Plasma Levels of Growth Differentiation Factor 15 and Adverse Kidney Outcomes
Clinical Journal of the American Society of Nephrology, 2026
Koh H., Kim H., Heo S., Park C., Kim H., Joo Y., Chang T., Park J., Yoo T., Kang S., Han S.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Nephrology | Pathophysiology Patient Stratification | Plasma |  Olink Explore 3072/384 |
Abstract
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 m 2 (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.