| Title: | Plasma Levels of Growth Differentiation Factor 15 and Adverse Kidney Outcomes: Proteomics-Based Mediation Analysis and Mendelian Randomization. |
| Journal: | Clinical Journal of the American Society of Nephrology |
| Published: | 25 Aug 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42640732/ |
| DOI: | https://doi.org/10.2215/cjn.0000001177 |
Publication 21144
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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.</p>
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.</p>
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).</p>
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.</p>
11 Authors
- Hee Byung Koh
- Hyo Jeong Kim
- Seok-Jae Heo
- Cheol Ho Park
- Hyung Woo Kim
- Young Su Joo
- Tae Ik Chang
- Jung Tak Park
- Tae-Hyun Yoo
- Shin-Wook Kang
- Seung Hyeok Han
Enabling scientific discoveries that improve human health