Clinical Management of Nonuremic Calcific Arteriolopathy: A Report of Three Cases

Calcific arteriolopathy is a subtype of calcinosis cutis, a disease process that involves the deposition of insoluble calcium salts in tissue.¹ Unlike other variants of calcinosis cutis in which calcium is deposited in the skin and soft tissue, calcific arteriolopathy also involves deposition of calcium in the arteries and arterioles of the soft tissues; this leads to ischemia, thrombosis, and cutaneous necrosis. Vascular ischemia can present clinically as violaceous nodules, plaques, retiform purpura, and ulceration. Calcinosis may also be evident as a histologic or radiologic finding (Figure 1); however, biopsy of lesions is considered the primary diagnostic modality.² Pain is a distinguishing feature and can be disproportionate to observed cutaneous findings.

Calcific arteriolopathy is most commonly associated with ESRD and patients undergoing hemodialysis, but the disease can also occur outside of ESRD,^3,4 in which case it is known as NUC. NUC has a high associated mortality rate of 52%, primarily owing to sepsis (50%).² Any systemic disorder that causes an elevation of serum calcium and/or phosphate levels can cause metastatic calcification and calcific arteriolopathy. The most common underlying cause is chronic renal failure, followed by hyperparathyroidism and alcoholic liver disease.⁵ Bone mineral disorders associated with conditions such as chronic renal failure are associated with dysfunction of the processes required to grow and rebuild bones. Calcium, phosphorus, parathyroid hormone, calcitriol, and fibroblast growth factor 23 are all associated with calcium bone resorption and deposition.⁶ Unlike other forms of calcinosis cutis, calcific arteriolopathy may involve disturbances in serum calcium and phosphate levels; however, this does not always occur.¹ Elevated phosphorous contributes to abnormal hormone regulation regardless of blood calcium level, promoting arterial calcifications. Therapeutic interventions, including the administration of STS, have historically been targeted toward the presumed etiology of uremic calcific arteriolopathy.² Less evidence of clinical success is available on the use of these interventions in patients with NUC. 

The current case series describes the clinical presentation and successful treatment of 3 patients (2 female, 1 male) with NUC in a community hospital-based outpatient wound center in southeastern Wisconsin. Wound management included multimodal treatment with an emphasis on wound hygiene. Wound hygiene is a wound management protocol that encompasses wound bed preparation and biofilm-based wound management. The wound, periwound, and extremity were cleansed with mild soap and water at each dressing change. At provider visits, sharp debridement of the wound was performed to the degree tolerated by the patient. This debridement was done to remove necrotic tissue, disrupt biofilm, expose endothelium, and reinitiate the healing cascade, as well as to remove any senescent cells at the wound base. All cases were initially unable to tolerate sharp debridement or therapeutic compression. Debridement techniques included sharp debridement, conservative sharp wound debridement, enzymatic ointments, concentrated surfactants, autolysis, ultrasound, and microfiber pads. In addition to the aforementioned interventions, case 2 also received NLFU 2 to 3 times per week throughout the course of healing. NLFU was used to augment the healing process, provide biofilm-based wound management, decrease inflammation, and decrease wound pain. 

Wound hygiene was then continued by using a hypochlorous acid soak at each dressing change. After the periwound was dried, a no-sting skin protectant was used as prophylaxis against periwound skin complications. Infection control was a key management strategy, with aggressive infection management of inhibitory microbial loads via the consistent use of topical antimicrobials. The principles of wound hygiene were used to guide treatment with multiple tools to accomplish cleansing and decontamination, debridement, compression, and moist wound management.

Case 1: Painful purpura of the lower extremity

Case 1 is an 89-year-old female who was known to the wound center for prior evaluations for pre-ulcerative calluses to both feet, an epithelialized venous leg ulcer that had exhibited protracted wound healing, and periodic skin tears to the lower extremities. Relative medical history included Raynaud disease, Sjögren syndrome, coronary artery disease, adrenal insufficiency with chronic steroid use (20 years), recurrent foot ulcers, lymphoma, Crohn disease, senile purpura, and autoimmune hepatitis.

The patient requested evaluation in the wound center owing to new-onset, increasing pain in the right lateral leg. The patient described the pain as sharp, causing her to awaken from sleep; the bedsheet brushing against her leg would elicit severe pain. The patient reported that the lesion began as a painless skin tear due to a scratch from her fingernail while applying her compression stockings 1 to 2 weeks prior. At presentation to the wound clinic, progressive purpura and early necrosis of the right lower extremity was noted, and the wound measured 3.5 cm × 3 cm × 0.2 cm (10.5 cm²). Two additional areas of purpura without evidence of necrosis were noted at the medial ankle and anterior distal shin (Figure 2). The patient reported pain at these sites in addition to pain in the right calf up to the knee. 

An aerobic/anaerobic bacterial culture was obtained, bacterial fluorescence imaging was performed, a 4-mm punch biopsy was performed at the lesion edge, and the patient’s rheumatologist was contacted with recommendations for further laboratory workup. Initial laboratory findings are noted in the Table. Bacterial fluorescence imaging revealed a lack of fluorescence in the wound bed. Culture results grew 3+ Enterococcus faecalis and 2+ Porphyromonas somerae. Biopsy results were interpreted by a general pathologist and indicated leukocytoclastic vasculitis with calcifications consistent with calciphylaxis. Further evaluation of laboratory results via consult with a dermatologist indicated calcific arteriolopathy as the primary diagnosis. The primary lesion proceeded to ulceration and necrosis (Figure 3).

Owing to concern for wound infection on presentation to the wound clinic, the patient was treated empirically with oral cefalexin 300 mg, 3 times a day for 5 days. Following culture results, oral metronidazole 500 mg, 2 times a day for 5 days was added to the antibacterial regimen. Pain was managed early and aggressively with hydrocodone 5 mg/325 mg. 

A PICC line was placed on an outpatient basis, and infusion of STS 25 g per 100 mL was initiated at week 3 following presentation to the wound clinic. At the time of STS initiation, the wound had increased in size to 5 cm × 4.7 cm × 0.2 cm (23.5 cm²), more than twice the size at initial presentation. The patient experienced nausea as a side effect and was subsequently premedicated with IV 4 mg to 8 mg of ondansetron prior to infusions. Infusions were delivered 3 times per week; they were discontinued when symptoms were resolved and the wound was nearly epithelialized. 

Topical wound management consisted of surgical debridement as tolerated followed by hypochlorous acid, collagen/ORC/silver, foam dressing, and a 2-layer light compression system (20 mm Hg–30 mm Hg). After 2 weeks the collagen/ORC/silver was discontinued, and use of methylene blue and gentian violet foam dressing was initiated.

After 3 weeks of STS infusion and routine wound hygiene, the wound had decreased in size by 27% to 4.3 cm × 4 cm × 0.1 cm (17.2 cm²). The wound continued to improve, with elimination of periwound erythema, decreased dimensions, reduction in necrotic tissue, and improved quality of life, with pain nearly eliminated. 

STS infusions were discontinued after 10 weeks 3 days of therapy. The patient received a total of 22 infusions. The total time to healing was 16 weeks. 

Case 2: Calcific arteriolopathy with a history of renal transplant

A 58-year-old White male was seen in the wound center with an established diagnosis of calcific arteriolopathy. His medical history included ESRD after renal transplant 5 years prior, immunosuppression with mycophenolate mofetil and prednisone, recent COVID-19 infection, hypertension, and atrial fibrillation. 

The patient developed purpuric patches on the posterior aspect of both calves (Figure 4). These patches were biopsied by a dermatologist. Punch biopsy of the lesion yielded medium vessel calcification with overlying epidermal and superficial dermal necrosis and focal thrombi. These lesions proceeded to rapid ulceration. Ankle-brachial and toe-brachial indices were within normal limits. Prior to being seen in the wound center the patient had been receiving STS infusions for calcific arteriolopathy 3 times per week for 3 months in the dermatology department, and he had been attempting to manage his wounds independently at home. The patient was then hospitalized for methicillin-susceptible Staphylococcus aureus sepsis and bacteremia requiring vasopressor support. He received IV antibiotic therapy including cefazolin, which was transitioned to daptomycin. At hospital discharge the patient was referred to the wound center. 

At his first visit to a wound provider, the patient presented with exquisitely painful and inflamed wounds to the posterior aspect of both calves with heavy bioburden encrusted with cat hair (Figure 5). The patient had been unable to sleep in bed for several months owing to severe pain in the calves. Instead, the patient was positioned in a recliner with his legs dependent throughout the night.

A PICC line was maintained on an outpatient basis, and infusion of STS 25 g per 100 mL was continued 3 times per week at the wound center. This was titrated down to twice weekly, and then weekly as wound and symptom improvement was noted. The patient experienced nausea as a side effect and was subsequently premedicated with IV ondansetron 4 mg to 8 mg prior to infusions. At the time of presentation, the right calf wound measurements had increased to 18 cm × 9 cm × 0.6 cm (162 cm²) and the left calf wound measurements had increased to 17.5 cm × 14.3 cm × 0.4 cm (250.25 cm²) (Figure 6). 

Topical wound management consisted of a hypochlorous acid 5-minute soak followed by a methylene blue and gentian violet foam dressing, an absorbent pad, and a 2-layer compression wrap system. A compression wrap system under a bandage pressure of 20 mm Hg to 30 mm Hg was chosen in the setting of adequate circulation (documented ankle-brachial and toe-brachial indices within normal limits as well as a lack of atrophic skin changes). Compression was initiated at this level to gradually reduce limb phlebolymphedema, because the patient was in significant pain. Eventually, compression was titrated to the full 30 mm Hg to 40 mm Hg 2-layer compression system. The compression resulted in an eczematic rash, and the patient was treated with triamcinolone cream and transitioned to tubular elastic compression with longitudinal fuzzy wales. Debridement was performed with the aid of microfiber pads and enzymatic ointment, because initially, sharp debridement was tolerated on a very limited basis. NLFU was used after soap and water cleansing as an adjunctive healing therapy (UltraMIST; Sanuwave). 

The patient was hospitalized for a wound infection 11 weeks after presentation to the wound center. He received IV cefepime while hospitalized and was discharged on cefdinir to receive care in the outpatient care center. The wound continued to improve, with elimination of periwound erythema, decreased dimensions, reduced necrotic tissue, and improved quality of life with pain nearly eliminated (Figure 7). The patient reported being able to sleep in bed at week 12 of care at the wound center. 

After the disease process had stabilized with no new lesions, and with improved pain and wound appearance, STS infusions were continued 3 times per week for 2 more months, then decreased to twice per week for 1 month, and then decreased to once per week for 1 month. STS infusions were discontinued after 3 months of therapy in the wound center. The patient received a total of 40 infusions while undergoing wound management. He received a total of 76 infusions during the disease course over 6 months of treatment. Infusions were discontinued prior to complete epithelialization. The mean total time to healing of the bilateral calf lesions was 19.5 weeks (Figure 8). 

Case 3: Calcific arteriolopathy following necrotizing pancreatitis

A 40-year-old Caucasian female presented with multiple ulcerations to the bilateral lower extremities that had been present for approximately 3 to 4 months prior to presentation to the wound center. She had a relative history of unspecified psychosis, asthma, alcohol misuse, and tobacco use. There was no history of kidney failure or long-term anticoagulation.

Following an extended period of alcohol sobriety of approximately 10 years, the patient returned to daily use of alcohol. Shortly after that, she developed a solitary lesion to the right medial calf and was initially misdiagnosed with cellulitis during evaluation in an out-of-state emergency department. Soon after this initial evaluation, the patient began to develop additional lesions to both calves and thighs. After relocating closer to support systems owing to her illness, the patient was hospitalized with severe panniculitis, pancreatitis, and sepsis. 

During this admission the patient was evaluated in the dermatology department. Punch biopsy taken from the left buttock and reviewed by a dermatopathologist revealed thrombi within vessels in the subcutaneous fat with associated fat necrosis and sparse inflammation. Special stains were performed and compared with appropriately stained control tissue. A von Kossa histological stain to identify mineralization was negative for calcium deposition within soft tissue or vessels.

Radiographs indicated calcium deposition in the soft tissue and arteries (Figure 1). The patient was diagnosed with NUC and started STS infusions 25 mg IV 3 times per week co-administered with ondansetron. Following discharge, the patient attempted to manage her wounds at home owing to significant transportation time to the hospital and wound center; however, she continued to experience difficulty with thorough cleansing of the wounds because of pain.

Transfer of wound care to the wound center was initially delayed owing to the need for insurance verification for the STS infusion at the new location. Upon assessment in the wound center, the newest lesions were those to the buttocks. Throughout the care period in the wound center the patient periodically developed patches of purpura, painful erythematous subcutaneous nodules to the pretibial surface, and subcutaneous indurated plaques. Following initial wound improvement (Figure 9), the patient was stepped down from 3 times per week to twice per week; however, she was continued on twice per week infusions after complete wound closure due to ongoing development of indurated plaques.

Compression was not tolerated initially. Over time compression was able to be advanced to the highest tolerated level. Pain management consisted of topical lidocaine prior to dressing changes. Debridement as tolerated was achieved via sharp debridement, conservative sharp wound debridement, autolysis, enzymatic ointment, concentrated surfactants, and microfiber pads. A hypochlorous acid soak was performed, after which a prophylactic no-sting skin protectant was used. Antimicrobial dressings were then applied, including next-generation silver dressings, collagen/ORC/silver, and cadexomer iodine. Cover dressings were used to maintain normothermia, protect the wound bed, manage drainage, and decrease dressing change frequency.

Infection recurred in the primary lesion of the left calf. An initial culture grew 4+ logarithmic quantification of multiple organisms, including Escherichia coli and Morganella morganii. Infections were treated with cefazolin in the wound center and transitioned to oral cephalexin and metronidazole. A total of 3 antibiotic courses were delivered over a 2-month period. Complete closure of all wounds was noted at 28 weeks.

Multimodal treatment with an emphasis on wound hygiene, pain management, and infection control were key management strategies. Pain management was an important factor in the patient’s ability to tolerate surgical debridement and thorough cleansing.

All 3 patients displayed increased tolerance of compression and debridement over the course of treatment. All 3 patients successfully epithelialized with no discernible effect on long-term function or quality of life. Wound infection occurred in each case. The overall mean time to healing was 20 weeks (Figures 10–12).

Case series are valuable tools to disseminate successful outcomes in novel therapies and rare diseases such as NUC; however, they are inherently subject to substantial limitations, including generalizability, cause-effect relationship attribution, possibility of overinterpretation, publication bias, and a retrospective design.⁷ A search of PubMed and the Cochrane Database of Systematic Reviews for literature regarding the clinical management of NUC demonstrated primarily pharmacologic management of calciphylaxis.^8-11 The review demonstrated a lack of literature specific to clinical management, and published evidence primarily focused on uremic calcific arteriolopathy as opposed to NUC.^2-4 

The initial differential diagnosis for case 1 consisted of calcific arteriolopathy, autoimmune vasculitis, and cellulitis. Initial suspicion of calcific arteriolopathy or other autoimmune etiologic mechanisms was related to perilesional purpura and pain out of proportion to observed findings. Diagnostic decision-making was aided by laboratory and biopsy evaluation. The presumed etiologic mechanisms for case 1 developing NUC were her history of chronic steroid intake in the setting of adrenal insufficiency and potential immune dysfunction related to multiple autoimmune disorders (Crohn disease, Sjögren syndrome, Raynaud disease, and autoimmune hepatitis). 

Owing to the high degree of association of calcific arteriolopathy with ESRD, STS infusions are typically managed by nephrology providers and delivered during dialysis. Because case 1 lacked vascular access for infusion, PICC line placement was required. STS infusion management was facilitated through referral to the dermatology department, and the remaining wound management was provided through the wound center. Additional team support and multidisciplinary care was delivered by general pathology and rheumatology providers. 

Narcotic pain medication was administered to enable thorough cleansing and for continued patient comfort. Infection control is a key management strategy, given the high degree of morbidity and mortality that is primarily associated with infection and sepsis.² In addition to initial oral antibiotic treatment, topical antimicrobials were consistently used.

The presumed etiologic mechanisms for the development of NUC in case 2 was a history of hyperparathyroidism in addition to a renal transplant 5 years prior owing to ESRD resulting from hypertension, with continued immunosuppression via prednisone and mycophenolate mofetil. Historical renal transplantation or other instigating factors of mineral bone disorder and immune dysfunction may represent a latent nidus of disease pathophysiology in calcific arteriolopathy. In the current case series, multidisciplinary care was delivered by general pathology and dermatology providers. The histopathologic features of calcification in medium-sized blood vessels with associated necrosis and thrombosis were compatible with a diagnosis of NUC even though the punch biopsy lacked the surrounding inflammation in the subcutaneous fat or dystrophic calcification often seen in calcific arteriolopathy. As a result, further workup to exclude coexistent thrombotic vasculopathy was recommended.

The presumed etiologic mechanisms for case 3 developing NUC were the patient’s history of necrotizing pancreatitis and sepsis from an exacerbation of alcohol misuse. Chronic inflammation was also promoted via continued tobacco use.

Management of cofactors in the inflammatory nature of the disease state of calcific arteriolopathy was complicated by insurance denial of multiple healing modalities, including smoking cessation medication, amniotic membrane allografts, xenografts, and NLFU. Continued tobacco use and exposure to indoor tanning was believed to contribute to the continuing inflammatory disease process. 

The recurrent infection seen in the primary lesion of the left calf in case 3 is believed to have been due to initial poor wound hygiene, because the patient was unable to clean the wound or tolerate surgical debridement of the necrotic tissue and undermining. After initiation of sharp debridement, the patient’s wounds improved precipitously (Figure 12).

In case 3 the differential diagnosis included calcific arteriolopathy versus pancreatic panniculitis versus vasculitis. Panniculitis, that is, inflammation affecting subcutaneous fat, and dystrophic calcification due to underlying fat necrosis, is a known sequela of calcific arteriolopathy. In pancreatic panniculitis, pancreatic enzymes from patients with pancreatic disease cause subcutaneous fat to dissolve into free fatty acids that form calcium soaps when they bind to calcium. The pretibial area is a common site for the painful erythematous subcutaneous nodules associated with pancreatic panniculitis.¹² Because case 3 in the current study was recovering from pancreatitis and eventually developed painful erythematous subcutaneous nodules to the pretibial surfaces, pancreatic panniculitis was not excluded from the differential diagnosis; it may have been a comorbid condition. However, pancreatic panniculitis presents histopathologically as fat necrosis (empty, ghost-like fat cells) intermixed with basophilic deposits of calcium. This was not seen on initial punch biopsy of the buttock lesion in case 3; however, the nodules were not biopsied.

Calcific arteriolopathy factors presumed to be involved in the cases detailed herein include chronic kidney disease–associated mineral bone disorder, dysregulation and deficiencies of the inhibitors of vascular calcifications, autoimmune dysfunction, and chronic inflammation. The cases represent successful multidisciplinary management of NUC provided by wound specialists and providers in rheumatology, dermatology, nursing, pharmacy, and dermatopathology.

The current case series has several limitations. As mentioned previously, these include limitations common to case series, including generalizability, cause-effect relationship attribution, possibility of overinterpretation, publication bias, and a retrospective design. The present case series consists of a limited number of patients treated at a single institution. Opportunities exist for future research of clinical management of NUC, including randomized clinical trials in which procedures described herein could represent a baseline control procedure. Skin tone as assessed and reported in the electronic health record was included for the purposes of future elucidations of disease incidence, prevalence as well as to provide context to the visual assessment and findings as presentation of cutaneous signs can vary amongst skin tones. 

The results of the current case series suggest that successful management of NUC can be achieved using IV STS, early and aggressive infection treatment, pain control, and wound hygiene. NLFU may be an appropriate adjunct to expedite healing in patients with NUC.