Role and Mechanism of Growth Differentiation Factor 15 in Chronic Kidney Disease

Tang, Yifang; Liu, Tao; Sun, Shibo; Peng, Youbo; Huang, Xiaoxiao; Wang, Shuangquan; Zhou, Zhu

doi:10.2147/jir.s451398

JIR

2024

DOI: 10.2147/jir.s451398

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Role and Mechanism of Growth Differentiation Factor 15 in Chronic Kidney Disease

Yifang Tang,

Tao Liu,

Shibo Sun

et al.

Abstract: GDF-15 is an essential member of the transforming growth factor-beta superfamily. Its functions mainly involve in tissue injury, inflammation, fibrosis, regulation of appetite and weight, development of tumor, and cardiovascular disease. GDF-15 is involved in various signaling pathways, such as MAPK pathway, PI3K/AKT pathway, STAT3 pathway, RET pathway, and SMAD pathway. In addition, several factors such as p53, ROS, and TNF-α participate the regulation of GDF-15. However, the specific mechanism of these facto… Show more

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Cited by 3 publications

References 126 publications

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Association between DNA methylation predicted growth differentiation factor 15 and mortality: results from NHANES 1999–2002

Luo,

Shen

2024

Aging Clin Exp Res

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Background Growth differentiation factor 15 (GDF15) is a crucial biomarker in various physiological and pathological processes. While elevated GDF15 levels are linked to increased mortality risk, the role of DNA methylation (DNAm)-predicted GDF15 in predicting mortality has not been extensively studied. The purpose of the study is to investigate the association between DNAm-predicted GDF15 levels and all-cause and cardiovascular disease (CVD) mortality in a nationally representative cohort. Methods Data from NHANES 1999–2002 were analyzed. DNAm-predicted GDF15 levels were estimated using a regression model. Weighted multivariate Cox regressions were employed to assess the relationship between DNAm-predicted GDF15 and mortality outcomes. Restricted cubic splines were used to explore dose-response relationships, and subgroup analyses were conducted to enhance result reliability. Results Higher DNAm-predicted GDF15 levels were significantly associated with increased all-cause mortality risk (HR = 1.08, 95% CI: 1.02–1.15). Participants in the highest DNAm-predicted GDF15 tertile showed significantly higher all-cause mortality risk (HR = 1.56, 95% CI: 1.16–2.10) and a 2.52-fold increased risk of cardiovascular mortality (HR = 2.52, 95% CI: 1.22–5.19). Kaplan-Meier curves revealed decreasing survival probability with higher DNAm-predicted GDF15 tertiles. Restricted cubic spline analysis demonstrated a non-linear dose-response relationship between DNAm-predicted GDF15 levels and cardiovascular mortality. The positive correlation between DNAm-predicted GDF15 and mortality remained robust in most of subgroups. Conclusions DNAm-predicted GDF15 independently predicts all-cause and cardiovascular mortality. This association persists across multiple models and stratified subgroups, supporting GDF15’s value as a biomarker for mortality risk stratification. Future research should elucidate underlying biological mechanisms and evaluate GDF15’s clinical utility in guiding mortality risk reduction interventions.

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Association between DNA methylation predicted growth differentiation factor 15 and mortality: results from NHANES 1999–2002

Luo,

Shen

2024

Aging Clin Exp Res

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Early Serum Biomarkers of Cardiovascular Disease in Elderly Patients with Chronic Kidney Disease

Zhang,

Liao

2024

Cardiorenal Med

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Background: The global population is aging. It is estimated that by 2050, the proportion of the elderly population will reach 16%. Various studies have suggested that elderly people have a greater incidence of CKD. These elderly patients are also susceptible to cardiovascular disease (CVD), which is the leading cause of death, resulting in poor prognosis in this population. However, CVD in such patients is often insidious and lacks early markers for effective evaluation. Fortunately, several studies have recently proposed biomarkers associated with this process. Summary: This study aimed to summarize the early biomarkers of CVD in elderly patients with CKD to provide a basis for its prevention and treatment. Key Messages: This review outlines four categories of potential early biomarkers. All of them have been shown to have some clinical value for these patients, but more research is still needed.

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Growth Differentiation Factor 15 and Matrix Metalloproteinase 3 in Plasma as Biomarkers for Neuropathy and Nephropathy in Type 1 Diabetes

Billeson,

Baldimtsi,

Wahlberg

et al. 2024

IJMS

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Diabetic neuropathy and nephropathy are common complications of type 1 diabetes (T1D). The symptoms are often elusive in the early stages, and available diagnostic methods can be improved using biomarkers. Matrix metalloproteinase 3 (MMP-3) has been identified in the kidneys and is thought to be involved in diabetic nephropathy. Growth differentiation factor 15 (GDF-15) has been suggested to have positive effects in diabetes, but is otherwise associated with adverse effects such as cardiovascular risk, declined kidney function, and neurodegeneration. This study aims to investigate plasma MMP-3 and GDF-15 as systemic biomarkers for diabetic neuropathy and nephropathy in T1D. The study involves patients with childhood-onset T1D (n = 48, age 38 ± 4 years) and a healthy control group (n = 30, age 38 ± 5 years). Neurophysiology tests, evaluations of albuminuria, and measurements of routine biochemical markers were conducted. The neuropathy impairment assessment (NIA) scoring system, where factors such as loss of sensation and weakened reflexes are evaluated, was used to screen for symptoms of neuropathy. MMP-3 and GDF-15 concentrations were determined in heparinized plasma using ELISA kits. In total, 9 patients (19%) had albuminuria, and 25 (52%) had diabetic neuropathy. No significant differences were found in MMP-3 concentrations between the groups. GDF-15 levels were higher in T1D, with median and interquartile range (IQR) of 358 (242) pg/mL in T1D and 295 (59) in controls (p < 0.001). In the merged patient group, a positive correlation was found between MMP-3 and plasma creatinine, a negative correlation was found between MMP-3 and estimated glomerular filtration rate (eGFR; rho = −0.358, p = 0.012), and there was a positive correlation between GDF-15 and NIA (rho = 0.723, p < 0.001) and high-sensitive C-reactive protein (rho = 0.395, p = 0.005). MMP-3 was increased in macroalbuminuria and correlated positively with NIA only in the nine T1D patients with albuminuria (rho = 0.836, p = 0.005). The present study indicates that high MMP-3 is associated with low eGFR, high plasma creatinine, and macroalbuminuria, and that GDF-15 can be a biomarker for diabetic neuropathy in T1D. MMP-3 may be useful as biomarker for neuropathy in T1D with albuminuria.

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Role and Mechanism of Growth Differentiation Factor 15 in Chronic Kidney Disease

Cited by 3 publications

References 126 publications

Association between DNA methylation predicted growth differentiation factor 15 and mortality: results from NHANES 1999–2002

Association between DNA methylation predicted growth differentiation factor 15 and mortality: results from NHANES 1999–2002

Early Serum Biomarkers of Cardiovascular Disease in Elderly Patients with Chronic Kidney Disease

Growth Differentiation Factor 15 and Matrix Metalloproteinase 3 in Plasma as Biomarkers for Neuropathy and Nephropathy in Type 1 Diabetes

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