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      Efficacy and safety of lanthanum carbonate on chronic kidney disease–mineral and bone disorder in dialysis patients: a systematic review

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          Abstract

          Background

          Chronic kidney disease–mineral and bone disorder (CKD–MBD) is a common complication in CKD patients, particularly in those with end-stage renal disease that requires dialysis. Lanthanum carbonate (LC) is a potent, non-aluminum, non-calcium phosphate binder. This systematic review evaluates the efficacy and safety of LC in CKD-MBD treatment for maintenance-dialysis patients.

          Methods

          A systematic review and meta-analysis on randomized controlled trials (RCTs) and quasi-RCTs was performed to assess the efficacy and safety of LC in maintenance hemodialysis or peritoneal dialysis patients. Analysis was performed using the statistical software Review Manager 5.1.

          Results

          Sixteen RCTs involving 3789 patients were identified and retained for this review. No statistical difference was found in all-cause mortality. The limited number of trials was insufficient to show the superiority of LC over other treatments in lowering vascular calcification or cardiovascular events and in improving bone morphology, bone metabolism, or bone turn-over parameters. LC decreased the serum phosphorus level and calcium × phosphate product (Ca × P) as compared to placebo. LC, calcium carbonate (CC), and sevelamer hydrochloride (SH) were comparable in terms of controlling the serum phosphorus, Ca × P product, and intact parathyroid hormone (iPTH) levels. However, LC resulted in a lower serum calcium level and a higher bone-specific alkaline phosphatase level compared with CC. LC had higher total cholesterol and low-density lipoprotein (LDL) cholesterol levels compared with SH. LC-treated patients appeared to have a higher rate of vomiting and lower risk of hypercalcemia, diarrhea, intradialytic hypotension, cramps or myalgia, and abdominal pain. Meta-analysis showed no significant difference in the incidence of other side effects. Accumulation of LC in blood and bone was below toxic levels.

          Conclusions

          LC has high efficacy in lowering serum phosphorus and iPTH levels without increasing the serum calcium. Current evidence does not show a higher rate of adverse effects for LC compared with other treatments, except for a higher incidence of vomiting. Moreover, LC accumulation in blood and bone was below toxic levels. Well-designed studies should be conducted to evaluate the long-term effects of LC.

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          Most cited references56

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          Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients.

          Elevated serum phosphorus and calcium are associated with arterial calcification and mortality in dialysis patients. Unlike calcium-based binders, sevelamer attenuates arterial calcification but it is unknown whether sevelamer affects mortality or morbidity. In a multicenter, randomized, open-label, parallel design trial we compared sevelamer and calcium-based binders on all-cause and cause-specific mortality (cardiovascular, infection, and other) in prevalent hemodialysis patients. A total of 2103 patients were initially randomized to treatment and 1068 patients completed the study. All-cause mortality rates and cause-specific mortality rates were not significantly different. There was a significant age interaction on the treatment effect. Only in patients over 65 years of age was there a significant effect of sevelamer in lowering the mortality rate. There was a suggestion that sevelamer was associated with lower overall, but not cardiovascular-linked, mortality in older patients. We suggest that further research is needed to confirm these findings.
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            Effects of sevelamer on HbA1c, inflammation, and advanced glycation end products in diabetic kidney disease.

            Increased inflammation and oxidative stress may be caused by proteins and lipids modified by cytotoxic advanced glycation end products (AGEs) in food. Restricting food containing elevated AGEs improves these risk factors in diabetic CKD. Because diet adherence can be problematic, this study aimed to remove cytotoxic AGEs from food already ingested and to determine whether sevelamer carbonate sequesters cytotoxic AGEs in the gut, preventing their uptake and thereby reducing AGE-induced abnormalities. This single-center, randomized, 2-month, open-label, intention-to-treat, crossover study compared sevelamer carbonate with calcium carbonate treatment in stage 2-4 diabetic CKD. Participants received 2 months of treatment with one drug, had a 1-week washout, and then received the opposite drug for 2 months. Sevelamer carbonate reduced HbA1c, serum methylglyoxal, serum (ε)N-carboxymethyl-lysine, triglycerides, and 8-isoprostanes. Total cholesterol and fibroblast growth factor 23 were reduced by sevelamer carbonate, relative to calcium carbonate. AGE receptor 1 and sirtuin 1 mRNA were increased and PMNC TNFα levels were decreased by sevelamer carbonate, but not calcium carbonate. Medications and caloric and AGE intake remained unchanged. Sevelamer carbonate reversibly bound AGE-BSA at intestinal, but not stomach, pH. Sevelamer carbonate significantly reduces HbA1c, fibroblast growth factor 23, lipids, and markers of inflammation and oxidative stress, and markedly increases antioxidant markers, independently of phosphorus in patients with diabetes and early kidney disease. These novel actions of sevelamer carbonate on metabolic and inflammatory abnormalities in type 2 diabetes mellitus may affect progression of early diabetic CKD.
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              Disordered mineral metabolism in hemodialysis patients: an analysis of cumulative effects in the Hemodialysis (HEMO) Study.

              Serum markers of disordered mineral metabolism have been associated with adverse outcomes in patients requiring long-term dialysis therapy. Although the values of these markers often evolve over time, no study has examined the accumulated effects of these abnormalities on important clinical end points. Retrospective cohort study. 1,846 prevalent hemodialysis patients randomly assigned in the Hemodialysis (HEMO) Study. Serum phosphorus, calcium, calcium-phosphorus (Ca x P) product, and intact parathyroid hormone, each analyzed at the time of randomization (baseline), as a standard time-dependent covariate and as a cumulative time-dependent covariate. All-cause mortality and the composite of all-cause mortality and first cardiac hospitalization. Cox proportional hazards models. In all analyses, serum phosphorus level greater than 6 mg/dL was associated with a heightened risk of mortality of approximately 25% compared with phosphorus values of 4.1 to 5 mg/dL. Serum calcium level greater than 11 mg/dL was associated with a 60% greater risk of death, but only when this parameter was analyzed as either a time-dependent or cumulative time-dependent variable. Ca x P product greater than 50 mg(2)/dL(2) was strongly associated with mortality, but only when assessed cumulatively. Similar relationships were observed when phosphorus, calcium, and Ca x P product values were related to the composite end point of all-cause mortality and first cardiac hospitalization. No relationships between baseline, time-dependent, and cumulative time-dependent intact parathyroid hormone levels and the outcomes of interest were observed. Residual confounding, lack of access to patient information before randomization in the HEMO Study, and concerns regarding generalizability given changes in practice patterns since the completion of the HEMO Study. Cumulative time-dependent analyses provide a different framework for analyzing the impact of factors that may mediate adverse events in hemodialysis patients. Our findings support maintaining serum phosphorus levels at less than 6 mg/dL, calcium levels at less than 11 mg/dL, and Ca x P product at less than 50 mg(2)/dL(2).
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                Author and article information

                Contributors
                Journal
                BMC Nephrol
                BMC Nephrol
                BMC Nephrology
                BioMed Central
                1471-2369
                2013
                17 October 2013
                : 14
                : 226
                Affiliations
                [1 ]Department of nephrology, West China Hospital of Sichuan University, Chengdu, China
                [2 ]Luzhou Medical College, Luzhou, China
                Article
                1471-2369-14-226
                10.1186/1471-2369-14-226
                3853136
                24134531
                29bc9721-aaef-4938-bf68-fbef165c454e
                Copyright © 2013 Zhang et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 April 2013
                : 11 October 2013
                Categories
                Research Article

                Nephrology
                lanthanum carbonate,chronic kidney disease mineral and bone disorder,hemodialysis,peritoneal dialysis,systematic review

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