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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,
ISSN: 1432-198X (Electronic) 0931-041X (Linking)

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., Martin, H., Sohn, C. M. and Ketteler, M.
Dtsch Med Wochenschr, 140(5):347-51
ISSN: 1439-4413 (Electronic) 0012-0472 (Linking)

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

Abstract: 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. and 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)
Schlieper, G., Schurgers, L., Brandenburg, V., Reutelingsperger, C. and Floege, J.
Vascular calcification in chronic kidney disease: an update
Nephrol Dial Transplant,
ISSN: 1460-2385 (Electronic) 0931-0509 (Linking)

Abstract: Cardiovascular calcification is both a risk factor and contributor to morbidity and mortality. Patients with chronic kidney disease (and/or diabetes) exhibit accelerated calcification of the intima, media, heart valves and likely the myocardium as well as the rare condition of calcific uraemic arteriolopathy (calciphylaxis). Pathomechanistically, an imbalance of promoters (e.g. calcium and phosphate) and inhibitors (e.g. fetuin-A and matrix Gla protein) is central in the development of calcification. Next to biochemical and proteinacous alterations, cellular processes are also involved in the pathogenesis. Vascular smooth muscle cells undergo osteochondrogenesis, excrete vesicles and show signs of senescence. Therapeutically, measures to prevent the initiation of calcification by correcting the imbalance of promoters and inhibitors appear to be essential. In contrast to prevention, therapeutic regression of cardiovascular calcification in humans has been rarely reported. Measures to enhance secondary prevention in patients with established cardiovascular calcifications are currently being tested in clinical trials.


Aoun, A., Baubion, E., Banydeen, R., Djiconkpode, I., Ekindi, N., Urena-Torres, P., Riaux, A., Sadreux, T., Dueymes, J. M., Quist, D. and 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)

Keywords: 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 Calciphylaxie Calciphylaxis End-stage renal disease Haemodialysis Hemodialyse Insuffisance renale chronique terminale Martinique Sodium thiosulphate Thiosulfate de sodium

Abstract: 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., Cozzolino, M. and Mazzaferro, S.
Calcific uremic arteriolopathy: a call for action
Semin Nephrol, 34(6):641-7
ISSN: 1558-4488 (Electronic) 0270-9295 (Linking)

Keywords: Antioxidants/*therapeutic use Biomedical Research Calciphylaxis/epidemiology/*etiology/metabolism/*therapy Diphosphonates/therapeutic use Humans Kidney Failure, Chronic/*complications Naphthalenes/therapeutic use Parathyroidectomy Risk Factors Thiosulfates/*therapeutic use Vitamin K/metabolism

Abstract: Calciphylaxis (calcific uremic arteriolopathy [CUA]) is a threatening disease that increasingly is acknowledged as a challenging condition at the interface of nephrology, dermatology, and cardiology. The primary CUA diagnosis is determined most often in nephrology care units because the vast majority of affected cases are detected in patients with advanced or end-stage renal disease. The typical clinical cascade starts with severe pain in initially often inconspicuous skin areas, which might progress to deep tissue ulcerations. Ulcer development is a severe complication with particularly high morbidity and mortality. Unfortunately, there has been a certain stagnancy regarding the slow progress in our understanding of how and why CUA develops. In addition, several important open issues regarding therapy have not been addressed successfully yet. Therefore, the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) scientific working group Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBD) has accepted the challenge and has initiated a call for action by defining calciphylaxis as one of the outstanding research targets for the upcoming years.

Brandenburg, V. M., Sinha, S., Specht, P. and Ketteler, M.
Calcific uraemic arteriolopathy: a rare disease with a potentially high impact on chronic kidney disease-mineral and bone disorder
Pediatr Nephrol, 29(12):2289-98
ISSN: 1432-198X (Electronic) 0931-041X (Linking)

Keywords: Arteries *Calcinosis Humans Renal Insufficiency, Chronic/*complications *Skin Diseases *Ulcer *Vascular Diseases

Abstract: Calciphylaxis [calcific uraemic arteriolopathy (CUA)] is a rare disease at the interface of nephrology, dermatology and cardiology. CUA most often occurs in adult dialysis patients. It is only rarely seen in patients without relevant chronic kidney disease, and only anecdotal reports about childhood calciphylaxis have been published. Clinically, CUA is characterized by a typical cascade, starting with severe pain in initially often inconspicuous skin areas, followed by progressive cutaneous lesions that may develop into deep tissue ulcerations. The typical picture is a mixture of large retiform ulceration with thick eschar surrounded by violaceous, indurated, tender plaques. The histopathological picture reveals arteriolar, often circumferential, calcification and extensive matrix remodelling of the subcutis. These findings explain the macroscopic correlation between skin induration and ulceration. The prognosis in CUA patients is limited due to underlying comorbidities such as uraemic cardiovascular disease and infectious complications. The etiology of CUA is multifactorial, and imbalances between pro- and anti-calcification factors, especially in the setting of end-stage renal disease play an outstanding role. Oral anticoagulant treatment with vitamin K antagonists is a predominant CUA trigger factor. It is speculative as to why children and adolescents only develop calciphylaxis in exceptional cases, although a seldom usage of vitamin K antagonists and the preserved mineral buffering capacity of the growing skeleton may be protective.

Deserno, T. M., Haak, D., Brandenburg, V., Deserno, V., Classen, C. and Specht, P.
Integrated image data and medical record management for rare disease registries. A general framework and its instantiation to theGerman Calciphylaxis Registry
J Digit Imaging, 27(6):702-13
ISSN: 1618-727X (Electronic) 0897-1889 (Linking)

Keywords: Calciphylaxis/*diagnosis Database Management Systems/organization & administration/*statistics & numerical data Databases, Factual/*statistics & numerical data Germany Humans Internet Medical Records Systems, Computerized/organization & administration/*statistics & numerical data Rare Diseases/*diagnosis Registries/*statistics & numerical data

Abstract: Especially for investigator-initiated research at universities and academic institutions, Internet-based rare disease registries (RDR) are required that integrate electronic data capture (EDC) with automatic image analysis or manual image annotation. We propose a modular framework merging alpha-numerical and binary data capture. In concordance with the Office of Rare Diseases Research recommendations, a requirement analysis was performed based on several RDR databases currently hosted at Uniklinik RWTH Aachen, Germany. With respect to the study management tool that is already successfully operating at the Clinical Trial Center Aachen, the Google Web Toolkit was chosen with Hibernate and Gilead connecting a MySQL database management system. Image and signal data integration and processing is supported by Apache Commons FileUpload-Library and ImageJ-based Java code, respectively. As a proof of concept, the framework is instantiated to the German Calciphylaxis Registry. The framework is composed of five mandatory core modules: (1) Data Core, (2) EDC, (3) Access Control, (4) Audit Trail, and (5) Terminology as well as six optional modules: (6) Binary Large Object (BLOB), (7) BLOB Analysis, (8) Standard Operation Procedure, (9) Communication, (10) Pseudonymization, and (11) Biorepository. Modules 1-7 are implemented in the German Calciphylaxis Registry. The proposed RDR framework is easily instantiated and directly integrates image management and analysis. As open source software, it may assist improved data collection and analysis of rare diseases in near future.

Evenepoel, P., Rodriguez, M. and Ketteler, M.
Laboratory abnormalities in CKD-MBD: markers, predictors, or mediators of disease?
Semin Nephrol, 34(2):151-63
ISSN: 1558-4488 (Electronic) 0270-9295 (Linking)

Keywords: Biomarkers Bone Diseases, Metabolic/blood/*complications/etiology Calcium/physiology Fibroblast Growth Factors/physiology Humans Parathyroid Hormone/physiology Phosphates/physiology Renal Insufficiency, Chronic/blood/*complications/etiology Toxins, Biological Uremia/etiology Vitamin D/physiology Calcium Fgf23 Pth hyperphosphatemia klotho uremic toxins vitamin D

Abstract: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is characterized by bone abnormalities, vascular calcification, and an array of laboratory abnormalities. The latter classically include disturbances in the parathyroid hormone/vitamin D axis. More recently, fibroblast growth factor 23 (FGF23) and klotho also have been identified as important regulators of mineral metabolism. Klotho deficiency and high circulating FGF23 levels precede secondary hyperparathyroidism in CKD patients. Levels of FGF23 and parathyroid hormone increase along the progression of CKD to maintain mineral homeostasis and to overcome end-organ resistance. It is hard to define when the increase of both hormones becomes maladaptive. CKD-MBD is associated with adverse outcomes including cardiovascular disease and mortality. This review summarizes the complex pathophysiology of CKD-MBD and outlines which laboratory abnormalities represent biomarkers of disease severity, which laboratory abnormalities are predictors of cardiovascular disease, and which laboratory abnormalities should be considered (direct) uremic toxins exerting organ damage. This information may help to streamline current and future therapeutic efforts.


Cozzolino, M.
Prevention and Treatment of CKD-MBD
Nephrourol Mon, 5(2):773-4
ISSN: 2251-7006 (Print) 2251-7006 (Linking)

Keywords: Renal Insufficiency, Chronic Vascular Calcification Vitamin D

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