What is Calciphylaxis?

Introduction

Calciphylaxis is a rare, potentially life-threatening syndrome characterized by progressive and painful skin ulcerations associated with medial calcification of medium-sized and small cutaneous arterial vessels. Calciphylaxis primarily affects patients on dialysis or after renal transplantation; however, exceptions have been reported in patients with normal renal function and in association with chronic-inflammatory disease, malignancy or primary hyperparathyroidism. Clinically, calciphylaxis is associated with a high mortality of up to 80%. Superinfection of necrotic skin lesions with subsequent sepsis significantly contributes to this outcome. Many patients also suffer from cardiovascular disease characterized by calcification of larger arterial vessels.
 
There are currently no exact numbers for the incidence of calciphylaxis. Based on small international surveys, incidence is estimated to be in the range of 1:1.000 to 1:1.500 cases in patients on chronic renal replacement therapy per year, but there is good reason to suspect under recognition caused by mild cases or misdiagnosis.
 
The term calciphylaxis was coined by Selye in 1962 as an analogy to the term “anaphylaxis”: His group was able to reproducibly induce skin calcifications by combining local trauma with additional “challenges” (such as with parathyroid hormone (PTH), active vitamin D and hypercalcaemia). Nowadays, calciphylaxis, or its synonym calcific uremic arteriopathy (CUA), describes a clinical entity starting with indurated and very painful cutaneous plaques, sometimes in the local setting of a livedo reticularis. The syndrome frequently develops in the lower extremities, but may also occur around the abdomen and hips and may affect peripheral sites (e.g., finger tips) or even skeletal muscle. Lesions of the penis, breasts and viscera have also been documented. Distal extremity lesions often raise suspicions of vasculitis, diabetic ulcerations or cholesterol emboli. Ulceration can occur very rapidly and progressively cover large skin regions, with significantly impaired wound healing. The key complication is superinfection of necrotizing areas.
 
 The histopathological hallmark of calciphylaxis is medial calcification of cutaneous arterioles, but also of neural sheaths and adipose tissues. If treatment is not initiated, these ulcerations may worsen and superinfection may cause septicaemia.
 
Due to the relative rarity of calciphylaxis, there are no systematic analyses of diagnostic tests. However, the painful character of the lesions and the association with advanced renal disease can be regarded as characteristic features. Under debate is the role of skin biopsy to confirm the diagnosis of calciphylaxis. On the one hand, there are concerns that additional trauma caused by the biopsy may induce a new focus of ulceration and worsen the disease course. On the other hand, biopsy is the only way to confirm calciphylaxis and exclude other entities such as vasculitis; pathognomomic arteriolar calcifications using staining based on silver nitrate (‘von Kossa’ staining) or alizarin red should be used, because standard staining may not demonstrate medial calcification of small arteries. Vice versa, skin biopsy obtained from patients with suspected vasculitis should also be evaluated to exclude calciphylaxis. Biopsy sites should preferably be at the margins of ulcers. If large areas are present, bone scintigraphy may be an effective non-invasive diagnostic tool showing tracer deposition in calcified subcutaneous areas.