extraskeletal metastatic calcifications are seen frequently in patients undergoing maintenance dialysis , and the incidence increases with dialysis vintage . calciphylaxis is a rare but life - threatening form , characterized by systemic medial calcification of the arterioles leading to ischemia and subcutaneous necrosis . it is reported to occur from as little as 1 month to as long as 12 years after the onset of end - stage renal disease ( esrd ) , with a median time of 2 years and 9 months . the term  calciphylaxis  was coined in 1962 by hans selye , who used it to describe a systemic anaphylactic reaction leading to soft - tissue and vascular calcification in animal models . it continues to be used widely to describe the phenomenon in humans , despite the introduction of  calcific uremic arteriolopathy the incidence of this condition appears to be increasing , due in part to the use of calcium - based phosphate binders and vitamin d analogs for the treatment of severe hyperparathyroidism . another contributing factor is a greater awareness and recognition of clinical signs and risk factors associated with calciphylaxis . it is estimated to have an incidence of 1% per year   and a prevalence of 4.1% in dialysis patients , with preponderance among obese , caucasian females [ 2 , 5 , 6 ] and diabetic patients . reports to the australian and new zealand dialysis and transplant registry ( anzdata ) identified calciphylaxis as a cause of death in 64 patients ( from 1985 until march 2004 ) and listed it as a comorbid condition in 86 cases . slowly progressive metastatic calcifications are much more common than calciphylaxis in patients with end - stage renal disease . common sites of involvement are the blood vessels , periarticular regions , heart , lungs , kidneys , gastric mucosa , central nervous system , breasts , and eyes . the liver , spleen , skeletal muscle , small and large bowel , peritoneal cavity , tongue , and larynx are less commonly affected . the pathogenesis of calciphylaxis is complex and poorly understood .   intimal fibrosis , mural calcifications of the dermohypodermic arterioles , and vascular thrombus formation all reduce arteriolar blood flow leading to microvascular ischemia . this results in areas of painful ischemic necrosis in the dermis and subcutaneous fat , mainly involving the abdomen , buttocks , and medial aspects of the thighs . it manifests as livedo reticularis and/or violaceous , painful , plaque - like subcutaneous nodules , which progress to ischemic / necrotic ulcers with eschars that often become superinfected ( figure 1 ) . less commonly involved organs and muscle groups include kidneys , heart , skeletal muscle , lungs , and gastrointestinal tract . abnormalities in mineral metabolism including hyperphosphatemia , hyperparathyroidism , an elevated plasma calcium and phosphate product   and active vitamin d supplementation   and deficiency of inhibitors of vascular calcifications , such as fetuin - a [ 15 , 16 ] and matrix gla protein , have all been implicated in this process . high level of 1,25-dihydroxy vitamin d3   has been associated with deleterious effect on the vascular smooth muscle cell ( smc ) phenotype causing medial wall calcification , suppression of endogenous inhibitors of smc calcification , stimulation of smc expression of alkaline phosphatase , and low bone turnover leading to hyperphosphatemia and hypercalcemia . in the only prospective trial of cua chronic inflammatory states including autoimmune disorders   and hypercoagulable states such as protein c and protein s deficiency [ 20 , 21 ] have also been identified as potential contributors . administration of certain medications including warfarin , systemic corticosteroids , iron - dextran , erythropoietin , and albumin   has been reported to be associated with calciphylaxis . early recognition is the key to better treatment outcomes . in lieu of any specific laboratory tests , the diagnosis is most often clinical , made apparent by the presence of proximal ulcers , intact peripheral pulses and the absence of neuropathy in a patient with the above - mentioned risk factors . the noninvasive tests including plain radiographs , high - resolution computed tomography , bone scans , and x - ray mammography are nonspecific for this condition .   in the absence of contraindications , the diagnosis may be confirmed by skin biopsy , which reveals calcifying septal panniculitis and arterial occlusion and calcification in the absence of vasculitic changes . skin biopsy may invite further infection in the presence of an active infection , can initiate ulcer formation and propagation , and is subject to sampling error . thus , it should be performed only after considering and discussing the risks and benefits of the procedure with the patient . calciphylaxis continues to be a lethal complication with an estimated one - year survival rate of 45.8 percent . the presence of advanced disease at the time of therapy and proximal ischemic lesions are poor prognostic features . ulceration carries a mortality of greater than 80 percent as a result of local and systemic infections and sepsis . the optimal therapy of calciphylaxis is to prevent its development by rigorous control of phosphate and calcium balance while avoiding or modifying the other risk factors . a multidisciplinary therapeutic approach is recommended in those with established disease , focusing on local wound care and metabolic control . an aggressive local wound care program should be initiated to prevent local and systemic infections . this typically involves the use of enzymatic debriding agents , wet - to - dry dressings , hydrocolloid or hydrogel dressings ,   and systemic antibiotics as needed for infections and avoidance of local tissue trauma , including subcutaneous injections . improved survival rates have been documented ; however , it predisposes the patient to increased risk of sepsis and worsening pain . a pain management specialist should be consulted to provide adequate pain control anticipating a prolonged duration of persistent discomfort . emotional support should be provided to the patient and family , as calciphylaxis is very painful and debilitating disease . an increase in dietary protein has been shown to promote wound healing in patients with low serum protein . every effort should be made to correct the underlying abnormalities in plasma calcium and phosphorus concentrations aiming for a target calcium and phosphorus product below 55 and serum levels of phosphate between 2.7 and 4.6  mg / dl . noncalcium - containing phosphate binders , such as sevelamer carbonate or lanthanum carbonate , rather than calcium - based phosphate binders should be administered as the latter increase the rate of hypercalcemia . though no study has demonstrated that the use of more frequent dialysis sessions or high - flux hemodialysis membranes alter the long - term outcome , the dialysis dose should be increased in patients with inadequate clearance . a low - calcium - containing dialysis solution ( for both hemodialysis and peritoneal dialysis ) may be used to lower serum calcium levels , but their success alone in healing the lesions remains unproven . since the activity of matrix gla protein is dependent on vitamin k carboxylation , discontinuation of warfarin therapy should be strongly considered . normalization of serum parathyroid hormone ( pth ) levels should be attempted using cinacalcet rather than vitamin d analogues , as the latter tends to raise the calcium and phosphate product . parathyroidectomy has been shown to provide pain relief and improve wound healing and short - term mortality , yet the long - term benefits are still unknown [ 5 , 12 , 31 ] . sodium thiosulfatesodium thiosulfate has been used therapeutically for more than one hundred years for a variety of conditions including acute cyanide poisoning , recurrent calcium urolithiasis , nephrocalcinosis , and tumoral calcinosis . intravenous sodium thiosulfate has been increasingly used as an adjunctive treatment in patients with debilitating calciphylactic necrotic lesions [ 32 , 33 ] . marked improvements with reduction of pain and inflammation and improved healing of ulcerative lesions have been demonstrated within a few days to six months of use . the proposed mechanism of action is that it dissolves insoluble calcium salts embedded in tissue into soluble calcium thiosulfate . other proposed mechanisms include reversal of endothelial dysfunction and increased vasodilatation through its antioxidant properties . sulfate retention causing increased anion gap metabolic acidosis has been occasionally reported with no documented morbidity or mortality in humans at the doses used clinically . the reported doses vary from 5 to 25  grams intravenously , three to four times per week for a period of 6 to 24 months . however , the optimum dosage schedule and duration of treatment remains to be determined . sodium thiosulfate has been used therapeutically for more than one hundred years for a variety of conditions including acute cyanide poisoning , recurrent calcium urolithiasis , nephrocalcinosis , and tumoral calcinosis . intravenous sodium thiosulfate has been increasingly used as an adjunctive treatment in patients with debilitating calciphylactic necrotic lesions [ 32 , 33 ] . marked improvements with reduction of pain and inflammation and improved healing of ulcerative lesions have been demonstrated within a few days to six months of use . the proposed mechanism of action is that it dissolves insoluble calcium salts embedded in tissue into soluble calcium thiosulfate . other proposed mechanisms include reversal of endothelial dysfunction and increased vasodilatation through its antioxidant properties . sulfate retention causing increased anion gap metabolic acidosis has been occasionally reported with no documented morbidity or mortality in humans at the doses used clinically . the reported doses vary from 5 to 25  grams intravenously , three to four times per week for a period of 6 to 24 months . however , the optimum dosage schedule and duration of treatment remains to be determined . bisphosphonatesbisphosphonates have a powerful inhibitory effect on osteoclast activity and bone resorption and are largely used in treatment of osteoporosis , tumoral hypercalcemia , and paget 's disease . they have also been shown to exert an inhibitory effect on macrophage activity and local proinflammatory cytokine production . animal models and few case reports have shown improvement of calciphylaxis lesions associated with systemic inflammatory response , when treated with intravenous pamidronate and oral etidronate [ 34 , 35 ] . this benefit has been ascribed more to their anti - inflammatory effect than to their effects on calcium metabolism . bisphosphonates have a powerful inhibitory effect on osteoclast activity and bone resorption and are largely used in treatment of osteoporosis , tumoral hypercalcemia , and paget 's disease . they have also been shown to exert an inhibitory effect on macrophage activity and local proinflammatory cytokine production . animal models and few case reports have shown improvement of calciphylaxis lesions associated with systemic inflammatory response , when treated with intravenous pamidronate and oral etidronate [ 34 , 35 ] . this benefit has been ascribed more to their anti - inflammatory effect than to their effects on calcium metabolism . hyperbaric oxygen therapy ( hbo)hbo consists of breathing 100% oxygen at a pressure higher than ambient atmospheric pressure ( 1 atmosphere absolute ) while the patient is situated inside a sealed treatment chamber . hypoxia also hinders with the oxygen - dependent polymorphonuclear leukocyte - mediated bacterial killing in the wound infections . hbo at 2.5 atmospheres absolute has been used for 90 minutes , 5 days per week for 5 to 7 consecutive weeks in reported cases . the therapy has been shown to be beneficial in healing cutaneous ulcers of calciphylaxis in some patients ; however , the treatments are costly and not readily available . it may also increase the pain in some patients and remains ineffective with organ involvement . hbo consists of breathing 100% oxygen at a pressure higher than ambient atmospheric pressure ( 1 atmosphere absolute ) while the patient is situated inside a sealed treatment chamber . hypoxia also hinders with the oxygen - dependent polymorphonuclear leukocyte - mediated bacterial killing in the wound infections . hbo at 2.5 atmospheres absolute has been used for 90 minutes , 5 days per week for 5 to 7 consecutive weeks in reported cases . the therapy has been shown to be beneficial in healing cutaneous ulcers of calciphylaxis in some patients ; however , the treatments are costly and not readily available . it may also increase the pain in some patients and remains ineffective with organ involvement . steroidsthe use of corticosteroids in the treatment of calciphylaxis remains controversial . in a single case report , the use of prednisone resulted in stabilization or improvement in nonulcerating lesions ; however , it may predispose the patient to systemic infection . moreover , systemic corticosteroids have even been reported to be a risk factor for calciphylaxis in non - esrd patients with an autoimmune disorder . the use of corticosteroids in the treatment of calciphylaxis remains controversial . in a single case report , the use of prednisone resulted in stabilization or improvement in nonulcerating lesions ; however , it may predispose the patient to systemic infection . moreover , systemic corticosteroids have even been reported to be a risk factor for calciphylaxis in non - esrd patients with an autoimmune disorder . sterile maggot therapylarvae of the species lucilia sericata have been used to debride and disinfect skin lesions of calciphylaxis . the maggots have enzymes that liquefy necrotic tissue and secrete phenylacetic acid and phenylacetyl aldehyde , which have antibacterial activity that helps to prevent infection . larvae of the species lucilia sericata have been used to debride and disinfect skin lesions of calciphylaxis . the maggots have enzymes that liquefy necrotic tissue and secrete phenylacetic acid and phenylacetyl aldehyde , which have antibacterial activity that helps to prevent infection . this treatment is almost painless , and results have been promising . the risks and long - term outcomes still need to be assessed . anticoagulation therapythere have been case reports of use of low - dose tissue plasminogen activator   and substitution of warfarin with low molecular weight heparin   with proven benefit in calciphylaxis . 
  there have been case reports of use of low - dose tissue plasminogen activator   and substitution of warfarin with low molecular weight heparin   with proven benefit in calciphylaxis . limb revascularizationlimb revascularization has been attempted to treat distal wound involvement , but gangrene and lower - extremity ischemia continues to progress in many patients , and the outcomes have been poor . it is debatable whether primary amputation should be the treatment of lower - extremity calciphylaxis when ischemia is also present.response to any therapy is assessed principally by physical examination . the disease continues to have high morbidity and mortality with poor response to any therapeutic regimen . limb revascularization has been attempted to treat distal wound involvement , but gangrene and lower - extremity ischemia continues to progress in many patients , and the outcomes have been poor . it is debatable whether primary amputation should be the treatment of lower - extremity calciphylaxis when ischemia is also present . the disease continues to have high morbidity and mortality with poor response to any therapeutic regimen . calciphylaxis is a severe form of metastatic calcification seen in esrd patients undergoing maintenance hemodialysis . it often presents as ischemic skin ulceration and is associated with high morbidity and mortality . abnormal mineral and bone metabolism is the strongest risk factor , and its correction along with local wound care is the cornerstone of the therapy . however , prevention is the best approach as the outcomes remain poor despite many novel treatment modalities .
metastatic calcification is a frequent complication encountered in patients undergoing maintenance dialysis and has a complex pathogenesis . 
 it is often difficult to treat and is associated with high morbidity and mortality . 
 early recognition and prompt initiation of treatment is vital . 
 local wound care and aggressive metabolic control remain the cornerstones of the therapy . 
 various novel treatment strategies including sodium thiosulfate and hyperbaric oxygen therapy have been utilized and reviewed in this paper . 
 the response rate to treatment is poor and prevention is the best approach .