==== Front Am J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2998341010.12659/AJCR.909546909546ArticlesA Fatal Case of Non-Uremic Calciphylaxis: A Case Report and Literature Review Abdalla Abubaker O. BEFGAl-Khafaji Jaafar ETaha Mohamed EMalik Samira EDepartment of Internal Medicine, School of Medicine, University of Nevada, Reno, NV, U.S.A.Authors’ Contribution: A Study Design B Data Collection C Statistical Analysis D Data Interpretation E Manuscript Preparation F Literature Search G Funds Collection Conflict of interest: None declared Corresponding Author: Abubaker O. Abdalla, e-mail: abubakera@med.unr.edu2018 09 7 2018 19 804 807 18 2 2018 01 5 2018 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 61 Final Diagnosis: Non-uremic calciphylaxis Symptoms: Pain • skin ulcers Medication: — Clinical Procedure: — Specialty: General and Internal Medicine Objective: Rare disease Background: Calciphylaxis is a rare cutaneous disease, also known as calcific uremic arteriolopathy, that occurs most frequently in patients with advanced chronic kidney disease and on long-term hemodialysis. Case Report: We describe the case of a 61-year-old female patient with worsening chronic kidney disease not on dialysis therapy, who presented with severe progressive calciphylaxis on both lower limbs. Conclusions: Calcific uremic arteriolopathy is a rare fatal condition that requires prompt diagnosis and treatment. It is classically described in patients with end-stage kidney disease on long-term renal replacement therapy but can present in patients with an earlier stage of kidney disease. Non-uremic calciphylaxis should be suspected in patients with earlier stages of kidney disease, especially in those with other concurrent risk factors or co-morbid conditions, to avoid the high risk of morbidity and mortality associated with such cases. MeSH Keywords: CalciphylaxisRenal Insufficiency, ChronicVascular Calcification ==== Body Background Calciphylaxis is a rare cutaneous disease, also known as calcific uremic arteriolopathy (CUA), that occurs most frequently in patients with advanced chronic kidney disease and on long-term hemodialysis [1]. It is a rare condition, described in 1% to 4% of patients on dialysis, mainly in those with a history of diabetes mellitus (DM), liver disease, and calcium-phosphate product level of more than 70 mg2/dL2 [2]. The term “calciphylaxis” was first used by Hans Selye in 1961; he performed laboratory experiments to induce diffuse subcutaneous soft tissue calcification in rats by using different preparations such as parathyroid extracts and vitamin D as sensitizing agents in addition to trauma as a challenging factor [3]. We describe a case of a 61-year-old female patient with chronic kidney disease who was not on hemodialysis and with no evidence of uremia, who presented with severe progressive calciphylaxis on proximal lower limbs bilaterally. Case Report The patient had a past medical history of chronic kidney disease (CKD) in the setting of poorly controlled hypertension with multiple emergency room and outpatient office visits secondary to hypertensive urgency. She also had diabetes mellitus (DM) type II that was poorly controlled, with average glycohemoglobin values of 9–18, due to medications non-compliance. Her medical record revealed well-controlled DM for the last year prior to admission after she was started on insulin therapy provided by her caregiver, with hemoglobin A1c readings of 6.5–7.0. Her past medical history was also significant for congestive heart failure with preserved ejection fraction (HFpEF), severe obesity (BMI of 56), and obstructive sleep apnea (OSA). Review of her medical records revealed CKD that was stage II at 2 years prior to her current presentation, which progressed to stage III several months prior to admission, with intermittently elevated alkaline phosphatase levels (80–400 s). The patient presented with progressive leg pain that was associated with painful skin ulcers on both thighs. Symptoms started several weeks prior to the emergency room visit, with no reported fever, chills, trauma, claudication, bleeding, puru-lent discharge, or history of previous similar lesions. Physical exam revealed an obese woman with peripheral edema and unstageable painful necrotic skin ulcers 4×7 cm in diameter on the medial side of proximal lower limbs bilaterally, with black eschar and surrounding erythema (Figures 1, 2). Laboratory investigations were consistent with acute kidney injury and worsening kidney function compared to her baseline (blood urea nitrogen of 44 and serum creatinine of 2.2) (Figure 3). Complete blood count was significant for a hemoglobin level of 7.4 due to anemia of chronic disease with no evidence of leukocytosis or band cells. Platelet count was 250 with a normal international normalized ratio (INR) of 1.1. Chemistry report was remarkable for normal anion gap metabolic acidosis, in addition to normal parathyroid hormone and calcium levels of 44.2 and 8.8, respectively. Phosphate level was 5.0 with calcium-phosphate product of 44 mg2/dL2. The glycohemoglobin level was 6.8 on admission, with no evidence of chronic liver disease or systemic infection. Calciphylaxis was suspected based on clinical and radiological data in the form of diffuse calcification of arterial blood vessels of the lower extremities (Figure 4). Skin biopsy and histological evaluation revealed non-specific inflammation and necrosis with calcification involving small arteries and surrounding fibroadipose tissue, but no findings suggestive of vasculitis. Ultrasound and MRI were performed and revealed no signs of infection, fasciitis, osteomyelitis, or abscess. Skin lesions were managed with daily wound care in the form of regular dressing and topical therapy with methylene blue and antibiotics. The vascular surgery team recommended continuing daily wound care with no invasive surgical interventions. The case was discussed with the nephrology team, who started the patient on systemic sodium thiosulfate therapy of 12.5 mg twice a day for a total duration of 4 weeks. The patient’s condition continued to worsen without improvement of her kidney function (eGFR of 18–25) or skin lesions. The nephrologist recommended a trial of dialysis but the patient and her family refused this option. The patient subsequently developed a wound infection complicated by clinical sepsis. Vancomycin and piperacillin/tazobactam were started empirically and wound debridement was performed by the surgical team. Blood cultures remained negative and her condition deteriorated with the development of toxic encephalopathy due to worsening kidney function in the setting of systemic infection. Goals of care and prognosis were discussed with the family, who continued to decline dialysis therapy and elected to proceed with palliative and comfort measures with no further invasive surgical or medical interventions. Prabhakar et al. described a similar case of non-uremic calciphylaxis in a patient with recent liver transplant, who was successfully treated with sodium thiosulfate and hyperbaric oxygen therapy [4]. Discussion Calcific uremic arteriolopathy (CUA) is a form of calciphylaxis that is more common in patients with end-stage renal disease requiring long-term renal replacement therapy in the form of either peritoneal dialysis or hemodialysis [5,6]. Other risk factors include female sex, obesity, white ethnicity, DM, liver disease, high alkaline phosphate, warfarin therapy, and elevated calcium and phosphate levels [5,7–10]. Calcific uremic arteriolopathy is associated with high morbidity and mortality, especially in a patient with ulcerated lesions and multiple comorbidities, with a reported 1-year mortality of 30–80% [11]. Calciphylaxis can occur in patients with chronic kidney disease who are not on renal replacement therapy and is termed nonuremic calciphylaxis (NUC). Nigwekar et al. conducted a systematic review on 36 cases of NUC and described risk factors seen in those patients. NUC seems to be related to hyperparathyroidism, underlying malignancies, alcoholic liver disease, and connective tissue disorders. Mortality due to NUC was found to be 52%, with sepsis as the leading cause of death [12]. The pathogenesis is not well understood, but is thought to be due to vascular calcification leading to soft tissue necrosis that is usually described in patients with end-stage kidney disease on dialysis [5]. Clinical manifestations in CUA are mainly due to diminished arteriolar supply caused by calcification and fibrosis. Various theories to explain calciphylaxis have been suggested and usually involve an elevated calcium-phosphate product, but the pathophysiology remains unclear [13]. One theory focuses on excess levels of parathyroid hormone and vitamin D as described in animal studies [14]. Another theory describes deficiency of vascular calcification inhibitors such as Fetuin-A, a glycoprotein that helps clear excess calcium-phosphate product [15]. Skin lesions are typically described as livedo reticularis-like plaques that progress to painful necrotic ulcers, which are more prone to infections due to poor healing secondary to diminished vascular supply. Common areas affected are the lower limbs and skin regions with dense adipose tissue [16]. Diagnosis requires a high degree of suspicion based on clinical features and can be supported by imaging studies. Skin biopsy remains the criterion standard method to provide a definitive diagnosis. Histologic findings on biopsy include intravascular calcification and intimal hyperplasia with inflammatory changes and tissue necrosis [17]. Treatment should utilize a multi-disciplinary approach. Management is mainly directed toward local wound care and prevention of local and systemic infection, in addition to optimizing medical therapy for associated co-morbid conditions [18]. Local wound care remains the mainstay of treatment and involves frequent wound dressing, while surgical interventions remain controversial [19,20]. Sodium thiosulfate has been shown to be an effective treatment option that can be administered as a local or systemic therapy to promote wound healing [21–23]. Local administration is in the form of intra-lesion injections as described by Strazzula et al. [24]. Hyperbaric oxygen therapy can also be used as an alternative form of treatment, with favorable results reported in prior studies [25,26]. Surgical and chemical wound debridement should be considered on a case-by-case basis, and systemic antibiotic therapy should be administered for ulcers complicated by infections or sepsis [27]. Conclusions Calciphylaxis remains a rare fatal condition that can present in patients with or without end-stage renal disease, regardless of presence of uremia. Early identification of such patients is important to allow prompt treatment to avoid the high morbidity and mortality associated with calciphylaxis. Conflicts of interest. None. Figure 1. Necrotic skin ulcer on proximal right lower extremity with black eschar and surrounding erythema. Figure 2. Necrotic skin ulcer on proximal left lower extremity with black eschar and surrounding erythema. Figure 3. Trend of blood urea nitrogen (blue), serum creatinine (purple), and estimated glomerulus filtration rate (brown) during hospitalization. Figure 4. Calcification of the anterior (orange arrow) and posterior (red arrow) tibial arteries. ==== Refs References: 1. Brandenburg VM Cozzolino M Ketteler M Calciphylaxis: A still unmet challenge J Nephrol 2011 24 2 142 48 21337312 2. Roncada EV Abreu MA Pereira MF Calciphylaxis, a diagnostic and therapeutic challenge: Report of a successful case An Bras Dermatol 2012 87 5 752 55 23044570 3. Selye H Gentile G Jean P An experimental model of “dermatomyositis” induced by calciphylaxis Can Med Assoc J 1961 85 14 770 76 13749961 4. Prabhakar S Tuffaha AM Non uremic calciphylaxis post liver transplantation: A case report and literature review of an unusual presentation of a rare disease Am J Case Rep 2018 19 118 22 29386500 5. Fine A Zacharias J Calciphylaxis is usually non-ulcerating: Risk factors, outcome and therapy Kidney Int 2002 61 6 2210 17 12028462 6. Angelis M Wong LL Myers SA Wong LM Calciphylaxis in patients on hemodialysis: A prevalence study Surgery 1997 122 6 1083 89 discussion 1089–90 9426423 7. Nigwekar SU Bhan I Turchin A Statin use and calcific uremic arteriolopathy: A matched case-control study Am J Nephrol 2013 37 4 325 32 23548843 8. Weenig RH Sewell LD Davis MD Calciphylaxis: natural history, risk factor analysis, and outcome J Am Acad Dermatol 2007 56 4 569 79 17141359 9. Mazhar AR Johnson RJ Gillen D Risk factors and mortality associated with calciphylaxis in end-stage renal disease Kidney Int 2001 60 1 324 32 11422768 10. Ahmed S O’Neill KD Hood AF Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells Am J Kidney Dis 2001 37 6 1267 76 11382698 11. Weenig RH Sewell LD Davis MDP Calciphylaxis: Natural history, risk factor analysis, and outcome J Am Acad Dermatol 2007 56 4 569 79 17141359 12. Nigwekar SU Wolf M Sterns RH Hix JK Calciphylaxis from nonuremic causes: A systematic review Clin J Am Soc Nephrol 2008 3 4 1139 43 18417747 13. Budisavljevic MN Cheek D Ploth DW Calciphylaxis in chronic renal failure J Am Soc Nephrol 1996 7 7 978 82 8829111 14. Weenig RH Pathogenesis of calciphylaxis: Hans Selye to nuclear factor kappa-B J Am Acad Dermatol 2008 58 3 458 71 18206262 15. Heiss A DuChesne A Denecke B Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calci-protein particles J Biol Chem 2003 278 15 13333 41 12556469 16. Brewster UC Dermatological disease in patients with CKD Am J Kidney Dis 2008 51 2 331 44 18215712 17. Mochel MC Arakaki RY Wang G Cutaneous calciphylaxis: A retrospective histopathologic evaluation Am J Dermatopathol 2013 35 5 582 86 23328789 18. Vedvyas C Winterfield LS Vleugels RA Calciphylaxis: A systematic review of existing and emerging therapies J Am Acad Dermatol 2012 67 6 e253 60 21821309 19. Baldwin C Farah M Leung M Multi-intervention management of calciphylaxis: A report of 7 cases Am J Kidney Dis 2011 58 6 988 91 21872378 20. Martin R Mysterious calciphylaxis: Wounds with eschar – to debride or not to debride? Ostomy Wound Manage 2004 50 4 64 66 68 70 discussion 71 21. Nigwekar SU Brunelli SM Meade D Sodium thiosulfate therapy for calcific uremic arteriolopathy Clin J Am Soc Nephrol 2013 8 7 1162 70 23520041 22. Meissner M Kaufmann R Gille J Sodium thiosulphate: A new way of treatment for calciphylaxis? Dermatology 2007 214 4 278 82 17460397 23. Sood AR Wazny LD Raymond CB Sodium thiosulfate-based treatment in calcific uremic arteriolopathy: A consecutive case series Clin Nephrol 2011 75 1 8 15 21176746 24. Strazzula L Nigwekar SU Steele D Intralesional sodium thiosulfate for the treatment of calciphylaxis JAMA Dermatol 2013 149 8 946 49 23760631 25. Podymow T Wherrett C Burns KD Hyperbaric oxygen in the treatment of calciphylaxis: A case series Nephrol Dial Transplant 2001 16 11 2176 80 11682664 26. Basile C Montanaro A Masi M Hyperbaric oxygen therapy for calcific uremic arteriolopathy: A case series J Nephrol 2002 15 6 676 80 12495283 27. Sato T Ichioka S How should we manage multiple skin ulcers associated with calciphylaxis? J Dermatol 2012 39 11 966 68 22385251