Effects of sevelamer treatment on cardiovascular abnormalities in mice with chronic renal failure

Maizel, Julien; Six, Isabelle; Dupont, Sébastien; Secq, Edouard; Dehedin, Benedicte; Barreto, Fellype Carvalho; Benchitrit, Joyce; Poirot, Sabrina; Slama, Michel; Tribouilloy, Christophe; Choukroun, Gabriel; Mazière, J.C.; Drueke, Tilman B.; Massy, Ziad A.

doi:10.1038/ki.2013.110

Cited by 54 publications

(49 citation statements)

References 47 publications

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“…We subsequently used the same animal model to test the effect of sevelamer administration on CKD-related CV abnormalities. 56 In line with the observed decrease in both hyperphosphatemia and FGF23 levels, sevelamer treatment reduced ED, aortic stiffness and left ventricular diastolic dysfunction and thus prevented the progression of left ventricular hypertrophy. We reported that sevelamer treatment is also associated with a decreased expression of proteins related to myocardial hypertrophy compared with CKD placebo mice.…”

Section: Animal Studiesmentioning

confidence: 60%

Vascular Toxicity of Phosphate in Chronic Kidney Disease

Gross

Six

Kamel

et al. 2014

Circ J

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In epidemiological studies of CKD patients and the general population, high phosphate levels are associated with CV disease (CVD). The association is even observed in early-stage CKD and is independent of other traditional CV risk factors. 5, 6 Along with other factors, hyperphosphatemia is involved in the development of vascular calcification (VC) and endothelial dysfunction (ED), 7-9 both of which are major nontraditional CV risk factors for CKD. Phosphate is able to act either directly on these parameters or indirectly via the FGF23/Klotho and PTH axes (Figure 1).We review the various effects of hyperphosphatemia on CV parameters, with a focus on its emerging role in ED. The efficacy of current therapies for improving phosphate-related CV outcomes is also discussed. Direct Effects of Phosphate on CV Calcification and ED Epidemiological and Interventional StudiesVC is deposition of calcium/phosphate, mostly as apatite, in the blood vessels, myocardium and cardiac valves. Calcification of both the intima and media occurs in CKD, 10 resulting in the stiffness of the large arteries (as evidenced by a higher pulse wave velocity) and thus promotion of CV morbidity/ mortality. The results of several epidemiological studies have highlighted an association between serum phosphate levels and VC in stage 5D CKD patients, 11,12 in early-stage CKD patients and in the general population (in whom serum phosphate levels are still within the normal range). 13, 14 Indeed, 2 elegant prospective studies of large cohorts of hosphate, principally provided by food, is involved in many physiological processes: it buffers the intracellular pH, ensures the stability of the skeleton and contributes to many essential biological functions (eg, DNA synthesis, cell membrane phospholipids, energy metabolism and intracellular signaling pathways that are regulated by phosphorylation/dephosphorylation).The physiological concentration of phosphate (0.8-1.5 mmol/L) is tightly regulated by, among others, the fibroblast growth factor 23 (FGF23)/Klotho axis, parathyroid hormone (PTH) and calcitriol (the active form of vitamin D). 1 In chronic kidney disease (CKD), the progressive loss of functional nephrons induces retention of phosphate, which in turn leads to (1) an increase in calcium/phosphate products and (2) FGF23 synthesis. With the aim of preventing hyperphosphatemia, FGF23 decreases circulating levels of calcitriol, thus inhibiting intestinal phosphate and calcium absorption. PTH, the overexpression of which is triggered by hypocalcemia, stimulates bone resorption for the primary purpose of restoring calcemia but in doing so it increases phosphatemia and thus the calcium/phosphate products. During the course of CKD, Klotho's downregulation in both the parathyroid gland and the kidney results in the loss of FGF23 being able to respectively (1) decrease PTH expression and (2) inhibit renal phosphate reabsorption. In late-stage CKD, the few remaining functional nephrons are no longer able to eliminate phosphate and a vicious circle (referred ...

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Section: Animal Studiesmentioning

confidence: 60%

Vascular Toxicity of Phosphate in Chronic Kidney Disease

Gross

Six

Kamel

et al. 2014

Circ J

Self Cite

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“…Even data from animal CKD models are unpersuasive, particularly in early progressive models of disease. Some studies either show a lack of response to phosphate restriction altogether (80) or relate improvement in cardiovascular function to changes in phosphate rather than FGF23 (103). While extreme, phosphate restriction (zero phosphate diet), however, has been associated with a paradoxical increase in plasma FGF23 (104).…”

Section: Dietary Phosphate Restriction and Oral Phosphate Bindersmentioning

confidence: 99%

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

Smith

2014

Clinical Journal of the American Society of Nephrology

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The emergence of fibroblast growth factor 23 as a potentially modifiable risk factor in CKD has led to growing interest in its measurement as a tool to assess patient risk and target therapy. This review discusses the analytical and clinical challenges faced in translating fibroblast growth factor 23 testing into routine practice. As for other bone mineral markers, agreement between commercial fibroblast growth factor 23 assays is poor, mainly because of differences in calibration, but also, these differences reflect the variable detection of hormone fragments. Direct comparison of readout from different assays is consequently limited and likely hampers setting uniform fibroblast growth factor 23-directed targets. Efforts are needed to standardize assay output to enhance clinical use. Fibroblast growth factor 23 is robustly associated with cardiovascular and renal outcomes in patients with CKD and adds value to risk assessments based on conventional risk factors. Compared with most other mineral markers, fibroblast growth factor 23 shows better intraindividual temporal stability, with minimal diurnal and week-to-week variability, but substantial interindividual variation, maximizing discriminative power for risk stratification. Conventional therapeutic interventions for the CKD-mineral bone disorder, such as dietary phosphate restriction and use of oral phosphate binders or calcimimetics, are associated with variable efficacy at modulating circulating fibroblast growth factor 23 concentrations, like they are for other mineral metabolites. Dual therapy with dietary phosphate restriction and noncalcium-based binder use achieves the most consistent fibroblast growth factor 23-lowering effect and seems best monitored using an intact assay. Additional studies are needed to evaluate whether strategies aimed at reducing levels or antagonizing its action have beneficial effects on clinical outcomes in CKD patients. Moreover, a better understanding of the mechanisms driving fibroblast growth factor 23 elevations in CKD is needed to inform the use of therapeutic interventions targeting fibroblast growth factor 23 excess. This evidence must be forthcoming to support the use of fibroblast growth factor 23 measurement and fibroblast growth factor 23-directed therapy in the clinic.

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“…To achieve the LPS binding in the gut, we used sevelamer, a LPS-sequestering, phosphate-binding drug that has been shown to reduce plasma LPS levels in patients with chronic kidney disease (15), in which the levels of microbial translocation are increased due to uremia-associated gut damage (16,17). We hypothesized that early in vivo blockade of microbial translocation in SIVsab-infected PTMs would result in the control of chronic immune activation/inflammation.…”

Section: Introductionmentioning

confidence: 99%

Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication

Kristoff¹,

Haret-Richter²,

Ma³

et al. 2014

J. Clin. Invest.

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Damage to the intestinal mucosa results in the translocation of microbes from the intestinal lumen into the circulation. Microbial translocation has been proposed to trigger immune activation, inflammation, and coagulopathy, all of which are key factors that drive HIV disease progression and non-HIV comorbidities; however, direct proof of a causal link is still lacking. Here, we have demonstrated that treatment of acutely SIV-infected pigtailed macaques with the drug sevelamer, which binds microbial lipopolysaccharide in the gut, dramatically reduces immune activation and inflammation and slightly reduces viral replication. Furthermore, sevelamer administration reduced coagulation biomarkers, confirming the contribution of microbial translocation in the development of cardiovascular comorbidities in SIV-infected nonhuman primates. Together, our data suggest that early control of microbial translocation may improve the outcome of HIV infection and limit noninfectious comorbidities associated with AIDS.

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Effects of sevelamer treatment on cardiovascular abnormalities in mice with chronic renal failure

Cited by 54 publications

References 47 publications

Vascular Toxicity of Phosphate in Chronic Kidney Disease

Vascular Toxicity of Phosphate in Chronic Kidney Disease

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication

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