The evolving clinical features of calciphylaxis.

ity rate, mainly due to secondary infections, sepsis, and PATHOGENIC CONSIDERATIONS ischemia. It is important to review certain pathogenic factors. Seyle [1] first described in 1962 a syndrome in the First, the presence of a uremic milieu together with a experimental animal and postulated that two steps are high Ca x P product has been in the majority of reports required to produce ectopic systemic calcifications. First, [2–5]. Diffuse vascular calcifications were frequently a systemic sensitization induced by agents such as paranoted in the early days of maintenance dialysis [6]. Extrathyroid hormone (PTH), vitamin D, or a diet high in skeletal calcifications were noted in 20% of dialysis pacalcium (Ca) and phosphorus (P). Second, after a time tients with secondary hyperparathyroidism (HPT) [6]; interval (the “critical period”), exposure to appropriate this number increased to 58% in patients with clinical challenging agents by subcutaneous injections resulted evidence of HPT, and to 75% in patients with severe in macroscopically visible deposits of calcium salts (hyovert HPT [7]. Still, even in the early days, at a time droxyapatite) systemically, and at the site of injection when secondary HPT was common, calciphylaxis was within two to three days. Challenging agents included uncommon. local trauma, iron salt, egg albumin, polymyxin, and gluSecond, the Ca content of the skin was an important cocorticoids. Selye named the syndrome “calciphylaxis.” pathogenic factor because it was noted to be high in A few years later a syndrome characterized by peripheral dialysis patients developing calcific uremic arteriolopaischemic tissue necrosis, vascular calcification, and cutathy (CUA) [8]. CUA also appeared to occur when a high neous ulcerations was reported in uremic patients.[2] dialysate Ca concentration of 4.0 mEq/L was used. [9] Because of its resemblance to Selye’s animal model, it In addition, a decrease in dialysate Ca dramatically imwas also named “calciphylaxis” [2]. However, the synproved CUA in some patients, whereas a high dialysate drome described in the uremic patient only resembles Ca concentration aggravated soft tissue calcification [9]. Selye’s model. Though a useful concept, the analogy to Furthermore, CUA was associated with hypercalcemia Selye’s model may not be warranted because the term induced by large oral doses of calcium carbonate, and it “calciphylaxis” has pathogenic implications that have not was reversed by discontinuing Ca carbonate [10]. It is been confirmed in humans. Thus, significant differences worth emphasizing that the use of Ca-containing binders exist between Selye’s model and uremic calciphylaxis. is common, and that many dialysis patients still ingest The former was characterized by metastatic systemic large doses of elemental Ca. The long-term effect of this calcifications that developed after significant invasive large Ca load on the dialysis population remains to be manipulations of the animal model, but vascular calcifiestablished. It is striking that almost all patients decations were not present. The latter occur primarily in scribed in recent years who developed CUA were ingestthe presence of uremia with abnormalities in divalent ing Ca-containing binders. ions (i.e., hypercalcemia, hyperphosphatemia, and high A third important pathogenic factor was the presence PTH), and most importantly, vascular calcifications were of high PTH levels. Earlier, it appeared that HPT was noted at the lesions. Retrospectively, it appears that urean important risk factor in the development of CUA [4]. mic soft tissue calcification (tumoral calcinosis) is the Gipstein et al [4] reported a series of patients with CUA, syndrome most analogous to Selye’s. It should be emphamost with peripheral digital ulcers, in whom parathyroid-