Fibroblast growth factor 23 and parathyroid hormone predict extent of aortic valve calcifications in patients with mild to moderate chronic kidney disease

Lullo, Luca Di; Gorini, Antonio; Bellasi, Antonio; Morrone, L F; Rivera, Rodolfo; Russo, Luigi; Santoboni, Alberto; Russo, Domenico

doi:10.1093/ckj/sfv073

Cited by 45 publications

(29 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this situation, the FGF23-mediated increase in renal-tubular calcium reabsorption may contribute to calcium retention and vascular calcification. The recently reported positive association between aortic valve calcification and serum FGF23 as well as serum PTH in patients with CKD supports this line or argumentation [76].…”

Section: Distal Tubular Calcium and Sodium Transportmentioning

confidence: 57%

FGF23-Klotho signaling axis in the kidney

Erben

Andrukhova

2017

Bone

138

110

View full text Add to dashboard Cite

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone protecting against the potentially deleterious effects of hyperphosphatemia by suppression of phosphate reabsorption and of active vitamin D hormone synthesis in the kidney. The kidney is one of the main target organs of FGF23 signaling. The purpose of this review is to highlight the recent advances in the area of FGF23-Klotho signaling in the kidney. During recent years, it has become clear that FGF23 acts independently on proximal and distal tubular epithelium. In proximal renal tubules, FGF23 suppresses phosphate reabsorption by a Klotho dependent activation of extracellular signal-regulated kinase-1/2 (ERK1/2) and of serum/glucocorticoid-regulated kinase-1 (SGK1), leading to phosphorylation of the scaffolding protein Na/H exchange regulatory cofactor (NHERF)-1 and subsequent internalization and degradation of sodium-phosphate cotransporters. In distal renal tubules, FGF23 augments calcium and sodium reabsorption by increasing the apical membrane expression of the epithelial calcium channel TRPV5 and of the sodium-chloride cotransporter NCC through a Klotho dependent activation of with-no-lysine kinase-4 (WNK4). In proximal and distal renal tubules, FGF receptor-1 is probably the dominant FGF receptor mediating the effects of FGF23 by forming a complex with membrane-bound Klotho in the basolateral membrane. The newly described sodium- and calcium-conserving functions of FGF23 may have major implications for the pathophysiology of diseases characterized by chronically increased circulating FGF23 concentrations such as chronic kidney disease.

show abstract

Section: Distal Tubular Calcium and Sodium Transportmentioning

confidence: 57%

FGF23-Klotho signaling axis in the kidney

Erben

Andrukhova

2017

Bone

138

110

View full text Add to dashboard Cite

show abstract

“…A large study including 6,814 people without cardiovascular disease demonstrated that higher serum phosphate levels were associated with a significantly greater prevalence of aortic valve calcification, without significant correlations of aortic valve calcification with serum FGF23 and iPTH levels or urinary phosphate excretion [30]. Another research reported that aortic valve calcification was significantly correlated with serum FGF23 and iPTH levels, but not with serum calcium, phosphate, or 25-hydroxyvitamin D levels in patients with mild to moderate CKD [31].…”

Section: Discussionmentioning

confidence: 99%

Serum Alkaline Phosphatase Level Predicts Cardiac Valve Calcification in Maintenance Hemodialysis Patients

Guo

Zhang

et al. 2020

Blood Purif

View full text Add to dashboard Cite

Cardiac valve calcification (CVC) is frequently occurred in maintenance hemodialysis (MHD) patients and is associated with cardiovascular and all-cause mortality. This study aimed to evaluate the relationships between risk factors and extent of CVC and further provide the treatment target in MHD patients. Methods: One hundred and fortyfive patients who received MHD ≥3 months were enrolled. CVC was assessed by an echocardiographic, semi-quantitative manner called global cardiac calcium scoring system (GCCS), and demographic, clinical, and laboratory parameters including mineral metabolism markers were collected. Results: The average age of the patients was 50 ± 12 years, and 54.5% were men. The mean GCCS was 1.8 ± 2.4; 57.2% of patients had GCCS ≥1. Age, dialysis vintage, serum alkaline phosphatase (ALP), and intact parathyroid hormone levels were positively correlated with CVC, whereas serum albumin levels were negatively related to CVC, based on univariate analysis. With multivariate linear regression analysis, serum ALP was the only bone-derived biomarker that showed significant correlation with CVC. Serum ALP ≥232 U/L was a robust predictor of CVC and was associated with the likelihood of GCCS ≥1 (OR 3.92, 95% CI 1.37-11.2, p = 0.011). The decision tree model was used to identify ALP ≥232 U/L and age ≥60 years as important determinative variables in the prediction of CVC in MHD patients. Conclusion: Serum ALP level is significantly associated with CVC in MHD patients. ALP is suggested to be a promising interventional target for cardiovascular calcification in MHD patients.

show abstract

“…Interestingly, aortic valve calcification score of patients is negatively correlated with circulating Klotho levels [41]. The Klotho −/− mouse model, which exhibits premature aging associated with hyperphosphatemia and low vitamin D, has been used to study age-related diseases, including CKD and vascular calcification.…”

Section: Discussionmentioning

confidence: 99%

Klotho suppresses high phosphate-induced osteogenic responses in human aortic valve interstitial cells through inhibition of Sox9

Yao

et al. 2017

J Mol Med

View full text Add to dashboard Cite

Elevated level of blood phosphate (Pi) associated with chronic kidney disease (CKD) is a risk factor of aortic valve calcification. Aortic valve interstitial cells (AVICs) display osteogenic responses to high Pi although the underlying mechanism is incompletely understood. Sox9 is a pro-chondrogenic factor and may play a role in ectopic tissue calcification. Circulating and kidney levels of Klotho are reduced in patients with CKD. We hypothesized that Sox9 mediates high Pi-induced osteogenic responses in human AVICs and that Klotho inhibits the responses. Treatment of human AVICs with high Pi increased protein levels of Runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP), and a prolonged exposure to high Pi caused calcium deposition. High Pi induced Sox9 upregulation through PKD and Akt activation. Knockdown of Sox9 essentially abolished the effect of high Pi on the osteogenic responses. Lower Klotho levels were observed in calcified aortic valve tissues. Interestingly, high Pi decreased Klotho levels in AVICs from normal valves, and treatment with recombinant Klotho markedly reduced the effect of high Pi on the levels of Sox9, Runx2, and ALP and suppressed calcium deposition. We conclude that high Pi induces human AVIC osteogenic responses through Sox9. Human AVICs express Klotho, and its levels in AVICs are modulated by high Pi and valvular calcification. Importantly, Klotho suppresses the pro-osteogenic effect of high Pi on human AVICs. These novel findings indicate that modulation of Klotho may have therapeutic potential for mitigation of valvular calcification associated with CKD.

show abstract

Fibroblast growth factor 23 and parathyroid hormone predict extent of aortic valve calcifications in patients with mild to moderate chronic kidney disease

Cited by 45 publications

References 37 publications

FGF23-Klotho signaling axis in the kidney

FGF23-Klotho signaling axis in the kidney

Serum Alkaline Phosphatase Level Predicts Cardiac Valve Calcification in Maintenance Hemodialysis Patients

Klotho suppresses high phosphate-induced osteogenic responses in human aortic valve interstitial cells through inhibition of Sox9

Contact Info

Product

Resources

About