Calciphylaxis M83.50

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 have not been clarified with certainty. In particular, disorders in the calcium-phosphate metabolism with an imbalance between the calcification inhibitors(matrix Gla protein, fetuin A) and calcification promoters (osteopontin) are being discussed.

In chronic terminal renal insufficiency, calcitriol synthesis is reduced, resulting in reduced calcium reabsorption and reduced phosphate excretion by the kidneys. This causes increased release of parathyroid hormone with secondary hyperparatheroidism, increased release of calcium and phosphate as well as calcium precipitation by exceeding the solubility limit. These show a particular affinity for the elastic fibers 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, calciphylaxis has also been described with a normal calcium-phosphate product.

Risk factors such as dialysis (in terminal renal insufficiency, the accompanying metabolic disorders, in particular hyperphosphatemia, hypercalcemia and parathyroid hormone resistance, lead to a tendency to calcification), obesity, systemic glucocorticoid administration, increased detection of aluminum in serum (> 25 ng/ml) and liver disease are discussed.

Warfarin (in Europe mostly phenprocoumon, which also belongs to the coumarin group) is often used in hemodialysis patients. One of the effects of coumarin therapy is the reduction of vitamin K-dependent regeneration of the matrix GLA protein. This protein is important for the prevention of vascular calcification. Therefore, coumarin treatment should be considered a risk factor for calciphylaxis, and a patient who develops this syndrome should discontinue this treatment and switch to alternative forms of anticoagulation.

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

Type I: proximal localization with involvement of the trunk, buttocks, hip, proximal thigh

Type II mainly affects the lower extremities.

Type III: mixed form

In a fully developed stadium, there are chronically persistent, symmetrical, linear or flat, 2.0 to 20 cm large, eminently painful, hard, red or even skin-colored plaques or nodules. The lesions are often indicated on the skin surface by a livedo (cause: calcifications of the cutaneous vascular plexus) and tend to ulcerate. Extremely poor healing tendency. Clinically, therefore, highly painful, poorly healing ulcers or an (exulcerated) livedo (racemosa) can occur as the initial dermatological finding. In addition to the cutaneous lesions, painful myopathies (gluteal and thigh muscles) and rhabdomyolysis are found. Less common are calcifications of the lungs or pancreas.

Vasculitides: Painful, usually multiple splatter-like ulcers with clinically detectable purpura. Histology is diagnostic.

Polyarteritis nodosa, cutaneous: Initially initially rough, often pressure-dolent, reddish to livid-colored nodules. Secondary ulceration, formation of flat, sometimes hyperpigmented scars. The anamnesis is therefore fundamentally different. No renal insufficiency!

AVK: Pain at rest, improvement of pain with deep positioning; distal ulcers; evidence of vascular occlusion.

Cholesterol embolism: In previously unchanged skin, suddenly appearing, differently sized, bizarrely configured, red-livid spots (picture of livedo racemosa in about 35% of cases). Further acutely occurring, usually very painful, bizarrely limited, often sparsely covered, flat ulcers. No renal insufficiency! Mostly clear arteriosclerosis. Signs of AVK!

Ulcus cruris hypertonicum: see below cholesterol embolism.

Ulcus cruris venosum: Chronic, never acute, mostly red, extensive, slightly painful ulcer in dermatosclerotic skin. Doppler sonographic evidence of venous insufficiency. CVI-typical localization of the ulcer (medial or lateral ankle).

Pyoderma gangraenosum: The anamnesis is clearly different: no renal insufficiency, no AVK; within a few days formation of extensive, initially shallow ulcerations, which over the course of a few weeks extend deep into the skin organ (subcutis, possibly affecting muscles and tendon beds). Characteristic and therefore of diagnostic significance is an extremely painful marginal zone with a wall-like, dark red or even gray, undermined border.

Panniculitis: Subcutaneous nodules, rarely ulcerated; mostly symmetrical, preferably on the thighs. No livedo pattern, no jagged ulcers.

Calcinosis cutis: Single or multiple, whitish-yellowish hard, sometimes painful plates or nodules of the skin with a tendency to ulceration; but also subcutaneous or in the musculature (riding bones).

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 woman has been suffering from renal insufficiency requiring dialysis for 18 years due to diabetic glomerulonephritis. Secondary hyperparathyroidism with consecutive resection of the parathyroid glands 4 years ago. 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, greasy ulcerations. Clear livedo pattern in the surrounding intact skin.

Laboratory: Elevated laboratory parameters: creatinine, urea, phosphate, parathyroid hormone. ANCA normal. Vit. _D3 was decreased. Calcium normal.

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

Therapy: Surgical debridement and wound bed 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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