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Sagar U Nigwekar - One of the best experts on this subject based on the ideXlab platform.
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assessment of outcomes of Calciphylaxis lesions treated with intralesional sodium thiosulfate
Journal of The American Academy of Dermatology, 2021Co-Authors: Colleen K Gabel, Sagar U Nigwekar, Lauren Strazzula, Emily D Nguyen, Allison S Dobry, Olesya Baker, Anna Cristina Garzamayers, Radhika Shah, Jessica St John, Daniela KroshinskyAbstract:● Calciphylaxis is a serious disorder with high morbidity and mortality and no approved therapy. Intralesional sodium thiosulfate (ILSTS) has not been well-studied as a treatment modality. ● This retrospective study identifies ILSTS as a potentially effective treatment option for Calciphylaxis with few adverse effects.
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vitamin k dependent carboxylation of matrix gla protein influences the risk of Calciphylaxis
Journal of The American Society of Nephrology, 2017Co-Authors: Sagar U Nigwekar, Sarah L. Booth, D Bloch, Rosalynn M Nazarian, Dihua Xu, Ravi Thadhani, Rajeev MalhotraAbstract:Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification. The ability of MGP to inhibit calcification requires the activity of a vitamin K–dependent enzyme, which mediates MGP carboxylation. We investigated how MGP carboxylation influences the risk of Calciphylaxis in adult patients receiving dialysis and examined the effects of vitamin K deficiency on MGP carboxylation. Our study included 20 patients receiving hemodialysis with Calciphylaxis (cases) and 20 patients receiving hemodialysis without Calciphylaxis (controls) matched for age, sex, race, and warfarin use. Cases had higher plasma levels of uncarboxylated MGP (ucMGP) and carboxylated MGP (cMGP) than controls. However, the fraction of total MGP that was carboxylated (relative cMGP concentration = cMGP/[cMGP + uncarboxylated MGP]) was lower in cases than in controls (0.58±0.02 versus 0.69±0.03, respectively; P =0.003). In patients not taking warfarin, cases had a similarly lower relative cMGP concentration. Each 0.1 unit reduction in relative cMGP concentration associated with a more than two-fold increase in Calciphylaxis risk. Vitamin K deficiency associated with lower relative cMGP concentration in multivariable adjusted analyses ( β =−8.99; P =0.04). In conclusion, vitamin K deficiency–mediated reduction in relative cMGP concentration may have a role in the pathogenesis of Calciphylaxis. Whether vitamin K supplementation can prevent and/or treat Calciphylaxis requires further study.
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increased bone morphogenetic protein signaling in the cutaneous vasculature of patients with Calciphylaxis
American Journal of Nephrology, 2017Co-Authors: Sagar U Nigwekar, Rajeev Malhotra, Rosalynn M Nazarian, Ravi Thadhani, Pawina Jiramongkolchai, Florian Wunderer, Emily G Bloch, Rika Ichinose, D BlochAbstract:Background: The objective of this study was to investigate the role of bone morphogenetic protein (BMP) signal transduction in the pathogenesis of Calciphylaxis. Methods: Skin biopsy specimens were obtained from 18 patients with, and 12 patients without, Calciphylaxis. Tissue sections were stained with antibodies directed against BMP effector proteins phosphorylated-SMAD (p-SMAD) 1/5/9, inhibitor of DNA 1 (Id1), inhibitor of DNA 3 (Id3), and Runx2. The intensity of staining was scored semi-quantitatively as strong versus weak or absent. Results: Of the 18 patients with Calciphylaxis (mean age: 59 ± 8 years), 9 were women and 15 had end-stage renal disease. Of the 12 control patients (mean age: 57 ± 10 years), 8 were women and 8 had end-stage renal disease. Strong staining for p-SMAD 1/5/9 was detected in blood vessels from all Calciphylaxis patients. In 1 patient with Calciphylaxis, strong staining for p-SMAD 1/5/9 was detected in a blood vessel that did not have evidence of calcification. Id1 and Id3 immunoreactivity was detected in blood vessels from all 12 patients with Calciphylaxis that were tested. Runx2 staining was detected in all 6 patients with Calciphylaxis who were tested. p-SMAD 1/5/9 immunoreactivity was weak or absent in blood vessels of 10 of the 12 control samples. Conclusions: The BMP signal transduction pathway is activated in the cutaneous vasculature of Calciphylaxis patients. The ability to detect p-SMAD 1/5/9, Id1, and Id3 in cutaneous vasculature may assist in the diagnosis of Calciphylaxis. As BMP signaling inhibitors become available, this pathway may serve as a future therapeutic target for Calciphylaxis.
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Calciphylaxis from Nonuremic Causes: A Systematic Review
2015Co-Authors: Sagar U Nigwekar, Myles Wolf, Richard H. Sterns, John K. HixAbstract:Background and objectives: Calciphylaxis, or calcific uremic arteriolopathy, is a well-described entity in end-stage kidney disease and renal transplant patients; however, little systematic information is available on Calciphylaxis from nonuremic causes. This systematic review was designed to characterize etiologies, clinical features, laboratory abnormalities, and prognosis of nonuremic Calciphylaxis. Design, setting, participants, & measurements: A systematic review of literature for case reports and case series of nonuremic Calciphylaxis was performed. Cases included met the operational definition of nonuremic Calciphylaxis–his-topathologic diagnosis of Calciphylaxis in the absence of end-stage kidney disease, renal transplantation, or acute kidney injury requiring renal replacement therapy. Results: We found 36 cases (75 % women, 63 % Caucasian, aged 15 to 82 yr) of nonuremic Calciphylaxis. Primary hyperpara-thyroidism, malignancy, alcoholic liver disease, and connective tissue disease were the most common reported causes. Preceding corticosteroid use was reported for 61 % patients. Protein C and S deficiencies were seen in 11 % of patients. Skin lesions were morphologically similar to calcific uremic arteriolopathy. Mortality rate was 52%, with sepsis being the leading cause of death. Conclusion: Calciphylaxis should be considered while evaluating skin lesions in patients with predisposing conditions even in the absence of end-stage kidney disease and renal transplantation. Nonuremic Calciphylaxis is reported most often i
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Calciphylaxis risk factors diagnosis and treatment
American Journal of Kidney Diseases, 2015Co-Authors: Sagar U Nigwekar, Rajeev Malhotra, Rosalynn M Nazarian, David J R Steele, Daniela Kroshinsky, Jeremy Goverman, Vicki A Jackson, Mihir M Kamdar, Ravi ThadhaniAbstract:Calciphylaxis is a rare but devastating condition that has continued to challenge the medical community since its early descriptions in the scientific literature many decades ago. It is predominantly seen in patients with chronic kidney failure treated with dialysis (uremic Calciphylaxis) but is also described in patients with earlier stages of chronic kidney disease and with normal kidney function. In this review, we discuss the available medical literature regarding risk factors, diagnosis, and treatment of both uremic and nonuremic Calciphylaxis. High-quality evidence for the evaluation and management of Calciphylaxis is lacking at this time due to its rare incidence and poorly understood pathogenesis and the relative paucity of collaborative research efforts. We hereby provide a summary of recommendations developed by a multidisciplinary team for patients with Calciphylaxis.
Daniela Kroshinsky - One of the best experts on this subject based on the ideXlab platform.
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assessment of outcomes of Calciphylaxis lesions treated with intralesional sodium thiosulfate
Journal of The American Academy of Dermatology, 2021Co-Authors: Colleen K Gabel, Sagar U Nigwekar, Lauren Strazzula, Emily D Nguyen, Allison S Dobry, Olesya Baker, Anna Cristina Garzamayers, Radhika Shah, Jessica St John, Daniela KroshinskyAbstract:● Calciphylaxis is a serious disorder with high morbidity and mortality and no approved therapy. Intralesional sodium thiosulfate (ILSTS) has not been well-studied as a treatment modality. ● This retrospective study identifies ILSTS as a potentially effective treatment option for Calciphylaxis with few adverse effects.
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fractures in Calciphylaxis patients following intravenous sodium thiosulfate therapy
Journal of The European Academy of Dermatology and Venereology, 2017Co-Authors: Allison S Dobry, Daniela KroshinskyAbstract:Calciphylaxis is a highly fatal syndrome of small vessel calcification that results in skin ischemia and necrosis.[1] Affected patients present with extremely painful, violaceous skin lesions that progress to non-healing ulcers, and can be complicated by superimposed infections and sepsis.[2] The mortality rate from Calciphylaxis is estimated at 60-80%.[2, 3] Sodium thiosulfate (STS), an increasingly popular treatment for Calciphylaxis, is theorized to work through vasodilation, antioxidation, and calcium chelation. Known adverse effects include volume overload, metabolic acidosis, and hypotension.[2, 4] We report four patients who experienced unusual fractures during or following treatment with intravenous STS (IVSTS), an adverse effect that has not yet been reported in the literature. This article is protected by copyright. All rights reserved.
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a 71 year old female with myocardial infarction and long standing ulcers on the thigh
Dermatopathology (Basel Switzerland), 2017Co-Authors: Eduardo De Flammineis, Patrick M Mulvaney, Stefan Kraft, Martin C Mihm, Daniela KroshinskyAbstract:: Calciphylaxis is most commonly encountered in patients with end-stage renal disease; however, it is increasingly observed in nonuremic patients as well. It is important to consider and diagnose nonuremic Calciphylaxis early, as prompt treatment and mitigation of associated risk factors is essential to improve long-term outcomes for these patients. Here, we present the case of a 71-year-old woman with atrial fibrillation on warfarin, but without renal disease, who presented with two long-standing ulcers on her thigh and was diagnosed with the aid of biopsy with Calciphylaxis. We review the existing literature on the subject and offer this case as a representative report of a clinicopathologic correlation for this disorder.
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Calciphylaxis risk factors diagnosis and treatment
American Journal of Kidney Diseases, 2015Co-Authors: Sagar U Nigwekar, Rajeev Malhotra, Rosalynn M Nazarian, David J R Steele, Daniela Kroshinsky, Jeremy Goverman, Vicki A Jackson, Mihir M Kamdar, Ravi ThadhaniAbstract:Calciphylaxis is a rare but devastating condition that has continued to challenge the medical community since its early descriptions in the scientific literature many decades ago. It is predominantly seen in patients with chronic kidney failure treated with dialysis (uremic Calciphylaxis) but is also described in patients with earlier stages of chronic kidney disease and with normal kidney function. In this review, we discuss the available medical literature regarding risk factors, diagnosis, and treatment of both uremic and nonuremic Calciphylaxis. High-quality evidence for the evaluation and management of Calciphylaxis is lacking at this time due to its rare incidence and poorly understood pathogenesis and the relative paucity of collaborative research efforts. We hereby provide a summary of recommendations developed by a multidisciplinary team for patients with Calciphylaxis.
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intralesional sodium thiosulfate for the treatment of Calciphylaxis
JAMA Dermatology, 2013Co-Authors: Lauren Strazzula, Sagar U Nigwekar, David J R Steele, William G Tsiaras, Meghan E Sise, Sabina Bis, Gideon P Smith, Daniela KroshinskyAbstract:Importance Calciphylaxis is a potentially fatal disorder of abnormal calcium deposition. Patients commonly present with painful retiform to stellate purpuric lesions that often undergo ulceration and necrosis, increasing the risk of infection and life-threatening sepsis. Treatment is multifaceted, and improved outcomes have been demonstrated with intravenous sodium thiosulfate; however, the use of this medication can be limited by its adverse effects. The use of topical sodium thiosulfate has been successfully reported for superficial calcium deposits in the skin from other processes. Therefore, we hypothesized that intralesional (IL) sodium thiosulfate may be an effective treatment for the deeper lesions of cutaneous Calciphylaxis. We provide a retrospective case review of 4 patients with Calciphylaxis who were treated with IL sodium thiosulfate. Observations Four patients with biopsy-proven cutaneous Calciphylaxis were treated with IL sodium thiosulfate (250 mg/mL) in areas of clinically active disease. The patients tolerated the medication well, with only transient localized discomfort during injection. All 4 patients had complete healing of their ulcers and remission of disease. Conclusions and Relevance Intralesional sodium thiosulfate may be an effective and well-tolerated treatment for localized Calciphylaxis. This novel approach requires further research and investigation.
Christoph Wanner - One of the best experts on this subject based on the ideXlab platform.
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ecto 5 nucleotidase cd73 nt5e vitamin d receptor and fgf23 gene polymorphisms may play a role in the development of calcific uremic arteriolopathy in dialysis patients data from the german Calciphylaxis registry
PLOS ONE, 2017Co-Authors: Hansjorg Rothe, Markus Ketteler, Vincent Brandenburg, Margot Haun, Barbara Kollerits, Florian Kronenberg, Christoph WannerAbstract:Introduction Calciphylaxis/calcific uremic arteriolopathy affects mainly end-stage kidney disease patients but is also associated with malignant disorders such as myeloma, melanoma and breast cancer. Genetic risk factors of Calciphylaxis have never been studied before. Methods We investigated 10 target genes using a tagging SNP approach: the genes encoding CD73/ ecto-5'-nucleotidase (purinergic pathway), Matrix Gla protein, Fetuin A, Bone Gla protein, VKORC1 (all related to intrinsic calcification inhibition), calcium-sensing receptor, FGF23, Klotho, vitamin D receptor, stanniocalcin 1 (all related to CKD-MBD). 144 dialysis patients from the German Calciphylaxis registry were compared with 370 dialysis patients without history of CUA. Genotyping was performed using iPLEX Gold MassARRAY(Sequenom, San Diego, USA), KASP genotyping chemistry (LGC, Teddington, Middlesex, UK) or sequencing. Statistical analysis comprised logistic regression analysis with adjustment for age and sex. Results 165 SNPs were finally analyzed and 6 SNPs were associated with higher probability for Calciphylaxis (OR>1) in our cohort. Nine SNPs of three genes (CD73, FGF23 and Vitamin D receptor) reached nominal significance (p< 0.05), but did not reach statistical significance after correction for multiple testing. Of the CD73 gene, rs4431401 (OR = 1.71, 95%CI 1.08–2.17, p = 0.023) and rs9444348 (OR = 1.48, 95% CI 1.11–1.97, p = 0.008) were associated with a higher probability for CUA. Of the FGF23 and VDR genes, rs7310492, rs11063118, rs13312747 and rs17882106 were associated with a higher probability for CUA. Conclusion Polymorphisms in the genes encoding CD73, vitamin D receptor and FGF23 may play a role in Calciphylaxis development. Although our study is the largest genetic study on Calciphylaxis, it is limited by the low sample sizes. It therefore requires replication in other cohorts if available.
Hansjorg Rothe - One of the best experts on this subject based on the ideXlab platform.
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ecto 5 nucleotidase cd73 nt5e vitamin d receptor and fgf23 gene polymorphisms may play a role in the development of calcific uremic arteriolopathy in dialysis patients data from the german Calciphylaxis registry
PLOS ONE, 2017Co-Authors: Hansjorg Rothe, Markus Ketteler, Vincent Brandenburg, Margot Haun, Barbara Kollerits, Florian Kronenberg, Christoph WannerAbstract:Introduction Calciphylaxis/calcific uremic arteriolopathy affects mainly end-stage kidney disease patients but is also associated with malignant disorders such as myeloma, melanoma and breast cancer. Genetic risk factors of Calciphylaxis have never been studied before. Methods We investigated 10 target genes using a tagging SNP approach: the genes encoding CD73/ ecto-5'-nucleotidase (purinergic pathway), Matrix Gla protein, Fetuin A, Bone Gla protein, VKORC1 (all related to intrinsic calcification inhibition), calcium-sensing receptor, FGF23, Klotho, vitamin D receptor, stanniocalcin 1 (all related to CKD-MBD). 144 dialysis patients from the German Calciphylaxis registry were compared with 370 dialysis patients without history of CUA. Genotyping was performed using iPLEX Gold MassARRAY(Sequenom, San Diego, USA), KASP genotyping chemistry (LGC, Teddington, Middlesex, UK) or sequencing. Statistical analysis comprised logistic regression analysis with adjustment for age and sex. Results 165 SNPs were finally analyzed and 6 SNPs were associated with higher probability for Calciphylaxis (OR>1) in our cohort. Nine SNPs of three genes (CD73, FGF23 and Vitamin D receptor) reached nominal significance (p< 0.05), but did not reach statistical significance after correction for multiple testing. Of the CD73 gene, rs4431401 (OR = 1.71, 95%CI 1.08–2.17, p = 0.023) and rs9444348 (OR = 1.48, 95% CI 1.11–1.97, p = 0.008) were associated with a higher probability for CUA. Of the FGF23 and VDR genes, rs7310492, rs11063118, rs13312747 and rs17882106 were associated with a higher probability for CUA. Conclusion Polymorphisms in the genes encoding CD73, vitamin D receptor and FGF23 may play a role in Calciphylaxis development. Although our study is the largest genetic study on Calciphylaxis, it is limited by the low sample sizes. It therefore requires replication in other cohorts if available.
Vincent Brandenburg - One of the best experts on this subject based on the ideXlab platform.
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ecto 5 nucleotidase cd73 nt5e vitamin d receptor and fgf23 gene polymorphisms may play a role in the development of calcific uremic arteriolopathy in dialysis patients data from the german Calciphylaxis registry
PLOS ONE, 2017Co-Authors: Hansjorg Rothe, Markus Ketteler, Vincent Brandenburg, Margot Haun, Barbara Kollerits, Florian Kronenberg, Christoph WannerAbstract:Introduction Calciphylaxis/calcific uremic arteriolopathy affects mainly end-stage kidney disease patients but is also associated with malignant disorders such as myeloma, melanoma and breast cancer. Genetic risk factors of Calciphylaxis have never been studied before. Methods We investigated 10 target genes using a tagging SNP approach: the genes encoding CD73/ ecto-5'-nucleotidase (purinergic pathway), Matrix Gla protein, Fetuin A, Bone Gla protein, VKORC1 (all related to intrinsic calcification inhibition), calcium-sensing receptor, FGF23, Klotho, vitamin D receptor, stanniocalcin 1 (all related to CKD-MBD). 144 dialysis patients from the German Calciphylaxis registry were compared with 370 dialysis patients without history of CUA. Genotyping was performed using iPLEX Gold MassARRAY(Sequenom, San Diego, USA), KASP genotyping chemistry (LGC, Teddington, Middlesex, UK) or sequencing. Statistical analysis comprised logistic regression analysis with adjustment for age and sex. Results 165 SNPs were finally analyzed and 6 SNPs were associated with higher probability for Calciphylaxis (OR>1) in our cohort. Nine SNPs of three genes (CD73, FGF23 and Vitamin D receptor) reached nominal significance (p< 0.05), but did not reach statistical significance after correction for multiple testing. Of the CD73 gene, rs4431401 (OR = 1.71, 95%CI 1.08–2.17, p = 0.023) and rs9444348 (OR = 1.48, 95% CI 1.11–1.97, p = 0.008) were associated with a higher probability for CUA. Of the FGF23 and VDR genes, rs7310492, rs11063118, rs13312747 and rs17882106 were associated with a higher probability for CUA. Conclusion Polymorphisms in the genes encoding CD73, vitamin D receptor and FGF23 may play a role in Calciphylaxis development. Although our study is the largest genetic study on Calciphylaxis, it is limited by the low sample sizes. It therefore requires replication in other cohorts if available.
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lack of evidence does not justify neglect how can we address unmet medical needs in Calciphylaxis
Nephrology Dialysis Transplantation, 2016Co-Authors: Vincent Brandenburg, Rafael Kramann, Pieter Evenepoel, J Floege, David Goldsmith, Ziad A Massy, Sandro Mazzaferro, Leon J Schurgers, Smeeta Sinha, Vicens TorregrosaAbstract:Calcific uraemic arteriolopathy (CUA), or Calciphylaxis, is a rare disease predominantly occurring in comorbidity with dialysis. Due to the very low frequency of CUA, prospective studies on its management are lacking and even anecdotal reports on treatment remain scarce. Therefore, Calciphylaxis is still a challenging disease with dismal prognosis urgently requiring adequate strategies for diagnosis and treatment.In an attempt to fill some of the current gaps in evidence on various, highly debated and controversial aspects of dialysis-associated Calciphylaxis, 13 international experts joined the 1st Consensus Conference on CUA, held in Leuven, Belgium on 21 September 2015. The conference was supported by the European Calciphylaxis Network (EuCalNet), which is a task force of the ERA-EDTA scientific working group on Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBD). After an intense discussion, a 9-point Likert scale questionnaire regarding 20 items on Calciphylaxis was anonymously answered by each participant. These 20 items addressed unsolved issues in terms of diagnosis and management of Calciphylaxis. On the one hand, the analysis of the expert opinions identified areas of general consensus, which might be a valuable aid for physicians treating such a disease with less experience in the field. On the other hand, some topics such as the pertinence of skin biopsy and administration of certain treatments revealed divergent opinions. The aim of the present summary report is to provide some guidance for clinicians who face patients with Calciphylaxis in the current setting of absence of evidence-based medicine.