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Short-term effects of sevelamer-carbonate on fibroblast growth factor 23 and pulse wave velocity in patients with normophosphataemic chronic kidney disease Stage 3.

ABSTRACT: Background:High concentrations of both phosphate and fibroblast growth factor 23 (FGF23) observed in chronic kidney disease (CKD) are associated with an increased risk of cardiovascular morbidity and mortality. Pulse wave velocity (PWV) is a surrogate marker for cardiovascular events and all-cause mortality. It is not known whether a reduction of FGF23 or phosphate alters cardiovascular risk. Sevelamer has shown to have the ability to reduce both phosphate and FGF23 concentrations. Furthermore, reduction of PWV is reported with sevelamer use as well, but it is unclear if this is mediated by decline of phosphate or FGF23. We investigated if sevelamer induced a decline in PWV and if this was associated with a reduction in FGF23. Methods:In all, 24 normophosphataemic CKD Stage 3 patients started treatment with a fixed dose of sevelamer-carbonate (Renvela®) 2.4 g twice daily, with their usual diet for 8?weeks in a single-arm study. PWV was measured and blood samples were obtained before, during and after washout of treatment with sevelamer. Vascular calcification was quantified using the Kauppila Index (KI). The primary outcome was the change of PWV from baseline to 8 weeks of treatment and the secondary endpoint was the difference of FGF23 following treatment with sevelamer. One of the linear mixed models was used to analyse the association between treatment and outcome. Mediation analysis was performed as a sensitivity analysis. The study was registered in the Dutch trial register (http://www.trialregister.nl: NTR2383). Results:A total of 18 patients completed 8?weeks of treatment with sevelamer and were analysed. Overall, treatment with sevelamer did not induce a significant reduction of PWV (? = -0.36, P = 0.12). However, in patients with less vascular calcification (lower KI score), there was a statistically significant reduction of PWV, adjusted for mean arterial pressure, after treatment (? = 0.63, P = 0.02). Addition of FGF23 to the model did not alter this association. Mediation analysis yielded similar results. FGF23 did not decrease during treatment with sevelamer. Conclusion:In this short-term pilot study in normophosphataemic CKD patients, treatment with sevelamer did not improve PWV. In subgroup analysis, however, PWV improved in patients with no or limited abdominal aorta calcifications. This was not associated with a decline of FGF23.

SUBMITTER: Bouma-de Krijger A

PROVIDER: S-EPMC6768309 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Short-term effects of sevelamer-carbonate on fibroblast growth factor 23 and pulse wave velocity in patients with normophosphataemic chronic kidney disease Stage 3.

Bouma-de Krijger Annet A van Ittersum Frans J FJ Hoekstra Tiny T Ter Wee Pieter M PM Vervloet Marc G MG

Clinical kidney journal 20190325 5

<h4>Background</h4>High concentrations of both phosphate and fibroblast growth factor 23 (FGF23) observed in chronic kidney disease (CKD) are associated with an increased risk of cardiovascular morbidity and mortality. Pulse wave velocity (PWV) is a surrogate marker for cardiovascular events and all-cause mortality. It is not known whether a reduction of FGF23 or phosphate alters cardiovascular risk. Sevelamer has shown to have the ability to reduce both phosphate and FGF23 concentrations. Furth ...[more]

PMID: 31584563

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Project description:BACKGROUND AND OBJECTIVES:Epidemiologic studies suggest that higher serum phosphaturic hormone fibroblast growth factor 23 levels are associated with increase morbidity and mortality. The aim of the FGF23 Reduction Efficacy of a New Phosphate Binder in CKD Trial was to evaluate the effect of sevelamer carbonate on serum C-terminal fibroblast growth factor 23 levels in normophosphatemic patients with CKD stage 3b/4. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Patients with CKD, eGFR between 45 and 15 ml/min per 1.73 m2, fasting serum phosphate concentration >3.1 mg/dl, and serum C-terminal fibroblast growth factor 23 >80 relative units/ml were included in our double-blind, placebo-controlled, randomized multicenter study. All patients received 100,000 IU cholecalciferol at time of randomization. Participants received either placebo or sevelamer carbonate 4.8 g daily during a 12-week period. Biologic parameters, including serum C-terminal fibroblast growth factor 23, intact fibroblast growth factor 23, and ?-klotho, were evaluated at baseline and 12 weeks after inclusion. RESULTS:Of 96 screened patients, 78 (mean±SD age: 63±13 years old; 70% men; mean eGFR: 27±9 ml/min per 1.73 m2) met the inclusion criteria. At baseline, mean eGFR was 27±9 ml/min per 1.73 m2, mean serum phosphate level was 3.8±0.5 mg/dl, and median (interquartile range) serum C-terminal fibroblast growth factor 23 level was 157 (120-241) relative units/ml. After 12 weeks of treatment, urinary phosphate-to-creatinine ratio fell significantly in the sevelamer group. The sevelamer and placebo groups did not differ significantly in terms of median change in serum C-terminal fibroblast growth factor 23 levels: the median (interquartile range) change was 38 (-13-114) relative units/ml in the placebo group and 37 (-1-101) relative units/ml in the sevelamer group (P=0.77). There was no significant difference in serum intact fibroblast growth factor 23, ?-klotho, or phosphate levels changes between the two groups. Serum total and LDL cholesterol levels fell significantly in the sevelamer group. CONCLUSIONS:In our double-blind, placebo-controlled, randomized study performed in normophosphatemic patients with CKD, a 12-week course of sevelamer carbonate significantly reduced phosphaturia without changing serum phosphorus but did not significantly modify serum C-terminal fibroblast growth factor 23 and intact fibroblast growth factor 23 or ?-klotho levels.

Project description:BackgroundFibroblast growth factor 23 (FGF23) is a phosphaturic hormone that is secreted from bone and serum level increases as renal function declines. Higher levels of FGF23 are associated with increased mortality in hemodialysis-patients and in patients with chronic kidney disease (CKD) stage 2-4. The use of active vitamin D and phosphate binders as recommended in international guidelines, may affect the level of FGF23 and thereby clinical outcome. We investigated the effects of a phosphate binder and active vitamin D on the serum levels of intact FGF23 (iFGF23) and intact parathyroid hormone (iPTH) in patients with CKD stage 3b (glomerular filtration rate (GFR) 30-44 ml/min/1.73 m(2)).MethodsSeven women and 14 men were included, mean age 65.6 ± 12.2 years. They were randomized in a 1:1 ratio to receive one of two treatment sequences. Group-1 (the alphacalcidol-sevelamer carbonate group): alphacalcidol 0.25 μg once daily for two weeks followed by sevelamer carbonate 800 mg TID with meals for two weeks after a two-week washout period. Group-2 (the sevelamer carbonate-alphacalcidol group): vice versa. Nineteen patients completed the study. The 25-hydroxyvitamin D level at baseline was 97.6 ± 25.0 nmol/l.ResultsThere were no treatment effects on the iFGF23 and iPTH levels overall. In group-1 the iFGF23 level was higher after treatment with alphacalcidol compared with sevelamer carbonate (mean 105.8 ± 41.6 vs. 79.1 ± 36.5 pg/ml, p = 0.047 (CI: 0.4-52.9), and the iPTH level was lower (median: 26.5, range: 14.6-55.2 vs. median 36.1, range 13.4-106.9 pg/ml, p = 0.011). In group-2 the iFGF23 level increased non-significantly after treatment with sevelamer carbonate and throughout the washout period.ConclusionsIn this crossover trial with alphacalcidol and sevelamer carbonate in patients with CKD stage 3b, the levels of iFGF23 were not significantly different after the two treatments. However, in the group of patients initiating therapy with sevelamer carbonate the iFGF23 levels seemed to increase while this response was mitigated in the group of patients given alphacalcidol followed by sevelamer carbonate. This may have therapeutic implications on choice of first line therapy. The number of patients is small and this conclusion is in part based on subgroup analysis. It is therefore important that these results are confirmed in larger studies.Trial registrationTrial registration numberEuropean Clinical Trial Database (EudraCT) 2010-020415-36 and Clinical Trials.gov NCT01231438.

Project description:BACKGROUND:In end-stage renal disease (ESRD) patients, increased arterial stiffness detected by carotid-femoral pulse wave velocity (cf-PWV) is associated with fatal cardiovascular events and all-cause mortality. Since cf-PWV is an operator-dependent technique, poor reproducibility may be a source of bias in the estimation of arterial stiffness. OBJECTIVES:We assessed the week-to-week reproducibility of cf-PWV and radial artery pulse wave analysis in healthy subjects and ESRD patients. We also determined the extent of patient eligibility, enrollment, acceptance, and comfort. METHODS:In a cohort study design, independent tonometric examinations of carotid, femoral, and radial arteries were conducted in 20 healthy subjects and 15 ESRD patients attending chronic hemodialysis treatments according to a randomized sequence by two operators on 2 days scheduled 1-week apart. cf-PWV, augmentation index (AIx@HR75) and central pulse pressure (CPP) were the outcome measures. Patients were tested at mid-week and prior to dialysis treatment. The variability on the distance measured between the suprasternal notch and femoral site using two different methods (standard vs direct) was compared. A post-examination survey assessed acceptance and comfort associated with examinations. Reproducibility was evaluated by intra-class correlations (ICCs). RESULTS:The mean age for healthy subjects and ESRD patients was 45?±?12 and 63?±?16 years, respectively. ESRD patients had higher cf-PWV (p?=?0.0002), elevated AIx@HR75 (p?=?0.003), and increased CPP (p?=?0.001) compared to healthy subjects. The mean inter-visit differences for all stiffness indices were non-significant (p?>?0.05), but the mean inter-operator differences for the cf-PWV were significant only in the healthy subject group (-0.7 m/s; p?=?0.02). The ICCs between operators and visits were higher for the ESRD group compared to the healthy subjects (between operators, 0.870 vs 0.461; between visits, 0.830 vs 0.570). Distances were longer (p?<?0.001), but less variable with the standard method compared to the direct method (healthy subjects, p?=?0.036; ESRD, p?=?0.39). There was a high rate of patient acceptance and minimal discomfort. CONCLUSIONS:Week-to-week measurements of cf-PWV and pulse wave analysis are highly reproducible in ESRD patients prior to hemodialysis treatment. The high reproducibility and minimal test-to-test variations encourage use of cf-PWV to monitor changes in arterial stiffness and the efficacy of interventions in ESRD patients. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02196610.

Dataset Information

Short-term effects of sevelamer-carbonate on fibroblast growth factor 23 and pulse wave velocity in patients with normophosphataemic chronic kidney disease Stage 3.

Publications

Short-term effects of sevelamer-carbonate on fibroblast growth factor 23 and pulse wave velocity in patients with normophosphataemic chronic kidney disease Stage 3.

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