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Calciphylaxis is a life-threatening disorder characterized by occlusion of microvessels in the subcutaneous adipose tissue and dermis. The authors outline the current understanding of calciphylaxis and provide a framework for interdisciplinary management.

Calciphylaxis is a rare but life-threatening disorder characterized by ectopic calcification affecting the subcutaneous tissues and blood vessels of the skin. Survival rates are less than a year after diagnosis, and yet despite the severity of the condition, the pathobiology of calciphylaxis is ill understood. Here, we created animal models of calciphylaxis that recapitulated many characteristics of the human phenotype. We demonstrate that cutaneous calcification is preceded by inflammatory cell infiltration. We show that increased local skin inflammation, regardless of the inciting cause, in the presence of hypercalcemia and hyperphosphatemia contributes to cutaneous ectopic calcification. Genetically modified rodents lacking immune activation of T and B cells or NK cells are resistant to developing cutaneous calcification. Consistent with this, administration of the immunosuppressive cyclophosphamide reduced calcific deposits, as did T cell suppression with cyclosporine. We demonstrate that IL-17 is upregulated in calcific skin and neutrophils are the predominant cell type expressing IL-17 and tissue-nonspecific alkaline phosphatase (TNAP) that are necessary for ectopic calcification. Targeting IL-17 with a monoclonal antibody or using a myeloperoxidase inhibitor to blunt neutrophil activation notably attenuated calcific deposits in vivo. Taken together, these observations provide fresh insight into the role of the immune system and the IL-17/neutrophil axis in mediating ectopic calcification in rodent models of calciphylaxis.

Calciphylaxis, also termed calcific uremic arteriolopathy (CUA) in patients with end-stage kidney disease (ESKD), is a rare and fatal condition characterized by cutaneous ischemic necrosis. Three patients with calciphylaxis and metastatic pulmonary calcification (MPC) were treated with human amnion-derived mesenchymal stem cells (hAMSCs). Effects were evaluated using the Visual Analogue Scale (VAS), modified Bates-Jensen Wound Assessment Tool for CUA (BWAT-CUA), wound quality of life questionnaire (Wound-QoL), and histological analysis. MPC was assessed by high-resolution CT (HRCT) and ᵐTc-methylene diphosphonate ( ᵐTc-MDP) bone scans. ᵐTc-labeled macroaggregated albumin ( ᵐTc-MAA) pulmonary perfusion imaging was conducted for the first time in patients with MPC. Three patients exhibited wound healing and improvement in skin symptoms. Two months before CUA, asymptomatic MPC was detected in Patient 1, who was treated with hAMSCs for 15 months. The condition progressed to chest pain and dyspnea. HRCT and ᵐTc-MDP bone scans showed worsening calcification, particularly in the upper and mid-thoracic lobes. ᵐTc-MAA pulmonary perfusion imaging revealed impaired or absent blood perfusion in the areas of metastatic calcification. Patient 1 died from respiratory failure. Patients 2 and 3 had asymptomatic MPC at calciphylaxis diagnosis. After 2 months of treatment, Patient 2, showed no significant imaging improvement and passed away 6 months after discontinuing hAMSC treatment. Patient 3 has shown no significant progression of pulmonary lesions and continues hAMSC therapy. We reported personalized early, noninvasive diagnosis and regenerative treatments for calciphylaxis patients with MPC. Although the current hAMSC treatment regimen is effective for skin lesions, its impact on MPC requires further investigation.

To define concomitant risk factors, treatment, and outcomes for patients with nonnephrogenic calciphylaxis (NNC). A retrospective review of Massachusetts General Hospital (MGH) medical records (January 1, 2014, through February 29, 2016) and a systematic literature review of PubMed, Google Scholar, EMBASE, MEDLINE, and CENTRAL (August 1, 1970, through July 31, 2016) were performed. Demographic characteristics and concomitant features were summarized and compared between patients with different lesion characteristics. Outcomes (lesion improvement and mortality) and their predictors were analyzed. Nine patients (median age, 72 years [interquartile range (IQR), 44-82 years]; 78% women; 89% white race) were identified through MGH records. The literature review identified 107 patients (median age, 60 years [IQR, 49-72 years]; 77% women; 86% white race). Vitamin K antagonism and obesity were the most common concomitant factors. In the literature review, lower age (P<.001) and higher body mass index (P=.03) were associated with the central location of lesions, whereas vitamin K antagonism was associated with the peripheral location (P=.009). In the MGH series, median survival was 24.0 months (95% CI, 7.8-36.0 months), and 33% (95% CI, 14%-60%) had lesion improvement by 6 months. In the literature review, median survival was 4.2 months (95% CI, 1.9-5.9 months), median time to lesion improvement was 5.9 months (95% CI, 3.9-8.9 months), and none of the treatments were associated with lesion improvement or survival. This description of concomitant traits may augment an earlier recognition of NNC. Future research is needed to investigate NNC pathogenesis and treatments.

Calciphylaxis is a rare and serious complication in patients with kidney disease. It has few treatment options and poor prognosis. Hyperbaric oxygen therapy (HBOT) may improve wound healing and was added to our conventional care in 2012. Data from all calciphylaxis patients treated from 2012 to 2022 were retrieved from hospital records. HBOT was added to our multidisciplinary care of calciphylaxis, which included sodium-thiosulphate, dialysis if indicated, medical optimization of calcium-phosphate homeostasis, substitution of vitamin K2, withdrawal of warfarin, iron and vitamin D, and minimization of systemic steroids. In addition, weight- and nutritional status was optimized, and wound care was thoroughly performed. 25 patients received a total number of 1,493 HBOT treatments in addition to conventional care in the study period. Median HBOT per patient was 45 (range 1 - 267). One year after diagnosis, 18 out of 25 patients were alive. 15 out of the 18 patients alive 1 year after diagnosis had completely resolved wound lesions. Seven patients died within the first year after diagnosis due to cardiovascular disease (n = 3), infection (n = 3), and cancer (n = 1). Our results suggest that HBOT is well-tolerated and may be associated with beneficial effects on survival and wound-healing when combined with multidisciplinary care.

Calciphylaxis is a rare but potentially fatal disease commonly occurred in dialysis patients. Despite some previous studies on risk factors for calciphylaxis, there is still a lack of data from Chinese population. The retrospective matched case-control study about calciphylaxis was performed in Zhongda Hospital affiliated to Southeast University. The case group involved 20 hemodialysis patients who were newly diagnosed with calciphylaxis from October 2017 to December 2018. The 40 noncalciphylaxis patients undergoing dialysis with the same age and duration of dialysis were randomly selected as controls. Most of calciphylaxis patients were male and elderly, while overweight people were more susceptible to the disease. Although incidence of secondary hyperparathyroidism was higher in calciphylaxis patients, the differences in duration of elevated serum intact parathyroid hormone (iPTH) and its highest value did not reach statistical significance compared with controls. No significant difference in warfarin therapy was discernible between two groups. The univariate regression analysis indicated that male, score of use of activated vitamin D and its analogues, corrected serum calcium level, serum phosphate, Ca × P product, iPTH, albumin, and alkaline phosphatase (ALP) level were significantly associated with calciphylaxis. Elevated levels of serum phosphate (OR 4.584, p = 0.027) and ALP (OR 1.179, p = 0.036), decreased level of serum albumin (OR 1.330, p = 0.013) were independent risk factors after multivariate analysis. This is the first report of risk factors associated with calciphylaxis in China. Increased levels of serum phosphate and ALP, decreased level of serum albumin were vital high-risk factors for calciphylaxis in Chinese hemodialysis population.

To report on the survival and the associations of treatments upon survival of patients with calciphylaxis seen at a single center. Using the International Classification of Diseases, Ninth Revision diagnosis code of 275.49 and the keyword “calciphylaxis” in the dismissal narrative, we retrospectively identified 101 patients with calciphylaxis seen at our institution between January 1, 1999, through September 20, 2014, using a predefined, consensus-developed classification scheme. The average age of patients was 60 years: 81 (80.2%) were women; 68 (68.0%) were obese; 19 (18.8%) had stage 0 to 2 chronic kidney disease (CKD), 19 (18.9%) had stage 3 or 4 CKD; 63 (62.4%) had stage 5 or 5D (dialysis) CKD. Seventy-five patients died during follow-up. Six-month survival was 57%. Lack of surgical debridement was associated with insignificantly lower 6-month survival (hazard ratio [HR]=1.99; 95% CI, 0.96-4.15; P=.07) and significantly poorer survival for the entire duration of follow-up (HR=1.98; 95% CI, 1.15-3.41; P=.01), which was most pronounced in stage 5 or 5D CKD (HR=1.91; 95% CI, 1.03-3.56; P=.04). Among patients with stage 5/5D CKD, subtotal parathyroidectomy (performed only in patients with hyperparathyroidism) was associated with better 6-month (HR=0.12; 95% CI, 0.02-0.90; P=.04) and overall survival (HR= 0.37; 95% CI, 0.15-0.87; P=.02). Calciphylaxis is associated with a high mortality rate. Significantly effective treatments included surgical debridement and subtotal parathyroidectomy in patients with stage 5/5D CKD with hyperparathyroidism. Treatments with tissue-plasminogen activator, sodium thiosulfate, and hyperbaric oxygen therapy were not associated with higher mortality.

PurposeTo perform a systematic review of case reports and case series to investigate risk factors, treatment modalities, and the outcome of penile calciphylaxis.MethodWe performed a systematic search of the MEDLINE and Scopus databases to identify case reports or case series of penile calciphylaxis. The patient characteristics, laboratory investigations, diagnostic modalities, treatment modalities, and outcomes were extracted. We compared clinical characteristics and treatment between patients who survived or demised and between patients with clinical improvement and those without to identify the poor prognostic risk factors.ResultsNinety-four articles were included from 86 case reports and 8 case series with 121 patients. Most of the patients were on hemodialysis (78.9%). The median time since starting dialysis was 48 months (24–96 months). Sodium thiosulfate was used to treat penile calciphylaxis in 23.6%. For surgical management, partial or total penectomy was performed in 45.5% of the patients. There was no association between sodium thiosulfate use, partial or total penectomy, and improvement in clinical outcomes. The mortality rate in patients with penile calciphylaxis was 47.8% and the median time to death was 3 months (0.75–9 months). The presence of extragenital involvement was significantly related to mortality (p = 0.03).ConclusionA calcified penile artery results in penile calciphylaxis, a rare vascular phenomenon associated with high morbidity and mortality. Management of penile calciphylaxis includes the medical management of risk factors, surgical debridement, or penectomy. Therefore, early prevention and diagnosis as well as immediate appropriate treatment are needed.

Calciphylaxis, also known as calcific uremic arteriolopathy and uremic small artery disease with medial wall calcification and intimal hyperplasia, is a multifactorial cutaneous vascular disease characterized by chronic, painful, non-healing wounds that occur frequently in patients with chronic kidney disease, predominantly in those with end-stage renal disease. The pathogenesis remains unclear, and the development of calciphylaxis lesions depends on medial calcification, intimal fibrosis of arterioles and thrombotic occlusion. Despite an increase in reports of calciphylaxis in the literature and clinical recognition of demographic characteristics and risk factors associated with calciphylaxis, it remains a poorly understood disease with high morbidity and mortality. In this review, we analyze and summarize the clinical manifestations, pathogenesis and pathophysiology, histopathology, differential diagnosis, diagnostic workup and treatment modalities for calciphylaxis. Because of the lack of consensus regarding the optimal approach to and treatment of this disorder, a high degree of clinical suspicion, early diagnosis, and multimodal and multidisciplinary treatment in collaboration with dermatology, nephrology, wound care, nutrition and pain management specialties may improve survival in patients with calciphylaxis.