Calciphylaxis in Stage 3 Chronic Kidney Disease on Apixaban Successfully Treated With Sodium Thiosulfate: A Case Report

Calciphylaxis, or calcific uremic arteriolopathy, is a rare, life-threatening disease characterized by vascular calcifications. Among patients with end-stage renal disease (ESRD) who are on chronic hemodialysis, the incidence of calciphylaxis is 3.5 new cases per 1000 patient-years.¹ Implying a systemic anaphylactic or hypersensitivity reaction, the term calciphylaxis is actually a misnomer.² Calciphylaxis is commonly seen in patients with ESRD.^3,4 It also is reported in patients who do not have ESRD,^3,4 such as those with acute kidney injury (AKI),⁵ recipients of kidney transplants,⁶ and, rarely, patients with normal kidney function.^3,4,7,8

It is characterized by microvascular occlusion of arterioles in subcutaneous adipose tissue and dermis, resulting in painful, indurated, and necrotic nodules.^3,9 A compromise in blood supply to the skin frequently manifests as livedo and reticulate (netlike) areas of erythema.⁹ Dusky discoloration of the skin is a red flag for impending necrosis.⁹ Initial lesions can quickly escalate to malodourous, stellate ulcers with black eschars,^10,11 which can lead to sepsis and death.^7,12,13 Hallmark histologic features include fibrointimal hyperplasia, calcification, thrombosis of microvessels, dermal-epidermal separation, necrotic adipose and epidermal tissue, extravascular calcifications, and dermal endothelial cell proliferation.^14,15

Patients who are nonuremic (normal renal function or earlier stages of chronic kidney disease [CKD]) have a better prognosis, with a 1-year mortality of 25% to 40%.^7,8 In comparison, patients with ESRD have a 1-year mortality of 45% to 80%^3,16,17; this may be attributed to the differences in coexisting comorbidities and the variation in location of lesions. In the literature, 50% of patients without ESRD have central lesions (ie, areas rich in adipose tissue including the breasts, abdominal pannus, thighs, and buttocks)^7,12 compared with 70% to 80% of patients with ESRD who have central distribution.^12,16 Patients with central lesions have been noted to have a higher body mass index (BMI), are more likely to be female,¹⁶ and have a higher risk of death.¹⁸ The presence of ulcerated (late) lesions is a poor prognostic indicator and decreases the 6-month survival rate to 20%.¹⁷ The average age at the time of diagnosis ranges between 50 and 70 years old.^3,4,12,19 Risk factors include diabetes mellitus (DM), obesity, dependence on dialysis for more than 2 years, hepatobiliary disease, elevated alkaline phosphatase, hypoalbuminemia, thrombophilia (eg, protein C deficiency, lupus anticoagulant, antithrombin deficiency), vitamin K deficiency, and female sex.^{1,7,8,16,19-23} Administration of recombinant parathyroid hormone (PTH)²⁰ and primary hyperparathyroidism⁷ are additional risk factors in patients who are nonuremic. Warfarin, a vitamin K antagonist, predisposes individuals to develop calciphylaxis and increases mortality among these patients.^16,19,24-26

Calciphylaxis is underrecognized, which can further jeopardize the health of patients with urgent, unmet clinical needs.²⁷ Once the diagnosis has been established, prognosis is usually poor, with survival estimated at less than 1 year.^3,16,17 

The patient was a 72-year-old female who presented with chest pain and shortness of breath and was diagnosed with non-ST-elevation myocardial infarction in November 2018. She had a left heart catheterization, which demonstrated significant 3-vessel disease, and was subsequently worked up for coronary artery bypass grafting. A transesophageal echocardiogram, performed after a trans-thoracic echocardiogram, demonstrated moderate aortic stenosis and mild to moderate aortic regurgitation. The patient’s past medical history included the following: morbid obesity (BMI = 35.46); type 2 DM, diagnosed 3 years prior; hypertension (HTN), diagnosed 9 years prior; CKD secondary to DM and HTN, with serum creatinine 1.49 mg/dL and eGFR 35 mL/minute at the time of presentation (baseline creatinine 1.4–1.8, eGFR 20–40 mL/minute); chronic systolic heart failure with a left ventricular ejection fraction of 48%; and coronary artery disease. For the coronary artery disease and valvular pathology, the patient underwent a 3-vessel coronary artery bypass surgery and aortic valve replacement in November 2018.

The postoperative period after the coronary artery bypass surgery and aortic valve replacement was complicated by methicillin-resistant Staphylococcus aureus sternal osteomyelitis, AKI, and paroxysmal atrial fibrillation. Atrial fibrillation was initially treated with warfarin for a period of 2 days, which was changed to apixaban upon discharge for ease of monitoring for the patient. Sternal osteomyelitis was treated with intravenous (IV) vancomycin and daptomycin. The patient was discharged from the hospital towards the end of January 2019.

In February 2019, 2-months postop, the patient noticed a non-blanching maculopapular rash on her lower extremities. On examination, there was mild tenderness on palpation, retiform purpura, and hemorrhagic crusting. On February 11, 2019, a biopsy from the right calf lesion was taken (Figure 1), which showed calciphylaxis. 

The histopathology report described an ulcer extending into the papillary dermis along with calcification seen occluding a vessel in the subcutis (Figures 2, Figure 3). Calcified elastic fibers with a Pseudoxanthoma elasticum-like appearance in the subcutaneous septae was seen with prominent red blood cells extravasation. 

She was seen in the nephrology office for the treatment of calciphylaxis. Examination showed a macular rash on the bilateral heels and abdomen as well as ulcers on both calves. She was extensively worked up for autoimmune, infectious, and mineral bone diseases.  

The hepatitis serologies, antineutrophil cytoplasmic antibodies, perinuclear antineutrophil cytoplasmic antibodies, C3 blood test, C4 blood test, antinuclear antibody, prothrombin time, partial thromboplastin time, calcium and phosphorus, and international normalized ratio were within normal range. The PTH was elevated with low vitamin D, which were attributed to the CKD. Anti-cardiolipin antibody IgA (low-medium elevation) was mildly elevated. Protein S and protein C tests were not conducted due to low suspicion for hypercoagulability (Figure 4).

She was started on twice weekly 6.25 g of sodium thiosulfate (STS) infusions, with a complete blood count and renal panel monitoring twice weekly (Figure 5). Intralesional STS was an option if the patient developed adverse reactions to the STS infusions. The patient tolerated STS infusions well and without complaint. Intralesional STS was never used.

In addition, the patient received supportive wound care, with the primary objectives to be less invasive and keep the lesions clean. The lesions were treated with a local application of mupirocin and daily wet-to-dry dressing changes. Foam bandage dressings also were used, but they were discontinued due to patient discomfort. The wound clinic recommended an army battle dressing and securing it with gauze and compression (Coban; 3M), and either covering with a foam border dressing or using a barrier film (Cavilon No Sting Barrier Film; 3M) if the lesions did not improve with wet-to-dry dressings. The patient was asked to keep the fingernails clipped to prevent secondary infection of lesions due to itching and scratching. Pain was treated with gabapentin and hydrocodone.

During treatment with STS, the serum creatinine remained stable around baseline (1.4–1.8 mg/dL), with a peak of 2.51 mg/dL after 6 weeks of treatment, which later declined to 1.7 mg/dL in the following 8 weeks. Serum bicarbonate also remained within normal limits (20–27 mmol/dL), and reached its lowest at 15 mmol/dL at 6 weeks after treatment, but then recovered to 24 mmol/dL after 2 months of treatment (Figure 6).

At the 2-month follow-up for STS treatment, the bilateral lower extremity ulcers had improved from intact, dry eschar to moist, soft, tightly adhered yellow slough. Additionally, the scattered maculopapular rash on the feet completely resolved (Figure 7).

Calciphylaxis is a poorly understood disorder. Narrowed and calcified microvessels lead to low-grade, chronic ischemia. Further occlusion of vessels, provoked by microthrombi and endothelial injury, causes infarction.^15,28 Irrespective of systemic hypercoagulability,²⁹ thrombosis could be due to a local prothrombotic state.²⁸ Microvascular calcification in calciphylaxis is an active cell-mediated process that depends on the balance between inhibitors and promoters of calcification^28,30,31; there is impaired inhibition of calcium phosphate precipitation,³² probably due to the deficiency of calcification inhibitors. 

Matrix G1a protein (MGP) is an extracellular matrix protein, synthesized by endothelial cells and vascular smooth muscle, which inhibit calcification. Another potent calcification inhibitor is carboxylated MGP.³³ A relative reduction of these proteins is noted in the circulation³⁴ and cutaneous tissue.²⁸ In addition, carboxylated MGP inhibits procalcifying factors, including bone morphogenetic protein (BMP) 2 and BMP-4.³⁵ Deficiency of carboxylated MGP upregulates the expression of BMP-2,²⁸ BMP-4,³⁶ and osteogenic transcription, with the latter characterized by increased runt-related transcription factor 2.^28,37 Reduced circulating levels of carboxylated MGP also predict ulcer formation and more extensive lesions.³⁴ 

Fetuin-A, involved in the transport of mineral nanocrystals via the formation of calciprotein particles, is another calcification inhibitor.²⁵ Fetuin-A is downregulated in CKD.^32,38 Severe, functional deficiency of fetuin-A in calciphylaxis is evidenced by a pronounced burden of calciprotein particles.^38,39 Polymorphisms in gene 5′-nucleotidase (NT5E) (rs4431401 and rs9444348) are overrepresented in calciphylaxis.²¹ The gene NT5E is involved in regulating pyrophosphate metabolism (a critical inhibitor of calcification).^40,41 Predominant inclusion of areas with abundant adipose tissue also suggests the involvement of adipocytes. Via the release of adipokines, mature adipocytes exposed to high levels of phosphate calcify and induce vascular smooth muscle cells calcification unidirectionally.⁴² A potential adipokine, vascular endothelial growth factor A (VEGF-A), produces a procalcific response through BMP-4. Polyneuropathy, Organomegaly, Endocrinopathy, M component, and Skin changes (POEMS) syndrome is characterized by marked elevations in VEGF-A and also has a high prevalence of calciphylaxis (4%)⁴³ (Figure 8).

Differential diagnoses of calciphylaxis include conditions like warfarin-induced skin necrosis, venous stasis ulcer, ischemia from atherosclerotic arterial occlusive disease, nephrogenic systemic fibrosis, cellulitis, necrotizing vasculitis, livedoid vasculopathy, pyoderma gangrenosum, purpura fulminans, Martorell’s ulcer, cholesterol embolism syndrome, dystrophic calcinosis cutis, oxalosis, and lipodermatosclerosis.^3,9

Due to the complexity of the condition, an interdisciplinary approach is recommended to expedite diagnosis and management (dermatology, nephrology, plastic surgery, nutrition, wound care, pain, and palliative medicine).⁹ Skin biopsy (ie, punch) is recommended in atypical or early lesions in a nonuremic patient. Specialized stains are necessary to avoid missing subtle calcifications (eg, von Kossa stain uncovers phosphate within hydroxyapatite).⁹ Plain radiographs showing subcutaneous calcification in a netlike pattern and nuclear bone scans demonstrating increased heterogenous radiotracer uptake in soft tissues have good specificity for calciphylaxis.^44,45 Currently, there are no approved therapies for calciphylaxis.

Adequate pain relief is essential for severe pain (high-dose opioids, ketamine, spinal anesthetics, and gabapentin have been used).⁴⁶ The ischemic tissue bed can be extremely painful, often healing poorly; operative debridement and negative pressure wound therapy are recommended, with split-thickness skin grafting for wound closure, once the wound has stabilized with the formation of granulation tissue.⁹ As transcutaneous oxygen tension is reduced in lesions,⁴⁷ hyperbaric oxygen may be associated with healing when intensive therapy sessions are administered over 2 months, especially in peripheral lesions.⁴⁸ Vitamin D and calcium intake (including calcium-based phosphate binders) should be discontinued.⁹ Cinacalcet (a calcimimetic agent) is preferred over parathyroidectomy (used in refractory cases, ie, PTH > 600 pg/mL), as the latter will cause irreversible reduction of PTH levels and hungry bone syndrome requiring calcium and calcitriol.⁴⁹ Warfarin use also must be discontinued, and, if ongoing anticoagulation is favored, an agent should be selected based on indication for anticoagulation and kidney function.⁵⁰ Bisphosphonates are pyrophosphate analogues that modify bone (ie, receptor activator of nuclear factor-κB ligand inhibitor and antisclerostin antibody) and have been successfully used to treat calciphylaxis patients with a genetic ectonucleotide pyrophosphatase and phosphodiesterase 1 deficiency.⁵¹ 

Since its first use in 2004, STS is frequently used to treat calciphylaxis. It has been demonstrated to heal lesions and improve the associated severe pain.⁵² Sodium thiosulfate has vasodilatory and antioxidant properties. It also inhibits calcification of adipocyte and blocks their ability to induce vascular smooth muscle cell calcification.^39,42 Sodium thiosulfate is not an acid, as it does not donate protons⁴⁰; however, thiosulfate is oxidized to sulfate by either intestinal bacteria or hepatic oxidation.⁵³ Unfortunately, there are no established evidence-based guidelines to follow with respect to treatment dose initiation in patients who are not on dialysis; thus, the dosages for nonuremic patients is not standardized. The optimal dose is unknown and requires titrations, depending on the estimated glomerular filtration rate (eGFR) and development of side effects. In patients with eGFR greater than 60 mL per minute per 1.73 msq, 25 g at 3 to 5 times weekly may be given.^54,55 For patients with an eGFR over 60 mL per minute per 1.73 msq, the initiating dose should be reduced, because STS is renally cleared. Further dose adjustments depend upon the development of side effects, including hypotension or metabolic acidosis. In patients with an eGFR less than 60 mL per minute per 1.73 msq, depending upon progress or response, so long as side effects (hypotension, metabolic acidosis) have not developed, the dose may be gradually increased to a maximum of 25 g 3 times weekly typically for a 3-month IV course.⁵⁶ A dramatic reduction in pain has been noted within 2 weeks of starting therapy⁵⁷ and almost complete resolution of lesions within 6 months.^57,58 The clinical response within the first couple of weeks of treatment may be a predictor of favorable response. Intralesional STS is an alternative for patients who do not tolerate the IV form. The use of 1 mL to 3 mL of 250 mg/mL STS injected weekly in the clinically active calciphylaxis areas may lead to improvement.⁵⁹ Important side effects include nausea, vomiting, severe metabolic acidosis, hypotension, hypocalcemia, QT prolongation, and volume overload.^60,61 Typically, STS is excreted quickly and hence only partially metabolized. Thus, the excretion of the nonmetabolized drug is decreased in patients on hemodialysis, causing an increase in its metabolism to sulfate. In these patients, high-bicarbonate dialysate use may help reduce STS-induced metabolic acidosis.⁵⁸ With long-term treatment involving IV formulation, an increased propensity for skeletal fractures has been reported.⁶² The role of supplementation of vitamin K is currently unsupported, with no available studies endorsing the superiority of specific forms of vitamin K (ie, K1 or K2).⁹

The present patient had no obvious triggers for calciphylaxis (ie, ESRD on dialysis, warfarin use, trauma due to subcutaneous injections, or the existence of an autoimmune process). The patient’s risk factors included female sex, obesity, DM, elevated alkaline phosphatase, and CKD. In addition, she had peripheral lesions (sparing breasts, thighs, buttocks), or more specifically, lesions that carry better a prognosis; 1 lesion on her abdomen resolved with treatment.

The present case used half of the dose of STS reported for patients without hemodialysis and with risk factors for calciphylaxis in the literature,^52,63,64 thus successfully showing a lower dose of STS can be used effectively for treatment of calciphylaxis in patients with stage 3 CKD. The authors recommend that serious consideration should be given to STS as a practical measure of treatment, as documented in a case series of 8 patients.⁶⁵ 

This case illustrates that early diagnosis, intervention, and an interdisciplinary approach are of utmost importance in the management of calciphylaxis. It highlights the fact that STS, when used in the correct clinical setting, can actually improve a patient's prognosis. 

Calciphylaxis is a serious disorder that presents with skin ischemia and necrosis and occurs most commonly in patients with ESRD and in nonuremic patients with connective tissue disorders, primary hyperparathyroidism, and malignancies. Nonuremic calciphylaxis is reported most often in white females; additional comorbidities and the administration of medications such as warfarin can accelerate lesion formation and complicate treatment attempts.⁶⁶ Its incidence may be increasing due to heightened awareness and earlier recognition of associated clinical signs. A high index of suspicion must be maintained when evaluating skin lesions in the predisposed patient population. With a poor prognosis, the pathogenesis of calciphylaxis is complex and multifactorial.⁷ Successful management of calciphylaxis is a multidisciplinary effort. Retrospective reviews have suggested a benefit of using IV STS, with adjusted dosing in hemodialysis patients, peritoneal dialysis patients, and nonuremic patients.⁵⁶ 

Note: The authors would like to express their sincere gratitude to Dr. Vivek Kak for his guidance.

Authors: Faria Ali, MD; Tarvinder Matharu, MD; R. Venkata Nagesh, MD; Elizabeth Gordon Spratt, MD; and Ben J. Friedman, MD, FAAD

Affiliation: Henry Ford Health System, Jackson, MI

Correspondence: Faria Ali, MD, Internal Medicine, PGY-3 Resident, Henry Ford Health System, Internal, Medicine, 205 Northeast Avenue, Jackson, MI 49201; fali2@hfhs.org

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