Randomized Trial of Etelcalcetide for Cardiac Hypertrophy in Hemodialysis

Dörr, Katharina; Kammer, Michael; Reindl‐Schwaighofer, Roman; Lorenz, Matthias; Prikoszovich, Thomas; Marculescu, Rodrig; Beitzke, Dietrich; Wielandner, Alice; Erben, Reinhold G.; Oberbauer, Rainer

doi:10.1161/circresaha.120.318556

Cited by 34 publications

(46 citation statements)

References 51 publications

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“…Noteworthy, these myocardial FGF-23 effects [6] were claimed to be independent of the FGF co-receptor Klotho. Furthermore, lowering FGF-23 levels has been shown to reduce LVM in dialysis patients [23], which is consistent with a study in Alport mice where lowing serum FGF-23 levels by DMP1 reintroduction resulted in reduced LVH [24].…”

Section: Discussion/conclusionsupporting

confidence: 85%

FGFR4 and Klotho Polymorphisms Are Not Associated with Cardiovascular Outcomes in Chronic Kidney Disease

et al. 2021

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Introduction: High plasma fibroblast growth factor 23 (FGF-23) predicts cardiovascular events in chronic kidney disease (CKD) patients. Experimental evidence suggests FGF receptor 4 (FGFR4) activation by FGF-23, and deficiency of the soluble form of its co-receptor Klotho promotes left-ventricular hypertrophy (LVH). To evaluate the clinical relevance of these findings, a Mendelian randomization study analyzed the association of genetic variants of FGFR4 and Klotho with echocardiographic parameters and cardiac events in CKD patients. Methods: The prospective Cardiovascular and Renal Outcome in CKD 2–4 Patients–The Fourth Homburg Evaluation study recruited CKD G2–G4 patients, of whom 519 consented to SNP genotyping (FGFR4: rs351855; Klotho: rs9536314). Echocardiographic examinations at baseline and 5 years later assessed prevalence of LVH by measurement of left-ventricular mass index (LVMI). Patients were followed for 5.1 ± 2.1 years for the primary endpoints of cardiac decompensation and atherosclerotic cardiovascular disease (ASCVD). Results: Carriers of the different alleles did neither differ in baseline LVMI (rs351855: p = 0.861; rs9536314: p = 0.379) nor in LVMI changes between baseline and follow-up (rs351855: p = 0.181; rs9536314: p = 0.995). Hundred and four patients suffered cardiac decompensation, and 144 patients had ASCVD. Time to cardiac decompensation (rs351855: p = 0.316; rs9536314: p = 0.765) and ASCVD (p = 0.508 and p = 0.800, respectively) did not differ between carriers of different alleles. Discussion/Conclusion: rs351855 and rs9536314 were not associated with LVMI or cardiac events. These findings do not provide evidence for a relevant clinical role of either FGFR4 stimulation or soluble form of Klotho deficiency in LVH development.

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Section: Discussion/conclusionsupporting

confidence: 85%

FGFR4 and Klotho Polymorphisms Are Not Associated with Cardiovascular Outcomes in Chronic Kidney Disease

et al. 2021

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“…This controversy has been fueled by a recent study showing that treatment of maintenance hemodialysis patients with secondary hyperparathyroidism and left ventricular hypertrophy with a vitamin D analog increased circulating intact FGF23 and aggravated left ventricular hypertrophy relative to a group treated with a calcimimetic that lowered circulating FGF23. (76) These findings support the notion that treatment of CKD patients with vitamin D analogs at the expense of increased FGF23 secretion may have untoward effects on cardiovascular endpoints.…”

Section: Physiological and Pathophysiological Role Of Fgf23-mediated Regulation Of Vitamin D Metabolismsupporting

confidence: 68%

FGF23 and Vitamin D Metabolism

Latic

Erben

2021

JBMR Plus

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Apart from its phosphaturic action, the bone-derived hormone fibroblast growth factor-23 (FGF23) is also an essential regulator of vitamin D metabolism. The main target organ of FGF23 is the kidney, where FGF23 suppresses transcription of the key enzyme in vitamin D hormone (1,25(OH) 2 D) activation, 1α-hydroxylase, and activates transcription of the key enzyme responsible for vitamin D degradation, 24-hydroxylase, in proximal renal tubules. The circulating concentration of 1,25(OH) 2 D is a positive regulator of FGF23 secretion in bone, forming a feedback loop between kidney and bone. The importance of FGF23 as regulator of vitamin D metabolism is underscored by the fact that in the absence of FGF23 signaling, the tight control of renal 1α-hydroxylase fails, resulting in overproduction of 1,25(OH) 2 D in mice and men. During recent years, big strides have been made toward a more complete understanding of the mechanisms underlying the FGF23-mediated regulation of vitamin D metabolism, especially at the genomic level. However, there are still major gaps in our knowledge that need to be filled by future research. Importantly, the intracellular signaling cascades downstream of FGF receptors regulating transcription of 1α-hydroxylase and 24-hydroxylase in proximal renal tubules still remain unresolved. The purpose of this review is to highlight our current understanding of the molecular mechanisms underlying the regulation of vitamin D metabolism by FGF23, and to discuss the role of these mechanisms in physiology and pathophysiology.

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“…Dörr found that FGF23 suppression by etelcalcetide inhibited the progression of LVH compared with alfacalcidol in hemodialysis patients [ 25 ]. New extended-release calcifediol deserved lesser impact on FGF-23 levels [ 26 ]. FGF-23 was not tested in this study.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D receptor gene polymorphism predicts left ventricular hypertrophy in maintenance hemodialysis

et al. 2022

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Background To verify that the single nucleotide polymorphisms (SNP) of vitamin D receptor (VDR) may lead to genetic susceptibility to left ventricular hypertrophy (LVH), the present study was designed to study four SNPs of VDR associated with LVH in maintenance hemodialysis (MHD) patients of Han nationality. Methods 120 MHD patients were recruited at Department of Nephrology, Zhongnan Hospital of Wuhan University to analyze the expression of genotype, allele and haplotype of Fok I, Bsm I, Apa I and Taq I in blood samples, and to explore their correlation with blood biochemical indexes and ventricular remodeling. Results The results showed that the risks of CVD included gender, dialysis time, heart rate, SBP, glycated hemoglobin, calcium, iPTH and CRP concentration. Moreover, LAD, LVDd, LVDs, IVST and LVMI in B allele of Bsm I increased significantly. Fok I, Apa I and Taq I polymorphisms have no significant difference between MHD with LVH and without LVH. Further study showed that VDR expression level decreased significantly in MHD patients with LVH, and the B allele was positively correlated with VDR Expression. Conclusion VDR Bsm I gene polymorphism may predict cardiovascular disease risk of MDH patients, and provided theoretical basis for early detection and prevention of cardiovascular complications.

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Randomized Trial of Etelcalcetide for Cardiac Hypertrophy in Hemodialysis

Cited by 34 publications

References 51 publications

FGFR4 and Klotho Polymorphisms Are Not Associated with Cardiovascular Outcomes in Chronic Kidney Disease

FGFR4 and Klotho Polymorphisms Are Not Associated with Cardiovascular Outcomes in Chronic Kidney Disease

FGF23 and Vitamin D Metabolism

Vitamin D receptor gene polymorphism predicts left ventricular hypertrophy in maintenance hemodialysis

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