Low-grade inflammation mediates the association between albuminuria and vision-threatening diabetic retinopathy in US adults with and without elevated blood pressure

Background Diabetic retinopathy and chronic kidney disease have been shown to share a microvascular basement membrane thickening and endothelial leakage pathway. However, the mechanistic role of systemic inflammation between these two target-organ complications is poorly defined. Purpose We examined how C-reactive protein (CRP) mediates the association between albuminuria and vision-threatening diabetic retinopathy (VTDR). Methods We used the data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2008. We limited the study population to adults aged ≥ 40 years with diabetes and gradable retinal image data (N=289). We defined VTDR as having severe non-proliferative diabetic retinopathy, diabetic retinopathy, or clinically significant macular oedema. We performed survey-weighted logistic regression and mediation analysis using the quasi-Bayesian approach with 1000 iterations to estimate the average causal mediation effect. Renal damage was assessed using uACR and categorised according to KDIGO guidelines. We adjusted the models for age, sex, systolic blood pressure (BP), insulin sensitivity, and diabetes duration. Subgroup analyses for blood pressure and dyslipidaemia were conducted to evaluate the effect modification in the mediation analysis. We accounted for skewness by transforming diabetes duration and CRP using natural logarithms before analysis. Results Among the 297 participants analysed, 9.7% had clinical albuminuria (A2/A3 stages). The prevalence of VTDR increased from 16.1% in those with normal uACR to 60.0% in those with macroalbuminuria. Each unit increase of albuminuria (In(uACR)) was independently associated with higher odds of VTDR (OR: 1.22, 95% CI: 1.01–1.49, p=0.041) and higher levels of systemic inflammation (In(CRP)) (OR = 1.15, 95% CI: 1.05–1.26, p=0.006), and In(CRP) remained a significant predictor of VTDR (OR: 1.46, 95% CI: 1.03–2.05, p=0.036). Casual mediation analysis revealed that In(CRP) significantly mediated the association of these VTDR and In(uACR) with average causal mediation effects (ACME p=0.012), accounting for 20.3% (95% CI: 4.2%–58.9%) of the total effect of albuminuria on VTDR. Among those with elevated BP, the proportion mediated by inflammation was 37.2% (p = 0.008), and the direct In(uACR)-VTDR association became non-significant. In contrast, those with dyslipidaemia exhibited the highest total effect (0.030) in comparison to baseline (0.022) and the elevated BP subgroup (0.021), but it was mediated by 18.7%. Conclusions Albuminuria was associated with vision-threatening diabetic retinopathy among the US adult population and was partially explained by systemic inflammation, especially among those with elevated blood pressure.