Calciphylaxis and Kidney Disease: A Review

Calciphylaxis is a life-threatening complication most often associated with chronic kidney disease that occurs as a result of the deposition of calcium in dermal and adipose microvasculature. However, this condition may also be seen in patients with acute kidney injury. The high morbidity and mortality rates associated with calciphylaxis highlight the importance to correctly diagnose and treat this condition. However, calciphylaxis remains a diagnosis that may be clinically challenging to make. Here, we review the literature on uremic calciphylaxis with a focus on its pathophysiology, clinical presentation, advances in diagnostic tools, and treatment strategies. We also discuss the unique histopathological features of calciphylaxis and contrast it with those of other forms of general vessel calcification. This review emphasizes the need for multidisciplinary collaboration including nephrology, dermatology, and palliative care to ultimately provide the best possible care to patients with calciphylaxis. Calciphylaxis is a life-threatening complication most often associated with chronic kidney disease that occurs as a result of the deposition of calcium in dermal and adipose microvasculature. However, this condition may also be seen in patients with acute kidney injury. The high morbidity and mortality rates associated with calciphylaxis highlight the importance to correctly diagnose and treat this condition. However, calciphylaxis remains a diagnosis that may be clinically challenging to make. Here, we review the literature on uremic calciphylaxis with a focus on its pathophysiology, clinical presentation, advances in diagnostic tools, and treatment strategies. We also discuss the unique histopathological features of calciphylaxis and contrast it with those of other forms of general vessel calcification. This review emphasizes the need for multidisciplinary collaboration including nephrology, dermatology, and palliative care to ultimately provide the best possible care to patients with calciphylaxis. A middle-aged man with cirrhosis secondary to alcohol-related liver disease was admitted for sepsis in the setting of pneumonia. His clinical course was complicated by acute kidney injury due to hypotension-induced acute tubular necrosis, for which he received hemodialysis for 2 weeks. Despite initial renal recovery, the patient’s course was complicated again by acute kidney injury due to acute interstitial nephritis in the setting of vancomycin, requiring dialysis for 5 more days along with high-dose systemic steroids. Kidney function recovered, and the patient was discharged to a rehabilitation facility before returning home. Within 1 week of the patient returning home, rapidly expanding, painful plaques of retiform purpura of the bilateral proximal thighs developed. Cutaneous punch biopsy confirmed the diagnosis of calciphylaxis. Calciphylaxis, also referred to as calcific uremic arteriolopathy, is a rare life-threatening vasculopathy that results from the deposition of calcium in the arteriolar microvasculature of the deep dermis and subcutaneous adipose tissue.1Nigwekar S.U. Thadhani R. Brandenburg V.M. Calciphylaxis.N Engl J Med. 2018; 378: 1704-1714https://doi.org/10.1056/NEJMra1505292Crossref PubMed Scopus (252) Google Scholar Painful evolving lesions of livedo reticularis, livedo racemosa, and retiform purpura signify progressive cutaneous necrosis (Fig 1). Sepsis from infection of cutaneous wounds is the leading cause of death in patients with calciphylaxis.2Weenig R.H. Sewell L.D. Davis M.D.P. McCarthy J.T. Pittelkow M.R. Calciphylaxis: natural history, risk factor analysis, and outcome.J Am Acad Dermatol. 2007; 56: 569-579https://doi.org/10.1016/j.jaad.2006.08.065Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar Calciphylaxis has a high risk of mortality; 1-year mortality rates are widely variable, ranging from 45% to 80%.2Weenig R.H. Sewell L.D. Davis M.D.P. McCarthy J.T. Pittelkow M.R. Calciphylaxis: natural history, risk factor analysis, and outcome.J Am Acad Dermatol. 2007; 56: 569-579https://doi.org/10.1016/j.jaad.2006.08.065Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar Calciphylaxis is classically associated with chronic kidney disease (CKD), particularly kidney failure treated with maintenance dialysis (referred to herein as end-stage kidney disease [ESKD]).3O’Keeffe C. Barbosa E. O’Kane M. Biopsy-proven calciphylaxis in the Irish National Kidney Transplant Center 2010-2019.Int J Dermatol. 2021; 60: 901-903https://doi.org/10.1111/ijd.15516Crossref PubMed Scopus (1) Google Scholar, 4McCarthy J.T. El-Azhary R.A. Patzelt M.T. et al.Survival, risk factors, and effect of treatment in 101 patients with calciphylaxis.Mayo Clin Proc. 2016; 91: 1384-1394https://doi.org/10.1016/j.mayocp.2016.06.025Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 5Markova A. Lester J. Wang J. Robinson-Bostom L. Diagnosis of common dermopathies in dialysis patients: a review and update.Semin Dial. 2012; 25: 408-418https://doi.org/10.1111/j.1525-139x.2012.01109.xCrossref PubMed Google Scholar The largest nationwide study to date estimates an incidence rate of 3.49 per 1,000 patient-years among patients receiving maintenance hemodialysis.6Nigwekar S.U. Zhao S. Wenger J. et al.A nationally representative study of calcific uremic arteriolopathy risk factors.J Am Soc Nephrol. 2016; 27: 3421-3429https://doi.org/10.1681/ASN.2015091065Crossref PubMed Scopus (147) Google Scholar The incidence of calciphylaxis in this population has increased in the past decade.7Nigwekar S.U. Solid C.A. Ankers E. et al.Quantifying a rare disease in administrative data: the example of calciphylaxis.J Gen Intern Med. 2014; 29: S724-S731https://doi.org/10.1007/s11606-014-2910-1Crossref PubMed Scopus (68) Google Scholar In the setting of impaired kidney function, decreased synthesis of vitamin D along with compromised calcium reabsorption and phosphate excretion results in secondary hyperparathyroidism, which promotes bone remodeling, thereby increasing serum calcium levels and facilitating arteriolar microcalcification. Calciphylaxis may develop in patients with CKD despite normal serum calcium and phosphate parameters.8Gallimore G.G. Curtis B. Smith A. Benca M. Curious case of calciphylaxis leading to acute mitral regurgitation.BMJ Case Rep. 2014; 2014https://doi.org/10.1136/bcr-2013-201803Crossref PubMed Scopus (6) Google Scholar Interestingly, polymorphism in vitamin D receptors has also been implicated in this syndrome.9Rothe H. Brandenburg V. Haun M. et al.Ecto-5’-nucleotidase CD73 (NT5E), vitamin D receptor and FGF23 gene polymorphisms may play a role in the development of calcific uremic arteriolopathy in dialysis patients - data from the German Calciphylaxis Registry.PloS One. 2017; 12e0172407https://doi.org/10.1371/journal.pone.0172407Crossref Scopus (17) Google Scholar Calciphylaxis with concurrent nephrogenic fibrosing dermopathy has been reported in a patient receiving maintenance dialysis.10Lewis K.G. Lester B.W. Pan T.D. Robinson-Bostom L. Nephrogenic fibrosing dermopathy and calciphylaxis with pseudoxanthoma elasticum-like changes.J Cutan Pathol. 2006; 33: 695-700https://doi.org/10.1111/j.1600-0560.2006.00490.xCrossref PubMed Scopus (45) Google Scholar In addition to ESKD, other notable risk factors for calciphylaxis include obesity, diabetes mellitus, female sex, hyperparathyroidism, warfarin, corticosteroids, vitamin K deficiency, vitamin D deficiency, hypoalbuminemia, protein C and S deficiencies, Crohn disease, autoimmune disorders, substantial weight loss, recurrent hypotension, and malignant neoplasms (cholangiocarcinoma, hematologic malignancies, and melanoma).1Nigwekar S.U. Thadhani R. Brandenburg V.M. Calciphylaxis.N Engl J Med. 2018; 378: 1704-1714https://doi.org/10.1056/NEJMra1505292Crossref PubMed Scopus (252) Google Scholar Although uremic calciphylaxis has predominantly been linked to ESKD, recent case reports suggest that this rare depositional vasculopathy may appear in the context of early kidney injury, including acute kidney injury.11Afridi S.M. Raja A. Zhou X. Jain A. Calciphylaxis due to metastatic well-differentiated neuroendocrine carcinoma.BMJ Case Rep. 2019; 12https://doi.org/10.1136/bcr-2019-230951Crossref PubMed Scopus (1) Google Scholar, 12Nseir V. Bradauskaite G. Pedroza M. Minimo C. Zaki R. Chewaproug D. A rare case of calciphylaxis in an orthotopic liver transplant recipient with acute kidney injury.Exp Clin Transplant. 2021; 19: 382-385https://doi.org/10.6002/ect.2017.0123Crossref PubMed Scopus (2) Google Scholar, 13Honda Y. Endo Y. Tanizaki H. et al.Calciphylaxis associated with acute renal failure in multicentric Castleman’s disease.Eur J Dermatol. 2015; 25: 497-499https://doi.org/10.1684/ejd.2015.2627Crossref PubMed Scopus (5) Google Scholar, 14Russell R. Omer W. Mudabal N. Wanat K.A. Calciphylaxis in a young adult with acute kidney injury and recently diagnosed end-stage liver disease.Am J Med Case Rep. 2021; 9: 544-547https://doi.org/10.12691/ajmcr-9-11-7Crossref Google Scholar, 15Zakher M. Chaudhry R.I. Monrroy M. et al.Clinical characteristics and outcomes of patients with calciphylaxis.Am J Med Sci. 2021; 361: 132-134https://doi.org/10.1016/j.amjms.2020.07.017Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 16Ababneh E.I. Hassanein M. Saad A.M. et al.Calciphylaxis in uraemic and nonuraemic settings: clinical risk factors and histopathological findings.Clin Exp Dermatol. 2022; 47: 700-708https://doi.org/10.1111/ced.15009Crossref PubMed Scopus (1) Google Scholar A case report described the bilateral appearance of calciphylaxis in the thighs of a woman 3 months after she experienced painless hematuria and nephrotic-range proteinuria in the setting of anti–glomerular basement membrane antibody disease.17Shahzad S.R. Alfaris F. Arslan M.E. Mehta S. Early onset calciphylaxis following acute kidney injury secondary to anti-glomerular basement membrane antibody disease.BMJ Case Rep. 2021; 14e241265https://doi.org/10.1136/bcr-2020-241265Crossref Scopus (1) Google Scholar Furthermore, a population of nonuremic (nontraditional) patients may experience calciphylaxis despite normal kidney and parathyroid function.18Kalajian A.H. Malhotra P.S. Callen J.P. Parker L.P. Calciphylaxis with normal renal and parathyroid function: not as rare as previously believed.Arch Dermatol. 2009; 145: 451-458https://doi.org/10.1001/archdermatol.2008.602Crossref PubMed Scopus (98) Google Scholar,19Gabel C.K. Nguyen E.D. Chakrala T. et al.Assessment of outcomes of calciphylaxis.J Am Acad Dermatol. 2021; 85: 1057-1064https://doi.org/10.1016/j.jaad.2020.10.067Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Nonnephrogenic calciphylaxis is associated with decreased mortality compared with uremic calciphylaxis.19Gabel C.K. Nguyen E.D. Chakrala T. et al.Assessment of outcomes of calciphylaxis.J Am Acad Dermatol. 2021; 85: 1057-1064https://doi.org/10.1016/j.jaad.2020.10.067Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar The specific pathogenesis of calciphylaxis remains to be fully elucidated. A retrospective study of 36 patients employed spectroscopy to demonstrate that vascular wall depositions in calciphylaxis are exclusively composed of calcium apatite and organized circumferentially in small and medium-sized arteries, suggesting a pathophysiology distinct from that of atherosclerosis.20Colboc H. Moguelet P. Bazin D. et al.Localization, morphologic features, and chemical composition of calciphylaxis-related skin deposits in patients with calcific uremic arteriolopathy.JAMA Dermatol. 2019; 155: 789-796https://doi.org/10.1001/jamadermatol.2019.0381Crossref PubMed Scopus (28) Google Scholar Although microvascular calcification is regarded as the main driver of pathogenesis, aberrant adipocyte proinflammatory cytokine signaling and recurrent vascular endothelial injury may also play roles.21Chen N.X. O’Neill K. Akl N.K. Moe S.M. Adipocyte induced arterial calcification is prevented with sodium thiosulfate.Biochem Biophys Res Commun. 2014; 449: 151-156https://doi.org/10.1016/j.bbrc.2014.05.005Crossref PubMed Scopus (49) Google Scholar,22Weenig R.H. Pathogenesis of calciphylaxis: Hans Selye to nuclear factor kappa-B.J Am Acad Dermatol. 2008; 58: 458-471https://doi.org/10.1016/j.jaad.2007.12.006Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar The notion that hypercoagulable states are important in the pathogenesis of calciphylaxis has been well described.23Harris R.J. Cropley T.G. Possible role of hypercoagulability in calciphylaxis: review of the literature.J Am Acad Dermatol. 2011; 64: 405-412https://doi.org/10.1016/j.jaad.2009.12.007Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar A matched case-control study of 152 individuals with CKD identified that the presence of lupus anticoagulant, protein C deficiency, and combined thrombophilias were significantly associated with calciphylaxis.24Dobry A.S. Ko L.N. St John J. Sloan J.M. Nigwekar S. Kroshinsky D. Association between hypercoagulable conditions and calciphylaxis in patients with renal disease: a case-control study.JAMA Dermatol. 2018; 154: 182-187https://doi.org/10.1001/jamadermatol.2017.4920Crossref PubMed Scopus (40) Google Scholar Furthermore, subsequent microvascular thrombosis may explain the characteristic exquisitely tender nature of calciphylaxis, as the presence of fibrin thrombi in skin biopsies has been associated with clinical pain severity.25Dutta P. Chaudet K.M. Nazarian R.M. Kroshinsky D. Nigwekar S.U. Correlation between clinical and pathological features of cutaneous calciphylaxis.PloS One. 2019; 14e0218155https://doi.org/10.1371/journal.pone.0218155Crossref Scopus (12) Google Scholar Aberrations in molecular mediators that normally inhibit microvascular calcification have been implicated in the pathogenesis of calciphylaxis. For example, carboxylated matrix G1a protein (MGP) is an extracellular matrix peptide produced by vascular and endothelial cells that directly inhibits calcification.1Nigwekar S.U. Thadhani R. Brandenburg V.M. Calciphylaxis.N Engl J Med. 2018; 378: 1704-1714https://doi.org/10.1056/NEJMra1505292Crossref PubMed Scopus (252) Google Scholar Fetuin A and pyrophosphate are additional inhibitors of calcification whose expression is decreased in CKD and calciphylaxis.1Nigwekar S.U. Thadhani R. Brandenburg V.M. Calciphylaxis.N Engl J Med. 2018; 378: 1704-1714https://doi.org/10.1056/NEJMra1505292Crossref PubMed Scopus (252) Google Scholar Ultimately, low levels of MGP, fetuin A, and pyrophosphate result in a favorable environment for calcification to occur. Cutaneous examination of patients with calciphylaxis typically reveals exquisitely painful retiform purpura or tender nodules. Tender induration, hyperpigmented plaques, and hemorrhagic bullae are also reported (Fig 2).1Nigwekar S.U. Thadhani R. Brandenburg V.M. Calciphylaxis.N Engl J Med. 2018; 378: 1704-1714https://doi.org/10.1056/NEJMra1505292Crossref PubMed Scopus (252) Google Scholar,2Weenig R.H. Sewell L.D. Davis M.D.P. McCarthy J.T. Pittelkow M.R. Calciphylaxis: natural history, risk factor analysis, and outcome.J Am Acad Dermatol. 2007; 56: 569-579https://doi.org/10.1016/j.jaad.2006.08.065Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar Retiform purpura presents as nonblanching purpuric or hyperpigmented patches with stellate borders and may be preceded by livedo reticularis (blanching, netlike, reticulated pink patches) or livedo racemosa (nonblanching violaceous to dusky branching patches with a broken-net appearance). Although most commonly seen on the abdomen and proximal lower extremities, calciphylaxis has been reported in relatively uncommon sites, including the penis, breasts, and digits.26Smilnak G. Jiang M. Jain B. Calciphylaxis of the penis and distal digits: a case report.J Med Case Rep. 2022; 16: 18https://doi.org/10.1186/s13256-021-03231-4Crossref PubMed Scopus (3) Google Scholar, 27Kawai Y. Banshodani M. Moriishi M. et al.Penile calciphylaxis in patients with end-stage kidney disease undergoing dialysis: invasive treatment and pain management. Ther Apher Dial. Published online January 5, 2022.doi:10.1111/1744-9987.13789Google Scholar, 28Elghobashy M. Vaquas S. Elshafie M. Kaneri S. Shaaban A.M. Unusual presentation of mammary calciphylaxis in a patient on long-standing renal dialysis.Pathobiology. 2020; 87: 317-321https://doi.org/10.1159/000508537Crossref PubMed Scopus (3) Google Scholar, 29Nisar U.S. Cheville J.C. Sturgis C.D. Images - penile pain in the setting of end-stage renal disease: an unusual anatomic location for calciphylaxis. Can Urol Assoc J. 16(5):E304–E305.doi:10.5489/cuaj.7618Google Scholar, 30Harada K. Araki J. Tokumasu K. Hagiya H. Otsuka F. Calciphylaxis of the fingers.J Gen Fam Med. 2020; 21: 25-26https://doi.org/10.1002/jgf2.296Crossref PubMed Scopus (2) Google Scholar The presence of ulceration is associated with an increased mortality rate (Fig 3).31Fine A. Zacharias J. Calciphylaxis is usually non-ulcerating: risk factors, outcome and therapy.Kidney Int. 2002; 61: 2210-2217https://doi.org/10.1046/j.1523-1755.2002.00375.xAbstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar Visceral calciphylaxis without primary cutaneous manifestations has also been reported, such as in mesenteric and colonic arteries.32Tan R.Y.P. Juneja R. Gunawardane D.N. Milton C.A. Isolated mesenteric calciphylaxis with ischemic colitis in a hemodialysis patient without active cutaneous calciphylaxis: a case report of calcific uremic arteriolopathy.Kidney Med. 2020; 2: 209-212https://doi.org/10.1016/j.xkme.2019.12.005Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar,33Mitchell T.A. Hoffer Z.S. Cancio L.C. Extracutaneous manifestations of calciphylaxis: Ogilvie’s syndrome with perforation.Am Surg. 2020; 86: 546-548https://doi.org/10.1177/0003134820919736Crossref PubMed Scopus (1) Google Scholar A recent retrospective chart review of 145 patients identified that, in 22 patients, the first calciphylaxis lesions appeared in areas of previous trauma, including direct injury from hitting an object (n = 4), abrasions (n = 3), insulin injections (n = 3), mechanical falls (n = 3), toe clipping or stubbed toe (n = 2), catheter placement (n = 1), and peritoneal dialysis catheter removal (n = 1).34Gabel C.K. Chakrala T. Dobry A.S. et al.The Koebner phenomenon may contribute to the development of calciphylaxis: a case series.JAAD Case Rep. 2021; 13: 57-61https://doi.org/10.1016/j.jdcr.2021.04.016Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar These findings support the hypothesis that calciphylaxis may be associated with the Koebner phenomenon (“Koebnerization”), a phenomenon in which dermatologic lesions emerge in areas of cutaneous trauma in otherwise intact skin. At least one case report has described calciphylaxis in a recent surgical site, consistent with the hypothesis that Koebnerization may be an important risk factor.35Bretschneider H. Helbig S. Kleber C. de With K. Stiehler M. Mimicry of surgical site infection - case report.Int J Surg Case Rep. 2020; 72: 212-214https://doi.org/10.1016/j.ijscr.2020.05.034Crossref PubMed Scopus (1) Google ScholarFigure 3Hyperpigmented retiform patches and erosions in a patient with punch biopsy–proven calciphylaxis after 4 weeks of intravenous sodium thiosulfate; the patient had hepatorenal syndrome and had initially presented with painful ulcerating nodules.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The diagnosis of calciphylaxis may be challenging. In patients with kidney disease, there should be high clinical suspicion of calciphylaxis after the appearance of painful nodules, indurated plaques, dusky livedoid plaques, and/or nonblanching retiform purpura. Calciphylaxis should still be suspected even if such lesions appear in sites other than the abdomen and lower extremities. Of note, retiform purpura is a cutaneous morphology that commands a broad differential; clinicopathologic correlation and judicious workup is necessary to rule out clinical mimickers.36Georgesen C. Fox L.P. Harp J. Retiform purpura: a diagnostic approach.J Am Acad Dermatol. 2020; 82: 783-796https://doi.org/10.1016/j.jaad.2019.07.112Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar In one retrospective study of 119 patients, there was a misdiagnosis rate of approximately 73% in patients with calciphylaxis.37Gabel C.K. Blum A.E. François J. et al.Clinical mimickers of calciphylaxis: a retrospective study.J Am Acad Dermatol. 2021; 85: 1520-1527https://doi.org/10.1016/j.jaad.2021.03.035Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The most frequent initial diagnoses were cellulitis (31.0%), unspecified skin infection (8.0%), and peripheral vascular disease (6.9%).37Gabel C.K. Blum A.E. François J. et al.Clinical mimickers of calciphylaxis: a retrospective study.J Am Acad Dermatol. 2021; 85: 1520-1527https://doi.org/10.1016/j.jaad.2021.03.035Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar However, patients with ESKD were less likely to be misdiagnosed on initial presentation (P = 0.01), suggesting that the classical association between ESKD and calciphylaxis may prime providers to maintain calciphylaxis higher in their differential diagnosis in these cases compared with situations in which there is no known kidney disease.37Gabel C.K. Blum A.E. François J. et al.Clinical mimickers of calciphylaxis: a retrospective study.J Am Acad Dermatol. 2021; 85: 1520-1527https://doi.org/10.1016/j.jaad.2021.03.035Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Other mimickers of calciphylaxis exist, including diffuse dermal angiomatosis, which may manifest as pink or hyperpigmented patches, retiform purpura, or ulceration in patients with ESKD.38Ayoubi N. Francois R.A. Braswell D.S. Ramos-Caro F.A. Motaparthi K. Diffuse dermal angiomatosis with clinical features simulating calciphylaxis in the setting of end-stage renal disease.JAAD Case Rep. 2020; 6: 826-828https://doi.org/10.1016/j.jdcr.2020.06.041Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Skin biopsy may be useful in the diagnosis of calciphylaxis. The relationship between the Koebner phenomenon and calciphylaxis highlights the importance of obtaining a punch biopsy in these patients. Punch biopsy rather than excisional biopsy is recommended to avoid nonhealing wounds even though it may not yield adequate tissue depth (Fig 4).39Bahrani E. Perkins I.U. North J.P. Diagnosing calciphylaxis: a review with emphasis on histopathology.Am J Dermatopathol. 2020; 42: 471-480https://doi.org/10.1097/DAD.0000000000001526Crossref PubMed Scopus (13) Google Scholar A telescoping punch biopsy (performing a second biopsy with a small punch biopsy tool that passes through the original defect to sample deeper adipose tissue) may allow for greater depth to be reached while minimizing further tissue traumatization. Even if a negative punch biopsy result is obtained, empirical treatment with sodium thiosulfate is still recommended if clinical suspicion is high in view of the mortality associated with this condition. Histopathologic findings may be subtle, and special staining (von Kossa) may aid in identifying stippled calcifications of small subcuticular vessels.40Mochel M.C. Arakaki R.Y. Wang G. Kroshinsky D. Hoang M.P. Cutaneous calciphylaxis: a retrospective histopathologic evaluation.Am J Dermatopathol. 2013; 35: 582-586https://doi.org/10.1097/DAD.0b013e31827c7f5dCrossref PubMed Scopus (85) Google Scholar On histopathology, calciphylaxis is characterized by calcification of small vessels (<100 μm) in the deep dermis and subcutaneous tissue, along with fibrin thrombin and, occasionally, evidence of ischemic epidermal and dermal necrosis. These findings are distinct from other forms of vessel calcification. For example, Mönckeberg’s sclerosis presents with medial calcification of small and medium-sized vessels that reduce vessel caliber, but there is no overlying epidermal or dermal necrosis. In classical atherosclerosis, intimal and subintimal lipid deposits and calcifications without skin necrosis are the dominant hallmarks. Diffuse dermal angiomatosis is a biopsy finding that may be seen in multiple clinical settings, including peripheral arterial disease, arteriovenous fistulas, macromastia, or calciphylaxis, and identification of diffuse dermal angiomatosis should raise suspicion for occult calciphylaxis. In the setting of calciphylaxis, diffuse dermal angiomatosis is more common in Black patients or patients with congestive heart failure, but it does not have any prognostic value.41O’Connor H.M. Wu Q. Lauzon S.D. Forcucci J.A. Diffuse dermal angiomatosis associated with calciphylaxis: A 5-year retrospective institutional review.J Cutan Pathol. 2020; 47: 27-30https://doi.org/10.1111/cup.13585Crossref PubMed Scopus (10) Google Scholar The role of imaging in the diagnosis of calciphylaxis has garnered attention, particularly when biopsy studies are inconclusive or invasive procedures are not possible.42Halasz C.L. Munger D.P. Frimmer H. Dicorato M. Wainwright S. Calciphylaxis: comparison of radiologic imaging and histopathology.J Am Acad Dermatol. 2017; 77: 241-246.e3https://doi.org/10.1016/j.jaad.2017.01.040Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 43Burdorf B.T. Calciphylaxis: The potential diagnostic role of radiologists.Radiol Case Rep. 2021; 16: 415-418https://doi.org/10.1016/j.radcr.2020.11.033Crossref PubMed Scopus (2) Google Scholar, 44Alniemi D.T. Kanner C. Stowman A.M. et al.Diagnosing calciphylaxis: a series of cases with both imaging and tissue biopsy.J Am Acad Dermatol. 2020; 24: 8-10https://doi.org/10.1016/j.jaad.2020.05.111Abstract Full Text PDF Scopus (3) Google Scholar Plain radiographic findings that have been associated with calciphylaxis include the presence of small-vessel calcification and a netlike pattern of calcification. Of these, one study found that, whereas the presence of vascular calcification had the highest sensitivity for calciphylaxis (89.2% [95% CI, 73.0%-100%]), a netlike pattern of calcification exhibited the greatest specificity (89.9% [95% CI, 82.7%-97%]).28Elghobashy M. Vaquas S. Elshafie M. Kaneri S. Shaaban A.M. Unusual presentation of mammary calciphylaxis in a patient on long-standing renal dialysis.Pathobiology. 2020; 87: 317-321https://doi.org/10.1159/000508537Crossref PubMed Scopus (3) Google Scholar,45Shmidt E. Murthy N.S. Knudsen J.M. et al.Net-like pattern of calcification on plain soft-tissue radiographs in patients with calciphylaxis.J Am Acad Dermatol. 2012; 67: 1296-1301https://doi.org/10.1016/j.jaad.2012.05.037Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Point-of-care ultrasound may also aid in diagnosis. Sonographic characteristics that have been associated with calciphylaxis include the presence of thin hyperechoic bands parallel to the epidermal surface, leading to a strong posterior acoustic shadow; hyperechoic spots with a narrow acoustic window; and linear hyperechoic bands parallel to the walls of a blood vessel with a narrow acoustic shadow.46Gamissans M. Giavedoni P. Roe E. et al.Multicentric study on high-frequency ultrasound characterization of calcium deposits in dermal and subcutaneous calciphylaxis and calcinosis.J Ultrasound Med. 2022; 41: 1975-1979https://doi.org/10.1002/jum.15878Crossref PubMed Scopus (1) Google Scholar,47Rosen R.J. Fernandez H.E. Shirazian S. Moses A.A. 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Calciphylaxis of the breast, mimicking advanced breast cancer with skin involvement.Radiol Case Rep. 2021; 16: 1211-1215https://doi.org/10.1016/j.radcr.2021.02.040Crossref PubMed Scopus (2) Google Scholar One study developed a radiomics-based method with computed tomography scanning and demonstrated a sensitivity and specificity of 0.89 and 0.80, respectively, in the diagnosis of calciphylaxis.51Yu Q. Liu Y. Xie X. et al.Radiomics-based method for diagnosis of calciphylaxis in patients with chronic kidney disease using computed tomography.Quant Imaging Med Surg. 2021; 11: 4617-4626https://doi.org/10.21037/qims-20-1211Crossref PubMed Scopus (7) Google Scholar Therefore, there may be a role for advanced radiographic methods and machine learning to result in quick and reliable diagnoses. The predictive value of serum markers such as serum calcium, phosphate, parathyroid hormone, and albumin levels in the development of calciphylaxis remains an important question.6Nigwekar S.U. Zhao S. Wenger J. et al.A nationally representative study of calcific uremic arteriolopathy risk factors.J Am Soc Nephrol. 2016; 27: 3421-3429https://doi.org/1