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Galassi, A., Bellasi, A., Auricchio, S., Papagni, S. and Cozzolino, M.
Which vitamin D in CKD-MBD? The time of burning questions
Biomed Res Int, 2013:864012
ISSN: 2314-6141 (Electronic)

Keywords: Animals Chronic Kidney Disease-Mineral and Bone Disorder/*drug therapy/*physiopathology *Evidence-Based Medicine Humans Treatment Outcome Vitamin D/*administration & dosage/*adverse effects

Abstract: Vitamin D is a common treatment against secondary hyperparathyroidism in renal patients. However, the rationale for the prescription of vitamin D sterols in chronic kidney disease (CKD) is rapidly increasing due to the coexistence of growing expectancies close to unsatisfactory evidences, such as (1) the lack of randomized controlled trials (RCTs) proving the superiority of any vitamin D sterol against placebo on patients centered outcomes, (2) the scanty clinical data on head to head comparisons between the multiple vitamin D sterols currently available, (3) the absence of RCTs confirming the crescent expectations on nutritional vitamin D pleiotropic effects even in CKD patients, (4) the promising effects of vitamin D receptors activators (VDRA) against proteinuria and myocardial hypertrophy in diabetic CKD cohorts, and (5) the conflicting data on the impact on mortality of VDRA versus calcimimetic centered regimens to control CKD-MBD. The present review arguments these issues focusing on the opened questions that nephrologists should consider dealing with the prescription of nutritional vitamin D or VDRA and with the choice of a VDRA versus a calcimimetic based regimen in CKD-MBD patients.

Kramann, R., Brandenburg, V. M., Schurgers, L. J., Ketteler, M., Westphal, S., Leisten, I., Bovi, M., Jahnen-Dechent, W., Knuchel, R., Floege, J. and Schneider, R. K.
Novel insights into osteogenesis and matrix remodelling associated with calcific uraemic arteriolopathy
Nephrol Dial Transplant, 28(4):856-68
ISSN: 1460-2385 (Electronic) 0931-0509 (Linking)

Keywords: Adult Aged Apoptosis Blotting, Western Calciphylaxis/metabolism/*pathology Calcium/*metabolism Case-Control Studies Cell Proliferation Cell Survival Enzyme-Linked Immunosorbent Assay Extracellular Matrix/*metabolism Female Humans Immunoenzyme Techniques Kidney Failure, Chronic/metabolism/*pathology Male Middle Aged Osteogenesis/*physiology RNA, Messenger/genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Skin Diseases/metabolism/*pathology Uremia/metabolism/*pathology Young Adult

Abstract: BACKGROUND: Calcific uraemic arteriolopathy (CUA) or calciphylaxis is a rare, life-threatening disease predominantly occurring in patients with end-stage renal disease. Its pathogenesis has been suggested to include ectopic osteogenesis in soft tissue and the vasculature associated with extracellular matrix (ECM) remodelling. METHODS: To gain further insights into the pathogenesis of CUA, we performed systematic analyses of skin specimens obtained from seven CUA patients including histology, immunohistochemistry, electron microscopy, electron dispersive X-ray analysis (EDX) and quantitative real-time RT-PCR. Skin specimens of (i) seven patients without chronic kidney disease and without CUA and (ii) seven dialysis patients without CUA served as controls. RESULTS: In the CUA skin lesions, we observed a significant upregulation of bone morphogenic protein 2 (BMP-2), its target gene Runx2 and its indirect antagonist sclerostin. Furthermore, we detected an increased expression of inactive uncarboxylated matrix Gla protein (Glu-MGP). The upregulation of osteogenesis-associated markers was accompanied by an increased expression of osteopontin, fibronectin, laminin and collagen I indicating an extensive remodelling of the subcutaneous ECM. EDX analysis revealed calcium/phosphate accumulations in the subcutis of all CUA patients with a molar ratio of 1.68 +/- 0.06 matching that of hydroxyapatite mineral. Widespread media calcification in cutaneous arterioles was associated with destruction of the endothelial layer and partial exfoliation of the endothelial cells (ECs). CD31 immunostaining revealed aggregates of ECs contributing to intraluminal obstruction and consecutive malperfusion resulting in the clinical picture of ulcerative necrosis in all seven patients. CONCLUSIONS: Our data indicate that CUA is an active osteogenic process including the upregulation of BMP-2 signalling, hydroxyapatite deposition and extensive matrix remodelling of the subcutis.

Kruger, T., Brandenburg, V., Schlieper, G., Marx, N. and Floege, J.
Sailing between Scylla and Charybdis: oral long-term anticoagulation in dialysis patients
Nephrol Dial Transplant, 28(3):534-41
ISSN: 1460-2385 (Electronic) 0931-0509 (Linking)

Keywords: Anticoagulants/*therapeutic use Coumarins/*therapeutic use Humans Kidney Failure, Chronic/*drug therapy Risk Assessment

Abstract: End-stage renal disease (ESRD) patients exhibit an increased risk of bleeding compared with non-chronic kidney disease (CKD) patients due to uraemic platelet dysfunction, altered vessel architecture and other factors. This renders any long-term oral anticoagulation potentially difficult. While there is little doubt that ESRD patients with recurrent thromboembolism or a mechanical cardiac valve should receive vitamin K antagonists (coumarins), the use of coumarins in ESRD patients with atrial fibrillation is a matter of debate. In non-CKD patients, current guidelines strongly recommend the use of oral anticoagulants for stroke prophylaxis in atrial fibrillation if certain risk factors are present (CHA2DS2-VASc score). This recommendation is often extrapolated to patients with advanced CKD or ESRD but data supporting this practice are weak to absent. Besides an increased bleeding risk in ESRD patients, coumarins will also accelerate cardiovascular calcification and are potent risk factors for the development of calcific uraemic arteriolopathy (calciphylaxis). Novel coumarin alternatives such as direct thrombin inhibitors are promising but none is currently approved for use in ESRD patients. Whether interventional treatment strategies such as atrial appendage occlusion are safe and effective options in advanced CKD is also as yet unresolved. This review attempts to balance the potential risks and benefits of coumarin usage in ESRD patients and to give the best possible recommendations for everyday patient care.


Brandenburg, V., Al-Fakhri, N., Nemeth, K., Goettsch, C., Schurgers, L. J., Vermeer, C., Hofbauer, L. C. and Schoppet, M.
Calcification inhibitors in vascular calciphylaxis associated with normal renal function
Thromb Haemost, 108(6):1241-3
ISSN: 0340-6245 (Print) 0340-6245 (Linking)

Keywords: Calcinosis/etiology/pathology/physiopathology Calciphylaxis/etiology/pathology/*physiopathology Calcium-Binding Proteins/blood/metabolism Extracellular Matrix Proteins/blood/metabolism Humans Kidney Function Tests Male Osteoprotegerin/blood/metabolism Vascular Diseases/etiology/pathology/*physiopathology Young Adult alpha-2-HS-Glycoprotein/metabolism

Brandenburg, V. M., Kramann, R., Specht, P. and Ketteler, M.
Calciphylaxis in CKD and beyond
Nephrol Dial Transplant, 27(4):1314-8
ISSN: 1460-2385 (Electronic) 0931-0509 (Linking)

Keywords: Anticoagulants/*adverse effects Calciphylaxis/*etiology Female Humans Kidney Failure, Chronic/*complications Male *Renal Dialysis Serum Albumin/*analysis Warfarin/*adverse effects

Abstract: Calciphylaxis is still an incompletely understood rare disease, which most often affects people on haemodialysis. For the majority of patients, calciphylaxis means a massive reduction in quality of life and is associated with high morbidity and mortality. We still know little about the concert of local and systemic risk factors and underlying causes that finally lead to the development of calciphylaxis. Recent work from Asia points towards persistent uncertainties in the diagnosis and management of the disease which the nephrology community has to address by establishing standards in both diagnosis as well as treatment strategies. Hayashi et al. have published results from a Japanese survey in which the authors collected data from calciphylaxis patients and compared clinical and laboratory data with those of control subjects. This innovative approach allowed the authors to calculate relative risks for various parameters in terms of calciphylaxis development. While uncontrolled hyperparathyroidism seemingly plays a secondary role, vitamin K antagonist usage proved to be of particular importance. Survey as well as registry data may help to close the gap in our knowledge about calciphylaxis which may ultimately result in improved prevention, patient care and outcome.

Cozzolino, M., Bruschetta, E., Cusi, D., Montanari, E., Giovenzana, M. E. and Galassi, A.
Phosphate handling in CKD-MBD from stage 3 to dialysis and the three strengths of lanthanum carbonate
Expert Opin Pharmacother, 13(16):2337-53
ISSN: 1744-7666 (Electronic) 1465-6566 (Linking)

Keywords: Animals Bone Diseases, Metabolic/*drug therapy/metabolism Fibroblast Growth Factors/metabolism Humans Lanthanum/*administration & dosage Phosphates/*metabolism Renal Dialysis Renal Insufficiency, Chronic/*drug therapy/metabolism

Abstract: INTRODUCTION: High phosphate levels are associated with unfavorable outcomes in ESRD. Recent data suggested that phosphate levels within the normal range are equally associated with poor outcomes in the community and CKD stage 3 - 4. Several concept papers support the potential role of phosphate load as a first-line toxin in the beginning of CKD-MBD processes via the activation of FGF23 cascade. Phosphate load is thereafter involved in the progression of vascular calcification (VC) and bone disorder typical of CKD-MBD. AREAS COVERED: Herein the authors cover the recent evidence on the pathophysiology of phosphate handling through the natural history of CKD, with particular emphasis on FGF23 cascade, its potential surrogate markers, VC and bone disorder. The major characteristics of lanthanum carbonate are therefore discussed, focusing on its potential advantages for the treatment of difficult cases in CKD-MBD. EXPERT OPINION: Lanthanum carbonate, being the most potent calcium-free phosphate binder available in clinical practice, could be decisive for those cases where controlling phosphate load is complicated by poor compliance to medications, stubborn high phosphorus intake, extended VC and bone disorders.


Brancaccio, D. and Cozzolino, M.
CKD-MBD: an endless story
J Nephrol, 24 Suppl 18:S42-8
ISSN: 1724-6059 (Electronic) 1121-8428 (Linking)

Keywords: Bone Diseases, Metabolic/*etiology/physiopathology Calcinosis/etiology/physiopathology Cardiovascular Diseases/etiology/physiopathology Chronic Disease Humans Kidney Diseases/*complications/physiopathology Minerals/*metabolism Receptors, Calcitriol/physiology Receptors, Calcium-Sensing/physiology

Abstract: Renal failure is a growing problem that involves a large part of the population and has a great social impact, with often incapacitating complications, mainly related to mineral bone disorders (MBD) and cardiovascular diseases. Analysis of the recent scientific literature confirms that a large number of chronic kidney disease (CKD) patients develop an early derangement of the parameters of Ca-P metabolism in which phosphate homeostasis and a reduced endogenous synthesis of calcitriol play a critical role. Recent findings from several large observational studies have also suggested that the benefits of vitamin D receptor activators may extend beyond the traditional parathyroid hormone-lowering effect, and could result in direct cardiovascular and metabolic benefits. Treatment of secondary hyperparathyroidism has become even more complex with the arrival of the calcium-sensing receptor agonist cinacalcet hydrochloride and with the uncovering of novel mechanisms responsible for secondary hyperparathyroidism. The aim of this review is the analysis of some of the recent contributions in the field of CKD-MBD, to update the understanding of the pathogenetic mechanisms and possibly the most appropriate therapeutic approach in this field.

Brandenburg, V. M., Cozzolino, M. and Ketteler, M.
Calciphylaxis: a still unmet challenge
J Nephrol, 24(2):142-8
ISSN: 1724-6059 (Electronic) 1121-8428 (Linking)

Keywords: Arterioles/pathology Calcinosis/physiopathology/prevention & control Calciphylaxis/drug therapy/*physiopathology/*prevention & control Chelating Agents/therapeutic use Chronic Disease Humans Kidney Diseases/*complications Skin/blood supply/pathology Thiosulfates/therapeutic use

Abstract: INTRODUCTION: Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is a rare disease most frequently occurring in patients with advanced chronic kidney disease (CKD). The clinical picture is typically characterized by very painful skin lesions and ulcerations following calcification and occlusion of small cutaneous arterioles. CUA is life-threatening due to infections and concomitant cardiovascular diseases. METHODS: We performed a literature search for the terms calciphylaxis and calcific uremic arteriolopathy and summarized current state-of-the-art knowledge about pathophysiology, clinical picture, course of the disease, as well as treatment options. We have filled out the literature data with our personal treatment experiences. RESULTS: A combination of various local and systemic risk factors are necessary to cause the development of calciphylaxis. This pathophysiological cascade is still incompletely understood. Patients with advanced CKD and dialysis patients are especially at risk to develop CUA. Regarding therapy, no randomized prospective trials are available, and treatment is rather based on pathophysiological considerations as well as on evidence derived from case reports or case series. Therapy focuses on optimized dialysis treatment, control of chronic kidney disease-mineral and bone disorder parameters, experimental anticalcification strategies and wound care. CONCLUSION: Facing the still deleterious outcome of patients with calciphylaxis, further studies on prophylaxis as well as treatment are urgently needed. Current treatment strategies may help ameliorate the course of the disease in some patients. However, it is still unclear if they are able to decrease mortality.

Brandenburg, V. M., Schmitz, S., Floege, J., Amann, K. and Ketteler, M.
[Calciphylaxis. A call for interdisciplinary cooperation]
Hautarzt, 62(6):452-8
ISSN: 1432-1173 (Electronic) 0017-8470 (Linking)

Keywords: Calciphylaxis/complications/*diagnosis/*therapy Humans Renal Insufficiency/complications/*diagnosis/*therapy Skin Diseases/complications/*diagnosis/*therapy Syndrome

Abstract: Calciphylaxis is a rare, often very painful and potentially life-threatening disorder at the interface between nephrology and dermatology. It is characterized by skin lesions and ulcerations following calcification and occlusion of cutaneous arterioles. Most patients have chronic kidney disease or are on dialysis. A concert of various, still incompletely understood local and systemic risk factors is necessary to cause the development of calciphylaxis. Since randomized prospective trials are missing, interdisciplinary treatment is based on pathophysiological considerations as well as evidence derived from case reports or case series. Normalization of mineral metabolism, intensifying dialysis and avoidance of coumarins, as well as administration of calcimimetics, bisphosphonates and sodium thiosulfate and hyperbaric oxygen therapy are often used. Supportive measures include analgesics, antibiotics and local wound care. We have initiated an internet-based registry for patients with calciphylaxis in order to collect data for improved patient care (with support from Amgen) (

Strehl, J. D., Brandenburg, V., Forster, C., Willam, C., Hartmann, A. and Amann, K.
[Calciphylaxis. A less well-known, clinically relevant disease]
Pathologe, 32(3):250-6
ISSN: 1432-1963 (Electronic) 0172-8113 (Linking)

Keywords: Aged Anti-Bacterial Agents/therapeutic use Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/pathology/therapy Arteries/pathology Calciphylaxis/etiology/*pathology/therapy Disease Progression Drug Therapy, Combination Fatal Outcome Female Humans Immunosuppressive Agents/adverse effects/therapeutic use Kidney/pathology Kidney Failure, Chronic/pathology/surgery/therapy *Kidney Transplantation Multiple Organ Failure/pathology Postoperative Complications/etiology/*pathology/therapy Renal Dialysis Risk Factors Shock, Septic/etiology/pathology/therapy Skin/pathology

Abstract: Calciphylaxis is a rare disease which has been increasingly reported in recent decades and has consequently shifted into the focus of clinical and scientific research. The clinical picture is characterized by extensive ischemic ulcerations of the skin and subcutis. Histologically, the small vessels in these lesions show prominent calcifications. Due to the extensive areas of ulceration and necrosis as well as frequently present comorbidities, patients with calciphylaxis are prone to infection and sepsis. In this work, we describe the case of a female kidney-transplant patient with vasculitis who, despite good graft function, developed a fulminant calciphylaxis of both thighs 4 years post transplantation and died of septic complications. The differential diagnoses as well as clinical procedures are described in detail in the case history. In the discussion, we give an overview of the current state of knowledge regarding the etiopathogenesis, risk factors, diagnostic measures and clinical management of calciphylaxis.

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