Endothelial Dysfunction in Chronic Kidney Disease, from Biology to Clinical Outcomes: A 2020 Update

Abstract

The vascular endothelium is a dynamic, functionally complex organ, modulating multiple biological processes, including vascular tone and permeability, inflammatory responses, thrombosis, and angiogenesis. Endothelial dysfunction is a threat to the integrity of the vascular system, and it is pivotal in the pathogenesis of atherosclerosis and cardiovascular disease. Reduced nitric oxide (NO) bioavailability is a hallmark of chronic kidney disease (CKD), with this disturbance being almost universal in patients who reach the most advanced phase of CKD, end-stage kidney disease (ESKD). Low NO bioavailability in CKD depends on several mechanisms affecting the expression and the activity of endothelial NO synthase (eNOS). Accumulation of endogenous inhibitors of eNOS, inflammation and oxidative stress, advanced glycosylation products (AGEs), bone mineral balance disorders encompassing hyperphosphatemia, high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23), and low levels of the active form of vitamin D (1,25 vitamin D) and the anti-ageing vasculoprotective factor Klotho all impinge upon NO bioavailability and are critical to endothelial dysfunction in CKD. Wide-ranging multivariate interventions are needed to counter endothelial dysfunction in CKD, an alteration triggering arterial disease and cardiovascular complications in this high-risk population.

Underlying Kidney Diseases and Complications for COVID-19: A Review

“…Thus, several mechanisms have been described through which SARS-CoV-2 can lead to acute and chronic kidney damage, such as via acute tubular necrosis, interstitial inflammation, injuries in renal vasculature and collapsing glomerulopathy. Endothelial dysfunction is a key characteristic of CKD per se already at an early stage (29) and endothelial damage such as pericyte detachment, expansion of sub-endothelial space and foam cell accumulation have been described in COVID-19 (30). Of note, ACE2 receptors are also expressed by endothelial cells (31), and the systemic endotheliitis in the course of COVID-19 can occur either by direct viral infection of the endothelium or it can be immune-mediated (32).…”

Role of Albuminuria in Detecting Cardio-Renal Risk and Outcome in Diabetic Subjects

“…In fact, ROS scavenges nitric oxide (NO) and peroxy-nitrite, which are increased in diabetic patients, resulting in a reduced NO bioavailability. Among the other products of oxidative stress in T2DM, the advanced glycation end-product (AGEs) can stimulate the production of free radicals, which seems closely related to the endothelial damage found in patients with CKD [ 20 , 21 ]. However, albuminuria/proteinuria still remains the most widely used marker of DN in both clinical practice and clinical trials, likely because microalbuminuria from the 1980s has been described not only as a renal, though also as a CV risk factor in diabetic patients [ 22 ].…”

“…Moreover, all these factors and others released by the activated endothelium (e.g., ICAM-1, VCAM-1, vWF and matrix metalloproteinases) can induce an activation of the NF-κBintracellular pathway, thus determining an alteration of both intercellular cross-talk and cytoskeleton. This damage has been observed in several chronic diseases, such as CKD and heart failure [ 20 ]. The alteration of this cross-talk between endothelial cells and these other glomerular cells favors and increases endothelial damage.…”

Assessment of Endothelial and Microvascular Function in CKD: Older and Newer Techniques, Associated Risk Factors, and Relations with Outcomes

“…Vascular adhesion molecule 1 (VCAM-1), intracellular adhesion molecule 1 (ICAM-1), and endothelial selectin (E-selectin) are considered endothelial-specific biomarkers [119]. Compounds involved in the coagulation cascade (i.e., fibrinogen and von Willebrand factor [VWF]) are considered related but not specific markers of endothelial dysfunction [120].…”