Delayed diagnosis of non-uremic calciphylaxis in an unlikely patient

Delayed diagnosis of non-uremic calciphylaxis in an unlikely patient | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF comment Delayed diagnosis of non-uremic calciphylaxis in an unlikely patient Ayesha Kothari, Bashir Khatib-Shahidi, Kurt Ashack, Daniel Dapprich This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6752050/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Calciphylaxis is a rare and often fatal condition most commonly associated with end-stage renal disease (ESRD). However, non-uremic calciphylaxis (NUC), occurring in the absence of severe renal dysfunction, remains a diagnostic challenge due to its rarity and nonspecific presentation. We report a rare case of non-uremic calciphylaxis in a 43-year-old African American woman with a history of alcoholic liver cirrhosis, an unusual presentation given her demographics and past medical history, which are not widely represented in the calciphylaxis literature. Further skewing the diagnostic challenge, initial skin biopsy ruled out calciphylaxis. The diagnostic complexity and risk of delayed treatment in such atypical presentations underscore the need for heightened clinical vigilance, especially in underrepresented populations. This case highlights the importance of considering NUC in the differential diagnosis of painful skin lesions, even in patients without traditional risk factors. non-uremic calciphylaxis calciphylaxis non-healing wounds ulcers Introduction Calciphylaxis, also known as calcific uremic arteriolopathy, is a painful, chronic and life-threatening condition characterized by calcification of small blood vessels in the dermis and subcutaneous fat, often resulting in tissue ischemia and necrosis. It typically occurs in patients with end-stage renal disease (ESRD) and carries a high annual mortality rate after diagnosis [ 1 ]. Calciphylaxis most commonly affects older white women aged 50–70 years. In the United States, the incidence ranges from 1 to 4% among patients undergoing hemodialysis [ 2 ]. However, in rare cases, calciphylaxis occurs in patients without renal failure, in which it is termed non-uremic calciphylaxis. These cases are rising, in part due to growing awareness, and non-uremic cases tend to have a better prognosis than their uremic counterparts [ 1 , 2 ]. Known risk factors include ESRD, obesity, female sex, diabetes mellitus, hyperparathyroidism, hypercalcemia, hyperphosphatemia, hypoalbuminemia, warfarin, vitamin K deficiency, vitamin D deficiency, corticosteroids, autoimmune disorders, coagulopathies (protein C or S deficiencies), cirrhosis, malignant neoplasms (cholangiocarcinoma, melanoma, chronic myeloid leukemia), and certain genetic polymorphisms (NT5E) [ 1 , 2 , 3 ]. Calciphylaxis is difficult to diagnose due to varied clinical presentation that can differ based on disease stage, anatomic location, and skin color. Early signs typically involve pain out of proportion to exam findings, indurations, subcutaneous nodules, and/or retiform purpura. Later signs may include necrotic, ulcerative plaques with black eschar, often in adipose-rich areas (thighs, abdomen, breast) but may also occur in the lower extremities, digits, and penis. Ulcerations are correlated with significantly worse prognosis, and sepsis secondary to infected wounds is the leading cause of death [ 2 , 3 ]. The differential diagnosis varies depending on the stage and clinical presentation. In early stages, conditions such as lupus panniculitis and pancreatic panniculitis may be considered. When lesions have a vasculopathic appearance, the differential should include warfarin-induced skin necrosis, cryoglobulinemia, cholesterol embolism, and various forms of vasculitis. Ulcerative lesions broaden the differential further to include pyoderma gangrenosum, arterial ulcers, infectious etiologies, and peripheral vascular disease [ 2 ]. There is no single definitive diagnostic test, but skin biopsies remain the gold standard as they can show calcification of small vessels in the dermis/subcutis, fibrin thrombi, fat necrosis, and ischemic changes. However, sensitivity is limited, and biopsies carry the risk of worsening necrosis or infection. Recently, the role of imaging, such as the use of plain radiographs, CT imaging, and point-of-care ultrasound, has drawn more interest, especially when biopsies are inconclusive or potentially harmful. Lab tests, while nonspecific, may reveal abnormalities in calcium, phosphate, PTH, albumin, and coagulation profiles [ 3 ]. Case report Here we present a case of a 43-year-old African American woman who presented to the ED with difficulty ambulating due to chronic, progressively worsening out of proportion pain and lesions of the left lower extremity, ongoing for nine months. She has a past medical history of chronic ulcers on lower extremities exposing fat layer, alcoholic cirrhosis, class III obesity, essential hypertension, chronic venous stasis dermatitis, peripheral artery disease, lymphedema, tobacco dependence, alcohol use disorder, hidradenitis suppurativa, esophageal varices, sleeve gastrectomy, chronic pancreatitis, and bronchial asthma. She did not have any history of chronic kidney disease or warfarin use. The patient was initially admitted for evaluation of chronic left lower extremity pain and skin lesions. The initial physical exam revealed an open, necrotic ulcer on the lower left extremity with exposed subcutaneous fat (10 x 14.5 x 0.1 cm with moderate eschar). The patient also had a painful hyperpigmented lesion on the left thigh that had not yet necrosed or ulcerated. Physical exam was also significant for an ulceration with purulent drainage of the abdominal wall (2 x 2 x 0.1 cm with no eschar), through which secondary sepsis occurred 2 weeks afterwards with severe, uncontrollable pain. At that time, the initial differential diagnosis included pyoderma gangrenosum, calciphylaxis, and infectious disease, but an initial biopsy of the abdominal lower left quadrant and left lower leg ulcer did not show evidence of calciphylaxis. Additionally, laboratory studies including parathyroid hormone level, ionized calcium level, and various infection markers were within normal limits, thus inconsistent with calciphylaxis, leading to a diagnosis of exclusion: pyoderma gangrenosum. Steroid tapers were initiated and began to improve her condition, before uncontrollable pain returned and the decision to maintain long-term high-dose steroid therapy was made by the wound care team. Later, the differential broadened to consider autoimmune disease, calcinosis cutis, and pancreatic panniculitis. Laboratory studies including C3 and C4, ANA IFA, ANA screen, and urine protein/creatinine ratios were unremarkable, reassuring the team of the initial diagnosis of pyoderma gangrenosum. A referral to dermatology was sought to further assess the underlying disease process. A skin biopsy of the now purulent and ulcerated left anterior distal thigh lesion (2 x 4 x 0.2 cm with extensive eschar) three months after initial presentation demonstrated microvascular calcification and thrombosis. A previously ruled out diagnosis of non-uremic calciphylaxis was made. The patient was then started on sodium thiosulfate 25 mg twice weekly. She continued to receive multidisciplinary care involving dermatology, nephrology, and wound management. Her course remained complicated by intermittent infection and poor wound healing, necessitating close outpatient monitoring. Discussion This case represents an atypical and diagnostically challenging presentation of non-uremic calciphylaxis in a young African American woman without underlying ESRD. Calciphylaxis classically affects older white women with ESRD and is strongly associated with dialysis dependence and disturbances in calcium-phosphate metabolism [ 4 ]. In contrast, our patient developed painful, nonhealing necrotic ulcers in the setting of preserved renal function and minimal bone abnormalities, which are hallmarks of non-uremic calciphylaxis, a rare and often underrecognized variant. A recent retrospective cohort study reviewed 60 calciphylaxis cases between 2012 and 2022, 21 of which were diagnosed with non-uremic calciphylaxis. Additionally, predilection sites of skin lesions were the lower legs in 88% (n = 53), and commonly associated comorbidities in the non-uremic calciphylaxis patients included liver disease, hypertension, obesity, diabetes mellitus, and peripheral artery disease, all of which were consistent findings within our patient’s past medical history [ 4 ]. Interestingly, this study showed no associations with cryoglobulinemia, contrary to findings in another study [ 2 , 4 ]. Non-uremic calciphylaxis requires a high level of suspicion to diagnose and it remains a diagnostic challenge to treat, as we saw here with the patient’s initial presentation that mimicked pyoderma gangrenosum. However, unlike inflammatory ulcers such as pyoderma gangrenosum, calciphylaxis ulcers are typically dry with black eschar due to underlying vascular occlusion rather than inflammation, which may be important to note especially when clinical features overlap [ 2 ]. Other clinical mimics include atherosclerotic vascular disease, cholesterol embolization, nephrogenic systemic fibrosis, oxalate vasculopathy, purpura fulminans, vasculitis, and warfarin necrosis [ 5 ]. Our first biopsy was negative for calciphylaxis, which highlights the limitations of early histopathology. Lab results of PTH, calcium, and phosphate within normal limits, and only a transient AKI, did not support the classic uremic calciphylaxis diagnosis. We saw an evolving presentation and the need for repeat biopsy and multidisciplinary evaluation involving wound care and infection control. Because therapeutic strategies for non-uremic calciphylaxis are based on those for uremic calciphylaxis, non-uremic calciphylaxis lacks standardized therapy beyond wound care, infection control, and risk factor management, though sodium thiosulfate infusion remains frequently used for management [ 3 , 5 ]. Common complications of non-uremic calciphylaxis include sepsis, chronic wound infections, severe pain, and poor wound healing, each of which presented within our patient and contributes to high morbidity and mortality. These challenges highlight the urgent need for further research into disease-specific treatment modalities and standardized management protocol tailored towards non-uremic presentations [ 6 ]. In addition to classic etiologies such as ESRD, calciphylaxis can occasionally be triggered by drug reactions, which further complicates the diagnostic process [ 7 ]. When the underlying cause is not readily apparent, a comprehensive workup that includes evaluation for occult malignancy may be appropriate. Management strategies for both uremic and non-uremic calciphylaxis continue to evolve and typically require a multidisciplinary approach. In uremic cases, especially those involving refractory hyperparathyroidism, parathyroidectomy may be considered, although cinacalcet is often trialed initially to reduce calcium and parathyroid hormone levels [ 8 , 9 ]. Supportive care is essential for all patients and includes optimizing nutrition, promoting smoking cessation, maintaining proper wound hygiene, preventing and treating infections, and providing effective pain control. Sodium thiosulfate remains a key therapy and can be administered either intravenously or topically, depending on patient tolerance. Radiologic imaging can also aid in diagnosis, with modalities such as CT, plain radiographs, Doppler ultrasound, and three-phase technetium Tc-99m methylene diphosphonate bone scintigraphy offering varying degrees of sensitivity for detecting soft tissue calcifications. Recent literature, including visual diagnostic guides, is contributing to improved recognition and more informed therapeutic decisions in these complex cases. Distinct risk factors such as a higher use of vitamin K antagonists (e.g. warfarin) are associated with disease onset, supporting vitamin K deficiency as a key player in calciphylaxis pathogenesis [ 4 , 10 ]. Vitamin K is involved in the activation of matrix G1a protein (MGP), which is an extracellular matrix protein produced in endothelial vascular smooth muscle cells and chondrocytes. MGP is also a potent inhibitor of calcification, so conditions associated with vitamin K deficiencies such as prolonged warfarin use, liver disease, gastric bypass, malnutrition, and obesity remove natural inhibitors of calcification [ 10 , 11 ]. In our patient, alcoholic liver disease, gastric sleeve surgery, and obesity are all coexisting conditions with features that potentially contribute to the mechanism of non-uremic calciphylaxis pathology. Conclusion This case highlights the diagnostic complexity of non-uremic calciphylaxis, a potentially fatal condition, particularly in unlikely patients like this young African American woman without classic risk factors such as ESRD, significant mineral imbalance, or warfarin use. The patient’s delayed diagnosis, despite early biopsy and normal lab parameters, underscores the limitations of current diagnostic tools and the need for persistent clinical suspicion of calciphylaxis in atypical presentations of necrotic ulcers. Her comorbidities (alcoholic cirrhosis, obesity, peripheral artery disease, and prior nutrient deficiencies) may have contributed to vascular calcification, though their exact roles are unclear but may lead to MGP inactivation. As non-uremic calciphylaxis becomes increasingly recognized, this case reinforces the need for multidisciplinary evaluations, repeated biopsies when clinical suspicion persists, and individualized management strategies to improve outcomes in underrepresented patient populations. Declarations The patient consented to publish their clinical case. No funds, grants, or other support was received. The authors have no relevant financial or non-financial interests to disclose. The authors have no competing interests to declare that are relevant to the content of this article. Funding: No funds, grants, or other support was received. Competing interest: The authors have no relevant financial or non-financial interests to disclose. The authors have no competing interests to declare that are relevant to the content of this article. Author Contribution A.K. and B.K. wrote the main manuscript text. All authors reviewed the manuscript. References Nigwekar SU, Thadhani R, Brandenburg VM, Calciphylaxis. N Engl J Med. 2018;378(18):1704–14. 10.1056/NEJMra1505292 . Rick J, Strowd L, Pasieka HB, et al. Calciphylaxis: Part I. Diagnosis and pathology. J Am Acad Dermatol. 2022;86(5):973–82. 10.1016/j.jaad.2021.10.064 . Gallo Marin B, Aghagoli G, Hu SL, Massoud CM, Robinson-Bostom L. Calciphylaxis and Kidney Disease: A Review. Am J Kidney Dis. 2023;81(2):232–9. 10.1053/j.ajkd.2022.06.011 . Yousuf S, Busch D, Renner R, Schliep S, Erfurt-Berge C. Clinical characteristics and treatment modalities in uremic and non uremic calciphylaxis - a dermatological single-center experience. Ren Fail. 2024;46(1):2297566. 10.1080/0886022X.2023.2297566 . Gomes F, La Feria P, Costa C, Santos R, Non-Uremic Calciphylaxis. A Rare Diagnosis with Limited Therapeutic Strategies. Eur J Case Rep Intern Med. 2018;5(12):000986. 10.12890/2018_000986 . Published 2018 Dec 27. 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. 10.2215/CJN.00530108 . Portales-Castillo I, Kroshinsky D, Malhotra CK, et al. Calciphylaxis-as a drug induced adverse event. Expert Opin Drug Saf. 2019;18(1):29–35. 10.1080/14740338.2019.1559813 . Girotto JA, Harmon JW, Ratner LE, Nicol TL, Wong L, Chen H. Parathyroidectomy promotes wound healing and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism. Surgery. 2001;130(4):645–51. 10.1067/msy.2001.117101 . Deen J, Schaider H. The use of cinacalcet for the treatment of calciphylaxis in patients with chronic kidney disease: A comprehensive review. Australas J Dermatol. 2019;60(3):e186–94. 10.1111/ajd.12992 . Nigwekar SU, Bloch DB, Nazarian RM, et al. Vitamin K-Dependent Carboxylation of Matrix Gla Protein Influences the Risk of Calciphylaxis. J Am Soc Nephrol. 2017;28(6):1717–22. 10.1681/ASN.2016060651 . Lucca LJ, Moysés RMA, Lima Neto AS. Diagnosis and treatment of calciphylaxis in patients with chronic kidney disease. J Bras Nefrol. 2021;43(4 Suppl 1):665–8. 10.1590/2175-8239-JBN-2021-S111 . Published 2021 Dec 3. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6752050","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"comment","associatedPublications":[],"authors":[{"id":464571040,"identity":"e1489183-1027-43a1-b7ed-4355e4c26c9c","order_by":0,"name":"Ayesha Kothari","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAx0lEQVRIiWNgGAWjYJACZgaGBAZ+OJtoLZINJGsxOECsFv4ZyYc/F9SkyRlfO/5MgqHCOrGBkBaJG2lp0jOO5Rib3c4xk2A4k05YC8ONHDNmHraKxG23c9gkGNsOE9YifyP/82eefxWJm2enP5Ng/EeEFoMbOQzSvG05iRukE8wkGBuI0GJ45pmZNG9fmrHE7Rxji4Rj6cYEtcgdT378medbshz/7PSHNz7UWMsS1MIgkIDEScChCBXwHyBK2SgYBaNgFIxkAABNSj2QYG+7pAAAAABJRU5ErkJggg==","orcid":"","institution":"Michigan State University College of Human Medicine","correspondingAuthor":true,"prefix":"","firstName":"Ayesha","middleName":"","lastName":"Kothari","suffix":""},{"id":464571041,"identity":"14f70e87-6a57-4ef5-911e-2775a90c7dd7","order_by":1,"name":"Bashir Khatib-Shahidi","email":"","orcid":"","institution":"Michigan State University College of Human Medicine","correspondingAuthor":false,"prefix":"","firstName":"Bashir","middleName":"","lastName":"Khatib-Shahidi","suffix":""},{"id":464571042,"identity":"2ef6ba80-a908-4c93-8ecb-af737bd5d2d3","order_by":2,"name":"Kurt Ashack","email":"","orcid":"","institution":"Dermatology Associates of West Michigan","correspondingAuthor":false,"prefix":"","firstName":"Kurt","middleName":"","lastName":"Ashack","suffix":""},{"id":464571043,"identity":"bf8bc310-e6a3-4248-9676-a9422d215278","order_by":3,"name":"Daniel Dapprich","email":"","orcid":"","institution":"Dermatology Associates of West Michigan","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Dapprich","suffix":""}],"badges":[],"createdAt":"2025-05-26 15:08:06","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6752050/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6752050/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83976283,"identity":"453701ee-4e03-4f28-a733-c13d5385d4ae","added_by":"auto","created_at":"2025-06-05 09:06:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":239843,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6752050/v1/5e890674-dcf1-4e69-b54e-c9cd4cd0751e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Delayed diagnosis of non-uremic calciphylaxis in an unlikely patient","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCalciphylaxis, also known as calcific uremic arteriolopathy, is a painful, chronic and life-threatening condition characterized by calcification of small blood vessels in the dermis and subcutaneous fat, often resulting in tissue ischemia and necrosis. It typically occurs in patients with end-stage renal disease (ESRD) and carries a high annual mortality rate after diagnosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Calciphylaxis most commonly affects older white women aged 50\u0026ndash;70 years. In the United States, the incidence ranges from 1 to 4% among patients undergoing hemodialysis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, in rare cases, calciphylaxis occurs in patients without renal failure, in which it is termed non-uremic calciphylaxis. These cases are rising, in part due to growing awareness, and non-uremic cases tend to have a better prognosis than their uremic counterparts [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eKnown risk factors include ESRD, obesity, female sex, diabetes mellitus, hyperparathyroidism, hypercalcemia, hyperphosphatemia, hypoalbuminemia, warfarin, vitamin K deficiency, vitamin D deficiency, corticosteroids, autoimmune disorders, coagulopathies (protein C or S deficiencies), cirrhosis, malignant neoplasms (cholangiocarcinoma, melanoma, chronic myeloid leukemia), and certain genetic polymorphisms (NT5E) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Calciphylaxis is difficult to diagnose due to varied clinical presentation that can differ based on disease stage, anatomic location, and skin color. Early signs typically involve pain out of proportion to exam findings, indurations, subcutaneous nodules, and/or retiform purpura. Later signs may include necrotic, ulcerative plaques with black eschar, often in adipose-rich areas (thighs, abdomen, breast) but may also occur in the lower extremities, digits, and penis. Ulcerations are correlated with significantly worse prognosis, and sepsis secondary to infected wounds is the leading cause of death [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The differential diagnosis varies depending on the stage and clinical presentation. In early stages, conditions such as lupus panniculitis and pancreatic panniculitis may be considered. When lesions have a vasculopathic appearance, the differential should include warfarin-induced skin necrosis, cryoglobulinemia, cholesterol embolism, and various forms of vasculitis. Ulcerative lesions broaden the differential further to include pyoderma gangrenosum, arterial ulcers, infectious etiologies, and peripheral vascular disease [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. There is no single definitive diagnostic test, but skin biopsies remain the gold standard as they can show calcification of small vessels in the dermis/subcutis, fibrin thrombi, fat necrosis, and ischemic changes. However, sensitivity is limited, and biopsies carry the risk of worsening necrosis or infection. Recently, the role of imaging, such as the use of plain radiographs, CT imaging, and point-of-care ultrasound, has drawn more interest, especially when biopsies are inconclusive or potentially harmful. Lab tests, while nonspecific, may reveal abnormalities in calcium, phosphate, PTH, albumin, and coagulation profiles [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e"},{"header":"Case report","content":"\u003cp\u003eHere we present a case of a 43-year-old African American woman who presented to the ED with difficulty ambulating due to chronic, progressively worsening out of proportion pain and lesions of the left lower extremity, ongoing for nine months. She has a past medical history of chronic ulcers on lower extremities exposing fat layer, alcoholic cirrhosis, class III obesity, essential hypertension, chronic venous stasis dermatitis, peripheral artery disease, lymphedema, tobacco dependence, alcohol use disorder, hidradenitis suppurativa, esophageal varices, sleeve gastrectomy, chronic pancreatitis, and bronchial asthma. She did not have any history of chronic kidney disease or warfarin use.\u003c/p\u003e \u003cp\u003eThe patient was initially admitted for evaluation of chronic left lower extremity pain and skin lesions. The initial physical exam revealed an open, necrotic ulcer on the lower left extremity with exposed subcutaneous fat (10 x 14.5 x 0.1 cm with moderate eschar). The patient also had a painful hyperpigmented lesion on the left thigh that had not yet necrosed or ulcerated. Physical exam was also significant for an ulceration with purulent drainage of the abdominal wall (2 x 2 x 0.1 cm with no eschar), through which secondary sepsis occurred 2 weeks afterwards with severe, uncontrollable pain. At that time, the initial differential diagnosis included pyoderma gangrenosum, calciphylaxis, and infectious disease, but an initial biopsy of the abdominal lower left quadrant and left lower leg ulcer did not show evidence of calciphylaxis. Additionally, laboratory studies including parathyroid hormone level, ionized calcium level, and various infection markers were within normal limits, thus inconsistent with calciphylaxis, leading to a diagnosis of exclusion: pyoderma gangrenosum. Steroid tapers were initiated and began to improve her condition, before uncontrollable pain returned and the decision to maintain long-term high-dose steroid therapy was made by the wound care team. Later, the differential broadened to consider autoimmune disease, calcinosis cutis, and pancreatic panniculitis. Laboratory studies including C3 and C4, ANA IFA, ANA screen, and urine protein/creatinine ratios were unremarkable, reassuring the team of the initial diagnosis of pyoderma gangrenosum. A referral to dermatology was sought to further assess the underlying disease process. A skin biopsy of the now purulent and ulcerated left anterior distal thigh lesion (2 x 4 x 0.2 cm with extensive eschar) three months after initial presentation demonstrated microvascular calcification and thrombosis. A previously ruled out diagnosis of non-uremic calciphylaxis was made.\u003c/p\u003e \u003cp\u003eThe patient was then started on sodium thiosulfate 25 mg twice weekly. She continued to receive multidisciplinary care involving dermatology, nephrology, and wound management. Her course remained complicated by intermittent infection and poor wound healing, necessitating close outpatient monitoring.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case represents an atypical and diagnostically challenging presentation of non-uremic calciphylaxis in a young African American woman without underlying ESRD. Calciphylaxis classically affects older white women with ESRD and is strongly associated with dialysis dependence and disturbances in calcium-phosphate metabolism [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In contrast, our patient developed painful, nonhealing necrotic ulcers in the setting of preserved renal function and minimal bone abnormalities, which are hallmarks of non-uremic calciphylaxis, a rare and often underrecognized variant. A recent retrospective cohort study reviewed 60 calciphylaxis cases between 2012 and 2022, 21 of which were diagnosed with non-uremic calciphylaxis. Additionally, predilection sites of skin lesions were the lower legs in 88% (n\u0026thinsp;=\u0026thinsp;53), and commonly associated comorbidities in the non-uremic calciphylaxis patients included liver disease, hypertension, obesity, diabetes mellitus, and peripheral artery disease, all of which were consistent findings within our patient\u0026rsquo;s past medical history [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Interestingly, this study showed no associations with cryoglobulinemia, contrary to findings in another study [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNon-uremic calciphylaxis requires a high level of suspicion to diagnose and it remains a diagnostic challenge to treat, as we saw here with the patient\u0026rsquo;s initial presentation that mimicked pyoderma gangrenosum. However, unlike inflammatory ulcers such as pyoderma gangrenosum, calciphylaxis ulcers are typically dry with black eschar due to underlying vascular occlusion rather than inflammation, which may be important to note especially when clinical features overlap [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Other clinical mimics include atherosclerotic vascular disease, cholesterol embolization, nephrogenic systemic fibrosis, oxalate vasculopathy, purpura fulminans, vasculitis, and warfarin necrosis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Our first biopsy was negative for calciphylaxis, which highlights the limitations of early histopathology. Lab results of PTH, calcium, and phosphate within normal limits, and only a transient AKI, did not support the classic uremic calciphylaxis diagnosis. We saw an evolving presentation and the need for repeat biopsy and multidisciplinary evaluation involving wound care and infection control. Because therapeutic strategies for non-uremic calciphylaxis are based on those for uremic calciphylaxis, non-uremic calciphylaxis lacks standardized therapy beyond wound care, infection control, and risk factor management, though sodium thiosulfate infusion remains frequently used for management [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Common complications of non-uremic calciphylaxis include sepsis, chronic wound infections, severe pain, and poor wound healing, each of which presented within our patient and contributes to high morbidity and mortality. These challenges highlight the urgent need for further research into disease-specific treatment modalities and standardized management protocol tailored towards non-uremic presentations [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn addition to classic etiologies such as ESRD, calciphylaxis can occasionally be triggered by drug reactions, which further complicates the diagnostic process [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. When the underlying cause is not readily apparent, a comprehensive workup that includes evaluation for occult malignancy may be appropriate. Management strategies for both uremic and non-uremic calciphylaxis continue to evolve and typically require a multidisciplinary approach. In uremic cases, especially those involving refractory hyperparathyroidism, parathyroidectomy may be considered, although cinacalcet is often trialed initially to reduce calcium and parathyroid hormone levels [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Supportive care is essential for all patients and includes optimizing nutrition, promoting smoking cessation, maintaining proper wound hygiene, preventing and treating infections, and providing effective pain control. Sodium thiosulfate remains a key therapy and can be administered either intravenously or topically, depending on patient tolerance. Radiologic imaging can also aid in diagnosis, with modalities such as CT, plain radiographs, Doppler ultrasound, and three-phase technetium Tc-99m methylene diphosphonate bone scintigraphy offering varying degrees of sensitivity for detecting soft tissue calcifications. Recent literature, including visual diagnostic guides, is contributing to improved recognition and more informed therapeutic decisions in these complex cases.\u003c/p\u003e \u003cp\u003eDistinct risk factors such as a higher use of vitamin K antagonists (e.g. warfarin) are associated with disease onset, supporting vitamin K deficiency as a key player in calciphylaxis pathogenesis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Vitamin K is involved in the activation of matrix G1a protein (MGP), which is an extracellular matrix protein produced in endothelial vascular smooth muscle cells and chondrocytes. MGP is also a potent inhibitor of calcification, so conditions associated with vitamin K deficiencies such as prolonged warfarin use, liver disease, gastric bypass, malnutrition, and obesity remove natural inhibitors of calcification [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In our patient, alcoholic liver disease, gastric sleeve surgery, and obesity are all coexisting conditions with features that potentially contribute to the mechanism of non-uremic calciphylaxis pathology.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case highlights the diagnostic complexity of non-uremic calciphylaxis, a potentially fatal condition, particularly in unlikely patients like this young African American woman without classic risk factors such as ESRD, significant mineral imbalance, or warfarin use. The patient\u0026rsquo;s delayed diagnosis, despite early biopsy and normal lab parameters, underscores the limitations of current diagnostic tools and the need for persistent clinical suspicion of calciphylaxis in atypical presentations of necrotic ulcers. Her comorbidities (alcoholic cirrhosis, obesity, peripheral artery disease, and prior nutrient deficiencies) may have contributed to vascular calcification, though their exact roles are unclear but may lead to MGP inactivation. As non-uremic calciphylaxis becomes increasingly recognized, this case reinforces the need for multidisciplinary evaluations, repeated biopsies when clinical suspicion persists, and individualized management strategies to improve outcomes in underrepresented patient populations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe patient consented to publish their clinical case.\u003c/p\u003e\u003cp\u003eNo funds, grants, or other support was received. The authors have no relevant financial or non-financial interests to disclose. The authors have no competing interests to declare that are relevant to the content of this article.\u003c/p\u003e\u003cp\u003eFunding:\u003c/h2\u003e No funds, grants, or other support was received.\u003c/p\u003e \u003cp\u003eCompeting interest: The authors have no relevant financial or non-financial interests to disclose. The authors have no competing interests to declare that are relevant to the content of this article.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eA.K. and B.K. wrote the main manuscript text. All authors reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNigwekar SU, Thadhani R, Brandenburg VM, Calciphylaxis. 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Published 2021 Dec 3.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"non-uremic calciphylaxis, calciphylaxis, non-healing wounds, ulcers","lastPublishedDoi":"10.21203/rs.3.rs-6752050/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6752050/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCalciphylaxis is a rare and often fatal condition most commonly associated with end-stage renal disease (ESRD). However, non-uremic calciphylaxis (NUC), occurring in the absence of severe renal dysfunction, remains a diagnostic challenge due to its rarity and nonspecific presentation. We report a rare case of non-uremic calciphylaxis in a 43-year-old African American woman with a history of alcoholic liver cirrhosis, an unusual presentation given her demographics and past medical history, which are not widely represented in the calciphylaxis literature. Further skewing the diagnostic challenge, initial skin biopsy ruled out calciphylaxis. The diagnostic complexity and risk of delayed treatment in such atypical presentations underscore the need for heightened clinical vigilance, especially in underrepresented populations. This case highlights the importance of considering NUC in the differential diagnosis of painful skin lesions, even in patients without traditional risk factors.\u003c/p\u003e","manuscriptTitle":"Delayed diagnosis of non-uremic calciphylaxis in an unlikely patient","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-05 08:58:36","doi":"10.21203/rs.3.rs-6752050/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3cbac117-9f7a-4e0b-af20-36582244fd1a","owner":[],"postedDate":"June 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-05T08:58:36+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-05 08:58:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6752050","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6752050","identity":"rs-6752050","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}