**1. Chronic Kidney Disease—A Public Health Issue**

In the last decade, chronic kidney disease (CKD) has been recognized as a global public health problem, due to its increasing incidence and prevalence rates [1,2]. Additionally, CKD is a significant contributor to early morbidity and mortality worldwide, as well as an important risk factor for cardiovascular diseases (CVD). In 2017, CKD was the 12th leading cause of death, globally, rising from 17th in 1990 [3].

CKD is a pathological condition that results from a gradual and permanent loss of renal function over time, characterized by the presence of kidney dysfunction and injury markers, over a period of at least three months. According to the '2012 Kidney Disease: Improving Global Outcomes' (KDIGO) guidelines, the severity of CKD is classified into five stages, according to glomerular filtration rate (GFR) and urinary albumin excretion [4]. Increased CKD severity is indicated by lower GFR and/or increased albuminuria levels.

The etiology of CKD depends on the setting, with diabetes and hypertension being the two major causes of kidney injury in developed countries [3]. However, irrespective of the

**Citation:** Lousa, I.; Reis, F.; Santos-Silva, A.; Belo, L. The Signaling Pathway of TNF Receptors: Linking Animal Models of Renal Disease to Human CKD. *Int. J. Mol. Sci.* **2022**, *23*, 3284. https://doi.org/ 10.3390/ijms23063284

Academic Editor: Andrea Huwiler

Received: 28 February 2022 Accepted: 16 March 2022 Published: 18 March 2022

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primary disease cause, CKD initiation and progression involves different pathophysiological pathways leading to kidney function decline [5], which involves a complex interaction between hemodynamic, metabolic, immunologic, and inflammatory mechanisms.

CKD is associated with a decreased quality of life, increased risk of hospitalization, cardiovascular complications and mortality, independently of other risk factors [1,3,6,7]. Importantly, CKD and its related comorbidities are largely preventable and manageable, if detected at an initial stage. Thus, early identification of CKD is essential, not only to predict and prevent CKD progression, but also to further improve patients' survival and reduce associated morbidities. Hence, more sensitive and earlier biomarkers of detection are necessary to achieve that goal, since the traditional biomarkers only increase when a significant filtration capacity has already been lost and kidney damage is advanced [8].

Several studies in the literature suggest that activation of inflammatory processes in the early stages of CKD drives kidney function impairment [5], meaning that the assessment of inflammatory markers might help in earlier diagnosis of CKD. Associations between biomarkers of inflammation and changes in GFR have been widely reported. Moreover, inflammation is a risk factor for CKD-associated morbidity and appears to contribute to cardiovascular mortality in CKD patients [9–12].
