Common Histological Features Suggesting Enchondral Ossification Pathways in Calciphylaxis of Various Origins: A Study of Human Subcutaneous Tissue Biopsies.

Calciphylaxis is a rare, yet underdiagnosed condition causing high mortality in patients with severe renal and cardiovascular disease. Since knowledge of the pathophysiology of calciphylaxis is limited, a differential analysis of histological alterations in patient subgroups with various comorbidities might expose different disease phenotypes and allow deeper insights into the pathophysiology of the condition. Histological markers of osteogenesis and calcification were investigated in a group of 18 patients with clinically and histologically verified calciphylaxis, using immunohistochemical staining. Analysis of staining intensity and distribution of marker proteins in histological structures was performed to evaluate distinct patterns between subgroups with different clinical comorbidities in comparison with a control group. In all cases, immunohistochemical staining for bone matrix proteins, bone-morphogenic proteins and matrix-Gla proteins co-localized with subcutaneous vascular and interstitial calcifications. Significant expression of bone-morphogenic protein-7 and active matrix-Gla protein was observed. Mortality was associated with renal comorbidities and increased expression of bone-morphogenic protein-7. However, no distinct histological patterns were found between subgroups with renal disease, warfarin intake or coexisting micro- and macro-angiopathies. The upregulation of osteogenic markers (including bone-morphogenic protein-7) plays a major role in the development of calciphylaxis. Clinical outcome correlates with kidney function and phosphate handling, suggesting different pathophysiological mechanisms. However, biopsy  at late-stage disease shows a common histological phenotype, involving enchondral ossification.

Penile and digital calciphylaxis: A case report and literature review.

Calcific uremic arteriolopathy (CUA) represents a rare but severe disease with high morbimortality. The authors present the case of a 58-year-old male patient with chronic kidney disease due to obstructive uropathy, on hemodialysis (HD). He started HD due to uremic syndrome with a severe renal dysfunction, dysregulation of calcium and phosphate metabolism, and he presented with distal penile ischemia, which was treated with surgical debridement and hyperbaric oxygen therapy. Four months later, painful distal digital necrosis of both hands was observed. Extensive arterial calcification was observed on X-ray. A skin biopsy confirmed the presence of CUA. Sodium thiosulfate was administered for 3 months, HD was intensified, and hyperphosphatemia control was achieved, with progressive improvement of the lesions. This case illustrates an uncommon presentation of CUA in a patient on HD for a few months, non-diabetic and not anticoagulated, but with a severe dysregulation of calcium and phosphate metabolism.

Characterization of Risk Factors for Calciphylaxis in Hemodialysis Patients in the Fraser Health Renal Program - A Matched Case-Control Retrospective Review.

Introduction: Calciphylaxis is a lethal and rare disease characterized by ischemic and necrotic skin lesions caused by vascular calcification of adipose tissue. There have been many risk factors analyzed in the literature; however, the pathogenesis of calciphylaxis is still not well understood and treatment options are limited due to the lack of interventional studies. Our objectives were to describe risk factors, prevalence, incidence, and outcomes for calciphylaxis in hemodialysis patients within the Fraser Health Renal Program. Methods: This was a retrospective matched case-control study of hemodialysis patients within the Fraser Health Renal Program. Hemodialysis patients with calciphylaxis were matched to hemodialysis patients without calciphylaxis in a 1:2 ratio for age and sex from September 2, 2017 to July 3, 2020. Findings: There was a total of 40 calciphylaxis cases matched to 80 controls. In the univariate analysis, peritoneal dialysis, higher body mass index, lower serum iron, lower transferrin saturation, sevelamer, cinacalcet, warfarin, iron (PO), and insulin were associated with increased risk of calciphylaxis. In the multivariate analysis, only peritoneal dialysis, serum iron, sevelamer, and warfarin were identified as significant and strong risk factors associated with calciphylaxis. A low prevalence of 1.9% and high mortality rate of 57.5% at 12 months was found for calciphylaxis cases. Discussion: Significant risk factors associated with calciphylaxis were peritoneal dialysis, serum iron, sevelamer, and warfarin. Future studies should further investigate the impact of minimizing exposure to these risk factors to reduce calciphylaxis development.

When a Biopsy Is Inadequate in Diagnosing Calciphylaxis.

Calciphylaxis is a rare disease that typically presents in patients with end-stage renal disease and can be a diagnostic challenge. Calcium deposition with fibrin thrombi and necrosis of the overlying epidermis may support the diagnosis; however, depending on the stage of the disease, skin biopsy can have low sensitivity and specificity, and may be contraindicated in some situations. We discuss the utility of imaging studies in supporting the diagnosis of calciphylaxis. (SKINmed. 2022;20:450-451).

Identifying subcutaneous tissue microcalcification by Fluo-3 AM imaging in cutaneous calciphylaxis.

Calciphylaxis, also known as calcific uremic arteriolopathy (CUA), is typically characterized by subcutaneous tissue calcification and excruciatingly painful cutaneous lesions with high mortality. It is critical for dermatologists to make early diagnosis and appropriate management, yet currently only 56% of calciphylaxis cases are correctly diagnosed by conventional histological stain1. Specially, the identification of subtle calcium deposits of subcutaneous can be challenging but is believed crucial for early diagnosis of calciphylaxis2. More sensitive calcification staining is in high demand. In this study, Fluo-3 AM was found to be a rapid, sensitive and reliable fluorescent probe for the detection of calcium deposits and could be a promising diagnostic tool for calciphylaxis.

Cutaneous vascular calcification. Perieccrine calcification as a diagnostic key for calciphylaxis.

BACKGROUND: Attempts have been made to establish discriminative criteria between classic calciphylaxis (CPX) and those cases in which cutaneous vascular calcification (CVC) represents an incidental finding (epiphenomenon). METHODS: Retrospective, observational cohort study of patients with CVC to distinguish clinicopathological features between CVC as classic CPX (CVC in cutaneous lesions with erythematous-violaceous plaques with or without ulceration) or as an epiphenomenon (CVC in cutaneous lesions with known diagnosis). Different clinicopathological parameters and the presence of perieccrine calcification and pseudoxanthoma elasticum (PXE)-like changes were evaluated. RESULTS: Sixty-six patients were studied. The CPX group showed a significantly higher percentage of renal failure, hypertension, altered laboratory parameters, painful lesions, and mortality rate. Histopathologically, the CPX group was associated with more than one vessel per field involved with subintimal concentric calcification and perieccrine calcification (observed exclusively in the CPX group), while PXE-like changes, although more frequent in the CPX group, were also observed in the epiphenomenon group. CONCLUSION: Perieccrine calcification and the presence of more than one vessel per field involved by concentric pattern calcification could be used as a diagnostic marker of CPX. Although PXE-like changes are not an exclusive marker, they could suggest CPX diagnosis.

Calciphylaxis: Part I. Diagnosis and pathology.

Calciphylaxis is an uncommon but devastating disorder characterized by vascular calcification and subsequent cutaneous tissue necrosis. This results in exquisitely painful and slow healing wounds that portend exceptionally high morbidity and mortality. The diagnosis of this condition can be complicated because there are no conclusive serologic, radiographic or visual signs that this disease is manifesting. The differential of tissue necrosis is broad, and identifying calciphylaxis requires an adroit understanding of the risk factors and physical signs that should raise suspicion of this condition. Reviews on this subject are uncommon and lack directed commentary from disease experts on the best diagnostic approach for patients suffering from this disease. The goal of this article is to update practicing dermatologists on the current standard of care for calciphylaxis.

An unexpected case of non-uremic calciphylaxis in a patient with multiple risk factors.

A 58-year-old woman with a history of morbid obesity, asthma, and prior warfarin use presented to the hospital with shortness of breath and a three-month history of painful, ulcerated ulcers with retiform purpura of her bilateral distal extremities. A punch biopsy specimen demonstrated focal necrosis and hyalinization of the adipose tissue with subtle arteriolar calcium deposition, findings consistent with calciphylaxis. We discuss the presentation of non-uremic calciphylaxis and review the risk factors, pathophysiology, and interdisciplinary management approach of this rare disease.

Calcifilaxis de la arteria temporal simulando arteritis temporal / Calciphylaxis of the temporal artery simulating temporal arteritis

La calcifilaxis se caracteriza por una intensa deposición de calcio en pequeños vasos sanguíneos, piel y otros órganos, descripta principalmente en pacientes con insuficiencia renal crónica, trasplante renal o disfunción paratiroidea. Hasta la fecha, solo hay siete casos descriptos en la literatura de calcifilaxis que imita arteritis de células gigantes (ACG). En esta revisión presentamos el octavo caso documentado patológicamente.

Calciphylaxis is characterized by intense deposition of calcium in small blood vessels, skin, and other organs, described mainly in patients with chronic renal insufficiency, renal transplant of parathyroid dysfunction. To date, there are only seven cases described in literature of calciphylaxis mimicking giant cell arteritis (GCA). In this review, we present the eighth case pathologically documented.

Calcifilaxis: factores de riesgo y hallazgos histológicos en una serie de casos de un hospital terciario / Calciphylaxis: Risk Factors and Histologic Findings in a Case Series From a Tertiary Care Referral Hospital

En los últimos años se han producido importantes avances en el conocimiento de la calcifilaxis, al haberse identificado nuevos factores de riesgo para su desarrollo, y hallazgos histológicos que podrían ser de ayuda al diagnóstico. Nuestro propósito al realizar este estudio ha sido revisar retrospectivamente los casos de calcifilaxis atendidos en nuestro hospital en los últimos 13 años, con especial atención a los aspectos más novedosos de esta patología. Se incluyó un total de 16 pacientes, 62,5% mujeres, con edad media de 67,9 años. Entre los factores asociados destacaron, aparte de la enfermedad renal avanzada (75%), los tratamientos relacionados con el metabolismo fosfocálcico (75%) y la anticoagulación (62,5%), en su mayoría con fármacos antagonistas de la vitamina K. En el estudio histológico se hallaron alteraciones en las fibras elásticas solo en un 25% de las biopsias. Once de los pacientes han fallecido, siendo la sepsis la primera causa de muerte (AU)

Recent years have seen important advances in our understanding of calciphylaxis, especially regarding newly identified risk factors and histologic findings that may aid diagnosis. This retrospective study of cases of calciphylaxis treated in our hospital in the last 13 years focuses on newly revealed aspects of this disease. We describe 16 patients (62.5% women; mean age, 67.9 years). In addition to advanced kidney disease (in 75% of our patients), other factors associated with the presence of calciphylaxis were a history of treatments related to phosphorus and calcium metabolism (75%) and anticoagulation (62.5%), usually with vitamin-K antagonists. Histology showed alterations in elastic fibers in only 25% of the biopsy specimens. Eleven of the patients died: sepsis was most often the cause (AU)

Cutaneous calciphylaxis of the glans penis presenting as a gangrenous ulceration.

Report _Case Presentation X Photo Vignette _Letter Authors declare that the contents of this article are their own original unpublished findings. Title: Cutaneous calciphylaxis of the glans penis presenting as a gangrenous ulceration Authors: Marie Danset, Cécile Lesort, Denis Jullien, Jean Kanitakis Affiliations: Dermatology Department, Edouard Herriot Hospital, Hospices Civils de Lyon, Claude Bernard Lyon I University, Lyon, France Corresponding Author: Jean Kanitakis, Department of Dermatology, Edouard Herriot Hospital Group, 69437 Lyon Cedex 03, France, Tel: 33-472110301, Email: jean.kanitakis@univ-lyon1.fr Abstract: Calciphylaxis is a rare microvascular disorder causing necrotic skin ulcers. It is characterized by deposits of calcium within vascular walls but its precise pathogenesis remains poorly understood. A major risk factor is end-stage renal disease on dialysis. We report a 67-year-old man with calciphylaxis revealed by an unusual necrotic ulcer of the glans penis. The patient also presented with bilateral panniculitis of the thighs and a calf ulcer. All those lesions were painful, highlighting the value of pain as a diagnostic clue. Penile involvement of calciphylaxis is rare and biopsy is often avoided in this area. However, rapid diagnosis of calciphylaxis is important because early treatment has a better chance of being successful. Our patient's condition deteriorated rapidly with development of bilateral retinal artery occlusion and he died shortly thereafter. This case further highlights the fact that calciphylaxis is a systemic vascular disease with an ominous prognosis.

Multiorgan failure with fatal outcome after stem cell tourism.

BACKGROUND: Unproven stem cell treatments may involve serious health, personal, and financial considerations. Due to worldwide spread, illegal stem cell therapies have become a major public health problem. We have already witnessed numerous reports in the mass media of severe and occasionally even fatal outcomes after such therapies. However, there are only few scientifically documented cases in which the causality between stem cell therapy and side effects cannot be refuted. CASE PRESENTATION: Here we present a case report of a 48-year-old patient with serious side effects, including disseminated skin ulcers, hepatitis, and cardiomyopathy, with eventual fatal outcome following unproven stem cell treatment. CONCLUSIONS: The case of the patient presented here draws attention to the worst possible outcome of stem cell tourism. To effectively combat this issue, professionals and patients should be empowered with the right knowledge on possible side effects.

Microstructural comparative analysis of calcification patterns in calciphylaxis versus arteriolosclerotic ulcer of Martorell.

BACKGROUND: Calciphylaxis and the arteriolosclerotic ulcer of Martorell (ASUM) represent two entities of cutaneous calcific arteriolopathies. Their differential diagnosis can be challenging, given similarities in their clinical and histological presentation. Calcification patterns have been proposed as a possible discriminative histological criterion, however, a systematic microstructural comparative analysis is lacking. OBJECTIVES: The study aimed at a systematic comparative microstructural analysis of the calcification patterns in calciphylaxis versus ASUM. MATERIALS & METHODS: Skin biopsies of patients with leg ulcers due to calciphylaxis (20) and ASUM (69) diagnosed at three European wound care centres (Vienna, Bern, Zurich) were included. The extent of calcification, arteriolar calcification pattern and presence of extra-arteriolar calcification were assessed. RESULTS: All calciphylaxis and most ASUM patients (77%) presented with arteriolar calcification. Although the mean number of calcified vessels and the proportion of calcified area were significantly higher in calciphylaxis specimens (p = 0.003 and p = 0.0171), there was no significant difference in the pattern of arteriolar calcification (p = 0.177). Interestingly, extra-arteriolar calcification was detected in the majority of both calciphylaxis (93.3%) and ASUM samples (85.2%, p = 0.639). Notably, Alizarin Red S staining was superior to H&E for the detection of calcifications of both entities (p = 0.014 and p < 0.0001), and to von Kossa staining for ASUM samples (p = 0.0001). However, no differences could be observed between cases with uraemic and non-uraemic calciphylaxis or ulcerations located on the upper and lower leg. CONCLUSION: Our results indicate that extra-arteriolar calcification is not only present in calciphylaxis, but can also be detected in ASUM suggesting a lack of specificity for this finding. However, more specific calcification stains, such as Alizarin Red S, should be used in suspected cases, as calcifications may be overlooked using conventional H&E staining.

Calciphylaxis: how specific are the pathological features: avoiding false-positives and false-negatives.

Calciphylaxis is considered a critical inflammatory dermatosis with potentially devastating clinical consequences. Skin biopsies are expedited for evaluation and are often considered as a gold standard for diagnostic confirmation and exclusion of other conditions. The key histopathological features include a combination of vascular and extra-vascular calcifications, intravascular microthrombi, and changes related to resulting ischemia. The pathological diagnosis of calciphylaxis is not always a straightforward process as it can be influenced by a number of factors. The specificity of pathological diagnosis of calciphylaxis has been questioned and a systematic approach with multidisciplinary collaboration is required to avoid potential errors.