Am J Nephrol. 2026 Oct 14:1. doi: 10.1159/ajn/ablag018. Online ahead of print.
ABSTRACT
INTRODUCTION: Chronic kidney disease (CKD) is associated with a markedly increased cardiovascular (CV) risk. The disruption of the αKlotho-Fibroblast Growth Factor 23 (FGF23)-FGF receptors (FGFR) axis has been implicated in chronic diseases and CV complications. We aimed to evaluate the impact of genetic variability across this pathway on renal function and CV outcomes in CKD patients.
METHODS: A total of 829 patients with CKD stages 1-5D were genotyped for 54 tag-SNPs (single nucleotide polymorphisms) and functional variants in KL, FGF23, FGFR1, and FGFR4. Associations with renal function, parameters of blood pressure (BP) and mineral and bone disorder (MBD) and CV events (CVE) were assessed using single- and multiple-marker approaches adjusting for clinical covariates.
RESULTS: FGF23 rs13312770 and KL rs211239 were associated with impaired [OR=1.77 (0.99-3.17), p=0.047] and preserved [OR=0.55 (0.31-0.98), p=0.035] renal function, respectively. Four KL SNPs were associated with BP traits, namely rs385564 and rs2283368 with diastolic BP [mean difference: -2.43 (-4.56--0.29), p=0.026 and 2.73 (0.21-5.25), p=0.034] and rs78425544 and rs9536314 with pulse pressure [5.07 (0.16-9.98), p=0.043 and 3.50 (0.06-6.93), p=0.047]. Six FGFR1 SNPs were associated with vitamin D levels, with rs2978083 showing the strongest association (p<0.0001). Seventy-three patients (8.8%) experienced CVE during follow-up. Carriers of FGFR4 rs351855 had improved CV event-free survival [HR=0.52 (0.28-0.96), p=0.037], whilst KL rs2283368, KLrs575536 and FGFR1 rs2956724 were associated with increased risk [HR=2.02 (1.09-3.78), p=0.022, HR=2.38 (1.25-4.50), p=0.007 and HR=2.18 (1.03-4.63), p=0.041, respectively]. The inclusion of these four SNPs in a clinical-only Cox model improved Harrell's C-index from 0.739 to 0.79 (ΔC=0.056, 7.6%). Haplotypes based on sliding-windows identified several 3-SNP and 2-SNP combinations with a relevant effect on CV risk. Finally, epistasis analysis showed that FGFR1 rs3758101 combined with three different KL variants in SNP pairs significantly impacted CV risk (p<0.001 in all instances).
CONCLUSION: Genetic variability within the αKlotho-FGF23-FGFR axis is significantly associated with renal function and CV outcomes in CKD. Multi-locus approaches reveal combined and interactive effects that enhance risk stratification beyond single-variant analyses.
PMID:42873722 | DOI:10.1159/ajn/ablag018