Calciphylaxis in 2024

Abstract

Calciphylaxis is a rare and potentially fatal disease manifested by progressive skin ulcerations due to calcification and obstruction of small-caliber arteries and arterioles. It mainly affects patients with chronic kidney disease treated by dialysis or renal transplantation but also individuals with normal kidney function, in which case it is often associated with chronic inflammatory diseases, neoplasia, primary hyperparathyroidism, and post-bariatric surgery. Necrotized ulcerations can become infected, leading to septic syndrome and a mortality rate of up to 80%. Its incidence varies from one case per 1,000 to one case per 1,500 hemodialysis patients per year, although this is probably underestimated. Clinical manifestations include very painful nodular or plaque-like indurations occurring in the extremities and central to the body. Lesions can also affect the fingers, penis, breasts, and visceral organs such as the lungs, intestines, and eyes. Its management is complex and requires a multimodal, individualized approach, involving close cooperation between nephrologists, dermatologists, surgeons, and other specialists. The aim of this review is to revise old and new aspects of this management while including the control of parameters of mineral and bone metabolism disorders, the replacement of vitamin K antagonists by alternative anticoagulants, the optimization of dialysis prescription, and the use of sodium thiosulfate, as well as new experimental therapies under development. We hope this review will help avoid common pitfalls and provide the highest quality care for patients with calciphylaxis.

Introduction

Calciphylaxis is a rare disease that is potentially life-threatening. It manifests essentially as progressive skin ulcerations resulting from the obstruction of small-caliber arteries and calcified arterioles. Calciphylaxis mainly affects subjects with chronic kidney disease (CKD) treated by dialysis or undergoing renal transplantation. However, it can exceptionally be seen in subjects with normal renal function, in which case it is often associated with chronic inflammatory diseases, neoplasia, and primary hyperparathyroidism, and after bariatric surgery[1][2][3]. The clinical manifestations of calciphylaxis are so disastrous, including superinfection of necrotic skin lesions and associated septic syndrome, that they often lead to death. The annual mortality rate can be as high as 80%. This is partly explained by the fact that most of these patients also present with other comorbidities, such as undernutrition and cardiovascular pathologies, including arterial and valvular calcification, ischemic heart disease, arrhythmia, hypertensive heart disease, and stroke[4].

Incidence and epidemiology

The exact prevalence of calciphylaxis is still poorly defined, ranging from 0.03 to 4.0% in the literature, and varies widely from country to country[5][6][7]. Its incidence in hemodialysis patients is estimated at between one case per 1,000 and one case per 1,500 patients per year, based on small series and small international registries. However, it is highly likely that this incidence is underestimated, as certain skin lesions, particularly those that are minor and doubtful, often go undiagnosed in a significant proportion of patients. The most recent and largest study of calciphylaxis has recently been carried out using Fresenius Medical Care North America (FMCNA) data collected between 2010 and 2014. It reports 1,030 cases of calciphylaxis and a mean annual incidence of 3.49 cases per 1,000 patients per year (95% CI 3.30 to 3.72)[7]. The incidence of calciphylaxis is thought to be even higher in French Polynesia, where it is around 10 times higher, although these results have not yet been published.

Diagnosis

Clinical

The term “calciphylaxis” was first used by Selye in 1961 as a contraction of “calcification” and “phylaxis” to describe a supposedly adaptive response to aggression[8]. Indeed, Selye and his colleagues succeeded in inducing skin calcifications by injecting inducers or facilitators such as parathyroid hormone (PTH) and vitamin D or by inducing hypercalcemia in rats subjected to local trauma.

Today, the term calciphylaxis is synonymous with calcific uremic arteriolopathy (CUA). It describes a clinical entity characterized initially by the appearance of patchy nodular or cutaneous indurations that are highly analgesic and often accompanied by reticular livedo. These lesions occur on the extremities (Figure 1A), and when they appear distally, below the knees and elbows, they can be defined as peripheral. They may also occur in more central, fat-rich areas, such as the abdomen, thorax, buttocks, hips, and thighs, and may extend deep down to the skeletal muscles (Figure 1B). These are described as central lesions. They can also be observed on the fingers, particularly affecting the fingertips. More rarely, calciphylaxis lesions may be observed in the penis, breasts, and visceral organs such as the lungs, intestines, or eyes, with retinal arterial thrombosis[9][10].

Figure 1A.Peripheral calciphylaxis lesions

Figure 1B.Central lesions

Calciphylaxis lesions affecting the lower extremities pose the problem of differential diagnosis with four diseases: lesions of vasculitis, ulcerations in connection with diabetic arteriopathy, lesions resulting from cholesterol emboli, and lesions of necrotizing angiodermatitis[4][11][12]. Central lesions may pose the problem of differential diagnosis with lesions of cutaneous necrosis induced by vitamin K antagonists (VKAs)[2]

Skin ulcerations can occur and progress rapidly, spreading over large areas of the body and significantly limiting healing capacity. The major complication, to be avoided wherever possible, is superinfection of necrotic lesions.

Histology

The characteristic histological lesions of calciphylaxis are calcification of the lamina media and intimal fibrosis of the arterioles of the dermis and hypodermis, resulting in a narrowing of the lumen. Calcification of nerve endings, adipocytes, and sweat glands is also frequently observed[13]. Fibrin thrombi may also be observed. If treatment of these lesions is not initiated early on, or if the lesions persist despite treatment, in most cases, the evolution is toward necrosis of adipose and cutaneous tissue, superinfection of the lesions, and septic complications in general.

Given the rarity of calciphylaxis, there is no standardized clinical procedure or radiological or biochemical analysis leading to its precise diagnosis. The very painful nature of the lesions and the association with advanced CKD and dialysis are very strong and characteristic features of calciphylaxis. The only way to make a precise diagnosis is by histological analysis of a lesion. Nevertheless, skin biopsy is still the subject of heated debate. On the one hand, opponents of skin biopsy argue that it causes additional trauma and creates a new focus for ulceration and necrosis, which can worsen the evolution of local lesions[14]. On the other hand, proponents of skin biopsy argue that it is the only way to formally diagnose calciphylaxis and exclude other pathologies such as vasculitis. However, it should be noted that the sensitivity diagnostic of biopsy is highly variable, ranging from 20-80%; that false negatives are frequent (47%); and that in a third of cases, samples are insufficient[15].

Vascular calcifications must be systematically detected using silver nitrate staining (von Kossa or alizarin red). Vascular calcifications may go undetected by conventional hematoxylin-eosin staining

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