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Skin Disorders in Patients With Chronic Kidney Disease

Skin Problems in Chronic Kidney Disease: Calcific Uremic Arteriolopathy (Calciphylaxis)


Calcific Uremic Arteriolopathy (Calciphylaxis)

Epidemiology and Clinical Characteristics

CUA, or calciphylaxis, is a potentially life-threatening vasculopathy of the skin and subcutaneous tissues that is usually associated with CKD. The incidence of CUA is estimated to be approximately 4% in patients on dialysis and less than 1% in patients with CKD.[51,52] The reported incidence of CUA has increased over the past 10 years as a result of improved clinical awareness.[53-55]

Risk factors for the development of CUA include obesity, diabetes mellitus, female sex, white ethnicity, time on renal replacement therapy and the use of coumarin anticoagulants.[51,53,55] Other factors reported to be associated with CUA include the use of vitamin D analogs, calcium-containing phosphate binders, iron-substitution therapy and glucocorticosteroids.[51,53,55]

CUA has an insidious onset that is marked by the occurrence of livedo-reticularis-like skin lesions predominantly on the abdomen, buttocks and thighs, all of which are areas with large amounts of subcutaneous fat. Over a period of days or weeks, these lesions transform into painful, subcutaneous, purpuric plaques and nodules and subsequently become necrotic ulcers covered by eschars (dry scabs or sloughs formed on the skin)[53] (Figure 2). These areas of ischemic, necrotic skin and subcutaneous fat can extend into deeper tissues including muscle and can become infected. The onset of CUA is often associated with a history of recent trauma, the initiation of coumarin treatment or with hypotensive episodes. Less commonly, CUA affects distal extremities such as the hands or lower legs; systemic involvement with ischemic infarction of the bowel, myocardium, brain, optic nerve or muscles, has been reported rarely.[51,53] CUA is associated with high mortality, with a 1-year survival rate of 45% and a 5-year survival rate of 35%; death is predominantly the result of infectious complications.[51,53-55]

Figure 2. (click image to zoom) Calcific uremic arteriolopathy in a 48-year-old female patient on hemodialysis with painful abdominal subcutaneous purpuric plaques and nodules and the start of necrotic ulcerations.

An early clinical diagnosis of the nonulcerative stage of CUA is very important as it allows the early initiation of therapeutic measures, which improves prognosis. The sudden appearance of painful violaceous plaques and nodules on the trunk or proximal extremities of patients with CKD and those on dialysis who are at risk of CUA should trigger prompt further diagnostic work-up. A histological diagnosis is preferable but skin biopsies must be obtained with caution as they might produce nonhealing ulcerations. The histological lesions characteristically involve epidermal ulceration, dermal necrosis, and vascular medial wall calcifications with subintimal or intimal hyperplasia and fibrosis of small and medium-sized blood vessels in the dermis and subcutaneous tissues[56] (Figure 3). Thrombotic occlusion of cutaneous vessels and extravascular calcium depositions are conspicuous. The histological lesions described, including calcifying septal panniculitis, are not pathognomonic for CUA.[51,56]

Figure 3. (click image to zoom) Histological skin lesions of calcific uremic arteriolopathy. (A) Hematoxylin and eosin stain (original magnification × 100) showing calcification (arrow). (B) Von Kossa stain (original magnification × 100) showing calcification (arrow). (C) Hematoxylin and eosin stain (original magnification × 100) showing a thrombus. Abbreviations: sc, subcutis; t, thrombus.

Radiological assessment with xerography (the X-ray technique used in mammography) might reveal small-vessel calcifications and measurement of transcutaneous oxygen saturation can confirm underlying tissue ischemia.[57,58] In some patients with CUA, a technetium-99m methylene diphosphate bone scan reveals superficial tracer localization in the subcutaneous tissues as well as visceral tracer activity.[59]

CUA should be differentiated from coumarininduced skin necrosis, atherosclerotic peripheral vascular disease, systemic vasculitis, cryoglobulinemia, cholesterol embolization, pyoderma gangrenosum, oxalosis and benign nodular calcification (a common condition in patients with CKD).


CUA is thought to involve an imbalance between inducers and inhibitors of calcification of the vascular wall.[60-62] In affected patients, the expression of osteopontin and bone morphogenic protein 4, both inducers of vascular calcification, is increased in vascular smooth muscle cells and dermal cells, respectively.[63,64] In addition, vascular smooth muscle cells in CUA transform into (osteogenic) osteoblast-like cells (via expression of core-binding factor-1) and express bone-related proteins such as osteocalcin, bone sialoprotein, type 1 collagen and osteopontin.[61,65] Conversely, some researchers have postulated that production of inhibitors of vascular calcification (e.g. fetuin A and osteoprotegerin) are suppressed (via the nuclear factor κB cascade) by the inflammatory changes encountered in uremia.[61,66] In addition, the actions of the matrix γ-carboxyglutamate (Gla) protein can be inhibited by coumarin-induced inhibition of vitamin-K-dependent carboxylation, which results in increased vascular calcifications.[67] Loss of pyrophosphate (which inhibits mineralization) from endothelial and vascular smooth muscle cells is associated with an increased risk of CUA in patients with CKD.[68] This complex balance can be shifted further in favor of tissue calcification by coexisting disturbances of calcium and phosphate metabolism, the use of vitamin D analogs, hyperparathyroidism, ischemia and deficiencies of proteins C and S. Indeed, very low protein C or protein S activities have been documented in patients on hemodialysis with CUA who have only slightly diminished protein levels.[52] Why CUA develops only in a small number of patients with CKD and what triggers it is not clear at present, but the occurrence of various procalcific events in concert with ischemia, inflammation and endothelial injury seems to ultimately lead to the initiation of this devastating disease.


The primary measures used to treat CUA focus on intensive wound care (including repeated surgical resections of necrotic tissue) and provision of systemic antibiotics and adequate opioid analgesia. In some cases, the use of vacuum dressings can be considered to improve wound healing. Aggressive surgical wound cleaning with autologous split-skin grafting has also been successfully attempted.[53,54]

Secondary treatment measures include restoring the patient's calcium and phosphate balance by use of intensified dialysis (with low-calcium dialysate), the use of non-calcium-based phosphate binders (e.g. sevelamer or lanthanum carbonate), and discontinuation of vitamin D analogs. In the presence of elevated intact parathyroid hormone levels, urgent parathyroidectomy might be necessary.[69,70] Case reports have described the calcimimetic cinacalcet to be effective for the rapid control of secondary hyperparathyroidism in patients with CUA, with complete healing of skin ulcers.[71] For patients in whom urgent surgical parathyroidectomy is contraindicated, calcimimetic therapy can be attempted. Vitamin K supplementation is advised in patients with coumarin-associated CUA.

Sodium thiosulfate, an inorganic salt, reduces metastatic tissue calcifications by chelating calcium from soft tissues. Sodium thiosulfate also acts as an antioxidant and induces endothelial nitric oxide synthesis, which improves blood flow and tissue oxygenation. Intravenous sodium thiosulfate at a dosage of 5-25 g during dialysis seems to be a successful treatment for CUA in combination with the above-mentioned therapies[72,73] (Figure 4). The main doselimiting adverse effect of sodium thiosulfate is nausea. Sodium thiosulfate treatment should be continued for a sufficiently long period (i.e. weeks to months) in order to maintain an initial positive response. A case study reported the successful use of intraperitoneal sodium thiosulfate in a patient with CUA.[74]

Figure 4. (click image to zoom) Calcific uremic arteriolopathy of the abdomen in a 44-year old male patient on hemodialysis. (A) Before treatment and (B) following treatment with intensified hemodialysis, parathyroidectomy and intravenous sodium thiosulfate 20 g thrice weekly for 7 weeks.

Both intravenous bisphosphonates (e.g. pamidronate and ibandronate) and oral bisphosphonates (e.g. etidronate) have also been used successfully to treat CUA, with rapid reduction in pain and decreased signs of inflammation.[75-77] The mechanism of action of bisphosphonates in CUA is unknown, but alterations in ectopic deposition of calcium phosphate, suppression of inflammatory changes and direct inhibition of calcification (via the nuclear factor κB cascade) are thought to be involved as bisphosphonates are structurally similar to pyrophosphate.[61] The use of bisphosphonates in patients with CKD and those on dialysis seems to be relatively safe, but only limited data are available.

Hyperbaric oxygen therapy improves oxygen delivery to damaged tissues and promotes wound healing through increased neoangiogenesis and collagen formation and improved neutrophil-mediated bacterial killing. Hyperbaric oxygen therapy has been used successfully in patients with CUA with few adverse effects.[78]

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