Fig 2 from Nigwekar et al AJKD, © National Kidney Foundation.

Calciphylaxis is a rare and devastating disease, affecting mostly patients with end-stage kidney disease, but also affecting patients with preserved kidney function. Due to the low prevalence of the disease, high quality evidence for the evaluation and management of calciphylaxis is lacking. Most of the current evidence and recommendations are based on small studies, case reports, and expert opinion. In an article published in the July issue of AJKD, Nigwekar et al thoroughly review the current literature on calciphylaxis and provide a summary of recommendations to evaluate and manage patients with calciphylaxis, developed by the Massachusetts General Hospital’s Multi-Disciplinary Calciphylaxis Team.

Clinically, calciphylaxis presents with severe painful skin lesions that are frequently complicated by blistering and ulcerations. Histologically, it is characterized by vascular and soft tissue calcification, intimal hypertrophy, and microthrombosis of small vessels, which result in necrotizing, non-healing ulcers with a high risk of sepsis. Although the pathogenesis of calciphylaxis is not well understood, several risk factors are implicated, and nicely summarized in Table 1 of the article. The dysregulation of mineral-bone disease axis clearly plays a major role in the development of calciphylaxis, but it is not the sole cause. Other risk factors include the use of calcium-containing phosphate binders, diabetes mellitus, obesity, malnutrition, female sex, autoimmune disease, hypercoagulability, and warfarin therapy. The association between warfarin and calciphylaxis is compelling because of the action of warfarin on the vitamin K-dependent inhibitors of vascular calcification.

The diagnosis of calciphylaxis requires a high index of suspicion. The differential diagnosis should include the following clinical mimics: atherosclerotic vascular disease, cholesterol emboli, nephrogenic systemic fibrosis, oxalate vasculopathy, purpura fulminans, vasculitis, and warfarin necrosis. Definitive diagnosis requires a skin biopsy performed by an experienced provider. The risk of biopsy includes ulceration, superimposed infection, propagation of the lesion, and necrosis. The authors recommend punch biopsy over incisional biopsy, as it has been safer in their experience. Biopsy of the ulcer or necrotic area should be avoided because of low yield.

Radiologic studies and biomarkers have not been systematically studied, and thus are currently not recommended. Laboratory studies are mainly aimed towards identifying risk factors and should be guided by the clinical presentation and suspicion.

The treatment of calciphylaxis is multifaceted and includes medical and surgical interventions. The authors recommend the following disciplines be involved in the treatment plan: nephrology, dermatology, dermatopathology, a wound or burn center, nutrition, and pain management. As with other aspects of calciphylaxis, the quality of evidence for the various treatment modalities is poor, thus relying largely on observational studies and expert opinion. Data on non-uremic calciphylaxis is very limited, thus the diagnostic and the treatment approach suggested is similar to that of uremic calciphylaxis.

A wound or burn center, along with dermatology teams, could recommend appropriate topical treatment, as well as weigh into the decision for surgical debridement. Hyperbaric oxygen may serve as a second line therapy for non-healing wounds. Since sepsis is the primary cause of mortality, the authors recommend a low threshold for initiating antibiotic therapy.

Management of mineral bone disease involves maintaining serum calcium and phosphorus levels in the normal range, and keeping serum parathyroid hormone level between 150-300 ng/mL. Cinacalcet is recommended to treat secondary hyperparathyroidism, and vitamin D preparations should be avoided. Surgical parathyroidectomy is an option in patients who do not respond to medical therapy. Excessive suppression of PTH to <100 ng/mL should be avoided. This may induce adynamic bone disease that is a risk factor for vascular calcification.

Warfarin should probably be substituted by an alternative anticoagulation in patients who develop calciphylaxis. There is no data to suggest that intensifying the dialysis prescription is beneficial in patients with calciphylaxis, and such approach is not recommended.

Medical treatment of calciphylaxis is limited to sodium thiosulfate (off-label indication). Initially this drug was used in the treatment of tumoral calcinois in hemodialysis patients, but several small case studies over the last decade have highlighted the benefit of sodium thiosulfate in patients with calciphylaxis. Possible mechanisms of action for sodium thiosulfate have been proposed. One theory is that it complexes with calcium and thereby increases the solubility of calcium deposits. Recently, however, there has been more emphasis on sodium thiosulfate therapy also having antioxidant and vasodilatory properties.

The recommended dose of sodium thiosulfate is 25 g in 100 mL of normal saline intravenously given towards the end of dialysis. Because there is currently no recommended blood level measurement, it is important that dosing regimens be based on the intensity and frequency of the dialysis sessions. The authors provide a table (Table 3) with suggested dosing based on pharmacokinetics simulation and treatment modality. Optimal duration of sodium thiosulfate treatment in not known, but clinical improvement is anticipated within a 2-week time frame. Improvement in pain symptoms usually precedes wound healing, and is considered an important predictor of response.

In summary, calciphylaxis is a rare but life-threatening disorder with complex and poorly understood pathogenesis. Prospective clinical trials are lacking and the treatment options are limited. This excellent review by Nigwekar et al. provides a comprehensive summary of recommendations that should help clinicians taking care of patients with this challenging disease.

– Post written by Olga Karasik, MD, and Abdo Asmar, MD, AJKD Blog Advisory Board member

To view the article full-text or PDF (freely available for a limited time), please visit AJKD.org.