The ACTN3 X allele frequency was significantly higher in hemodialysis patients (83.7%) than controls (64.4%), and X allele carriers started hemodialysis up to 11 years earlier than RR genotype individuals (p=0.022).
Observational (n=630)
No
Is the ACTN3 R577X polymorphism associated with susceptibility to end-stage renal disease and renal fibrosis?
The ACTN3 X allele is associated with an earlier onset of renal failure and increased susceptibility to tubulointerstitial disease, suggesting its potential as a genetic marker for CKD progression risk.
Effect estimate: p < 0.0001 (allele frequency difference)
Absolute Event Rate: 83.7% vs 64.4%
p-value: p=<0.0001
ABSTRACT The X allele of ACTN3 R577X polymorphism results in α‐actinin‐3 deficiency and has been associated with muscle damage and impaired recovery. While its role has been explored in musculoskeletal and cardiac contexts, no studies have evaluated its impact on chronic kidney disease (CKD). To investigate the prevalence of the ACTN3 R577X polymorphism in patients with end‐stage renal disease undergoing hemodialysis (HD) and explore its potential involvement in renal fibrosis through experimental models. A total of 217 HD patients and 413 healthy controls were genotyped for the ACTN3 R577X polymorphism. Associations with clinical variables were analyzed using multivariate regression. Renal Actn3 expression was evaluated in mice subjected to folic acid‐induced acute and chronic kidney injury. In vitro, fibroblasts were exposed to TGF‐β or LPS to assess gene expression responses. The X allele was significantly more frequent in HD patients (83.7% vs. 64.4%, p < 0.0001), and XX individuals began HD up to 11 years earlier than RR homozygotes. Experimental models showed persistent upregulation of Actn3 in fibrotic kidneys and in TGF‐β‐treated fibroblasts, but not in inflammatory conditions. Actn3 expression paralleled that of fibrosis markers such as Col1a1 and Acta2. The ACTN3 X allele is associated with earlier onset of renal failure and increased susceptibility to tubulointerstitial disease. Experimental data support its involvement in renal fibrosis. ACTN3 genotyping may help identify patients at greater risk for CKD progression.
Santos et al. (2026) conducted an observational in Adults with end-stage chronic kidney disease undergoing hemodialysis (n=630). ACTN3 R577X polymorphism genotyping vs. Healthy controls from same geographic area without CKD was evaluated on Frequency of ACTN3 R577X polymorphism alleles and age at initiation of hemodialysis (p < 0.0001 (allele frequency difference), p=<0.0001). The ACTN3 X allele frequency was significantly higher in hemodialysis patients (83.7%) than controls (64.4%), and X allele carriers started hemodialysis up to 11 years earlier than RR genotype individuals (p=0.022).