Fibroblast Growth Factor 23 and Cause-Specific Mortality in the General Population: The Northern Manhattan Study

Souma, Nao; Isakova, Tamara; Lipiszko, David; Sacco, Ralph L.; Elkind, Mitchell S.V.; DeRosa, Janet T.; Silverberg, Shonni J.; Mendez, Armando J.; Dong, Chuanhui; Wright, Clinton B.; Wolf, Myles

doi:10.1210/jc.2016-2215

Cited by 71 publications

(62 citation statements)

References 39 publications

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“…CVD was the major cause of mortality in our study, which is in accordance with the original observation of Gutierrez in CKD patients undergoing hemodialysis [6] and subsequent reports [7][8][9] . However, in the Northern Manhattan population study in which 53.6% of the volunteers were Hispanic with a mean GFR of 79.9 mL/min, they showed an increase in mortality due to both increased vascular and nonvascular causes [12] . There were more nonvascular deaths mainly due to cancer, chronic obstructive pulmonary disease, and infections.…”

Section: Discussionmentioning

confidence: 93%

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Fibroblast Growth Factor 23 Predicts Mortality and End-Stage Renal Disease in a Canadian Asian Population with Chronic Kidney Disease

Jialal

Camacho

Nathoo

et al. 2017

Nephron

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Background: Chronic kidney disease (CKD) is a leading cause of morbidity and mortality. Biomarkers that predict end-stage renal disease (ESRD) and/or mortality could usher in new therapeutics to halt this onslaught. While fibroblast growth factor (FGF)23 can predict both ESRD and mortality, it has not been studied in North American CKD patients of Asian ethnicity. Method: This is a prospective investigation about the role of FGF23 in 998 Canadian patients of Asian descent with CKD defined by an estimated glomerular filtration rate (eGFR) <60 mL/min/m² and followed up for 3 years. Results: The mean age of patients was 68.9 years and 68.3% were males. The mean (range) eGFR, and median FGF23 were 40.2 (11.0-59.0) mL/min and 154.1 (7.0-7,823.0) RU/mL, respectively. Over the 3 years, higher values of FGF23 levels at baseline were associated with higher risk of ESRD (hazard ratio [HR] for log[Fgf23] = 2.16 [95% CI 1.20-3.89]). Despite the short follow-up, 42 patients died due to cardiovascular diseases (38.8%), cancer (14.9%), and infections (12.7%). Log-FGF23 levels were independently associated with death, HR 1.94, 95% CI 1.24-3.03. Mortality risk increased in FGF23 subgroups from <100 to >400 RU/mL. In a time-changing covariate analysis, serial log-FGF23 levels over the 3 years predicted mortality with a HR of 2.66 (95% CI 1. 79-3.95). Conclusion: In a Canadian Asian population with CKD, FGF23 levels obtained at 6-monthly intervals for 3 years predicted ESRD and mortality suggesting that it is also a risk marker in Asians.

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Section: Discussionmentioning

confidence: 93%

“…Thus, we added this information to the published data in Hispanics, African-Americans, and whites show- [3,6,10,12,13] . Also, our finding that in the entire cohort of 2,061 patients with CKD, FGF23-predicted mortality concurs with the general consensus, since the remaining patients were all whites.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor 23 Predicts Mortality and End-Stage Renal Disease in a Canadian Asian Population with Chronic Kidney Disease

Jialal

Camacho

Nathoo

et al. 2017

Nephron

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“…1,2 In patients with chronic kidney disease (CKD), circulating FGF-23 is elevated. 3,4 An association between increased FGF-23 levels and mortality in patients suffering from CKD is well appreciated, 5,6 and several authors observed an association between FGF-23 and outcome in the general population 7,8 and under several pathological conditions, including congestive heart failure (CHF). [9][10][11] The underlying mechanism resulting in increased FGF-23 levels in CHF patients, the origin of FGF-23 in CHF (bone vs. myocardium), and the effect of FGF-23 on the cardiovascular system are incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Bone marrow and plasma FGF‐23 in heart failure patients: novel insights into the heart–bone axis

et al. 2019

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Aims Fibroblast growth factor 23 (FGF‐23) is known to be elevated in patients with congestive heart failure (CHF). As FGF‐23 is expressed in the bone but can also be expressed in the myocardium, the origin of serum FGF‐23 in CHF remains unclear. It is also unclear if FGF‐23 expressed in the bone is associated with outcome in CHF. The aim of the present study was to investigate FGF‐23 levels measured in bone marrow plasma (FGF‐23‐BM) and in peripheral blood (FGF‐23‐P) in CHF patients to gain further insights into the heart–bone axis of FGF‐23 expression. We also investigated possible associations between FGF‐23‐BM as well as FGF‐23‐P and outcome in CHF patients. Methods and results We determined FGF‐23‐P and FGF‐23‐BM levels in 203 CHF patients (85% male, mean age 61.3 years) with a left ventricular ejection fraction (LVEF) ≤45% and compared them with those of 48 healthy controls (48% male, mean age 39.2 years). We investigated the association between FGF‐23‐BM and FGF‐23‐P with all‐cause mortality in CHF patients, 32 events, median follow‐up 1673 days, interquartile range [923, 1828]. FGF‐23‐P (median 60.3 vs. 22.0 RU/mL, P < 0.001) and FGF‐23‐BM (median 130.7 vs. 93.1 RU/mL, P < 0.001) levels were higher in CHF patients compared with healthy controls. FGF‐23‐BM levels were significantly higher than FGF‐23‐P levels in both CHF patients and in healthy controls ( P < 0.001). FGF‐23‐P and FGF‐23‐BM correlated significantly with LVEF ( r = −0.37 and r = −0.33, respectively), N terminal pro brain natriuretic peptide levels ( r = 0.57 and r = 0.6, respectively), New York Heart Association status ( r = 0.28 and r = 0.25, respectively), and estimated glomerular filtration rate ( r = −0.43 and r = −0.41, respectively) ( P for all <0.001) and were independently associated with all‐cause mortality in CHF patients after adjustment for LVEF, estimated glomerular filtration rate, New York Heart Association status, and N terminal pro brain natriuretic peptide, hazard ratio 2.71 [confidence interval: 1.18–6.20], P = 0.018, and hazard ratio 2.80 [confidence interval: 1.19–6.57], P = 0.018, respectively. Conclusions In CHF patients, FGF‐23 is elevated in bone marrow plasma and is independently associated with heart failure severity and all‐cause mortality. The failing heart seems to interact via FGF‐23 within a heart–bone axis.

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“…[8][9][10][11][12] Elevated FGF-23 is also associated with hypertension, left ventricular hypertrophy (LVH), and increased mortality in CKD. [13][14][15][16][17][18][19][20] These cardiovascular effects are attributed, at least in part, to effects of FGF-23 activation of FGFRs/a-Klotho coreceptors in the kidney to enhance sodium (Na) reabsorption, and suppress angiotensin converting enzyme 2 (Ace2) and a-Klotho expression. [13][14][15][16][17] FGF ligands produced in the kidney have paracrine/autocrine functions to regulate kidney development through heparin sulfate proteoglycan cofactor-dependent activation of FGF receptors.…”

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confidence: 99%

Cardiovascular Effects of Renal Distal Tubule Deletion of the FGF Receptor 1 Gene

Han

Ross²,

Kolumam³

et al. 2017

JASN

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The bone-derived hormone fibroblast growth factor-23 (FGF-23) activates complexes composed of FGF receptors (FGFRs), including FGFR1, and -Klotho in the kidney distal tubule (DT), leading to increased sodium retention and hypertension. However, the role of FGFR1 in regulating renal processes linked to hypertension is unclear. Here, we investigated the effects of selective FGFR1 loss in the DT. Conditional knockout (cKO) of in the DT ( mice) resulted in left ventricular hypertrophy (LVH) and decreased kidney expression of -Klotho in association with enhanced BP, decreased expression of angiotensin converting enzyme 2, and increased expression of the Na-K-2Cl cotransporter. Notably, recombinant FGF-23 administration similarly decreased the kidney expression of -Klotho and induced LVH in mice. Pharmacologic activation of FGFR1 with a monoclonal anti-FGFR1 antibody (R1MAb1) normalized BP and significantly attenuated LVH in the mouse model of excess FGF-23, but did not induce a response in mice. The hearts of mice showed increased expression of the transient receptor potential cation channel, subfamily C, member 6 (TRPC6), consistent with cardiac effects of soluble Klotho deficiency. Moreover, administration of recombinant soluble Klotho lowered BP in the mice. Thus, FGFR1 in the DT regulates systemic hemodynamic responses opposite to those predicted by the actions of FGF-23. These cardiovascular effects appear to be mediated by paracrine FGF control of kidney FGFR1 and subsequent regulation of soluble Klotho and TRPC6. FGFR1 in the kidney may provide a new molecular target for treating hypertension.

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Fibroblast Growth Factor 23 and Cause-Specific Mortality in the General Population: The Northern Manhattan Study

Abstract: Elevated FGF23 was independently associated with increased risk of vascular and nonvascular mortality in a diverse general population and with increased risk of cancer death specifically in Hispanic individuals.

Cited by 71 publications

References 39 publications

Fibroblast Growth Factor 23 Predicts Mortality and End-Stage Renal Disease in a Canadian Asian Population with Chronic Kidney Disease

Fibroblast Growth Factor 23 Predicts Mortality and End-Stage Renal Disease in a Canadian Asian Population with Chronic Kidney Disease

Bone marrow and plasma FGF‐23 in heart failure patients: novel insights into the heart–bone axis

Cardiovascular Effects of Renal Distal Tubule Deletion of the FGF Receptor 1 Gene

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