Corresponding Author(s)
Read the article
INTRODUCTION
FIGURE 1:
Right posterior calf lesion on initial presentation
Three weeks later, the patient was re-admitted to the hospital with multifocal pneumonia. During this admission, she was found to have worsening of her right posterior calf lesion. (Figure 2) Physical examination revealed that a majority of the distal lesion was now encased in necrotic, black eschar. As before, there was no significant warmth to the touch, erythema or purulent exudate of the lesion. The radiograph was negative for bony destructive changes.
FIGURE 2:
Right posterior calf lesion three weeks later
QUESTIONS:
What is the most likely diagnosis?
Squamous cell carcinoma
Venous ulcers
Calciphylaxis
Pressure ulcers
Which patient population is at the highest risk for this diagnosis?
End-stage renal disease
Congestive heart failure
Coronary artery disease
Diabetes mellitus
What is the treatment of choice for this condition?
Warfarin
Intravenous sodium thiosulfate
Vitamin D
All of the above
QUESTIONS:
What is the most likely diagnosis?
Squamous cell carcinoma
Venous ulcers
Calciphylaxis
Pressure ulcers
Which patient population is at the highest risk for this diagnosis?
End-stage renal disease
Congestive heart failure
Coronary artery disease
Diabetes mellitus
What is the treatment of choice for this condition?
Warfarin
Intravenous sodium thiosulfate
Vitamin D
All of the above
ANSWERS:
What is the most likely diagnosis?
Correct Answer:
C.) Calciphylaxis
The most likely diagnosis for this patient’s leg lesion is calcific uremic arteriolopathy or calciphylaxis. Calciphylaxis is a rare syndrome seen primarily in patients with end-stage renal disease, characterized by areas of intense pain and ischemic necrosis of the subcutaneous fat and dermis.1-3 Calcification of arterioles and capillaries in these regions is thought to lead to chronic ischemia. Clinically, this presents as changes to the overlying skin. Lesions can initially present in various ways but rapidly progress to characteristic necrotic ulcers with black eschars.1,4-6 In this patient, medical history and the unique physical appearance of the lesions are suggestive of calciphylaxis.
Differential includes cellulitis, skin carcinoma, venous ulcers, arterial ulcers, pressure ulcers, diabetic ulcers and pyoderma gangrenosum. There was no leukocytosis, erythema/warmth or purulent exudate on examination suggestive of cellulitis. Squamous cell carcinoma typically appears as a smooth or hyperkeratotic papule/plaque with central ulceration in a sun-exposed region.7 The location in this patient would be atypical for a squamous cell carcinoma. Melanoma presents in a variety of ways and is beyond the scope of this current article. Venous ulcers are often irregular, shallow and located over bony prominences, such as the medial malleolus.8 In this patient, the lesion was located on the posterior calf, not a typical location of a venous ulcer.
Additionally, the patient was ambulatory upon presentation, making pressure ulcers of the posterior calf unlikely. This patient had diabetes, so diabetic ulceration was on the differential. However, one would expect a diabetic ulcer to develop on the plantar aspect of the foot, likely in the setting of extensive callus formation.9 The history provided in this case did not fit this description.
Similar to this patient’s lesion, arterial ulcers can produce eschars; however, this patient did have palpable pulses. Notably, throughout several admissions, the patient underwent a comprehensive vascular evaluation with no significant findings seen in the ipsilateral extremity.
Which patient population is at the highest risk for this diagnosis?
Correct Answer:
A.) End-stage renal disease
Calciphylaxis is most often seen in patients with end-stage renal disease, although it can occur in earlier stages of chronic kidney disease and occasionally patients with normal renal function.1-3 Diabetes mellitus is also a risk factor for calciphylaxis,1,10 but it is not as strongly associated with the condition as end-stage renal disease. Notably, calciphylaxis is rare; even in patients with risk factors, most never develop the condition.1
What is the treatment of choice for this condition?
Correct Answer:
B.) Intravenous sodium thiosulfate
Although treatment remains under investigation, sodium thiosulfate is often given in the treatment for calciphylaxis.1,6,11 Warfarin is associated with an increased risk of developing calciphylaxis and should be discontinued.6,10 Additionally, vitamin D supplementation should be stopped during treatment.1
DISCUSSION
Calciphylaxis, or calcific uremic arteriolopathy, is a rare, life- threatening syndrome that primarily affects patients with end-stage renal disease.1-3 Although the exact pathogenesis is unknown, in calciphylaxis, calcification of arterioles and capillaries in the subcutaneous fat and dermis leads to chronic ischemia.1 Subsequent endothelial injury and microthrombosis cause further occlusion of associated vessels. This presents clinically as painful, ischemic skin lesions. Lesions can initially present in various ways, including induration, livedo reticularis or violaceous, plaque-like subcutaneous nodules.4-6 These initial lesions classically progress to necrotic ulcers with black eschars.1,4-6
Calciphylaxis is rare, with an annual incidence of 35 per 10,000 patients on hemodialysis in the United States.10 Risk factors include end-stage renal disease, diabetes mellitus, female sex, obesity, hyperphosphatemia, hypercalcemia, hyperparathyroidism and warfarin use, among others.1,6,10
However, most patients with risk factors do not develop calciphylaxis. It is thought that an inciting event in patients with underlying risk factors likely triggers the development of calciphylaxis, such as repetitive trauma from subcutaneous injections.10 However, in many cases, no clear trigger is identified.1
Diagnosis may be made via clinical suspicion alone in patients with classic presentation. Skin biopsies may be used to confirm clinical suspicion; however, this practice is often discouraged due to the risk of developing new non-healing ulcers and sampling error.6
Treatment remains under investigation. Modalities include wound care, pain control and infection prevention. Additionally, correction of abnormal calcium and phosphate levels should be undertaken, including stopping vitamin D supplements, intensifying dialysis regimens and using low/non-calcium-containing phosphate binders.1,6 Warfarin should also be held and vitamin K supplementation considered.
Although there are no approved therapies for calciphylaxis, one medication often given in the treatment of calciphylaxis is sodium thiosulfate. Sodium thiosulfate works by increasing the solubility of calcium.11 It is administered intravenously at the end of every hemodialysis session. Efficacy has been demonstrated in case studies, but randomized controlled trials are currently under investigation.1
Despite advancements in treatment, calciphylaxis remains a life- threatening syndrome with high morbidity and mortality. The one- year mortality rate is estimated to be 45–52% in those with end- stage renal disease.8,10,12
CONCLUSION
In this case, nephrology was consulted and the patient was started on intravenous sodium thiosulfate. Calcium-based medications were held. Biopsy was not recommended due to the risk of poor wound healing. Due to the development of metabolic acidosis, sodium thiosulfate was later replaced with an intralesional form administered by vascular surgery. Wound care also followed the patient throughout admission, and she remained on a pain regimen for symptomatic relief.
Unfortunately, despite aggressive treatment, the patient had minimal improvement on the sodium thiosulfate and ended up being re-admitted multiple times over several months for uncontrolled pain and later infection. Ultimately, the ulcer continued to progress, leading to wasting the limb, loss of ambulation and an above-the-knee amputation approximately five months after the initial presentation. A few months following amputation, the patient opted to pursue hospice and stop dialysis.
Calciphylaxis is a rare, life-threatening syndrome with a very high mortality rate and limited treatment options. The purpose of this photographic clinical case is to aid in the early identification and treatment of this rapidly progressive syndrome.
REFERENCES:
Nigwekar SU, Thadnani R, Brandenburg VM. Calciphylaxis. N Engl J Med. 2018;378:1704-14.
McCarthy JT, El-Azhary RA, Patzelt MT, et al. Survival, risk factors, and effects of treatment in 101 patients with calciphylaxis. Mayo Clin Proc. 2016;91:1384-94.
Brandenburg VM, Kramann R, Rothe H, et al. Calcific uraemic arteriolopathy (calciphylaxis): data from a large national registry. Nephro Dial Transplant. 2017;32:126-32.
Ghosh T, Winchester DS, Davis MDP, EL-Azhary R, Comfere NI. Early clinical presentations and progression of calciphylaxis. Int J Dermatol. 2017;56:856-61.
Daudén E, Oñate MJ. Calciphylaxis. Dermatol Clin. 2008;26:557-68.
Evenepoel, Pieter; Kuypers, Dirk R. "Comprehensive Clinical Nephrology- Sixth Edition." Edinburg. Elsevier Inc. 2019. 87:1013-1021.
Firnhaber Jonathon M. Diagnosis and treatment of basal cell and squamous cell carcinoma. Am Fam Physician. 2012;86(2):161-168.
Bonkemeyer Millan S, Gan R, Townsend PE. Venous ulcers: diagnosis and treatment. Am Fam Physician. 2019;100(5):298-305.
Bowers S, Franco E. Chronic wounds: evaluation and management. Am Fam Physician. 2020;101(3):159-166.
Nigwekar SU, Zhao S, Wenger J, et al. A nationally representative study of calcific uremic arteriolopathy risk factors. J Am Soc Nephrol. 2016;27:3421-9.
Schlieper G, Brandenburg V, Ketteler M, Floege J. Sodium thiosulfate in the treatment of calcific uremic arteriolopathy. Nat Rev Nephrol. 2009;5:539-543.
Weenig RH, Sewell LD, Davis MDP, et al. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol. 2007;56:569-579.