Mechanisms of Cardiovascular Disorders in Patients With Chronic Kidney Disease: A Process Related to Accelerated Senescence

Abstract

Cardiovascular diseases (CVDs), especially those involving a systemic inflammatory process such as atherosclerosis, remain the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). CKD is a systemic condition affecting approximately 10% of the general population. The prevalence of CKD has increased over the past decades because of the aging of the population worldwide. Indeed, CVDs in patients with CKD constitute a premature form of CVD observed in the general population. Multiple studies indicate that patients with renal disease undergo accelerated aging, which precipitates the appearance of pathologies, including CVDs, usually associated with advanced age. In this review, we discuss several aspects that characterize CKD-associated CVDs, such as etiopathogenic elements that CKD patients share with the general population, changes in the cellular balance of reactive oxygen species (ROS), and the associated process of cellular senescence. Uremia-associated aging is linked with numerous changes at the cellular and molecular level. These changes are similar to those observed in the normal process of physiologic aging. We also discuss new perspectives in the study of CKD-associated CVDs and epigenetic alterations in intercellular signaling, mediated by microRNAs and/or extracellular vesicles (EVs), which promote vascular damage and subsequent development of CVD. Understanding the processes and factors involved in accelerated senescence and other abnormal intercellular signaling will identify new therapeutic targets and lead to improved methods of diagnosis and monitoring for patients with CKD-associated CVDs.

Keywords: atherosclerosis; cardiovascular diseases; cellular senescence; chronic kidney disease; epigenetic alterations; extracellular vesicles; microRNAs; reactive oxygen species.

FIGURE 1

Risk factors for cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Traditional risk factors (such as hypertension and diabetes mellitus) and specific CKD risk factors (such as albuminuria or inflammation) lead to remodeling of the myocardium and blood vessels. This process may contribute to the development and progression of cardiomyopathy, atherosclerosis, arterial stiffness, and calcification. Without treatment, these alterations may progress to ischemic heart disease, heart failure, cerebrovascular disease, renal progression, and cardiovascular death.

FIGURE 2

Relationship between oxidative stress and CKD-associated cardiovascular disease (CVDs). CKD leads to increased damage of biomolecules (such as lipids, proteins, and DNA), impairment of the antioxidant system, increased levels of reactive oxygen species (ROS), decreased ROS clearance, and high concentration of uremic toxins in circulation. This process increases the levels of oxidative stress. CKD is also associated with systemic inflammation, mitochondrial dysfunction, loss of proteostasis, altered intercellular communication, and cellular senescence. Combined, these factors contribute to increased levels of oxidative stress in this patient population. However, cellular senescence and inflammation also participate in the development and progression of CVDs.

FIGURE 3

Changes in the immune system in CKD lead to the development of CVD. The populations of classical (CD14++CD16-) monocytes in CKD decrease, while those of intermediate (CD14++CD16+) and non-classical (CD14+CD16+) monocytes increase. The intermediate (CD14++CD16+) and non-classical (CD14+CD16+) monocytes promote inflammation and proatherogenic milieu by upregulating the expression of adhesion molecules and production of microvesicles (MVs) in the endothelium; this contributes to the development of CVD in patients with CKD. Lymphopenia of both T and B lymphocytes is observed in CKD. The T lymphopenia is caused by the reduction of T regulatory cells (Treg), contrariwise the increase of pro-inflammatory T helper 17 lymphocytes (Th17). These changes in proportion of regulatory cells to proinflammatory cells can lead to inflammation. B lymphopenia is caused by decreased numbers of B1 and B2 cells. The numbers of B1 lymphocytes generally show a greater decline than those of B2, resulting in a B-lymphocyte imbalance. These two processes also participate in the development of CKD-associated CVD.