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Background and rationale

Background

 
Calciphylaxis (or calcific uraemic arteriolopathy) is an uncommon condition that generally affects patients with chronic kidney disease (CKD). It is often a very painful and potentially life-threatening disorder characterized by medial calcification of small arterioles, intimal proliferation, fibrosis and thrombosis resulting in ischaemia, necrosis and superinfection of the skin and subcutis. A concert of various, still incompletely understood local and systemic risk factors is necessary for the development of calciphylaxis.
 
When renal function is normal, calciphylaxis has been reported infrequently, associated with conditions such as primary hyperparathyroidism. However, amongst patients with CKD on dialysis, the annual incidence has been estimated at 1–4%, with an apparent increase over the past decades that may reflect an increased use of calcium-based phosphate binders. For patients on dialysis, mortality rates are increased 8-fold if calciphylaxis develops. The poor outcome is often due to fatal cardiovascular and septic complications. The mortality of non-ulcerating types is approximately 30% and for ulcerating types around 80%, with most deaths occurring within 6 months. In this setting, calciphylaxis is usually associated with poorly controlled secondary hyperparathyroidism. However, cases have been reported in association with low bone turnover and following parathyroid surgery.
 

Pathogenesis

 
Patients with CKD are prone to developing soft tissue calcification due to disturbed mineral metabolism and an imbalance between factors that promote and inhibit calcification. An important mechanism for vascular calcification is the induction of vascular type III sodium-dependent phosphate co-transporters, which occurs in response to increased levels of serum calcium and phosphate. Secondary hyperparathyroidism predisposes to increased release of calcium and phosphate from bone due to uncoupling of bone resorption from formation, but abnormal calcium and phosphate homeostasis also occurs when bone turnover is low or adynamic because of a reduced capacity of bone to incorporate or ‘buffer’ calcium and phosphate.
 
Increased activity of the sodium-dependent phosphate co-transporters and an increase of intracellular phosphate induce the master osteoblast regulator Cbfa-1. In turn this can promote transdifferentiation of vascular smooth muscle cells to cells with an osteoblast phenotype, capable of producing ALP, osteocalcin, osteopontin, collagen rich extracellular matrix and matrix vesicles that initiate hydroxyapatite crystallization. As renal function worsens, the effectiveness of natural inhibitors of this process that include matrix Gla protein, fetuin-A, osteoprotegerin, klotho, BMP7, PTHrP and pyrophosphate, declines.
 

Current management

 
Evidence-based therapeutic options are unfortunately lacking. Normalisation of mineral metabolism disorders (high levels of serum calcium and phosphate), intensifying dialysis treatment, avoidance of warfarin treatment as well as hyperbaric oxygen therapy, supportive wound care and pain management, are frequently applied strategies. Parathyroidectomy, bisphosphonates, sodium thiosulfate and cinacalcet are amongst therapies that have been used with varying success when calciphylaxis is associated with hyperparathyroidism and high bone turnover, while for low or adynamic bone turnover, the use of rhPTH-(1–34) has been reported. Surgical management forms an integral aspect of therapy and a number of therapies using natural inhibitors of calcification have been proposed.
 
Collecting cases of calciphylaxis ‘by chance’ (such as in published case reports and cases series) however is not a suitable tool to approach improvement in treatment options. More robust information about the epidemiology, risk factors and associations, and pathogenesis of calciphylaxis is crucial to determine optimal preventative and therapeutic interventions.
 

The role of national registries

 
National registries have proven to be valuable resources as a means of sharing information on more common entities such as breast cancer and renal failure, with the Australian and New Zealand Dialysis and Transplant registry (ANZDATA) an excellent example. For less common conditions registries perform the task of amalgamating information that would be unavailable from a single centre. Examples of Australian registries that have been established for this purpose are those for transmissible spongiform encephalopathies and for genetic heart disease; The Australian National Creutzfeldt-Jakob Disease Registry under the auspices of the University of Melbourne and The National Genetic Heart Disease Registry under the auspices of the Centenary Institute affiliated with University of Sydney and Royal Prince Alfred Hospital.
 

Necessity for a calciphylaxis registry

 
The established German Calciphylaxis Registry has highlighted the need for ongoing data collection about the occurrence, risk factors and outcomes of episodes of calciphylaxis. Published data from case reports and case series is too limited to provide general recommendations for clinical management.  Registry data is mandatory to identify beneficial therapeutic options and potentially lead to the initiation of prospective interventional studies. An Australian Calciphylaxis Registry is necessary to determine the incidence, predictors, co-morbidities and associated factors, and outcomes of patients developing calciphylaxis in Australia.