Retinal structural and vascular alterations in diabetic kidney disease: A bidirectional Mendelian randomization study

Growing evidence indicates retinal thickness and microvascular changes have been associated with diabetic kidney disease (DKD). Nevertheless, the causal links between them have yet to be fully elucidated. We utilized Mendelian randomization (MR) to investigate the bidirectional causal relationship between DKD and retinal structural and vascular alterations.

The bidirectional two-sample MR was conducted using genome-wide association studies (GWAS) summary statistics from European populations. Eight DKD-related phenotypes were investigated in relation to retinal layer thickness and microvascular traits.

The forward MR revealed that macroalbuminuria was associated with increased inner nuclear layer (INL) thickness (OR 1.006 [95% CI 1.000-1.012], P = 0.040), and the combined phenotype of chronic kidney disease and diabetic kidney disease (CKD-DN) was linked to greater choroidal thickness (OR 1.005 [95% CI 1.000-1.009], P = 0.047). All DKD showed negative associations with retinal vascular density (RVD) (OR 0.979 [95% CI 0.965-0.993], P = 0.003) and retinal vascular fractal dimension (RVFD) (OR 0.980 [95% CI 0.966-0.993], P = 0.004). In reverse MR, increased INL thickness predicted higher risk of end-stage renal disease (ESRD) (OR 1.444 [95% CI 1.110-1.878], P = 0.006) and extreme chronic kidney disease (CKD) (OR 1.322 [95% CI 1.026-1.704], P = 0.031). Thickening of outer retinal layers was associated with CKD (OR 1.144 [95% CI 1.020-1.284], P = 0.021).

These findings highlight a potential bidirectional causal link between renal dysfunction and retinal neurovascular changes. Retinal imaging biomarkers may serve as noninvasive indicators of DKD risk and progression, warranting further validation.