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Unilateral calciphylaxis in a patient with systemic lupus erythematosus, chronic kidney disease, and hemodialysis-associated steal syndrome

  • Author(s): Onofiok, Ekama;
  • Sivamani, Raja K;
  • Barr, Keira L
  • et al.
Main Content

Unilateral calciphylaxis in a patient with systemic lupus erythematosus, chronic kidney disease, and hemodialysis-associated steal syndrome
Ekama Onofiok PhD1, Raja K Sivamani MD2, Keira L Barr MD2,3
Dermatology Online Journal 17 (9): 3

1. School of Medicine
2. Department of Dermatology
3. Department of Pathology
University of California, Davis, Sacramento, California


Abstract

Calciphylaxis is a rare but life-threatening disease characterized by deposition of calcium within small and medium sized vessels, with subsequent thrombosis, cutaneous ischemia, and necrosis. Because of its systemic nature, calciphylaxis is typically a symmetrical, bilaterally-distributed phenomenon. Here, we present an unusual case of unilateral leg calciphylaxis in the setting of relative chronic arterial insufficiency of the affected extremity secondary to steal syndrome.



Introduction

Calciphylaxis is a rare but life-threatening phenomenon characterized by deposition of calcium within small and medium sized vessels, with subsequent thrombosis, cutaneous ischemia and necrosis. It is a known complication of chronic renal disease in patients on hemodialysis, commonly associated with elevated parathyroid hormone levels and aberrations in calcium and phosphate metabolism. However, other identified risk factors include obesity [1, 2], protein C and S deficiencies [3], autoimmune diseases such as systemic lupus erythematosus [4], and exposures to corticosteroids [5], warfarin and calcium-containing phosphate binders. Underlying these disease states is a prothrombotic milieu characterized by hypercoagulability and vascular injury. Because of its systemic nature, calciphylaxis is typically a symmetrical and bilateral phenomenon. Herein we report a patient with unilateral leg calciphylaxis in the setting of relative chronic arterial insufficiency of the affected extremity secondary to steal syndrome.


Case history

A 33-year-old non-smoking woman presented to our consult service with a three-week history of painful lesions on her left leg. Her past medical history was significant for a longstanding history of systemic lupus erythematosus, anti-phospholipid antibody syndrome on long-term anticoagulation with warfarin for multiple arterial thromboses and chronic kidney disease secondary to lupus nephritis. She was treated with hemodialysis and had multiple failed upper extremity AV fistulae; her current access was via a left thigh arteriovenous fistula (left superficial femoral artery to left superficial vein), with associated steal syndrome of the left lower extremity. In addition, she was status-post total parathyroidectomy for persistent secondary hyperparathyroidism with autotransplantation to the forearm.


Figure 1Figure 2

On physical exam, she had several angulated, necrotic plaques of the left lower leg (Figure 1). Her newest plaques on the left anterior shin were dusky red in color with no evidence of surface alterations, whereas older plaques were a deeper purple-black with overlying flaccid bullae, eschar, and a thin rim of erythema (Figure 1). The right leg was not affected.

Laboratory findings were remarkable for mildly elevated serum phosphorus (5.5 mg/dL), low albumin (2.9 g/dL), normal uncorrected and corrected calcium, elevated blood urea nitrogen, and creatinine consistent with her chronic renal failure. Her internal normalized ratio (INR) was within therapeutic range on warfarin. The uncorrected and corrected calcium-phosphate product (CaP) upon admission was 51 and 56 mg²/dL², respectively.

Histopathology of deep punch biopsies from the edge of her plaques revealed calcium deposits in the subcutis, mostly within walls of small and medium sized vessels, with sections of partial to full thickness epidermal necrosis (Figure 2). No organizing microthrombi within vessels were noted. Her pathology findings were consistent with calciphylaxis.

Her management included phosphate-lowering therapy and increased frequency of dialysis. Corticosteroids were continued in light of her SLE, but her mycophenolate mofetil was discontinued. She had gradual resolution of her painful symptoms within days and slow improvement in the appearance of her plaques over the following weeks.


Discussion

The general distribution of calciphylaxis lesions is thought to be of prognostic significance; distally-located lesions have been associated with more favorable outcomes compared to proximal presentations. However, large studies showing this phenomenon are lacking [1,6]. Less studied is the significance of unilateral versus bilateral patterns of lesion distribution. In a small case study of 36 patients with calciphylaxis, the presentation was almost universally bilateral [7]. Otherwise, most reported cases offered no additional classification of pattern distribution beyond describing lesions as proximally or distally located. A search of the literature did reveal one case of unilateral calciphylaxis in a 59-year-old woman, which occurred in the context of unilaterally worsened peripheral arterial disease [8]. In contrast, our patient was younger, with a prothrombotic autoimmune disease, and her unilateral peripheral arterial disease was the result of a dialysis-associated steal syndrome. Dialysis-associated steal syndrome has been noted to occur in up to 10% of patients with an arteriovenous (AV) bypass, although these are typically described in the upper extremities [9].

Whereas there is no known “perfect storm” of factors that reliably predict the development of the disease, calciphylaxis has several well-documented risk factors. These include chronic use of warfarin, autoimmune disease, exposure to systemic corticosteroids, chronic renal disease requiring dialysis, and derangement in the calcium phosphate product [1, 4]. Warfarin, an independent risk factor for calciphylaxis, is thought to trigger this process through the induction of vascular calcification [10, 11]. In a few isolated cases, cessation of warfarin therapy resulted in clinical improvement and resolution of calciphylactic lesions [12, 13]. Weenig et al [1] identified chronic kidney failure as the most important risk factor associated with the development of calciphylaxis, whereas associated perturbations in the parathyroid-calcium-phosphate axis neither precluded nor reliably confirmed the diagnosis. Markedly elevated calcium-phosphate product (> 70 mg²/dL²) showed strong, highly specific association with calciphylaxis, but the majority (51%) of patients had normal levels (< 50 mg²/dL²) [1]. Hyperphosphatemia is a known risk factor in the development of calciphylaxis, possibly by upregulation of osteopontin, a glycoprotein that mediates vascular calcification [14]. Interestingly, although our patient’s background of ischemia to the left leg likely predisposed her to calciphylaxis, she responded to phosphate lowering measures, despite having only mildly abnormal phosphate levels (phosphorus 5.5 mg/dL, CaP 56.1 mg²/dL²). However, measurements obtained at the time of clinical presentation may not have been representative of the conditions that triggered her disease [15].

Whereas our patient had multiple risk factors for calciphylaxis, the unilateral ischemia in the affected limb likely played an additional predisposing role in her disease. Chronic arterial insufficiency may contribute to the ischemic effect and progression of calciphylaxis by two mechanisms. Thrombotic occlusion may occur more readily in arterioles with low or near-static blood flow. Secondly, the compensatory vasodilation necessary to supply hypoperfused areas in the cutis may be impaired owing to existing vessel injury caused by medial calcification, thus worsening the already hypoxic state found in calciphylaxis. As such, a chronically ischemic background may contribute further to vascular calcification, which may explain localization of calciphylactic lesions to the ischemic limb as seen in this patient.

Effectiveness of the various treatment modalities remains largely unproven in the absence of any randomized controlled trials. The role of parathyroidectomy in the treatment of calciphylaxis is controversial and only recommended in cases of severely elevated PTH levels refractory to other treatment methods [1, 16, 17]. In our patient, a total parathyroidectomy (with autotransplantation) was not preventative for the development of her disease, and there have been similar reported cases of this phenomenon [18]. Sodium thiosulfate (STS), a potent antioxidant and calcium chelator, has in recent years, begun to receive considerable attention for its use in the treatment of calciphylaxis. It has been shown to produce rapid relief of subdermal ischemia and associated pain, improved wound healing, and regression of vascular and subcutaneous calcifications [14, 19, 20]. The postulated mechanism of action of lies in its ability to scavenge free reactive oxygen species present at sites of vascular and subcutaneous tissue injury, resulting in increased bioavailability of endothelial nitric oxide (NO). In turn, this promotes antithrombotic, anti-proliferative, and anti-inflammatory functions within the endothelium [14]. Patient response to STS treatment, however, is variable [21] and there is a lack of prospective, randomized controlled studies to critically evaluate its role in treatment.

In summary, we present a second case of unilateral plaques consistent with calciphylaxis on a background of unilaterally worsened ischemia. Our case highlights a unique scenario in which ischemia developed as a result of unilateral steal syndrome. As further understanding of the etiological and pathophysiological processes of calciphylaxis is gained, we will better understand the role of chronic ischemia in the predisposition for the development of calciphylaxis.

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