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Heine, G. H., Brandenburg, V. and Schirmer, S. H.
Oral Anticoagulation in Chronic Kidney Disease and Atrial Fibrillation
Dtsch Arztebl Int, 115(17):287-294
ISSN: 1866-0452 (Electronic) 1866-0452 (Linking)

Abstract: BACKGROUND: Cardiological societies recommend, in their guidelines, that patients with atrial fibrillation and an intermediate (or higher) risk of stroke and systemic embolization should be treated with oral anticoagulant drugs. For patients who do not have mitral valve stenosis or a mechanical valve prosthesis, non-vitamin-K dependent oral anticoagulants (NOAC) are preferred over vitamin K antagonists (VKA) for this purpose. It is unclear, however, whether patients with chronic kidney disease and atrial fibrillation benefit from oral anticoagulation to the same extent as those with normal kidney function. It is also unclear which of the two types of anti - coagulant drug is preferable for patients with chronic kidney disease; NOAC are, in part, renally eliminated. METHODS: This review is based on pertinent publications retrieved by a selective literature search, and on international guidelines. RESULTS: Current evidence suggests that patients with atrial fibrillation who have chronic kidney disease with a glomerular filtration rate (GFR) above 15 mL/ min/1.73 m(2) should be treated with an oral anticoagulant drug if they have an at least intermediate risk of embolization, as assessed with the CHA2DS2-VASc score. For patients with advanced chronic kidney disease (GFR from 15 to 29 mL/ min/1.73 m(2)), however, this recommendation is based only on registry studies. For dialysis patients with atrial fibrillation, decisions whether to give oral anticoagulant drugs should be taken on an individual basis, in view of the elevated risk of hemorrhage and the unclear efficacy of such drugs in these patients. The subgroup analyses of the NOAC approval studies show that, for patients with atrial fibrillation and chronic kidney disease with a creatinine clearance of >25-30 mL/min, NOAC should be given in preference to VKA, as long as the patient does not have mitral valve stenosis or a mechanical valve prosthesis. For those whose creatinine clearance is less than 25 mL/min, the relative merits of NOAC versus VKA are still debated. CONCLUSION: The cardiological societies' recommendation that patients with atrial fibrillation should be given oral anticoagulant drugs applies to the majority of such patients who also have chronic kidney disease.

Nigwekar, S. U., Thadhani, R. and Brandenburg, V. M.
N Engl J Med, 379(4):399-400
ISSN: 1533-4406 (Electronic) 0028-4793 (Linking)

Keywords: *Calciphylaxis Humans

Nigwekar, Sagar U, Thadhani, Ravi and Brandenburg, Vincent M
New England Journal of Medicine, 378(18):1704-1714
ISSN: 0028-4793


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

Keywords: Esrd anticoagulation calcification calciphylaxis cardiovascular

Abstract: 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.

Brandenburg, V. M. and Sinha, S.
Calciphylaxis: Another Piece of the Puzzle
Am J Nephrol, 46(5):427-428
ISSN: 1421-9670 (Electronic) 0250-8095 (Linking)
Rothe, H., Brandenburg, V., Haun, M., Kollerits, B., Kronenberg, F., Ketteler, M. and 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
ISSN: 1932-6203 (Electronic) 1932-6203 (Linking)

Abstract: 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.


Brandenburg, V. M., D'Haese, P., Deck, A., Mekahli, D., Meijers, B., Neven, E. and 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
ISSN: 1432-198X (Electronic) 0931-041X (Linking)

Keywords: 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

Abstract: 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.

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. and 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
ISSN: 1460-2385 (Electronic) 0931-0509 (Linking)

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

Abstract: 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.

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

Keywords: Cua calcific uraemic arteriolopathy cinacalcet parathyroid hormone skin ulcers

Abstract: 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.


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

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

Abstract: 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 ( 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 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.

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