Nail in the Coffin for Fibroblast Growth Factor 23 as a Predictor of Kidney Function Decline

Background: Fibroblast growth factor 23 (FGF-23) is a hormone that regulates phosphorus levels and vitamin D metabolism. Previous studies have shown FGF-23 to be a risk factor for incident end-stage renal disease; however, there are less data on the association of FGF-23 with earlier kidney-related outcomes. Methods: Serum FGF-23 was assayed using an intact ELISA assay in 2,496 participants of the Healthy Aging and Body Composition Study, a cohort of well-functioning older adults. Kidney function was estimated by assaying cystatin C at baseline and years 3 and 10. The associations between FGF-23 and decline in kidney function (defined by estimated glomerular filtration rate (eGFR) decline ≥30% or ≥3 mL/min/year) and incident chronic kidney disease (CKD; incident eGFR <60 mL/min/1.73 m2 and ≥1 mL/min/year decline) were evaluated. Models were adjusted for demographics, baseline eGFR, urine albumin/creatinine ratio, comorbidity, and serum calcium, phosphorus, 25(OH) vitamin D and parathyroid hormone. Results: The mean (SD) age was 75 (3) years, with 52% female and 38% black. There were 405 persons with 30% decline, 702 with >3 mL/min/year decline, and 536 with incident CKD. In fully adjusted continuous models, doubling of FGF-23 concentrations was not associated with kidney function decline (OR [95% CI] = 0.98 [0.82–1.19] for ≥30% decline and OR 1.17 [95% CI 1.00–1.37] for ≥3 mL/min/year decline), or incident CKD (incident rate ratio [IRR] 1.05 [95% CI 0.91–1.22]). In adjusted quartile analysis, the highest quartile of FGF-23 was significantly associated with incident CKD (IRR 1.27 [95% CI 1.02–1.58] for highest vs. lowest quartile). Conclusion: Higher FGF-23 concentrations were not consistently associated with decline in kidney function or incident CKD in community-dwelling older adults.

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Lipocalin 2 stimulates bone fibroblast growth factor 23 production in chronic kidney disease

Bone Research ◽

10.1038/s41413-021-00154-0 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Guillaume Courbon ◽

Connor Francis ◽

Claire Gerber ◽

Samantha Neuburg ◽

Xueyan Wang ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Growth Factor ◽

Kidney Disease ◽

Iron Deficiency ◽

Fibroblast Growth Factor ◽

Kidney Function ◽

Fibroblast Growth Factor 23 ◽

Left Ventricular ◽

Fibroblast Growth ◽

Lipocalin 2

AbstractBone-produced fibroblast growth factor 23 (FGF23) increases in response to inflammation and iron deficiency and contributes to cardiovascular mortality in chronic kidney disease (CKD). Neutrophil gelatinase-associated lipocalin (NGAL or lipocalin 2; LCN2 the murine homolog) is a pro-inflammatory and iron-shuttling molecule that is secreted in response to kidney injury and may promote CKD progression. We investigated bone FGF23 regulation by circulating LCN2. At 23 weeks, Col4a3KO mice showed impaired kidney function, increased levels of kidney and serum LCN2, increased bone and serum FGF23, anemia, and left ventricular hypertrophy (LVH). Deletion of Lcn2 in CKD mice did not improve kidney function or anemia but prevented the development of LVH and improved survival in association with marked reductions in serum FGF23. Lcn2 deletion specifically prevented FGF23 elevations in response to inflammation, but not iron deficiency or phosphate, and administration of LCN2 increased serum FGF23 in healthy and CKD mice by stimulating Fgf23 transcription via activation of cAMP-mediated signaling in bone cells. These results show that kidney-produced LCN2 is an important mediator of increased FGF23 production by bone in response to inflammation and in CKD. LCN2 inhibition might represent a potential therapeutic approach to lower FGF23 and improve outcomes in CKD.

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Fibroblast Growth Factor 23 and Mortality in Patients With Type 2 Diabetes and Normal or Mildly Impaired Kidney Function

Diabetes Care ◽

10.2337/dc19-0528 ◽

2019 ◽

Vol 42 (11) ◽

pp. 2151-2153 ◽

Cited By ~ 4

Author(s):

Stanley M.H. Yeung ◽

S. Heleen Binnenmars ◽

Christina M. Gant ◽

Gerjan Navis ◽

Ron T. Gansevoort ◽

...

Keyword(s):

Type 2 Diabetes ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Kidney Function ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth

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Fibroblast growth factor-23 is associated with imaging markers of diabetic cardiomyopathy and anti-diabetic therapeutics

Cardiovascular Diabetology ◽

10.1186/s12933-020-01135-z ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

Martin H. Sørensen ◽

Annemie S. Bojer ◽

Niklas R. Jørgensen ◽

David A. Broadbent ◽

Sven Plein ◽

...

Keyword(s):

Type 2 Diabetes ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Kidney Function ◽

Fibroblast Growth Factor 23 ◽

Left Ventricular ◽

Fibroblast Growth ◽

Cardiovascular Morbidity And Mortality ◽

Fgf 23

Abstract Background The biomarker fibroblast growth factor-23 (FGF-23) has been associated with increased cardiovascular morbidity and mortality in both patients with and without type 2 diabetes. The aim of this study was to evaluate the relationship between FGF-23 and cardiac structure, function and perfusion in patients with type 2 diabetes and normal or mildly impaired kidney function. Furthermore, to investigate the association between FGF-23, anti-diabetes therapy and the classic complications and risk factors associated with type 2 diabetes. Methods In this cross-sectional study, 246 patients with type 2 diabetes underwent echocardiography and advanced cardiac magnetic resonance imaging to assess left ventricular (LV) structure and function. In addition, myocardial blood flow (MBF) during rest and pharmacological stress (adenosine 140 µg/kg/min) were evaluated in 183 of the patients. Patients with eGFR < 60 ml/min/1.73 m2 were excluded. Results Median (Q1–Q3) FGF-23 was 74 (58–91) ng/L. Patients with FGF-23 above the median had lower MBF during stress (2.3 ± 0.9 vs. 2.7 ± 0.9 ml/min/g, P = 0.001) and lower overall myocardial perfusion reserve (MPR) (2.7 ± 0.8 vs. 3.3 ± 1.1, P < 0.001). LV mass (143 ± 40 vs. 138 ± 36 g, P = 0.04) and E/e* (8.5 ± 3.2 vs. 7.6 ± 2.7, P = 0.04) were higher in patients with FGF-23 above the median. In a linear model adjusted for age, sex, eGFR and hypertension, increasing FGF-23 was associated with decreased MPR (P < 0.01, R2 = 0.11) and increased E/e* (P < 0.01, R2 = 0.07). FGF-23 was lower in patients receiving glucagon like peptide-1 (GLP-1) analogues (71 (57–86) vs. 80 (60–98) ng/L, P = 0.01) than in those who did not receive GLP-1 analogues. Conclusions In patients with type 2 diabetes and normal or mildly impaired kidney function, increased levels of FGF-23 are associated with impaired cardiac diastolic function and decreased MPR, caused by a decrease in maximal MBF during stress. Use of GLP-1 analogues is associated with decreased levels of FGF-23. Clinical trial registrationhttps://www.clinicaltrials.gov. Unique identifier: NCT02684331. Date of registration: February 18, 2016

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Soluble α-Klotho and Its Relation to Kidney Function and Fibroblast Growth Factor-23

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2013-4171 ◽

2014 ◽

Vol 99 (5) ◽

pp. E855-E861 ◽

Cited By ~ 15

Author(s):

Alexandra Scholze ◽

Ying Liu ◽

Lise Pedersen ◽

Shengqiang Xia ◽

Heinz J. Roth ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Kidney Function ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth

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Fibroblast Growth Factor 23 and Adverse Clinical Outcomes in Type 2 Diabetes: a Bitter-Sweet Symphony

Current Diabetes Reports ◽

10.1007/s11892-020-01335-7 ◽

2020 ◽

Vol 20 (10) ◽

Author(s):

Stanley M. H. Yeung ◽

Stephan J. L. Bakker ◽

Gozewijn D. Laverman ◽

Martin H. De Borst

Keyword(s):

Type 2 Diabetes ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Kidney Function ◽

Fibroblast Growth Factor 23 ◽

Adverse Outcomes ◽

Fibroblast Growth ◽

Antidiabetic Medication ◽

Related Factors

Abstract Purpose of Review Fibroblast growth factor 23 (FGF23) is a key phosphate-regulating hormone that has been associated with adverse outcomes in patients with chronic kidney disease (CKD). Emerging data suggest that FGF23 plays a specific role in type 2 diabetes, partly independent of kidney function. We aimed to summarize current literature on the associations between FGF23 and outcomes in patients with type 2 diabetes with or without CKD. Recent Findings Several cohort studies have shown strong associations between plasma FGF23 and cardiovascular outcomes in diabetic CKD. Moreover, recent data suggest that FGF23 are elevated and may also be a risk factor for cardiovascular disease and mortality in type 2 diabetes patients without CKD, although the magnitude of the association is smaller than in CKD patients. Summary Diabetes-related factors may influence plasma FGF23 levels, and a higher FGF23 levels seem to contribute to a higher cardiovascular and mortality risk in patients with type 2 diabetes. Although this risk may be relevant in diabetic individuals with preserved kidney function, it is strongly accentuated in diabetic nephropathy. Future studies should clarify if FGF23 is merely a disease severity marker or a contributor to adverse outcomes in type 2 diabetes and establish if antidiabetic medication can modify FGF23 levels.

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