Successful Surgical Treatment of Severe Calciphylaxis Using a Bilayer Dermal Replacement Matrix

Cutaneous calciphylaxis is a rare and often intractable disease that involves subcutaneous vascular calcification, ischemia, and subsequent necrosis. Calciphylaxis has an associated 60%-80% mortality rate with sepsis as the leading cause of death. However, despite variable success rates, the proper treatment of calciphylaxis remains controversial. In this case report, the authors present a 42-year-old female who presented with bilateral lower extremity calciphylaxis in conjunction with long-standing liver disease and acute renal failure. Cure of the patient’s calciphylaxis was achieved through a surgical approach using staged debridement, placement of a dermal regenerative template (Integra Dermal Regeneration Template, Integra Lifesciences, Plainsboro, NJ), and followed by successful skin grafting. This is the first successful treatment of calciphylaxis in the literature to date using dermal regenerative template material.

Calciphylaxis, or calcific uremic arteriolopathy (CUA), is defined by a systemic calcification of the arterioles progressing to ischemia and subcutaneous necrosis.¹ The condition is most often observed in patients with renal failure and secondary hyperparathyroidism,² affecting up to 4% of patients on hemodialysis.³ However, the condition can also develop in conjunction with sufficient renal function.⁴ Calcific uremic arteriolopathy lesions are extremely painful and typically present on the lower limbs, trunk, or genital regions as tender red areas which progress to subcutaneous nodules, dermal plaques, and eschar.² An estimated 50% of all patients with calciphylaxis will die within 1 year,⁵ commonly due to sepsis.⁶ The progression to ulcerating skin lesions has been associated with more than 80% mortality.⁷ Additional risk factors and conditions linked to calciphylaxis include female gender, obesity, corticosteroid use, diabetes mellitus, hyperphosphatemia, and liver disease.^2-5

There is currently no established cure for calciphylaxis and treatment often involves combination therapy. Medical treatments typically include drugs to reduce calcification-promoting mineral and hormone imbalances, such as parathyroid hormone (PTH)-reducing medications (eg, cinacalcet), bisphosphonates, and use of low-calcium dialysate and calcium-free phosphate binding agents.^8,9 Sodium thiosulfate is also a notable broad-spectrum therapeutic for CUA thought to act as an antioxidant, vasodilator, and calcium chelator.⁹ Wound management therapies consist of hyperbaric oxygen therapy (HBOT) and nonsurgical wound cleansing.⁹ Major surgical treatments include parathyroidectomy, although this is generally reserved for patients with known primary hyperparathyroidism.^5,10,11 Surgical debridement to remove necrotic tissue and promote the healing of healthy tissue is more widely used, but its efficacy is controversial due to the possibility of causing further tissue damage.¹² The conundrum of debridement followed by wound progression makes the question of when to further debride when visibly necrotic tissue is present difficult to answer. The authors present a case in which conventional surgical debridement was successfully utilized to manage calciphylaxis in combination with supportive care during rapid progression of the disease. Staged wound coverage was achieved with the use of a dermal regenerative template (Integra Dermal Regeneration Template, Integra Lifesciences, Plainsboro, NJ) to prepare the wound bed, in combination with negative pressure wound therapy and subsequent skin grafting.

The patient, a 42-year-old female with past medical history significant for Child class B cirrhosis, had a prior squamous cell carcinoma of the vulva for which she underwent surgical resection with lymph node dissection of the inguinal region in 2002, and recurrent left lower extremity lymphedema. The patient first presented to her local emergency room with sudden onset of fever, back pain, jaundice, and an inability to walk. She was ultimately diagnosed with Staphylococcus aureus bacteremia involving an L4-S1 dural mass. Following surgical drainage of the abscess, the patient developed acute renal failure and underwent dialysis for 1 month. Within 2 months of dialysis, the patient presented to the Keck Hospital of USC, Los Angeles, CA with bilateral inner thigh pain and lower extremity edema. She also had what initially appeared as a red and inflamed 4-cm mass, which subsequently turned black (Figures 1 and 2). At that time, the patient had low albumin (1.6 g/dL), elevated blood urea nitrogen (25 mg/dL), low hemoglobin (11g/L), and low hematocrit (34%). She had normal aspartate aminotransferase (AST), alanine transaminase (ALT), creatinine, bilirubin, and white blood cell count. An echocardiogram showed normal heart physiology, function, and ejection fraction. Liver biopsy showed stage 3 fibrosis and no evidence of malignancy, hemosiderin, or alpha-1-antitrypsin deficiency. Skin biopsy of bilateral inner thighs revealed benign fibroadipose tissue with vascular calcification, full-thickness necrosis, and granulation consistent with calciphylaxis.

As the disease progressed rapidly, severe skin necrosis was identified (Figure 2). The patient underwent 2 surgical debridements for full-thickness necrosis. During the first debridement for a necrotic area of 220 cm², she was noted to have further full-thickness tissue loss, requiring a second debridement. During the second debridement, 6.25% of total body surface area was resected: 300 cm² on the right inner thigh, 200 cm² on the left inner thigh (Figures 3 and 4), and a 125-cm² spread divided between a small area of the right calf and left thigh (not shown). After complete debridement, the authors decided to close the patient’s wounds with placement of a dermal matrix, which is a bilayer porous membrane that contains an outer removable layer of silicone that inhibits loss of moisture and an inner matrix of bovine tendon collagen and glycosaminoglycans necessary for dermal regeneration.¹³ While the dermal matrix was initially used for burns and traumatic wounds, it is now widely used in soft tissue reconstruction of breasts, limbs, tendons, and scalp as well as pressure ulcers and diabetic infections.^14-17 In the described patient, the dermal matrix was placed bilaterally, and negative pressure-assisted closure devices (KCI, an Acelity company, San Antonio, TX) were used to bolster the larger areas of debridement. 

One month after the dermal matrix placement, the outer silicon layer was removed intraoperatively. Well-vascularized wound beds were visualized without recurrent subcutaneous necrosis. Split thickness skin grafts were harvested from bilateral lower extremities and transferred to the wound regions. Negative pressure devices were used to bolster large graft sites. The skin grafts took without complication and healed completely within 1 month (Figures 5 and 6). Since then, the patient did not require any additional surgical or medical intervention other than wound care to skin graft and donor sites. The patient is now 2.5 years status post bilateral lower extremity reconstruction with the dermal matrix placement and skin grafting without any evidence of recurrent calciphylaxis. Figures 7 and 8.

This report describes a presentation of calciphylaxis that was successfully treated with surgical debridement complemented by utilization of a dermal matrix regeneration template and negative pressure wound therapy. The 42-year-old female patient presented with bilateral calciphylactic lesions on the inner thighs and hypoalbuminemia following history of acute renal failure with dialysis treatment, immobilization, and malnutrition coupled with long-standing cirrhosis, all of which are consistent with previously described risk factors for calciphylaxis development.^2-5

Conventional medical treatment options for calciphylaxis include sodium thiosulfate, low-calcium dialysate, phosphate-binding agents, and cinacalcet to treat the localized vascular stenosis, elevated mineral levels, and hyperparathyroidism often associated with the disease, as well as specific thrombolytic agents and HBOT to mitigate clotting and promote wound healing. However, concern for the high cost of therapies such as HBOT, although effective,⁹ make them unsuitable for all cases of CUA. Further, low-calcium dialysate, phosphate-binding agents, and cinacalcet are used to directly counteract particular pathological findings that regularly but not always accompany calciphylaxis, such as hypercalcemia and hyperparathyroidism. In the case of the authors’ patient, there was no evidence of primary or secondary hyperparathyroidism, hypercalcemia, or hyperphosphatemia to indicate therapy with such clinical agents. She was also not in acute renal failure at the time of calciphylaxis diagnosis. Further, the rapid development of calciphylaxis over an 8-week interval in this case supported the appropriateness of immediate surgical intervention. Given the accelerated nature of calciphylaxis progression in the setting of normal liver function enzymes and white blood cell count, the patient was deemed a suitable candidate for surgery.

Liver function tests can be normal in advanced cirrhosis,¹⁸ as it was the case for this patient. Elevated AST and ALT are commonly used indicators of hepatocyte injury, but in cases of extensive or chronic scarring of the liver where hepatocytes can no longer release AST or ALT, liver function tests (LFTs) can be normal. Despite normal appearing LFTs, the patient had low albumin upon admission, which suggests compromised liver function secondary to chronic liver disease and malnutrition. Upon adequate nutrition via tube feeds, the patient showed increasing prealbumin and albumin levels by the time of debridement and dermal matrix placement.

Surgical debridement of the lesions was performed secondary to the presence of frankly necrotic tissue and possible subsequent infection. The concern surrounding surgical debridement is the increased risk for further ulcerations and creating nidi for sepsis.^6-12 A number of authors support the use of surgical debridement and report eventual resolution of lesions with its use^19-21; however, debridement in such cases can be extensive and aggressive surgical management might still be accompanied by unfavorable outcomes. In 1 particular case of extensive calciphylaxis of the right leg complicated by diabetes-induced osteomyelitis, 3 debridements and 2 amputations were needed to ultimately manage the patient’s disease.¹⁹ For the patient in the report, staged debridement was carried out to prevent further complications of the disease. Following complete and stable debridement, the dermal matrix and negative pressure therapy were implemented to enhance the healing process. After placement of the dermal matrix, there was no progression of the disease, despite no adjunctive medical treatments.

The success of the dermal matrix synthetic collagen template when used in promoting dermal wound healing is widely documented.^13-22 The dermal matrix used in this case is a bilaminar membrane system consisting of bovine tendon type I collagen and shark glycosaminoglycan (chondroitin-6-sulfate), covered by a temporary epidermal substitute made of silicone to prevent excessive moisture loss and formation of granulation tissue on the matrix surface.¹³ The technology has been used in combination with negative pressure therapy to accelerate integration and reduce length of hospital stay in cases of acute and chronic wounds.²³ However, its application when the patient has calciphylaxis is not well established. To the authors’ knowledge, only 1 other report is published utilizing a synthetic dermal template to treat calciphylaxis.²⁴ The matrix was applied after surgical debridement but the patient had the matrix removed and died of subsequent sepsis. The patient had a history of diabetes mellitus, chronic renal failure, multiple renal lithiasis, and warfarin use, which may serve as possible explanations for the negative clinical outcome.

There are many different types of acellular and cellular dermal matrices and further research is required for comparison of clinical and cost efficacy.²⁵ However, a dermal matrix was chosen in this case for several reasons. First, because of the intense pain the patient was experiencing, staging the skin grafting procedure would allow additional time for pain-free dressing changes and an opportunity for immediate closure of the wounds. Second, due to the unpredictable nature of calciphylaxis, skin graft staging would provide further opportunity for evaluation of possible wound progression, as the authors did not want to risk morbidity associated with failed skin grafting. Third, although the mechanism of action of the dermal matrix in treating calciphylaxis is not clear, the authors hypothesized that its generalized local and systemic anti-inflammatory nature²⁶ would assist with the healing process in this patient. It is possible this feature, along with the purported ability of the dermal matrix to shorten the acute phase of wound healing,²⁶ contributed to the resolution of lesions and the absence of calciphylaxis recurrence observed to date in this patient.

This case is unique in that the authors describe what is, to their knowledge, the first successful use of a dermal regenerative matrix and negative pressure-assisted wound closure device in the treatment of calciphylaxis. Surgical debridement followed by placement of the dermal matrix and negative pressure device to promote wound closure and healing eliminated the need for subsequent debridement and resulted in a complete cure of calciphylaxis without recurrence or postoperative infection for this patient. This case suggests a combined approach of surgical debridement and reconstruction with a dermal matrix, with its dermal healing and anti-inflammatory properties, can help maximize wound healing and prevent further complications and recurrence of calciphylaxis.

Affiliations: ¹Mayo Medical School, Rochester, Minnesota; and ²Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California

Correspondence:
Dipesh Solanky, BS
Solanky.Dipesh@mayo.edu

Disclosure: The authors disclose no financial or other conflicts of interest.