EuCalNet Calciphylaxis Registry

Calcific uremic arteriolopathy (CUA) or calciphylaxis is a rare condition of accelerated calcification of skin arterioles [1] (diameter around 100μ) which mainly develops in end-stage renal disease patients (ESRD) patients. It does also occur in patients with malignant diseases (such as myeloma [2], melanoma [3] and breast cancer [4]) and normal renal function [5]. It reduces quality of life considerably and still carries a one-year-mortality risk of approximately 50%, mainly due to superimposed sepsis [1]. The yearly incidence is <1% in patients on maintenance dialysis [1].

The diagnosis is made clinically in the presence of progressive, painful, retiform violaceous (later black/necrotic) skin lesions, which develop into large retiform ulcerations with thick eschar due to microthrombi formation and tissue necrosis [1]. Skin biopsies may sometimes clarify the diagnosis, but additional invasive procedures should generally be used with great caution, whereas the recently proposed method of showing calcified material in debrided tissue by microcomputed tomography (Raman spectroscopy) is not usually available [6]. Particularly in proximal lesions large deep fat tissue ulcerations may develop, carrying an especially poor prognosis.

The pathophysiology remains poorly understood but recent advances in vascular biology have demonstrated that vascular calcification is a highly regulated process. If this process can therefore be comprehensively examined through phenotypic, genotypic and proteomic analysis, the opportunity to identify therapeutic targets within or without the current therapeutic armamentarium and design intervention studies in calciphylaxis may become feasible.

Although chronic kidney disease is the most important clinical risk factor, followed by malignancies, CUA does also occur in association with normal kidney function and liver cirrhosis [7]. Other risk factors are female sex [1], obesity [1], thrombophilia syndromes such as Protein S or C deficiency [8], treatment with vitamin K antagonists [9] and/or corticosteroids and low albumin levels [1].

Regarding the pathogenesis of CUA, the scientific community had pursued the hypothesis of the calcification process as a continuum, from vascular calcification in general to extra-skeletal osteogenesis and CUA [10], over the last two decades. However, recent surveys and registry data suggest that conditions associated with high calcium-phosphorus product (primary and secondary hyperparathyroidism) play only a secondary role for CUA [11]. Therefore it has been argued that extra-skeletal osteogenesis and CKD-MDB might be regarded as a sensitization, which after a latency period is followed by an acute trigger event. This etiology theory is quite close to the one that had already been proposed by Hans Selye [12] who coined the term calciphylaxis in 1965. The fact that only a minority of patients with the same risk profile will develop the unique picture of CUA is reflected better by this two-step hypothesis as compared with the continuum one.

The hypothesis was developed further with the discovery of autosomal recessive CD73 deficiency [13], a calcification syndrome causing a phenotype which resembles the classical picture of medial artery calcification [14]. The purinergic signalling pathway, which the ecto-5'-nucleotidase CD73, also referred to as NT5E, belongs to, emerged as a possible mechanism for this acute CUA triggering event. Moreover, CD73 is a key regulatory molecule of cancer cell proliferation, migration and invasion in vitro, tumor angiogenesis, and tumor immune escape in vivo [15].

The EuCalNet registry was set-up by the CKD-MBD working group of the ERA-EDTA. It aims to determine the following:

• What is the natural history of the disease?
• What risk factors are associated with development and progression of calciphylaxis?
• Which treatments currently in clinical practice confer a favourable outcome?
• What are the underlying disease processes?

These aims will be achieved by collecting information on medications, clinical parameters, local laboratory tests, measuring specific proteins and molecules in blood and tissue as well as studying patient’s DNA profiles. Please contact Hansjörg Rothe first for advice on how to recruit patients.