Risk Factors

Data concerning the epidemiology of calciphylaxis is limited. The two most comprehensive publications are case-control studies comprising 19 and 36 patients. Summarizing the results, female gender, diabetes mellitus, peritoneal dialysis, obesity, hypalbuminemia in the context of malnutrition and chronic inflammation, hyperphosphatemia, elevated calcium x phosphorous product and combined use of active vitamin D analogues with high doses of calcium-containing phosphate binders appear to be risk factors associated with calciphylaxis manifestation. In case reports, calciphylaxis episodes were repeatedly reported in association with derangements of the calcium x phosphorous product in the context of severe secondary or tertiary hyperparathyroidism. Along this line, some case reports and a recently published case series from the University of Wisconsin have demonstrated dramatic improvements of calciphylaxis following “emergency” parathyroidectomy; however, some reports have described de novo calciphylaxis with severe disease courses in patients who were previously parathyroidectomized. Both disorders, severe (tertiary) hyperparathyroidism (HPT) and adynamic bone disease (ABD) in patients with relative or absolute hypoparathyroidism, may cause elemental derangements in mineral metabolism predisposing for calciphylaxis: In both situations, calcium x phosphorous homeostasis is massively deranged, either due to increased bone turnover (as in HPT) or due to bone “paralysis” (as in ABD). It is thought that the inability of the bone to serve as a „calcium buffer“ may create an environment favouring extraosseous soft-tissue calcifications. Finally, in a number of case reports, a connection between the use of vitamin K antagonists (warfarin etc.) and the development of calciphylaxis has been reported. The potential pathophysiological relevance of this observation will be discussed below.

Therapeutic Approaches

Therapeutic approaches are limited in calciphylaxis. As pointed out above, the available data is restricted to case reports and small case-control studies, while prospective studies are not available. Once calciphylaxis is suspected or diagnosed in a uremic patient, the first therapeutic aim must be normalization of the calcium x phosphate product, i.e. by intensifying dialysis treatment, by using a low dialysate calcium and by high-dose treatment with (preferably calcium-free) phosphate binders. Reduction or withdrawal of active vitamin D treatment must be considered depending on the corresponding levels of PTH and calcium x phosphorous product. In calciphylaxis patients with hyperparathyroidism and signs of high bone turnover, „emergency“ parathyroidectomy must be considered immediately. However, in such patients administration of calcimimetics may represent an effective therapeutic alternative – promising case reports on this conservative intervention have been published recently. Once progressive ulcerations and necrosis are observed, early broad-spectrum antibiotics should probably be initiated.

Some data are available concerning the use of sodium thiosulfate and of bisphosphonates in the treatment of calciphylaxis. Thiosulfate is available as a chelating agent indicated for the treatment of cyanide intoxication. On the one hand, it possesses a high affinity to calcium ions, which may interfere with calcium and phosphate precipitation producing soluble calcium thiosulfate which can potentially be removed by dialysis. On the other hand, thiosulfate may also interfere with the local inflammation process by antioxidant properties. Both concepts currently lack proof.

It is currently unclear, whether bisphosphonates interact with extraosseous calcification processes via their antiresorptive bone effects or via direct peripheral pyrophosphate-like effects at the tissue sites. Although case reports on beneficial effects of pamidronate in calciphylaxis patients have recently been published, caution is advised concerning uncritical use of bisphosphonates in this patient group unless ABD is excluded or highly unlikely, since ABD will be aggravated by these compounds, especially in renal failure patients.

In calciphylaxis patients on warfarin treatment, warfarin withdrawal and switch to heparin use is urgently recommended, despite a lack of clear-cut prospective clinical evidence. However, the biological plausibility that vitamin K antagonism favors vascular calcification is regarded as extremely relevant and subsequent vitamin K supplementation may have to be addressed by future studies in this patient group. Basile et al. reported on succesful hyperbaric oxygen therapy in a small number of calciphylaxis patients. This approach is based on the attempt to improve wound healing in ischemic tissues. In this study, affected areas were exposed 100% oxygen under 2.5-fold elevated atmospheric pressure in a closed chamber for 90 minutes per session in order to significantly increase local oxygen pressure in the ulcerated and necrotic areas (number of session per patient ranged between 20 and 108). 8 out of 11 patients showed effective healing of calciphylactic ulcerations. Finally, Fine and Zacharias reported on 36 calciphylaxis patients in different stages of the disease and on successful glucocorticoid treatment in early, non-ulcerated stages. However, with regard to the threat of superinfection, glucocorticoids should certainly be avoided in patients with advanced lesions because of their immunosuppressive properties.

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