Effect of infliximab against cisplatin-induced nephrotoxicity

Objectives:

To investigate whether infliximab (Ib), an inhibitor of tumor necrosis factor alpha (TNF-α), prevents cisplatin (Cis)-induced nephrotoxicity.

Methods:

The study was performed in the Department of Internal Medicine, Recep Tayyip Erdogan University, Rize, Turkey, between November 2012 and May 2013. Thirty male Wistar albino rats were divided into 3 groups, a control group, a Cis group, and a Cis+Ib group. The animals of the Cis group were injected with a single dose (7 mg/kg) of Cis intraperitoneally. The animals of the Cis+Ib group were injected with a single dose (7 mg/kg) of Ib 72 hours prior to Cis injection.

Results:

The TNF-α, interleukin-1 beta (IL-1β), nitric oxide (NO) and adenosine deaminase (ADA) levels of the Cis group were higher than both the control group TNF-α (p<0.001), IL-1a (p<0.001), NO (p<0.001) and ADA (p<0.001), and the Cis+Ib group TNF-α (p<0.001), IL-1β (p<0.001), NO (p<0.001), and ADA (p=0.003). Histopathological examination revealed extensive damage in the Cis group, while the damage in the Cis+Ib group was lower. While the carbonic anhydrase II (CA-II) level of the Cis group was lower than both groups, it was similar in the Cis+Ib and the control groups.

Conclusion:

Infliximab acts against Cis-induced nephrotoxicity by a strong inhibition of TNF-α. Additionally, the combination of these 2 drugs does not obviously change the level of CA-II.Cisplatin (Cis) is an antineoplastic drug used to treat solid tumors. Although it is used in most chemotherapy regimens, its nephrotoxic effect is a common problem. The mechanisms for Cis-induced nephrotoxicity have been attributed to renal cell apoptosis, oxidative stress, and inflammation.1,2 Cisplatin leads to the formation of reactive oxygen species (ROS) by increasing the release of pro-inflammatory cytokines such as tumor necrosis alpha (TNF-α), stimulating apoptosis through the direct effect of the cytokines, and increasing inflammation.3 Moreover, it causes nephrotoxicity by increasing the turnover of purine metabolism to its metabolites.4 Cisplatin induced nephrotoxicity is one of the important side effects that limit the use of Cis. Therefore, effective treatment is still sought to prevent it. Infliximab (Ib) is a potent TNF-α inhibitor that can safely be used to treat many chronic diseases with inflammation.5 Previous studies have shown that Ib prevents organ damage,6,7 and decreases nitric oxide (NO) and ROS formation.8 It has no nephrotoxic effect and can be used in patients with renal impairment.9 Carbonic anhydrase II (CA-II), which is a zinc metalloenzyme, catalyzes the reversible hydration reaction of carbon dioxide form carbonic acid. It is found in many tissues, mainly the kidneys.10 Over-expression of CA-II is observed in many cancers, including renal cell cancer.11 This condition leads to cancer cell growth and invasion. On the contrary, the suppression of CA-II or its deficiency leads to metabolic acidosis.12 In this study, we aimed to investigate whether Ib could prevent cis-induced nephrotoxicity, and whether this combination would affect the CA-II enzyme.