Erythropoietin induces bone marrow and plasma fibroblast growth factor 23 during acute kidney injury

Toro, Luis; Barrientos, Víctor; León, P Betancor; Rojas, Macarena; González, Magdalena; González-Ibáñez, Alvaro M.; Illanes, Sebastián E.; Sugikawa, Keigo; Abarzúa, Néstor; Bascuñán, César; Arcos, Katherine; Fuentealba, C; Tong, Ana; Elorza, Álvaro A.; Pinto, Maria Eugênia Bresolin; Alzamora, Rodrigo; Romero, Carlos; Michea, Luis

doi:10.1016/j.kint.2017.11.018

Cited by 83 publications

(88 citation statements)

References 54 publications

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“…Specifically, we found that higher urine Klotho/creatinine levels were associated with a decreased risk of MAKE-90, whereas higher serum intact FGF23 levels were associated with an increased risk of MAKE-90 in this subset of critically ill patients. These findings are timely and relevant because increased circulating FGF23 levels (33)(34)(35) and reduced Klotho expression (18,(36)(37)(38) have been consistently described in experimental models of AKI. Although higher circulating FGF23 levels have been previously associated with human AKI (22,23) and increased morbidity and mortality in critically ill patients (25,26,39), data related to soluble Klotho levels are scarce (40).…”

Section: Discussionmentioning

confidence: 75%

“…Elevated plasma FGF23 levels have been reported in murine models of AKI (33)(34)(35)50). Nonetheless, the mechanisms of FGF23 elevation in AKI are not known.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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: 75%

“…Elevated plasma FGF23 levels have been reported in murine models of AKI (33)(34)(35)50). Nonetheless, the mechanisms of FGF23 elevation in AKI are not known.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…FGF23 is a very sensitive biomarker for impaired kidney function . Impaired renal function in CKD or acute kidney injury (AKI) is a major stimulus of FGF23 production . In animal models of AKI, FGF23 rises within hours and before onset of hyperphosphataemia .…”

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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“…The loss of FGF23 or injection of an FGF23-blocking peptide in mice results in increased erythropoiesis, reduced erythroid cell apoptosis, and increased renal and bone marrow erythropoietin (EPO) expression with increased circulating EPO levels. On the other hand, the increased EPO or acute blood loss increases FGF23 expression in the bone marrow with a concomitant increase in serum FGF23 [172,173]. A recent study suggests that FGF23 is involved in the association between functional iron deficiency, increased EPO levels, and death.…”

Section: Fgf23 Metabolic Axismentioning

confidence: 99%

The FGF metabolic axis

2019

Front. Med.

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Members of the fibroblast growth factor (FGF) family play pleiotropic roles in cellular and metabolic homeostasis. During evolution, the ancestor FGF expands into multiple members by acquiring divergent structural elements that enable functional divergence and specification. Heparan sulfate-binding FGFs, which play critical roles in embryonic development and adult tissue remodeling homeostasis, adapt to an autocrine/paracrine mode of action to promote cell proliferation and population growth. By contrast, FGF19, 21, and 23 coevolve through losing binding affinity for extracellular matrix heparan sulfate while acquiring affinity for transmembrane α-Klotho (KL) or β-KL as a coreceptor, thereby adapting to an endocrine mode of action to drive interorgan crosstalk that regulates a broad spectrum of metabolic homeostasis. FGF19 metabolic axis from the ileum to liver negatively controls diurnal bile acid biosynthesis. FGF21 metabolic axes play multifaceted roles in controlling the homeostasis of lipid, glucose, and energy metabolism. FGF23 axes from the bone to kidney and parathyroid regulate metabolic homeostasis of phosphate, calcium, vitamin D, and parathyroid hormone that are important for bone health and systemic mineral balance. The significant divergence in structural elements and multiple functional specifications of FGF19, 21, and 23 in cellular and organismal metabolism instead of cell proliferation and growth sufficiently necessitate a new unified and specific term for these three endocrine FGFs. Thus, the term "FGF Metabolic Axis," which distinguishes the unique pathways and functions of endocrine FGFs from other autocrine/paracrine mitogenic FGFs, is coined.

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Erythropoietin induces bone marrow and plasma fibroblast growth factor 23 during acute kidney injury

Cited by 83 publications

References 54 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

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

The FGF metabolic axis

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