Differential Effects of Dabigatran and Warfarin on Bone Volume and Structure in Rats with Normal Renal Function.

BACKGROUND: Warfarin, a widely used anticoagulant, is a vitamin K antagonist impairing the activity of vitamin K-dependent Bone Gla Protein (BGP or Osteocalcin) and Matrix Gla Protein (MGP). Because dabigatran, a new anticoagulant, has no effect on vitamin K metabolism, the aim of this study was to compare the impact of warfarin and dabigatran administration on bone structure and vascular calcification. METHODS: Rats with normal renal function received for 6 weeks warfarin, dabigatran or placebo. Bone was evaluated immuno-histochemically and hystomorphometrically after double labelling with declomycin and calcein. Aorta and iliac arteries were examined histologically. RESULTS: Histomorphometric analysis of femur and vertebrae showed significantly decreased bone volume and increased trabecular separation in rats treated with warfarin. Vertebra analysis showed that the trabecular number was higher in dabigatran treated rats. Osteoblast activity and resorption parameters were similar among groups, except for maximum erosion depth, which was higher in warfarin treated rats, suggesting a higher osteoclastic activity. Therefore, warfarin treatment was also associated with higher bone formation rate/bone surface and activation frequency. Warfarin treatment may cause an increased bone turnover characterized by increased remodelling cycles, with stronger osteoclast activity compared to the other groups. There were no differences among experimental groups in calcium deposition either in aortic or iliac arteries. CONCLUSIONS: These findings suggest for the first time that dabigatran has a better bone safety profile than warfarin, as warfarin treatment affects bone by reducing trabecular size and structure, increasing turnover and reducing mineralization. These differences could potentially result in a lower incidence of fractures in dabigatran treated patients.

Which cannulation technique for which patient.

Cannulation of arteriovenous (AV) access is a crucial part of vascular access management in hemodialysis patients. It can significantly affect survival of the AV access, and consequently, it probably influences patient survival. The best type of cannulation technique, rotating site versus constant site (or buttonhole), is currently debated, but the increase in infectious complications observed with the buttonhole technique suggests a prudent use of this technique, restricting it to specific patients. Even in cases with a specific indication, the balance between advantages of the constant site needling and the potentially severe consequences of access related systemic infection should be considered. Educational efforts in improving cannulation skills of dialysis staff are important for improving outcomes, as the proper use of the rotating site technique might still be the best approach to cannulation.

Dialysis central venous catheter types and performance.

The choice of both short-term (nontunneled) and long-term (tunneled) central venous catheters (CVCs) for hemodialysis is a difficult one, due to the large number of available catheters, with very different characteristics and cost.CVC-related complications (in particular infections, thrombosis and inefficient dialysis) can determine ominous consequences and death, with extremely elevated costs due to prolonged hospitalization and expensive procedures. Thus, the correct balance between cost and quality of CVC is required when deciding which kind of CVC should be adopted.In this regard, the design of CVCs has become a very active area of industrial and clinical research, with the ultimate goal of improving the long-term function of the catheter and of reducing complication rates, because even small improvements in the complication or reintervention rates have a positive impact on individual patient care and cost to society. In this article we review the general features of CVCs, including differences between tunneled and nontunneled CVCs, materials and their compatibility with lock solutions, the implications of straight versus precurved design in nontunneled CVCs, lumen and tip features with their clinical implications, catheter coatings and their effect on infection and thrombosis.

Management of secondary hyperparathyroidism in the elderly patient with chronic kidney disease.

Patients with chronic kidney disease (CKD) are generally affected by secondary hyperparathyroidism (SHPT). High phosphate, low calcium and vitamin D deficiency represent the classical 'triad' involved into the pathogenesis of SHPT in renal insufficiency, in which downregulation of the parathyroid vitamin D receptor and calcium-sensing receptor represents a critical step. Recently, new studies indicate that fibroblast growth factor 23 may play a central role in the regulation of phosphate-vitamin D metabolism in patients with CKD. These new insights into the pathogenesis of SHPT will possibly improve the treatment of this condition in patients with CKD. The 'modern' treatment of SHPT in CKD patients consists of free-calcium and aluminium phosphate binders, vitamin D receptor activators and calcimimetics. However, calcium- and aluminium-based phosphate binders and calcitriol are therapeutic tools that are not without complications, including increasing the risk of cardiovascular calcification in patients with CKD. This review summarizes the current understanding and evidence supporting strategies for SHPT treatment in CKD patients, with particular focus on the elderly, although specific guidelines for control of this disorder in this age group are lacking.

Importance of vitamin D receptor activation in clinical practice.

Continuously emerging evidence indicates that defi ciencies in 25-hydroxyvitamin D and consequently vitamin D receptor (VDR) activation play crucial roles in adversely affecting cardiovascular (CV) health in the general population and those at high risk of CV disease, as well as in patients with chronic kidney disease (CKD). In CKD patients, a lack of VDR activation is one of the main pathophysiological factors contributing to secondary hyperparathyroidism (SHPT). However, this lack of VDR activation has numerous additional implications on CV and renal function, with SHPT being only one symptom of a much more extensive disorder. VDRs are widely expressed throughout the body with manifold activities that involve feedback loops within the CV, immune, and renal systems. Modulation of VDR activator levels results in correlative regulatory effects on mineral homeostasis, hypertension, vascular disease, and vascular calcifi cation, as well as a number of other endpoints in cardiac and renal pathology. Among compounds available for the treatment of SHPT, paricalcitol is a selective VDR activator. The term 'selective' refers to paricalcitol being more selective in affecting VDR pathways in the PTH gland compared with bone and intestine. As such, paricalcitol's selectivity allows for a wider therapeutic window with effects beyond PTH control and mineral management, and may explain, in part, the increased survival advantage with paricalcitol treatment.

New acquisitions in therapy of secondary hyperparathyroidism in chronic kidney disease and peritoneal dialysis patients: role of vitamin D receptor activators.

Secondary hyperparathyroidism is a serious complication of chronic renal disease when function decline and is characterized by abnormalities in serum calcium and phosphate profile, along with a decline in calcitriol synthesis. A reduced density of specific receptors for vitamin D and calcium in several tissues and organs are also present, thus contributing to parathyroid hyperplasia and abnormal parathyroid hormone synthesis and secretion. This metabolic derangement is observable early in the course of chronic renal failure (stages 3 and 4) and on this basis it should also be treated early in order to avoid important clinical consequences. To afford secondary hyperparathyroidism, several strategies should be considered: phosphate oral intake control (diet and phosphate binders), adequate calcium oral intake, vitamin D receptor activation. More specifically, the concept of selective vitamin D receptor activation will be considered as well as its biological effects, the use of paricalcitol (a selective vitamin D receptor activator) given orally to patients on peritoneal dialysis, and stages 3 and 4 of chronic renal failure. Finally, we will consider a series of nonclassical interesting potential mechanisms of selective vitamin D receptor activation leading to reduced cardiovascular and all-cause mortality.

Pathogenesis of secondary hyperparathyroidism.

Chronic renal failure is the primary cause of secondary hyperparathyroidism (SHPT). Patients with mineral metabolism disorders commonly present with low serum calcium levels, hyperphosphatemia, and calcitriol deficiency. In normal renal function subjects, parathyroid cells have a low turnover and rarely undergo mitoses. In uremic conditions, however, parathyroid glands become hyperplasic and leave quiescence. During the last ten years, new molecular mechanisms have been investigated to better understand the pathogenesis of SHPT: the emerging role of the Calcium Sensing Receptor (CaSR); the importance of the parathyroid expression of the Vitamin D receptor (VDR); the growing evidence on the central role of the Fibroblast Growth Factor 23 (FGF-23). In contrast, the discovery of a parathyroid phosphate sensor or receptor has yet to be made.

Vitamin D: physiology and pathophysiology.

Although vitamin D was initially considered a nutrient, it has been recognized that the molecules derived from vitamin D metabolism are best considered as a complex endocrine system. In this review article we summarize the basic concepts regarding vitamin D metabolism, transport, and genomic activity through the vitamin D receptor, facilitating activation or suppression of target genes. We also examine non-genomic actions, biological responses to vitamin D in classic target organs (intestine, bone, kidneys, and parathyroid glands), and in organs and tissues not related to mineral homeostasis.

Preventive measures and new pharmacological approaches of calcium and phosphate disorders.

Abnormalities of bone mineral parameters (calcium, phosphate, vitamin D, and parathyroid hormone) are nearly omnipresent in patients with advanced chronic kidney disease (CKD). These typically consist of hypocalcemia, hyperphosphatemia, abnormalities of vitamin D metabolism, and secondary hyperparathyroidism (SHPT). Currently, several lines of evidence suggest that these abnormalities may have consequences beyond the typical consequence of renal bone disease, with a major role in determining cardiovascular disease, including arterial calcification. The 'classical' treatment of SHPT and hyperphosphatemia in HD patients consists of phosphate binders, vitamin D receptor activators (VDRAs), and/or calcimimetics. Calcium- or aluminum-based phosphate binder prescriptions and calcitriol administration are therapeutic tools not free of complications, increasing the risk of cardiovascular calcification in the HD population. New calcium- and aluminum-free phosphate binders, such as lanthanum carbonate and sevelamer hydrochloride, new VDRA (paricalcitol), and cinacalcet hydrochloride can be used to treat SHPT, slow down the atherosclerotic process, and prevent vascular calcification in HD patients.