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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
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.

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,
ISSN: 1460-2385 (Electronic) 0931-0509 (Linking)

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.

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,
ISSN: 1460-2385 (Electronic) 0931-0509 (Linking)

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.

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
ISSN: 2048-8505 (Print) 2048-8505 (Linking)

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.


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
ISSN: 2048-8505 (Print) 2048-8505 (Linking)

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 ( 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.

Brandenburg, V. M., Martin, H., Sohn, C. M. und Ketteler, M.
Dtsch Med Wochenschr, 140(5):347-51
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 ( support data collecting and analysis upon good clinical practice and may stimulate exchange of expertise and networking.

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
ISSN: 1555-905X (Electronic) 1555-9041 (Linking)


Aoun, A., Baubion, E., Banydeen, R., Djiconkpode, I., Ekindi, N., Urena-Torres, P., Riaux, A., Sadreux, T., Dueymes, J. M., Quist, D. und Derancourt, C.
[Incidence and characteristics of calciphylaxis in Martinique (2006-2012)]
Ann Dermatol Venereol, 141(12):743-9
ISSN: 0151-9638 (Print) 0151-9638 (Linking)

Schlüsselwörter: Amputation Calciphylaxis/*epidemiology/etiology/therapy Female Humans Hyperparathyroidism, Secondary/complications Incidence Kidney Failure, Chronic/complications/surgery/therapy Kidney Transplantation Leg Ulcer/etiology Male Martinique/epidemiology Postoperative Complications/epidemiology/etiology Prognosis Renal Dialysis Retrospective Studies Thiosulfates/therapeutic use

Zusammenfassung: BACKGROUND: Calciphylaxis is a rare and severe disease with an annual incidence of around 1 % in dialysis patients. The main study aim was to determine its incidence in Martinique, where there is a significant population of patients on dialysis. PATIENTS AND METHODS: All patients diagnosed with calciphylaxis between 2006 and 2012 and living in Martinique were included, retrospectively. Social, demographic, biological, anatomic, pathological, histological and outcome data were analysed. RESULTS: Fifteen patients were included (8 women, 7 men). The incidence of calciphylaxis in this population was about 4.62/1,000,000 inhabitants per year. All patients presented very painful skin ulcerations and necrosis, chiefly on the lower extremities in 53.3 % of cases. All patients were on haemodialysis and two had undergone renal transplantation. Fourteen of the 15 patients were presenting secondary hyperparathyroidism, 12 had hypertension, 9 peripheral arterial disease, 8 obesity and 8 diabetes mellitus. Raised calcium and phosphorus were noted in 8 patients, with hypoalbuminaemia in 9 patients. Treatment with sodium thiosulfate was given for 8 patients, and was beneficial for all after a mean duration of 3.4 months. After 6 months of follow-up, 8 of the 15 patients were cured, 1 showed improvement and 6 had died. CONCLUSION: To our knowledge, this is the first study to examine the incidence of calciphylaxis in the general population. The relatively large number of patients could be accounted for by the high number of comorbidities in end-stage renal disease patients in Martinique, including obesity, diabetes, hypertension and arteritis. Treatment with sodium thiosulfate was beneficial for 8 patients.

Brandenburg, V. M. und Kruger, T.
Calcifediol - more than the stepchild of CKD-MBD therapy?
Curr Vasc Pharmacol, 12(2):286-93
ISSN: 1875-6212 (Electronic) 1570-1611 (Linking)

Schlüsselwörter: Calcifediol/blood/*therapeutic use Fibroblast Growth Factors/blood Humans Liver/metabolism Parathyroid Hormone/blood Renal Insufficiency, Chronic/*drug therapy/metabolism Renal Osteodystrophy/drug therapy Vitamin D/metabolism Vitamin D Deficiency/complications

Zusammenfassung: In patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), 25OH-vitamin D (calcidiol) deficiency or insufficiency is a common finding with high prevalence. Numerous epidemiological studies have found an independent association of low levels of calcidiol with increased morbidity and mortality. Within different patient cohorts, application of cholecalciferol or ergocalciferol (native vitamin D) as well as calcifediol can help replenish vitamin D levels in patients with and without renal disease. However, it is unclear if such an approach is effective in modifying relevant clinical end-points. Currently available data are insufficient to clearly define situations in which calcifediol therapy might be superior to ergocalciferol or cholecalciferol therapy in terms of increasing calcidiol levels in CKD / ESRD. Similar to ergocalciferol or cholecalciferol application, also calcifediol therapy needs to undergo testing in randomized, controlled trials (RCT) in severe CKD or ESRD with reasonable end-points before recommendations about therapy can be established.

Cozzolino, M., Urena-Torres, P., Vervloet, M. G., Brandenburg, V., Bover, J., Goldsmith, D., Larsson, T. E., Massy, Z. A., Mazzaferro, S. und ERA-EDTA, Ckd-Mbd Working Group of
Is chronic kidney disease-mineral bone disorder (CKD-MBD) really a syndrome?
Nephrol Dial Transplant, 29(10):1815-20
ISSN: 1460-2385 (Electronic) 0931-0509 (Linking)

Schlüsselwörter: *Bone Density Bone Diseases, Metabolic/metabolism/*pathology Calcinosis/metabolism/*pathology Humans Hyperphosphatemia/metabolism/*pathology Renal Insufficiency, Chronic/metabolism/*pathology Syndrome

Zusammenfassung: The concept of chronic kidney disease-mineral bone disorder (CKD-MBD) does not appear to fulfil the requirements for a syndrome at first glance, but its definition has brought some clear-cut benefits for clinicians and patients, including wider and more complex diagnostic and therapeutic approaches to the management of this challenging set of issues. Admittedly, not all components of CKD-MBD are present in all patients at all times, but these are highly interrelated, involving mineral and bone laboratory abnormalities, clinical and histological bone disease and finally, cardiovascular disease. The presence of typical biological bone ossification processes in an ectopic anatomical location in CKD has helped to define the existence of an unprecedented bone-vascular relationship, extending its interest even to other medical specialities. For now, we believe that CKD-MBD does not reach full criteria to be defined as a syndrome. However, this novel concept has clearly influenced current clinical guidelines. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF/KDOQI) guidelines in 2003 for instance recommended that calcium-based phosphate binders should be avoided to treat hyperphosphataemia in the presence of cardiovascular calcifications. In 2009, the KDIGO and other guidelines reinforced and extended this recommendation by stating that it is reasonable to choose oral phosphate binder therapy by taking into consideration other components of CKD-MBD. Similarly, it is also considered reasonable to use information on vascular/valvular calcification to guide the management of CKD-MBD. Our current assumption as a working group 'CKD-MBD' is that CKD-MBD has the potential to be defined a true syndrome, such as a constellation of concurrent signs and symptoms that suggest a common underlying mechanism for these components as opposed to the term disease. The term 'syndrome' also implies that in any patient at risk due to the presence of one or a few components of the entire syndrome, the screening for additional components is highly recommended. However, it has not currently been demonstrated that there is an additive predictive value, which can be derived from identifying individual components. Despite all we have learned about this putative syndrome, we have been left with only a hypothetical framework about how to treat patients. So while we agree that the concept of CKD-MBD has influenced, and continues to influence, our current clinical hypotheses, definitive proof of a benefit of interventions in CKD-MBD is still lacking and a global-multiple therapeutic approach to treat simultaneously several components of CKD-MBD should be tested by well-designed new randomized controlled trials.

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