To our knowledge, this study is the first investigation of associations of the Gal-1 level with all-cause mortality and AKI in critically ill patients. It demonstrated that higher serum Gal-1 concentrations increase the risk of mortality in the ICU and at 90 days. This increase remained significant after controlling for the body mass index, malignancy, sepsis, SOFA score, and serum lactate level and was consistent across subgroups. The incidences of AKI and dialysis dependency after discharge were also greater in the high Gal-1 group than in the low Gal-1 group. In multivariate analysis, the serum Gal-1 concentration remained an independent risk factor for AKI and renal replacement therapy dependency after controlling for the SOFA score and initial renal function.
Galectins are abundant in the skeletal, smooth, and cardiac muscles; motor and sensory neurons; thymus; kidney; and placenta [16, 17]. The function of galectin depends on the cellular location. Intracellular Gal-1 regulates cell growth via protein–protein interaction [18]. Secreted Gal-1 mediates cell aggregation and adhesion to the extracellular matrix, which are crucial for tumor invasion of surrounding tissues [19]. Gal-1 in CD8 T lymphocytes is a negative regulator of anti-tumor immunity. It helps tumors to escape immunosurveillance [20], and inhibits the immunosuppressive effects of mesenchymal stem cells. It stops cell proliferation in the G0 and G2 phases, when its concentration increases [21]. However, in chronic inflammation and autoimmune disorders, Gal-1 has immunosuppressive and anti-inflammatory effects [22, 23]. It prevents severe inflammation–induced neurodegeneration and improves neurogenesis after ischemic stroke [24]. Gal-1 is secreted early after acute myocardial infarction. It promotes the apoptosis of CD8, Th1, and Th17 lymphocytes, and is associated with adverse remodeling after acute coronary syndrome. Thus, Gal-1 upregulation may influence the resolution of cardiac inflammation and restore hemostasis. In an experimental study, mice lacking Gal-1 showed increased cardiac dilatation after acute myocardial infarction [6].
Sepsis remains a significant challenge in medicine and is the most common cause of death in critically ill patients admitted to the ICU [25]. SIRS, another common reason for ICU admission, is a clinical syndrome that results from deregulation of the inflammatory response to infections or non-infectious insults, such as acute pancreatitis, vasculitis, and autoimmune disorders [26]. Biomarkers have been developed to diagnose, predict, or influence the disease severity of sepsis or SIRS. In this study, the risk of mortality increased with the serum concentration of Gal-1, a regulator of the inflammatory response. Additionally, serum Gal-1 concentrations were higher in patients with critical illnesses than in those who underwent CAG. These findings may reflect the severity of infection or inflammation and the host response to it. A complicated and overwhelming host response that involves immune, inflammatory, metabolic, and neuroendocrine factors leads to multiorgan dysfunction [27], thereby increasing mortality [28].
AKI occurs in up to 5.7% of critically ill patients during their ICU stays [29]. Its causes include sepsis, inflammation, hepatorenal and cardiorenal syndromes, and nephrotoxic agents. AKI is associated with increased morbidity, mortality, and duration of hospitalization [30]. At the time of hospital discharge, 9–14% of patients in whom AKI occurred during hospitalization are dependent on renal replacement therapy [31]. Galectin has been associated with progressive renal fibrosis, and its absence may protect against renal failure [32]. GAL-1 was reported to regulate podocin production and podocyte damage [33]. GAL-1 elevation has been associated with diabetic nephropathy[34] and renal function decline [13]. Our findings further strengthen the association of GAL-1 with AKI.
Patients with solid tumors comprised 40% of our study population. With recent progress in intensive chemotherapeutic regimens and hematopoietic stem cell transplantation, the cancer-related mortality rate has declined gradually. Thus, ICUs are required to provide life-sustaining treatments for infection or chemotherapy-related toxicity events to patients with cancer [35]. Corapi et al. [20] found that the absence of Gal-1 in the T lymphocytes of patients with prostate cancer potentiated anti-tumor immune responses. In patients with cancer, high levels of Gal-1, most likely secreted from tumor cells, may help tumor cells to evade immune responses.
Limitations
This study has several limitations. First, it was conducted at a single-center with relatively few patients. Second, given the lack of a reference Gal-1 range, we could only divide patients into three equally sized serum Gal-1 groups. Third, co-morbidities and disease severity differed significantly among groups, indicting the presence of selection bias. Although we performed adjusted analyses, some confounding factors may not have been accounted for. Finally, the study was observational and the causality of relationships could not be established.