Plasma Levels of Growth Differentiation Factor 15 and Adverse Kidney Outcomes: Proteomics-Based Mediation Analysis and Mendelian Randomization.

BACKGROUND: Growth differentiation factor-15 (GDF-15) has been implicated in adverse outcomes in cardiovascular disease and diabetes, highlighting its potential as a prognostic marker. However, its association with chronic kidney disease (CKD) development remains unclear. Therefore, we investigated the association between GDF-15 and incident CKD and explored potential causal mechanisms. METHODS: We analyzed 31,965 UK Biobank participants without pre-existing CKD. The primary outcome was incident CKD, defined by diagnostic codes or an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (eGFR-based CKD). Proteomics-based mediation and protein-protein interaction analyses identified potential mediators linking GDF-15 to CKD. A bidirectional two-sample Mendelian randomization (MR) analysis using genome-wide association study summary statistics evaluated the potential causal relationship between GDF-15 and eGFR. RESULTS: In multivariable cause-specific analyses, higher GDF-15 levels were significantly associated with increased CKD risk (hazard ratios: Q2, 1.05 [0.87-1.26]; Q3, 1.21 [1.01-1.45]; Q4, 1.87 [1.56-2.26] vs. Q1; P-for-trend <0.001). Similar results were observed for eGFR-based CKD. Mediation analysis identified candidate proteins potentially involved in TNF receptor signaling, extracellular matrix organization, and immune cell chemotaxis. MR analysis demonstrated a significant association between genetically predicted higher GDF-15 levels and higher eGFR (IVW coefficient: 0.003; 95% confidence interval [CI]: 0.001-0.004; P =0.004). Conversely, higher genetically predicted eGFR was associated with lower GDF-15 levels (IVW coefficient: -1.238; 95% CI: -1.591 to -0.886; P <0.001). CONCLUSIONS: This study provides evidence supporting the role of GDF-15 as a prognostic biomarker for CKD and MR analyses provide suggestive evidence of a possible protective association of GDF-15 with kidney function. Further studies are needed to explore the mechanistic pathways and therapeutic implications of GDF-15 in kidney diseases.