RARE DISEASE
Calciphylaxis
Calciphylaxis
Calciphylaxis
Drug discovery
14
drugs
With orphan designations
Overview
Calciphylaxis is a rare, life-threatening vasculopathy characterized by calcification and thrombosis of dermal/subcutaneous arterioles, leading to ischemic tissue necrosis and painful ulcerations. Predominantly seen in end-stage renal disease (ESRD) patients on dialysis, it carries high morbidity from intractable pain, infections, and a 1-year mortality of 45-80% [1][4][7].
Therapies
Multidisciplinary care: wound debridement, infection control, and opioid analgesia [6][16].
Sodium thiosulfate (calcium chelation), intensified dialysis, and discontinuation of triggers (warfarin, calcium supplements) [1][6][8].
Emerging therapies: bisphosphonates, hyperbaric oxygen, and vitamin K supplementation in trials [3][20].
Categories: rare circulatory system diseases, rare systemic and rheumatological diseases
Research Papers
717 drug discovery papers about Calciphylaxis, with 3 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
717 drug discovery papers about Calciphylaxis, with 3 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-10-01 | A Case of Chronic Hypophosphatemia Leading to Identification of a Rare Mutation
Introduction: Hypophosphatemia occurs not infrequently in the inpatient setting. Inherited causes should be suspected when it is accompanied by musculoskeletal symptoms or extra-skeletal calcification. Case Description: A 47-year-old Asian man was referred for evaluation of chronic hypophosphatemia. His history included congenital bilateral conductive hearing loss, congenital hip dysplasia requiring childhood surgery and hip arthroplasty at age 39, and ossification of the posterior longitudinal ligament (OPLL) s/p numerous spinal surgeries since age 38. He had a bicuspid aortic valve with moderate calcification and severe stenosis. His brother also had chronic hypophosphatemia and OPLL requiring spinal surgery. Our patient had asymptomatic chronic mild-moderate hypophosphatemia. Further outpatient work-up revealed renal phosphate wasting (TMP/GFR 1.78 mg/dL, ref: >4.2), normal serum calcium and creatinine, elevated FGF23(129 pg/mL, ref:<59), PTH (111 pg/mL, ref: 25-105) and Alkphos (163 U/L, ref: 40-150)). Genetic testing ultimately identified a novel homozygous mutation in Ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1) c.1437+1G>C (splice donor). Discussion: ENPP1 hydrolyzes extracellular ATP to pyrophosphate, an endogenous inhibitor of hydroxyapatite formation. It regulates soft tissue mineralization and vascular endothelial proliferation, while inhibiting extra-skeletal calcification. ENPP1 deficiency results in phenotypes ranging from generalized arterial calcification of infancy to autosomal recessive hypophosphatemic rickets type 2 (ARHR2), and OPLL. Clinically, ARHR2 resembles the more common X-linked hypophosphatemia (XLH) with FGF23-mediated renal phosphate wasting, but diagnosis is often delayed, and treatment differs significantly: Burosumab, a monoclonal antibody inhibiting FGF23 approved for XLH, can potentially exacerbate extra-skeletal calcification in ARHR2. Recombinant ENPP1-Fc enzyme replacement therapy showed promising results in mouse models of ARHR2 and vascular calcification in CKD, and is being studied in humans with ARHR2 and calciphylaxis. In summary, ARHR2 from ENPP1 deficiency causes significant multi-system morbidities, including hypophosphatemia, musculoskeletal complications like rickets and OPLL, and early-onset vascular calcification. Diagnosis requires high clinical suspicion and prompt genetic testing, and burosumab should be avoided in affected patients.
2025-09-16 | A Composite Dermal Matrix Comprising Ovine Forestomach Matrix and Hyaluronic Acid in the Treatment of Chronic Wounds Secondary to Calciphylaxis: A Case Series and Literature Review.
To evaluate the efficacy and safety of composite ovine forestomach matrix and hyaluronic acid (OFM-HA) graft in facilitating tissue regeneration in atypical wounds secondary to calciphylaxis. This retrospective case series included 3 patients with a total of 4 wounds (n = 4) who were diagnosed with wounds secondary to calciphylaxis in an outpatient setting. All wounds were treated with surgical debridement and a composite OFM-HA graft. Healing progress was monitored, and the total time to wound closure was assessed. All 4 wounds in the study achieved 100% wound healing, with a 12-week incidence of closure of 75%. The mean wound area at the time of OFM-HA treatment was 28.6 ± 26.9 cm 2 , with a mean depth of 0.2 ± 0.1 cm. The mean time to wound closure was 43.5 ± 37.0 days and all patients experienced a marked reduction in pain. No adverse events were reported, and all wounds remained healed after achieving 100% closure at final follow-up. Ovine forestomach matrix and hyaluronic acid, in combination with wound bed preparation, were found to be safe and effective treatments for wounds associated with calciphylaxis; they may reduce the time to wound closure compared with traditional wound care and reduce complications associated with calciphylaxis-related wounds.
2022-12-15 | Correction of Vascular Calcification and Hyperphosphatemia in CKD Rats Treated with ASARM Peptide.
Abnormalities in calcium, phosphorus, PTH, vitamin D metabolism, bone, and vascular calcification occur in chronic kidney disease mineral bone disorder (CKD-MBD). Calciphylaxis, involving painful, ulcerative skin lesions, is also a major problem associated with CKD-MBD. There are no quality medical interventions to address these clinical issues. Bone ASARM peptides are strong inhibitors of mineralization and induce hypophosphatemia by inhibiting phosphate uptake from the gut. We hypothesize treatment of CKD-MBD rats with ASARM peptides will reverse hyperphosphatemia, reduce soft-tissue calcification, and prevent calciphylaxis. To test our hypothesis, we assessed the effects of synthetic ASARM peptide in rats that had undergone a subtotal 5/6th nephrectomy (56NEPHREX), a rodent model of CKD-MBD. All rats were fed a high phosphate diet (2% Pi) to worsen mineral metabolism defects. Changes in serum potassium, phosphate, BUN, creatinine, PTH, FGF23, and calcium were assessed in response to 28 days of ASARM peptide infusion. Also, changes in bone quality, soft-tissue calcification, and expression of gut Npt2b (Slc34a2) were studied following ASARM peptide treatment. Rats that had undergone 56NEPHREX treated with ASARM peptide showed major improvements in hyperphosphatemia, blood urea nitrogen (BUN), and bone quality compared with vehicle controls. Also, ASARM-infused 56NEPHREX rats displayed improved renal, brain, and cardiovascular calcification. Notably, ASARM peptide infusion prevented the genesis of subdermal medial blood vessel calcification and calciphylaxis-like lesions in 56NEPHREX rats compared with vehicle controls. ASARM peptide infusion corrects hyperphosphatemia and improves vascular calcification, renal calcification, brain calcification, bone quality, renal function, and skin mineralization abnormalities in 56NEPHREX rats. These findings confirm our hypothesis and support the utility of ASARM peptide treatment in patients with CKD-MBD.
2022-04-11 | Tissue chaperoning—the expanded functions of fetuin-A beyond inhibition of systemic calcification
Traditionally, fetuin-A embodies the prototype anti-calcification protein in the blood, preventing cardiovascular calcification. Low serum fetuin-A is generally associated with mineralization dysbalance and enhanced mortality in end stage renal disease. Recent evidence indicates that fetuin-A is a crucial factor moderating tissue inflammation and fibrosis, as well as a systemic indicator of acute inflammatory disease. Here, the expanded function of fetuin-A is discussed in the context of mineralization and inflammation biology. Unbalanced depletion of fetuin-A in this context may be the critical event, triggering a vicious cycle of progressive calcification, inflammation, and tissue injury. Hence, we designate fetuin-A as tissue chaperone and propose the potential use of exogenous fetuin-A as prophylactic agent or emergency treatment in conditions that are associated with acute depletion of endogenous protein.
2020-02-19 | Microvasculopathy and soft tissue calcification in mice are governed by fetuin-A, magnesium and pyrophosphate
Calcifications can disrupt organ function in the cardiovascular system and the kidney, and are particularly common in patients with chronic kidney disease (CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2 exhibit particularly severe soft tissue calcifications, while fetuin-A deficient C57BL/6 mice remain healthy. We employed molecular genetic analysis to identify risk factors of calcification in fetuin-A deficient mice. We sought to identify pharmaceutical therapeutic targets that could be influenced by dietary of parenteral supplementation. We studied the progeny of an intercross of fetuin-A deficient DBA/2 and C57BL/6 mice to identify candidate risk genes involved in calcification. We determined that a hypomorphic mutation of the Abcc6 gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate the Trpm6 magnesium transporter in kidney were associated with severity of calcification. Calcification prone fetuin-A deficient mice were alternatively treated with parenteral administration of fetuin-A dietary magnesium supplementation, phosphate restriction, or by or parenteral pyrophosphate. All treatments markedly reduced soft tissue calcification, demonstrated by computed tomography, histology and tissue calcium measurement. We show that pathological ectopic calcification in fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major extracellular and systemic inhibitors of calcification, namely fetuin-A, magnesium, and pyrophosphate. All three of these are individually known to contribute to stabilize protein-mineral complexes and thus inhibit mineral precipitation from extracellular fluid. We show for the first time a compound triple deficiency that can be treated by simple dietary or parenteral supplementation. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum fetuin-A, magnesium and pyrophosphate levels.
small molecules
2026-06-12 | Triple therapy for calciphylaxis: A retrospective analysis of sodium thiosulfate, iloprost, and anticoagulation.
Calciphylaxis is a severe condition with no established therapy, characterized by painful skin ulcerations and necrosis resulting from occlusion of small blood vessels. Given the high mortality rate, effective treatment strategies are urgently needed. We hypothesize that a combination of sodium thiosulphate with the prostaglandin analog iloprost and a low-molecular-weight heparin may be a beneficial treatment option for calciphylaxis. In a retrospective data analysis, 19 patients with calciphylaxis were included who were treated in our clinic between 2019 and 2023. Demographic factors, clinical symptoms, comorbidities, laboratory results, histology, and treatment-related factors were collected. 68.4% were female and mean age was 67.8 years. In 63% of cases, a combination therapy consisting of sodium thiosulfate, iloprost and anticoagulation was used. In a cohort of 12 patients who underwent at least 2 treatment cycles complete healing occurred in 75.0% of cases and partial improvement in 25.0%. The median time to healing was 3.0 treatment cycles. The median duration until complete pain relief was 2.5 treatment cycles. In our cohort, a combination therapy consisting of sodium thiosulfate, iloprost, and anticoagulation was associated with favorable treatment response, good tolerability, improved wound healing, and pain relief.
2026-06-10 | Calciphylaxis complicated by NDM-1-producing Pseudomonas aeruginosa: first experience with cefepime-zidebactam alongside phage therapy in the USA.
We report a case of calciphylaxis-a rare vasculopathy characterised by arteriolar calcification and ischaemic skin necrosis-in a young woman with acute myeloid leukaemia. Her ulcerated skin lesions became superinfected with a pan-resistant New Delhi metallo-β-lactamase-1-producing Pseudomonas aeruginosa. Although such infections in the USA have largely been associated with international travel, our patient harboured one of the earliest domestically acquired isolates. Management required novel therapeutic strategies, including the first use of cefepime-zidebactam in the USA alongside bacteriophage therapy and calciphylaxis-directed treatment. This case highlights the diagnostic complexity of calciphylaxis in atypical populations and shows the potential for innovative therapeutic approaches to achieve favourable outcomes in this rare, potentially fatal condition.
2026-04-27 | Early Calciphylaxis Mimicking Infection in a Patient With End-Stage Renal Disease and Sarcoidosis: A Diagnostic and Wound Management Challenge.
Calciphylaxis is a rare, life-threatening disorder primarily affecting patients with end-stage renal disease (ESRD) on dialysis. Early lesions can mimic infection, leading to delays in diagnosis and wound-directed care. We describe an atypical early presentation of calciphylaxis in a patient with ESRD and sarcoidosis, initially misdiagnosed as cellulitis. Despite early sodium thiosulfate therapy and metabolic control, the patient developed progressive necrotic wounds. This case underscores that calciphylaxis can progress despite controlled mineral metabolism and standard therapy, particularly when potentiated by conditions like sarcoidosis. Early dermatologic evaluation and a high index of suspicion are critical to avoid misdiagnosis.
2025-12-18 | Navigating Calciphylaxis in End-Stage Renal Disease: A Case Report Highlighting the Complexities of Pain Control and the Need for Greater Clinical Vigilance.
We present this case to increase awareness of calciphylaxis to promote early diagnosis and, therefore, improved clinical outcomes. Calciphylaxis is a rare, life-threatening complication of end-stage renal disease (ESRD) characterised by vascular calcification, thrombosis, and skin necrosis. We describe a 48-year-old female on long-term haemodialysis with obesity and prior warfarin use who developed painful abdominal plaques progressing to necrotic ulcers over six weeks. A skin biopsy performed at seven weeks confirmed focal calciphylaxis. Management involved intensified haemodialysis, intravenous sodium thiosulfate (12.5 g five times a week), and switching from warfarin to apixaban (2.5 mg twice daily). Despite specialist input and multimodal analgesia with opioids and adjuvant agents, pain control remained extremely challenging and significantly impacted quality of life. The case highlights the need for early recognition, prompt multidisciplinary management, and greater awareness among healthcare professionals of the severe pain burden and high morbidity associated with calciphylaxis to facilitate timely diagnosis and improve patient outcomes.
2025-12-04 | The Assessment and Management of Complications Arising from the Disordered Calcium Homeostasis of Diabetes Mellitus and Chronic Kidney Disease
Background Chronic kidney disease (CKD) and type 2 diabetes are associated with disordered calcium homeostasis, including the complications of cardiovascular disease. Cardiovascular disease rates are correlated with the severity of CKD as reflected in the Kidney Disease Improving Global Outcomes (KDIGO) CKD severity-based classification system. Diabetes is also associated with CKD, but the absence of an accepted diabetes severity system makes it more difficult to define the association. Potential parameters that could provide a basis for defining diabetes severity are glycaemic control, duration of disease and treatment intensity. Of these, an association with rates of cardiovascular disease is only well established for glycaemic control. Fracture is another manifestation of disordered calcium homeostasis. Fracture rates are reported to be moderately increased in both CKD and diabetes, although the underlying pathophysiological processes remain poorly defined. A rare but severe presentation of disordered calcium homeostasis is calciphylaxis, an acute condition marked by medial arteriolar vascular calcification that is associated with advanced CKD, particularly in the presence of diabetes. This thesis aims to broaden knowledge of the evaluation and mitigation of complications arising from disordered calcium homeostasis in diabetes and CKD. Methods The association of cardiovascular risk with glycaemic control, treatment intensity and disease duration as markers of diabetes disease severity is explored in two large cohorts. The aetiological hypotheses for fracture in type 2 diabetes and CKD are explored through the creation of multivariable models in a secondary analysis of a large clinical cohort with coexisting diabetes and CKD. The lack of treatments for calciphylaxis is addressed through the development of a trial protocol. Major Findings and Conclusions The parameters of treatment intensity, glycaemic control and disease duration all effectively distinguished cardiovascular complication rates in a large trial-based cohort of people with type 2 diabetes. Higher treatment intensity was associated with poorer glycaemic control in a large cohort with prospectively collected clinical data. Despite plausible disease-specific hypotheses for increased vulnerability to fracture in coexisting type 2 diabetes mellitus and CKD, variables associated with these hypotheses did not improve the prediction of fracture in a cohort with these two conditions. Instead, fracture was predicted by the same variables that predict fracture in the general population. A better understanding of fracture pathophysiology in the presence of diabetes and CKD is needed. Potential mitigators of altered calcium homeostasis could be tested in the rare condition of calciphylaxis using an efficient multi-arm platform design. The complications of disordered calcium homeostasis are associated with increasing severity of diabetes and CKD. A better understanding of their pathophysiology and efficient approaches to evidence generation is needed in order to improve clinical outcomes.
cell therapies
2026-07-01 | Proteomics and human microchips identify Thrombospondin-1 as a potential biomarker for calciphylaxis stem cell therapy.
Calciphylaxis (calcific uremic arteriolopathy, CUA) is a rare, fatal disorder primarily affecting chronic kidney disease patients, characterized by microvascular calcification, thrombosis, and skin necrosis. In a discovery cohort (3 CUA, 10 uremic), plasma proteomics identified Thrombospondin-1 (THBS1) as the top upregulated hub in CUA, significantly reduced after human amnion-derived mesenchymal stem cell (hAMSC) therapy, alongside latent TGF-β binding protein 1, both linked to coagulation and wound healing. In vitro proteomics indicated that THBS1/TGF-β1 blockade impaired CUA serum-induced endothelial adhesion and coagulation. ELISA in combined discovery and validation cohorts (8 CUA, 20 uremic) confirmed this reduction post-treatment (6 patients), independent of systemic inflammation. Multiplex immunofluorescence revealed THBS1 and CD47 co-localized with CD31 and integrin β3 in injured microvessels. A human microvascular chip showed that THBS1 inhibition or hAMSC-conditioned medium alleviates injury. These findings implicate THBS1 as a key factor and potential biomarker in calciphylaxis, suggesting hAMSC therapy as a promising mechanism-based approach.
2026-05-26 | Proteomics and Microvascular Chip Identify Blood Biomarker Candidates in Calciphylaxis Stem Cell Therapy. Hu et al.
This de-identified dataset encompasses clinical, laboratory, and proteomic data from patients with calciphylaxis, a rare and high-mortality condition also known as calcific uremic arteriolopathy (CUA), who were treated with human amnion-derived mesenchymal stem cells (hAMSCs). This disorder predominantly arises in the context of chronic kidney disease. The dataset further includes information from uremic control subjects, comprising demographics, comorbidities, dialysis history, and medication records across discovery (3 CUA cases and 10 uremic controls) and independent validation (8 CUA cases and 20 uremic controls) cohorts. The data comprise: 1. Proteomics: Static and dynamic proteomic profiles from the discovery cohort, deposited in iProX, identified Thrombospondin-1 (THBS1) as a leading upregulated hub associated with coagulation and wound healing. In vitro proteomic analyses further demonstrated that blockade of the THBS1/TGF-β1 axis attenuates endothelial dysfunction induced by CUA serum (data deposited in iProX). 2. Potential Biomarker Validation (ELISA): Quantitative validation of elevated plasma THBS1 and TGF-β1 levels was conducted using ELISA in both discovery and validation cohorts, confirming a significant reduction three days post-hAMSC therapy. However, in Patient 1 from the discovery cohort, plasma THBS1 and TGF-β1 levels remained low throughout the 15-month follow-up period but increased as the frequency of hAMSC treatment decreased. 3. Microvascular Chip Analysis: Quantitative assessment of integrated density and cell viability using a human microvascular chip to analyze calciphylaxis-associated vascular injury and evaluate the therapeutic effects of hAMSCs in vitro. 4. Clinical Outcomes: Longitudinal evaluations of wound healing utilizing the Bates-Jensen Wound Assessment Tool for CUA (BWAT-CUA), pain measured by the Visual Analog Scale (VAS), and systemic inflammation assessed via high-sensitivity C-reactive protein (hs-CRP). These integrated findings implicate THBS1 as a potential biomarker and therapeutic target, supporting hAMSCs as a mechanism-based treatment for calciphylaxis. All data are anonymized to ensure patient privacy.
2026-03-25 | WCN26-3714 EFFICACY EVALUATION AND DYNAMIC SKIN PATHOLOGICAL ANALYSIS OF STEM CELL THERAPY IN CALCIPHYLAXIS: A CASE STUDY
The hAMSC product is manufactured by the hospital's stem cell technology platform and has passed quality re-evaluation by the National Institutes for Food and Drug Control.The administration regimen is individualized and combined: intravenous infusion at a dose of 1.010 6 cells/kg and local intralesional injection at 2.010 4 cells/cm 2 of wound surface (Fig 3).Acute adverse events are closely monitored throughout treatment, with established emergency response protocols.Preliminary long-term follow-up data suggest that hAMSC therapy is both safe and effective.Conclusion: Based on these encouraging results, larger-scale, multicenter studies are warranted to validate the long-term efficacy and safety of hAMSC therapy.Future research should incorporate dynamic biomarker monitoring, optimize treatment protocols, strengthen multidisciplinary collaboration, and promote the standardized and precision-driven translation of stem cell therapies, ultimately establishing safer, more effective, and cost-efficient regenerative medicine approaches for patients.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.
2026-02-28 | Wound Management and Surgery for Calcific Uremic Arteriolopathy (Calciphylaxis): A Retrospective Observational Cohort Study.
Wound care in calciphylaxis remains poorly defined without evidence-based consensus on timing and technique of surgical intervention. We demonstrate that surgical debridement and subsequent wound closure are safe and effective in calciphylaxis and describe a systematic multidisciplinary approach to intervention. We retrospectively reviewed a cohort of patients with calciphylaxis at our institution. Those who underwent surgical debridement and wound closure were analysed with emphasis on wound healing, progression to amputation and mortality. Sixty-two patients with calciphylaxis underwent surgical debridement. Twenty patients had wound closure by skin grafting, five were excised with primary wound closure, and 37 were debrided and allowed to heal by secondary intention. There were excellent rates of healing in all groups, and no patients demonstrated wound progression or new lesions following operative intervention. Surgical debridement and wound closure are safe and effective in treating wounds related to calciphylaxis.
2025-10-23 | A case of penile calciphylaxis development shortly after initiation of dialysis for graft dysfunction following living donor kidney transplantation: a case report.
Penile calciphylaxis is a rare condition with a poor prognosis. Although the median time to onset in patients undergoing dialysis is approximately 48 months, reports of early onset shortly after dialysis initiation are rare. A 50-year-old man with diabetic nephropathy underwent an ABO-incompatible living donor kidney transplantation from his father and continued immunosuppressive therapy with steroids and calcineurin inhibitors. Despite transplantation, glycemic control remained poor, and renal function gradually deteriorated. Maintenance dialysis was initiated 6 years and 8 months after transplantation. Immunosuppressive therapy, including steroids, was tapered but continued after dialysis initiation. Eight months later, the patient developed pain and discoloration at the tip of the penis and was hospitalized with suspected calciphylaxis. Imaging revealed severe calcification of the dorsal and deep penile arteries. Although conservative treatment was initially considered, the patient developed delirium due to persistent severe pain and experienced multiple falls, resulting in a right femoral trochanteric fracture. Considering the limitations of conservative management, surgical resection of the necrotic penile tissue was performed. Postoperatively, his pain improved, and there was no further progression of necrosis, allowing transfer to a rehabilitation facility. Histopathological examination using Von Kossa staining confirmed the diagnosis of calciphylaxis. This case suggests that calciphylaxis can develop shortly after dialysis initiation if multiple risk factors are present. Awareness that calciphylaxis can affect the penis is important, and early detection and treatment may be facilitated by close monitoring of penile arterial calcification in patients with multiple risk factors.
antibodies
2025-10-01 | Pharmacological targeting of the IL-17/neutrophil axis attenuates calcific deposits in rat models of calciphylaxis.
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.
2025-04-23 | Activation and targetability of TYMP-IL-6-TF signaling in the skin microenvironment in uremic calciphylaxis.
Calciphylaxis is an orphan disease characterized by dermal microvessel thrombosis, inflicting painful cutaneous necrosis. It occurs predominantly in patients with end-stage kidney disease and has high mortality, elusive pathogenesis, and no approved therapies. We demonstrate that sera from patients with calciphylaxis induced de novo synthesis of interleukin-6 (IL-6) and soluble IL-6 receptor (IL-6R) and stimulated Janus kinase-2 (JAK) and signal transducer and activator of transcription (STAT)-3 phosphorylation in primary human dermal microvascular endothelial cells (ECs). Calciphylaxis skin demonstrated an altered microenvironment characterized by a gain of proximal and distal IL-6 ligand-receptor interactions. Microvessels are the predominant senders and recipients of IL-6 signaling, which, along with up-regulated A disintegrin and metalloproteinase 17 in dermal vasculature and interstitial IL-6R, supported trans-IL-6 signaling in calciphylaxis lesions. Calciphylaxis serum up-regulated thymidine phosphorylase (TYMP) in ECs. TYMP up-regulated IL-6, which activated tissue factor (TF), a primary trigger of the extrinsic coagulation cascade. IL-6-TF signaling in ECs was partially triggered by elevated IL-6 and kynurenine amounts in calciphylaxis serum and was inhibited by anti-IL-6 treatment. The TF-inducing ability of calciphylaxis serum is correlated with disease activity and response to IL-6 inhibitors in ECs. Calciphylaxis is therefore a combination of serum-inducing TYMP-IL-6-TF signaling in ECs and a heterogeneous permissive local dermal microenvironment. The latter is characterized by microvessels initiating IL-6 signaling and multiway cross-talk with adipocytes and eccrine glands, perpetuating the sinister thrombotic milieu. Our results support exploring the IL-6-TF-inducing ability of calciphylaxis serum as an activity marker and IL-6 as a therapeutic target for uremic calciphylaxis.
2022-07-02 | Rituximab Used for the Treatment of Nonuremic Calciphylaxis: A Complication of Prolonged Steroid Use in Lupus Nephritis
Nonuremic calciphylaxis (NUC) is a rare and debilitating form of panniculitis. NUC is associated with a high mortality rate within the first year of diagnosis. Connective tissue diseases account for a small fraction of the reported cases. However, there have also been reported cases of patients developing NUC while on treatment with chronic corticosteroid immunosuppressive therapy. The pathophysiology of NUC is still not fully established. Several risk factors including underlying diseases, obesity, female gender, and medications have been associated with the development of NUC. The diagnosis remains challenging due to the condition's similarities with other forms of panniculitis. The gold standard for diagnosis is a tissue biopsy showing calcifications within the medial layer of arterioles and the presence of microthrombi with surrounding necrosis. The treatment for NUC has not advanced much in recent years and focuses on the management of the underlying condition, wound care, and treating any superimposed infection. Treating superimposed infections remains important as most of the associated mortality from NUC occurs due to sepsis. We describe a case of a young woman with lupus nephritis who developed NUC while on prolonged corticosteroid therapy. She did not respond to several immunosuppressive agents and was ultimately treated with rituximab, a monoclonal antibody against CD20 antigen, as salvage therapy.
2017-05-01 | MP667PRECLINICAL AND CLINICAL VALIDATION OF A NOVEL PHARMACODYNAMIC ASSAY TO EVALUATE THE EFFECT OF CALCIFICATION INHIBITORS ON CALCIUM PHOSPHATE CRYSTALLIZATION IN PLASMA
RESULTS:The administration of the drug was clinically well tolerated.Corrected serum calcium before treatment was 9.360.3mg/dl, 9.760.8mg/dl at 12 months, and 10.36 0.7 mg/dl at 24 months.Whole PTH before treatment was 153699 pg/ml, 1986120 at 12 months, and 110683 pg/dl at 24 months.Episodes of hypocalcemia associated with PTH increase were seen, but easily overcome by increase carbonate calcium, calcitriol or alfacalcidol.At one year, BMD at the distal third of radius increased 5.266.6% in donosumab group and decreased 5.465.7 % in control group (P<0.0001).At two year, BMD increased 3.966.0%in denosumab group and decreased 7.4 6 7.0% in control group (P<0.0001).CONCLUSIONS: In this observational study, denosumab represents a useful tool for dialysis female patients with low BMD.
2016-04-15 | We Do Too Many Parathyroidectomies for Calciphylaxis
Abstract Calciphylaxis, a disorder of dermal arteriolar calcification with a distinct predilection for patients with advanced kidney disease, remains an enigmatic condition that challenges clinicians. Observations regarding positive associations between levels of circulating parathyroid hormone ( PTH ) and the risk of calciphylaxis, combined with experimental data suggesting a pathogenic role of secondary hyperparathyroidism in vascular calcification, have led to the assumption that reducing PTH levels will improve the outcomes in patients with calciphylaxis. This editorial communicates the contemporary data regarding surgical parathyroidectomy as a treatment option for these patients. We raise concerns regarding the quality of available data and discuss the direction of future comparative effectiveness research in this field.
proteins
2025-10-01 | A Case of Chronic Hypophosphatemia Leading to Identification of a Rare Mutation
Introduction: Hypophosphatemia occurs not infrequently in the inpatient setting. Inherited causes should be suspected when it is accompanied by musculoskeletal symptoms or extra-skeletal calcification. Case Description: A 47-year-old Asian man was referred for evaluation of chronic hypophosphatemia. His history included congenital bilateral conductive hearing loss, congenital hip dysplasia requiring childhood surgery and hip arthroplasty at age 39, and ossification of the posterior longitudinal ligament (OPLL) s/p numerous spinal surgeries since age 38. He had a bicuspid aortic valve with moderate calcification and severe stenosis. His brother also had chronic hypophosphatemia and OPLL requiring spinal surgery. Our patient had asymptomatic chronic mild-moderate hypophosphatemia. Further outpatient work-up revealed renal phosphate wasting (TMP/GFR 1.78 mg/dL, ref: >4.2), normal serum calcium and creatinine, elevated FGF23(129 pg/mL, ref:<59), PTH (111 pg/mL, ref: 25-105) and Alkphos (163 U/L, ref: 40-150)). Genetic testing ultimately identified a novel homozygous mutation in Ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1) c.1437+1G>C (splice donor). Discussion: ENPP1 hydrolyzes extracellular ATP to pyrophosphate, an endogenous inhibitor of hydroxyapatite formation. It regulates soft tissue mineralization and vascular endothelial proliferation, while inhibiting extra-skeletal calcification. ENPP1 deficiency results in phenotypes ranging from generalized arterial calcification of infancy to autosomal recessive hypophosphatemic rickets type 2 (ARHR2), and OPLL. Clinically, ARHR2 resembles the more common X-linked hypophosphatemia (XLH) with FGF23-mediated renal phosphate wasting, but diagnosis is often delayed, and treatment differs significantly: Burosumab, a monoclonal antibody inhibiting FGF23 approved for XLH, can potentially exacerbate extra-skeletal calcification in ARHR2. Recombinant ENPP1-Fc enzyme replacement therapy showed promising results in mouse models of ARHR2 and vascular calcification in CKD, and is being studied in humans with ARHR2 and calciphylaxis. In summary, ARHR2 from ENPP1 deficiency causes significant multi-system morbidities, including hypophosphatemia, musculoskeletal complications like rickets and OPLL, and early-onset vascular calcification. Diagnosis requires high clinical suspicion and prompt genetic testing, and burosumab should be avoided in affected patients.
2025-09-16 | A Composite Dermal Matrix Comprising Ovine Forestomach Matrix and Hyaluronic Acid in the Treatment of Chronic Wounds Secondary to Calciphylaxis: A Case Series and Literature Review.
To evaluate the efficacy and safety of composite ovine forestomach matrix and hyaluronic acid (OFM-HA) graft in facilitating tissue regeneration in atypical wounds secondary to calciphylaxis. This retrospective case series included 3 patients with a total of 4 wounds (n = 4) who were diagnosed with wounds secondary to calciphylaxis in an outpatient setting. All wounds were treated with surgical debridement and a composite OFM-HA graft. Healing progress was monitored, and the total time to wound closure was assessed. All 4 wounds in the study achieved 100% wound healing, with a 12-week incidence of closure of 75%. The mean wound area at the time of OFM-HA treatment was 28.6 ± 26.9 cm 2 , with a mean depth of 0.2 ± 0.1 cm. The mean time to wound closure was 43.5 ± 37.0 days and all patients experienced a marked reduction in pain. No adverse events were reported, and all wounds remained healed after achieving 100% closure at final follow-up. Ovine forestomach matrix and hyaluronic acid, in combination with wound bed preparation, were found to be safe and effective treatments for wounds associated with calciphylaxis; they may reduce the time to wound closure compared with traditional wound care and reduce complications associated with calciphylaxis-related wounds.
2022-12-15 | Correction of Vascular Calcification and Hyperphosphatemia in CKD Rats Treated with ASARM Peptide.
Abnormalities in calcium, phosphorus, PTH, vitamin D metabolism, bone, and vascular calcification occur in chronic kidney disease mineral bone disorder (CKD-MBD). Calciphylaxis, involving painful, ulcerative skin lesions, is also a major problem associated with CKD-MBD. There are no quality medical interventions to address these clinical issues. Bone ASARM peptides are strong inhibitors of mineralization and induce hypophosphatemia by inhibiting phosphate uptake from the gut. We hypothesize treatment of CKD-MBD rats with ASARM peptides will reverse hyperphosphatemia, reduce soft-tissue calcification, and prevent calciphylaxis. To test our hypothesis, we assessed the effects of synthetic ASARM peptide in rats that had undergone a subtotal 5/6th nephrectomy (56NEPHREX), a rodent model of CKD-MBD. All rats were fed a high phosphate diet (2% Pi) to worsen mineral metabolism defects. Changes in serum potassium, phosphate, BUN, creatinine, PTH, FGF23, and calcium were assessed in response to 28 days of ASARM peptide infusion. Also, changes in bone quality, soft-tissue calcification, and expression of gut Npt2b (Slc34a2) were studied following ASARM peptide treatment. Rats that had undergone 56NEPHREX treated with ASARM peptide showed major improvements in hyperphosphatemia, blood urea nitrogen (BUN), and bone quality compared with vehicle controls. Also, ASARM-infused 56NEPHREX rats displayed improved renal, brain, and cardiovascular calcification. Notably, ASARM peptide infusion prevented the genesis of subdermal medial blood vessel calcification and calciphylaxis-like lesions in 56NEPHREX rats compared with vehicle controls. ASARM peptide infusion corrects hyperphosphatemia and improves vascular calcification, renal calcification, brain calcification, bone quality, renal function, and skin mineralization abnormalities in 56NEPHREX rats. These findings confirm our hypothesis and support the utility of ASARM peptide treatment in patients with CKD-MBD.
2022-04-11 | Tissue chaperoning—the expanded functions of fetuin-A beyond inhibition of systemic calcification
Traditionally, fetuin-A embodies the prototype anti-calcification protein in the blood, preventing cardiovascular calcification. Low serum fetuin-A is generally associated with mineralization dysbalance and enhanced mortality in end stage renal disease. Recent evidence indicates that fetuin-A is a crucial factor moderating tissue inflammation and fibrosis, as well as a systemic indicator of acute inflammatory disease. Here, the expanded function of fetuin-A is discussed in the context of mineralization and inflammation biology. Unbalanced depletion of fetuin-A in this context may be the critical event, triggering a vicious cycle of progressive calcification, inflammation, and tissue injury. Hence, we designate fetuin-A as tissue chaperone and propose the potential use of exogenous fetuin-A as prophylactic agent or emergency treatment in conditions that are associated with acute depletion of endogenous protein.
2020-02-19 | Microvasculopathy and soft tissue calcification in mice are governed by fetuin-A, magnesium and pyrophosphate
Calcifications can disrupt organ function in the cardiovascular system and the kidney, and are particularly common in patients with chronic kidney disease (CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2 exhibit particularly severe soft tissue calcifications, while fetuin-A deficient C57BL/6 mice remain healthy. We employed molecular genetic analysis to identify risk factors of calcification in fetuin-A deficient mice. We sought to identify pharmaceutical therapeutic targets that could be influenced by dietary of parenteral supplementation. We studied the progeny of an intercross of fetuin-A deficient DBA/2 and C57BL/6 mice to identify candidate risk genes involved in calcification. We determined that a hypomorphic mutation of the Abcc6 gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate the Trpm6 magnesium transporter in kidney were associated with severity of calcification. Calcification prone fetuin-A deficient mice were alternatively treated with parenteral administration of fetuin-A dietary magnesium supplementation, phosphate restriction, or by or parenteral pyrophosphate. All treatments markedly reduced soft tissue calcification, demonstrated by computed tomography, histology and tissue calcium measurement. We show that pathological ectopic calcification in fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major extracellular and systemic inhibitors of calcification, namely fetuin-A, magnesium, and pyrophosphate. All three of these are individually known to contribute to stabilize protein-mineral complexes and thus inhibit mineral precipitation from extracellular fluid. We show for the first time a compound triple deficiency that can be treated by simple dietary or parenteral supplementation. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum fetuin-A, magnesium and pyrophosphate levels.
small molecules
2026-06-12 | Triple therapy for calciphylaxis: A retrospective analysis of sodium thiosulfate, iloprost, and anticoagulation.
Calciphylaxis is a severe condition with no established therapy, characterized by painful skin ulcerations and necrosis resulting from occlusion of small blood vessels. Given the high mortality rate, effective treatment strategies are urgently needed. We hypothesize that a combination of sodium thiosulphate with the prostaglandin analog iloprost and a low-molecular-weight heparin may be a beneficial treatment option for calciphylaxis. In a retrospective data analysis, 19 patients with calciphylaxis were included who were treated in our clinic between 2019 and 2023. Demographic factors, clinical symptoms, comorbidities, laboratory results, histology, and treatment-related factors were collected. 68.4% were female and mean age was 67.8 years. In 63% of cases, a combination therapy consisting of sodium thiosulfate, iloprost and anticoagulation was used. In a cohort of 12 patients who underwent at least 2 treatment cycles complete healing occurred in 75.0% of cases and partial improvement in 25.0%. The median time to healing was 3.0 treatment cycles. The median duration until complete pain relief was 2.5 treatment cycles. In our cohort, a combination therapy consisting of sodium thiosulfate, iloprost, and anticoagulation was associated with favorable treatment response, good tolerability, improved wound healing, and pain relief.
2026-06-10 | Calciphylaxis complicated by NDM-1-producing Pseudomonas aeruginosa: first experience with cefepime-zidebactam alongside phage therapy in the USA.
We report a case of calciphylaxis-a rare vasculopathy characterised by arteriolar calcification and ischaemic skin necrosis-in a young woman with acute myeloid leukaemia. Her ulcerated skin lesions became superinfected with a pan-resistant New Delhi metallo-β-lactamase-1-producing Pseudomonas aeruginosa. Although such infections in the USA have largely been associated with international travel, our patient harboured one of the earliest domestically acquired isolates. Management required novel therapeutic strategies, including the first use of cefepime-zidebactam in the USA alongside bacteriophage therapy and calciphylaxis-directed treatment. This case highlights the diagnostic complexity of calciphylaxis in atypical populations and shows the potential for innovative therapeutic approaches to achieve favourable outcomes in this rare, potentially fatal condition.
2026-04-27 | Early Calciphylaxis Mimicking Infection in a Patient With End-Stage Renal Disease and Sarcoidosis: A Diagnostic and Wound Management Challenge.
Calciphylaxis is a rare, life-threatening disorder primarily affecting patients with end-stage renal disease (ESRD) on dialysis. Early lesions can mimic infection, leading to delays in diagnosis and wound-directed care. We describe an atypical early presentation of calciphylaxis in a patient with ESRD and sarcoidosis, initially misdiagnosed as cellulitis. Despite early sodium thiosulfate therapy and metabolic control, the patient developed progressive necrotic wounds. This case underscores that calciphylaxis can progress despite controlled mineral metabolism and standard therapy, particularly when potentiated by conditions like sarcoidosis. Early dermatologic evaluation and a high index of suspicion are critical to avoid misdiagnosis.
2025-12-18 | Navigating Calciphylaxis in End-Stage Renal Disease: A Case Report Highlighting the Complexities of Pain Control and the Need for Greater Clinical Vigilance.
We present this case to increase awareness of calciphylaxis to promote early diagnosis and, therefore, improved clinical outcomes. Calciphylaxis is a rare, life-threatening complication of end-stage renal disease (ESRD) characterised by vascular calcification, thrombosis, and skin necrosis. We describe a 48-year-old female on long-term haemodialysis with obesity and prior warfarin use who developed painful abdominal plaques progressing to necrotic ulcers over six weeks. A skin biopsy performed at seven weeks confirmed focal calciphylaxis. Management involved intensified haemodialysis, intravenous sodium thiosulfate (12.5 g five times a week), and switching from warfarin to apixaban (2.5 mg twice daily). Despite specialist input and multimodal analgesia with opioids and adjuvant agents, pain control remained extremely challenging and significantly impacted quality of life. The case highlights the need for early recognition, prompt multidisciplinary management, and greater awareness among healthcare professionals of the severe pain burden and high morbidity associated with calciphylaxis to facilitate timely diagnosis and improve patient outcomes.
2025-12-04 | The Assessment and Management of Complications Arising from the Disordered Calcium Homeostasis of Diabetes Mellitus and Chronic Kidney Disease
Background Chronic kidney disease (CKD) and type 2 diabetes are associated with disordered calcium homeostasis, including the complications of cardiovascular disease. Cardiovascular disease rates are correlated with the severity of CKD as reflected in the Kidney Disease Improving Global Outcomes (KDIGO) CKD severity-based classification system. Diabetes is also associated with CKD, but the absence of an accepted diabetes severity system makes it more difficult to define the association. Potential parameters that could provide a basis for defining diabetes severity are glycaemic control, duration of disease and treatment intensity. Of these, an association with rates of cardiovascular disease is only well established for glycaemic control. Fracture is another manifestation of disordered calcium homeostasis. Fracture rates are reported to be moderately increased in both CKD and diabetes, although the underlying pathophysiological processes remain poorly defined. A rare but severe presentation of disordered calcium homeostasis is calciphylaxis, an acute condition marked by medial arteriolar vascular calcification that is associated with advanced CKD, particularly in the presence of diabetes. This thesis aims to broaden knowledge of the evaluation and mitigation of complications arising from disordered calcium homeostasis in diabetes and CKD. Methods The association of cardiovascular risk with glycaemic control, treatment intensity and disease duration as markers of diabetes disease severity is explored in two large cohorts. The aetiological hypotheses for fracture in type 2 diabetes and CKD are explored through the creation of multivariable models in a secondary analysis of a large clinical cohort with coexisting diabetes and CKD. The lack of treatments for calciphylaxis is addressed through the development of a trial protocol. Major Findings and Conclusions The parameters of treatment intensity, glycaemic control and disease duration all effectively distinguished cardiovascular complication rates in a large trial-based cohort of people with type 2 diabetes. Higher treatment intensity was associated with poorer glycaemic control in a large cohort with prospectively collected clinical data. Despite plausible disease-specific hypotheses for increased vulnerability to fracture in coexisting type 2 diabetes mellitus and CKD, variables associated with these hypotheses did not improve the prediction of fracture in a cohort with these two conditions. Instead, fracture was predicted by the same variables that predict fracture in the general population. A better understanding of fracture pathophysiology in the presence of diabetes and CKD is needed. Potential mitigators of altered calcium homeostasis could be tested in the rare condition of calciphylaxis using an efficient multi-arm platform design. The complications of disordered calcium homeostasis are associated with increasing severity of diabetes and CKD. A better understanding of their pathophysiology and efficient approaches to evidence generation is needed in order to improve clinical outcomes.
cell therapies
2026-07-01 | Proteomics and human microchips identify Thrombospondin-1 as a potential biomarker for calciphylaxis stem cell therapy.
Calciphylaxis (calcific uremic arteriolopathy, CUA) is a rare, fatal disorder primarily affecting chronic kidney disease patients, characterized by microvascular calcification, thrombosis, and skin necrosis. In a discovery cohort (3 CUA, 10 uremic), plasma proteomics identified Thrombospondin-1 (THBS1) as the top upregulated hub in CUA, significantly reduced after human amnion-derived mesenchymal stem cell (hAMSC) therapy, alongside latent TGF-β binding protein 1, both linked to coagulation and wound healing. In vitro proteomics indicated that THBS1/TGF-β1 blockade impaired CUA serum-induced endothelial adhesion and coagulation. ELISA in combined discovery and validation cohorts (8 CUA, 20 uremic) confirmed this reduction post-treatment (6 patients), independent of systemic inflammation. Multiplex immunofluorescence revealed THBS1 and CD47 co-localized with CD31 and integrin β3 in injured microvessels. A human microvascular chip showed that THBS1 inhibition or hAMSC-conditioned medium alleviates injury. These findings implicate THBS1 as a key factor and potential biomarker in calciphylaxis, suggesting hAMSC therapy as a promising mechanism-based approach.
2026-05-26 | Proteomics and Microvascular Chip Identify Blood Biomarker Candidates in Calciphylaxis Stem Cell Therapy. Hu et al.
This de-identified dataset encompasses clinical, laboratory, and proteomic data from patients with calciphylaxis, a rare and high-mortality condition also known as calcific uremic arteriolopathy (CUA), who were treated with human amnion-derived mesenchymal stem cells (hAMSCs). This disorder predominantly arises in the context of chronic kidney disease. The dataset further includes information from uremic control subjects, comprising demographics, comorbidities, dialysis history, and medication records across discovery (3 CUA cases and 10 uremic controls) and independent validation (8 CUA cases and 20 uremic controls) cohorts. The data comprise: 1. Proteomics: Static and dynamic proteomic profiles from the discovery cohort, deposited in iProX, identified Thrombospondin-1 (THBS1) as a leading upregulated hub associated with coagulation and wound healing. In vitro proteomic analyses further demonstrated that blockade of the THBS1/TGF-β1 axis attenuates endothelial dysfunction induced by CUA serum (data deposited in iProX). 2. Potential Biomarker Validation (ELISA): Quantitative validation of elevated plasma THBS1 and TGF-β1 levels was conducted using ELISA in both discovery and validation cohorts, confirming a significant reduction three days post-hAMSC therapy. However, in Patient 1 from the discovery cohort, plasma THBS1 and TGF-β1 levels remained low throughout the 15-month follow-up period but increased as the frequency of hAMSC treatment decreased. 3. Microvascular Chip Analysis: Quantitative assessment of integrated density and cell viability using a human microvascular chip to analyze calciphylaxis-associated vascular injury and evaluate the therapeutic effects of hAMSCs in vitro. 4. Clinical Outcomes: Longitudinal evaluations of wound healing utilizing the Bates-Jensen Wound Assessment Tool for CUA (BWAT-CUA), pain measured by the Visual Analog Scale (VAS), and systemic inflammation assessed via high-sensitivity C-reactive protein (hs-CRP). These integrated findings implicate THBS1 as a potential biomarker and therapeutic target, supporting hAMSCs as a mechanism-based treatment for calciphylaxis. All data are anonymized to ensure patient privacy.
2026-03-25 | WCN26-3714 EFFICACY EVALUATION AND DYNAMIC SKIN PATHOLOGICAL ANALYSIS OF STEM CELL THERAPY IN CALCIPHYLAXIS: A CASE STUDY
The hAMSC product is manufactured by the hospital's stem cell technology platform and has passed quality re-evaluation by the National Institutes for Food and Drug Control.The administration regimen is individualized and combined: intravenous infusion at a dose of 1.010 6 cells/kg and local intralesional injection at 2.010 4 cells/cm 2 of wound surface (Fig 3).Acute adverse events are closely monitored throughout treatment, with established emergency response protocols.Preliminary long-term follow-up data suggest that hAMSC therapy is both safe and effective.Conclusion: Based on these encouraging results, larger-scale, multicenter studies are warranted to validate the long-term efficacy and safety of hAMSC therapy.Future research should incorporate dynamic biomarker monitoring, optimize treatment protocols, strengthen multidisciplinary collaboration, and promote the standardized and precision-driven translation of stem cell therapies, ultimately establishing safer, more effective, and cost-efficient regenerative medicine approaches for patients.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.
2026-02-28 | Wound Management and Surgery for Calcific Uremic Arteriolopathy (Calciphylaxis): A Retrospective Observational Cohort Study.
Wound care in calciphylaxis remains poorly defined without evidence-based consensus on timing and technique of surgical intervention. We demonstrate that surgical debridement and subsequent wound closure are safe and effective in calciphylaxis and describe a systematic multidisciplinary approach to intervention. We retrospectively reviewed a cohort of patients with calciphylaxis at our institution. Those who underwent surgical debridement and wound closure were analysed with emphasis on wound healing, progression to amputation and mortality. Sixty-two patients with calciphylaxis underwent surgical debridement. Twenty patients had wound closure by skin grafting, five were excised with primary wound closure, and 37 were debrided and allowed to heal by secondary intention. There were excellent rates of healing in all groups, and no patients demonstrated wound progression or new lesions following operative intervention. Surgical debridement and wound closure are safe and effective in treating wounds related to calciphylaxis.
2025-10-23 | A case of penile calciphylaxis development shortly after initiation of dialysis for graft dysfunction following living donor kidney transplantation: a case report.
Penile calciphylaxis is a rare condition with a poor prognosis. Although the median time to onset in patients undergoing dialysis is approximately 48 months, reports of early onset shortly after dialysis initiation are rare. A 50-year-old man with diabetic nephropathy underwent an ABO-incompatible living donor kidney transplantation from his father and continued immunosuppressive therapy with steroids and calcineurin inhibitors. Despite transplantation, glycemic control remained poor, and renal function gradually deteriorated. Maintenance dialysis was initiated 6 years and 8 months after transplantation. Immunosuppressive therapy, including steroids, was tapered but continued after dialysis initiation. Eight months later, the patient developed pain and discoloration at the tip of the penis and was hospitalized with suspected calciphylaxis. Imaging revealed severe calcification of the dorsal and deep penile arteries. Although conservative treatment was initially considered, the patient developed delirium due to persistent severe pain and experienced multiple falls, resulting in a right femoral trochanteric fracture. Considering the limitations of conservative management, surgical resection of the necrotic penile tissue was performed. Postoperatively, his pain improved, and there was no further progression of necrosis, allowing transfer to a rehabilitation facility. Histopathological examination using Von Kossa staining confirmed the diagnosis of calciphylaxis. This case suggests that calciphylaxis can develop shortly after dialysis initiation if multiple risk factors are present. Awareness that calciphylaxis can affect the penis is important, and early detection and treatment may be facilitated by close monitoring of penile arterial calcification in patients with multiple risk factors.
antibodies
2025-10-01 | Pharmacological targeting of the IL-17/neutrophil axis attenuates calcific deposits in rat models of calciphylaxis.
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.
2025-04-23 | Activation and targetability of TYMP-IL-6-TF signaling in the skin microenvironment in uremic calciphylaxis.
Calciphylaxis is an orphan disease characterized by dermal microvessel thrombosis, inflicting painful cutaneous necrosis. It occurs predominantly in patients with end-stage kidney disease and has high mortality, elusive pathogenesis, and no approved therapies. We demonstrate that sera from patients with calciphylaxis induced de novo synthesis of interleukin-6 (IL-6) and soluble IL-6 receptor (IL-6R) and stimulated Janus kinase-2 (JAK) and signal transducer and activator of transcription (STAT)-3 phosphorylation in primary human dermal microvascular endothelial cells (ECs). Calciphylaxis skin demonstrated an altered microenvironment characterized by a gain of proximal and distal IL-6 ligand-receptor interactions. Microvessels are the predominant senders and recipients of IL-6 signaling, which, along with up-regulated A disintegrin and metalloproteinase 17 in dermal vasculature and interstitial IL-6R, supported trans-IL-6 signaling in calciphylaxis lesions. Calciphylaxis serum up-regulated thymidine phosphorylase (TYMP) in ECs. TYMP up-regulated IL-6, which activated tissue factor (TF), a primary trigger of the extrinsic coagulation cascade. IL-6-TF signaling in ECs was partially triggered by elevated IL-6 and kynurenine amounts in calciphylaxis serum and was inhibited by anti-IL-6 treatment. The TF-inducing ability of calciphylaxis serum is correlated with disease activity and response to IL-6 inhibitors in ECs. Calciphylaxis is therefore a combination of serum-inducing TYMP-IL-6-TF signaling in ECs and a heterogeneous permissive local dermal microenvironment. The latter is characterized by microvessels initiating IL-6 signaling and multiway cross-talk with adipocytes and eccrine glands, perpetuating the sinister thrombotic milieu. Our results support exploring the IL-6-TF-inducing ability of calciphylaxis serum as an activity marker and IL-6 as a therapeutic target for uremic calciphylaxis.
2022-07-02 | Rituximab Used for the Treatment of Nonuremic Calciphylaxis: A Complication of Prolonged Steroid Use in Lupus Nephritis
Nonuremic calciphylaxis (NUC) is a rare and debilitating form of panniculitis. NUC is associated with a high mortality rate within the first year of diagnosis. Connective tissue diseases account for a small fraction of the reported cases. However, there have also been reported cases of patients developing NUC while on treatment with chronic corticosteroid immunosuppressive therapy. The pathophysiology of NUC is still not fully established. Several risk factors including underlying diseases, obesity, female gender, and medications have been associated with the development of NUC. The diagnosis remains challenging due to the condition's similarities with other forms of panniculitis. The gold standard for diagnosis is a tissue biopsy showing calcifications within the medial layer of arterioles and the presence of microthrombi with surrounding necrosis. The treatment for NUC has not advanced much in recent years and focuses on the management of the underlying condition, wound care, and treating any superimposed infection. Treating superimposed infections remains important as most of the associated mortality from NUC occurs due to sepsis. We describe a case of a young woman with lupus nephritis who developed NUC while on prolonged corticosteroid therapy. She did not respond to several immunosuppressive agents and was ultimately treated with rituximab, a monoclonal antibody against CD20 antigen, as salvage therapy.
2017-05-01 | MP667PRECLINICAL AND CLINICAL VALIDATION OF A NOVEL PHARMACODYNAMIC ASSAY TO EVALUATE THE EFFECT OF CALCIFICATION INHIBITORS ON CALCIUM PHOSPHATE CRYSTALLIZATION IN PLASMA
RESULTS:The administration of the drug was clinically well tolerated.Corrected serum calcium before treatment was 9.360.3mg/dl, 9.760.8mg/dl at 12 months, and 10.36 0.7 mg/dl at 24 months.Whole PTH before treatment was 153699 pg/ml, 1986120 at 12 months, and 110683 pg/dl at 24 months.Episodes of hypocalcemia associated with PTH increase were seen, but easily overcome by increase carbonate calcium, calcitriol or alfacalcidol.At one year, BMD at the distal third of radius increased 5.266.6% in donosumab group and decreased 5.465.7 % in control group (P<0.0001).At two year, BMD increased 3.966.0%in denosumab group and decreased 7.4 6 7.0% in control group (P<0.0001).CONCLUSIONS: In this observational study, denosumab represents a useful tool for dialysis female patients with low BMD.
2016-04-15 | We Do Too Many Parathyroidectomies for Calciphylaxis
Abstract Calciphylaxis, a disorder of dermal arteriolar calcification with a distinct predilection for patients with advanced kidney disease, remains an enigmatic condition that challenges clinicians. Observations regarding positive associations between levels of circulating parathyroid hormone ( PTH ) and the risk of calciphylaxis, combined with experimental data suggesting a pathogenic role of secondary hyperparathyroidism in vascular calcification, have led to the assumption that reducing PTH levels will improve the outcomes in patients with calciphylaxis. This editorial communicates the contemporary data regarding surgical parathyroidectomy as a treatment option for these patients. We raise concerns regarding the quality of available data and discuss the direction of future comparative effectiveness research in this field.
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Drug Discovery Landscape
14 orphan drug designations for Calciphylaxis.
14 orphan drug designations for Calciphylaxis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Recombinant human ectonucleotide pyrophosphatase/phosphodiesterase 1 fused to the Fc fragment of IgG1 | proteins | EMA | 2025-05-22 | — | Inozyme Pharma Ireland Limited |
hexasodium salt of myo-inositol hexaphosphate (IP6, phytate) hexasodium phytate | small molecules | FDA | 2021-02-08 | — | Vifor Pharma, Inc. |
peritoneal dialysis solution containing combination of D-glucose and L-carnitine | — | FDA | 2019-02-21 | — | CoreQuest Sagl |
Sodium thiosulfate | small molecules | EMA | 2015-01-15 | — | Hope Pharmaceuticals Limited |
Vonapanitase | — | EMA | 2013-12-18 | — | Pharma Gateway AB |
hexasodium phytate | small molecules | FDA | 2012-12-02 | — | Vifor Pharma, Inc. |
sodium thiosulfate | small molecules | FDA | 2012-11-19 | — | Edinburg BioQuarter |
menaquinone | small molecules | FDA | 2012-09-04 | — | Nu Science Trading, LLC |
Hexasodium phytate | small molecules | EMA | 2012-07-17 | — | Vifor France |
Sodium thiosulfate | small molecules | EMA | 2012-04-02 | — | Aptiv Solutions (UK) Limited |
Sodium Thiosulfate | small molecules | FDA | 2012-02-16 | — | Luitpold Pharmaceuticals, Inc. |
sodium thiosulfate | small molecules | FDA | 2011-11-09 | — | Hope Pharmaceuticals |
Allogeneic aortic endothelial cells [Vascugel] | — | EMA | 2011-02-23 | — | Shire Pharmaceuticals Ireland Limited |
Sodium thiosulfate | small molecules | EMA | 2011-02-23 | — | Koehler Pharma GmbH |
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