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      Role of etelcalcetide in the management of secondary hyperparathyroidism in hemodialysis patients: a review on current data and place in therapy

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          Abstract

          Secondary hyperparathyroidism (sHPT) is a frequently occurring severe complication of advanced kidney disease. Its clinical consequences include extraskeletal vascular and valvular calcifications, changes in bone metabolism resulting in renal osteodystrophy, and an increased risk of cardiovascular morbidity and mortality. Calcimimetics are a cornerstone of parathyroid hormone (PTH)-lowering therapy, as confirmed by the recently updated 2017 Kidney Disease: Improving Global Outcomes chronic kidney disease – mineral and bone disorder clinical practice guidelines. Contrary to calcitriol or other vitamin D-receptor activators, calcimimetics reduce PTH without increasing serum-calcium, phosphorus, or FGF23 levels. Etelcalcetide is a new second-generation calcimimetic that has been approved for the treatment of sHPT in adult hemodialysis patients. Whereas the first-generation calcimimetic cinacalcet is taken orally once daily, etelcalcetide is given intravenously thrice weekly at the end of the hemodialysis session. Apart from improving drug adherence, etelcalcetide has proven to be more effective in lowering PTH when compared to cinacalcet, with an acceptable and comparable safety profile. The hope for better gastrointestinal tolerance with intravenous administration did not come true, as etelcalcetide did not significantly mitigate the adverse gastrointestinal effects associated with cinacalcet. Enhanced adherence and strong reductions in PTH, phosphorus, and FGF23 could set the stage for a future large randomized controlled trial to demonstrate that improved biochemical control of mineral metabolism with etelcalcetide in hemodialysis patients translates into cardiovascular and survival benefits and better health-related quality of life.

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          Most cited references 51

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          Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.

          Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 is thought to be an early biomarker of disordered phosphorus metabolism in the initial stages of chronic kidney disease (CKD). We measured FGF23 in baseline samples from 3879 patients in the Chronic Renal Insufficiency Cohort study, which is a diverse cohort of patients with CKD stage 2-4. Mean serum phosphate and median parathyroid hormone (PTH) levels were in the normal range, but median FGF23 was markedly greater than in healthy populations, and increased significantly with decreasing estimated glomerular filtration rate (eGFR). High levels of FGF23, defined as being above 100 RU/ml, were more common than secondary hyperparathyroidism and hyperphosphatemia in all strata of eGFR. The threshold of eGFR at which the slope of FGF23 increased was significantly higher than the corresponding threshold for PTH based on non-overlapping 95% confidence intervals. Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increased phosphate or PTH. Hence, FGF23 measurements may be a sensitive early biomarker of disordered phosphorus metabolism in patients with CKD and normal serum phosphate levels.
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            Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.

            Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride. Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose. Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism. Copyright 2004 Massachusetts Medical Society
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              Fibroblast growth factor-23 and cardiovascular events in CKD.

              An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2-4 (baseline estimated GFR [eGFR], 44±15 ml/min per 1.73 m(2)). During a median follow-up of 3.7 years, 360 participants were hospitalized for CHF (27 events/1000 person-years) and 287 had an atherosclerotic event (22 events/1000 person-years). After adjustment for demographic characteristics, kidney function, traditional cardiovascular risk factors, and medications, higher FGF-23 was independently associated with graded risk of CHF (hazard ratio [HR], 1.45 per doubling [95% confidence interval (CI), 1.28 to 1.65]; HR for highest versus lowest quartile, 2.98 [95% CI, 1.97 to 4.52]) and atherosclerotic events (HR per doubling, 1.24 [95% CI, 1.09 to 1.40]; HR for highest versus lowest quartile, 1.76 [95% CI, 1.20 to 2.59]). Elevated FGF-23 was associated more strongly with CHF than with atherosclerotic events (P=0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, sodium intake, income, fat-free mass, left ventricular mass index, and ejection fraction. Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2-4.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                01 June 2018
                : 12
                : 1589-1598
                Affiliations
                [1 ]Department of Internal Medicine, Clinical Division of Nephrology, Medical University of Graz, Graz
                [2 ]Department of Internal Medicine III, Nephrology and Dialysis, Feldkirch Academic Teaching Hospital, Feldkirch, Austria
                Author notes
                Correspondence: Emanuel Zitt, Department of Internal Medicine III, Nephrology and Dialysis, Feldkirch Academic Teaching Hospital, 47 Carinagasse, Feldkirch 6800, Austria, Tel +43 5522 303 2700, Fax +43 5522 303 7506, Email emanuel.zitt@ 123456lkhf.at
                Article
                dddt-12-1589
                10.2147/DDDT.S134103
                5989700
                © 2018 Friedl and Zitt. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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