**2. Inflammation as an Essential Component of CKD**

The persistent low-grade inflammatory status that characterizes CKD plays a key role in the pathophysiology of the disease. Inflammation starts early in the onset of renal diseases [13,14] and worsens with disease progression [15], being particularly marked in hemodialysis patients [16]. Interestingly, inflammation can be identified either as a trigger or a consequence of CKD. The etiology of inflammation is multifactorial and can result from a primary cause of disease (diabetes, obesity) [17], from renal dysfunction comorbidities (uremia, metabolic acidosis, intestinal dysbiosis, vitamin D deficiency, oxidative stress) [17–19], and/or from dialysis procedures (intercurrent infections and thrombotic events) [20].

Inflammation is a well-established risk factor of both morbidity and mortality in CKD patients [21–23], leading to renal function deterioration and fibrosis. CKD patients present low to moderate levels of circulating inflammatory mediators [24,25] as a result of a deregulation of their synthesis, increased release, and/or impaired renal clearance [15,26]. It is broadly accepted that inflammation plays a role in CKD progression, but the association between disease initiation and the establishment of inflammation is debatable. Glomerular hypertrophy, endothelial dysfunction, podocytes damage, proteinuria, and tubular cells injury are some of the identified kidney insults that can trigger the development of inflammation [27].

The initial inflammatory response occurs to overcome renal injury, promote tissue remodeling and wound healing. However, when this process outreaches the physiological limit, a chronic inflammatory state may arise, with undesirable systemic consequences [14]. The dysregulated immune response results in a continuous activation of inflammatory mediators, contributing to renal scarring and fibrosis [24], the final common pathological manifestation of renal diseases.

The inflammatory state is characterized by activation of inflammatory cells, releasing an array of acute phase proteins, cytokines, and chemokines [19,25], which are able to interact with renal parenchymal cells and resident immune cells, and trigger the recruitment and activation of circulating monocytes, lymphocytes, and neutrophils, into renal tissue [13,14]. The activation of inflammatory response and the infiltration of inflammatory cells induce cellular transdifferentiation into myofibroblasts, which are responsible for the production and deposition of extracellular matrix components and cytoskeletal components, which leads to renal remodeling. In renal fibrosis, myofibroblasts seem to be derived from different cell types, such as tubular epithelial cells, interstitial fibroblasts, macrophages, as well as pericytes and endothelial cells [28]. The imbalance in matrix formation/degradation leads to accumulation of an extracellular matrix, which might lead to glomerulosclerosis

and/or tubulointerstitial fibrosis and a consequent GFR decline [25,29]. Under chronic inflammatory activation, resident kidney cells exhibiting a proinflammatory phenotype, coupled with the activated immune cells, are responsible for perpetuating the ongoing inflammatory process, leading to renal fibrosis. Once renal fibrosis sets in, CKD progression is irreversible, irrespective of the initial cause [29]. Kidney hypoxia/ischemia, inflammation, and oxidative stress are simultaneously a cause and an effect of renal damage and fibrosis. Those events form a vicious cycle in CKD progression.

Cytokines and acute phase proteins are simultaneously key mediators and biomarkers of inflammation. Even though their circulating concentrations show a tendency to increase with the worsening of disease, the rate and magnitude of the increase depends on the molecule itself. It has been shown in several CKD models, that the classical proinflammatory signaling pathway, the NF-kB system [18,30], is activated by multiple inflammatory mediators, mainly by tumor necrosis factor alpha (TNF-α).
