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2017

33.
Brandenburg, V. M., Kramann, R., Rothe, H., Kaesler, N., Korbiel, J., Specht, P., Schmitz, S., Kruger, T., Floege, J. und Ketteler, M.
Calcific uraemic arteriolopathy (calciphylaxis): data from a large nationwide registry
Nephrol Dial Transplant, 32(1):126-132
2017
ISSN: 1460-2385 (Electronic) 0931-0509 (Linking)

Schlüsselwörter: Esrd anticoagulation calcification calciphylaxis cardiovascular

Zusammenfassung: Background.: Calcific uraemic arteriolopathy (CUA, calciphylaxis) is a rare disease predominantly in dialysis patients and associated with high mortality. Painful skin ulcerations and calcification of cutaneous arterioles characterize calciphylaxis. Methods.: We established an observational, Internet-based registry allowing online notification for all German CUA cases. The registry recorded data about patient characteristics, biochemistry and therapies. Blood samples were stored in a central biobank. Results.: Between 2006 and 2015, 253 CUA patients were recorded: median age 70 [interquartile range (IQR) 61-76] years, 60% females and 86% ( n = 207) dialysis patients, translating into an estimated annual incidence rate of 0.04% in German dialysis patients. Fifty-two per cent received vitamin K antagonists (VKAs) prior to CUA. Skin lesions were localized in 71% on the legs or gluteal region. In dialysis CUA patients median total serum calcium was 2.20 (IQR 2.06-2.37) mmol/L, phosphorus 1.67 (IQR 1.35-2.03) mmol/L, intact parathyroid hormone 147 (IQR 72-276) pg/mL and fetuin-A 0.21 (IQR 0.16-0.26) g/L (normal range 0.35-0.95). Median sclerostin, osteoprotegerin, TRAP5b, bone-specific alkaline phosphatase and c-terminal FGF23 levels were all elevated. The most frequently recorded therapeutic procedures in dialysis CUA patients were as follows: wound debridement (29% of cases), stopping VKA (25%), lowering calcium supply (24%), sodium thiosulphate (22%), application of vitamin K (18%), increase of dialysis duration/frequency (17%) and stoping active vitamin D (16%). Conclusions.: Approximately 50% of CUA patients used VKA. Our data suggest that uncontrolled hyperparathyroidism is not the key determinant of calciphylaxis. Therapeutic strategies were heterogeneous. The experience of the German registry will help substantially to initiate a large-scale multinational CUA registry.

32.
Rothe, H., Brandenburg, V., Haun, M., Kollerits, B., Kronenberg, F., Ketteler, M. und Wanner, C.
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, 12(2):e0172407
2017
ISSN: 1932-6203 (Electronic) 1932-6203 (Linking)

Zusammenfassung: 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.

2016

31.
Brandenburg, V. M., D'Haese, P., Deck, A., Mekahli, D., Meijers, B., Neven, E. und Evenepoel, P.
From skeletal to cardiovascular disease in 12 steps-the evolution of sclerostin as a major player in CKD-MBD
Pediatr Nephrol, 31(2):195-206
2016
ISSN: 1432-198X (Electronic) 0931-041X (Linking)

Schlüsselwörter: Animals Bone Density/physiology Bone Diseases/metabolism/*physiopathology Bone Morphogenetic Proteins/*metabolism Bone Remodeling Bone and Bones/*metabolism Cardiovascular Diseases/*metabolism Genetic Markers Humans Renal Insufficiency, Chronic/metabolism/*physiopathology Signal Transduction Bone mineralization Cardiovascular calcification Chronic kidney disease mineral and bone disorder Sclerostin Wnt signaling

Zusammenfassung: Canonical Wnt signaling activity contributes to physiological and adaptive bone mineralization and is an essential player in bone remodeling. Sclerostin is a prototypic soluble canonical Wnt signaling pathway inhibitor that is produced in osteocytes and blocks osteoblast differentiation and function. Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Accordingly, rodent sclerostin-deficiency models exhibit a strong bone phenotype. Moreover, blocking sclerostin represents a promising treatment perspective against osteoporosis. Beyond the bone field novel data definitely associate Wnt signaling in general and sclerostin in particular with ectopic extraosseous mineralization processes, as is evident in cardiovascular calcification or calciphylaxis. Uremia is characterized by parallel occurrence of disordered bone mineralization and accelerated cardiovascular calcification (chronic kidney disease - mineral and bone disorder, CKD-MBD), linking skeletal and cardiovascular disease-the so-called bone-vascular calcification paradox. In consequence, sclerostin may qualify as an emerging player in CKD-MBD. We present a stepwise review approach regarding the rapidly evolving field sclerostin participation in CKD-MBD. Starting from data originating in the classical bone field we look separately at three major areas of CKD-MBD: disturbed mineral metabolism, renal osteodystrophy, and uremic cardiovascular disease. Our review is intended to help the nephrologist revise the potential importance of sclerostin in CKD by focusing on how sclerostin research is gradually evolving from the classical osteoporosis niche into the area of CKD-MBD. In particular, we integrate the limited amount of available data in the context of pediatric nephrology.

30.
Brandenburg, V. M., Evenepoel, P., Floege, J., Goldsmith, D., Kramann, R., Massy, Z., Mazzaferro, S., Schurgers, L. J., Sinha, S., Torregrosa, V., Urena-Torres, P., Vervloet, M., Cozzolino, M. und CKD-MBD, Era-Edta Working Group on
Lack of evidence does not justify neglect: how can we address unmet medical needs in calciphylaxis?
Nephrol Dial Transplant, 31(8):1211-9
2016
ISSN: 1460-2385 (Electronic) 0931-0509 (Linking)

Schlüsselwörter: Ckd-mbd calciphylaxis cardiovascular chronic renal failure mineral metabolism

Zusammenfassung: 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.

29.
Russo, D., Capuano, A., Cozzolino, M., Napolitano, P., Mosella, F., Russo, L., Saviano, C. und Zoccali, C.
Multimodal treatment of calcific uraemic arteriolopathy (calciphylaxis): a case series
Clin Kidney J, 9(1):108-12
2016
ISSN: 2048-8505 (Print) 2048-8505 (Linking)

Schlüsselwörter: Cua calcific uraemic arteriolopathy cinacalcet parathyroid hormone skin ulcers

Zusammenfassung: BACKGROUND: This is an incident series of five dialysis patients with late-diagnosed calcific uraemic arteriolophathy (CUA), severe uncontrolled hyperparathyroidism and infected skin ulcerations. METHODS: A multimodal intervention was based on wound care, antibiotics, surgical debridement, sodium thiosulphate and cinacalcet and associated with regression of skin disease in four cases after varying treatment time periods ranging from 4 to 33 months. RESULTS: Multimodal treatment including sodium thiosulphate and cinacalcet was associated with very favourable local outcomes and survival. This series further confirms that the diagnosis of CUA is rarely made at the nodular, non-ulcerative phase of the disease. CONCLUSIONS: This series contributes to the build-up of case series reporting on the treatment of CUA, and will hopefully serve as a basis of well-conceived comparative effectiveness studies investigating the value of the combined interventions applied so far in this severe condition.

2015

28.
Brandenburg, V., Adragao, T., van Dam, B., Evenepoel, P., Frazao, J. M., Ketteler, M., Mazzaferro, S., Urena Torres, P., Ramos, R., Torregrosa, J. V. und Cozzolino, M.
Blueprint for a European calciphylaxis registry initiative: the European Calciphylaxis Network (EuCalNet)
Clin Kidney J, 8(5):567-71
2015
ISSN: 2048-8505 (Print) 2048-8505 (Linking)

Schlüsselwörter: calcific uraemic arteriolopathy calcification chronic kidney disease dialysis vascular disease

Zusammenfassung: Calcific uraemic arteriolopathy (CUA) is a rare disease and continues to be a clinical challenge. The typical course of CUA is characterized by painful skin discolouration and induration evolving to necrotic ulcerations. Medial calcification of cutaneous arterioles and extensive extracellular matrix remodelling are the hallmarks of CUA. The epidemiology and risk factors associated with this disease are still not fully understood. Moreover, CUA treatment strategies vary significantly among centres and expert recommendations are heterogeneous. Registries may provide important insights and information to increase our knowledge about epidemiology and clinical aspects of CUA and may help to optimize its therapeutic management. In 2006, we established an internet-based registry in Germany (www.calciphylaxie.de) to allow online notification of patients with established or suspected CUA. The registry includes a comprehensive database with questions covering >70 parameters and items regarding patient-related and laboratory data, clinical background and presentation as well as therapeutic strategies. The next phase will be to allow international patient registration via www.calciphylaxis.net as part of the multinational EuCalNet (European Calciphylaxis Network) initiative, which is supported by the ERA-EDTA scientific working group 'CKD-MBD'. Based on the valuable experience with the previous German CUA registry, EuCalNet will be a useful tool to collect data on the rare disease CUA and may become a basis for prospective controlled trials in the near future.

27.
Brandenburg, V. M., D'Haese, P., Deck, A., Mekahli, D., Meijers, B., Neven, E. und Evenepoel, P.
From skeletal to cardiovascular disease in 12 steps-the evolution of sclerostin as a major player in CKD-MBD
Pediatr Nephrol,
2015
ISSN: 1432-198X (Electronic) 0931-041X (Linking)

Zusammenfassung: Canonical Wnt signaling activity contributes to physiological and adaptive bone mineralization and is an essential player in bone remodeling. Sclerostin is a prototypic soluble canonical Wnt signaling pathway inhibitor that is produced in osteocytes and blocks osteoblast differentiation and function. Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Accordingly, rodent sclerostin-deficiency models exhibit a strong bone phenotype. Moreover, blocking sclerostin represents a promising treatment perspective against osteoporosis. Beyond the bone field novel data definitely associate Wnt signaling in general and sclerostin in particular with ectopic extraosseous mineralization processes, as is evident in cardiovascular calcification or calciphylaxis. Uremia is characterized by parallel occurrence of disordered bone mineralization and accelerated cardiovascular calcification (chronic kidney disease - mineral and bone disorder, CKD-MBD), linking skeletal and cardiovascular disease-the so-called bone-vascular calcification paradox. In consequence, sclerostin may qualify as an emerging player in CKD-MBD. We present a stepwise review approach regarding the rapidly evolving field sclerostin participation in CKD-MBD. Starting from data originating in the classical bone field we look separately at three major areas of CKD-MBD: disturbed mineral metabolism, renal osteodystrophy, and uremic cardiovascular disease. Our review is intended to help the nephrologist revise the potential importance of sclerostin in CKD by focusing on how sclerostin research is gradually evolving from the classical osteoporosis niche into the area of CKD-MBD. In particular, we integrate the limited amount of available data in the context of pediatric nephrology.

26.
Brandenburg, V. M., Martin, H., Sohn, C. M. und Ketteler, M.
[Calciphylaxis]
Dtsch Med Wochenschr, 140(5):347-51
2015
ISSN: 1439-4413 (Electronic) 0012-0472 (Linking)

Schlüsselwörter: Calciphylaxis/*diagnosis/etiology/therapy Humans Long-Term Care Palliative Care Prognosis Risk Factors

Zusammenfassung: Calciphylaxis (calcific uremic arteriolopathy, CUA) is a rare disease at the interface of nephrology, dermatology and cardiovascular medicine. CUA typically occurs in chronic dialysis patients. However, anecdotal reports also exist about cases in patients without relevant kidney disease. Clinically CUA is characterized by the stepwise development of superficial painful sensations and cutaneous lesions similar to livedo reticularis. Skin necrosis and ulceration represent the full-blown, "late" clinical picture. Panniculitis and circumferential calcification of cutaneous arterioles dominate the histological picture together with endothelial detachment. The prognosis of CUA is poor due to high morbidity and mortality largely resulting from underlying cardiovascular disease or septicemia. The aetiology of CUA is incompletely understood. Previous oral anticoagulation with vitamin K antagonists is considered as a risk factor. Unfortunately, evidence-based therapeutic options are absent, since controlled treatment trials have not been conducted yet. Long-term pain and wound management are mandatory. In the absence of controlled prospective trials registry studies such as the German CUA registry (www.calciphylaxis.net) support data collecting and analysis upon good clinical practice and may stimulate exchange of expertise and networking.

25.
Ketteler, M. und Biggar, P. H.
Evolving calciphylaxis--what randomized, controlled trials can contribute to the capture of rare diseases
Clin J Am Soc Nephrol, 10(5):726-8
2015
ISSN: 1555-905X (Electronic) 1555-9041 (Linking)
24.
Ketteler, M. und Biggar, P. H.
Evolving calciphylaxis--what randomized, controlled trials can contribute to the capture of rare diseases
Clin J Am Soc Nephrol, 10(5):726-8
2015
ISSN: 1555-905X (Electronic) 1555-9041 (Linking)

Schlüsselwörter: Calcimimetic Agents/*therapeutic use Calciphylaxis/*epidemiology Cinacalcet Hydrochloride/*therapeutic use Female Humans Hyperparathyroidism, Secondary/*drug therapy Kidney Failure, Chronic/*therapy Male calcimimetics hemodialysis hyperparathyroidism parathyroid hormone vascular calcification

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