The FGF23–Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease—a prospective cohort study

Lindblad, Ylva Tranæus; Olauson, Hannes; Vavilis, Georgios; Hammar, Ulf; Herthelius, Maria; Axelsson, Jonas; Bárány, Peter

doi:10.1007/s00467-017-3766-5

Cited by 20 publications

(18 citation statements)

References 50 publications

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“…There is good evidence from clinical and experimental studies that both acute and chronic renal failure are associated with reduced expression of Klotho in the kidney, and with reduced sKlotho levels in the blood [ 43 ▪▪ , 44 – 47 ]. In agreement with these data, kidney transplantation in CKD patients results in a rapid rise in circulating sKlotho, and a decline in circulating FGF23 levels [ 48 ▪ , 49 ▪ ]. Conversely, treatment of mice with sKlotho improves outcome in acute and chronic renal injury models [ 50 ▪▪ ].…”

Section: Pathophysiological Role Of Klotho In Acute and Chronic Renalsupporting

confidence: 53%

α-Klothoʼs effects on mineral homeostasis are fibroblast growth factor-23 dependent

Erben

2018

Current Opinion in Nephrology and Hypertension

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Purpose of reviewα-Klotho (Klotho) occurs in three isoforms, a membrane-bound form acting as a coreceptor for fibroblast growth factor-23 (FGF23) signalling, a shed soluble form consisting of Klotho's large ectodomain thought to act as an enzyme or a hormone, and a secreted truncated form generated by alternative splicing of the Klotho mRNA with unknown function. The purpose of this review is to highlight the recent advances in our understanding of Klotho's function in mineral homeostasis.Recent findingsA number of seminal discoveries have recently been made in this area, shifting existing paradigms. The crystal structure of the ternary FGF receptor (FGFR)-1c/Klotho/FGF23 complex has been uncovered, revealing how the ligand FGF23 interacts with FGFR1c and the coreceptor Klotho at atomic resolution. Furthermore, it was shown that soluble Klotho lacks any glycosidase activity and serves as a bona fide coreceptor for FGF23 signalling. Experiments with a combination of Klotho and Fgf23-deficient mouse models demonstrated that all isoforms of Klotho lack any physiologically relevant, FGF23-independent functions in mineral homeostasis or ageing. Finally, it was demonstrated that the alternatively spliced Klotho mRNA is degraded and is not translated into a secreted Klotho protein isoform in humans.SummaryTaken together, there is now overwhelming evidence that the main physiological function of transmembrane and soluble Klotho for mineral homeostasis is their role as coreceptors mediating FGF23 actions. In light of these findings, the main pathophysiological consequence of the downregulation of Klotho observed in acute and chronic renal failure may be the induction of renal FGF23 resistance.

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Section: Pathophysiological Role Of Klotho In Acute and Chronic Renalsupporting

confidence: 53%

α-Klothoʼs effects on mineral homeostasis are fibroblast growth factor-23 dependent

Erben

2018

Current Opinion in Nephrology and Hypertension

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“…In those patients, high FGF23 and low Klotho levels were strongly associated with impaired left ventricular diastolic function [67]. In addition to this finding, FGF23 signaling via fibroblast growth factor receptor 4 (FGFR4) activates the phospholipase Cγ/calcineurin/nuclear factor of the activated T-cell pathway, and thus promotes cardiac myocyte hypertrophy, independent of its co-receptor Klotho [60,67]. Furthermore, FGFR4 signaling is responsible for FGF23-mediated increased cardiac contractility [68].…”

Section: Klothomentioning

confidence: 98%

“…In pediatric CKD patients, serum FGF23 levels increased and Klotho levels decreased with progressing renal failure, while phosphorus levels were maintained in the normal range [67]. In those patients, high FGF23 and low Klotho levels were strongly associated with impaired left ventricular diastolic function [67]. In addition to this finding, FGF23 signaling via fibroblast growth factor receptor 4 (FGFR4) activates the phospholipase Cγ/calcineurin/nuclear factor of the activated T-cell pathway, and thus promotes cardiac myocyte hypertrophy, independent of its co-receptor Klotho [60,67].…”

Section: Klothomentioning

confidence: 98%

“…Using Klotho-deficient mice, it could be shown that the Klotho-FGF23 axis plays a key role in pathologic cardiac remodeling in CKD, but also in phosphotoxicity and aging [66]. In pediatric CKD patients, serum FGF23 levels increased and Klotho levels decreased with progressing renal failure, while phosphorus levels were maintained in the normal range [67]. In those patients, high FGF23 and low Klotho levels were strongly associated with impaired left ventricular diastolic function [67].…”

Section: Klothomentioning

confidence: 99%

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Cardiac Remodeling in Chronic Kidney Disease

Kaesler

Babler

Floege

et al. 2020

Toxins

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Cardiac remodeling occurs frequently in chronic kidney disease patients and affects quality of life and survival. Current treatment options are highly inadequate. As kidney function declines, numerous metabolic pathways are disturbed. Kidney and heart functions are highly connected by organ crosstalk. Among others, altered volume and pressure status, ischemia, accelerated atherosclerosis and arteriosclerosis, disturbed mineral metabolism, renal anemia, activation of the renin-angiotensin system, uremic toxins, oxidative stress and upregulation of cytokines stress the sensitive interplay between different cardiac cell types. The fatal consequences are left-ventricular hypertrophy, fibrosis and capillary rarefaction, which lead to systolic and/or diastolic left-ventricular failure. Furthermore, fibrosis triggers electric instability and sudden cardiac death. This review focuses on established and potential pathophysiological cardiorenal crosstalk mechanisms that drive uremia-induced senescence and disease progression, including potential known targets and animal models that might help us to better understand the disease and to identify novel therapeutics.

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“…A two-dimensional guided M-mode measurement and conventional pulse wave Doppler were performed according to the American Society of Echocardiography guidelines [14]. Left atrial diameter, left ventricular end-diastolic volume (LVEDD), left ventricular posterior wall thickness (PWT), interventricular septal thickness (IVST), and LVEF were determined.…”

Section: Methodsmentioning

confidence: 99%

Relationship of Serum Soluble Klotho Levels and Echocardiographic Parameters in Patients on Maintenance Hemodialysis

Zhang

Guo

et al. 2019

Kidney Blood Press Res

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Background: Cardiovascular disease is the leading cause of morbidity and mortality in maintenance hemodialysis (MHD) patients. Uremic cardiomyopathy, characterized by myocardial hypertrophy and fibrosis, has a significant contribution to these adverse cardiac outcomes. The protective effect of soluble Klotho (s-Klotho) on myocardial damage was demonstrated in in vitro and animal experiments. However, data from MHD patients is limited. The present study was designed to identify potential correlations between echocardiographic parameters and serum s-Klotho levels in MHD patients. Methods: This is a cross-sectional study involving 105 MHD patients from the Dialysis Center of Capital Medical University affiliated Beijing Friendship Hospital between March and October 2014. The general information for each patient was recorded. Fasting blood samples were collected prior to hemodialysis during the mid-week session in all patients. The echocardiogram and left lateral lumbar spine radiograph were performed after the same mid-week session. The dialysis records for each session within 3 months before the blood tests were documented. According to the quartiles of s-Klotho levels, patients were divided into four groups (Group 1–4). The demographic and clinical characteristics, echocardiographic parameters, and abdominal aortic calcification scores among the groups were compared. Results: The enrolled 105 patients were predominantly male (54.3%) with an average age of 59.9 ± 11.2 years. Previous hemodialysis durations were 76 (42–133) months. Sixteen (15.2%) patients had diabetes mellitus. Mean serum s-Klotho level was 411.83 ± 152.95 pg/mL, and the 25th percentile, 50th percentile, and 75th percentile values of serum s-Klotho levels were 298.9, 412, and 498.2 pg/mL, respectively. Individuals in the bottom quartile of s-Klotho levels (Group 1) had significantly increased interventricular septal thickness (IVST) compared to those in the other three quartiles of s-Klotho levels (Group 1: 1.12 ± 0.16 cm; vs. Group 2: 1.12 ± 0.16 cm, p = 0.008; vs. Group 3: 0.94 ± 0.13 cm, p < 0.001; vs. Group 4: 1.03 ± 0.1 5 cm, p = 0.022). There were significant differences in the ratios of IVST and posterior wall thickness (PWT) between patients of Group 1 and Group 3 (1.12 ± 0.1 2 vs. 1.00 ± 0.1 4, p = 0.004). No significant differences were found for other parameters among the groups. The univariate correlation analyses showed that gender (r = –0.211, p = 0.030), Kt/V urea (r = –0.240, p = 0.014), hypersensitive C reactive protein (hs-CRP) (r = 0.196, p = 0.045), and serum s-Klotho levels (r = –0.260, p = 0.007) significantly correlated with IVST. Ultimately, only hs-CRP and serum s-Klotho levels were entered into a multiple regression model. Conclusions: The present study showed that patients with lower circulating s-Klotho levels were more often associated with larger IVST and greater ratios of IVST and PWT. There was an independent association between s-Klotho and IVST, and lower s-Klotho levels seem to be a potential risk factor of uremic...

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The FGF23–Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease—a prospective cohort study

Cited by 20 publications

References 50 publications

α-Klothoʼs effects on mineral homeostasis are fibroblast growth factor-23 dependent

α-Klothoʼs effects on mineral homeostasis are fibroblast growth factor-23 dependent

Cardiac Remodeling in Chronic Kidney Disease

Relationship of Serum Soluble Klotho Levels and Echocardiographic Parameters in Patients on Maintenance Hemodialysis

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