Novel Perspectives in Chronic Kidney Disease-Specific Cardiovascular Disease

Abstract

Chronic kidney disease (CKD) affects > 10% of the global adult population and significantly increases the risk of cardiovascular disease (CVD), which remains the leading cause of death in this population. The development and progression of CVD-compared to the general population-is premature and accelerated, manifesting as coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. CKD and CV disease combine to cause multimorbid cardiorenal syndrome (CRS) due to contributions from shared risk factors, including systolic hypertension, diabetes mellitus, obesity, and dyslipidemia. Additional neurohormonal activation, innate immunity, and inflammation contribute to progressive cardiac and renal deterioration, reflecting the strong bidirectional interaction between these organ systems. A shared molecular pathophysiology-including inflammation, oxidative stress, senescence, and hemodynamic fluctuations characterise all types of CRS. This review highlights the evolving paradigm and recent advances in our understanding of the molecular biology of CRS, outlining the potential for disease-specific therapies and biomarker disease detection.

Keywords: Chronic kidney disease; biomarkers; cardiorenal syndrome; cardiovascular disease; inflammation.

Figure 2

Factors involved in cardiorenal inflammation. The kidney and heart functions are interdependently linked, and several common factors have been involved in the chronic inflammation demonstrated in chronic kidney disease (CKD) and cardiovascular disease (CVD). Abbreviation: RAAS, renin angiotensin aldosterone systems.

Figure 3

Inflammation underlies the molecular mechanisms in cardiorenal syndrome (CRS). The innate and adaptive immune system are composed of various immune cells that can respond to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) through recognising cytosolic or surface pattern recognition receptors (PPRs). Effector responses include the release of cytokines, e.g., interleukin (IL)-1β, IL-6, and tumour necrosis factor (TNF)-α. The excess and/or prolonged existence of these cytokines can lead to the clinical manifestations of left ventricular hypertrophy (LVH), fibrosis, and diastolic dysfunction. With or without treatment, the disease can typically progress into heart failure (HF), which can be differentiated into HF with preserved ejection fraction (HFpEF) and/or HF with reduced EF (HFrEF).

Figure 4

Gut-derived metabolites and the immune response. Dietary proteins, e.g., tryptophan, tyrosine, and L-carnitine (lysine), are digested by intestinal bacteria into bioactive compounds—such as indole, p-cresol, and trimethylamine (TMA)—that can either be removed via faeces or (passively) across the intestinal barrier into the circulation. The remaining precursor molecules are metabolized by hepatic enzymes into indoxyl sulphate (IS), p-cresol sulphate (pCS), and trimethylamine-N-oxide (TMAO), which are excreted by the kidneys. In CRS, the gut microbiota is altered, resulting in increased toxin production; a “leaky” cellular barrier promotes absorption; and reduced kidney clearance promotes the retention of organic compounds. These act as ligands for the aryl hydrocarbon receptor (AhR) in cells. AhR is typically inactivated in the cytoplasm as a part of a complex with heat shock protein (HSP) 90, AhR-interacting protein (AIP), p23, and pp60 Src. Ahr can be activated by the binding of endogenous or exogenous ligands, translocating to the nucleus to interact with the AhR nuclear translocator (ARNT) and binding to dioxin-response elements (DREs), leading to the NF-κB- and MAPK-dependent production of pro-inflammatory cytokines.

Figure 1

Cellular components of adult human heart. Human adult heart tissue consists of cardiomyocytes (42.7%), fibroblasts (28.9%), endothelial cells (9.8%), vascular smooth muscle cells (2.0%), pericytes (6.4%), adipocytes (3.0%), neuronal cells (0.5%), and various types of immune cells (leukocytes 6.1% and lymphocytes 0.5%). The cells are supported and segregated within a dynamic three-dimensional network—an extracellular matrix (ECM)—which is involved in regulating intercellular communication.