Introduction

Calciphylaxis is a rare, but potentially life-threatening syndrome characterized by progressive and painful skin ulcerations associated with media calcification of medium-size 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. Clinical manifestation of calciphylaxis is associated with high mortality of up to 80%, superinfection of necrotic skin lesions with subsequent sepsis significantly contributing to this dramatic outcome. However, many calciphylaxis patients also suffer from advanced cardiovascular disease characterized by severe calcifications of larger arterial vessels. There are currently no exact numbers on the incidence of calciphylaxis available. 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 underrecognition caused by mild cases or misdiagnosis in a relevant percentage of patients.

The term calciphylaxis was coined by Selye in 1962 by Selye in analogy to the term “anaphylaxis”: His group was able to reproducibly induce skin calcifications by combining local trauma with additional “challenges” (inductors such as parathyroid hormone (PTH), active vitamin D, hypercalcemia). 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 (figure 1), but may also manifest around the abdomen and hips and may affect peripheral sites (e.g., finger tips) or even skeletal muscle. In case reports, lesions on the penis, breasts and in visceral organs were also documented . Especially those lesions located at the distal extremities often raise suspicion of differential diagnoses of vasculitis, diabetic ulcerations or cholesterol emboli. Exulceration can occur very rapidly and progressively cover large skin regions, with significantly impaired wound healing capacity. The key complication is superinfection of such necrotizing areas. The histopathological hallmark of calciphylaxis is media calcification of cutaneous arterioles, but also of neural sheats and adipose tissues. If treatment is not initiated early or remains unresponsive, these ulcerations worsen progressively and superinfections cause deleterious septic disease courses.

Due to the relative rarity of calciphylaxis, there are no systematic analyses of standardized clinical diagnostic tests. The painful character of the lesions and the association with advanced renal disease can, however, be regarded as very 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 microtraumatization caused by biopsy may by itself induce a new focus of ulceration and worsen the disease course. On the other hand, biopsy is the only way to ascertain the diagnosis of calciphylaxis and to exclude other entities such as vasculitis. However, it is imperative to actively look for the pathognomic arteriolar calcifications by staining based on silver nitrate ("von Kossa" staining) or alizarin red, because standard staining may not demonstrate media calcification of small arteries. Vice versa, skin biopsy obtained from patients with suspected vasculitis should probably also be actively 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.

Calciphylaxis and calcification inhibitors

In recent years, numerous observations support the assumption that dysregulation in the balance of local or systemic calcium-regulatory factors may be involved in the development of unwanted calcification processes in the body. Current data focus on the importance of matrix Gla protein (MGP) and fetuin-A (alpha2-Heremans Schmid Glykoprotein, AHSG) as prototypic calcification inhibitors.

MGP is a 10 kD protein exclusively expressed in vascular smooth muscle cells (VSMC) and chondrocytes. This protein requires post-translational vitamin K-dependent gamma-carboxylation for activation. Accordingly, warfarin treatment suppresses MGP activation. Knockout of the MGP gene in mice (MGP-/-) causes severe media calcification of large arteries with subsequent rupture of the ossified aorta – MGP-/- mice actually die of internal arterial hemorrhage at the age of 6 – 8 weeks. MGP acts purely as local inhibitor, systemic overexpression is not capable of counteracting arterial calcification induced by MGP-/-. Analogously, media calcification can also be induced by treatment with vitamin K antagonists. In rats, warfarin-induced vascular calcification can be partially reversed by feeding supraphysiological doses of vitamin K1 or K2 following withdrawal of warfarin, whereas calcification progresses when only low doses of vitamin K are fed.

The second potentially important calcification inhibitor with regard to the pathophysiology of calciphylaxis is fetuin-A. Fetuin-A is a 60-kD glycoprotein produced in the liver and probably the most potent circulating calcification inhibitor. Extracellular concentrations are as high as 0.5 – 1.0 g/l under normal conditions, fetuin-A represents a major proportion of the alpha2-band of serum electrophoresis. Importantly, this glycoprotein is regulated as a negative phase protein, thus, in situations of acute or chronic inflammation, blood and tissue levels of this calcification inhibitor may drop significantly and deficiency may occur. Of note, most of the very rare cases of calciphylaxis in patients with normal renal function were reported in active chronic inflammatory diseases.

Fetuin-A knockout (fetuin-A-/-) mice spontaneously develop massive organ and soft-tissue calcification. A large proportion of patients on dialysis show fetuin-A serum levels below the normal range, and fetuin-A deficiency is related to increased all-cause and cardiovascular mortality in this patient group. In eight well-characterized calciphylaxis patients, we were able to detect very low fetuin-A serum levels (range: 0.09 – 0.25 g/l) in the context of highly elevated CRP levels.

Calciphylaxis Registries

There is no doubt that current data on incidence, pathophysiology, diagnostic and therapeutic strategies on calciphylaxis is insufficient. This situation was considered by the „Kidney Disease – Improving Global Outcomes“ (KDIGO) initiative, a global and independent non-profit organization, aiming at improvements of the general prognosis of all CKD-associated outcomes. KDIGO developed the concept of prospectively collecting as many calciphylaxis cases as possible to improve understanding of the epidemiology of this syndrome and to collect samples (serum, DNA, biopsy tissues etc.) for evaluation of novel pathomechanisms and risk factors and for setting up data and tissue banking. For these purposes, calciphylaxis registries have been founded in the United Kingdom (Manchester) and Germany (Aachen/Coburg) representing the initial stage of an „International Collaborative Calciphylaxis Network (ICCN).

The German Calciphylaxis Registry

The German part of this registry started collecting patients via a web-based online form in October 2006 and has since accumulated data and samples from 87 patients (June 2009). A preliminary analysis of this data set revealed that 50% of the cases were associated with warfarin use and that there was no relationship to PTH serum levels. The internet pages are currently solely in German, but can be reached by entering the following URLs: www.calciphylaxie-register.ukaachen.de (active), www.calciphylaxie-register.klinikum-coburg.de (active) and www.calciphylaxie.de (from August 2008). Once such registries are more widely recognized, they may represent the basis for future prospective treatment trials.

Summary

  • Calciphylaxis is a rare, but desastrous complication in the course of chronic kidney disease, associated with extremely high mortality and possibly occurring with increasing incidence. In general, treatment aims at lowering the calcium x phosphorous product. In some cases with clinically significant HPT, parathyroidectomy must be considered. Treatment with vitamin K antagonists should be discontinued and replaced by heparin. Novel scientific insights point to a pathophysiological role of deficiencies of calcification inhibitors (MGP, Fetuin-A) in the induction and manifestation of calciphylaxis.
  • New potential therapeutic strategies including vitamin K supplementation, calcimimetics, bisphosphonates and sodium thiosulfate may find their way into clinical practice in the future, presently however, they must be considered with appropriate caution in individual cases. Information obtained by calciphylxis registries will hopefully contribute to improvements in outcomes of this deleterious syndrome.

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