Calciphylaxis (Calcific uremic arteriolopathy)

Are You Confident of the Diagnosis?

The diagnosis of calciphylaxis, also known as calcific uremic arteriolopathy (CUA) in the setting of end-stage renal disease (ESRD), is a rare yet often fatal condition caused by calcification of dermal arterioles. Patients with ESRD and secondary hyperparathyroidism are primarily affected; however, other conditions may be associated with calciphylaxis. These include alcoholic liver disease, primary hyperparathyroidism, Crohn's disease, AIDS, and rheumatoid arthritis. Accurate diagnosis and treatment is critical, as prognosis is dismal.

  • Characteristic features on physical examination

Clinically the lesions of calciphylaxis are heterogeneous; however patients often first report dysesthesia in a small area of erythema or livedo reticularis prior to the rapid eruption of multiple tender, violaceous nodules or plaques. These lesions progress to central necrosis or a painful eschar surrounded by angulate or stellate ulcerations, rarely preceded by hemorrhagic flaccid bullae (Figure 1). Patients may also demonstrate palpable subcutaneous calcified nodules and plaques associated with surrounding pruritus.

Figure 1.

Calciphylaxis: Retiform purpura with ulceration.

Lesions are usually symmetric, bilateral, and well-demarcated, typically overlying thick adipose tissue (usually as trunk, buttocks, and thighs) or areas of trauma (including heparin or insulin injections). In men, scrotal or penile involvement is common. Other unusual locations include the neck, breast, tongue, and vulva. Acral and distal distributions have been reported to have a better prognosis than those with a proximal distribution. Pulses are preserved distal to the necrotic areas. Complications include secondary wound infection and gangrene. The leading cause of death is sepsis.

There are no definitive criteria for the diagnosis of calciphylaxis. Laboratory assessment should include testing of renal function, as well as quantification of serum calcium, phosphate, parathyroid hormone, vitamin D, and erythrocyte sedimentation rate (ESR) levels. Patients with calciphylaxis may have a calcium–phosphate product higher than 70, in addition to elevated levels of urea, parathyroid hormone, and/or ESR. However, normal laboratory values do not preclude diagnosis of calciphylaxis. For example, serum calcium levels may be normal or depressed at diagnosis due to intravascular deposition. While elevated PTH levels have traditionally been associated with an increased risk for developing calciphylaxis, low PTH levels (<100) may promote adynamic bone disease, which also increases the risk for vascular calcification.

Autoimmune connective tissue disease, cryoglobulinemia, vasculitides, and hypercoagulable states may mimic calciphylaxis; thus an antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), cryoglobulin, cryofibrinogen levels, and hepatitis B/C panels are indicated. Additionally, serum amylase and lipase should be tested to exclude pancreatic panniculitis. White blood cell count levels higher than 15,000 cells/mm3have been associated with a worse prognosis.

  • Expected results of diagnostic studies

A deep wedge biopsy is the standard for confirming the diagnosis, as a punch biopsy may be too superficial. Biopsies show medial calcification and intimal fibroplasia of small and medium-sized arterioles. A Von Kossa stain may be used to highlight calcium deposits which appear black. Calcium deposition is segmental or circumferential with resulting atrophy of the smooth muscle fibers of the media. Subcutaneous calcification with ischemic necrosis of the epidermis, hair follicle, and surrounding nerves has been reported.

Fibrin thrombi are often found in the small vessels of the dermis and subcutis. Extravasated erythrocytes with scant inflammation are seen in early lesions; however, in well-formed lesions, there is a moderately dense infiltrate composed of neutrophils, lymphocytes, and histiocytes surrounding vessels (Figure 2, Figure 3).

Figure 2.

Medial calcification and fibrin thrombi at dermal subcutaneous junction. (H&E, X40)

Figure 3.

Calcification of capillaries and medial calcification of small arterioles in subcutaneous tissue. (H&E stain, X4)

The value of radiology is limited in the diagnosis of calciphylaxis. Plain-film radiographs may show large-vessel pipe-stem calcifications and a fine double-lined, lacy network from the medial calcification. These findings are not specific and are often seen in ESRD, long-term dialysis and hyperparathyroidism patients, as well as with aging.

Mammography is the most sensitive radiologic technique for the detection of arteriolar calcification. One study found that in contrast to plain soft-tissue radiography and three-dimensional computed tomography (CT) scanning, mammography can identify microcalcifications as small as 130 micrometers.

Xeroradiography has also proven useful to differentiate between the arteriolar calcification of calciphylaxis and atherosclerosis. Oscillography and duplex ultrasonography may also be utilized to assess peripheral pulses in order to exclude atherosclerotic disease.

  • Diagnosis confirmation

The differential diagnosis of calciphylaxis includes:

Hematologic abnormalities (disseminated intravascular coagulation: differentiated by complete blood count and coagulation panel; warfarin necrosis: with documented history of warfarin use and protein C deficiency)

Hypercoagulable states (cryoglobulinemia: detected hepatitis B or C antibodies, presence of serum cryoglobulins, protein C deficiency: complete blood count (CBC), coagulation panel)

Infectious etiologies (cellulitis: clinical history +/- culture; panniculitis: deep skin biopsy and culture, and necrotizing fasciitis: systemic findings of fever, tachycardia, and hypotension, tense edema outside the involved skin, disproportionate pain, blisters/bullae, crepitus, and subcutaneous gas)

Vasculitides (Wegener's granulomatosis: c-ANCA, elevated ESR; Henoch-Schönlein purpura: leukocystoclastic vasculitis with IgA deposition on skin biopsy; levamisole-induced vasculopathy: commonly affects earlobe, contaminates an estimated 70% of cocaine and 3% of heroin supply in the U.S.)

Embolic phenomena (with infection or cholesterol embolization)

Connective tissue disease (the antiphospholipid syndrome: check lupus anticoagulant, anticardiolipin antibodies, anti-beta 2-glycoprotein)

Who is at Risk for Developing this Disease?

One percent of patients with chronic renal failure and 4% of patients on hemodialysis have been shown to develop calciphylaxis. The mean age is 48 years (ranging from 6 months to 83 years). A higher incidence has been suggested in women and Caucasian individuals. Other risk factors include hyperparathyroidism, end-stage renal disease of any etiology, elevated calcium-phosphate product (>70 mg2/dL2), and vitamin D exposure.

Additionally, obesity, diabetes, liver disease, immunosuppression, lymphoma, blood transfusions, serum aluminum > 25ng/mL, hypoalbuminemia, calcitriol, HIV, systemic corticosteroids, and local trauma (including insulin or heparin injections) may trigger calciphylaxis in patients who are already predisposed. Laboratory values within normal limits have been found in patients with calciphylaxis and do not exclude this diagnosis.

Certain medications, specifically warfarin, may contribute to the development of calciphylaxis by preventing vitamin-K dependent activation of Matrix Gla protein, an endogenous inhibitor of vascular calcification. The potential role of vitamin K in the pathogenesis of calciphylaxis is currently being investigated (NCT02278692).

What is the Cause of the Disease?

  • Etiology

  • Pathophysiology

The etiology of calciphylaxis is controversial; however, several molecular mechanisms have been postulated to play a role in the multifactorial pathogenesis of calciphylaxis in ESRD. Calciphylaxis has traditionally been thought to result from passive vascular deposition of calcium. However, recent research suggests that this hypothesis is simply one piece of a larger more complex process. Smooth muscle cells lining the vasculature may acquire osteoblastic properties, thus initiating development of calciphylaxis. This would explain why osteogenic markers, such as osteopontin and bone morphogenic protein 4, are often elevated in calciphylaxis patients, leading to extraskeletal calcification of vascular smooth muscle cells and periarterial dermal cells, respectively. This process may be exacerbated by the presence of hypercoaguable disorders, most commonly Protein C or S deficiency, which further promote thrombosis.

Additionally, decreased inhibitors of calcification have been noted. In healthy individuals, gamma-carboxylation binds calcium and inhibits vessel calcification; however, warfarin inhibits this vitamin K-dependent carboxylation and may result in increased calcification in those patients on this anticoagulation therapy. Fetuin A, an inhibitor of vascular calcification, was also decreased in hemodialysis patients.

Furthermore, ESRD patients are unable to adequately remove excess phosphorus causing extraosseous calcification. Although calcium deposition results in progressive narrowing of the vessel lumen, the sudden vascular occlusion and thrombosis results in calciphylaxis. Vascular mural calcification is believed to be an early and essential process in the development of the plaque.

Systemic Implications and Complications

Vascular and extravascular calcification of soft tissues and internal organs may be seen. Musculoskeletal manifestations may include muscle weakness, tenderness, or severe myositis with rhabodomyolysis. Effects on the nervous system are seen as calcific cerebral embolism, dementia and infarction of the CNS.

Metastatic calcification involving the pulmonary system may manifest as acute respiratory failure. “Bony heart,” the calcification of the cardiac system may result in cardiac valvular dysfunction, atrioventricular block, and conduction derangements. Gastrointestinal involvement has also been reported, presenting in patients as bowel infarction with massive hemorrhage, calcification of the stomach, pancreas or adrenals.

Treatment Options

Treatment options are summarized in Table I.

Table I.

Treatment options for calciphylaxis
Medical Treatment Surgical Procedures Physical Modalities
Hydrocolloid and biologic wound dressings Wound care & debridement Skin grafts Autologous keratinocyte grafts Hyperbaric oxygen therapy
Phosphate-binding agents Bisphosphonates Cinacalcet Sodium thiosulfate Systemic antibiotics Prednisone with subsequent cimetidine Oral pentoxifylline combined with maggot therapy    Analgesics for pain management    Parathyroidectomy (total or subtotal)     
  Revascularization and amputation  

Optimal Therapeutic Approach for this Disease

Primary prevention is ideal.

Factors associated with or suspected to aggravate calciphylaxis, such as renal failure, obesity, diabetes mellitus, hypertension, exogenous vitamin D or albumin, local trauma, corticosteroids, and immunosuppressants should be minimized. A low phosphate diet (<43 mg/day), low calcium dialysate, and use of non-calcium-based phosphate binders (e.g., sevelamer hydrochloride 1600 mg three times daily) are essential components of primary prevention.

There are no clear guidelines for the treatment of calciphylaxis.

In general, a multipronged, multidisciplinary approach involving dermatology, nephrology, pain management, and wound care should be undertaken. Primary goals include normalization of calcium and phosphate levels, pain management, and wound care.

More recently, multiple novel therapies have been proposed, although these are largely based on anecdotal evidence and small-scale studies. Optimal doses, duration, and frequency are ill-defined. Further, many of these novel therapies have rare yet serious adverse effects which may contribute to high mortality rates observed among calciphylaxis patients.

The most widely used of these is sodium thiosulfate.

Sodium thiosulfate (5-25 g IV over 10 minutes at the end of each hemodialysis treatment) may be used intravenously, and tolerated intraperitoneally. Its mechanism of action includes calcium chelation, direct vasodilation, and potent antioxidant properties, all of which improve tissue blood flow and oxygenation. Thiosulfate binds calcium and the resulting calcium thiosulfate is significantly more soluble. Common side effects include nausea. Rare sequelae include prolonged QT intervals and an anion gap metabolic acidosis secondary to the production of thiosulfuric acid.

Bisphosphonates decrease arterial calcification and normalize calcium and phosphate levels through inhibition of osteoclasts. Recent research suggests that bisphosphonates may also decrease pain through inhibition of macrophages and inflammatory cytokines involved in pain pathways. Options include intravenous pamidronate (30 mg in 250 mL of 0.9% NaCl in three alternate dialysis sessions) and oral etidronate disodium (200 mg/day). Despite effective control of serum calcium and phosphate levels, some patients may experience progression of their lesions.

Promoting healing and preventing sepsis are the two main goals of wound care. Sepsis is the most common cause of mortality in these patients. Aggressive wound care including surgical debridement of necrotic tissue, systemic antibiotics, hydrocolloid dressings, biologic dressing, and skin grafts may be attempted. It is important to monitor the patient for signs of infection at the wound site.

Calcimimetics such as cinacalcet (30-120 mg/day may be used as a safer alternative to surgical parathyroidectomy in patients with secondary hyperparathyroidism or in patients who are not candidates for this procedure. By decreasing sensitivity of calcium-sensing receptors, cinacalcet suppresses the release of PTH.

Finally, parathyroidectomy with autotransplantation is a controversial treatment modality for calciphylaxis. There is significant variability in post-surgical outcomes and may be detrimental in patients with low PTH levels. Parathyroidectomy may be considered when medical therapy and local wound care attempts are unsuccessful.

In calciphylaxis refractory to medical and surgical management, hyperbaric oxygen therapy may be particularly valuable for those patients undergoing both peritoneal and hemodialysis. This modality promotes wound healing by improving angiogenesis, phagocytosis and inhibiting bacterial growth within the diseased tissue, and decreasing local tissue edema. Risks of hyperbaric oxygen therapy include seizures from high oxygen ranges and are resolved by cessation of oxygen therapy.

Substantial pain management with systemic analgesics, such as high-dose opioids, ketamine, and benzodiazepines, is often necessary as the lesions are exquisitely painful.

Patient Management

Patients should be informed of the natural history, including morbidity, associated with calciphylaxis before beginning therapy. Treatment modalities largely consist of supportive therapy and overall prognosis is poor. Mortality ranges between 60-87%. Calciphylaxis is a heterogeneous disorder with a seemingly multifactorial etiology, and therefore response to treatment is variable.

Patients should be encouraged to minimize all aggravating factors. Additionally, patient education on recognizing signs and symptoms of wound infection are important in order to receive early wound care and appropriate intervention.

Risks of surgical debridement must be explained, as any physical trauma may in itself exacerbate calciphylaxis. If parathyroidectomy is pursued, patients should be informed of the equivocal data regarding the effect on survival.

Unusual Clinical Scenarios to Consider in Patient Management

While the vast majority of calciphylaxis patients have a history of chronic kidney disease, patients with normal renal function and with postrenal transplant successful grafting have also been reported to experience calciphylaxis. Rarely, malignancies such as cholangiocarcinoma, leukemia, melanoma, and multiple myeloma have been documented as possible etiologies of calciphylaxis.

Autoimmune conditions including connective tissue diseases, Crohn disease, rheumatoid arthritis, and AIDS have also been infrequently reported as causes of calciphylaxis.

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