Antioxidants as Renoprotective Agents for Ischemia during Partial Nephrectomy

Abstract

Small renal masses have been diagnosed increasingly in recent decades, allowing surgical treatment by partial nephrectomy. This treatment option is associated with better renal function preservation, in comparison with radical nephrectomy. However, for obtaining a bloodless field during surgery, occlusion of renal artery and veins is often required, which results in transitory ischemia. The renal ischemia-reperfusion injury is associated with increased reactive oxygen species production leading to renal tissue damage. Thus, the use of antioxidants has been advocated in the partial nephrectomy perioperative period. Several antioxidants were investigated in regard to renal ischemia-reperfusion injury. The present manuscript aims to present the literature on the most commonly studied antioxidants used during partial nephrectomy. The results of experimental and clinical studies using antioxidants during partial nephrectomy are reported. Further, alimentary sources of some antioxidants are presented, stimulating future studies focusing on perioperative antioxidant-rich diets.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction

Renal cell cancer (RCC) arises mainly from the renal parenchyma and accounts for over 90% of kidney cancers. Incidence rates of RCC vary greatly worldwide, from 1.2 cases/100,000 in females from South Korea to 15.3/100,00 in males from Czech Republic [1]. In the United States the incidence of RCC rose consistently over the past three decades specially among early stage tumors [2]. Risk factors related to RCC include cigarette smoking, obesity, and hypertension. Physical activity and diets rich in antioxidants are inversely related to RCC. A status of increased reactive oxygen species (ROS) production and lipid peroxidation has been implicated in RCC carcinogenesis [3]. In favor of this hypothesis, several studies have evidenced a protective mechanism of antioxidants against RCC [4, 5].

As small renal masses are diagnosed more frequently, the incidence of nephron-sparing procedures has also increased [6]. Partial nephrectomy (PN) is the preferred treatment option for localized renal tumors according to most urological associations achieving oncological outcomes comparable to radical nephrectomy [7, 8]. In order to achieve a bloodless field during surgery, occlusion of renal artery and veins is often required.

Ischemia has been considered historically as a major factor in reducing renal function after PN [9]. Several measures to decrease the effects of ischemia have been used such as hypothermia and pharmacologic interventions [10, 11]. In this review, we assess some of the antioxidants that may be used for renal function preservation during PN.

2. Renal Ischemia-Reperfusion (I/R) Injury

The kidney is an organ supplied by end arteries, which means that the area irrigated by a given arterial branch will become ischemic if blood flow is interrupted by any reason. In contrast, the venous drainage has no segmental organization and anastomoses freely. During partial nephrectomy, ischemia may occur by both arterial and venous occlusion. However, the procedure may be carried by arterial occlusion only. Clinical and experimental studies have shown that when renal artery is clamped alone instead of both renal artery and vein, the injury is attenuated [12, 13]. Therefore, ischemic injury during partial nephrectomy may occur heterogeneously.

There are regions of the kidney that are more susceptible to ischemic injury. Epithelial cells located in the corticomedullary region are more susceptible to ischemia, since they have a greater oxidative activity and are located in an area with low oxygen reserve. The cells of the renal papilla reside in a naturally hypoxic environment and can withstand short periods of ischemia with anaerobic metabolism. The outer cortex is usually more resistant to ischemia because of its greater oxygen reserve [14]. Nevertheless, for very long periods of warm ischemia, all regions of the kidney are affected.

As previously mentioned interruption of arterial supply is often necessary during PN, and it gives rise to a chain of events that culminates in cell death if blood flow is not restored in a timely manner. Sutton and colleagues proposed a division of the clinical events of ischemic acute renal failure into 4 phases [15]: initiation, extension, maintenance, and recovery phase.

The initiation phase is characterized by cellular adenosine 5’-triphosphate (ATP) depletion with subsequent cellular electrolyte shifts, cellular swelling, and the induction of cellular stress responses. There are two biochemical events that must be emphasized as consequence of ATP depletion: rise in the concentration of hypoxanthine [16] and rise in both mitochondrial and cytosolic calcium levels [17].

Hypoxanthine is a breakdown product of ATP metabolism and is, normally, oxidized by the enzyme xanthine dehydrogenase to uric acid. Hypoxanthine can also be oxidized by xanthine oxidase (XO), which is an isoform of xanthine dehydrogenase and transfers an electron to oxygen forming the free radical superoxide (O₂•-). Conversion of xanthine dehydrogenase to oxidase may be influenced by several mechanisms during ischemia, and it takes about 30 minutes to occur in the kidney [18]. This may be a biochemical explanation for the safety limit of 25 minutes of warm ischemia observed in the clinical setting [19], although experimental studies have not supported this theory [20, 21]. Dysfunction of ATP-dependent membrane ion pumps with consequent rise in both mitochondrial and cytosolic calcium levels is another important event. Calcium overload leads to mitochondrial membrane dysfunction and irreversible damage (Figure 1).

[figure omitted; refer to PDF]

The extension phase is characterized by the restoration of renal blood flow that starts various inflammatory events. Although blood flow is restored, reperfusion may lead to further injury as already shown in other organs [22]. Production of oxygen-derived free radicals is a major event that leads to tubular, vascular, and interstitial injury [23]. The segment S3 of proximal tubules is particularly susceptible to I/R injury [24]. Decreased renal function may ensue by backleak of the glomerular ultrafiltrate across the tubular epithelium. Also, tubular obstruction by cell debris may contribute to reduced glomerular filtration rate. Microvasculature injury is another important event during extension phase [15]. Endothelial and epithelial cells secrete inflammatory cytokines and express adhesion molecules that promote the activation of lymphocytes, margination, and diapedesis. Leukocyte infiltration, especially by neutrophils, leads to further production of cytokines and oxygen-derived free radicals, which in turn cause additional injury of to the epithelium and stroma.

During the maintenance phase, glomerular filtration rate stabilizes as cellular repair processes are initiated in order to maintain and reestablish organ integrity. The repair phase is characterized by cell proliferation and tissue repair with the recovery of subsequent kidney function and may last for weeks or months.

3. Free Radicals

A free radical, also known as reactive oxygen species (ROS), has one or more unpaired electron and so is chemically highly reactive. ROS are commonly related to aerobic metabolism and birth immunity. On the other hand, they may have also important signaling and/or regulatory function in living organisms [25]. In the renal parenchyma, free radicals are produced by components of connective tissue, epithelial and muscular, like fibroblasts, endothelial cells, vascular smooth muscle cells, mesangial cells, tubular cells, and podocytes cells [26]. Ordinary ROS implicated in ischemic kidney injury are as follows: superoxide (O₂•-), hydrogen peroxide (H₂O₂), hydroxyl (OH⁻), nitric oxide (NO), and the peroxynitrite anion. O₂•- is a byproduct of normal cellular metabolism and is generated as oxygen accepts a single electron and can inactivate specific enzymes but, more meaningfully, it may lead to production of two other highly reactive species: H₂O₂ and OH⁻. The dismutation of O₂•- by superoxide dismutase (SOD) generates H₂O₂, which in turn can inactivate DNA [27], impair ATP synthesis, and inhibit glycolysis [28] leading to elevation in intracellular calcium, disruption of the cytoskeleton, blebbing of the plasma membrane, and finally cell death. The deleterious effects of superoxide, however, can be offset by catalase (CAT) and glutathione peroxidase (GPx) (Figure 2).

[figure omitted; refer to PDF]

The interaction of O₂•- and H₂O₂ catalyzed by molecular iron (Fenton reaction) originates OH⁻ [29]. The OH⁻ radical is extremely reactive and is supposed to be in charge for most of the cellular damage that occurs from ROS [30] (Figure 2). Fortunately, there are several scavengers that stabilize OH⁻ effect, comprehending tryptophan, histidine, ascorbate, and alpha-tocopherol [31].

NO and O₂•- anions can react to compose peroxynitrite, which may lead to oxidation of a wide chain of biological targets including amino acids such as cysteine, methionine, tyrosine and tryptophan, nucleic bases, and antioxidants [32]. Peroxynitrite reacts with aim molecules through two potential pathways: it may react directly with a target molecule or it can dissociate in peroxynitrous acid and homolyze to form nitrogen dioxide and OH⁻ radicals, which in turn react with the aim molecule (Figure 2). S-methylisothiourea, an iNOS inhibitor, and mercaptoethylguanidine, a scavenger of peroxynitrite, have shown protective effect on renal I/R injury [33].

One of the most abundant enzymes liberated on neutrophil activation, myeloperoxidase (MPO), is a 140-kDa heme protein released by activated phagocytes in the course of inflammatory process. It catalyzes the reaction of H₂O₂ with physiological convergences of chloride and bromide anions to produce hypochlorous acid (HOCl) and hypobromous acid (HOBr), respectively [34], which are oxidants and electrophiles that react easily with biological components such as proteins, lipids, and DNA as well [35–37] (Figure 2). Thus, cellular damage resulting from excessive or misplaced production of hypohalous acids has been implicated in reperfusion injury [38]. A research used MPO-deficient mice (Mpo -/-) compared to controls after kidney I/R found 24 hours later significant reduction in renal function decrease in Mpo -/- mice compared with I/R controls, as a reduced neutrophil influx [39]. Another study used the porcine kidney with gene deletion for MPO+ neutrophils and found a 91% decrease of apoptosis in nephrotic tubule cells and amelioration of renal function after I/R [40].

To evaluate the role played by ROS, indirect biomarkers are usually searched [39, 41], because it is difficult to perform straight assessment of such unstable reactive species [42]. The antioxidant activity is measured through enzymes as CAT, GPx, MPO, and SOD. Besides the enzymes, the lipid peroxidation may be evaluated through TBARS determination (directly related to the production of malondialdehyde (MDA)). SOD, CAT, GPx, and MPO are evaluated from tissues samples by immunohistochemistry and TBARS by Enzyme-Linked Immunosorbent Assay (ELISA). To systemic assessment, f2-isoprostanes (F2IP) from plasma can be useful to observe lipid peroxidation [43–45].

4. Antioxidants and Renal I/R Injury

Several antioxidants are investigated regarding I/R injury. Commonly studied antioxidants are listed in Table 1. A brief description of some of the most important antioxidants follows.

Table 1

Antioxidants commonly used in renal ischemia-reperfusion injury.

Antioxidant	Mechanism of action	Improvement of I-R injury	Reference
Allopurinol	Xanthine oxidase inhibitor	Yes	[85]
Amifostine	Increase in glutathione peroxidase	Yes	[86, 87]
Bilirrubin	Superoxide scavenger / peroxyl radical trapping antioxidant	Yes	[88, 89]
Catalase	Superoxide scanvenger	Yes	[46–49]
Ceruloplasmine	ROS scavenger / Fenton reaction inhibition	Yes	[90]
Coenzyme Q10	ROS scavenger / enhance antioxidants / quench perferryl radical	Yes	[91, 92]
Crocin	ROS scavenger	Yes	[93]
Curcumin	ROS scavenger / enhance antioxidants	Yes	[56–58]
Desferrioxamine	Iron-chelator / enhance antioxidants	Yes	[90, 94]
Edaravone	ROS scavenger	Yes	[95]
Ferulic acid	ROS scavenger/ enhance antioxidants/ Modulates MPO and other enzymes	Yes	[61–66]
Glutathione peroxidase	ROS scavenger / NF-κB pathway inhibitor	Yes	[48, 50–52]
Ligustrazine	ROS scavenger	Yes	[67, 68]
Mannitol	ROS scavenger / enhance antioxidants	Yes	[81]
Nitric Oxide	Modulates xanthine oxidase activity / vasodilation	Yes	[96–99]
Quercetin	ROS scavenger	Yes	[69–72]
Resveratrol	ROS scavenger	Yes	[71–76]
Superoxide dismutase	Superoxide scavenger	Yes	[48, 53–55]
Vitamin C	ROS scavenger / enhance antioxidants	Yes	[77–79, 100–102]
Vitamin E	ROS scavenger / enhance antioxidants	Yes	[81–84]

4.1. Naturally Occurring Enzymatic Antioxidants

Catalase (CAT): Enzyme which is present mainly in the peroxisomes of mammalian cells. If the concentration of H₂O₂ is high, CAT acts catalytically and removes H₂O₂ by forming H₂O and O₂ [46]. A study made use of this chemical reaction both to determine whether the inhibition of the H₂O₂ catalyzing enzyme would influence ischemic renal injury and to determine the rates of H₂O₂ formation after ischemia. Inhibition of CAT prior to ischemia led to an increasement of ischemic injury. The production of H₂O₂ occurs in both normal and ischemic kidneys even though intracellular sites and production rates are likely to be diverse. CAT is an essential protective enzyme, since its inhibition leads to exaggerated post-ischemic renal dysfunction [47]. Overexpression of CAT prevented apoptosis-inducing factor (AIF) translocation from mitochondria to the nucleus, reducing ROS charge after ischemia [48]. A research in rats concluded that CAT protein overexpression by adenoviral CAT gene (Adv-CAT) transfection improved I/R-induced injury in the kidney by reducing H₂O₂, serum urea, and glutathione s-transferase levels. During post-ischemic reperfusion, leftover ROS production from mitochondria begins apoptosis via the release of cytochrome c from it, which was restrained by Adv-CAT, accordingly, depressing I/R-enhanced autophagy-related proteins and apoptosis-mediated proteins expression. This technique does not impel nephrotoxicity and CD4+/CD8+-mediated immune response in the treated kidneys, which gives to this kind of treatment a greater translational aspect [49].

Glutathione peroxidase (GPx): This enzyme is one of the main endogenous antioxidant defenses that work in higher organisms and catalyze the reduction of H₂O₂ or organic hydroperoxides to H₂O or analogous alcohols. A classic study in rats used the redox ratio of GPx to assess levels of peroxidation through the H₂O₂ present in the renal parenchyma to fix upon the severity of the ischemic injury and obtained significant results [50]. There is a research which used the murine model with human GPx1 and GPxP gene overexpression that showed up more resistant to damage caused by I/R in the kidneys by reduction of mortality and serum urea and creatinine levels, tubular necrosis, apoptosis, oxidative stress and lipid peroxidation, MDA, MPO activity, expression of mRNA, and inflammatory cytokines six hours after reperfusion. The most relevant of cytokines was MIP-2, related to greatest migration of leukocytes which also had a lower activity in the transgenic groups GPx1 and GPxP. There was also a decrease in the activity of NF-kB, a transcription factor acknowledged to be responsible for the activation of numerous genes mediating the inflammatory process in general as well as during I/R in groups GPx1 and GPxP, so GPx seems to be involved in the inhibition of the activation of the MIP-2 promoter gene by NF-kB [51]. Zemlyak and colleagues tested the overexpression of GPx in cells after ischemia and it prevented apoptosis-inducing factor (AIF) translocation from mitochondria to the nucleus. This could reflect mainly non-specific scavenging ROS [48]. Another study shows that the use of glutamine amino acid supplementation, a precursor of GPx, prior to renal I/R elevates this powerful endogenous antioxidant in rats, which again proved to be efficient as an endogenous scavenger that preserved renal function [52].

Superoxide dismutase (SOD): It is possible that SOD is an enzyme with real anti-aging consequences and can act positively over all the degenerative processes. The preventive effects of intravenously exogenous SOD on acute renal failure were investigated in the kidneys of rats exposed to warm ischemia. In an experiment, SOD was given just before primary ischemia and in the early recirculation phase. It was found to ameliorate the red cell aggregation in the renal medulla in the inner stripe of the outer zone. The volume of trapped red cells decreased in treated animals, thus allowing better restoration of medullary blood flow. SOD also restored the capillary macromolecular permeability as shown by standardization of plasma to lymph transport of proteins. Ischemically damaged but untreated kidneys had the tubules obstructed and that the proximal tubular pressure rose to such a level that the net driving force for filtration approached zero, explaining the marked decrease in glomerular filtration rate (GFR) from a normal value [53]. Dogs were used as models for evaluation whether the administration of SOD can alleviate I/R renal damage and whether there is a relationship between oxygen free radicals and thromboxane (Tx). Blood samples were drawn from the renal vein before ischemia and after reperfusion to assess serum levels of thromboxane B2 (TxB2). All untreated dogs died within seven days of renal failure and the treated ones demonstrated transient renal failure, with a significant difference being found between groups. A significant difference in TxB2 levels was found in the untreated dogs before and after ischemia and between the two groups after reperfusion. Animals that were treated with exogenous SOD after the ischemic event has occurred but before reperfusion showed a favorable clinical course in terms of survival and renal function [54]. A study in rats showed that the renal protective effect of free SOD on warm ischemic-reperfusion injury is conditional on the time of administration, being further effective when given prior to reperfusion. On the other hand, the renal protective effect of liposomal SOD did not depend on the time of administration since efficacy was similar when given before reperfusion or ischemia. It was concluded that liposomal SOD shows a higher renal protective effect in warm ischemia than free SOD [55]. Zemlyak and colleagues tested the overexpression of CuZnSOD (extracellular and cytosolic SOD) or MnSOD (mitochondrial SOD) in cells after ischemia and both prevented AIF translocation from mitochondria to the nucleus which could reflect broadly non-specific protection due to reducing ROS [48].

4.2. Naturally Occurring Exogenous Antioxidants

Curcumin: Curcumin is a frequently studied phenolic compound. Extracted from Curcuma longa, curcumin is a bifunctional antioxidant, often added to mustard, condiments, and sauces and it exerts antioxidant activity in a direct and an indirect way by scavenging reactive oxygen species or inducing an antioxidant response, respectively [56]. In a study, rat kidneys with I/R injury were analyzed for serum and tissue NO, protein carbonyl, MDA, SOD, and GPx levels. Histopathological examinations were also performed. Reduction of serum GPx was significantly improved by curcumin, but SOD enzyme activity was not altered. Treatment with curcumin also resulted in significant reduction in serum and tissue MDA, NO, and protein carbonyl. In histological examination, the rats treated with curcumin had nearly normal morphology of the kidney [57]. Another research, also with rat kidneys, aimed to investigate the role of N-methyl-d-aspartate (NMDA) receptors in curcumin-mediated renoprotection against I/R injury. In separate groups, NMDA receptor agonists (glutamic acid and spermidine) were injected prior to curcumin treatment followed by renal I/R, and administration of curcumin resulted in significant protection against I/R injury in the sham group. However, glutamic acid and spermidine pretreatments prevented curcumin-mediated renoprotection allowing the conclusion that NMDA receptor antagonism significantly contributes towards curcumin-mediated protection against I/R injury in rats [58].

Ferulic acid belongs to the phenolic acid group commonly found in plant tissues [59] and is most commonly found in grains, spinach, parsley, grapes, rhubarb, and cereal seeds, being more easily absorbed and stays in the blood longer than any other phenolic acids [60]. The antioxidant mechanism of ferulic acid is based on raising inhibition and scavenging of ROS and on blocking enzymes that catalyze their production, such as MPO, and is also an enhancer of scavenger enzyme activity [61–64]. Antioxidant activity of ferulic acid is forming stable phenoxyl radicals by the reaction of the radical molecule with the stable antioxidant molecule and may also act as hydrogen donor. As a secondary antioxidant, ferulic acids and their related compounds can bind transition metals such as iron and copper, preventing the formation of toxic OH⁻ radicals [65]. A recent study in the rodent model of I/R showed that ferulic acid significantly attenuated kidney damage by decreasing levels of urea and creatinine, pathological structural changes, and tubular cells apoptosis, inhibited I/R-induced renal proinflammatory cytokines and neutrophils recruitment, and increased adenosine generation and CD39 and CD73 expression [66].

Ligustrazine: Ligustrazine is an alkaloid isolated from the rhizome of Chuanxiong (Ligusticum chuanxiong Hort), which is notorious by its antioxidant, anti-inflammatory, anti-fibrosis, and immunomodulative effects [67]. It is found in cocoa bean or soybean-based fermented foods, Chinese alcohols, and soybeans culture media of Bacillus subtilis, among others. The effects of ligustrazine on oxidative stress, neutrophils recruitment, proinflammatory mediators, and adhesion molecules caused by renal I/R injury were assayed in mice, and its pretreatment attenuated dramatically the injuries in kidneys caused by warm ischemia, reducing MPO activity and decreasing MDA level, while SOD activity increased, suggesting an effective reduction of oxidative stress. Moreover, ligustrazine also inhibited cell apoptosis, abrogated neutrophils recruitment, and suppressed the overexpression of tumor necrosis factor-alpha (TNF-α) [68].

Quercetin: Quercetin is one of the most potent scavengers of ROS in the family of polyphenolic compounds [69], found in fruits (citrus fruits, apples, grapes, dark cherries, and dark berries), vegetables (onions, parsley, and sage), tea, olive oil, and red wine. TBARS, protein carbonyl content, TNF-α, GSH levels, MPO, CAT, and SOD activities were determined in renal tissue in a study with renal I/R rat model. Its administration previously to I/R decreased the oxidation and inflammatory parameters (TBARS, TNF-α levels, MPO activity, and protein carbonyl content). Quercetin treatment significantly increased reduced glutathione (GSH) levels and activities of SOD and CAT when compared to the I/R group [70]. This substance made MDA levels significantly decrease after I/R in another research in rats and significantly increased glutathione level. In histological results, the number of apoptotic and endothelial nitric oxide synthase (eNOS) expression levels were significantly decreased in the quercetin treated group [71]. A third study determined the effects of quercetin on AMPK and autophagy signals in the kidneys of mice after I/R. Quercetin significantly increased the phosphorylation of AMPK and decreased the phosphorylation of the mammalian target of rapamycin (mTOR), one of the downstream targets of AMP-activated protein kinase (AMPK) [72].

Resveratrol: As quercetin, it is a bioflavonoid. Resveratrol is a polyphenolic compound found in grapes, berries, and peanuts. It possesses a variety of bioactivities, including antioxidant, anti-inflammatory, and renal protective effects [73]. Previous studies have shown that resveratrol can directly scavenge reactive oxygen species (ROS) [74]. In addition to scavenging ROS, exogenously administered resveratrol modulates the expression and activity of antioxidant enzymes, such as SOD, GPx, and CAT, either through transcriptional regulation via nuclear factor E2-related factor 2 (Nrf2), activatorprotein (AP) 1, and forkhead box protein O (FOXO), or through enzymatic modifications [75]. A recent study demonstrated that resveratrol activates 2 homolog sirtuin 1 (SIRT1) that may regulate multiple cellular functions, including apoptosis, mitochondrial biogenesis, inflammation, glucose/lipid metabolism, autophagy, and adaptations to cellular stress, through the deacetylation of target proteins through the activation of AMPK [76].

Vitamin C: Ascorbic acid, also known as vitamin C, is found in fruits (citrus fruits, mango, and avocado) and vegetables (broccoli, cauliflower, peppers, and asparagus) being widely accepted as an anti-oxidant and is an essential nutrient required for various metabolic reactions. The active part of ascorbic acid is ascorbate ion that acts as an electron-donating entity and is involved in biosynthesis of steroids, collagen, and peptide hormones. Vitamin C is a redox catalyst which itself gets reduced and neutralizes ROS such as H₂O₂. The donation of one electron by ascorbate results in semi-dehydroascorbate radical that is reduced by glutathione and NADPH-dependent enzymes [77]. Moreover, ascorbic acid increases the activity of endogenous antioxidant defense including SOD, GSH, and CAT in rats whose had induced I/R injury [78]. The administration of ascorbic acid in a study with rats showed significant increase in NO level along with decrease in oxidative stress. NO level may be due to scavenging of oxidative species such as O₂•-. The same research proves that NO and soluble guanylyl cyclase pathway finds its definite involvement in ascorbic acid mediated protection against I/R injury [79]. Vitamin C supplementation preserved kidney morphology and renal function following I/R injury and decreased resistance index of renal artery, ameliorating oxidative stress secondary to I/R in a recent research performed in rat model [80].

Vitamin E: This liposoluble vitamin acts as a scavenger, protective against free oxygen species occurring during the reperfusion phase after renal ischemia, prevents lipid peroxidation, and acts against the effects of oxidative stress. Various foods provide vitamin E such as meat (egg and fish), nuts, seeds, vegetable oils, and fruits (tomato and avocado) [81]. A study in rats showed that the administration of vitamin E before and after renal I/R normalized the parameters of GSH, y-glutamyl-transpeptidase, and TBARS. It also improved the survival rate in adult rats up to 100% [82]. Another research used young adult, middle-aged, and aged rats to prove that a diet with vitamin E supplementation is essential for protecting aging kidneys against ischemic acute renal failure. The older animals with vitamin E deficiency had aggravated acute damage caused by I/R and in the absence of vitamin E and MDA levels increased with age [83]. Histopathologic examination of the rabbit kidney submitted to I/R pretreated with vitamin E showed normal histologic appearance with no sign of tubular necrosis and the nontreated showed moderate to severe ischemic changes. So, the intensity of I/R injury is less extensive in rabbits that received intravenous pretreatment with vitamin E before surgery [84].

4.3. Other Studied (and Utilized) Antioxidants in Renal I/R Injury

Allopurinol: Allopurinol is an inhibitor of XO which inhibits the conversion of hypoxanthine into xanthine and then uric acid as the final product of purine catabolism. During hypoxanthine conversion, O₂•- and another ROS are generated. The inhibitory effect of allopurinol blocks the chain of events of the oxidative stress in an early stage. Recently, Prieto-Moure and colleagues [85] reviewed several studies in which the renoprotective effect of allopurinol was assessed. In most studies, allopurinol was administered prior to the ischemia period and the effective dose was 100 mg/kg. Clinical studies showed that allopurinol can be safely used in patients with chronic kidney disease (CKD) [103]. It also may delay progression of CKD although confirmation is still needed. Allopurinol is also used in organ transplantation. One of the most used preservation solutions developed by the University of Winscosin has allopurinol on its formulation [104]. Future studies to address the role of allopurinol in the context of partial nephrectomy are needed.

Mannitol: Mannitol, an osmotic diuretic, is used in the clinical perioperative setting in the belief that it exerts renoprotective properties. Bragadottir and colleagues evidenced renal vasodilation and redistributes systemic blood flow to the kidneys [105]. In the rabbit model, administration of mannitol before ischemia and before reperfusion reduced ROS production significantly. Glomerular function measured 48 h after reperfusion was significantly better after pretreatment mannitol [106]. A study using rats as a model showed that mannitol treatment significantly decreased the level of MDA, SOD, and MPO activity and increased GSH level (nonenzymatic antioxidant in the kidney tissues). Histological evaluation of kidneys demonstrates that mannitol significantly decreased tubular necrosis and inflammatory infiltration [81]. A recent study used the porcine model of I/R with positive results: kidneys subjected to ischemia displayed decreased weight, volume, and number of glomeruli in comparison to the sham operated and mannitol groups and concluded that using this antioxidant significantly reduces nephron loss during warm ischemia in this animal model [107].

Nitric Oxide (NO): Endogen endothelial NO is an autacoid whose primary function is to decrease renal vascular resistance. There is a basal level of NO release, which acts to prevent excessive vasoconstriction in the kidneys, allowing a good excretion of sodium and water. It has been noticed that NO, this small molecule with multiple physiological functions, plays an important role in modulating tissue injury and renal blood flow in the healthy kidneys as well as several pathologic kidney conditions. The role of NO in I/R injury is controversial [108]. Exogenous NO has a beneficial effect in renal I/R injury, while endogenous NO does not appear to be an important contributor to renal I/R injury. The infiltration of neutrophils (migration) was decreased in a study in animals pretreated with the NO donor: Na-nitroprusside [96]. In vitro studies have shown that NO and peroxynitrite at high concentrations regulate XO activity [97]. A study utilized an exogenous Na-nitroprusside, to treat rats during reperfusion. The lipid peroxidation level was measured to determine oxidative damage, XO specific activity to evaluate O₂•- production as well as renal GSH level, GPx, and SOD specific activities to determine the antioxidative capacity in renal tissue. It was examined whether exogenous NO has an in vivo inhibitory effect on XO activity in renal I/R injury and whether it has a protective effect on oxidative stress. GSH levels were lower in all treated kidneys compared to their control counterparts. The XO activity of ischemic kidneys of the group treated with Na-nitroprusside was lower than those of the other groups. Histological evaluation revealed that the median value of the damage grade of the Na-nitroprusside group was lower than that of the control group [98].

5. Antioxidants and Partial Nephrectomy

Several measures to decrease the impact of ischemia or even to avoid ischemia have been developed for the treatment of renal neoplasms. An experimental imaging study using in vivo murine model of renal ischemia made contribution showing usefulness of novel imaging technologies (electron paramagnetic resonance, EPRI) in measuring renal reducing activity and the evaluation of oxidative stress in post-ischemic renal disease [109]. In the surgical field, ablative procedures such as cryoablation and radiofrequency ablation are examples of procedures that avoid ischemia of the remaining parenchyma. Technical modifications of the partial nephrectomy procedure have also been used to reduce ischemia. “Zero ischemia” PN has been described by Gill and colleagues [110], although systemic hypotension is induced during tumor resection which may cause ischemia in a lesser degree. Partial nephrectomy assisted by focal radiofrequency is another example of nonischemic technique [98]. Even though occlusion of renal vessels during PN is necessary in several occasions, ablative procedures such as radiofrequency and cryoablation may also be used without ischemia. Nonetheless, PN remains the standard treatment of renal cell cancer in most cases.

Antioxidants have already been used in clinical practice to decrease renal I/R injury in transplant procedures. Clinical studies on the use of antioxidants during partial nephrectomy are scarce. The most frequently used renoprotective medication is mannitol [111], which is supposed to exert antioxidant effects [106, 112] as well as diuretic activity. Nonetheless, its beneficial effect on renal function is controversial. Two retrospective studies have shown no advantage from the administration of mannitol during partial nephrectomy [113, 114]. In both studies, however, a randomized controlled trial is suggested in order to clarify the role of mannitol during partial nephrectomy.

An ideal renoprotective medication for PN should be effective in preventing I/R injury as well as having low incidence of adverse events. Vasoactive drugs and medications that interfere with coagulation should be of concern because of the risk of bleeding in the intra- and postoperative period, for example. Also, medications should have a favorable posology and low cost.

In addition to the potential benefits of antioxidants in the acute setting of PN, their long-term use might also be investigated. The relation of lipid peroxidation to the pathogenesis of renal cell cancer as stated by Gago-Dominguez et al. [4] opens a great field of investigation in the preventive medicine. The effect of antioxidants on cancer recurrence may be considered for those already treated with curative intent.

6. Conclusions

Since the beginning of renal surgery, studies with medications to help preserve kidney function have been suggested. Nonetheless, little progress has been made in the context of PN. Antioxidants have the potential to improve the functional outcomes of partial nephrectomy, although both experimental and clinical data are still missing. Most studied antioxidant for application during partial nephrectomy can be found in dietary sources. Pre- and postoperative diets with nutraceuticals (antioxidant) aliments should be investigated for possible applications in partial nephrectomy perioperative nutrition.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Acknowledgments

This study was supported by grants from the National Council for Scientific and Technological Development (CNPq), the Coordination for the Improvement of Post-Graduate Students (CAPES), and the Foundation for Research Support of Rio de Janeiro (FAPERJ), Brazil.

References

[1] W.-H. Chow, L. M. Dong, S. S. Devesa, "Epidemiology and risk factors for kidney cancer," Nature Reviews Urology, vol. 7 no. 5, pp. 245-257, DOI: 10.1038/nrurol.2010.46, 2010.

[2] J. M. Hollingsworth, D. C. Miller, S. Daignault, B. K. Hollenbeck, "Rising incidence of small renal masses: a need to reassess treatment effect," Journal of the National Cancer Institute, vol. 98 no. 18, pp. 1331-1334, DOI: 10.1093/jnci/djj362, 2006.

[3] M. Gago-Dominguez, J. E. Castelao, J. Yuan, R. K. Ross, M. C. Yu, "Lipid peroxidation: a novel and unifying concept of the etiology of renal cell carcinoma (United States)," Cancer Causes & Control, vol. 13 no. 3, pp. 287-293, DOI: 10.1023/A:1015044518505, 2002.

[4] C. Shen, Y. Huang, S. Yi, Z. Fang, L. Li, "Association of vitamin E intake with reduced risk of kidney cancer: A meta-analysis of observational studies," Medical Science Monitor, vol. 21, pp. 3420-3426, DOI: 10.12659/MSM.896018, 2015.

[5] J. Hu, C. La Vecchia, E. Negri, M. DesMeules, L. Mery, Canadian Cancer Registries Epidemiology Research Group, "Dietary vitamin C, E, and carotenoid intake and risk of renal cell carcinoma," Cancer Causes & Control : CCC, vol. 20 no. 8, pp. 1451-1458, DOI: 10.1007/s10552-009-9371-6, 2009.

[6] M. P. Laguna, F. Algaba, J. Cadeddu, R. Clayman, I. Gill, G. Gueglio, M. Hohenfellner, A. Joyce, J. Landman, B. Lee, H. Van Poppel, "Current patterns of presentation and treatment of renal masses: A clinical research office of the endourological society prospective study," Journal of Endourology, vol. 28 no. 7, pp. 861-870, DOI: 10.1089/end.2013.0724, 2014.

[7] S. C. Campbell, A. C. Novick, A. Belldegrun, M. L. Blute, G. K. Chow, I. H. Derweesh, M. M. Faraday, J. H. Kaouk, R. J. Leveillee, S. F. Matin, P. Russo, R. G. Uzzo, "Guideline for management of the clinical T1 renal mass," The Journal of Urology, vol. 182 no. 4, pp. 1271-1279, DOI: 10.1016/j.juro.2009.07.004, 2009.

[8] B. Ljungberg, K. Bensalah, S. Canfield, S. Dabestani, F. Hofmann, M. Hora, M. A. Kuczyk, T. Lam, L. Marconi, A. S. Merseburger, P. Mulders, T. Powles, M. Staehler, A. Volpe, A. Bex, "EAU guidelines on renal cell carcinoma: 2014 update," European Urology, vol. 67 no. 5, pp. 913-924, DOI: 10.1016/j.eururo.2015.01.005, 2015.

[9] A. Volpe, M. L. Blute, V. Ficarra, I. S. Gill, A. Kutikov, F. Porpiglia, C. Rogers, K. A. Touijer, H. Van Poppel, R. H. Thompson, "Renal ischemia and function after partial nephrectomy: A collaborative review of the literature," European Urology, vol. 68 no. 1, pp. 61-74, DOI: 10.1016/j.eururo.2015.01.025, 2015.

[10] A. C. Novick, "Renal hypothermia: In vivo and ex vivo," Urologic Clinics of North America, vol. 10 no. 4, pp. 637-644, 1983.

[11] N. Stowe, M. Magnusson, A. Novick, J. Palleschi, W. Pechan, P. Khairallah, R. Gifford, R. Straffon, "Pharmacologic protection against prolonged ischemia during harvesting and preservation of canine kidneys," Transplantation Proceedings, vol. 13 no. 1, pp. 699-701, 1981.

[12] E. M. Gong, K. C. Zorn, M. A. Orvieto, A. Lucioni, L. P. Msezane, A. L. Shalhav, "Artery-only occlusion may provide superior renal preservation during laparoscopic partial nephrectomy," Urology, vol. 72 no. 4, pp. 843-846, DOI: 10.1016/j.urology.2008.05.020, 2008.

[13] H. J. S. Bagetti-Filho, F. J. B. Sampaio, R. G. Marques, M. A. Pereira-Sampaio, "Different from renal artery only clamping, artery and vein clamping causes a significant reduction in number of rat glomeruli during warm ischemia," Journal of Endourology, vol. 26 no. 10, pp. 1335-1339, DOI: 10.1089/end.2012.0166, 2012.

[14] P. Silva, "Energy and fuel substrate metabolism in the kidney," Seminars in Nephrology, vol. 10 no. 5, pp. 432-444, 1990.

[15] T. A. Sutton, C. J. Fisher, B. A. Molitoris, "Microvascular endothelial injury and dysfunction during ischemic acute renal failure," Kidney International, vol. 62 no. 5, pp. 1539-1549, DOI: 10.1046/j.1523-1755.2002.00631.x, 2002.

[16] L. J. Mandel, T. Takano, S. P. Soltoff, S. Murdaugh, "Mechanisms whereby exogenous adenine nucleotides improve rabbit renal proximal function during and after anoxia," The Journal of Clinical Investigation, vol. 81 no. 4, pp. 1255-1264, DOI: 10.1172/JCI113443, 1988.

[17] D. B. Fitzpatrick, M. Karmazyn, "Comparative effects of calcium channel blocking agents and varying extracellular calcium concentration on hypoxia/reoxygenation and ischemia/reperfusion-induced cardiac injury," The Journal of Pharmacology and Experimental Therapeutics, vol. 228 no. 3, pp. 761-768, 1984.

[18] J. M. McCord, "Oxygen-derived free radicals in postischemic tissue injury," The New England Journal of Medicine, vol. 312 no. 3, pp. 159-163, DOI: 10.1056/NEJM198501173120305, 1985.

[19] X. Rod, B. Peyronnet, T. Seisen, B. Pradere, F. D. Gomez, G. Verhoest, C. Vaessen, A. De La Taille, K. Bensalah, M. Roupret, "Impact of ischaemia time on renal function after partial nephrectomy: a systematic review," BJU International, vol. 118 no. 5, pp. 692-705, DOI: 10.1111/bju.13580, 2016.

[20] H. Okabe, "The role of xanthine dehydrogenase (xanthine oxidase) in ischemia-reperfusion injury in rat kidney," Nihon Jinzo Gakkai Shi, vol. 38 no. 12, pp. 577-584, 1996.

[21] M. Joannidis, G. Gstraunthaler, W. Pfaller, "Xanthine oxidase: evidence against a causative role in renal reperfusion injury," American Journal of Physiology - Renal Fluid and Electrolyte Physiology, vol. 258 no. 2, pp. F232-F236, DOI: 10.1152/ajprenal.1990.258.2.F232, 1990.

[22] D. A. Parks, D. N. Granger, "Contributions of ischemia and reperfusion to mucosal lesion formation," American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 250 no. 6, pp. G749-G753, DOI: 10.1152/ajpgi.1986.250.6.G749, 1986.

[23] L. Baud, R. Ardaillou, "Involvement of reactive oxygen species in kidney damage," British Medical Bulletin, vol. 49 no. 3, pp. 621-629, DOI: 10.1093/oxfordjournals.bmb.a072635, 1993.

[24] M. A. Venkatachalam, D. B. Bernard, J. F. Donohoe, N. G. Levinsky, "Ischemic damage and repair in the rat proximal tubule: Differences among the S1, S2, and S3 segments," Kidney International, vol. 14 no. 1, pp. 31-49, DOI: 10.1038/ki.1978.87, 1978.

[25] S. G. Rhee, "Cell signaling. H 2 O 2 , a necessary evil for cell signaling," Science, vol. 312 no. 5782, pp. 1882-1883, DOI: 10.1126/science.1130481, 2006.

[26] P. S. Gill, C. S. Wilcox, "NADPH oxidases in the kidney," Antioxidants & Redox Signaling, vol. 8 no. 9-10, pp. 1597-1607, DOI: 10.1089/ars.2006.8.1597, 2006.

[27] I. U. Schraufstatter, D. B. Hinshaw, P. A. Hyslop, R. G. Spragg, C. G. Cochrane, "Oxidant injury of cells. DNA strand-breaks activate polyadenosine diphosphate-ribose polymerase and lead to depletion of nicotinamide adenine dinucleotide," The Journal of Clinical Investigation, vol. 77 no. 4, pp. 1312-1320, DOI: 10.1172/JCI112436, 1986.

[28] P. A. Hyslop, D. B. Hinshaw, W. A. Halsey, I. U. Schraufstatter, R. D. Sauerheber, R. G. Spragg, J. H. Jackson, C. G. Cochrane, "Mechanisms of oxidant-mediated cell injury. The glycolytic and mitochondrial pathways of ADP phosphorylation are major intracellular targets inactivated by hydrogen peroxide," The Journal of Biological Chemistry, vol. 263 no. 4, pp. 1665-1675, 1988.

[29] B. Halliwell, "Oxidants and human disease: some new concepts," The FASEB Journal, vol. 1 no. 5, pp. 358-364, DOI: 10.1096/fasebj.1.5.2824268, 1987.

[30] M. Kadkhodaee, Z. H. Endre, R. A. Towner, M. Cross, "Hydroxyl radical generation following ischaemia-reperfusion in cell-free perfused rat kidney," BBA - General Subjects, vol. 1243 no. 2, pp. 169-174, DOI: 10.1016/0304-4165(94)00141-J, 1995.

[31] H. B. Demopoulos, E. S. Flamm, D. D. Pietronigro, M. L. Seligman, "The free radical pathology and the microcirculation in the major central nervous system disorders," Acta Physiologica Scandinavica, vol. 110 no. 492, pp. 91-119, 1980.

[32] C. Ducrocq, B. Blanchard, B. Pignatelli, H. Ohshima, "Peroxynitrite: An endogenous oxidizing and nitrating agent," Cellular and Molecular Life Sciences, vol. 55 no. 8-9, pp. 1068-1077, DOI: 10.1007/s000180050357, 1999.

[33] A. Guven, B. Uysal, O. Akgul, H. Cermik, G. Gundogdu, I. Surer, H. Ozturk, A. Korkmaz, "Scavenging of peroxynitrite reduces renal ischemia/reperfusion injury," Renal Failure, vol. 30 no. 7, pp. 747-754, DOI: 10.1080/08860220802213039, 2008.

[34] A. L. P. Chapman, O. Skaff, R. Senthilmohan, A. Kettle, M. J. Davies, "Hypobromous acid and bromamine production by neutrophils and modulation by superoxide," Biochemical Journal, vol. 417 no. 3, pp. 773-781, DOI: 10.1042/BJ20071563, 2009.

[35] M. J. Davies, C. L. Hawkins, D. I. Pattison, M. D. Rees, "Mammalian heme peroxidases: from molecular mechanisms to health implications," Antioxidants & Redox Signaling, vol. 10 no. 7, pp. 1199-1234, DOI: 10.1089/ars.2007.1927, 2008.

[36] C. L. Hawkins, D. I. Pattison, M. J. Davies, "Hypochlorite-induced oxidation of amino acids, peptides and proteins," Amino Acids, vol. 25 no. 3-4, pp. 259-274, DOI: 10.1007/s00726-003-0016-x, 2003.

[37] D. I. Pattison, M. J. Davies, "Reactions of myeloperoxidase-derived oxidants with biological substrates: Gaining chemical insight into human inflammatory diseases," Current Medicinal Chemistry, vol. 13 no. 27, pp. 3271-3290, DOI: 10.2174/092986706778773095, 2006.

[38] J. M. McCord, "Oxygen-derived radicals: a link between reperfusion injury and inflammation," Federation Proceedings, vol. 46 no. 7, pp. 2402-2406, 1987.

[39] R. A. Matthijsen, D. Huugen, N. T. Hoebers, B. De Vries, C. J. Peutz-Kootstra, Y. Aratani, M. R. Daha, J. W. C. Tervaert, W. A. Buurman, P. Heeringa, "Myeloperoxidase is critically involved in the induction of organ damage after renal ischemia reperfusion," The American Journal of Pathology, vol. 171 no. 6, pp. 1743-1752, DOI: 10.2353/ajpath.2007.070184, 2007.

[40] B. Yang, S. A. Hosgood, S. J. F. Harper, M. L. Nicholson, "Leucocyte depletion improves renal function in porcine kidney hemoreperfusion through reduction of myeloperoxidase+ cells, caspase-3, IL-1 β , and tubular apoptosis," Journal of Surgical Research, vol. 164 no. 2, pp. e315-e324, DOI: 10.1016/j.jss.2010.07.044, 2010.

[41] B. Halliwell, M. Whiteman, "Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean?," British Journal of Pharmacology, vol. 142 no. 2, pp. 231-255, DOI: 10.1038/sj.bjp.0705776, 2004.

[42] H. K. Vincent, K. E. Innes, K. R. Vincent, "Oxidative stress and potential interventions to reduce oxidative stress in overweight and obesity," Diabetes, Obesity and Metabolism, vol. 9 no. 6, pp. 813-839, DOI: 10.1111/j.1463-1326.2007.00692.x, 2007.

[43] T. D. J. M. G. Filho, T. B. de Mendonça, G. Gabiatti, G. Rodrigues, N. A. P. Marroni, L. Treis, S. D. de Rossi, C. O. Corso, "Topical hepatic hypothermia plus ischemic preconditioning. Analysis of bile flow and ischemic injuries after initial reperfusion in rats," Acta Cirurgica Brasileira, vol. 26 no. 3, pp. 194-201, DOI: 10.1590/S0102-86502011000300007, 2011.

[44] R. N. McCoy, K. E. Hill, M. A. Ayon, J. H. Stein, R. F. Burk, "Oxidant stress following renal ischemia: Changes in the glutathione redox ratio," Kidney International, vol. 33 no. 4, pp. 812-817, DOI: 10.1038/ki.1988.72, 1988.

[45] E. B. dos Santos, W. J. Koff, T. D. J. M. Grezzana Filho, S. D. De Rossi, L. Treis, S. R. Bona, K. L. Pêgas, B. Katz, F. S. Meyer, N. A. P. Marroni, C. O. Corso, "Oxidative stress evaluation of ischemia and reperfusion in kidneys under various degrees of hypothermia in rats," Acta Cirurgica Brasileira, vol. 28 no. 8, pp. 568-573, DOI: 10.1590/S0102-86502013000800003, 2013.

[46] M. M. Goyal, A. Basak, "Human catalase: Looking for complete identity," Protein & Cell, vol. 1 no. 10, pp. 888-897, DOI: 10.1007/s13238-010-0113-z, 2010.

[47] M. S. Paller, "Hydrogen peroxide and ischemic renal injury: Effect of catalase inhibition," Free Radical Biology & Medicine, vol. 10 no. 1, pp. 29-34, DOI: 10.1016/0891-5849(91)90018-X, 1991.

[48] I. Zemlyak, S. M. Brooke, M. H. Singh, R. M. Sapolsky, "Effects of overexpression of antioxidants on the release of cytochrome c and apoptosis-inducing factor in the model of ischemia," Neuroscience Letters, vol. 453 no. 3, pp. 182-185, DOI: 10.1016/j.neulet.2009.02.020, 2009.

[49] C.-C. Yang, S.-P. Hsu, K.-H. Chen, C.-T. Chien, "Effect of adenoviral catalase gene transfer on renal ischemia/reperfusion injury in rats," The Chinese Journal of Physiology, vol. 58 no. 6, pp. 420-430, DOI: 10.4077/CJP.2015.BAD324, 2015.

[50] R. Margis, C. Dunand, F. K. Teixeira, M. Margis-Pinheiro, "Glutathione peroxidase family-an evolutionary overview," FEBS Journal, vol. 275 no. 15, pp. 3959-3970, DOI: 10.1111/j.1742-4658.2008.06542.x, 2008.

[51] N. Ishibashi, M. Weisbrot-Lefkowitz, K. Reuhl, M. Inouye, O. Mirochnitchenko, "Modulation of chemokine expression during ischemia/reperfusion in transgenic mice overproducing human glutathione peroxidases," The Journal of Immunology, vol. 163 no. 10, pp. 5666-5677, 1999.

[52] V. T. Gouvêa, C. Caporossi, A. B. Salomão, E. Côrtes, M. F. Munhoz, J. E. A. de Nascimento, "Effect of glutamine on the total antioxidant system of rats subjected to renal ischemia and reperfusion," Acta Cirurgica Brasileira, vol. 26 no. 6, pp. 445-450, DOI: 10.1590/S0102-86502011000600007, 2011.

[53] A. Bayati, O. Hellberg, B. Odlind, M. Wolgast, "Prevention of ischaemic acute renal failure with superoxide dismutase and sucrose," Acta Physiologica Scandinavica, vol. 130 no. 3, pp. 367-372, DOI: 10.1111/j.1748-1716.1987.tb08150.x, 1987.

[54] A. Greenstein, D. Aravot, Z. Braf, S. Lelcuk, "The role oxygen free radicals and prostaglandins in reperfusion injury to warm ischemic kidneys," Urolithiasis, vol. 19 no. 6, pp. 393-395, DOI: 10.1007/BF00310157, 1991.

[55] J. Torras, D. Seron, I. Herrero, A. Martinez‐Castelao, M. Carrera, J. Alsina, J. M. Griño, "Renal protective effect of liposomed superoxide dismutase in an experimental warm ischemia model," Transplant International, vol. 7, pp. 472-475, DOI: 10.1111/j.1432-2277.1994.tb01421.x, 1994.

[56] J. Trujillo, Y. I. Chirino, E. Molina-Jijón, A. C. Andérica-Romero, E. Tapia, J. Pedraza-Chaverrí, "Renoprotective effect of the antioxidant curcumin: recent findings," Redox Biology, vol. 1 no. 1, pp. 448-456, DOI: 10.1016/j.redox.2013.09.003, 2013.

[57] O. Bayrak, E. Uz, R. Bayrak, F. Turgut, A. F. Atmaca, S. Sahin, M. E. Yildirim, A. Kaya, E. Cimentepe, A. Akcay, "Curcumin protects against ischemia/reperfusion injury in rat kidneys," World Journal of Urology, vol. 26 no. 3, pp. 285-291, DOI: 10.1007/s00345-008-0253-4, 2008.

[58] A. Kaur, T. Kaur, B. Singh, D. Pathak, H. Singh Buttar, A. Pal Singh, "Curcumin alleviates ischemia reperfusion-induced acute kidney injury through NMDA receptor antagonism in rats," Renal Failure, vol. 38 no. 9, pp. 1462-1467, DOI: 10.1080/0886022X.2016.1214892, 2016.

[59] P. Mattila, J. Kumpulainen, "Determination of free and total phenolic acids in plant-derived foods by HPLC with diode-array detection," Journal of Agricultural and Food Chemistry, vol. 50 no. 13, pp. 3660-3667, DOI: 10.1021/jf020028p, 2002.

[60] P. Tee-Ngam, N. Nunant, P. Rattanarat, W. Siangproh, O. Chailapakul, "Simple and rapid determination of ferulic acid levels in food and cosmetic samples using paper-based platforms," Sensors, vol. 13 no. 10, pp. 13039-13053, DOI: 10.3390/s131013039, 2013.

[61] G. S. N. Bezerra, M. A. V. Pereira, E. A. Ostrosky, E. G. Barbosa, M. D. F. V. de Moura, M. Ferrari, C. F. S. Aragão, A. P. B. Gomes, "Compatibility study between ferulic acid and excipients used in cosmetic formulations by TG/DTG, DSC and FTIR," Journal of Thermal Analysis and Calorimetry, vol. 127 no. 2, pp. 1683-1691, DOI: 10.1007/s10973-016-5654-9, 2017.

[62] M. Lodovici, F. Guglielmi, M. Meoni, P. Dolara, "Effect of natural phenolic acids on DNA oxidation in vitro," Food and Chemical Toxicology, vol. 39 no. 12, pp. 1205-1210, DOI: 10.1016/S0278-6915(01)00067-9, 2001.

[63] R. Masella, R. Varì, M. D'Archivio, R. Di Benedetto, P. Matarrese, W. Malorni, B. Scazzocchio, C. Giovannini, "Extra virgin olive oil biophenols inhibit cell-mediated oxidation of LDL by increasing the mRNA transcription of glutathione-related enzymes," Journal of Nutrition, vol. 134 no. 4, pp. 785-791, DOI: 10.1093/jn/134.4.785, 2004.

[64] Y. Kato, A. Nagao, J. Terao, T. Osawa, "Inhibition of myeloperoxidase-catalyzed tyrosylation by phenolic antioxidants in vitro," Bioscience, Biotechnology, and Biochemistry, vol. 67 no. 5, pp. 1136-1139, DOI: 10.1271/bbb.67.1136, 2003.

[65] J. Kiewlicz, H. Szymusiak, R. Zielinski, "Symthesis, Thermal stability andantioxidant activity of long-chain alkyl esters od ferulic acid," ZYWNOSC-Nauka Technologia Jakosc, vol. 4, pp. 188-200, 2015.

[66] Q. Zhou, X. Gong, G. Kuang, R. Jiang, T. Xie, H. Tie, X. Chen, K. Li, J. Wan, B. Wang, "Ferulic acid protected from kidney ischemia reperfusion injury in mice: possible mechanism through increasing adenosine generation via HIF-1 α," Inflammation, vol. 41 no. 6, pp. 2068-2078, DOI: 10.1007/s10753-018-0850-3, 2018.

[67] L. Xiong, Z.-Y. Fang, X.-N. Tao, M. Bai, G. Feng, "Effect and mechanism of ligustrazine on Th1/Th2 cytokines in a rat asthma model," American Journal of Chinese Medicine, vol. 35 no. 6, pp. 1011-1020, DOI: 10.1142/S0192415X07005478, 2007.

[68] L. Feng, N. Ke, F. Cheng, Y. Guo, S. Li, Q. Li, Y. Li, "The protective mechanism of ligustrazine against renal ischemia/reperfusion injury," Journal of Surgical Research, vol. 166 no. 2, pp. 298-305, DOI: 10.1016/j.jss.2009.04.005, 2011.

[69] Y. Hanasaki, S. Ogawa, S. Fukui, "The correlation between active oxygens scavenging and antioxidative effects of flavonoids," Free Radical Biology & Medicine, vol. 16 no. 6, pp. 845-850, DOI: 10.1016/0891-5849(94)90202-x, 1994.

[70] A. Kahraman, N. Erkasap, M. Serteser, T. Köken, "Protective effect of quercetin on renal ischemia/reperfusion injury in rats," Journal of Nephrology, vol. 16 no. 2, pp. 219-224, 2003.

[71] M. Kenan Kinaci, N. Erkasap, A. Kucuk, T. Koken, M. Tosun, "Effects of quercetin on apoptosis, NF-kappaB and NOS gene expression in renal ischemia/reperfusion injury," Experimental and Therapeutic Medicine, vol. 3 no. 2, pp. 249-254, DOI: 10.3892/etm.2011.382, 2012.

[72] B.-L. Chen, L.-T. Wang, K.-H. Huang, C.-C. Wang, C.-K. Chiang, S.-H. Liu, "Quercetin attenuates renal ischemia/reperfusion injury via an activation of AMP-activated protein kinase-regulated autophagy pathway," The Journal of Nutritional Biochemistry, vol. 25 no. 11, pp. 1226-1234, DOI: 10.1016/j.jnutbio.2014.05.013, 2014.

[73] G. Albertoni, N. Schor, "Resveratrol plays important role in protective mechanisms in renal disease - mini-review," Jornal Brasileiro de Nefrologia, vol. 37 no. 1, pp. 106-114, DOI: 10.5935/0101-2800.20150015, 2015.

[74] J. H. Holthoff, K. A. Woodling, D. R. Doerge, S. T. Burns, J. A. Hinson, P. R. Mayeux, "Resveratrol, a dietary polyphenolic phytoalexin, is a functional scavenger of peroxynitrite," Biochemical Pharmacology, vol. 80 no. 8, pp. 1260-1265, DOI: 10.1016/j.bcp.2010.06.027, 2010.

[75] M. Kitada, S. Kume, N. Imaizumi, D. Koya, "Resveratrol improves oxidative stress and protects against diabetic nephropathy through normalization of Mn-SOD dysfunction in AMPK/SIRT1- independent pathway," Diabetes, vol. 60 no. 2, pp. 634-643, DOI: 10.2337/db10-0386, 2011.

[76] S. J. Park, F. Ahmad, A. Philp, K. Baar, T. Williams, H. Luo, H. Ke, H. Rehmann, R. Taussig, A. L. Brown, M. K. Kim, M. A. Beaven, A. B. Burgin, V. Manganiello, J. H. Chung, "Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases," Cell, vol. 148 no. 3, pp. 421-433, DOI: 10.1016/j.cell.2012.01.017, 2012.

[77] J. X. Wilson, "The physiological role of dehydroascorbic acid," FEBS Letters, vol. 527 no. 1-3,DOI: 10.1016/S0014-5793(02)03167-8, 2002.

[78] M. Conti, P. Eschwège, M. Ahmed, V. Paradis, S. Droupy, S. Loric, P. Bedossa, B. Charpentier, A. Legrand, G. Benoit, "Antioxidant enzymatic activities and renal warm ischemia: Correlation with the duration of ischemia," Transplantation Proceedings, vol. 32 no. 8, pp. 2740-2741, DOI: 10.1016/S0041-1345(00)01860-1, 2000.

[79] R. Hansson, S. Johansson, O. Jonsson, "Kidney protection by pretreatment with free radical scavengers and allopurinol: Renal function at recirculation after warm ischaemia in rabbits," Clinical Science, vol. 73 no. 3, pp. 245-251, DOI: 10.1042/cs0710245, 1986.

[80] S. Bratell, G. Haraldsson, H. Herlitz, O. Jonsson, S. Pettersson, T. Schersten, J. Waldenstrom, "Protective effects of pretreatment with superoxide dismutase, catalase and oxypurinol on tubular damage caused by transient ischaemia," Acta Physiologica Scandinavica, vol. 139 no. 3, pp. 417-425, DOI: 10.1111/j.1748-1716.1990.tb08942.x, 1990.

[81] H. Sies, "Carotenoids and tocopherols as antioxidants and singlet oxygen quenchers," Journal of Nutritional Science and Vitaminology, vol. 38 no. Special, pp. 27-33, DOI: 10.3177/jnsv.38.Special_27, 1992.

[82] C. Fleck, D. Haubold, T. Hillmann, H. Bräunlich, "Influence of vitamin E treatment on glutathione system after renal ischemia in immature and adult rats," Experimental and Toxicologic Pathology, vol. 49 no. 1-2, pp. 81-86, DOI: 10.1016/S0940-2993(97)80072-3, 1997.

[83] M. H. M. Shimizu, M. Araujo, S. M. M. Borges, E. M. C. De Tolosa, A. C. Seguro, "Influence of age and vitamin E on post-ischemic acute renal failure," Experimental Gerontology, vol. 39 no. 5, pp. 825-830, DOI: 10.1016/j.exger.2004.02.009, 2004.

[84] M. Salehipour, A. Monabbati, H. Salahi, S. Nikeghbalian, A. Bahador, V. E. Marvasti, H. Rezaei, K. Kazemi, M. Dehghani, R. Mohammadian, S. A. Malek-Hosseini, "Protective effect of parenteral vitamin E on ischemia-reperfusion injury of rabbit kidney," Urology, vol. 75 no. 4, pp. 858-861, DOI: 10.1016/j.urology.2009.04.062, 2010.

[85] B. Prieto-Moure, A. Carabén-Redaño, A. Aliena-Valero, D. Cejalvo, A. H. Toledo, M. Flores-Bellver, N. Martínez-Gil, L. H. Toledo-Pereyra, J. M. Lloris Carsí, "Allopurinol in renal ischemia," Journal of Investigative Surgery, vol. 27 no. 5, pp. 304-316, DOI: 10.3109/08941939.2014.911395, 2014.

[86] M. K. Chok, M. Conti, A. Almolki, S. Ferlicot, S. Loric, A. Dürrbach, G. Benot, S. Droupy, P. Eschwège, "Renoprotective potency of amifostine in rat renal ischaemiareperfusion," Nephrology Dialysis Transplantation, vol. 25 no. 12, pp. 3845-3851, DOI: 10.1093/ndt/gfq314, 2010.

[87] A. A. Merter, B. Mayir, O. Erdogan, T. Colak, "Protective effects of amifostine on ischemia-reperfusion injury of rat kidneys," Indian Journal of Pharmacology, vol. 47 no. 2, pp. 185-189, DOI: 10.4103/0253-7613.153427, 2015.

[88] C. A. Adin, B. P. Croker, A. Agarwal, "Protective effects of exogenous bilirubin on ischemia-reperfusion injury in the isolated, perfused rat kidney," American Journal of Physiology-Renal Physiology, vol. 288 no. 4, pp. F778-F784, DOI: 10.1152/ajprenal.00215.2004, 2005.

[89] P. E. Deetman, D. M. Zelle, J. J. Homan van der Heide, G. J. Navis, R. O. B. Gans, S. J. L. Bakker, "Plasma bilirubin and late graft failure in renal transplant recipients," Transplant International, vol. 25 no. 8, pp. 876-881, DOI: 10.1111/j.1432-2277.2012.01515.x, 2012.

[90] P. Baron, O. Gomez-Marin, C. Casas, J. Heil, N. Will, R. Condie, B. Burke, J. S. Najarian, D. E. R. Sutherland, "Renal preservation after warm ischemia using oxygen free radical scavengers to prevent reperfusion injury," Journal of Surgical Research, vol. 51 no. 1, pp. 60-65, DOI: 10.1016/0022-4804(91)90070-3, 1991.

[91] W. Peerapanyasut, K. Thamprasert, O. Wongmekiat, "Ubiquinol supplementation protects against renal ischemia and reperfusion injury in rats," Free Radical Research, vol. 48 no. 2, pp. 180-189, DOI: 10.3109/10715762.2013.858148, 2014.

[92] M. Takenaka, Y. Tatsukawa, K. Dohi, H. Ezaki, K. Matsukawa, T. Kawasaki, "Protective effects of α -tocopherol and coenzyme Q10 on warm ischemic damages of the rat kidney," Transplantation, vol. 32 no. 2, pp. 137-141, DOI: 10.1097/00007890-198108000-00010, 1981.

[93] H. Hosseinzadeh, H. R. Sadeghnia, T. Ziaee, A. Danaee, "Protective effect of aqueous saffron extract (Crocus sativus L.) and crocin, its active constituent, on renal ischemia-reperfusion-induced oxidative damage in rats," Journal of Pharmacy & Pharmaceutical Sciences, vol. 8 no. 3, pp. 387-393, 2005.

[94] J. Pincemail, J. O. Defraigne, O. Detry, C. Franssen, M. Meurisse, R. Limet, "Ischemia-reperfusion injury of rabbit kidney: Comparative effects of desferrioxamine and N-Acetylcysteine as antioxidants," Transplantation Proceedings, vol. 32 no. 2, pp. 475-476, DOI: 10.1016/S0041-1345(00)00848-4, 2000.

[95] M. Matsuyama, T. Hayama, K. Funao, K. Tsuchida, Y. Takemoto, K. Sugimura, Y. Kawahito, H. Sano, T. Nakatani, R. Yoshimura, "Treatment with edaravone improves the survival rate in renal warm ischemia-reperfusion injury using rat model," Transplantation Proceedings, vol. 38 no. 7, pp. 2199-2200, DOI: 10.1016/j.transproceed.2006.06.077, 2006.

[96] F. Lopez-Neblina, L. H. Toledo-Pereyra, R. Mirmiran, A. J. Paez-Rollys, "Time dependence of Na-nitroprusside administration in the prevention of neutrophil infiltration in the rat ischemic kidney," Transplantation, vol. 61 no. 2, pp. 179-183, DOI: 10.1097/00007890-199601270-00002, 1996.

[97] C.-I. Lee, X. Liu, J. L. Zweier, "Regulation of xanthine oxidase by nitric oxide and peroxynitrite," The Journal of Biological Chemistry, vol. 275 no. 13, pp. 9369-9376, DOI: 10.1074/jbc.275.13.9369, 2000.

[98] I. S. Zeltser, A. Gupta, K. Bensalah, W. Kabbani, A. Jenkins, S. Park, M. S. Pearle, J. Cadeddu, "Focal radiofrequency coagulation-assisted laparoscopic partial nephrectomy: A novel nonischemic technique," Journal of Endourology, vol. 22 no. 6, pp. 1269-1273, DOI: 10.1089/end.2008.0022, 2008.

[99] D. Unal, E. Yeni, O. Erel, M. Bitiren, H. Vural, "Antioxidative effects of exogenous nitric oxide versus antioxidant vitamins on renal ischemia reperfusion injury," Urolithiasis, vol. 30 no. 3, pp. 190-194, DOI: 10.1007/s00240-002-0254-5, 2002.

[100] A. Korkmaz, D. Kolankaya, "The protective effects of ascorbic acid against renal ischemia-reperfusion injury in male rats," Renal Failure, vol. 31 no. 1, pp. 36-43, DOI: 10.1080/08860220802546271, 2009.

[101] V. Koul, A. Kaur, A. P. Singh, "Investigation of the role of nitric oxide/soluble guanylyl cyclase pathway in ascorbic acid-mediated protection against acute kidney injury in rats," Molecular and Cellular Biochemistry, vol. 406 no. 1,DOI: 10.1007/s11010-015-2392-4, 2015.

[102] Y.-B. Zhu, Y.-P. Zhang, J. Zhang, Y.-B. Zhang, "Evaluation of Vitamin C supplementation on kidney function and vascular reactivity following renal ischemic injury in mice," Kidney and Blood Pressure Research, vol. 41 no. 4, pp. 460-470, DOI: 10.1159/000443447, 2016.

[103] T. Kanji, M. Gandhi, C. M. Clase, R. Yang, "Urate lowering therapy to improve renal outcomes in patients with chronic kidney disease: systematic review and meta-analysis," BMC Nephrology, vol. 16, article 58,DOI: 10.1186/s12882-015-0047-z, 2015.

[104] E. E. Guibert, A. Y. Petrenko, C. L. Balaban, A. Y. Somov, J. V. Rodriguez, B. J. Fuller, "Organ preservation: current concepts and new strategies for the next decade," Transfusion Medicine and Hemotherapy, vol. 38 no. 2, pp. 125-142, DOI: 10.1159/000327033, 2011.

[105] G. Bragadottir, B. Redfors, S.-E. Ricksten, "Mannitol increases renal blood flow and maintains filtration fraction and oxygenation in postoperative acute kidney injury: a prospective interventional study," Critical Care, vol. 16 no. 4, article R159,DOI: 10.1186/cc11480, 2012.

[106] G. Haraldsson, V. Sorensen, U. Nilsson, S. Pettersson, M. Rashid, T. Scherstén, S. Åkerlund, O. Jonsson, "Effect of pre-treatment with desferrioxamine and mannitol on radical production and kidney function after ischaemia-reperfusion. A study on rabbit kidneys," Acta Physiologica Scandinavica, vol. 154 no. 4, pp. 461-468, DOI: 10.1111/j.1748-1716.1995.tb09931.x, 1995.

[107] J. A. Damasceno-Ferreira, L. A. Abreu, G. R. Bechara, W. S. Costa, M. A. Pereira-Sampaio, F. J. Sampaio, D. B. De Souza, "Mannitol reduces nephron loss after warm renal ischemia in a porcine model," BMC Urology, vol. 18 no. 1,DOI: 10.1186/s12894-018-0328-5, 2018.

[108] S. C. Weight, P. N. Furness, M. L. Nicholson, "Biphasic role for nitric oxide in experimental renal warm ischaemia-reperfusion injury," British Journal of Surgery, vol. 86 no. 8, pp. 1039-1046, DOI: 10.1046/j.1365-2168.1999.01162.x, 1999.

[109] A. Hirayama, S. Nagase, A. Ueda, T. Oteki, K. Takada, M. Obara, M. Inoue, K. Yoh, K. Hirayama, A. Koyama, "In vivo imaging of oxidative stress in ischemia-reperfusion renal injury using electron paramagnetic resonance," American Journal of Physiology-Renal Physiology, vol. 288 no. 3, pp. F597-F603, DOI: 10.1152/ajprenal.00020.2004, 2005.

[110] I. S. Gill, M. S. Eisenberg, M. Aron, A. Berger, O. Ukimura, M. B. Patil, V. Campese, D. Thangathurai, M. M. Desai, ""Zero ischemia" partial nephrectomy: Novel laparoscopic and robotic technique," European Urology, vol. 59 no. 1, pp. 128-134, DOI: 10.1016/j.eururo.2010.10.002, 2011.

[111] M. Cosentino, A. Breda, F. Sanguedolce, J. Landman, J.-U. Stolzenburg, P. Verze, J. Rassweiler, H. Van Poppel, H. C. Klingler, G. Janetschek, A. Celia, F. J. Kim, G. Thalmann, U. Nagele, A. Mogorovich, C. Bolenz, T. Knoll, F. Porpiglia, M. Alvarez-Maestro, F. Francesca, F. Deho, S. Eggener, C. Abbou, M. V. Meng, M. Aron, P. Laguna, D. Mladenov, A. D'Addessi, P. Bove, R. Schiavina, O. De Cobelli, A. S. Merseburger, O. Dalpiaz, F. C. H. D'Ancona, T. J. Polascik, R. Muschter, T. J. Leppert, H. Villavicencio, "The use of mannitol in partial and live donor nephrectomy: An international survey," World Journal of Urology, vol. 31 no. 4, pp. 977-982, DOI: 10.1007/s00345-012-1003-1, 2013.

[112] W. Khoury, M. Namnesnikov, D. Fedorov, S. Abu-Ghazala, A. A. Weinbroum, "Mannitol attenuates kidney damage induced by xanthine oxidase-associated pancreas ischemia-reperfusion," Journal of Surgical Research, vol. 160 no. 1, pp. 163-168, DOI: 10.1016/j.jss.2008.10.016, 2010.

[113] N. E. Power, A. C. Maschino, C. Savage, J. L. Silberstein, D. Thorner, T. Tarin, A. Wong, K. A. Touijer, P. Russo, J. A. Coleman, "Intraoperative mannitol use does not improve long-term renal function outcomes after minimally invasive partial nephrectomy," Urology, vol. 79 no. 4, pp. 821-825, DOI: 10.1016/j.urology.2011.11.064, 2012.

[114] K. Omae, T. Kondo, T. Takagi, J. Iizuka, H. Kobayashi, Y. Hashimoto, K. Tanabe, "Mannitol has no impact on renal function after open partial nephrectomy in solitary kidneys," International Journal of Urology: Official Journal of the Japanese Urological Association, vol. 21 no. 2, pp. 200-203, DOI: 10.1111/iju.12213, 2014.