Calciphylaxis

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Background

Calciphylaxis (also referred to as calcific uremic arteriolopathy) is a poorly understood and highly morbid syndrome of vascular calcification and skin necrosis. Bryant and White first reported it in association with uremia in 1898. However, the significance of this relationship became uncertain when vascular calcification was subsequently shown to be prevalent in uremia, yet the syndrome of vascular calcification with cutaneous necrosis was less common.[1]

In a 1962 experimental study, Selye was able to precipitate systemic calcification, somewhat analogous to this syndrome, in nephrectomized rats. He was the first to coin the term calciphylaxis to characterize this enigma. Over the years, many other names have been suggested to characterize the pathogenic process, which has remained elusive. The clinical importance of this syndrome was not recognized until the mid-1970s. Since then, a multitude of case reports of calciphylaxis have documented data outlining its morbidity and therapeutic dilemmas. Efforts to achieve a better understand of the etiology and pathogenesis of calciphylaxis have continued. Unfortunately, this syndrome remains a conundrum.[2]

Pathophysiology

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[3] 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. Experimental sensitizing events and agents included nephrectomy and exposure to parathyroid hormone (PTH) and vitamin D. Substances used as challengers included egg albumin and metallic salts. Calciphylaxis was the end result.

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.[4, 5] Uremia-induced defects in this system may predispose to calciphylaxis.[6]

Corticosteroids, aluminum, hyperparathyroidism, liver disease, warfarin therapy, and various inflammatory processes all can alter this balance and promote vascular calcification.[7, 8] Chronic inflammatory conditions may predispose to calciphylaxis by reducing serum levels of fetuin-A, an important inhibitor of calcification produced in the liver.[9, 10, 11] Some authors have suggested that calciphylaxis is an active form of osteogenesis with upregulation of bone morphogenic protein 2 (BMP-2), Runx2, its target gene, and its indirect antagonist sclerostin.[12]

Most investigators have noted that the common endpoint of calciphylaxis is vascular occlusion and thrombosis, which results in cutaneous ischemia[13, 14, 15] ; however, the factors associated with thrombosis are not uniform.

Etiology

Disorders associated with the development of calciphylaxis include the following[4, 16, 17, 18] :

The cause of calciphylaxis remains obscure. Most cases occur in the setting of CKD, abnormal calcium-phosphate homeostasis, and hyperparathyroidism. Both hypercalcemia and hyperphosphatemia may be present, and the calcium-phosphate product frequently exceeds 60-70 mg2/dL2. However, calciphylaxis may occur in the setting of normal, or minimally elevated, calcium and phosphate levels.

Case reports exist of calciphylaxis occurring in primary hyperparathyroidism, cirrhosis, Crohn disease, malignancy, and rheumatoid arthritis, without renal disease. The pathogenesis of calciphylaxis in these cases is uncertain.[19, 16, 20, 21] The exact role of PTH is uncertain because calciphylaxis may occur after total parathyroidectomy, in the absence of measurable PTH levels.

Patients at an increased risk appear to be those who are obese and those who have been exposed to immunosuppressive agents, including glucocorticoids.[16] Calciphylaxis occurs more frequently in areas where body fat is most abundant (eg, thighs, buttocks, and lower abdomen).[17, 18]  Fatty areas may be at higher risk for thrombosis, owing to lower blood flow, increased potential for vascular kinking, or, more likely, involvement of adipocytes in the pathogenesis of calciphylaxis.[22]

Persons with diabetes mellitus may also be at an increased risk[16, 17, 18] ; insulin injections may pose an independent risk through trauma to the subcutis.

The clinical appearance of the lesions of calciphylaxis (livedo reticularis and stellate purpura) suggests that the common endpoint of the process is small-vessel occlusion. Indeed, microthrombi are found in most cases.

Hypercoagulable conditions, including protein C and protein S deficiencies, vitamin K deficiency, and the presence of a circulating anticoagulant have been described in a number of patients.[23, 24, 25, 26, 27, 22] However, conditions of hypercoagulability are not found uniformly. If they do exist, they could possibly precipitate or exacerbate calciphylaxis in a predisposed patient.

Vascular calcification is a constant finding in cases of calciphylaxis. Theoretically, various pathologic roles may be attributed to this vascular calcification, including the following:

These theories remain speculative.[6, 9]

Epidemiology

United States and international statistics

Calciphylaxis is an uncommon condition that affects 1-4% of the population with ESRD.[28, 29] A concern exists that the incidence has increased during the last decade because of a number of possible factors, including more widespread use of parenteral vitamin D and iron dextran.

In a study using data from the Australia and New Zealand Dialysis and Transplant Registry, the incidence of calciphylaxis episodes among patients on dialysis was found to be 4.5 (range, 4.1-5.1) per 1000 patient-years on dialysis.[30]

The incidence of calciphylaxis in the general population without ESRD is not known with certainty, but it is even lower. Nonuremic disease is being identified more commonly, especially in patients with rapid weight loss. Some cases are associated with warfarin use, but that association does not appear to alter prognosis.[31]

Age-, sex-, and race-related demographics

Calciphylaxis has been reported in individuals ranging in age from 6 months to 83 years. From a large series of patients, a mean patient age of 48 (± 16) years has been calculated. Individuals seemingly more predisposed are younger patients who have had a longer duration of renal replacement therapy.

Females are affected more often than males, with a female-to-male ratio of approximately 3:1. Females also appear to be more commonly affected with nonuremic calciphylaxis.

Although the disease may affect persons of any race, it appears to be more prevalent in Whites.

Prognosis

The prognosis is generally not good, with mortality as high as 60-80% having been reported in patients with ulcerative disease.[7]  In a retrospective cohort study (N = 302) by Tan et al, the 1-year mortality was 36.70% for nephrogenic calciphylaxis and 30.77% for nonnephrogenic calciphylaxis.[32]  Mortality is higher in patients with proximal disease than in those with only distal or acral disease.

Patients who do not die of sepsis or organ failure frequently undergo amputation of an involved limb. Vascular calcification is theoretically reversible with aggressive management, but many patients have numerous comorbid diseases, and intervention may be too late.[7]  A multidisciplinary approach with wound debridement, possible parathyroidectomy, and aggressive medical management may improve survival.[4] The impact of sodium thiosulfate on the overall survival rate remains to be determined.[33]

Patient Education

It is essential to emphasize compliance with the dialysis prescription. Patients must be educated regarding dietary restrictions and the need for phosphate binders. If anticoagulation is chosen,  the risks and the benefits of this therapy must be explained to the patient.

History

Most patients with calciphylaxis (also referred to as calcific uremic arteriolopathy) have a long-standing history of chronic kidney disease (CKD; or chronic renal failure) and renal replacement therapy. On rare occasions, calciphylaxis may occur in a patient with CKD before the initiation of replacement therapy; very rarely, it may occur in an individual with no history of CKD.

Many persons who develop calciphylaxis have undergone renal allograft transplantation. The allograft may still be functional when calciphylaxis develops. Frequently, patients have been noncompliant with dietary, medical, or dialysis prescriptions before the onset of calciphylaxis.

Lesions of calciphylaxis typically develop suddenly and progress rapidly. Lesions may be singular or numerous, and they generally occur on the lower extremities (see the image below); however, lesions also may develop on the hands and torso. Intense pain is a constant finding, likely related to vascular ischemia and cutaneous infarction.



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Several lesions of calciphylaxis that occurred on the lower extremity of a patient undergoing dialysis. These lesions developed in areas of livedo ret....

The patient's history may reveal an event that is a suspected trigger or risk factor for the development of calciphylaxis. These triggers include the following[4, 7, 6, 19, 16, 17, 18, 22, 34, 35] :

Review of the patient's medical record usually reveals a history of hyperphosphatemia with hyperparathyroidism and hypoalbuminemia. Patients with nonuremic calciphylaxis frequently have a history of primary hyperparathyroidism, malignancy, alcoholic liver disease, or underlying connective-tissue disease or proinflammatory condition.[19, 16, 20, 21, 36]

Physical Examination

Early lesions of calciphylaxis manifest as nonspecific violaceous mottling; as livedo reticularis; or as erythematous papules, plaques, or nodules. More developed lesions have a stellate purpuric configuration with central cutaneous necrosis (see the image below).



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An isolated lesion of calciphylaxis manifesting as an enlarging necrotic plaque on the lower extremity of a patient undergoing dialysis. The stellate ....

Multiple lesions of variable age may be present, following the path of the vasculature. Less commonly, lesions may manifest as either bullae (see the image below) or distinct subcutaneous, erythematous nodules suggestive of erythema nodosum. Lesions are excruciatingly tender and extremely firm.



View Image

Calciphylaxis may manifest as rapidly progressive, diffuse and extensive, cutaneous necrosis, as is seen in this patient with chronic renal failure. B....

The distribution of the lesions may be characterized as proximal (on the thighs or the trunk) or distal (below the knees). Ninety percent of lesions of calciphylaxis occur on the lower extremities. Proximally distributed lesions occur in 44-68% of patients, with lesions developing predominantly on the thighs, the buttocks, and the lower part of the abdomen. Distal and visceral involvement are not uncommon.

An intact peripheral pulse helps distinguish acral calciphylaxis from atherosclerotic peripheral vascular disease. Ulceration is considered a late finding and is associated with a higher mortality.

Complications

Complications of calciphylaxis range from moderate interference with activity to death. Lesions of calciphylaxis frequently result in nonhealing ulcers and cutaneous gangrene. Acral lesions may fail to heal with conservative therapy and lead to amputation. Sepsis may result from the nonhealing wounds.

Patients with internal involvement may develop gastrointestinal hemorrhage, infarction, or organ failure.

Patients treated with calcimimetics, sodium thiosulfate, and parathyroidectomy must be monitored for hypocalcemia. Those on sodium thiosulfate should be monitored for metabolic acidosis.

Laboratory Studies

In the workup for calciphylaxis (also referred to as calcific uremic arteriolopathy), the following laboratory measurements may be considered:

Imaging Studies

Plain radiography uniformly demonstrates an arborization of vascular calcification within the dermis and the subcutaneous tissue (see the image below). Although calcification is common in persons with end-stage renal disease (ESRD) and is not specific for calciphylaxis, a study by Shmidt et al showed that patients with calciphylaxis had more vascular calcifications, more small-vessel calcifications, and a netlike pattern of calcifications.[37] This netlike pattern, when present, was strongly associated with the presence of calciphylaxis.



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Radiologic findings of a hand in a patient with calciphylaxis. Extensive calcification of the radial and ulnar arteries is readily visible.

Bone scintigraphy may be used as a noninvasive diagnostic tool because the bone matrix protein osteopontin has been demonstrated in calciphylaxis lesions.[38]  Serial bone scanning may also be useful for monitoring progression or regression of disease.[39, 40]

Procedures

Punch biopsies may not be adequate, because the quantity or depth of tissue obtained may not be enough for diagnosis. An incisional cutaneous biopsy is usually diagnostic.[41] Ample subcutaneous tissue must be available for adequate evaluation.

The decision to perform a biopsy on a nonulcerated lesion should not be made lightly, because it could result in a nonhealing wound. Although calciphylaxis lesions have a clinical appearance suggestive of avascular necrosis (AVN), the tissue often bleeds freely during surgery. Furthermore, lesional ulceration doubles the mortality.

Histologic Findings

Biopsy specimens typically demonstrate calcification within the media and intima of small and medium-sized arterioles with extensive intimal hyperplasia and fibrosis, but this also may be seen in uninvolved skin in patients with chronic kidney disease (CKD; or chronic renal failure) or atherosclerosis.[42] A mixed inflammatory infiltrate frequently occurs. Subcutaneous calcium deposits with panniculitis and fat necrosis may sometimes be found. Vascular microthrombi are frequently evident. (See the image below.)



View Image

Calcification of capillaries within the subcutaneous fat, characteristic of calciphylaxis. Image courtesy of Dirk Elston, MD.

Medical Care

Therapy for calciphylaxis (also referred to as calcific uremic arteriolopathy) is multifaceted and includes medical and surgical intervention.[43, 44] Aggravating conditions should be addressed, and trigger factors should be eliminated. This may involve discontinuing parenteral iron therapy, calcium supplementation, and vitamin D supplementation. Cessation of warfarin therapy should be considered. Systemic glucocorticoids, tthough frequently implicated as a trigger, may benefit when given early, unless ulcerated lesions are present. Early use of sodium thiosulfate should be considered.[45, 46]

In patients with an elevated calcium-phosphate product, serum calcium and phosphate concentrations must be brought to low-normal levels as quickly and safely as possible.[47, 48] Conservative therapy should be tried first, including dietary alteration, use of noncalcium, nonaluminum phosphate binders, and low-calcium bath dialysis.[49] Some benefit may be achieved by increasing the frequency or duration of dialysis sessions.

Calcimimetics (eg, cinacalcet hydrochloride) may be beneficial in cases of hyperparathyroidism.[50, 51, 52] These agents increase the sensitivity of the calcium receptors to available calcium, thereby decreasing parathyroid hormone (PTH) secretion. They have been shown to be effective in lowering PTH, calcium, and phosphate levels. Successful use of these agents as adjunctive therapy for calciphylaxis has been reported.[53, 54]

Bisphosphonates (eg, pamidronate[55, 56]  and etridronate[57] ) increase osteoprotegerin production and inhibit arterial calcification. Case reports have suggested that these agents may be helpful in some cases of calciphylaxis, even without changing calcium or phosphate levels.[53, 58, 59, 60]

Parathyroidectomy should be considered if conservative management fails, but only if hyperparathyroidism is present.

Marked improvement of calciphylaxis has now been reported with the use of intravenous (IV) sodium thiosulfate. Sodium thiosulfate is a potent antioxidant, and it also increases the solubility of calcium deposits. Success has been reported in uremic and nonuremic calciphylaxis.[6, 53, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70]

The use of sodium thiosulfate to treat calciphylaxis is off label, but reports of success have been published. A study of 14 patients suggested that several factors may impact patient outcome.[71] Earlier intervention or a higher total dose of sodium thiosulfate may be more effective but less well tolerated. More obese patients and patients on long-term renal replacement therapy may not fare as well. A case report by Smith et al described successful use of IV sodium thiosulfate in a nonuremic patient.[72] A multimodality approach using sodium thiosulfate, cinacalcet, and sevelamer has also been used.[73]

Sodium thiosulfate has been administered IV, intralesionally,[74] or topically; intraperitoneal administration is not recommended owing to the risk of chemical peritonitis.[22] It has been used in both adults and children.[75] IV doses have ranged from 5 to 75 g after or during hemodialysis in adults; the most commonly reported dose has been 25 g after each dialysis. Some have used weight-based dosing (especially in children) at 12 g/1.7 m2. Infusion times range from 30 to 60 minutes.

Although sodium thiosulfate is generally well tolerated, adverse effects have include nausea with emesis and the development of an anion gap metabolic acidosis that can be managed by altering the bicarbonate level of the dialysate. (See the Anion Gap calculator.) Symptomatic relief and clinical improvement may occur within 2 weeks.

Oral sodium thiosulfate has also been reported to suppress calciphylaxis, though oral absorption may be poor. A 2 M (molar) solution can be prepared with 74.4 g in 150 mL free water; 2.6 g can be given orally daily or three times a week. Dosing is limited by diarrhea.

Judicious use of antibiotics may be advantageous. Additionally, in some cases, hyperbaric oxygen may be beneficial to promote wound healing.[76, 77]

Conditions of hypercoagulability should be sought and addressed. Patients with documented conditions of hypercoagulability may benefit from proper and adequate anticoagulation.[78]  Successful treatment of calciphylaxis with low-dose tissue plasminogen activator (t-PA) was described in a case report by Sewell et al.[79] Laboratory evaluation of the reported patient demonstrated low antithrombin III antigen and activity, as well as low protein C antigen and activity before intervention with t-PA therapy.

The role of anticoagulation in all cases of calciphylaxis is controversial. Random prophylactic use of warfarin or heparin is not indicated, because precipitation of calciphylaxis has occurred with such use.[80, 81] In addition, most patients with ESRD have a prolonged bleeding time due to the uremic condition, and anticoagulation or t-PA therapy should be approached cautiously. Nonetheless, in the setting of thrombotic occlusion and cutaneous ischemia, restoration of blood flow is critical.[13] Although the anticoagulant of choice in a dialysis patient is up for debate, the two best options are probably unfractionated heparin (UFH) and the factor Xa inhibitor apixaban.[22]

Studies are ongoing regarding the effectiveness of vitamin K supplementation.[22]

Studies are also ongoing regarding the use of IV SNF472 (hexasodium phytate), the hexasodium salt of myoinositol hexaphosphate, which binds to calcium hydroxyapatite crystals within blood vessels, inhibiting further growth.[82]  In the CALCIPHYX trial (N = 71), patients with calciphylaxis were randomly assigned to receive either hexasodium phytate (n = 37) or placebo (n = 34).[83]  Hexasodium phytate was not found to be significantly more efficacious than placebo, but it was associated with lower mortality and a lower rate of calciphylaxis-related events leading to hospitalization.

Pain management is also crucially important.[84] Hyperbaric oxygen (HBO) therapy may help alleviate pain in these patients.[85] ; it may also have benefits with respect to wound healing and mortality.[86]

Surgical Care

Aggressive wound care and debridement of necrotic tissue may be necessary to avoid wound infection and sepsis.[4] However, some have advised against debridement. No consensus on wound management has been established.[15] The decision whether to debride, and to what extent, depends on the patient's overall health and the clinical picture.

Use of a vacuum-assisted closure (VAC) device has been successful in several cases of calciphylaxis after extensive debridement and prior to skin grafting.[87]

Total or subtotal parathyroidectomy with autotransplantation may be of therapeutic benefit.[4, 49, 88, 89]  Small case studies have demonstrated some benefit; however, larger retrospective studies have not demonstrated a significant difference in survival.[15] Decisions should be made on a case-to-case basis.

Diet

Patients with abnormalities in calcium and phosphate homeostasis should be referred to a dietitian well versed in the dietary needs and restrictions of patients with end-stage renal disease (ESRD). Special consideration should be given to phosphate restriction.

Activity

The patient's activity may be greatly hampered by the pain and the ulceration of calciphylaxis lesions. Patients are generally hospitalized in intensive care units (ICUs) during the acute illness.

Consultations

Consultation with a surgeon regarding wound debridement and possible parathyroidectomy is appropriate.

Consultation with a dietitian regarding dietary alterations is appropriate.

Consultation with a pain-management specialist may be warranted.

What is calciphylaxis?What is the historical importance of calciphylaxis?What is the pathogenesis of calciphylaxis?What molecular and chemical factors are involved in the pathophysiology of calciphylaxis?Which disorders are associated with the development of calciphylaxis?What causes calciphylaxis?Which patients are at an increased risk for calciphylaxis?What do the lesions of calciphylaxis (livedo reticularis and stellate purpura) suggest?What is the role of hypercoagulable conditions in the etiology of calciphylaxis?What is the role of vascular calcification in the etiology of calciphylaxis?What is the prevalence of calciphylaxis?What are the racial predilections for calciphylaxis?How does the prevalence of calciphylaxis vary by sex?How does the prevalence of calciphylaxis vary by age?What is the prognosis of calciphylaxis?What is included in patient education about calciphylaxis?Which clinical history is characteristic of calciphylaxis?What are risk factors for the development of calciphylaxis?What should be the focus of history in suspected calciphylaxis?What are the physical findings characteristic of calciphylaxis?What are potential complications of calciphylaxis?What should be included in the differential diagnoses for calciphylaxis?What are the differential diagnoses for Calciphylaxis?Which lab tests are performed in the workup of calciphylaxis?What is the role of imaging studies in the workup of calciphylaxis?What is the role of biopsy in the workup of calciphylaxis?Which histologic findings are characteristic of calciphylaxis?What is the initial therapy for calciphylaxis?What are the treatment options for patients with an elevated calcium-phosphate product and calciphylaxis?What is the role of calcimimetics in the treatment of calciphylaxis?What is the role of bisphosphonates in the treatment of calciphylaxis?What is the role of sodium thiosulfate in the treatment of calciphylaxis?How should patients with calciphylaxis be monitored?What is the role of antibiotics in the treatment of calciphylaxis?How are hypercoagulability conditions managed in patients with calciphylaxis?How is pain managed in calciphylaxis?What is the role of surgery in the treatment of calciphylaxis?Which dietary restrictions are needed in the treatment of calciphylaxis?How should activity be restricted during the treatment of calciphylaxis?Which specialist consultations may be considered in the treatment of calciphylaxis?

Author

Julia R Nunley, MD, Professor, Department of Dermatology, Virginia Commonwealth University Medical Center

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Board of Dermatology<br/>Author for: Up-to-date.

Specialty Editors

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Smeena Khan, MD Private Practice, Adult and Pediatric Dermatology Associates

Smeena Khan, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

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Several lesions of calciphylaxis that occurred on the lower extremity of a patient undergoing dialysis. These lesions developed in areas of livedo reticularis and followed the path of the vasculature.

An isolated lesion of calciphylaxis manifesting as an enlarging necrotic plaque on the lower extremity of a patient undergoing dialysis. The stellate purpuric morphology can be appreciated surrounding the area of necrosis.

Calciphylaxis may manifest as rapidly progressive, diffuse and extensive, cutaneous necrosis, as is seen in this patient with chronic renal failure. Bullae may also be seen as a rare manifestation of calciphylaxis.

Radiologic findings of a hand in a patient with calciphylaxis. Extensive calcification of the radial and ulnar arteries is readily visible.

Calcification of capillaries within the subcutaneous fat, characteristic of calciphylaxis. Image courtesy of Dirk Elston, MD.

Several lesions of calciphylaxis that occurred on the lower extremity of a patient undergoing dialysis. These lesions developed in areas of livedo reticularis and followed the path of the vasculature.

An isolated lesion of calciphylaxis manifesting as an enlarging necrotic plaque on the lower extremity of a patient undergoing dialysis. The stellate purpuric morphology can be appreciated surrounding the area of necrosis.

Calciphylaxis may manifest as rapidly progressive, diffuse and extensive, cutaneous necrosis, as is seen in this patient with chronic renal failure. Bullae may also be seen as a rare manifestation of calciphylaxis.

Radiologic findings of a hand in a patient with calciphylaxis. Extensive calcification of the radial and ulnar arteries is readily visible.

Calcification of capillaries within the subcutaneous fat, characteristic of calciphylaxis. Image courtesy of Dirk Elston, MD.