Potential Causal Relationship Between Hypertension and Type 2 Diabetic Nephropathy: Integrating Mendelian Randomization Evidence with Global Burden of Disease 2021 Analysis

Background: Hypertension (HTN) and type 2 diabetes mellitus are major global health challenges, and diabetic nephropathy (DN) is a critical complication of diabetes. Although observational studies link HTN to DN progression, causal evidence remains limited. We investigated the potential causal relationship between HTN and DN and quantified the global burden of HTN-attributable type 2 diabetic nephropathy (HTN-T2DN). Methods: We integrated two-sample Mendelian randomization (MR), Bayesian weighted MR, and sensitivity analyses with Global Burden of Disease (GBD) 2021 analyses. The burden of HTN-T2DN was assessed from 1990 to 2021 and projected to 2045. Results: MR provided genetic evidence supporting a potential causal role of HTN in DN (inverse-variance weighted odds ratio = 4.219, 95% CI: 1.807–9.853; p = 0.001). Globally, HTN-T2DN deaths increased to 50,689 and DALYs to 1,151,216 in 2021. Females had higher age-standardized mortality and DALY rates than males, and low-middle sociodemographic index (SDI) regions had the highest burden. By 2045, deaths and DALYs were projected to reach 162,392 and 4.04 million, respectively. Conclusions: HTN may play a potential causal role in DN development and progression. Strengthened blood pressure control, early screening, and tailored policies are essential, particularly for women, older adults, and populations in lower-SDI settings.