Calciphylaxis or calcific uremic arteriolopathy is a devastating disease; it generally occurs with little warning and is associated with severe pain resulting in a marked reduction in quality of life for those patients who are unfortunate enough to develop it [rx]. Evidence-based treatment options with proven effectiveness and safety are absent, which in turn makes management of the condition particularly challenging.
Calciphylaxis is a rare but devastating disorder most commonly observed in patients with end-stage renal disease, although it does occasionally develop in patients with acute renal failure, normal renal function, or earlier stages of chronic kidney disease (non-uremic calciphylaxis). Also known as calcific uremic arteriolopathy, it is characterized by painful skin lesions caused by cutaneous arteriolar calcification leading to tissue ischemia and infarction. Calciphylaxis is associated with substantial morbidity due to severe pain, nonhealing wounds, and frequent hospitalizations. It is a highly fatal condition with 1-year mortality rates greater than 50%, most often due to sepsis.
Calciphylaxis, also known as calcific uremic arteriolopathy (CUA), is a rare and poorly understood vascular calcification disorder with a predilection for patients with end-stage renal disease (ESRD) [rx–rx]. Case reports of patients with calciphylaxis were first published in the medical literature in the 1960s [rx,rx]. However, the current understanding of calciphylaxis pathogenesis, risk factors, and natural history is limited and there is a striking lack of high-quality data and randomized controlled trials regarding calciphylaxis treatment.
Calciphylaxis typically results from calcification of the medial layer of arterioles and small arteries. Blood flow is further reduced by endothelial injury and formation of microthrombi leading to luminal narrowing and occlusion. These changes cause tissue ischemia, necrosis, and ulceration.
The cause and mechanisms leading to calciphylaxis remain poorly understood, and its development is likely dependent on multiple factors that lead to medial calcification of arterioles. Elevated calcium x phosphate product, increased parathyroid hormone levels, and administration of activated vitamin D have been associated with the development of calciphylaxis. However, abnormalities of bone-mineral parameters such as these are typically not sufficient to cause calciphylaxis on their own in most patients. Disturbances in bone-mineral parameters are extremely common in dialysis patients. However, most do not develop calciphylaxis. Further, calciphylaxis may develop even if parathyroid hormone, phosphorus, and calcium levels are normal.
Deficiency of vascular calcification inhibitors such as fetuin-A, osteoprotegerin, and matrix G1a protein may play a role in the development of calciphylaxis. Fetuin-A is a glycoprotein that binds calcium and phosphorus and may help to prevent calcification of vessels and soft tissue.[rx] Fetuin-A is downregulated in dialysis patients. Matrix G1a protein may also prevent vascular calcification and is dependent on vitamin K dependent carboxylation for its activity. Warfarin use has been implicated as a risk factor for calciphylaxis, which may be related to its interference with vitamin K dependent activation of matrix G1a.[rx]
Causes of Calciphylaxis
Risk Factors for Calciphylaxis
Risk factors and associations for calciphylaxis include the following:
Autoimmune conditions such as lupus, rheumatoid arthritis, and antiphospholipid antibody syndrome
Calcium-based phosphate binders
Activated vitamin D
Abnormalities of the Chronic Kidney Disease-Bone Mineral Disease Axis
Adynamic bone disease
Diagnosis of Calciphylaxis
- Biopsy of the affected skin is needed to make the diagnosis of calciphylaxis. Both dermis and epidermis are often ulcerated and necrotic with various secondary changes.
- Calcification of small to medium-sized blood vessels are seen. The intimal layer of blood vessels id most commonly fibrosed and intravascular thrombi may be seen. The characteristic feature is the diffuse calcification of small capillaries in the adipose tissue.
History and Physical
- Calciphylaxis typically presents with extremely painful ischemic cutaneous lesions or painful subcutaneous nodules without skin changes, although at times, pain may precede the development of the lesions.[rx]
- Skin lesions often appear as violaceous or erythematous subcutaneous nodules and plaques. Livedo reticularis can also result from ischemia. As the lesions progress, they may become ulcerated with the development of necrosis, eschar, and infection.
- Proximal areas with increased adipose tissue such as the abdomen, thighs, and buttocks are most commonly involved, although distal sites such as the digits can also be affected. Extreme pain is a hallmark of calciphylaxis leading to considerable morbidity.
While skin manifestations are dominant, calciphylaxis is a systemic condition that may involve other organs including the eyes, penis, muscle, brain, intestines, and lungs.
- Diagnosing calciphylaxis requires a high index of suspicion. A definitive diagnosis is made after a skin biopsy of one of the lesions. The histologic evaluation shows medial calcification of dermal arterioles or small arteries and may show fibrointimal hyperplasia, microthrombi, and vascular narrowing or occlusion, often with evidence of necrosis.[rx]
- The need for biopsy in the diagnosis of calciphylaxis is debatable. While a biopsy is often performed to differentiate early stages of calciphylaxis from other skin lesions, the biopsy itself carries some risk, particularly for patients with only subcutaneous nodules. A skin punch biopsy may precipitate ulceration, bleeding, infection, or necrosis. Thus, if the clinical suspicion for calciphylaxis is high, some clinicians will forego a biopsy and treat based on a presumptive diagnosis.
Laboratory workup should include a metabolic panel, hepatic function, partial thromboplastin time, international normalized ratio, and albumin tests. In some cases, a hypercoagulable workup may be appropriate.
Laboratory evaluation should be conducted to further evaluate potential risk factors:
- 1) Renal function evaluation – serum blood urea nitrogen, creatinine, and estimated glomerular filtration rate (urinalysis, urine protein: creatinine ratio, and 24-hour urine collection for creatinine clearance to be considered for non-dialysis patients),
- 2) Mineral bone parameters evaluation – serum calcium, phosphorous, alkaline phosphatase, intact parathyroid hormone, and 25-hydroxyvitamin D,
- 3) Liver evaluation – serum transaminases, alkaline phosphatase, and albumin,
- 4) Infection – evaluation-complete blood count with differential (in all cases), and blood cultures (if leukocytosis or fever present),
- 5) Coagulation evaluation– prothrombin time, international normalized ratio, and partial thromboplastin time,
- 6) Inflammation evaluation – serum high sensitivity C-reactive protein and albumin,
- 7) Hypercoagulation evaluation – protein C, protein S, antithrombin III, and antiphospholipid antibody, and
- 8) Evaluation for autoimmune disease – and malignancy as guided by clinical suspicion.
Treatment of Calciphylaxis
- The wound care team should be involved in recommendations regarding the selection of dressings, chemical debriding agents, frequency of dressing changes, and negative pressure wound therapy.
- Surgical wound debridement should be considered on a case-by-case basis.
- Hyperbaric oxygen therapy can be considered as a second-line treatment if wounds not improving. Claustrophobia, access to treatment, and cost can be significant limiting factors of this therapy.[rx]
- Antibiotic administration should be guided by the clinical appearance of lesions and accompanying systemic features.
- Often narcotic analgesics are required to control severe pain associated with calciphylaxis
- Fentanyl may be preferred over morphine to minimize potential hypotension episodes associated with morphine.131
- Intravenous sodium thiosulfate at doses ranging from 12.5 to 25 grams in the last 30 minutes of each hemodialysis session for patients on 3 times a week dialysis schedule.[rx] For patients with other hemodialysis prescriptions dose adjustments are needed according to published algorithms.[rx]
- Nausea, metabolic acidosis, hypotension, and volume overload are potential adverse effects.[rx]
- Intra-lesional sodium thiosulfate has been described to aid in the resolution of calciphylaxis lesions.117
Management of mineral bone disease
-Serum calcium and phosphorous levels should be maintained in the normal range and serum parathyroid hormone level should be maintained between 150-300 ng/mL.
-Calcium supplements, high dialysate calcium bath, vitamin D preparations should be avoided and instead cinacalcet to be considered to treat secondary hyperparathyroidism in patients with calciphylaxis. Surgical parathyroidectomy is indicated in patients with refractory hyperparathyroidism.
-Excessive suppression of parathyroid hormone should be avoided.[rx]
-Nutrition consult to address protein-energy malnutrition should be obtained.
Dialysis modality and dialysis prescription
- Dialysis prescription should be optimized to achieve the recommended K/DOQI goals of dialysis adequacy.[rx] Intensifying dialysis by increasing duration or frequency has been described.[rx] In the absence of confirmatory data to support, we do not routinely recommend intensification of dialysis beyond the goals of dialysis adequacy.
- In the literature, peritoneal dialysis is described to confer higher calciphylaxis risk when compared to hemodialysis; rx] however, experience at our center is not consistent with this observation and we do not routinely transition patients from peritoneal dialysis to hemodialysis for calciphylaxis management.
- We recommend a nutrition consult to address malnutrition that is frequently present in calciphylaxis patients. If patients are not able to improve dietary intake then consideration should be given to nutrition via gastric tube and parenteral nutrition; however, evidence to support these interventions is lacking.
- Intravenous sodium thiosulfate is probably the most common intervention used to treat calciphylaxis (off-label indication). It is a reducing agent that forms water-soluble complexes with many metals and minerals. Its use in calciphylaxis was first reported over 10 years ago in a case report.[rx] However, there is no prospective trial data on this agent.
Management of other risk factors
-Risk vs. benefit discussion is needed to decide whether to continue warfarin and iron compounds in patients with calciphylaxis
Given the possible role of bone-mineral disorders in the pathophysiology of calciphylaxis, careful attention should be paid to avoid hypercalcemia, with phosphorus levels maintained at less than 5.5 mg/dL. At a minimum, dialysis adequacy criteria should be met, and dialysis frequency can be increased if necessary to optimize the clearance of uremic molecules and improve bone-mineral markers. Patients should discontinue the use of calcium supplements, and calcium-based phosphate binders should be converted to non-calcium containing binders. High calcium dialysate baths (greater than 2.5 meq/L) should also be avoided. The parathyroid hormone should be maintained between 150-300 ng/mL. For patients with secondary hyperparathyroidism, cinacalcet, a calcimimetic agent used to lower parathyroid hormone, should be used in place of activated vitamin D to avoid increasing serum calcium and phosphorus levels. In the evaluation of cinacalcet hydrochloride therapy to lower cardiovascular events (EVOLVE) trial, dialysis patients with secondary hyperparathyroidism were randomized to cinacalcet or placebo, and those who received cinacalcet were found to be less likely to develop calciphylaxis, although the overall incidence was low in both groups.[rx] Etelcalcetide, a new intravenous calcimimetic, has not been studied in calciphylaxis but may be a reasonable alternative in patients intolerant of cinacalcet. The role of surgical parathyroidectomy in the treatment of calciphylaxis has not been established.[rx]
In addition to addressing bone mineral parameters, the patient should discontinue any potentially problematic medications if possible. Given the association between warfarin and calciphylaxis, patient education regarding the risks and benefits of stopping anticoagulation or switching to a direct-acting oral anticoagulant is important.[rx] Studies regarding the use of vitamin K supplementation to activate matrix G1a protein have been proposed to study vitamin K as a possible treatment option for calciphylaxis, but the efficacy of this approach has not been evaluated.
Sodium thiosulfate is now routinely used off-label in the treatment of calciphylaxis. In a case series evaluating the efficacy of sodium thiosulfate, more than 70% of patients receiving it had improvement or resolution of their skin lesions, and the mortality rate was lower than historically published data.[rx] Sodium thiosulfate is typically given intravenously during hemodialysis, but the use of oral and intralesional delivery is being investigated. The mechanism by which sodium thiosulfate treats calcific uremic arteriolopathy remains unknown. Previously, it was believed to work through calcium chelation, however recent studies suggest that sodium thiosulfate may inhibit soft tissue calcification through mechanisms independent of calcium-binding. Side effects of sodium thiosulfate include metabolic acidosis and fluid overload.
Wound care and pain management are important.[rx] Debridement may be needed to remove devitalized and necrotic tissue, prevent infection, and promote healing. Prophylactic antibiotics are not recommended. However, wounds often become infected, and clinicians should have a low threshold to start antibiotics. Recent reports suggest a possible role of hyperbaric oxygen therapy which has been shown to facilitate wound healing in some patients.[rx]
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