FGF23 is synthesised locally by renal tubules and activates injury-primed fibroblasts

Smith, Edwin R.; Tan, Sven‐Jean; Holt, Stephen; Hewitson, Tim D.

doi:10.1038/s41598-017-02709-w

Cited by 78 publications

(79 citation statements)

References 61 publications

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“…Nonetheless, the mechanisms of FGF23 elevation in AKI are not known. Impaired excretion or catabolism of FGF23 by the kidneys or increased production from bone or other organs could be reasonable explanations for this elevation (33)(34)(35)(50)(51)(52). Measurement of intact FGF23-the biologically active form-is less represented than FGF23 assays with C-terminal reagents (nondiscriminatory between full length and C-terminal fragments) in human AKI literature.…”

Section: Discussionmentioning

confidence: 99%

Urine Klotho Is Lower in Critically Ill Patients With Versus Without Acute Kidney Injury and Associates With Major Adverse Kidney Events

Neyra

Mescia³

et al. 2019

Critical Care Explorations

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Objectives: Klotho and fibroblast growth factor-23 were recently postulated as candidate biomarkers and/or therapeutic targets in acute kidney injury. We examined whether urine Klotho and serum intact fibroblast growth factor-23 levels were differentially and independently associated with major adverse kidney events in critically ill patients with and without acute kidney injury. Design: Single-center, prospective, case-control study. Setting: ICU in a tertiary medical center. Patients: Fifty-four acute kidney injury patients and 52 controls without acute kidney injury admitted to the ICU. Interventions: None. Measurements and Main Results: Acute kidney injury was defined by Kidney Disease: Improving Global Outcomes criteria and included only acute kidney injury stage greater than or equal to 2. Controls were matched by age, gender, and baseline estimated glomerular filtration rate. Paired serum and urine samples were obtained 24–48 hours after acute kidney injury diagnosis (cases) or ICU admission (controls). The primary outcome was 90-day major adverse kidney events, which was the composite of all-cause death, dependence on renal replacement therapy, or a 50% or higher decrease in estimated glomerular filtration rate from baseline. Major adverse kidney events, which was the composite of all-cause death, dependence on renal replacement therapy, or a 50% or higher decrease in estimated glomerular filtration rate from baseline. Major adverse kidney events developed in 44 patients (41.5%). Patients in whom major adverse kidney events developed had more comorbidity, higher acuity of illness scores, and more prevalent acute kidney injury. Levels of urine Klotho adjusted by creatinine were lower, and serum intact fibroblast growth factor-23 levels were higher in acute kidney injury patients versus ICU controls. In adjusted models, the highest versus lowest tertile of urine Klotho/creatinine was independently associated with an overall 95% lower risk of major adverse kidney events (81% lower risk in patients with acute kidney injury). The highest versus lowest tertile of serum intact fibroblast growth factor-23 was associated with more than 300% higher risk of major adverse kidney events. Conclusions: Urine Klotho/creatinine levels were significantly lower and serum intact fibroblast growth factor-23 levels were significantly higher in critically ill patients with acute kidney injury versus matched controls without acute kidney injury. When measured in the first 48 hours of ICU admission or acute kidney injury diagnosis, urine Klotho/creatinine independently associated with major adverse kidney events, particularly in patients with acute kidney injury. These results show promise for testing these biomarkers—individually or in combination—as part of novel risk prediction models of renal outcomes in the ICU.

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Section: Discussionmentioning

confidence: 99%

Urine Klotho Is Lower in Critically Ill Patients With Versus Without Acute Kidney Injury and Associates With Major Adverse Kidney Events

Neyra

Mescia³

et al. 2019

Critical Care Explorations

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“…Recent studies found that in addition to classic effects on kidney phosphate handling and vitamin D metabolism, iFGF23 also has myriad "off-target" effects. These include toxic effects on the cardiovascular system through promotion of left ventricular hypertrophy and endothelial dysfunction (30,31), profibrotic effects on the kidneys (32), proinflammatory effects demonstrated by upregulation of hepatic IL-6 production (33), and impairment of immune function (34,35). Specifically, iFGF23's effects on the immune system include reduced monocyte mRNA expression of the antimicrobial peptide, LL37 (34), and impairment of neutrophil activation and recruitment into inflamed tissues (35).…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor 23 Associates with Death in Critically Ill Patients

Leaf¹,

Siew²,

Eisenga³

et al. 2018

CJASN

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“…Renal FGF23 expression occurs in CKD , but has been suggested to be irrelevant for the elevated plasma FGF23 concentration typical of this condition . Local FGF23 production regulating fibroblasts in a paracrine manner occurs in injured kidneys .…”

Section: Fgf23 Regulation: Insights From Rare Disorders and Renal Dismentioning

confidence: 99%

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

et al. 2019

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Fibroblast growth factor 23 (FGF23) is mainly produced in the bone and, upon secretion, forms a complex with a FGF receptor and coreceptor αKlotho. FGF23 can exert several endocrine functions, such as inhibiting renal phosphate reabsorption and 1,25‐dihydroxyvitamin D3 production. Moreover, it has paracrine activities on several cell types, including neutrophils and hepatocytes. Klotho and Fgf23 deficiencies result in pathologies otherwise encountered in age‐associated diseases, mainly as a result of hyperphosphataemia‐dependent calcification. FGF23 levels are also perturbed in the plasma of patients with several disorders, including kidney or cardiovascular diseases. Here, we review mechanisms controlling FGF23 production and discuss how FGF23 regulation is perturbed in disease.

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FGF23 is synthesised locally by renal tubules and activates injury-primed fibroblasts

Cited by 78 publications

References 61 publications

Urine Klotho Is Lower in Critically Ill Patients With Versus Without Acute Kidney Injury and Associates With Major Adverse Kidney Events

Urine Klotho Is Lower in Critically Ill Patients With Versus Without Acute Kidney Injury and Associates With Major Adverse Kidney Events

Fibroblast Growth Factor 23 Associates with Death in Critically Ill Patients

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

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