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Further vitamin D analogs
No full textIn this brief review we point out the specificities of the vitamin D system that are necessary to understand why each change in the molecule can result in significantly different biologic effects. Vitamin D, with a specific receptor in most of the tissues, has innumerable potential therapeutic applications in many clinical fields. However, excessive pharmacologic increments of circulating natural metabolites carry the risk of significant side effects. To avoid this, natural vitamin D molecules have been modified to more selectively stimulate some tissues. Changes have been attempted on particular parts of the molecule in order to affect some specific step of the complex machinery that characterize the vitamin D system. The first modifications were those in the side chain of the molecule, which are expected to affect, either or both, the steps of binding to transfer protein or the interaction with catabolic enzymes. More recently other regions, like A-ring (involved with receptor interaction) or CD bicyclic ring (involved with molecule stability), have been modified to obtain always more selective products. Notably each modification of the molecule also affects its shape thus further and variably modifying its interaction with the VDR, with the transport proteins or the catabolic enzymes. As a consequence, the biologic effects of new molecules become less predictable and require in vitro evaluation, experimental animal studies and a complete and specific clinical validation in specific disease states. With thousands of analogs synthesized in the laboratories, only a minority are approved for clinical employment. Besides secondary hyperparathyroidism and osteoporosis, Vitamin D analogs can be employed in other clinical conditions like cancer and autoimmunity diseases. We briefly report on some new experimental or already approved analogs in their main clinical fields of employment
The bone and the kidney
No full textRenal tubular diseases may present with osteopenia, osteoporosis or osteomalacia, as a result of significant derangements in body electrolytes. In case of insufficient synthesis of calcitriol, as in renal failure, the more complex picture of renal osteodystrophy may develop. Hypothetically, also disturbed renal production of BMP-7 and Klotho could cause bone disease. However, the acknowledgment that osteocytes are capable of producing FGF23, a phosphaturic hormone at the same time modulating renal synthesis of calcitriol, indicates that it is also bone that can influence renal function. Importantly, a feed-back mechanism exists between FGF23 and calcitriol synthesis, while Klotho, produced by the kidney, determines activity and selectivity of FGF23. Identification of human diseases linked to disturbed production of FGF23 and Klotho underlines the importance of this new bone-kidney axis. Kidney and bone communicate reciprocally to regulate the sophisticated machinery responsible for divalent ions homeostasis and for osseous or extraosseous mineralisation processes. (C) 2010 Elsevier Inc. All rights reserved
[Update on the pathogenesis and possible therapeutic approach to vascular calcifications in patients with chronic renal failure].
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Parathyroidectomy in Chronic Kidney Disease
No full textChronic Kidney Disease (CKD) associates with disturbed modulation of hormones involved in calcium and phosphate homeostasis, with development of secondary hyperparathyroidism (SHPT). SHPT includes not only divalent ions derangements, but also renal bone disease (high turnover, low turnover and/or osteomalacia) and accelerated vascular and ectopic calcifications. In this way, SHPT resembles a true clinical syndrome named CKD-MBD, which is a recognized risk factor of all-causeand cardiovascular death. Long lasting stimulation of parathyroid hormone synthesis and secretion, as observed in CKD, causes specific and progressive histological changes responsible for the development of nodular hyperplastic glands unresponsive to physiologic inhibitors and thus characterized by hypercalcemia, elevated PTH levels and resistance to the available medical therapies. In these cases, surgicalparathyroidectomy (PTX) becomes the only therapeutic option. In this chapter we review current evidence on indications, types and clinical outcomes of PTX from a practical and clinical point of view
Oxygen extraction ratio to identify patients at increased risk of intradialytic hypotension
No full textIntradialytic hypotension (IDH) is a hemodynamic phenomenon recently associated with decreased blood oxygen saturation (SO2). The ratio between peripheral oxygen saturation (SpO2) and central venous SO2 (ScvO2) or Oxygen Extraction Ratio (OER), which represents a roughly estimate of the amount of oxygen claimed by peripheral tissues, might be used to estimate haemodialysis (HD) related hypoxic stress. Aim of this pilot study was to evaluate the relationship between OER increments during dialysis sessions (DeltaOER) and episodes of IDH. We enrolled chronic HD patients with permanent central venous catheter (CVC) and no fistula, in whom ScvO2 measurement is at hand. OER ([(SpO2-ScvO2)/SpO2]*100) was measured in three consecutive HD sessions (HD OER sessions) before HD, after 15', 30' and 60' min and at the end of HD. Then, a one-year follow-up was planned to record the number of IDH episodes. In the 28 enrolled patients (age 74±2.6years), during 12±1.2months of follow up, incidence of IDH was 3.6%. We divided patients into two groups, above or below the median value of DeltaOER at the end of HD, which was 36%. In these groups, the average incidence of IDH was 7% and 2% respectively (p<0.01), while OER values before HD were not different. Notably, in the high DeltaOER group the OER increment was evident since after 15' and was significantly higher than in the low ∆OER group (∆OER-15'=19±3.0% vs. 9.0±3.0%; p<0.05). By comparison, blood volume changes overlapped in the two groups (average change -9±0.8%). Values of ∆OER>19% after only 15' of HD treatment or>36% at the end of the session characterize patients with higher rates of hypotension. Intradialytic ∆OER, a parameter of tissue hypoxic stress, identifies more fragile patients at greater risk of IDH
A simple visual clot scoring system allows reduction of the dose of low molecular weight heparin in hemodialysis
No full textPrevention of HD extracorporeal circuit clotting with LMWH is mandatory for adequate of hemodialysis treatment. The LMWH recommended dosage is 100-50 IU/Kg/HD given in a single pre-dialysis bolus but LMWH has dose-dependent side effects and clinical tools are needed to optimize the dose with the aim of reducing it. We have used a visual clots score identifying the post treatment clotting status of the hemodialysis circuit. It is based on the presence or absence of clots in dialyzer and/or in arterial and/or in venous HD circuit chambers at the end of the HD session with a score ranging from 0 (no clot) to 3 (clots in the 3 segments of the HD circuit Fig 1). Our aim was to modify the standard and routinely fixed dose of LMWH according to the average monthly score (reduction if clots score ≤ 0,5; increment if > 1,5). We then compared the average total dose administered to 90 HD patients one year before and one year after the introduction of the scoring system. The average dose of LMWH per single patient dropped from 64.6±18.5IU/kg/HD (equal to a total 645.457±219.488 IU/year) in 2016 to 53.6±18.3 IU/Kg /HD (equal to a total 484,492±235,546 IU/year) in 2017 (Figure2.p<0.001) without increments of the coagulation score. Our experience shows that a rather simple clots score system allows to individualize LMWH therapy, with a significant reduction of the dosage. The potential reduction of the renowned and dose-dependent side-effects of this drug should evaluated in further studie
Positioning novel biologicals in CKD-mineral and bone disorders
Full text linkRenal osteodystrophy (ROD), the histologic bone lesions of chronic kidney disease (CKD), is now included in a wider syndrome with laboratory abnormalities of mineral metabolism and extra-skeletal calcifications or CKD-mineral and bone disorders (CKD-MBD), to highlight the increased burden of mortality. Aging people, frequently identified as early CKD, could suffer from either the classical age-related osteoporosis (OP) or ROD. Distinguishing between these two bone diseases may not be easy without bone biopsy. In any case, besides classical therapies for ROD, nephrologists are now challenged by the possibility of using new drugs developed for OP. Importantly, while therapies for ROD mostly aim at controlling parathyroid secretion with bone effects regarded as indirect, new drugs for OP directly modulate bone cells activity. Thus, their action could be useful in specific types of ROD. Parathyroid hormone therapy, which is anabolic in OP, could be useful in renal patients with low turnover bone disease. Denosumab, the monoclonal antibody against receptor activator of NF-κB ligand (RANK-L) that inhibits osteoclast activity and proliferation, could be beneficial in cases with high turnover bone. Use of romosozumab, the monoclonal antibody against sclerostin, which both stimulates osteoblasts and inhibits osteoclasts, could allow both anabolic and anti-resorptive effects. However, we should not forget the systemic role now attributed to CKD-MBD. In fact, therapies targeting bone cells activity could also result in unpredicted extra-bone effects and affect cardiovascular outcomes. In conclusion, the new biologicals established for OP could be useful in renal patients with either OP or ROD. In addition, their potential non-bone effects warrant investigation
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