Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Kidney360. 2020 Jul;1(7):648-656. doi: 10.34067/KID.0001692020. Epub 2020 Jul 30.
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)D] 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]D, 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 () annualized change in eGFR; () mean annualized percentage change in height-corrected total kidney volume (Study A only); and () 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; =0.03) and mean±SD 1,25(OH)D 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; =0.02) according to PKD genotype. There was a significant interaction between iFGF23 and genotype (=0.02) for the composite end point in fully adjusted models, but no significant interaction between 1,25(OH)D 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.
在 HALT-PKD 研究中，较高的血清完整成纤维细胞生长因子 23（iFGF23）与常染色体显性多囊肾病（ADPKD）患者的疾病进展相关。PKD 突变也是疾病进展的重要决定因素。我们假设，根据 ADPKD 突变，血清 iFGF23 和维生素 D 代谢物（1,25-二羟维生素 D [1,25(OH)D]和 25-羟维生素 D [25(OH)D]）水平存在差异，并且根据基因型（基因型与矿物质代谢物之间存在显著交互作用）差异预测临床终点。
共有 864 名参与 HALT-PKD 研究 A 或 B 且具有矿物质代谢物（1,25(OH)D、25(OH)D、iFGF23）测量值的 ADPKD 患者，根据 PKD 突变（PKD1 截断、PKD1 非截断、PKD2 或未检测到突变 [NMD]）进行分类。使用线性回归和 Cox 比例风险回归评估基因型×iFGF23、基因型×1,25(OH)2D 和基因型×25(OH)D 与（）eGFR 年平均变化的交互作用；（）研究 A 中身高校正总肾体积的平均年变化百分比；以及（）eGFR 降低 50%、ESKD 或死亡的复合终点的时间。
中位数（四分位距）iFGF23 不同（PKD1 截断，55.8 [40.7-76.8]；PKD1 非截断，49.9 [37.7-71.0]；PKD2，49.0 [33.8-70.5]；NMD，50.3 [39.7-67.4]pg/ml；=0.03），1,25(OH)D 的平均值±标准差也不同（PKD1 截断，32.8±12.8；PKD1 非截断，33.4±12.5；PKD2，34.1±13.1；NMD，38.0±14.6pg/ml；=0.02），根据 PKD 基因型。在完全调整的模型中，iFGF23 和基因型之间存在显著的交互作用（=0.02），但 1,25(OH)D 或 25(OH)D 与基因型之间不存在显著的交互作用。
ADPKD 基因型与 FGF23 显著相互作用，影响临床终点。尽管 PKD1 截断或非截断突变和最高 iFGF23 三分位的个体预后最差，但根据 iFGF23，PKD1 非截断和 PKD2 组的复合终点风险差异最大。
