CalciphylaxisM83.50

Rare, severe clinical picture, observed almost exclusively in patients with renal insufficiency who are required to undergo dialysis (pathognomic is the secondary hyperparathyroidism associated with it), characterized by calcifying dermatitis and panniculitis with thrombotic occlusions and wall calcifications of small and medium-sized vessels of the dermis and frequently subsequent skin necrosis.

Characteristic is the triad of arteriolar media calcification, thrombotic cutaneous ischemia and suddenly occurring (overnight) highly painful, jaggedly limited necroses of the skin.

Incidence (average population): 0.45/100,000 inhabitants/year.

Dialysis patients: prevalence 1-4% of all dialysis patients, especially if dialysis duration > 1 year.

As paraneoplastic syndrome in breast cancer. Individual case reports have also been published on the occurrence in patients with chronic intestinal diseases and primary hyperparathyroidism.

Ultimately, the causes are not known with certainty. In particular, disturbances in the calcium-phosphate metabolism with imbalance between calcification inhibitors (Matrix-Gla-Protein, Fetuin A) and calcification promoters (Osteopontin) are discussed.

In chronic end-stage renal failure, there is reduced calcitriol synthesis and consequently reduced calcium absorption and phosphate excretion in the kidney. This results in increased secretion of parathyroid hormone with secondary hyperparatheroidism, increased release of calcium and phosphate and calcium precipitation due to exceeding the solubility limit. These show a particular affinity for the elastic fibres of the vessels. Obviously, active processes in the cell wall (differentiation of smooth muscle cells into osteoclasts) and the inhibitory effect of inhibitors are also involved. However, calciphylaxies have also been described for standard calcium phosphate products.

Risk factors such as dialysis (in case of terminal renal failure, the accompanying metabolic disorders, in particular hyperphosphatemia, hypercalcaemia and parathyroid resistance, lead to a tendency to calcify), obesity, systemic glucocorticoid administration, increased detection of aluminium in serum (> 25 ng/ml) and liver diseases are discussed.

Women are affected 3-4 times more often than men.

• Type I: proximal location with infestation of trunk, buttocks, hip, proximal thigh
• Type II mainly affects the lower extremities.
• Type III: mixed form

Symmetrical, chronic, linear or even planar, 2.0 to 20 cm in size, eminently painful, hard, red or even skin-coloured plaques or nodules. The lesions are often indicated on the skin surface by livedo (cause: calcification of the cutaneous vascular plexus) and tend to ulceration. Very poor healing tendency. Clinically, highly painful, poorly healing ulcers, or an (excised) livedo (racemosa) may be the initial dermatological finding. In addition to cutaneous lesions, painful myopathies (gluteal and thigh muscles) and rhabdomyolysis can be found. Less frequent are calcifications of the lung or pancreas.

• Vasculitides: Painful, usually multiple spatter ulcers with clinically detectable purpura. Histology is diagnostic.
• Polyarteritis nodosa, cutaneous: Initially coarse, often pressure-dolent, reddish to livid coloured nodules. Secondary ulceration, formation of flat, partly hyperpigmented scars. The medical history is therefore fundamentally different. No renal insufficiency!
• AVK: Pain at rest, improvement of pain at low position; distal ulcers; evidence of vascular occlusion.
• Cholesterol embolism: Red-livid spots of varying size, bizarrely configured, suddenly appearing in previously unchanged skin (image of livedo racemosa in about 35% of cases). Acutely occurring, usually very painful, bizarrely limited, often poorly documented, flat ulcers. No renal insufficiency! Mostly clear arteriosclerosis. Sign of AVK!
• Ulcus cruris hypertonicum: S.u. Cholesterol embolism.
• Ulcus cruris venosum: Chronic, never acutely occurring, mostly red, extensive, not very painful ulcer in dermatosclerotic skin. Doppler sonographic evidence of venous insufficiency. Localization of the ulcer typical of CVI (medial or lateral ankle).
• Pyoderma gangraenosum: The history is clearly different: no renal insufficiency, no AVK; within a few days, the ulcers develop flat, initially shallow, within a few weeks deep ulcerations which extend beyond the skin organ (subcutis, possibly affecting muscles and tendon beds). Characteristic and thus of diagnostic importance is an extremely painful marginal zone with a walled-like, dark red or even grey, undermined hem.
• Panniculitis: Subcutaneous nodules, rarely ulcerated; mostly symmetrical, preferably on the thighs. No live pattern, no jagged ulcers.
• Calcinosis cutis: Single or multiple, white-yellowish hard, sometimes painful plates or nodules of the skin with a tendency to ulceration; but also subcutaneously or in the muscles (equine bone).

The therapy is purely supportive.

Most important is lowering the calcium phosphate product: intensified and modified dialysis regimen, temporary administration of aluminum-containing PO4 _binders instead of calcium salts to lower the elevated _CaPO4 product.

Cinacalcet, an allosteric modulator of the calcium-sensitive receptor is published for prophylaxis of calciphylaxis. It leads to a conformational change of the receptor. This causes an increase in the sensitivity of the receptor to calcium and to a decreased release of the bone metabolic hormone parathyroid hormone.

Parathyroidectomy appears useful only in the presence of elevated phosphate levels.

Experimental: In a small clinical trial, the use of NOACs (New Oral Anticoagulants/FactorXa Inhibitors) was found to be beneficial in this patient group.

Cave! Delayed wound healing and tendency to ulceration even in small wounds (patient education)! Important: In addition to conservative wound management, surgical wound care with consistent debridement is also important.

Poor prognosis due to involvement of internal organs, especially the lungs (calcification of the pleura), vascular calcification and calcification of heart valves. Two types of vascular calcification can be distinguished:

• Calcification of the media of the vessel wall of the Mönckeberg type
• Calcification of atherosclerotic intimal plaques.

The 1-year survival rate is 46%. Cardiovascular and septic complications of the patients, who in most cases have to undergo dialysis, are responsible for the high death rate.

Kaliphylaxie is an artificial word coined by Hans Seleye from "potassium" and "anaphylaxis".

All cases of calciphylaxis can be entered in a form provided by the German Society of Nephrology at: www. calciphylaxie.de.

Some authors assign the ulcer cruris hypertonicum Matorell as a distal affection pattern to calciphylaxis without nerve insufficiency.

The 58-year-old, obese housewife has been suffering for 18 years from renal failure requiring dialysis due to diabetic glomerulonephritis. 4 years ago secondary hyperparathyroidism with consecutive resection of the parathyroid glands. Aortic and mitral valve replacement 3 years ago with Marcumar therapy. Severe peripheral arterial occlusive disease of the thigh type (Fontaine stage III).

Findings: Now, on both lower legs, acutely occurring, multiple, up to 3.0 x 5.0 cm large, bizarrely configured, extremely painful, bluish-livid plaques and flat, crusty-smeary ulcerations. Clear livedo pattern in the surrounding intact skin.

Laboratory: Increased laboratory parameters: creatinine, urea, phosphate, parathormone. ANCA normal. Vit.-D3 was decreased. Calcium normal.

Histology (area with livedo drawing): Thrombosed dermal and subcutaneous vessels with pronounced basophilic calcium deposits in the lumen and walls.

Therapy: Surgical debridement and wound conditioning with low-frequency power ultrasound and hydrocolloid dressings. Intravenous prostaglandin E1 40 µg/day. Antihyperphosphatemic with sevelamer (Renagel) 3 times/day 1600 mg p.o.

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6. Klode J et al (2006) Calciphylaxis: An overview. Vasomed 18: 6-11

7. McCarthy JT et al (2016) Survival, Risk Factors, and Effect of Treatment in 101 Patients With Calciphylaxis. Mayo Clin Proc 91: 1384-1394.
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