Interactions between FGF23 and Genotype in Autosomal Dominant Polycystic Kidney Disease

Abstract

BackgroundHigher serum intact fibroblast growth factor 23 (iFGF23) was associated with disease progression in participants with autosomal dominant polycystic kidney disease (ADPKD) in the HALT-PKD Studies. PKD mutation is also an important determinant of progression. We hypothesized that serum levels of iFGF23 and vitamin D metabolites (1,25-dihydroxyvitamin D [1,25(OH)2D] and 25-hydroxyvitamin D [25[OH]D]) differ according to ADPKD mutation and differentially predict clinical end points according to genotype (significant interaction between genotype and mineral metabolites).MethodsA total of 864 individuals with ADPKD who participated in the HALT-PKD Study A or B and had measurements of mineral metabolites (1,25[OH]2D, 25[OH]D, iFGF23) were categorized by PKD mutation (PKD1 truncating, PKD1 nontruncating, PKD2, or no mutation detected [NMD]). The association of the interactions of genotype × iFGF23, genotype × 1,25(OH)2D, and genotype × 25(OH)D with (1) annualized change in eGFR; (2) mean annualized percentage change in height-corrected total kidney volume (Study A only); and (3) time to a composite of 50% reduction in eGFR, ESKD, or death were evaluated using linear regression and Cox proportional hazards regression.ResultsMedian (interquartile range) iFGF23 differed (PKD1 truncating, 55.8 [40.7–76.8]; PKD1 nontruncating, 49.9 [37.7–71.0]; PKD2, 49.0 [33.8–70.5]; NMD, 50.3 [39.7–67.4] pg/ml; P=0.03) and mean±SD 1,25(OH)2D differed (PKD1 truncating, 32.8±12.8; PKD1 nontruncating, 33.4±12.5; PKD2, 34.1±13.1; NMD, 38.0±14.6 pg/ml; P=0.02) according to PKD genotype. There was a significant interaction between iFGF23 and genotype (P=0.02) for the composite end point in fully adjusted models, but no significant interaction between 1,25(OH)2D or 25(OH)D and genotype for clinical end points.ConclusionsADPKD genotype interacts significantly with FGF23 to influence clinical end points. Whereas the worst outcomes were in individuals with a PKD1-truncating or -nontruncating mutation and the highest iFGF23 tertile, risk of the composite end point differed according to iFGF23 the most in the PKD1-nontruncating and PKD2 groups.

Effect of Early and Delayed Commencement of Paricalcitol in Combination with Enalapril on the Progression of Experimental Polycystic Kidney Disease

“…In that regard, in this study, the hypothesis was investigated using a genetic ortholog of NPHP-9 rather than that of ADPKD. It is noteworthy that in a post-hoc analysis of the HALT-PKD consisting of 864 individuals with ADPKD, levels of vitamin D metabolites did not predict either change in Ht-TKV and eGFR decline consistent with the results of this study [42]. In any case, further interventional studies using genetic orthologs of ADPKD are needed to fully evaluate the role of VDRAs.…”

“…In any case, our findings suggest that while paricalcitol may have some beneficial effects in PKD, the use of VDRAs with lower calcaemic-inducing activity may be required in future studies. In addition, given that serum levels of FGF23 are elevated innately in PKD models [42,43] and increased by paricalcitol [30], further understanding of the effects of VDRAs on this endpoint is also needed.…”

Pharmacological intervention of the FGF–PTH axis as a potential therapeutic for craniofacial ciliopathies

“…FGF23, a member of the endocrine subfamily of FGF ligands, is essential for bone homeostasis. Expressed in osteocytes and osteoblasts, FGF23 systemically interacts with parathyroid hormone (PTH) to control both bone mineralization and calcium levels throughout the body ( Blau and Collins, 2015 ; Grau et al, 2020 ; Lu and Feng, 2011 ; Takashi et al, 2021 ). Misexpression of FGF23 and PTH results in impaired bone mineralization and osteogenic dysfunction, respectively ( Iwasaki-Ishizuka et al, 2005 ; Lu and Feng, 2011 ).…”

Pharmacological intervention of the FGF-PTH axis as a potential therapeutic for craniofacial ciliopathies

“…Fgf23, a member of the endocrine subfamily of FGF ligands, is essential for bone homeostasis. Expressed in osteocytes, Fgf23 systemically interacts with parathyroid hormone (PTH) to control both bone mineralization and calcium levels throughout the body (Blau and Collins, 2015; Grau et al, 2020; Lu and Feng, 2011; Takashi et al, 2021). Misexpression of Fgf23 and PTH result in impaired bone mineralization and osteoblastic dysfunction, respectively (Iwasaki-Ishizuka et al, 2005; Lu and Feng, 2011).…”

“…Misexpression of Fgf23 and PTH result in impaired bone mineralization and osteoblastic dysfunction, respectively (Iwasaki-Ishizuka et al, 2005; Lu and Feng, 2011). Interestingly, the Fgf23-PTH axis relies heavily on proper kidney function for propagation, as Fgf23 signaling induces the secretion of active Vitamin D (1,25-D3) from the kidney, which subsequently influences Ca 2+ levels (Blau and Collins, 2015; Grau et al, 2020; Lu and Feng, 2011; Takashi et al, 2021). Although the impact of impaired FGF23-PTH signaling on bone development has been described, its correlation with skeletal phenotypes observed in ciliopathic mutants has yet to be explored.…”