Calciphylaxis causing skin gangrene in an old woman with end-stage renal disease

Dear Editor,

Calciphylaxis is a rare but devastating disease that is predominantly observed in patients suffering from chronic kidney failure who are treated with dialysis. Mortality rates in chronic hemodialysis patients with calciphylaxis were almost three times higher than those without calciphylaxis. In this report, we describe an old woman who presented with skin gangrene caused by calciphylaxis.

A 68-year-old woman presented with a 3-month history of ulceration in her lower extremities. The lesion started as a painful erythematous patch in her right lower leg and rapidly developed into crusted ulcers. Subsequently, the same type of lesion appeared in her left lower leg. She was diagnosed with end-stage renal disease secondary to chronic glomerulonephritis and had been on regular hemodialysis for 3 years. Physical examination showed a big ulcer, 5×5 cm in size, mostly covered by black eschar near the right ankle [Figure 1a]. Two smaller violaceous plaques with central eschar-covered ulcers were seen in the left lower limb [Figure 1b]. Peripheral pulse was normal.

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Figure 1a:

Skin ulcers and tissue necrosis on the right leg. Well-demarcated necrotic ulcer covered with black eschar

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Figure 1b:

Skin ulcers and tissue necrosis on the right leg. Well-demarcated necrotic ulcer covered with black eschar

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Routine parameters showed white blood cells: 7.23 × 10⁹/L, haemoglobin: 93 g/L, and red blood cells: 1.56 × 10¹²/L. Renal function tests showed serum creatinine: 687 µmol/L, parathyroid hormone (PTH): 23 pmol/L, and glomerular filtration rate (GFR): 11 mL/min. Serum electrolyte showed potassium levels to be 3.17 mmol/L and calcium levels to be 2.61 mmol/L. Human serum albumin was calculated to be 33.7 g/L, erythrocyte sedimentation rate was found to be 92 mm/h, and C-reactive protein to be 33.7 mg/l. Arteriovenous ultrasound of both lower extremities showed lower extremity dorsal pedis artery stenosis, arteriosclerosis and extensive plaque formation, suggesting the recanalization after stenosis and the insufficiency of the popliteal vein valve. The skin biopsy showed calcification, intimal fibrosis of the blood vessel wall in the subcutis [Figure 2a]. Haemorrhage and numerous neutrophils were observed around the small vessels in the dermis [Figure 2b]. Alizarin red staining was positive around the vessels [Figure 2c].

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Figure 2a:

Heamorrhage and numerous neutrophils around the small vessels in the dermis (H&E, ×100)

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Figure 2b:

Calcification and fibrosis of a vessel wall (H&E, ×400)

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Figure 2c:

Alizarin red staining positivity around the vessels (H &E, ×100)

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Based on clinical data and histological features, the diagnosis of calciphylaxis was confirmed. During her hospital stay, the frequency and duration of heamodialysis was increased. She was treated with zinc oxide pastes to repair local wounds, sodium thiosulfate to resist calcification, lanthanum carbonate to reduce phosphate absorption, and cinacalcet to ameliorate PTH. Unfortunately, she succumbed to sepsis from a recurrent wound infection and passed away one year after diagnosis.

Calciphylaxis is a rare and fatal vascular disease that often occurs in patients with end-stage renal disease treated with heamodialysis. ^1,2 Calciphylaxis mostly affects the female gender and its aetiology remains unclear. Other risk factors include diabetes, obesity, vitamin K deficiency, hypoalbuminemia, thrombophilia, medications (warfarin, vitamin D, and phosphate binders), altered mineral metabolism and hyperparathyroidism. ^1,3 Calciphylaxis may be a manifestation of Koebner phenomenon, suggesting trauma is a risk factor. ⁴

Cutaneous calciphylaxis is caused as a result of ischemic injuries of the cutaneous blood vessels. The process involves calcification within the media layer, fibrosis underneath the intima of vessel walls, and thrombotic occlusion in the vessel lumen. ^1,3,5 The typical clinical manifestations of calciphylaxis include skin lesions with severe pain, mainly livedo reticularis, violaceous plaques, or sclerotic nodules in the early stage, rapidly progressing skin ulceration and necrosis, secondary infection and poor prognosis. ⁶ Histologically, calciphylaxis is characterized by calcium deposition in small and medium vessels and vascular thrombosis leading to tissue ischemia, which in turn leads to skin tissue ulceration and necrosis. ^1,5 Other histopathological features include extravascular tissue calcification, especially perieccrine calcification, calcium in elastic fibers, panniculitis, and epidermal necrosis. ^1,3

Calciphylaxis with a painful ulceration may be mistaken for pyoderma gangrenosum. Pyoderma gangrenosum often occurs with comorbidities such as inflammatory bowel disease, connective tissue diseases, and heamatoproliferative disorders. ⁷ The lesion of pyoderma gangrenosum manifests initially as a papulopustule and rapidly develops into a painful deep ulcer with a raised and rolled bluish margin. Histopathological features of pyoderma gangrenosum show neutrophilic infiltration in the dermis and subcutaneous tissue. ⁷ Other diseases with eschar-covered ulcers, such as warfarin and heparin-induced necrosis, antiphospholipid antibody syndrome, diabetic ulcer may also imitate calciphylaxis ^1,3,5 [Table 1].

The treatment of calciphylaxis primarily requires a high-quality wound care, surgical debridement, pain relief, and other general treatments ⁵ [Table 2]. Therapeutic options aimed at vascular calcification and thrombosis should also be emphasised. Targeted therapy such as sodium thiosulfate and vitamin K can be administered [Table 2]. For refractory skin lesions and advanced lesions, new treatments such as human amniotic stem cell transplantation, hyperbaric oxygen therapy, and bisphosphonates can be considered. ^1,2,6

In conclusion, we report this case to increase awareness of this rare disease, and to emphasize the importance of systemic testing in the diagnosis of ulcerative diseases.