**3. Chronic Kidney Disease (CKD)**

Chronic kidney disease (CKD) is a growing global problem associated with a high risk of morbidity and mortality. This condition adversely affects both human health and the expenditure of healthcare systems worldwide [56,57]. The international guidelines provided by KDIGO define CKD as an abnormality in kidney structure or function, present for >3 months, with health implications. CKD is an irreversible clinical condition associated with a definitive alteration of renal function and structure, with a slow and progressive evolution. In addition, due to the long course of CKD, one or more episodes of Acute Kidney Disease are observed, superimposed on CKD [58,59]. The loss of renal function and the progression to endstage renal failure are evidenced by the loss of tubular cells and their replacement by collagen scars, as well as the high density of infiltrating macrophages [59–61]. In addition, in kidneys with CKD, the activation of the renin-angiotensin system and a reduced number of glomeruli also induce hyperfiltration and increased tubular oxygen consumption, worsening the imbalances between oxygen demand and release [62]. However, the progressive loss of renal function is linked to inflammation, the overproduction of reactive species, decreased antioxidant defences in endothelial cells (EC), the stimulation of cross-talk between EC and macrophages, and the increased expression of adhesion molecules (E-selectin, P-selectin,

ICAM-1, and VCAM-1) with infiltration by monocytes and macrophages into the activated endothelium. Neutrophils are the first cells to accumulate in the renal parenchyma, further releasing reactive molecules, proteinases, elastases, myeloperoxidases, cationic peptides, cytokines, and pro-inflammatory chemokines to recruit and activate other neutrophils but also natural killer cells, monocytes, and macrophages, exacerbating renal damage through a synergistic interaction [63–65]. These events, which can occur in both the renal cortex and medulla, are therefore associated with a wide range of detrimental effects such as altered renal blood flow, sodium/fluid retention, inflammation, fibrotic changes, and proteinuria [66]. An event that frequently occurs with declining kidney function is the retention of toxic metabolites that are not excreted and subsequently accumulate in the systemic circulation. These metabolites are called uremic toxins, and they lead to uremic syndrome, which, in addition to the progressive loss of kidney function, is associated with symptoms such as nausea, vomiting, fatigue, anorexia, muscle cramps, itching, altered mental status and others, leading to a reduced quality of life, morbidity, and mortality [67]. Uremic toxins can be classified according to their physico-chemical characteristics, such as water-soluble free solutes with a low molecular weight (<500 Da; e.g., Guanidine, Creatinine, Urea, Trimethylamine N-oxide, Inorganic phosphorus), protein-bound uremic toxins (<200 Da; e.g., Indoxyl Sulfate (IS), p-Cresyl Sulfate (pCS), Indole-3-acetic acid, Phenol Quinolinic acid, Putrescine), and medium molecules (≥500 Da; e.g., β2- microglobulin, Leptin, IL-6, β-trace protein, Parathyroid hormone). Despite the fact that most of these metabolites are eliminated by dialysis, except the plasma protein-bound [68], the resulting accumulation of uremic toxins is associated with CKD progression and related complications, such as cardiovascular, central nervous system, gastrointestinal, and other areas, also trigger inflammation and oxidative stress and impaired immune response [69–78].
