Interactions between FGF23 and Genotype in Autosomal Dominant Polycystic Kidney Disease

Higher 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).

A 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.

Median (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.

ADPKD 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.