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Coburg, Germany

Brandenburg V.M.,RWTH Aachen | Sinha S.,Foundation Medicine | Specht P.,RWTH Aachen | Ketteler M.,Klinikum Coburg
Pediatric Nephrology

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. © 2014 IPNA. Source

Cozzolino M.,University of Milan | Ketteler M.,Klinikum Coburg | Zehnder D.,Warwick Medical School
European Journal of Heart Failure

Chronic kidney disease (CKD) independently increases the rates of cardiovascular disease, whereas the severity of kidney disease correlates with increased cardiovascular morbidity and death. Vitamin D is modified in the liver and the kidney to its active form (1,25-dihydroxyvitamin D) by the 25-hydroxy vitamin D 1-hydroxylase enzyme (CYP27B1). The activated vitamin D brings about its actions through the vitamin D receptor (VDR). The VDRs and CYP27B1 have recently been shown to be expressed in several tissues, not directly involved in mineral homeostasis, including the cardiovascular, immune, and epithelial systems. The action of vitamin D in these tissues is implicated in the regulation of endothelial, vascular smooth muscle, and cardiac cell function, the renin-angiotensin system, inflammatory and fibrotic pathways, and immune response. Impaired VDR activation and signalling results in cellular dysfunction in several organs and biological systems, which leads to reduced bone health, an increased risk for epithelial cancers, metabolic disease, and uncontrolled inflammatory responses. Failure of cardiovascular VDR activation results in hypertension, accelerated atherosclerosis and vascular calcification, cardiac hypertrophy with vascular rarification and fibrosis, and progressive renal dysfunction. An emerging body of evidence has prompted attention to the relationship between CKD, mineral bone disorder (CKD-MBD), and cardiovascular disease in the new guidelines from Kidney Disease: Improving Global Outcomes. Vitamin D receptor activators, commonly used to treat CKD-MBD, and an appropriate treatment of vitamin D hormonal system failure in patients with CKD, may help to reduce cardiovascular morbidity and mortality in these patients. © 2010 The Author. Source

Brandenburg V.M.,RWTH Aachen | Cozzolino M.,University of Milan | Ketteler M.,Klinikum Coburg
Journal of Nephrology

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. © 2011 Società Italiana di Nefrologia. Source

Jahnen-Dechent W.,RWTH Aachen | Ketteler M.,Klinikum Coburg
CKJ: Clinical Kidney Journal

As a cofactor in numerous enzymatic reactions, magnesium fulfils various intracellular physiological functions. Thus, imbalance in magnesium status - primarily hypomagnesaemia as it is seen more often than hypermagnesaemia - might result in unwanted neuromuscular, cardiac or nervous disorders. Measuring total serum magnesium is a feasible and affordable way to monitor changes in magnesium status, although it does not necessarily reflect total body magnesium content. The following review focuses on the natural occurrence of magnesium and its physiological function. The absorption and excretion of magnesium as well as hypo- and hypermagnesaemia will be addressed. © The Author 2012. Source

Ketteler M.,Klinikum Coburg
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

Paricalcitol and cinacalcet are common therapies for patients on haemodialysis with secondary hyperparathyroidism (SHPT). We conducted a multi-centre study in 12 countries to compare the safety and efficacy of paricalcitol and cinacalcet for the treatment of SHPT. Patients aged ≥18 years with Stage 5 chronic kidney disease receiving maintenance haemodialysis and with intact parathyroid hormone (iPTH) 300-800 pg/mL, calcium 8.4-10.0 mg/dL (2.09-2.49 mmol/L) and phosphorus ≤6.5 mg/dL (2.09 mmol/L) were randomized within two strata defined by the mode of paricalcitol administration to treatment with paricalcitol- (intra-venous, US and Russian sites, IV stratum; oral, non-US and non-Russian sites, oral stratum) or cinacalcet-centred therapy. The primary endpoint is the proportion of patients in each treatment group who achieve a mean iPTH value of 150-300 pg/mL during Weeks 21-28 of treatment. Assuming efficacy response rates of 36 and 66% for cinacalcet and paricalcitol, respectively, and a 20% discontinuation rate, 124 subjects in each stratum were estimated to provide 81% power to detect a 30% absolute difference in the primary endpoint. Of 746 patients screened, 272 (mean age, 63 years; mean iPTH, 509 pg/mL) were randomized. Mean duration of haemodialysis at baseline was 3.7 years. Comorbidities included hypertension (90.4%), Type 2 diabetes (40.4%), congestive heart failure (17.3%), coronary artery disease (34.6%) and gastrointestinal disorders (75%). The study participants are representative of a multinational cohort of patients on haemodialysis with elevated iPTH. The study results will provide valuable information on the best available treatment of SHPT in patients on haemodialysis. Source

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