How FGF23 shapes multiple organs in chronic kidney disease

Abstract

Chronic kidney disease (CKD) is associated with distinct alterations in mineral metabolism in children and adults resulting in multiple organ dysfunctions. Children with advanced CKD often suffer from impaired bone mineralization, bone deformities and fractures, growth failure, muscle weakness, and vascular and soft tissue calcification, a complex which was recently termed CKD-mineral and bone disorder (CKD-MBD). The latter is a major contributor to the enhanced cardiovascular disease comorbidity and mortality in these patients. Elevated circulating levels of the endocrine-acting phosphaturic hormone fibroblast growth factor (FGF) 23 are the first detectable alteration of mineral metabolism and thus CKD-MBD. FGF23 is expressed and secreted from osteocytes and osteoblasts and rises, most likely due to increased phosphate load, progressively as kidney function declines in order to maintain phosphate homeostasis. Although not measured in clinical routine yet, CKD-mediated increased circulating levels of FGF23 in children are associated with pathological cardiac remodeling, vascular alterations, and increased cognitive risk. Clinical and experimental studies addressing other FGF23-mediated complications of kidney failure, such as hypertension and impaired bone mineralization, show partly conflicting results, and the causal relationships are not always entirely clear. This short review summarizes regulators of FGF23 synthesis altered in CKD and the main CKD-mediated organ dysfunctions related to high FGF23 levels.

New developments in the biology of fibroblast growth factors

“…Circulating levels of FGF23 are increased dramatically in response to acute kidney injury (AKI) and CKD (Christov et al, 2019; Leifheit‐Nestler & Haffner, 2021). Inflammation and iron deficiency associated with CKD may directly and via iron‐related mechanisms induce Fgf23 production in bone (David et al, 2016; Francis et al, 2019; Francis & David, 2016).…”

Low Klotho/Fibroblast Growth Factor 23 Ratio Is an Independent Risk Factor for Renal Progression in Chronic Kidney Disease: Finding From KNOW-CKD

“…This indicates that the off-target effects of FGF23, independent of Klotho, affect cardiac myocytes. In patients with elevated FGF23, there have been studies in which aortic or coronary artery calcification scores were higher than in those with lower FGF23 (13), but there have been conflicting results (51). Moreover, up-regulation of Klotho expression protects against vascular calcification in CKD (52).…”

Vitamin D and Secondary Hyperparathyroidism in Chronic Kidney Disease: A Critical Appraisal of the Past, Present, and the Future

“…Circled arrows indicate increases (↑)/decreases (↓). Adapted from Germain (2020) [ 13 ] and Leifheit-Nestler and Haffner (2021) [ 14 ]. CKD—chronic kidney disease, 25(OH)D—Calcidiol, 1,25(OH) 2 D—Calcitriol, Ca—calcium, P—phosphorus, FGF23—Fibroblast growth factor-23, iFGF23—intact FGF23, PTH—parathyroid hormone, CYP27B1—1α-hydroxylase.…”

“…In addition, high phosphate levels also lower serum-Ca 2+ levels by forming insoluble Ca—P complexes and by decreasing the expression of the 1α-hydroxylase CYP27B1, which further aggravates vitamin D deficiency-related hypocalcemia. Additionally, phosphate stabilizes intact FGF23 [ 14 ], enhancing the secretion of the FGF23 [ 16 ], which also downregulates the expression of CYP27B1 [ 17 ]. The third main pathway is the CKD-induced suppression of transcription of the FGF23 coreceptor Klotho: without Klotho, FGF23 cannot downregulate PTH and serum phosphate [ 6 , 11 , 14 , 15 ].…”

“…Additionally, phosphate stabilizes intact FGF23 [ 14 ], enhancing the secretion of the FGF23 [ 16 ], which also downregulates the expression of CYP27B1 [ 17 ]. The third main pathway is the CKD-induced suppression of transcription of the FGF23 coreceptor Klotho: without Klotho, FGF23 cannot downregulate PTH and serum phosphate [ 6 , 11 , 14 , 15 ].…”