Calciphylaxis, also known as calcific uremic arteriolopathy, occurs secondary to calcification of arterioles and arteries.1 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.2 Small-vessel vasculopathy should be considered particularly in patients with chronic renal disease with abnormal levels of calcium, phosphorus, and parathyroid hormone (PTH) levels who develop skin lesions.3
Calciphylaxis can be life-threatening, with mortality rates ranging from 50% to 80% at 2 years.1,3 The mortality rate is dependent on location. Distal lesions typically have a better prognosis than proximal lesions.3,4 Mortality is usually secondary to disruption of the skin barrier by ulcerations that lead to infection and sepsis.3
Epidemiology and Incidence
The annual incidence of calciphylaxis has significantly increased in the last decade with rates reported in 1% in the general population to up to 4% in end-stage renal disease (ESRD) patients on dialysis.3,4 Although most cases of calciphylaxis are associated with ESRD, case reports of occurrences in patients with normal renal function have been published.3,5,6 Risk factors associated with calciphylaxis not linked to renal disease include hyperparathyroidism; elevated calcium, phosphate, and PTH levels; and use of high calcium-phosphate products.3 Other associations include obesity, diabetes, White race, increased levels of aluminum, liver disease, deficiency of protein S and protein C, low albumin levels, use of warfarin, and increased serum alkaline phosphatase.3 The disease occurs in a 3:1 ratio for women to men with a mean age at onset of 48 years.3,7
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Pathophysiology
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.1 The pathophysiology is likely multifactorial and appears to be related to elevated serum levels of calcium and phosphate causing blood vessel calcification.8 Evidence for these mechanisms includes resolution of calciphylaxis after parathyroidectomy in some patients with chronic renal failure.4 However, not all cases are secondary to derangement of the calcium-PTH metabolism, with a case series reporting patients with no abnormalities in calcium, phosphate, PTH, or calcium-phosphate production.9
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-κB, receptor activator of nuclear factor-κB ligand, and osteoprotegerin.10 More research is needed to determine the exact pathway of calciphylaxis.
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.11
Clinical Presentation
Lesions typically start with a mottled, violaceous coloring in a livedo reticularis pattern (Figure).3 However, in the early stages of the disease, patients may have nonspecific skin findings including subcutaneous nodules without overlying skin change, indurated plaques, cellulitis-like erythema, and edema, or small ulcers with hemorrhagic crust.12 It is therefore critical to maintain a low threshold for early calciphylaxis in patients with renal disease.12
Physical examination may reveal thickened blood vessels and/or palpable nodules or plaques from the deposition of calcium.3 These ischemic areas can progress to areas that infarct, ulcerate, and necrose.3 Ulcerations are a key signal of the disease although there are cases of patients presenting without ulcers.3,13 Another feature of the disease is severe pain from the ulcers, which was endorsed by 63 out of 64 (98%) patients in a study.3,14
The lesions may develop anywhere on the skin but tend to involve sites of the body with adipose-rich tissue such as acral skin, buttocks, or thighs.3 The lesions typically develop symmetrically and the lower extremity is most commonly involved.3,14
Calciphylaxis Overview1-23
| Patient characteristics and risk factors | • ESRD and chronic renal disease • Hyperparathyroidism • Elevated PTH • High calcium-phosphate level • More frequent in women than men, 3:1 ratio • Obesity • Diabetes • Middle age • Liver disease • Deficiency of protein C and S • Low albumin levels • Use of warfarin • Increase serum alkaline phosphatase |
| Physical examination findings | • Painful, mottled, violaceous lesions in livedo reticularis pattern • Thickened blood vessels • Palpable nodules or plaques • Areas of infarction, ulceration, or necrosis • Tend to involve sites of the body with adipose rich tissue such as acral, buttocks, or thighs • Distal pulses in extremities |
| Diagnosis | • Skin biopsy revealing vessel calcium deposits, tissue ischemia, necrosis, extravascular calcification, intimal fibroplasia, or thrombosis • Elevated calcium-phosphate products >70 mg2/dL2 • Elevated PTH • Bone scintigraphy |
| Treatment | • Reduction of risk factors • Wound care and debridement • Topical antibodies • Pain management • Systemic antibiotics for infection • Medical management may include cinacalcet, phosphate-binding agents, or sodium thiosulfate • Parathyroidectomy when applicable • Hyperbaric oxygen therapy as adjuvant treatment |
| Prognosis | • Distal lesions have a better prognosis than proximal lesions • Ulcerations can lead to infection and sepsis • Mortality can be as high as 80%; typically from sepsis |
Diagnosis and Workup
Diagnosis can be made clinically, although skin biopsy and histology may help in the diagnosis.1 Histologic evidence may not always be present but findings can include tissue ischemia, necrosis, extravascular calcification, intimal fibroplasia, thrombosis, and subcutaneous vessel calcium deposits.15 A wedge biopsy is preferred to a punch biopsy to include the subcutaneous vessels to help with diagnosis.8 Multiple biopsies may be needed to yield a diagnosis as a single biopsy may be negative for the disease.8 A risk to consider is the possibility of creating a nonhealing ulcer from biopsy sites.3,15 Bone scintigraphy is a noninvasive diagnostic tool that has a sensitivity of 97% in establishing abnormal calcifications.13
Calciphylaxis appears to be multifactorial with unknown pathogenesis and, therefore, no serologic or hematologic confirmatory test is available.3 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.1 An elevated calcium-phosphate product (>70 mg2/dL2) has a specificity of 95% and sensitivity of 21%.14 However, normal laboratory values do not rule out the diagnosis of calciphylaxis; 51% of cases in 1 study had calcium-phosphate products less than 50 mg2/dL2.14
Identification and treatment of hypercoagulable states may be a method to reduce calciphylaxis incidence. A case-control study including 38 patients and 104 controls indicated that patients with calciphylaxis were significantly more likely to have lupus anticoagulant, protein C deficiency, or combined thrombophilia, compared with controls, and were also significantly more likely to have been exposed to warfarin.16 There was no significant difference in other hypercoagulable conditions tested (antithrombin III deficiency, anticardiolipin antibodies, elevated factor VIII, heparin-platelet factor 4 antibodies, or mutations in prothrombin or factor V Leiden).16 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.16
Differential diagnosis of the cutaneous lesions seen in calciphylaxis includes venous stasis ulcers, pyoderma gangrenosum, vasculitis, brown recluse spider bite, and necrotizing fasciitis.8 Other conditions to consider are disseminated intravascular coagulation, clotting disorders, antiphospholipid syndrome, infections, cryoprecipitate disorders, cholesterol emboli, atheroemboli, marantic endocarditis, warfarin-induced skin necrosis, and myxoma.3,9
Treatment
Treatment of calciphylaxis should include a multimodal approach with a focus on supportive care, infection prevention, pain management, and wound healing.14 The focus should be to normalize calcium, dissolve calcium deposits, and general wound care.17
Wound care consists of wound dressing, debridement, and analgesics.1 Debridement can be conducted surgically or mechanically with extreme cases potentially requiring amputation.3 However, no standard protocol for debridement exists. Studies have shown that surgical debridement can increase 1-year survival rates from 27.4% without intervention to 61.6%.14
Ulcers are susceptible to infections and antibiotic treatment may be required.1 Sepsis is a leading cause of mortality in patients; thus, intensive monitoring for signs of (local or systemic) infection is warranted with a low threshold to start systemic antibiotics.14 Care should also be taken to prevent any trauma or further skin damage and, therefore, subcutaneous or intramuscular injections should be avoided if possible.17 Pain management may include the use of narcotics because severe pain is typically present.
Reduction of risk factors associated with calciphylaxis is another component of care, such as avoidance of warfarin and systemic corticosteroid use.3,9 Abnormalities in serum calcium and phosphate levels should be corrected with a goal of lowering the plasma calcium-phosphate level to <55 mg2/dL2.1,18 A low phosphate diet may be implemented and/or use of noncalcium containing phosphate binders (eg, sevelamer or lanthanum) for the treatment of hyperphosphatemia.3,18
For patients with chronic kidney disease on hemodialysis, options include increasing the frequency and duration of hemodialysis, using a low calcium dialysate, or temporarily switching to venovenous hemofiltration in patients with rapidly ulcerating calciphylaxis.1 To decrease calcium absorption, all calcium supplementation, vitamin D therapies, and vitamin D-based ligands with a calcium base should be held.19
Patients with primary or tertiary hyperparathyroidism refractory to wound care and medical management may consider a parathyroidectomy.1 Postoperatively, patients have a variable response in outcomes; a retrospective study reported no apparent decrease in mortality rate compared with that in patients who did not undergo parathyroidectomy.14 The role of parathyroidectomy is controversial with studies showing either improvement or no improvement in survival.10
Management of patients with risk factors for thrombosis utilizing direct oral anticoagulants (DOACs) in addition to other multimodal supportive therapies was shown to be a potential treatment option in a review of 16 cases, with 13 patients treated with DOACs having stable or improved cutaneous disease, and 3 patients having progressive disease.20 One clinically relevant but nonmajor bleeding event occurred in the 16 patients while being treated with DOACs.20 Further research in this area is needed, as the study findings are limited by the lack of a control group and a small number of patients.
Cinacalcet may be used in patients on dialysis with refractory secondary hyperparathyroidism in whom parathyroidectomy is contraindicated.1,11 Cinacalcet works by decreasing PTH by acting as an agonist at the calcium-sensing receptors on the parathyroid gland.1
Off-label use of sodium thiosulfate in patients with ESRD or normal kidney function has been detailed in multiple case reports detailing the use of sodium thiosulfate in patients with ESRD or normal kidney function.1 The mechanism behind this agent’s effects is not clearly defined although it does not depend on resolving abnormalities in calcium or phosphate levels.21 Infusions of 25 g IV sodium thiosulfate over 30 to 60 minutes 3 times weekly after hemodialysis is the empirical protocol for this agent, although the regimen varies depending on the individual patient and study protocols; randomized controlled trials are needed to determine the ideal dosage.21 Sodium thiosulfate has demonstrated successful outcomes in the treatment of calciphylaxis, with some patients having complete resolution of lesions.1
Hyperbaric oxygen therapy is another treatment option to consider if medical or surgical methods have failed. This therapy promotes angiogenesis, vasoconstriction of arterioles, bactericidal activity of neutrophils, and stimulation of fibroblasts.4 In a recent retrospective study of 34 patients receiving a full course of hyperbaric oxygen treatment, over half of patients demonstrated some benefit, and patients with complete resolution of lesions survived 3 more years on average.22
Palliative care is an important component to consider as part of the multidisciplinary approach to calciphylaxis management. A 2017 systematic review of patient-reported measures evaluated quality of life outcomes and utilization of palliative care in patients with calciphylaxis. Palliative care use was not often reported in patients with calciphylaxis, with only 12 articles meeting the inclusion criteria.23 Palliative care was commonly a referral for “intractable pain secondary to treatment failure or end-stage disease” in these studies.23 It is possible that earlier involvement of palliative care could be beneficial for both management of symptomatic challenges with pain, pruritus, wound healing, insomnia, anorexia, and cognition, as well as psychological coping strategies.23
Conclusion
Calciphylaxis is a severe disease with a high mortality rate and limited treatment options. Focusing on disease prevention is key, including treatment of renal failure, limiting risk factors, and recognizing the disease early in its onset.20
Amelia Hoelscher, MD, is a dermatologist at Warthan Dermatology in Fort Worth, Texas; Jayci Givens is a third-year medical student at Baylor College of Medicine in Houston, Texas; and Maura Holcomb, MD, is a dermatologist at Montana Skin Cancer and Dermatology Center in Bozeman, MT.
References
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3. Yalin AS, Altiparmak MR, Trabulus S, Yalin SF, Yalin GY, Melikoglu M. Calciphylaxis: a report of six cases and review of literature. Ren Fail. 2013;35(1):163-169. doi:10.3109/0886022X.2012.741426
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5. Ozbalkan Z, Calguneri M, Onat AM, Ozturk MA. Development of calciphylaxis after long-term steroid and methotroxate use in a patient with rheumatoid arthritis. Intern Med. 2005;44(11):1178-81. doi:10.2169/internalmedicine.44.1178
6. Korkmaz C, Dündar E, Zubaroğlu I. Calciphylaxis in a patient with rheumatoid arthritis without renal failure and hyperparathyroidism: the possible role of long-term steroid use and protein S deficiency. Clin Rheumatol. 2002;21(1):66-69. doi:10.1007/s100670200016
7. Hafner J, Keusch G, Wahl C, et al. Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): a complication of chronic renal failure and benefit from parathyroidectomy. J Am Acad Dermatol. 1995;33(6):954-962. doi:10.1016/0190-9622(95)90286-4
8. Harb J, Watt AW, Elston JB, Harrington MA. Calciphylaxis. Eplasty. 2015;15:ic11
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14. Weenig RH, Sewell LD, Davis MD, McCarthy JT, Pittelkow MR. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol. 2007;56(4):569-579. doi:10.1016/j.jaad.2006.08.065
15. Mochel MC, Arakaki RY, Wang G, Kroshinsky D, Hoang MP. Cutaneous calciphylaxis: a retrospective histopathologic evaluation. Am J Dermatopathol. 2013;35(5):582-586. doi:10.1097/DAD.0b013e31827c7f5d
16. Dobry AS, Ko LN, St John J, Sloan JM, Nigwekar S, Kroshinsky D. Association between hypercoagulable conditions and calciphylaxis in patients with renal disease: a case-control study. JAMA Dermatol. 2018;154(2):182-187. doi:10.1001/jamadermatol.2017.4920
17. Yerram P, Chaudhary K. Calcific uremic arteriolopathy in end stage renal disease: pathophysiology and management. Ochsner J. 2014;14(3):380-385.
18. Vedvyas C, Winterfield LS, Vleugels RA. Calciphylaxis: a systematic review of existing and emerging therapies. J Am Acad Dermatol. 2012;67(6):e253-260. doi:10.1016/j.jaad.2011.06.009
19. Strippoli D, Simonetti V, Russo G, Motolese A. Calciphylaxis: a case report. Derm Therapy. 2008;21:S26-S28.
20. King BJ, El-Azhary RA, McEvoy MT, et al. Direct oral anticoagulant medications in calciphylaxis. Int J Dermatol. 2017;56(10):1065-1070. doi:10.1111/ijd.13685
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22. An J, Devaney B, Ooi KY, Ford S, Frawley G, Menahem S. Hyperbaric oxygen in the treatment of calciphylaxis: A case series and literature review. Nephrology (Carlton). 2015;20(7):444-450. doi:10.1111/nep.12433
23. Riemer CA, El-Azhary RA, Wu KL, Strand JJ, Lehman JS. Underreported use of palliative care and patient-reported outcome measures to address reduced quality of life in patients with calciphylaxis: a systematic review. Br J Dermatol. 2017;177(6):1510-1518. doi:10.1111/bjd.15702
