Unveiling the Causal Relationship Between Thyroid and Kidney Function: A Multivariable Mendelian Randomization

Background: Recent studies suggest an association between thyroid dysfunction and kidney function, but the causal relationship remains uncertain. The complex interactions between thyroid-stimulating hormone (TSH), free thyroxine (fT4), and thyroid peroxidase antibodies (TPOAb) complicate the assessment of this link. This study employed multivariable Mendelian randomization (MVMR) to elucidate the causal relationship between thyroid dysfunction and kidney function in East Asian and European populations. Methods: We conducted a cross-sectional study and MVMR analysis using data from 17,733 participants in the Taiwan Biobank. Thyroid function was assessed by measuring TSH, fT4 and TPOAb levels, with hypothyroidism classified as subclinical or overt. The primary outcome was creatinine-based estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease-EPIdemiology Collaboration equation. Observational analyses were adjusted for age, sex, body mass index, and metabolic and cardiovascular factors. MVMR analyses used genetic variants associated with TSH, fT4, and TPOAb levels to assess their causal effects on eGFR. Data from the ThyroidOmics and CKDGen Consortium were used to replicate findings in European populations. Results: Both TSH and fT4 levels were inversely associated with eGFR, and hypothyroidism was correlated with lower eGFR. Conversely, TPOAb was positively associated with eGFR. Mendelian randomization analyses, using 26 genetic variants for TSH, four for fT4, and eight for TPOAb confirmed a causal relationship between TSH and eGFR. Significant causal effects of TSH were observed across various MVMR methods ( P values from <0.001 to 0.01), whereas fT4 and TPOAb showed no significant causal effects (both P >0.05). These findings were consistent in European populations. Conclusions: The study found that elevated TSH levels are causally associated with reduced kidney function, highlighting the potential importance of thyroid function in kidney health. These findings suggest that thyroid dysfunction should be considered in managing patients with chronic kidney disease.