Case Reports

Nonuremic Calciphylaxis Triggered by Rapid Weight Loss and Hypotension

Cutis. 2020 January;105(01):E11-E14

References

Au S, Crawford RI. Three-dimensional analysis of a calciphylaxis plaque: clues to pathogenesis. J Am Acad Dermatol. 2007;47:53-57.
Weenig RH, Sewell LD, Davis MD, et al. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol. 2007;56:569-579.
Nigwekar SU, Wolf M, Sterns RH, et al. Calciphylaxis from nonuremic causes: a systematic review. Clin J Am Soc Nephrol. 2008;3:1139-1143.
Fine A, Zacharias J. Calciphylaxis is usually non-ulcerating: risk factors, outcome and therapy. Kidney Int. 2002;61:2210-2217.
Angelis M, Wong LL, Myers SA, et al. Calciphylaxis in patients on hemodialysis: a prevalence study. Surgery. 1997;122:1083-1090.
Chavel SM, Taraszka KS, Schaffer JV, et al. Calciphylaxis associated with acute, reversible renal failure in the setting of alcoholic cirrhosis. J Am Acad Dermatol. 2004;50:125-128.
Bosler DS, Amin MB, Gulli F, et al. Unusual case of calciphylaxis associated with metastatic breast carcinoma. Am J Dermatopathol. 2007;29:400-403.
Buxtorf K, Cerottini JP, Panizzon RG. Lower limb skin ulcerations, intravascular calcifications and sensorimotor polyneuropathy: calciphylaxis as part of a hyperparathyroidism? Dermatology. 1999;198:423-425.
Brouns K, Verbeken E, Degreef H, et al. Fatal calciphylaxis in two patients with giant cell arteritis. Clin Rheumatol. 2007;26:836-840.
Munavalli G, Reisenauer A, Moses M, et al. Weight loss-induced calciphylaxis: potential role of matrix metalloproteinases. J Dermatol. 2003;30:915-919.
Bae GH, Nambudiri VE, Bach DQ, et al. Rapidly progressive nonuremic calciphylaxis in setting of warfarin. Am J Med. 2015;128:E19-E21.
Essary LR, Wick MR. Cutaneous calciphylaxis. an underrecognized clinicopathologic entity. Am J Clin Pathol. 2000;113:280-287.
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;33:954-962.
Coates T, Kirkland GS, Dymock RB, et al. Cutaneous necrosis from calcific uremic arteriolopathy. Am J Kidney Dis. 1998;32:384-391.
Selye H, Gentile G, Prioreschi P. Cutaneous molt induced by calciphylaxis in the rat. Science. 1961;134:1876-1877.
Kalajian AH, Malhotra PS, Callen JP, et al. Calciphylaxis with normal renal and parathyroid function: not as rare as previously believed. Arch Dermatol. 2009;145:451-458.
Malabu U, Roberts L, Sangla K. Calciphylaxis in a morbidly obese woman with rheumatoid arthritis presenting with severe weight loss and vitamin D deficiency. Endocr Pract. 2011;17:104-108.
Schäfer C, Heiss A, Schwarz A, et al. The serum protein alpha 2–Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest. 2003;112:357-366.
Cozzolino M, Galassi A, Biondi ML, et al. Serum fetuin-A levels link inflammation and cardiovascular calcification in hemodialysis patients. Am J Nephrol. 2006;26:423-429.
Luo G, Ducy P, McKee MD, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386:78-81.
Weenig RH. Pathogenesis of calciphylaxis: Hans Selye to nuclear factor kappa-B. J Am Acad Dermatol. 2008;58:458-471.
Ketteler M, Bongartz P, Westenfeld R, et al. Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet. 2003;361:827-833.
Wallin R, Cain D, Sane DC. Matrix Gla protein synthesis and gamma-carboxylation in the aortic vessel wall and proliferating vascular smooth muscle cells a cell system which resembles the system in bone cells. Thromb Haemost. 1999;82:1764-1767.
Sowers KM, Hayden MR. Calcific uremic arteriolopathy: pathophysiology, reactive oxygen species and therapeutic approaches. Oxid Med Cell Longev. 2010;3:109-121.
Allegretti AS, Nazarian RM, Goverman J, et al. Calciphylaxis: a rare but fatal delayed complication of Roux-en-Y gastric bypass surgery. Am J Kidney Dis. 2014;64:274-277.
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Gupta D, Tadros R, Mazumdar A, et al. Breast lesions with intractable pain in end-stage renal disease: calciphylaxis with chronic hypotensive dermatopathy related watershed breast lesions. J Palliat Med. 2013;16:551-554.
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Selk N, Rodby, RA. Unexpectedly severe metabolic acidosis associated with sodium thiosulfate therapy in a patient with calcific uremic arteriolopathy. Semin Dial. 2011;24:85-88.
Martin R. Mysterious calciphylaxis: wounds with eschar—to debride or not to debride? Ostomy Wound Manage. 2004:50:64-66, 68-70.
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Comment

Background on Calciphylaxis
Calciphylaxis is a rare but deadly disease that affects both ESRD patients receiving dialysis and patients without ESRD who have known risk factors for calciphylaxis, including female gender, white race, obesity, alcoholic liver disease, primary hyperparathyroidism, connective tissue disease, underlying malignancy, protein C or S deficiency, corticosteroid use, warfarin use, diabetes, iron or albumin infusions, and rapid weight loss.^3,6-9,11 Although the molecular pathogenesis of calciphylaxis is not completely understood, it is believed to be caused by local deposition of calcium in the tunica media of small- to medium-sized arterioles and venules in the skin.¹² This deposition leads to intimal proliferation and progressive narrowing of the vessels with resultant thrombosis, ischemia, and necrosis. The cutaneous manifestations and histopathology of calciphylaxis classically follow its pathogenesis. Calciphylaxis typically presents with livedo reticularis as vessels narrow and then progresses to purpura, bullae, necrosis, and eschar formation with the onset of acute thrombosis and ischemia. Histopathology is characterized by small- and medium-sized vessel calcification and thrombus, dermal necrosis, and septal panniculitis, though the histology can be highly variable.¹² Unfortunately, the already poor prognosis for calciphylaxis worsens when lesions become either ulcerative or present on the proximal extremities and trunk.^4,13 Sepsis is the leading cause of death in calciphylaxis patients, affecting more than 50% of patients.^2,3,14 The differential diagnoses for calciphylactic-appearing lesions include warfarin-induced skin necrosis, disseminated intravascular coagulation, pyoderma gangrenosum, cholesterol emboli, and various vasculitides and coagulopathies.

Risk Factors
Our case demonstrates the importance of risk factor minimization, trigger avoidance, and early intervention due to the high mortality rate of calciphylaxis. Selye et al¹⁵ coined the term calciphylaxis in 1961 based on experiments that induced calciphylaxis in rat models. Their research concluded that there were certain sensitizers (ie, risk factors) that predisposed patients to medial calcium deposition in blood vessels and other challengers (ie, triggers) that acted as inciting events to calcium deposition. Our patient presented with multiple known risk factors for calciphylaxis, including obesity (body mass index, 40 kg/m²), female gender, white race, hypoalbuminemia, and chronic corticosteroid use.¹⁶ In the presence of a milieu of risk factors, the patient’s rapid weight loss and episodes of hypotension likely were triggers for calciphylaxis.

Other case reports in the literature have suggested weight loss as a trigger for NUC. One morbidly obese patient with inactive rheumatoid arthritis had onset of calciphylaxis lesions after unintentional weight loss of approximately 50% body weight in 1 year¹⁷; however, the weight loss does not have to be drastic to trigger calciphylaxis. Another study of 16 patients with uremic calciphylaxis found that 7 of 16 (44%) patients lost 10 to 50 kg in the 6 months prior to calciphylaxis onset.¹⁴ One proposed mechanism by Munavalli et al¹⁰ is that elevated levels of matrix metalloproteinases during catabolic weight loss states enhance the deposition of calcium into elastic fibers of small vessels. The authors found elevated serum levels of matrix metalloproteinases in their patients with NUC induced by rapid weight loss.¹⁰

A meta-analysis by Nigwekar et al³ found a history of prior corticosteroid use in 61% (22/36) of NUC cases reviewed. However, it is unclear whether it is the use of corticosteroids or chronic inflammation that is implicated in NUC pathogenesis. Chronic inflammation causes downregulation of anticalcification signaling pathways.^18-20 The role of 2 vascular calcification inhibitors has been evaluated in the pathogenesis of calciphylaxis: fetuin-A and matrix gla protein (MGP).²¹ The activity of these proteins is decreased not only in calciphylaxis but also in other inflammatory states and chronic renal failure.^18-20 One study found lower fetuin-A levels in 312 hemodialysis patients compared to healthy controls and an association between low fetuin-A levels and increased C-reactive protein levels.²² Reduced fetuin-A and MGP levels may be the result of several calciphylaxis risk factors. Warfarin is believed to trigger calciphylaxis via inhibition of gamma-carboxylation of MGP, which is necessary for its anticalcification activity.²³ Hypoalbuminemia and alcoholic liver disease also are risk factors that may be explained by the fact that fetuin-A is synthesized in the liver.²⁴ Therefore, liver disease results in decreased production of fetuin-A that is permissive to vascular calcification in calciphylaxis patients.

There have been other reports of calciphylaxis patients who were originally hospitalized due to hypotension, which may serve as a trigger for calciphylaxis onset.²⁵ Because calciphylaxis lesions are more likely to occur in the fatty areas of the abdomen and proximal thighs where blood flow is slower, hypotension likely accentuates the slowing of blood flow and subsequent blood vessel calcification. This theory is supported by studies showing that established calciphylactic lesions worsen more quickly in the presence of systemic hypotension.²⁶ One patient with ESRD and calciphylaxis of the breasts had consistent systolic blood pressure readings in the high 60s to low 70s between dialysis sessions.²⁷ Due to this association, we recommend that patients with calciphylaxis have close blood pressure monitoring to aid in preventing disease progression.²⁸

Management
Calciphylaxis treatment has not yet been standardized, as it is an uncommon disease whose pathogenesis is not fully understood. Current management strategies aim to normalize metabolic abnormalities such as hypercalcemia if they are present and remove inciting agents such as warfarin and corticosteroids.²⁹ Other medical treatments that have been successfully used include sodium thiosulfate, oral steroids, and adjunctive bisphosphonates.^29-31 Sodium thiosulfate is known to cause metabolic acidosis by generating thiosulfuric acid in vivo in patients with or without renal disease; therefore, patients on sodium thiosulfate therapy should be monitored for development of metabolic acidosis and treated with oral sodium bicarbonate or dialysis as needed.^30,32 Wound care also is an important element of calciphylaxis treatment; however, the debridement of wounds is controversial. Some argue that dry intact eschars serve to protect against sepsis, which is the leading cause of death in calciphylaxis.^2,14,33 In contrast, a retrospective study of 63 calciphylaxis patients found a 1-year survival rate of 61.6% in 17 patients receiving wound debridement vs 27.4% in 46 patients who did not.² The current consensus is that debridement should be considered on a case-by-case basis, factoring in the presence of wound infection, size of wounds, stability of eschars, and treatment goals of the patient.³⁴ Future studies should be aimed at this issue, with special focus on how these factors and the decision to debride or not impact patient outcomes.

Conclusion

Calciphylaxis is a potentially fatal disease that impacts both patients with ESRD and those with nonuremic risk factors. The term calcific uremic arteriolopathy should be disregarded, as nonuremic causes are being reported with increased frequency in the literature. In such cases, patients often have multiple risk factors, including obesity, primary hyperparathyroidism, alcoholic liver disease, and underlying malignancy, among others. Certain triggers for onset of calciphylaxis should be avoided in at-risk patients, including the use of corticosteroids or warfarin; iron and albumin infusions; hypotension; and rapid weight loss. Our fatal case of NUC is a reminder to dermatologists treating at-risk patients to avoid these triggers and to keep calciphylaxis in the differential diagnosis when encountering early lesions such as livedo reticularis, as progression of these lesions has a 1-year mortality rate of more than 50% with the therapies being utilized at this time.

Nonuremic Calciphylaxis Triggered by Rapid Weight Loss and Hypotension

References

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