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.