Enhanced Kidney Damage in Individuals with Diabetes Who Are Chronically Exposed to Cadmium and Lead: The Emergent Role for β2-Microglobulin

Elevated levels of circulating β₂-microglobulin (β₂M) are linked to an increased risk of hypertension and mortality from diabetes. The present study tests the hypothesis that the environmental pollutants, cadmium (Cd) and lead (Pb), by increasing plasma β₂M levels, promote the development of hypertension and progression of diabetic kidney disease. Herein, we analyzed data from a Thai cohort of 72 individuals with diabetes and 65 controls without diabetes who were chronically exposed to low levels of Cd and Pb. In all subjects, serum concentrations of β₂M inversely correlated with the estimated glomerular filtration rate (eGFR) (<i>r</i> = -0.265) and directly with age (<i>r</i> = 0.200), fasting plasma glucose (<i>r</i> = 0.210), and systolic blood pressure (<i>r</i> = 0.229). The prevalence odds ratio (POR) for hyperglycemia increased 7.7% for every 1-year increase in age and increased 3.9-fold, 3.1-fold, and 3.7-fold in those with serum β₂M levels ≥ 5 mg/L, Cd/Pb exposure categories 2 and 3, respectively. The POR for hypertension increased 2.9-fold, 3-fold, and 4-fold by hyperglycemia (<i>p</i> = 0.011), Cd/Pb exposure categories 2 and 3. The POR for albuminuria increased 3.5-fold by hyperglycemia. In conclusion, kidney damage, evident from albuminuria, was particularly pronounced in participants with diabetes who had a serum β₂M above 5 mg/L plus chronic exposure to low-dose Cd and Pb. For the first time, through a mediation analysis, we provide evidence that links Cd exposure to the <i>SH2B3</i>-β₂M pathway of blood pressure homeostasis in people with and without diabetes.