**5. Considerations for Future Research**

Despite recent breakthroughs in CKD care, the rates of morbidity and mortality are still unacceptable. Chronic inflammation is a common feature in kidney diseases, regardless of its etiology, and which plays a key role in disease pathophysiology, progression, and development of associated complications. Unresolved inflammatory processes generally lead to renal fibrosis and ESRD.

The role of TNF-α in the pathogenesis of kidney diseases depends on the engagement of receptor-specific and/or common signaling cascades. The differential expression of both receptors in different cell types, and the fact that soluble and transmembrane TNF-α present different affinities to each receptor, are other factors that contribute to the complexity of TNF-α signaling.

Circulating TNFRs have been associated with renal damage in several animal and human studies. Based on the available data, increased levels of TNFRs associate with decreased eGFR and increased albuminuria. Overall, TNFRs have proven to be useful and effective in predicting renal function decline and CKD progression, as well as CKDassociated morbidity and mortality, among different cohorts of patients in both crosssectional and longitudinal studies. The consistency of the published literature evidences their potential role as prognostic and risk-predictive biomarkers in CKD, along with the traditional markers already used in clinical practice.

The mechanisms by which the TNFRs initiate and perpetuate renal damage are not completely understood. In fact, there is evidence that TNF-α is not the only molecule involved in the regulation of its receptors during renal function decline [84], suggesting that other molecules and chemokines act as potential downstream effectors on TNFRs. Moreover, the interplay between TNFR1 and TNFR2, the role of each receptor in specific kidney diseases (particularly in more rare diseases), and their prognostic value in patient outcomes deserve further investigation.

To date, there are no anti-inflammatory treatments for CKD patients. Treating inflammation and preventing the progression of renal fibrosis is complex, due to the crosstalk between the inflammatory signaling pathways. The approved therapeutic use of anti-TNF monoclonal antibodies is currently limited to autoimmune diseases, such as rheumatoid arthritis, Chron's disease, or psoriatic arthritis [170]. Considering the relevance of the TNF signaling pathways in CKD pathophysiology, studies on the efficacy of the existing TNF biologics in renal diseases would be useful. Furthermore, individual inhibition of TNFR1 or TNFR2 may further clarify the balance of proinflammatory/immunomodulatory roles for each of these receptors.

Future research should focus on validating the promising findings in large, multicentered studies, with standardized methodologies, to allow their translation into clinical

practice. TNFRs could be important tools to improve CKD patient's characterization and management, with direct implications for strategies to prevent or postpone the progression of CKD. This may possibly result in a better prognosis for patients, as well as in financial benefits; lowering healthcare costs in CKD management.

**Author Contributions:** Conceptualization, I.L., A.S.-S., L.B. and F.R.; writing—original draft preparation, I.L.; writing—review and editing, I.L., A.S.-S., L.B., F.R. and L.B.; supervision, A.S.-S., L.B. and F.R. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was financially supported by national funds from FCT—Fundação para a Ciência e a Tecnologia, I.P., in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences—UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB.

**Acknowledgments:** This work was financially supported by national funds from FCT—Fundação para a Ciência e a Tecnologia, I.P., in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences—UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB; by FEDER COMPETE2020 funds UIDP/04539/2020 (CIBB); by PTDC/SAU-NUT/31712/2017, POCI-01-0145-FEDER-007440 and POCI-01-0145-FEDER-031712, and by FCT doctoral grant SFRH/BD/145939/2019; by funds from Portugal Regional Coordination and Development Commissions (Norte-01-0145-FEDER-000024; Centro-01-0145-FEDER-000012) and FEDER/COMPETE 2020 (POCI-01-0145-FEDER-031322)]. Figure 1 was created with BioRender.

**Conflicts of Interest:** The authors declare no conflict of interest.
