Primary aldosteronism results in a decline estimated glomerular filtration rate independent of blood pressure: evidence from a case-control and mendelian randomization study

ABSTRACT Background: Primary aldosteronism (PA) is the predominant cause of secondary hypertension, leading to cardiovascular and renal damage via mechanisms such as oxidative stress and fibrosis. However, current epidemiology findings on the association between PA and estimated glomerular filtration rate (eGFR) remain inconsistent. Methods: A 1:1 sex- and age-matched case-control study was conducted among participants with PA, essential hypertension (EH), and normotension, with 204 participants in each group. Multiple linear regression was used to explore the correlations of PA, plasma aldosterone concentration (PAC), plasma renin concentration (PRC), and the aldosterone-to-renin ratio (ARR) with eGFR. Additionally, we performed a bidirectional two-sample mendelian randomization (MR) analysis to assess the causal relationship between PA and eGFR based on public genome wide association study (GWAS) databases, and established a multivariable MR (MVMR) analysis to further explore whether the causal effect of PA on eGFR decline independent of systolic (SBP) or diastolic blood pressure (DBP). Results: Multiple linear regression model showed that PA was associated with a decline eGFR (β = -0.234, [95% CI, -0.099, -0.039], P<0.001) after adjusted potential confounders. When stratified the PA patients into three groups according to the levels of PAC, PRC and ARR, patients in the highest PAC groups (β = -0.146 [95% CI, -0.093, -0.008], P =0.021), the lowest PRC group (β = -0.127 [95% CI, -0.084, -0.004], P =0.033), and the highest ARR group (β = -0.147 [95% CI, -0.092, -0.009], P =0.017) had much lower eGFR compared to the EH group. The inverse associations mentioned above remained significant even further adjusted for SBP or DBP, respectively. Besides, MR results indicated that genetically predicted PA was causally associated with a decline eGFR (β =-6.671×10-4[95% CI,-1.291×10-4,-4.328×10-5], P = 0.036), consistent effects were further detected in SBP (β =-1.121×10-3 [95% CI,-2.132×10-3,-1.110×10-4], P = 0.029) or DBP (β =-1.542×10-3,[95% CI,-2.693×10-3,-3.912×10-4], P = 0.008) adjusted model using MVMR analysis. Conclusion: Our study indicates that PA is causally associated with lower eGFR independent of blood pressure, and the adverse effects might be greater than negative controls or EH patients.