Ectopic calcification is a frequent complication of many degenerative diseases. Here we identify the serum protein alpha2-Heremans-Schmid glycoprotein (Ahsg, also known as fetuin-A) as an important inhibitor of ectopic calcification acting on the systemic level. Ahsg-deficient mice are phenotypically normal, but develop severe calcification of various organs on a mineral and vitamin D-rich diet and on a normal diet when the deficiency is combined with a DBA/2 genetic background. This phenotype is not associated with apparent changes in calcium and phosphate homeostasis, but with a decreased inhibitory activity of the Ahsg-deficient extracellular fluid on mineral formation. The same underlying principle may contribute to many calcifying disorders including calciphylaxis, a syndrome of severe systemic calcification in patients with chronic renal failure. Taken together, our data demonstrate a critical role of Ahsg as an inhibitor of unwanted mineralization and provide a novel therapeutic concept to prevent ectopic calcification accompanying various diseases.

Calciphylaxis is a small vessel vasculopathy involving mural calcification with intimal proliferation, fibrosis, and thrombosis. This syndrome occurs predominantly in individuals with renal failure and results in ischemia and necrosis of skin, subcutaneous fat, visceral organs, and skeletal muscle. The syndrome causes significant morbidity in the form of infection, organ failure, and pain. Mortality rates are high. In individuals with renal failure, risk factors for the development of calciphylaxis include female sex, Caucasian race, obesity, and diabetes mellitus. Many cases occur within the first year of dialysis treatment. Several recent reports demonstrate that prolonged hyperphosphatemia and/or elevated calcium x phosphorus products are associated with the syndrome. Protein malnutrition increases the likelihood of calciphylaxis, as does warfarin use and hypercoagulable states, such as protein C and/or protein S deficiency. Recent advances in diagnostic tools and therapeutic strategies have helped in the management of patients with calciphylaxis.

Seven diphosphonate analogs were treated for their effects on myocardial and cardiovascular degeneration and calcification in an experimental model of cardiac calciphylaxis. A single oral dose of dihydrotachysterol (DHT) administered to rats induced myocardial and vascular degeneration, focal myocarditis and vasculitis, and myocardial and vascular mineralization. The results demonstrated a considerable variation among the various diphosphonates in their ability to block the pathological changes observed in this model. Ethane-1-hydroxy-1,1-diphosphonate (EHDP) was the most effective diphosphonate in reducing myocardial and vascular degeneration and calcification, whereas diphosphonates such as ethane-1-amino-1,1-diphosphonate (EADP) and hydroxymethylene diphosphonate (HMDP) had little or no effect compared to saline controls. For those diphosphonates which were effective, e.g., EHDP, the tissue-protective effects were observed whether the rats were treated with drug prior to the administration of DHT, or whether drug treatment commenced after DHT administration. The results are discussed in terms of the known biological properties of the diphosphonate drugs.

BACKGROUND: Calciphylaxis is a rare, painful and debilitating disease in which calcification of the skin and subcutaneous tissues or of internal organs can lead to skin necrosis, discolouration, and other skin lesions. The typical patient has end-stage renal disease (ESRD) and hyperparathyroidism. Selye originally characterized this syndrome in rats and distinguished it from other syndromes of abnormal calcification by the following sequence: sensitizers, latent period, and challengers. There has been recent debate regarding misdiagnosis and failure to differentiate this category of patients even in clinical studies. OBJECTIVE: In this article the clinical manifestations of calciphylaxis are described; the importance of distinguishing this condition from other calcification syndromes is explained; risk factors, sensitizers, and challenges are reviewed; treatments of choice are discussed; and the merits of parathyroidectomy are evaluated. CONCLUSION: It is important to consider calciphylaxis in a differential diagnosis of calcification syndromes and in treating patients with ESRD and hyperparathyroidism, because early diagnosis and treatment can interrupt the progression of the disease process; the disease is painful and debilitating; and inappropriate treatment such as corticosteroid administration may aggravate the condition. Skin biopsy is an important diagnostic tool when the condition is suspected. Parathyroidectomy may be justified because the untreated disease itself has significant rates of morbidity and mortality and because this treatment occasionally leads to dramatic clinical improvement.

Calciphylaxis is a local tissue calcific reaction at the site of an injection of challenger substance given a critical time period after the oral administration of a sensitizer substance such as dihydrotachysterol (DHT), vitamin D or parathormone. Cutaneous calciphylaxis is readily induced in the rat but not in the mouse and this may be because, in the latter, the challenger substance is absorbed rapidly by macrophages. In the rat the administration of 500 micrograms/0.1 ml of DHT followed after 24 h by the subcutaneous (SC) injection of ferric chloride (FeCl3)(30 micrograms/0.1 ml) is followed rapidly by calcification of the SC site. There is an early transient acute inflammatory reaction with the incrustation of collagen fibres by the iron salt and an apparent exudation of calcium and phosphate ions from the bloodstream. These ions also become associated with collagen fibres. Two days after injection macrophages and multinucleated giant cells become the dominant cells. Calciphylaxis is a useful experimental model of ectopic calcification and is associated with an initial hypercalcaemia. The diphosphonates ethane-1-hydroxy-1, 1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl2MDP) are effective inhibitors of the calciphylactic reaction when administered prior to the initiation of the experimental procedure.