*4.3. Anti-TNF-α Theraphy in Patients with Impaired Kidney Function*

The huge amount of scientific evidence linking TNF signaling with the pathophysiology of CKD raises questions regarding the utility and safety of therapeutic strategies targeting TNF-α in humans with impaired kidney function.

Nephrotoxicity is a rare side effect of anti-TNF-α medications, and a few reports of this occurrence have been described in the literature. Premuži´c et al. reported an association of TNF-α inhibitors (adalimumab and golimumab) and the development of IgA nephropathy in three patients with both rheumatoid arthritis and diabetes, but without history of renal disease [139]. Moreover, Stokes et al. showed that a subset of patients on anti-TNF-α therapy, who had no prior evidence of renal diseases, developed glomerulonephritis. This was supported by serologic abnormalities and by the presence and formation of autoantibodies [140].

However, other studies demonstrated the therapeutic benefit of TNF-α blocking in improving renal inflammation and function. In patients with rheumatoid arthritis and CKD, the administration of anti-TNF-α was associated with less renal function decline [141]. In addition, the use of anti-TNF-α agents showed promising results in renal vasculitis [142] and kidney transplant recipients with rheumatic disease [143].

There is a limitation to the beneficial effects of anti-TNF-α agents, which seems to be related to their ability to induce autoimmunity by disrupting TNF-α normal immune regulation. Their use in clinical practice would require surveillance for complications. Indeed, the biological functions of cytokines are complex, and, thereby, blocking of cytokines might induce other unexpected and unclear effects in vivo. Furthermore, the effects of anti-TNF-α agents might be modulated by other factors, such as their distribution into diseased tissues, and degradation by proteases. Given the potential benefits of these therapies, a deeper understanding of the TNF signaling pathway and the mechanisms of action of the anti-TNF-α agents and their correlation with the clinical settings is needed for a more appropriate and personalized selection of therapeutic agents, and even for the development of new biological preparations, to be applied in the treatment of inflammatory diseases.


**Table 2.** Association of TNF-α and TNF receptors with renal dysfunction and disease, as well as with adverse clinical outcomes in human studies.






