Plasma Leucine-Rich α-2-Glycoprotein 1 Predicts Cardiovascular Disease Risk in End-Stage Renal Disease

Abstract

plasma leucine-Rich α-2-glycoprotein 1 (LRG1) is an innovative biomarker for inflammation and angiogenesis. Many adverse pathophysiological changes including inflammation, atherosclerosis, and premature mortality is associated with End-stage renal disease (ESRD). However, whether levels of plasma LRG1 correlate with the co-morbidities of ESRD patients is unknown. Plasma LRG1 and high-sensitivity C-reactive protein (hsCRP) were analyzed by ELISA in 169 hemodialysis patients from the Immunity in ESRD (iESRD) study. Patient demographics and comorbidities at the time of enrollment were recorded. Peripheral blood monocyte and T cell subsets were assessed by multicolor flow cytometry. In the univariate analysis, a higher level of LRG1 was associated with the presence of cardiovascular disease (CVD) and peripheral arterial occlusive disease (PAOD). In multivariate logistic regression models, higher LRG1 tertile was significantly associated with PAOD (odds ratio = 3.49) and CVD (odds ratio = 1.65), but not with coronary artery disease, history of myocardial infarction, or stroke after adjusting for gender, diabetes, hemoglobin, albumin, calcium-phosphate product, and level of hsCRP. In addition, the level of LRG1 had a positive correlation with IL-6, hsCRP, and also more advanced T cell differentiation. The association suggests that LRG1 participates in the progression of atherosclerosis by inducing inflammation. Therefore, the role of LRG1 in coexisting inflammatory response should be further investigated in the pathogenesis of cardiovascular morbidity and mortality in patients with ESRD. Cardiovascular mortality in patients with end-stage renal disease (ESRD) remains the leading cause of death 1,2. These patients exhibit a strikingly higher risk (20-400 folds) of cardiovascular mortality compared to age-matched health subjects without any kidney disease 3. Traditional risk factors as well as non-traditional risk factors, such as inflammation, are believed to contribute to the excessively heavy burden of cardiovascular disease in chronic kidney disease (CKD) and ESRD patients 3. The pro-inflammatory microenvironment is collectively caused by uremic milieu, infection, and tissue ischemia even before the initiation of dialysis 4. Innate immunity is the evolutionarily conserved host response mediated by pattern recognition receptors (PRRs), which bind endogenous or exogenous ligands and initiate downstream signaling pathways to establish an immediate responses as the first line of defense. Two types of PRRs, Toll-like receptors (TLRs) over the cell surface and inflammasomes in the cytoplasm can interact with endogenous ligands. They are involved in the development of pro-inflammatory microenvironment in renal failure. Activation of these innate immune pathways is

LRG1: an emerging player in disease pathogenesis

“…In chronic kidney disease, for example, inflammation promotes atherosclerosis and is associated with a high incidence of cardiovascular disease. In patients with end-stage renal disease, LRG1 significantly correlates with other markers of inflammation such as IL-6 and hsCRP, as well as T cell immunosenescence, and increased LRG1 levels are independently associated with the presence of peripheral arterial occlusive disease and cardiovascular disease [ 125 ].…”

Uncovering Potential lncRNAs and mRNAs in the Progression From Acute Myocardial Infarction to Myocardial Fibrosis to Heart Failure

“…In mouse models of MI, LRG1 ablation leads to aggravate MF and heart dysfunction (66). In addition, LRG1 participates in vascular remodeling during HF (67). RNASE1 is upregulated in patients with a history of early MI (68).…”

Serum biomarker discovery related to pathogenesis in acute coronary syndrome by proteomic approach

“…LRG is produced and secreted by endothelial cells, neutrophils, macrophages, and hepatocytes, and is induced by cytokines such as interleukin-6 (IL-6) during inflammatory reaction [54][55][56], other inflammatory diseases also increase LRG levels [57]. Furthermore, LRG level has a Downloaded from http://portlandpress.com/bioscirep/article-pdf/doi/10.1042/BSR20210344/911318/bsr-2021-0344-t.pdf by guest on 24 May 2021 positive correlation with IL-6 and also may be associated with the differentiation of inflammatory T-lymphocytes [58]. This T-lymphocytes produce and secrete granzyme, a serine protease that degrades extracellular matrix (ECM) components such as collagen, fibronectin, and proteoglycan [15].…”