The aim of this study was to investigate the causal relationship between high levels of galectin-3 and VC and all-cause mortality in ESRD patients who newly started on HD. First, we found that 57% of HD patients had AoAC at baseline, and higher serum galectin-3 levels were associated with an increased risk of VC. The more severe the AoAC score, the higher the galectin-3 levels were observed. In addition, the high galectin-3 levels significantly increased the risk of all-cause mortality. The mediation analysis showed that the significant effect of high galectin-3 levels on mortality was mediated by the induction of VC and inflammatory state.
Galectin-3, a soluble β-galactoside-binding lectin involved in cell proliferation, adhesion, migration and apoptosis, appears to promote inflammation or tissue fibrosis. Over the past decades, the prognostic role of serum galectin-3 as a biomarker linking oxidative stress, inflammation and fibrosis has been demonstrated in many pathological conditions such as HF, atherosclerosis, CKD and cancer5,20,21,22. Especially in patients with CKD, a recent large meta-analysis of 5226 patients showed that high galectin-3 levels were associated with an increased risk of all-cause mortality and CV events10. Similarly, in HD patients, Hogas et al. showed that a level of galectin-3 > 23.73 ng/mL was an independent predictor of mortality (HR: 2.60; 95% CI[1.09, 6.18])23, and a more long-term data also showed similar results11. Confirming a previous study, our data also showed that high galectin-3 ≥ 37.0 ng/mL was an independent predictor of mortality (HR 1.71, 95% CI 1.02–2.92, p = 0.048) even after adjustment of various CV risk factors.
However, galectin-3 levels were not associated with cause-specific mortality. In fact, there was no significant difference in galectin-3 levels by cause of death, and the prognostic role was consistent across cause-specific mortality. In univariate analysis, higher galectin-3 levels were significantly associated with each cause of death—CV death, infection-related death, and malignancy-related death, respectively. Although it lost statistical significance in multivariate analysis, we felt that this was due to the relatively small number of cases. We therefore believe that high galectin-3 levels are not a predictor limited to specific diseases, but are also associated with death from any cause, because galectins regulate basic cellular functions such as cell–cell and cell–matrix interactions, growth, proliferation, differentiation, and inflammation. It is therefore not surprising that this protein is associated with many causes of death24. In support of this, in the field of HF, galectin-3 has been shown to have diagnostic and prognostic value and has been recommended as a novel biological indicator for disease risk stratification of disease. In addition, abnormal galectin-3 expression is known to be associated with cancer initiation, progression, and metastasis21. In this context, galectins have become a focus of therapeutic research for clinical intervention against many pathological disorders25,26.
One of the most likely mechanisms linking galectin-3 and poor outcome is its proinflammatory properties. Galectin-3 is involved in macrophage chemotaxis, phagocytosis, neutrophil activation, oxidative stress and apoptosis, which are major pathogenesis of atherosclerosis27. In support of this, our data showed that serum galectin-3 levels correlated well with peripheral WBC count, circulating neutrophil count, NLR, and hsCRP levels, which are well-known markers of advanced atherosclerosis. This finding may indicate a strong link between galectin-3 and atherosclerosis via vascular inflammation.
Recently, it has also been suggested that galectin-3 may be involved in the osteogenic differentiation of VSMCs and the resultant development and progression of VC. As VC is a key feature of atherosclerosis, its early detection and treatment are of great importance for CV risk stratification and prevention. Especially in CKD, the burden of CV complications is significantly higher, which may be related to the widespread presence of VC in CKD patients. Our data showed that the higher the level of serum galectin-3, the more severe the degree of AoAC, providing clinical evidence that galectin-3 may play a role in VC in uremia. galectin-3 level above 37 ng/mL were associated with a twofold increased risk of VC. Other studies also showed the expression of galectin-3 at the site of calcified atherosclerotic plaque28,29, and Ibarrola et al. confirmed that inhibition of galectin-3 can reduce calcification of the heart valve in animal study30, suggesting the pathological role of galectin-3 in inducing VC.
In addition, very interestingly, we found negative association between galectin-3 and serum HDL-C levels. HDL-C is known as an antioxidant that plays a protective role against inflammation and oxidative stress in the human body31,32. Consistent with our data, previous data have reported that galectin-3 levels were negatively associated with HDL-C levels in the general population and in patients with MI6, suggesting that galectin-3 may be a link between dyslipidemia and inflammation. In addition, Zeng et al. reported that the combination of high galectin-3 and low HDL-C significantly improved the predictive value of recurrent stroke, and vascular events in patients with ischemic stroke7, suggesting that the benefit of the combination of the galectin-3 and HDL-C for predicting poor prognosis. In mechanism, both low HDL-C and high galectin-3 can induce lipid modification in oxidized LDL-C and enhance the phagocytosis of macrophages in taking up the oxidized LDL-C, exacerbating atherosclerosis and plaque rupture in vascular inflammation.
In this regard, we tried to find the mediation effect of various vascular risk factors on the relationship between galectin-3 and mortality. We found that AoAC and hsCRP significantly contribute to the overall indirect effect, however, BNP and HDL-C did not mediate the relationship. The results demonstrate the importance of VC and inflammatory status in mediating galectin-3 and all-cause mortality in HD patients.
Several limitations of our study should be mentioned. First, this is a single-center study with a retrospective analysis of a prospectively collected cohort. However, with a well-managed dialysis cohort, longitudinal follow-up data were available, which made it possible to obtain survival data and exact causes of death. So, with the mediation analysis, we can get a causal relationship between serum galectin-3 levels, AoAC, and mortality. Second, we could not get data on other VC scores such as AAC or coronary artery calcification. Because chest radiographs were performed in all patients, we used only the AoAC score. However, AoAC has been reported to correlate well with AAC or coronary artery calcium. Third, we did not investigate several factors that affect VC, such as vitamin K. However, we believe that this bias is minimal because it is unlikely that participants would choose not to take medications that affect vitamin K levels.
In summary, this study may suggest a potential causal relationship between serum galectin-3 and increased mortality in HD patients by providing evidence that galectin-3 increases VC and high inflammatory status.
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- Source: https://www.nature.com/articles/s41598-024-51383-2