Calciphylaxis With Recalcitrant Ulcers in the Presence of Moderate Renal Insufficiency

A 69-year-old woman with painful crural ulcers of 3 months’ duration presented at the authors’ outpatient clinic. Dermatological examination revealed a necrotic ulceration with eschar formation localized on the anterior left crural region and the lateral malleolus of the right ankle. According to the clinical and histopathological findings, she was diagnosed with calciphylaxis. She had moderate renal insufficiency and secondary hyperparathyroidism due to hypertension. The ulcers improved significantly after 3 months of topical wound therapy. This case of calciphylaxis with recalcitrant ulcers in the presence of moderate renal insufficiency is presented to stress the importance of early diagnosis and management in this life-threatening disorder.

Calciphylaxis (calcific uremic arteriolopathy) is a syndrome of calcium deposition in the small and intermediate dermal vessels which can lead to epidermal ischemia, ulceration, and necrosis.¹ The first case of calciphylaxis was described by Bryant and White in 1898.² They described vascular calcification and cutaneous necrosis in association with renal insufficiency in a 6-month-old child. Selye³ coined the term calciphylaxis. In 1962, following experimental observations in animal models Selye utilized “sensitizing” agents (parathyroid hormone, dihydrotachysterol) followed by “challenging” agents such as metal salts, egg white or yolk, and albumin to induce calcification. As the process was considered to be one of induced hypersensitivity, resulting in local calcification, following the two-step process of sensitizing and challenging (ie, analogous to anaphylaxis), it was termed calciphylaxis.^3–5

Calciphylaxis occurs mostly in patients with chronic renal failure and secondary hyperparathyroidism, although it can occur in the absence of renal or parathyroid disease.⁶ There are isolated reports of calciphylaxis in patients with cancer (eg, metastatic breast carcinoma), as well as Crohn’s disease, liver cirrhosis, and primary hyperparathyroidism.⁴ Most reported observations suggest that calciphylaxis is associated with terminal renal insufficiency.^3–6

Calciphylaxis is a rare disorder and affects 1%–4% of the dialysis population.⁷ The condition was previously identified mainly in older patients on dialysis, but younger individuals may be at risk and cases in the pediatric population have been reported.^8,9

Kidney transplant recipients account for 32% to 38% of calciphylaxis cases, including patients with normal functioning grafts. Among this group, women outnumber men by a ratio of 3:1.⁸ Female gender, young age, obesity, diabetes, and suboptimal dialysis efficacy are all recognized risk factors.¹⁰ Predilection sites for calciphylaxis are the proximal extremities, especially the thighs, abdomen, buttocks, and breasts. There are also reports of fatal pulmonary, visceral, or muscular involvement in association with calciphylaxis.³ Involvement of the penis has also occured.¹¹

Calciphylaxis may begin as a small area of redness and tenderness or sometimes with a broad livedo reticularis pattern that evolves into intense erythema. This may progress to violaceous indurated plaques and nodules or frank necrosis with eschar formation and subsequent gangrenous infection and sepsis. Reported mortality rates are high (60%–80%).⁸

A 69-year-old woman with painful crural ulcers of 3 months’ duration presented to our outpatient clinic. The patient had no history of ulceration or predisposing trauma. Dermatological examination revealed a necrotic ulceration (7.7 cm x 4.6 cm) with eschar formation localized on the anterior left crural region and an ulcer (4.2 cm x 1.8 cm) on the lateral malleolus of the right ankle (Figure 1).

The patient was hospitalized and an incisional skin biopsy was performed. Histopathological findings revealed ulceration, chronic inflammatory granulation tissue, and calcium deposition in an intermediate dermal vessel in one microscobic area (Figure 2). Calciphylaxis was diagnosed based on the clinical and histopathological findings.

Laboratory findings revealed a high plasma concentration of parathyroid hormone (508 pg/mL) and elevated urea, creatinine, and phosphate levels (5.9 mg/dL). The patient had normal serum calcium and low albumin levels (2.6 g/dL). Arterial duplex Doppler scan excluded peripheral vascular disease. Platelet counts and clotting were normal. Arterial hypertension was the cause of renal failure and secondary hyperparathyroidism. Hypertension was treated with the combination of diuretic, beta-adrenergic blocker, and calcium channel blocker. After Nephrology consultation, a phosphate-binding agent and a low-phosphate diet were initiated to normalize the serum phosphate level. The endocrinologist who was consulted in this case did not recommend anything different from the nephrologist, but did mention that parathyroidectomy was not necessary based on the ultrasound and scintigraphic examinations; parathyroid glands were normal and the Ca x P product did not exceed 55 mg²/dL.²

The wound culture revealed Pseudomonas aeruginosa and systemic antibiotherapy was administered. Rivanol (0.1%) solution and fucidic acid cream was applied topically to the lesions. Collagenase ointment and Ag nitrate was applied to the necrotic tissue. After 3 months of topical wound care therapy, the ulcers showed significant improvement (Figure 3). The patient’s arterial hypertension was regulated with antihypertensive therapy. After 3 months of treatment, albumin (3.5 g/dL) and phosphate levels (4.5 mg/dL) were normal.

Calciphylaxis is well conceptualized as the skin equivalent of a myocardial infarction. Cutaneous arterioles, narrowed by medial calcification and subintimal fibrosis, are predisposed to thrombotic occlusion that eventuates in ischemic skin necrosis. Calciphylaxis is recognized clinically by painful ischemic purpura and necrotic ulceration. More than 50% of patients with calciphylaxis die within 1 year of diagnosis; related sepsis is the leading cause of death.¹²

Hans Selye coined the term “calciphylaxis” in 1962.³ He initially postulated that anaphylactic inflammation was followed by calcium deposition and linked this to the term calciphylaxis—today it is known that the process is not mediated by immunoglobulin E (IgE). Many authors consider the term “calciphylaxis” as a misnomer as it implies an immune-type reaction and prefer the term “calcific uremic arteriolopathy.”⁸

Today, the combined contributions from the fields of endocrinology, vascular medicine, nephrology, and bone science have been used to identify many molecular regulators of skeletal and extraskeletal mineralization. In the context of modern understanding, Selye’s definition of calciphylaxis (a condition of induced systemic hypersensitivity in which tissues respond to appropriate challenging agents with a precipitous, though sometimes evanescent, local calcification) closely approximates the description of vascular calcification that occurs in human calciphylaxis.³ However, medial arteriolar calcification in human calciphylaxis typically does not occur as precipitously as it did in Selye’s experiments, which showed soft-tissue calcium deposition in 3 to 5 days. Furthermore, vascular calcification alone is insufficient to produce acute cutaneous ischemia in human calciphylaxis. Notably, ischemic skin necrosis was not observed in Selye’s experiments. Cutaneous arteriolar stenosis and vascular (thrombotic) occlusion are both required to produce the clinical lesion of calciphylaxis.¹²

Histology reveals three important pathological findings involving venules, arterioles, and small cutaneous arteries with an average vessel diameter of 100 µm (30 µm–600 µm). Findings frequently include: extensive intimal hyperplasia, fibrosis, some vascular thrombosis, calcification within the media of vessels, necrosis of the overlying epidermis, and sometimes surrounding dermis and subcutaneous adipose tissue. Some histological analyses report giant cells, especially in areas affected by calcification.¹³ Von Kossa staining is particularly well-suited for identification of calcium salts and accurately shows calcification of vessel walls.⁴ The diagnosis of calciphylaxis is made based on pathologic findings (ie, arteriolar calcification, thrombosis, and ischemic cutaneous necrosis) and clinical presentation.¹² Aside from clinical findings, histopathological examination in the presented case also suggested the diagnosis of calciphylaxis.

Lesions are usually located in two distinct patterns: 1) distal, with lesions on the lower extremities, or 2) proximal, involving the abdomen, inner thighs, and buttocks. Unusual sites of involvement include the neck, breast, tongue, and genitalia.^8,14 Distribution of the disease is an important prognostic factor. Patients with the disease confined to the distal extremities often have better outcomes compared with those who have lesions on the trunk or for patients with visceral organ involvement.^1,8 The patient in the present case had lesions on distal extremities.

In a case series of 6 patients with calciphylaxis, a relationship between distal location of the lesions, normal serum albumin, and early diagnosis, were related to survival rather than the type of treatment a patient received.¹⁴ It was advantageous that our patient’s diagnosis was made early.

Calciphylaxis has a wide differential diagnosis and therefore, in addition to the routine hematological and biochemical parameters, investigations such as a vasculitis screen, estimation of cryoglobulins and cryofibrinogens, fibrin degradation products (FDPs), antiphospholipid antibodies, and Doppler assessment of limb vessels must be considered.⁶ In the presented case, arterial duplex Doppler scan excluded peripheral vascular disease.

Although the clinical morphology and histopathologic findings are crucial elements in defining calciphylaxis, other tests may be helpful in further supporting the diagnosis as well as directing therapy.⁸ Elevated PTH, phosphate, alkaline phosphatase, calcium phosphorous (Ca x P) product levels, high calcium, urea and creatinine values, and anemia may be noted. However, calciphylaxis can occur despite normal calcium and phosphate levels.⁶ The patient had a high plasma concentration of parathyroid hormone (508 pg/mL), and elevated urea, creatinine, and phosphate levels. The patient had a normal serum calcium level and a low albumin level. Ca x P product did not exceed 55 mg2/dL.²

Risk factors that contribute to the development of calciphylaxis have been described in the literature and include elevated serum concentrations of calcium and phosphate, obesity, Type 2 diabetes mellitus, hyperparathyroidism, protein C and protein S deficiency, vitamin K antagonists, hypoalbuminemia, vitamin D3 analogues, and calcium-containing phosphate binders.³ The sensitizing agent suspected in most clinical cases is parathyroid hormone, but the challenging agent is often more difficult to identify. Most cases occur on a background of secondary hyperparathyroidism. Elevated levels of parathyroid hormone (or hyperphosphatasemia) act as the sensitizing agent causing acute calcium deposition, which leads to inflammation and necrosis.¹

In 1976, Gipstein et al¹⁵ reported for the first time that patients with calciphylaxis and significantly elevated parathyroid hormone levels who underwent parathyroidectomy experienced improved ulcer healing. In a recent study of 15 patients, Duffy et al¹⁶ showed a significantly longer life expectancy among patients who underwent parathyroidectomy. Several reports indicate that treating calciphylaxis with hyperparathyroidism with parathyroidectomy resulted in significant symptom improvement and in some cases, complete ulcer healing.^8,17–20 Surgical management is strongly recommended especially in patients with extremely high parathyroid hormone levels because it can considerably increase the patient’s long-term survival.¹⁶ An endocrinologist was consulted for the patient in the present case, and since ultrasonographic and scintigraphic examination of the parathyroid glands were normal and Ca x P product did not exceed 55mg2/dL,² parathyroidectomy was not suggested.

In patients with terminal renal insufficiency, the evidence is convincing that atherosclerosis, similar to calcification of heart valves, is inversely proportional to serum albumin concentration.⁴ Bleyer et al²¹ and Mazahr et al²² achieved similar results in independent studies on calciphylaxis. In their studies, the severity of hypoalbuminemia was significantly correlated with the risk of developing calciphylaxis. The patient in the presented case had a low albumin level.

Many patients with terminal renal insufficiency take vitamin D3 analogs or calcium-containing phosphate binders to treat secondary hyperparathyroidism. Each of these therapies is considered a risk factor for increased vascular calcification. On the basis of experimental research as well as clinical observations, Jono et al²³ and Goldsmith et al²⁴ both showed increased vascular calcification in patients with terminal renal insufficiency who were on vitamin D3 analog treatment. Calcium-containing phosphate binders should also be avoided in these patients. Non-calcium phosphate binders (eg, sevelamer) should be used instead, as long as they effectively reduce phosphate levels. Use of vitamin D3 analog therapy and calcium salts to treat secondary hyperparathyroidism should be discontinued; if the patient has excessively high parathyroid hormone levels, parathyroidectomy should be considered.²⁵ In the presented case, a non-calcium phosphate binding agent and a low-phosphate diet was used to normalize the serum phosphate level.

Treatment options for calciphylaxis are to reduce calcium and phosphate levels as well as Ca x P product, parathyroidectomy, atraumatic wound management, substitute alternative anticoagulants for vitamin K antagonists, prevent sepsis, pain therapy, increase dialysis, hyperbaric oxygen therapy, sodium thiosulfate, cinacalcet, bisphosphonate, and substitute for vitamin D3 analogs.³ Treatment of calciphylaxis is largely supportive. Early recognition will avoid or remove potential sensitizers and challengers. Diet, binding agents, low-calcium dialysis, and parathyroidectomy may help normalize abnormal calcium and phosphorus levels. Aggressive wound care, careful debridement of necrotic tissue, and monitoring for infection are also important. Calciphylaxis remains an important diagnosis to consider in patients with renal failure because early recognition will expedite direct therapy and decrease mortality and morbidity.¹¹    

This case of calciphylaxis appearing with recalcitrant ulcers in the presence of moderate renal insufficiency was reported to stress the importance of early diagnosis and management of this life-threatening disorder.

Address correspondence to:
Aylin Türel Ermertcan, MD
Celal Bayar Üniversitesi
Tıp Fakültesi Dermatoloji
Anabilim Dalı 45010 Manisa, Turkey
Phone: +90 532 2243384
E-mail: draylinturel@hotmail.com