such as abdomen or upper thighs.

• #11 Calciphylaxis (Calcific uremic arteriolopathy) – Dermatology Advisor

  https://www.dermatologyadvisor.com/home/decision-support-in-medicine/dermatology/calciphylaxis-calcific-uremic-arteriolopathy/

  The etiology of calciphylaxis is controversial; however, several molecular mechanisms have been postulated to play a role in the multifactorial pathogenesis of calciphylaxis in ESRD. […] Calciphylaxis has traditionally been thought to result from passive vascular deposition of calcium. However, recent research suggests that this hypothesis is simply one piece of a larger more complex process. Smooth muscle cells lining the vasculature may acquire osteoblastic properties, thus initiating development of calciphylaxis. […] This would explain why osteogenic markers, such as osteopontin and bone morphogenic protein 4, are often elevated in calciphylaxis patients, leading to extraskeletal calcification of vascular smooth muscle cells and periarterial dermal cells, respectively. […] This process may be exacerbated by the presence of hypercoaguable disorders, most commonly Protein C or S deficiency, which further promote thrombosis.

• #12 Pathogenesis of Calciphylaxis | Rare Vascular Conditions | Wound Info

  https://woundeducators.com/calciphylaxis-pathogenesis/?srsltid=AfmBOoq-0_UPa1l9h8M4tCttuQn0H8EmZs7dPW7ex1FeID4CnJwyvcod

  Calciphylaxis, a rare condition involving subcutaneous vascular calcification and cutaneous necrosis, is most commonly seen in patients with renal failure where it has a dismal mortality rate of up to 80 percent. […] Calciphylaxis is a complex disorder associated with multiple histologic abnormalities and a multifactorial etiology. […] However, it is thought that in the initial stages of the disease, the presence of uremia and the decrease of local vascular calcification inhibitory proteins causes the vascular smooth muscle cells (VSMCs) to differentiate into osteoblast-like cellular phenotypes. Bone morphogenic proteins induce de novo bone formation leading to calcification outside the bones. The nuclear factor kappa B (NFB) and its receptor activator (RANK), levels of which are raised in chronic inflammatory states such as alcoholic steatohepatitis, chronic kidney disease, and end-stage renal disease, also play an important role in bone homeostasis and vascular calcification. In addition, cytokines such as tumor necrosis factor alpha (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6), which are elevated in obesity, contribute to the pathogenesis. The elevated concentration of reactive oxygen species (ROS) in uremia is also thought to be important in the development of calciphylaxis, leading to an inflammatory cytokine surge, VSMC apoptosis, endothelial dysfunction, and a decrease in bioavailable nitric oxide (NO). […] Because of the large number of interacting systems involved in the pathogenesis of calciphylaxis, considerable research effort is currently devoted to understanding the exact nature of the different processes involved.

• #13 Management and mechanism of calciphylaxis in a patient treated with the FGFR inhibitor pemigatinib—a case report – Chandana – Journal of Gastrointestinal Oncology

  https://jgo.amegroups.org/article/view/82986/html

  Calciphylaxis is associated with skin lesions and affects the dermal microvasculature in addition to the vascular calcification. […] We highlight the unclear pathophysiology behind this disease by identifying key players in the signaling and molecular pathways in the microenvironment that are needed to trigger this pathology. […] While the pathogenesis of calciphylaxis is unclear, there is a plethora of in-vitro data outlining a common pathway. Risk factors (e.g., hypercalcemia, hyperphosphatemia) initially stimulate vascular smooth muscle cells (VSMCs) to transdifferentiate from a contractile phenotype to an osteoblast-like state, upregulating transcription factors important in bone formation (e.g., RUNX2). […] Thus, FGF pathway inhibition mediates calciphylaxis through two avenues: facilitating high calcium-phosphate product that directly and indirectly powers a feed-forward loop of osteogenic VSMC transdifferentiation that fuels vascular and tissue calcification.

• #14 Calciphylaxis in patients with chronic kidney disease: A disease which is still bewildering and potentially fatal | Nefrología

  https://www.revistanefrologia.com/en-calciphylaxis-in-patients-with-chronic-articulo-S2013251418301068

  Calciphylaxis, also known as calcific uremic arteriolopathy, is a rare syndrome that typically causes skin necrosis and usually affects dialysis patients. Its pathogenesis is multifactorial and is the consequence of many factors causing ectopic calcifications in patients with chronic kidney disease, such as calcium-phosphate metabolism disorders, hyper- or hypo-parathyroidism, diabetes, obesity, systemic inflammation and the use of vitamin K antagonists, among others. […] Calciphylaxis, also called calcific uremic arteriolopathy (CUA), is a clinical syndrome characterized by necrotic ulceration of the skin due to arteriolar calcification of the media plus fibrosis of the intima and subsequent cutaneous ischemia due to thrombosis of the arteriole. It is manifested in patients on renal replacement therapy or with low glomerular filtration, whose alteration of phosphorus and calcium metabolism seems to represent the main cause of this pathology.

• #15 Calciphylaxis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/calciphylaxis/symptoms-causes/syc-20370559

  Calciphylaxis (kal-sih-fuh-LAK-sis) is a rare, serious disease. It involves a buildup of calcium in small blood vessels of fat tissues and skin. […] The exact cause of calciphylaxis isn’t clear. But people with the disease usually have kidney failure. […] Calciphylaxis can happen in people without kidney disease too. […] The disease involves the buildup of calcium in the smallest parts of the arteries in fat tissues and skin. […] Many people who get calciphylaxis also have kidney failure or receive dialysis. It’s not known why people with kidney failure or people receiving dialysis are at higher risk of calciphylaxis. […] For some people, the calcium buildup in calciphylaxis is linked with small organs in the neck called parathyroid glands. […] Other factors that seem to play roles in calciphylaxis include: A greater tendency for blood to clot. Blood clots can deprive fat tissues and skin of oxygen and nourishment.

• #16 Calciphylaxis | 5-Minute Clinical Consult

  https://www.unboundmedicine.com/5minute/view/5-Minute-Clinical-Consult/816114/2.0/Calciphylaxis

  Rare, highly morbid, obliterative vasculopathy, characterized by ischemic or necrotic skin lesions. […] Pathogenesis involves medial calcification and intimal proliferation in subcutaneous vessels along with hypercoagulable state leading to ischemia. […] Pathogenesis is a two-step process involving initial obliterative medial wall calcification, followed by ischemic, occlusion, and tissue necrosis. […] Vascular lesions characterized by arteriolar medial calcification, intimal proliferation, endovascular fibrosis. […] Local trauma, hypotension, thrombosis, procoagulant states may trigger process. […] Disturbances in Ca/P/parathyroid hormone (PTH) homeostasis have been implicated but are inconclusive. […] Obesity is an important etiologic factor.

• #17 Calciphylaxis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519020/

  Deficiency of vascular calcification inhibitors such as fetuin-A, osteoprotegerin, and matrix G1a protein may play a role in the development of calciphylaxis. Fetuin-A is a glycoprotein that binds calcium and phosphorus and may help to prevent calcification of vessels and soft tissue. Fetuin-A is downregulated in dialysis patients. Matrix G1a protein may also prevent vascular calcification and is dependent on vitamin K dependent carboxylation for its activity. Warfarin use has been implicated as a risk factor for calciphylaxis, which may be related to its interference with vitamin K dependent activation of matrix G1a.

• #18 Calciphylaxis – Wikipedia

  https://en.wikipedia.org/wiki/Calciphylaxis

  Adipocytes have been shown to calcify vascular smooth muscle cells when exposed to high phosphate levels in vitro, mediated by vascular endothelial growth factor A (VEGF-A) and leptin released by adipocytes. Given that calciphylaxis tends to affect adipose tissue, this may be a contributing explanation. […] Another hypothesis has been proposed, that vitamin K deficiency contributes to the development of calciphylaxis. Vitamin K acts as an inhibitor of calcification in vessel walls by activating matrix Gla protein (MGP), which in turn inhibits calcification. End-stage kidney disease patients are more likely to have vitamin K deficiency due to dietary restrictions meant to limit potassium and sodium. Many end-stage kidney disease patients are also on a medication called warfarin, a vitamin K antagonist, that limits vitamin K recycling in the body.

• #19 SciELO Brazil – Diagnosis and treatment of calciphylaxis in patients with chronic kidney disease Diagnosis and treatment of calciphylaxis in patients with chronic kidney disease

  https://www.scielo.br/j/jbn/a/RVkm7hnwxgvvh8NhdWK9CYy/

  The presence of secondary hyperparathyroidism (SHPT), administration of vitamin D analogues (calcitriol or paricalcitol), hyperphosphatemia and an elevated CaxP product have often been implicated in the development of calciphylaxis. […] Deficiency of VC inhibitors might also act in the pathogenesis of calciphylaxis, the most studied being fetuin-A (2-Heremans-Schmid glycoprotein) and matrix Gla protein (MGP). […] Obesity is also acknowledged as a risk factor, suggesting the contribution of adipocytes in the process. […] The deficiency of CD73, also referred to as NT5E (autosomal recessive disease), leads to a syndrome in which the phenotype resembles calciphylaxis. […] Other risk factors associated with calciphylaxis are: presence of CKD (in which there would be an inflammatory environment conducive to the development of calciphylaxis), female gender (with usual greater fat distribution, in addition to the possible presence of genetic factors associated with gender), diabetes mellitus (having a proinflammatory environment, malnutrition), hereditary thrombophilia, protein C deficiency, lupus anticoagulant, autoimmune diseases, repeated subcutaneous injections, accelerated weight loss, and use of other drugs, such as intravenous iron and recombinant PTH.

• #20 Warfarin and Calciphylaxis — A Rare but Serious Adverse Event

  https://www.medsafe.govt.nz/profs/PUArticles/September2017/WarfarinAndCalciphylaxis.htm

  Calciphylaxis is a very rare but serious condition characterised by vascular calcification and cutaneous necrosis. […] The exact pathogenesis of calciphylaxis is unknown. Small blood vessels deep in the skin become blocked due to calcification and thrombosis. The resulting skin lesions are typically purpuric, indurated plaques with central necrosis. […] The mechanism by which warfarin causes calciphylaxis may be mediated through the matrix Gla protein, which is a vitamin-K-dependent protein that prevents calcium deposition in arteries. Warfarin inhibits Gla protein and may therefore promote vascular calcification in susceptible individuals. […] The authors of a recent review suggest that warfarin-associated calciphylaxis is distinct from classic calciphylaxis in pathogenesis, course and particularly outcome as the survival rate of nonuremic patients was remarkably high (83%).

• #21

  https://link.springer.com/article/10.1007/s12325-020-01504-w

  The preceding factors that alter smooth muscle cells promote the narrowing and induration of the affected arteriolar lumens, compromising their structural integrity, and ultimately foster a more conducive environment for thrombotic development. […] Thrombosis, once manifest, catalyzes the vessel occlusion that leads to the development of ischemic injuries, which in advanced cases leads to dermal necrosis and secondary infections that can promote sepsis. […] The major risk factors for calciphylaxis are renal failure as previously mentioned, aberrations in calcium and phosphate homeostasis as in hyperphosphatemia, hypercalcemia, hyper- and hypoparathyroidism, and vitamin K deficiency. […] Vitamin K deficiency is another prominent risk factor due to the vitamins role in activating the matrix Gla protein (MGP), which acts as a strong inhibitor of calcification in the vessel walls.

• #22 Warfarin: reports of calciphylaxis – GOV.UK

  https://www.gov.uk/drug-safety-update/warfarin-reports-of-calciphylaxis

  Calciphylaxis is poorly understood and the exact pathogenesis is unknown. […] The mechanism could be mediated through the matrix Gla protein, which is a vitamin-K-dependent protein involved in the inhibition of calcification. Warfarin inhibits Gla protein and may therefore promote vascular calcification in susceptible individuals.

• #23 Warfarin-induced calciphylaxis in a chronic hypercalcemic patient – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/warfarin-induced-calciphylaxis-in-a-chronic-hypercalcemic-patient/

  Calciphylaxis most commonly occurs in patients with end-stage renal disease under dialysis. […] Warfarin can inhibit the activation of matrix G1A protein, which inhibits vascular calcification and reduces functional protein C levels to cause hypercoaguability. […] Combination of hypercalcemia and warfarin therapy can lead to calciphylaxis. […] Calciphylaxis is a condition with high morbidity and mortality usually due to infection. […] The current therapeutic trend for calciphylaxis consists of reducing calcium phosphate product, improving hypercoaguability, improving wound care, prevention of infection and using a trial of intravenous sodium thiosulfate.

• #24 Calciphylaxis of the penis and distal digits: a case report | Journal of Medical Case Reports | Full Text

  https://jmedicalcasereports.biomedcentral.com/articles/10.1186/s13256-021-03231-4

  Calciphylaxis is a rare, often fatal disease resulting from calcification of dermal arterioles and capillaries. […] The exact mechanism of pathogenesis is unknown, but hyperparathyroidism, hypervitaminosis D, and elevated serum calcium and phosphorus have all been implicated. […] It is thought that calcium deposition and subsequent endothelial injury promotes formation of microthrombi, which reduces luminal caliber leading to ischemia and necrosis of overlying tissues. […] Involvement of the penis, as in our patient, is a particularly poor prognostic indicator, with 6-month mortality rates as high as 70%. […] Even with appropriate management, calciphylaxis is a lethal disease: 6-month mortality rate is estimated to be 50%, with most patients dying from overwhelming infection. […] Despite theoretical benefits, anticoagulation does not play a major role in management; in fact, warfarin therapy has been established as a risk factor for calciphylaxis, possibly through inhibition of vitamin K-dependent regulatory proteins that prevent vascular calcification.

• #25 Calciphylaxis Prevention and Treatment Strategies- Clinical Advisor

  https://www.clinicaladvisor.com/features/calciphylaxis-prevention-treatment-strategies/

  It is unclear if calciphylaxis affects visceral blood vessels along with cutaneous blood vessels. Histologic findings in an autopsy study of 3 patients with calciphylaxis revealed cutaneous calcification but no evidence of calciphylaxis within organs, suggesting that the disorder did not affect visceral blood vessels. […] Calciphylaxis appears to be multifactorial with unknown pathogenesis and, therefore, no serologic or hematologic confirmatory test is available. However, diagnostic tests that can be included in the initial workup to identify abnormalities include complete blood count, urea and creatinine, corrected calcium, phosphate, calcium-phosphorus index, PTH, coagulation profile, and thrombophilia screen. […] These findings indicate that the listed hypercoagulable states may contribute to the pathogenesis of calciphylaxis, and could be a possible screening tool for patients with chronic kidney disease and/or ESRD.

• #26 Calciphylaxis Diagnosis and Management in Primary Care

  https://www.clinicaladvisor.com/features/calciphylaxis-diagnosis-treatment-primary-care/

  Calciphylaxis is a relatively rare condition characterized by ischemic skin lesions resulting from calcium deposits occluding microvessels creating painful areas of ecchymoses that lead to dark-colored lesions and eventually necrosis. The pathogenesis of calciphylaxis is unclear. One possible mechanism is dysregulation of bone morphogenic proteins 2 and 4 (BMP-2 and BMP-4). Dysregulation of BMPs leads to excess calcium deposits in the vasculature and subcutaneous fat. Microvascular calcifications may lead to ischemia, malodorous nonhealing ulcers, and pain. Calciphylaxis is prevalent in body areas with increased adipose tissue such as the abdomen and thighs. The role of adipose tissue in manifestations of calciphylaxis is poorly understood. […] The most common site of calciphylaxis injury is the lower extremities followed by the breasts and abdomen. […] Morbidity and mortality associated with septicemia are high as the integrity of the skin and underlying subcutaneous fat is compromised resulting in an environment conducive to bacterial colonization. […] One-year mortality rates are greater than 50%.

• #27

  https://link.springer.com/article/10.1007/s12325-020-01504-w

  The hypercoagulation risk factor is linked to the increased propensity for development of thrombosis in calcified vessels, accelerating the advanced morbid effects of calciphylaxis on cutaneous tissue. […] One possible explanation for the stronger tendency for the disease to manifest in adipose tissue is that adipocytes exposed to high phosphate concentrations can cause vascular smooth muscle cells to calcify in vitro. […] It has been shown with obesity that the rate of growth of adipose tissue outpaces the capacity for existing capillary density to function effectively and provide requisite metabolic support.

• #28 Atypical Wounds – Calciphylaxis | AccessMedicine Network

  http://www.accessmedicinenetwork.com/users/253399-rose-hamm/posts/atypical-wounds-calciphylaxis

  Calciphylaxis, also known as calcific uremic arteriolopathy, is a potentially fatal condition characterized clinically by progressive cutaneous necrosis as a result of calcification and thrombosis of the dermal arterioles. […] The pathogenesis of calciphylaxis involves progressive narrowing of the cutaneous blood vessels as a result of calcification within the media layer of the vessel walls and proliferation of endothelial cells with fibrosis under the intima of the vessel. Subsequently, thromboses develop in the vessel lumen, leading to tissue ischemia and necrosis. The vascular calcification is actually like ectopic bone formation in the vessel walls, which is related to hyperphosphatemia, hypercalcemia, and hyperglycemia. VEGF-A and leptin appear to be the mediators that transform the vascular cells from smooth muscle cells to calcified cells; both of these are released from adipocytes. These same conditions that cause vessel calcification are the conditions that exist in the above mentioned risk factors.

• #29 Pulmonary Calciphylaxis Associated with Acute Respiratory and Renal Failure Due to Cryptogenic Hypercalcemia: An Autopsy Case Report

  https://www.jpatholtm.org/journal/view.php?number=3125

  Metastatic calcification is rare; it is found during autopsy in patients who underwent hemodialysis. […] Calciphylaxis, also called uremic calcific arteriolopathy, is a rare life-threatening entity of progressive cutaneous necrosis secondary to calcification of small and medium-sized blood vessels, which shows rapid development. […] Calciphylaxis is characterized by diffuse precipitation of tissue calcium, and is a rare fatal entity of calcific vasculopathy associated with tissue necrosis. […] Metastatic calcification and calciphylaxis are metabolic disorders, for which the precise pathogenesis has not yet been determined. […] Multifactorial causes have been suggested: persistent or transient hyperphosphatemia, vitamin D intoxication, hypercalcemia, steroid therapy in renal transplant recipients, and deficiencies or functional abnormalities of proteins C and S, warfarin therapy, or secondary hyperparathyroidism.

• #30 Management of patients with calciphylaxis: current perspectives | CWCMR

  https://www.dovepress.com/management-of-patients-with-calciphylaxis-current-perspectives-peer-reviewed-fulltext-article-CWCMR

  However, the serum calcium and phosphate levels can be affected by a large number of possible underlying disorders beyond chronic kidney disease and these have to be clarified. […] Chronic inflammatory states are discussed as possible risk factors for vascular calcification as TNF-a induces an osteogenic phenotype of human smooth-muscle cells in vitro. […] Aluminum excess has also been discussed to be at least a co-factor in the pathogenesis of some CP cases by involvement in the NFkB pathway which itself might influence vascular calcification. […] Warfarin is one of the best known factors associated with CP and the course of disease. […] It has been shown that warfarin can negatively influence vitamin K-dependent proteins which prevent vascular calcification. […] Some authors even postulated distinguishing between warfarin-associated and -unassociated CP.

• #31 SciELO Brazil – Diagnosis and treatment of calciphylaxis in patients with chronic kidney disease Diagnosis and treatment of calciphylaxis in patients with chronic kidney disease

  https://www.scielo.br/j/jbn/a/RVkm7hnwxgvvh8NhdWK9CYy/

  1. Its pathophysiology is not completely known. However, histological findings show calcification of arterioles, besides thrombosis and endothelial damage of these vessels. These changes cause ischemia and necrosis of the subcutaneous tissue, with necrotic ulcers appearing in more advanced stages (Evidence). […] Calciphylaxis is associated with the use of vitamin K inhibitors. This inhibition prevents the activation of matrix Gla protein (MGP), an extracellular matrix protein synthesized in the endothelial, vascular smooth muscle and in the chondrocytes. It is a potent inhibitor of calcification. […] The presence of alterations in mineral metabolism, as hypercalcemia, hyperphosphatemia and PTH extremes is another risk factor. These changes might promote the appearance of all forms of vascular calcification (VC): of the intima layer of the arteries (atherosclerosis), of the media layer (arteriosclerosis, also known as Mnckeberg arteriosclerosis), valve calcification and calciphylaxis. VC is not only a passive process of mineral deposition, but rather an active one. Vascular smooth muscle cells, depending on various stimuli, modify their phenotype and express factors such as RUNX2, which is a key transcription factor for osteoblast differentiation. Once transdifferentiated, the smooth muscle cells produce matrix vesicles containing calcium and phosphorus, which will promote vessel mineralization, or calcification.

• #32 Calciphylaxis Prevention and Treatment Strategies- Clinical Advisor

  https://www.clinicaladvisor.com/features/calciphylaxis-prevention-treatment-strategies/

  Calciphylaxis, also known as calcific uremic arteriolopathy, occurs secondary to calcification of arterioles and arteries. The occlusion of the blood vessels leads to a spectrum of clinical findings including thrombosis and skin ischemia that can progress to skin infarcts, necrosis, and ulceration. […] The etiology of the disease is unknown, but a cardinal feature is cutaneous necrosis associated with calcium deposits in the medial layer of the small to medium blood vessels along with intramural thrombus. The pathophysiology is likely multifactorial and appears to be related to elevated serum levels of calcium and phosphate causing blood vessel calcification. […] A component of the pathogenesis may be dysregulation in the pathway involved in both bone and vascular calcification that includes receptor activator of nuclear factor-B, receptor activator of nuclear factor-B ligand, and osteoprotegerin. More research is needed to determine the exact pathway of calciphylaxis.

• #33 ABSTRACT

  https://www.ejcrim.com/index.php/EJCRIM/article/download/986/1573?inline=1

  Calciphylaxis is a rare disease characterized by arterial and arteriole calcification, soft tissue calcification, and thrombosis, resulting in ischaemia and skin necrosis. […] Calciphylaxis is characterized by an insidious asymptomatic medial arteriolar calcification, resulting in clinical manifestations when vascular thrombosis occurs. Vascular calcification results from active cellular processes involved in biomineralization and the NFkB pathway, being regulated by several factors. Prothrombotic factors are additionally involved in the acute development of vascular occlusion. […] The diagnosis of NUC requires a high level of suspicion and depends on the identification of the typical clinical features in the presence of risk factors and related conditions, while excluding clinical mimics.

• #34 Calciphylaxis (Calcific uremic arteriolopathy) – Dermatology Advisor

  https://www.dermatologyadvisor.com/home/decision-support-in-medicine/dermatology/calciphylaxis-calcific-uremic-arteriolopathy/

  Additionally, decreased inhibitors of calcification have been noted. In healthy individuals, gamma-carboxylation binds calcium and inhibits vessel calcification; however, warfarin inhibits this vitamin K-dependent carboxylation and may result in increased calcification in those patients on this anticoagulation therapy. […] Furthermore, ESRD patients are unable to adequately remove excess phosphorus causing extraosseous calcification. […] Although calcium deposition results in progressive narrowing of the vessel lumen, the sudden vascular occlusion and thrombosis results in calciphylaxis. […] Vascular mural calcification is believed to be an early and essential process in the development of the plaque.

• #35 Calciphylaxis pathology

  https://dermnetnz.org/topics/calciphylaxis-pathology

  Calciphylaxis is seen almost exclusively in patients with end stage kidney disease. Calcification of vessels and soft tissue cause skin infarction and subsequent necrosis. […] A deep biopsy to sample the subcutis is needed to make the diagnosis of calciphylaxis. The epidermis and dermis is often ulcerated and necrotic with numerous secondary changes. There is calcification of small-medium sized vessels. The intima of the vessels is commonly fibrosed and there may be intravascular thrombi. Diffuse calcification of small capillaries in the fat is a characteristic feature. There may also be calcification of adipocytes. […] Calcium can be demonstrated with special stains such as Von Kossa. […] A clinical history of renal failure and necrotic skin lesions can be helpful in providing confidence in diagnosing calciphylaxis. Vascular thrombosis and calcification of numerous capillaries/fat suggest calciphylaxis.

• #36 Calciphylaxis and Hypotension: Report of a Case and Review of the Literature

  https://www.heraldopenaccess.us/openaccess/calciphylaxis-and-hypotension-report-of-a-case-and-review-of-the-literature

  Non-calcium and PTH related etiologies include several conditions rooted in hypercoagulability, which include warfarin use. […] Other calciphylaxis risk factors include female sex, and obesity or significant weight loss, with the latter two working via effects on fibroelastic septae. […] Thus, beyond the more obvious decrease in local cutaneous perfusion, hypotension contributes to calciphylaxis progression through contribution to vascular calcification as well. […] Thus, hypotension and hemodynamic instability contribute in a multifactorial way to calciphylaxis pathogenesis. […] The exact pathogenesis of calciphylaxis remains unclear and is the topic of continued research and debate. […] Our case is the first to our knowledge to demonstrate a consistent temporal relationship of episodes of hemodynamic instability with disease progression indicating that aggressive blood pressure control may be a vital component of a multimodal treatment plan in the calciphylaxis patient.

• #37 Calciphylaxis in patients with chronic kidney disease: A disease which is still bewildering and potentially fatal | Nefrología

  https://www.revistanefrologia.com/en-calciphylaxis-in-patients-with-chronic-articulo-resumen-S2013251418301068

  In some cases, patients have had a previous trauma in areas where subsequently develop necrosis or, in the case of diabetics, necrosis is observed in areas of repeated insulin injections such as abdomen or upper thighs. […] The risk factors mostly associated with the development of calciphylaxis are the time in renal replacement therapy, alterations in calcium and phosphate metabolism, female gender, obesity and treatment with vitamin K antagonists.

• #38 Phenprocoumon based anticoagulation is an underestimated factor in the pathogenesis of calciphylaxis | BMC Nephrology | Full Text

  https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-019-1301-6

  Calciphylaxis is a life threatening complication in renal patients. […] The evaluation of biopsy proven calciphylaxis demonstrates that especially treatment with vitamin K antagonists and liver dysfunction are most important concomitant factors in development of calciphylaxis. […] Most patients suffered from secondary hyperparathyroidism due to CKD and consecutive disturbed calcium and phosphate metabolism, which in turn poses a factor associated with the outbreak of calciphylaxis, as many previous studies have shown. […] The most noticeable result of our study was the high percentage of treatment with VKA (almost 90%). […] VKA is an established concomitant factor for the development of calciphylaxis and accelerates the calcification process. […] Impaired liver function seems to be, as up to now, an underestimated contributing factor. […] Furthermore obesity seems to be a major contributing factor. […] In summary, there seems to be no single determinant causing calciphylaxis, however, interaction of different contributing factors with different weight may lead to disease outbreak.

• #39 Calciphylaxis: A Review | JCAD – The Journal of Clinical and Aesthetic Dermatology

  https://jcadonline.com/calciphylaxis-a-review/

  Calciphylaxis is a complex disorder with a multifactorial etiology. The exact pathogenesis of calciphylaxis is unclear. Medial calcification and intimal fibrosis of the cutaneous arterioles combined with thrombotic occlusion leading to ischemic skin necrosis is seen in calciphylaxis. […] In humans, most of the cases are associated with chronic renal failure and end-stage renal disease (ESRD). […] Most of the calcium in the calciphylaxis plaque is derived from preformed bone. […] Excess aluminum greater than 25ng/mL confers a four-fold increased risk and is thought to play a role in the pathogenesis of calciphylaxis. […] In humans, vascular calcification is an active process and is not sufficient to produce skin necrosis. Vascular calcification and thrombosis are both required to produce lesions of calciphylaxis. Activation of nuclear factor kB (NFkB) is thought to be the final common pathway leading to vascular calcification. […] Calciphylaxis is a complex disorder with a multifactorial etiology. The exact cause is unknown, but it is seen more commonly in patients with renal failure.

• #40 ABSTRACT

  https://www.ejcrim.com/index.php/EJCRIM/article/download/986/1573?inline=1

  The most recommended strategy is to combine treatments to address both vascular calcification and thrombosis, and taking account of the metabolic and coagulation status of each patient. […] This disease represents a diagnostic and therapeutic challenge, with treatment currently limited to debridement, analgesia, and control of triggers and septic complications.

• #41 Management of patients with calciphylaxis: current perspectives | CWCMR

  https://www.dovepress.com/management-of-patients-with-calciphylaxis-current-perspectives-peer-reviewed-fulltext-article-CWCMR

  The systemic application of STS or bisphosphonates is confirmed as successful in several case studies. […] Randomized controlled studies on larger cohorts are needed to clear upcoming issues about dosage, treatment duration and long-term outcomes. […] Diagnosis and treatment are hindered for the non-uremic forms of CP where so far the concepts of CUA can only be transferred in lack of distinct recommendations.

• #42 STS in Calciphylaxis — NephJC

  http://www.nephjc.com/news/sts-cua

  Calciphylaxis, more accurately now called calcific uremic arteriolopathy (CUA), is characterized by vascular calcification of the microvessels in subcutaneous adipose tissue and dermis that results in intensely painful, ischemic skin lesions (Nigwekar et al, NEJM 2018). […] Sodium thiosulphate (STS) chelates calcium salts and is also an antioxidant agent. STS reduces intravascular and extravascular calcifications by forming a more soluble product, calcium thiosulfate. This effectively attenuates the burden of calcification in adipocytes and vascular smooth muscle cells. […] The possible mechanism of STS on the vascular wall can be seen in the following figure (Hyden et al, Semin Dial 2010). […] Many observational studies reporting the effectiveness of STS in patients with calciphylaxis lack a comparator arm, thus limiting the interpretation of their findings.

• #43 Sodium Thiosulfate for Calciphylaxis Treatment in Patients on Peritoneal Dialysis: A Systematic Review

  https://www.mdpi.com/1648-9144/59/7/1306

  While the exact mechanism of action of sodium thiosulfate in the treatment of calciphylaxis is not completely understood, studies suggest that sodium thiosulfate can effectively treat calciphylaxis by binding to calcium ions in the bloodstream and soft tissue, preventing the formation of calcium deposits and reducing tissue calcification. Additionally, it possesses antioxidant and anti-inflammatory properties that can help reduce tissue damage and promote healing. The administration routes and doses varied depending on the study. For intravenous (IV) administration, STS doses ranged from 3.2 g twice daily to 25 g three times weekly for 5 weeks to 8 months. Outcomes included 44% of patients experiencing successful wound healing, 6% discontinuing STS due to adverse effects, 67% transitioning to HD, and 50% dying from calciphylaxis complications. For intraperitoneal (IP) administration, STS doses ranged from 12.5 to 25 g three to four times weekly for 12 h to 3 months. Results showed 80% of patients achieving successful wound healing, 80% discontinuing STS due to adverse effects, 40% transitioning to HD, and 20% dying from IP STS-related chemical peritonitis.

• #44 Penile Calciphylaxis – A Rare, Yet Medically Treatable Disease – Indian Journal of Nephrology

  https://indianjnephrol.org/penile-calciphylaxis-a-rare-yet-medically-treatable-disease/

  Calciphylaxis is an obliterative calcific vasculopathy most commonly occurring in end-stage renal disease (ESRD) patients on hemodialysis (HD) or peritoneal dialysis (PD) or renal transplant recipients. […] The hypothesized mechanism is due to reduction in the arteriolar blood flow, which is caused by calcification, intimal fibrosis, and thrombus formation primarily involving the media of dermo-hypodermic small arterioles and capillaries (600 m in diameter), with fibrosis and thrombosis leading to tissue necrosis. […] The possible mechanism of STS is unknown, but it is speculated that it is due to chelation of calcium ions, dissolution of insoluble calcium deposits, and restoration of endothelium; also, its role as a potent antioxidant has been noted to promptly decrease pain. […] Calciphylaxis is a treatable disease with a high morbidity and mortality. Early recognition of the condition, appropriate treatment with analgesics, and prevention and treatment of the infection by wound care with antibiotics and STS are critical to allow wound healing, which significantly decreases morbidity and mortality in these patients.

• #45 University of Illinois Chicago

  https://dig.pharmacy.uic.edu/faqs/2020-2/january-2020-faqs/what-data-are-available-to-support-the-use-of-bisphosphonates-in-calciphylaxis/

  Calciphylaxis, also known as calcific uremic arteriolopathy, is a rare but life-threatening cutaneous vascular disease. […] Although the pathogenesis of calciphylaxis is still uncertain, the blood vessel calcification seen in this disease is likely the result of an imbalance between calcification promoting factors and calcification inhibiting factors. Decreased levels of calcification inhibiting factors have been observed in patients with calciphylaxis. Calcification and narrowing of microvessels results in chronic, low-grade ischemia. When endothelial injury and microthrombosis occurs in calcified vessels, it results in further occlusion and eventual infarction. […] The mechanism of action for bisphosphonates in calciphylaxis is not well understood. Bisphosphonates are pyrophosphate analogues; pyrophosphate is a potent inhibitor of calcium hydroxyapatite formation. Bisphosphonates have also been noted to produce anti-inflammatory effects, which may help decrease the calcification of vascular smooth muscle.

• #46 University of Illinois Chicago

  https://dig.pharmacy.uic.edu/faqs/2020-2/january-2020-faqs/what-data-are-available-to-support-the-use-of-bisphosphonates-in-calciphylaxis/

  The majority of experts on the 2015 consensus panel were not in favor of recommending bisphosphonates as a first-line treatment option for dialysis-associated calciphylaxis. […] The authors of the consensus statement note that the published evidence for bisphosphonates is scarce, and that bisphosphonates have the potential to worsen adynamic bone disease, particularly in patients with stage 4 or 5 CKD. Therefore, bisphosphonates should only be considered in cases where adynamic bone disease has been ruled out or determined to be highly unlikely. […] The evidence for bisphosphonate therapy in calciphylaxis is limited to case reports and small case series. Although positive outcomes have been observed in some patients who received bisphosphonates as part of a multimodal intervention, evidence from prospective trials is needed to determine the place in therapy for bisphosphonates, as well as optimal dosing and treatment duration.

• #47 Calciphylaxis in POEMS Syndrome: A Case Treated with Etidronate | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-0968

  Calciphylaxis is a rare disease presenting as systemic deposition of calcium salts. […] The pathogenesis of calciphylaxis remains obscure, but is considered to involve abnormal calcium metabolism and hyperparathyroidism. […] Most patients have end-stage renal disease, and some receive haemodialysis or peritoneal dialysis. […] Patients with calciphylaxis frequently have increased serum levels of calcium, phosphate and/or PTH which appear to promote calcium deposition within blood vessels. […] However, calciphylaxis is not always associated with metabolic abnormalities in these patients. […] In addition, VEGF is an activator of the coagulation pathway. […] Chronically elevated VEGF activity may be involved in the development of vessel calcification. […] Furthermore, interleukin (IL)-1, IL-6 and tumour necrosis factor- have also been implicated in POEMS syndrome, and these factors may also have roles in the pathogenesis of calciphylaxis. […] Therefore, bisphosphonates appear to be an effective treatment for calciphylaxis, as they control macrophages without affecting serum calcium levels. […] The present case suggests that bisphosphonates are effective in treating calciphylaxis, even in patients with normal serum calcium levels.

• #48 Update on Calciphylaxis Etiopathogenesis, Diagnosis, and Management | MDedge

  https://blogs.the-hospitalist.org/content/update-calciphylaxis-etiopathogenesis-diagnosis-and-management

  Calciphylaxis is thought to have a multifactorial etiology with the exact cause or trigger unknown. A long list of risk factors and triggers is associated with the condition. Calciphylaxis primarily affects small arteries (40-600 µm in diameter) that become calcified due to an imbalance between inhibitors and promoters of calcification. Fetuin-A and matrix Gla protein inhibit vascular calcification and are downregulated in calciphylaxis. Dysfunctional calcium, phosphate, and parathyroid hormone regulatory pathways provide an increased substrate for the process of calcification, which causes endothelial damage and microthrombosis, resulting in tissue ischemia and infarction. Notably, there is growing interest in the role of vitamin K in the pathogenesis of calciphylaxis. Vitamin K inhibits vascular calcification, possibly by increasing the circulating levels of carboxylated matrix Gla protein. […] The limited understanding of the etiopathogenesis of calciphylaxis and the lack of data on its management are reflected in the limited treatment options for the disease.

• #49 Calciphylaxis – What Do We Know? – AJKD Blog

  https://ajkdblog.org/2015/07/13/calciphylaxis-what-do-we-know/

  Calciphylaxis is a rare and devastating disease, affecting mostly patients with end-stage kidney disease, but also affecting patients with preserved kidney function. […] Although the pathogenesis of calciphylaxis is not well understood, several risk factors are implicated, and nicely summarized in Table 1 of the article. The dysregulation of mineral-bone disease axis clearly plays a major role in the development of calciphylaxis, but it is not the sole cause. […] In summary, calciphylaxis is a rare but life-threatening disorder with complex and poorly understood pathogenesis.

• #50 Calciphylaxis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1095481-overview

  Although extrapolation of animal data to humans is conjectural, it seems to be true that serial events, most consistently involving renal failure-induced abnormalities in calcium homeostasis, are required to occur over time for calciphylaxis to develop. The cause of calciphylaxis has been elusive, most likely because it is the common endpoint of a heterogeneous group of disorders. […] Many molecular and cytochemical factors have been identified as crucial in bone metabolism. The receptor activator of nuclear factor-kB (RANK), RANK ligand, and osteoprotegerin appear to regulate skeletal and extraskeletal mineralization. Uremia-induced defects in this system may predispose to calciphylaxis. […] Corticosteroids, aluminum, hyperparathyroidism, liver disease, warfarin therapy, and various inflammatory processes all can alter this balance and promote vascular calcification.

• #51 Sodium Thiosulfate for Calciphylaxis Treatment in Patients on Peritoneal Dialysis: A Systematic Review

  https://www.mdpi.com/1648-9144/59/7/1306

  Calciphylaxis, also known as calcific uremic arteriolopathy (CUA) or uremic small-vessel disease, is an infrequent yet serious complication that can develop in patients with end-stage kidney disease (ESKD). The condition arises due to the deposition of calcium in the small blood vessels of the skin and other organs, resulting in painful tissue necrosis and skin ulcers. While the exact cause of calciphylaxis remains unknown, an imbalance in calcium and phosphate metabolism is thought to contribute to its development. Various studies have indicated that the incidence of calciphylaxis is higher in patients undergoing peritoneal dialysis (PD) compared to those receiving hemodialysis (HD). The reasons behind the higher incidence of calciphylaxis in PD patients in comparison to HD patients are not yet fully understood. However, several factors have been suggested to contribute to the increased risk. Firstly, PD patients are likely to have a higher exposure to calcium-containing dialysate fluids, which could contribute to the development of calciphylaxis. During PD, the peritoneal membrane is used to filter blood, and it can absorb calcium from the dialysate fluid. This may result in higher calcium levels in the blood, which can increase the risk of calcification in small blood vessels. Secondly, PD patients may have a higher prevalence of comorbidities such as diabetes and obesity, which are known to be risk factors for calciphylaxis. Thirdly, PD patients may have a higher rate of prescription for calcium and vitamin D supplements to manage their calcium and phosphate levels. This may increase the risk of calciphylaxis. Finally, PD patients may have impaired clearance of calcium and phosphate due to their reduced kidney function. This can result in an imbalance in calcium and phosphate metabolism in the body, leading to an increased risk of calciphylaxis.

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