DISCUSSION
The kidney plays vital roles in maintaining homeostasis, including the regulation of water and electrolyte balance and the elimination of endogenous and exogenous metabolites [20]. Despite the known nephrotoxicity of CIS since its introduction to the market many years ago, it continues to be widely prescribed, despite efforts to find less toxic but equally effective alternatives [21]. CIS-induced nephrotoxicity is associated with oxidative stress, which plays a significant role in the pathogenesis of the condition [1, 4].
Numerous studies have demonstrated that CIS-induced nephrotoxicity causes a decrease in kidney function, with an increase in serum creatinine and BUN levels. For instance, in a clinical trial involving 400 patients, serum creatinine reached the upper limit of normal during follow-up in 42% of patients after CIS administration, which was defined as nephrotoxicity [22]. Consistent with the literature, our study showed that BUN and creatinine levels increased in the CIS group but remained similar in the other groups [23]. Furthermore, a study showed that prophylactic administration of RAN preserved BUN and creatinine values in patients with contrast-induced kidney damage. The protective effect of RAN on renal function can be attributed to its modulation of intracellular Ca2+ homeostasis, oxidative stress, and suppression of apoptosis [24].
Research findings indicate that CIS irreversibly binds to albumin, a plasma protein [25]. Consequently, predicting the safe drug range in tissues based on plasma CIS levels is challenging. Burns et al. proposed a clinical risk score algorithm that incorporated patient age, dosage, hypertension, and albumin levels to forecast CIS nephrotoxicity [26]. Another study found a correlation between low pre-treatment albumin levels and neutropenia after CIS treatment [27]. However, albumin was regarded as a risk parameter rather than a marker of nephrotoxicity. In our investigation, no significant changes in albumin levels were observed.
The renal tubules regulate the serum levels of electrolytes by reabsorbing them. In an experimental study on CIS nephrotoxicity, renal losses were believed to be the cause of hypomagnesemia, hypocalcemia, and hypokalemia [28]. Goren et al. noted that electrolyte imbalances may be influenced by the cumulative dose of CIS [29]. It is possible that the study design did not induce cumulative dose toxicity, which may explain why other electrolytes did not change as expected. Additionally, Oronsky et al. conducted an extensive review of CIS and electrolyte disorders [30]. The variability in electrolyte levels may be due to their different mechanisms and presence in various tissues (e.g., Ca2+ is influenced by parathormone and vitamin D, and losses occur from bone to kidney and intestine) and measurement methods. A clinical study demonstrated a significant reduction in the incidence of nephrotoxicity with the administration of Mg, Ca, and K supplements during CIS treatment [31]. Moreover, in their study, Ma et al. evaluated intracellular Na flow by confocal microscopy, which contributed to the renoprotective effect of RAN due to its impact on the late Na+ channel [24].
The formation and removal of ROS must be balanced to prevent oxidative stress. Disturbance of this balance can lead to oxidative stress, emphasizing the importance of measuring it with appropriate biomarkers and treating it with suitable antioxidant substances [32]. MDA is among the most commonly used markers of oxidative stress, as it indicates lipid peroxidation. Non-enzymatic elements of the antioxidant system that help reduce ROS levels include GSH, vitamin C, and E, while enzymatic antioxidants comprise SOD, CAT, and GSH [33-35].
Yu et al. investigated the effectiveness of Hesperetin against CIS nephrotoxicity, utilizing techniques such as Western blot analysis, fluorescence staining, and tissue biochemistry similar to those in our study. Additionally, inflammation and apoptosis were responsible for CIS-induced renal damage [36]. Our findings were consistent with their results, as MDA levels were among the increased oxidant parameters in CIS-administered rats [37, 38]. Furthermore, a study examining the antidiabetic effect of RAN demonstrated a significant decrease in MDA levels in pancreatic tissue [39]. However, in another study, RAN did not cause changes in MDA levels in rat hearts [40].
Superoxide anion, hydrogen peroxide, and hydroxyl radical are substances that play a significant role in CIS-induced organ damage [41]. SOD, CAT, and GSH are enzymatic antioxidants that convert these harmful substances into harmless forms through different enzymatic steps [33]. In a study by Ehsan et al., Casticin was used as an antioxidant against CIS-induced renal toxicity. They found that Casticin application increased the levels of SOD, CAT, and GSH, which were reduced by CIS. Additionally, the levels of thiobarbituric acid reactive substances, hydrogen peroxide, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin that they examined also supported their hypothesis [42]. Similarly, in a lung malignancy study where the antioxidant effect of RAN at doses of 50 and 100 mg was measured using MDA, SOD, CAT, and GSH, a significant decrease was observed in MDA values, and an increase in the antioxidant parameters SOD, CAT, and GSH compared to the malignancy group. These findings suggested the protection of RAN through a dose-dependent antioxidant mechanism, as reported in the literature [43]. Based on these results, we believe that further studies could demonstrate the same antioxidant effect on the kidney.
ROS can disrupt mitochondrial permeability and lead to cell necrosis and apoptosis. In the context of acute kidney injury caused by ischemia and nephrotoxic agents, ROS is considered an early pathological factor [44]. In our study, we observed necrosis in the cortical tubule epithelium and dilatation in the medullary tubules, accompanied by caste formation in some tubules, upon histopathological examination of the kidney tissue at the end of the study period. These findings are consistent with the results of a study by Parlakpinar et al. where necrosis and tubular dilatation were also observed in the tubule epithelium [45]. RAN was administered as a pre-treatment against contrast-induced kidney damage in a study where histopathological changes were found to be improved [24]. In our study, we observed that there was no significant difference in damage between the CIS+RAN group and the CIS group, with a nonsignificant increase in the degree of dilatation observed in the former group.