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 Table of Contents  
Year : 2018  |  Volume : 35  |  Issue : 1  |  Page : 89-96

Erythropoietin versus allopurinol on ischemia/reperfusion-induced acute kidney injury in rats

1 Clinical Pharmacology Department, Faculty of Medicine, Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Egypt
2 Pathology Department, Faculty of Medicine, Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Egypt
3 Veterinarian Team, Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Egypt
4 Clinical Pathology Department, Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Egypt
5 Department of Public Health, Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Egypt
6 Urology and Nephrology Center, Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Egypt

Date of Submission16-Aug-2017
Date of Acceptance15-Oct-2017
Date of Web Publication28-Feb-2018

Correspondence Address:
Rehab H Ashour
Clinical Pharmacology Department, Faculty of Medicine, Mansoura University, 35511
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bmfj.bmfj_165_17

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Objective Renal ischemia/reperfusion (I/R) injury involves multiple mechanisms including oxidative stress. Erythropoietin (EPO) and allopurinol have an antioxidant effect and are protective against I/R-induced kidney injury. This study compares the ability of EPO to compete oxidative stress and kidney injury induced by I/R with that of allopurinol.
Materials and methods A total of 72 male Sprague–Dawley rats were randomized into the following groups: sham group, I/R group, EPO-treated I/R group, and allopurinol-treated I/R group (n=18 in each group). I/R was persuaded by 45 min clamping of the left renal pedicle followed by right nephrectomy. The therapeutic intervention started before the operative procedure. In each group, animals were killed at 1, 3, and 7 days after the operation. Serum creatinine, serum aspartate aminotransferase, tissue malondialdehyde, and pathological score for injury and regeneration were determined.
Results We found that both EPO and allopurinol were able to attenuate the elevation of serum creatinine. EPO was more effective than allopurinol in reducing aspartate aminotransferase and malondialdehyde levels. Both drugs were equally effective regarding their effect on the active injury and regeneration scores.
Conclusion These results indicate that although EPO or allopurinol can effectively reduce kidney damage, EPO is a better choice as an antioxidant and for reducing the overall damage of I/R-induced kidney injury.

Keywords: allopurinol, erythropoietin, ischemia/reperfusion, kidney injury, oxidative stress

How to cite this article:
Ashour RH, Abd-Allah MA, Mostafa FE, Osman BH, Kahter YT, El-Biomy AA, AEl-Gilany AH, Saad MAA, Sobh MA. Erythropoietin versus allopurinol on ischemia/reperfusion-induced acute kidney injury in rats. Benha Med J 2018;35:89-96

How to cite this URL:
Ashour RH, Abd-Allah MA, Mostafa FE, Osman BH, Kahter YT, El-Biomy AA, AEl-Gilany AH, Saad MAA, Sobh MA. Erythropoietin versus allopurinol on ischemia/reperfusion-induced acute kidney injury in rats. Benha Med J [serial online] 2018 [cited 2022 Jan 25];35:89-96. Available from: http://www.bmfj.eg.net/text.asp?2018/35/1/89/226410

  Introduction Top

Acute kidney injury (AKI) is a serious medical problem with great morbidity and mortality [1]. Ischemia and/or reperfusion (I/R) is one of the major factors contributing to AKI [2]. In clinical practice, renal I/R may result from either systemic causes that end with circulatory derangement or local renal hypoperfusion [3]. The harmful effect of I/R to the kidney involves multiple series of cellular reactions that ultimately lead to renal cell death [4]. Reperfusion itself may also initiate additional mechanisms that may be more destructive than ischemia alone and mainly comprises the production of reactive oxygen species (ROS) [5] that may be derived from different sources in the postischemic tissue including mitochondrial respiration that generates superoxide, xanthine oxidase enzyme, and other cellular enzymes [6].

In the past few years, erythropoietin (EPO) demonstrated a powerful tissue protection against the damaging effect of I/R in different organs including the kidney [7],[8],[9]. Following I/R, the number of EPO receptors were increased [10],[11], leading to activation of multiple intracellular signaling [12],[13],[14], and induction of the transcription of several antiapoptotic [15] and antioxidative genes [16]. Among several studies that confirmed the benefits of EPO against I/R cellular injury, few studies have addressed the role of the antioxidant property of EPO in I/R to the kidney [17],[18],[19],[20].

With ischemia, ATP is decayed into ADP and AMP. By turn, AMP is then processed leading to the formation of inosine, adenosine, and hypoxanthine; the latter could be changed to uric acid by xanthine oxidase. In this process, ROS are generated and this can participate in the ischemic damage [6]. Administration of allopurinol, xanthine oxidase inhibitor, decreases free-radical production, and restricts the damaging effect of I/R injury [21],[22].

Few studies focused on the antioxidant effects of either drug but none compared them head to head. In the complex system of oxidant/antioxidant, it might be difficult to find out the pathway that plays the key role in AKI except through comparing drugs that act through different mechanisms. In this study, we compared the possible protection of EPO with that of allopurinol in a murine model of renal I/R. Tissue malondialdehyde (MDA) level was used as a marker of oxidative stress, whereas histologic changes in the kidney have been evaluated using a scoring system that considers different features of tissue damage and renewal.

  Materials and methods Top

The design of the experiment was authorized by the Local Research Ethics Committee. Animals’ care was adherent to the code of ethics of the World Medical Association (Declaration of Helsinki).

Renal ischemia/reperfusion model

Male Sprague–Dawley rats (250–300 g) were used. Rats received regular rat chow and water ad libitum. The model of renal I/R injury was established according to a standard method [23]. Rats were anesthetized using a combination of 15 mg/kg intraperitoneal diazepam and 150 mg/kg intraperitoneal ketamine; halothane inhalation anesthesia was added as required. The abdominal cavity was opened through a midline approach and the left kidney was exposed and its pedicle was occluded for 45 min with a nontraumatic clamp. Just before reperfusion, right nephrectomy was carried out. The color changes of the left kidney were observed during I/R. Then, 1 ml of 0.9% saline at 37°C was installed into the peritoneal cavity and the surgical wound was closed in two layers. The rats were kept warm in the postoperative period by a warm light.

Drugs and dosage selection

Previous experimental studies in the context of I/R used either allopurinol or EPO in a large single dose. So, we hypothesized to compare allopurinol and EPO in multiple lower daily doses instead of a single large dose. Regarding EPO, dose selection was based on a pilot study that was first conducted to compare different doses of the commercially available drug ranging from 100 to 1000 IU/kg. In addition, previous studies such as Patel et al. [17], and others indicated that EPO administration [1000 IU/kg/day, subcutaneous injection (SC)] in the range of 0–3 days before ischemia was effective in reducing oxidative stress. For allopurinol, the dose used was 30 mg/kg/day by mouth (PO), which was selected to be comparable to the human therapeutic dose used in gout (300 mg/day) according to Paget and Barnes [24], after reviewing the literature, whereas the drug kinetics and rapid onset of action made 2 h before ischemia is a reasonable choice to fulfill the aim of the study [25].

Sample size calculation

The sample size was calculated by G*Power (Faul, Erdfelder, Lang, & Buchner, 2007) analysis using the F tests statistics, effect size f of 0.41, α error probability of 0.05, and power of 82% to calculate total sample size of 72 animals that were divided into four main groups.

Study design

A total of 72 rats were randomly distributed into four main groups: (a) sham group (n=18), rats were anesthetized for 45 min and exposed to the same surgery but without closure of the hilum of left kidney; (b) renal I/R nontreated group (n=18), rats underwent 45 min left renal ischemia followed by clamp release; (c) renal I/R-EPO group (n=18), rats received EPO (1000 IU/kg, SC) 24 h before the operative procedure and continued daily until the day of sacrifice; and (d) renal I/R-allopurinol group (n=18), rats received allopurinol (30 mg/kg, orally) 2 h before the induction of ischemia and continued daily until the day of sacrifice. In each group, rats were killed 24 h, 3, and 7 days after renal I/R injury (n=6 for each time point). Rats were killed with thiopental overdose. Blood was collected by cardiac puncture and the left kidney was harvested for further biochemical and histopathologic evaluation.

Biochemical measurements

Sera were obtained by centrifuging the blood samples at 3000 g for 10 min. Serum creatinine (sCr) and serum aspartate aminotransferase (AST) levels were assessed using original kits and spectrophotometer (Slim Plus; SEAC, Florence, Italy). AST is released from damaged cells of some organs including the kidney after any type of injury, as it is physiologically present in the cells of proximal tubules and it was previously used as an indicator of renal reperfusion injury [26].

Measurement of malondialdehyde

MDA levels (nmol/g tissue) of renal tissue homogenate were determined by spectrophotometry. Renal tissue homogenate was prepared by adding 2 ml of ice cold trichloroacetic acid (10%) to 0.5 g of fresh tissue followed by centrifugation at 1620 g for 10 min. The MDA concentration in the supernatant was determined by the formation of thiobarbituric acid reactive substance and the absorbance was measured at 533 nm [27]. Previous studies used assay of MDA level in the renal tissue as a marker of lipid peroxidation [26].

Renal morphology

After cutting a portion of the fresh kidney to prepare the homogenate, the left kidney was perfused through the aorta using 0.9% saline and then 10% neutral buffered formalin. The kidney was picked up, cut vertically, and conveyed for histopathological examination. Renal tissue was fixed in paraffin, cut at 4 μm thickness, and stained with hematoxylin and eosin. Renal histopathology was evaluated in separate kidney areas (cortex, the outer stripe of the outer medulla ‘OSOM’, the inner stripe of the outer medulla ‘ISOM’, and the inner medulla). In each region, a new scoring system [28] was used as detailed in [Table 1].
Table 1 Scoring of active injury, regenerative, and chronic changes in the kidney

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Data analysis

Statistical analysis was achieved sing the SPSS software (version 16.0; SPSS Inc., Chicago, Illinois, USA). Data were tested for normal distributions by Kolmogorov–Smirnov test. Biochemical parameters and tissue MDA were evaluated by one-way analysis of variance and post-hoc Bonferroni test and expressed as mean±SD. Pathological scores were expressed as median (minimum–maximum) and evaluated by Kruskal–Wallis, followed by Mann–Whitney U-test for significance between individual groups. Statistical significant was considered with a P values less than 0.05.

  Results Top

Effect of EPO and allopurinol on I/R-induced renal dysfunction: creatinine level

At 24 h after reperfusion, renal I/R led to a significant rise in sCr level compared with the sham group. Pretreatment with either EPO or allopurinol significantly reduced the rise of sCr level compared with the untreated ischemic group at 24 h ([Table 2]).
Table 2 Changes in serum creatinine (mg/dl), AST levels (U/l), and tissue MDA (nmol/g) in Sham, renal I/R, EPO-treated, and allopurinol-treated renal I/R groups at 24 h, 3 days, and 7 days postreperfusion

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Effect of EPO and allopurinol on I/R-induced renal tissue damage: AST level

Compared with the sham group, I/R led to a significant rise in AST at 24 h, 3 days, and 7 days, indicating some degree of renal tissue damage. Unexpectedly, allopurinol-treated renal I/R group showed a significant increase of AST level 24 h after reperfusion compared with the other I/R groups. However, continued administration of EPO or allopurinol significantly lowered AST level 3 days postreperfusion compared with the untreated renal I/R group ([Table 2]).

Effect of EPO and allopurinol on I/R-induced renal oxidative stress: tissue MDA levels

Compared with the sham group, I/R led to a significant rise in the renal tissue MDA levels, indicating considerable oxidative stress derived lipid peroxidation. Administration of EPO significantly lowered serum MDA level at each time point compared with the untreated renal I/R group. However, allopurinol failed to reduce renal MDA level 24 h after reperfusion compared with the EPO group. At the third and seventh day, the effect of allopurinol on MDA levels was comparable to that of EPO ([Table 2]).

Effect of EPO and allopurinol on I/R-induced renal damage: histopathology assessment

Active injury changes

Sham group showed normal renal tubule brush border with no evidence of necrosis. Renal I/R group showed the picture of acute tubular necrosis. When compared with the sham group, injury score was significantly higher in renal I/R group at 1, 3, and 7 days in both OSOM and the cortex ([Figure 1]). Injury score in the ISOM was also significantly increased in the I/R group at 1 day after reperfusion. Compared with the renal I/R group, EPO treatment brought out a significant attenuation of the injury score in the ISOM at 1 day after reperfusion and in the renal cortex at day 7 ([Table 3]). Administration of allopurinol resulted in a significant decrease of active injury score and tubular necrosis in the cortex, ISOM, and inner medulla ([Figure 1] and [Table 3]). Nevertheless, no significant differences were detected when EPO-treated and allopurinol-treated groups were compared.
Figure 1 Photomicrograph showing active injury of the OSOM of a kidney section from rats killed 3 days after I/R. Evidence of tubular necrosis and intraluminal necrotic cells (a) and inflammatory cell infiltration (b) on untreated rats. Treatment with either erythropoietin (c) or allopurinol (d) resulted in attenuation of injury score. Magnification, ×200 (a, d); ×400 (b, c). I/R, ischemia/reperfusion; OSOM, outer stripe of the outer medulla.

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Table 3 Active injury score in the renal cortex, OSOM, ISOM, and IM of sham, renal I/R, EPO-treated, and allopurinol-treated renal I/R groups at 24 h, 3 days, and 7 days post reperfusion (n=6 in each group for each time point)

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Regenerative changes

In I/R groups, the regenerative changes were evident in the OSOM and were more prominent at day 3 after perfusion compared with absence in the sham group. However, no statistically significant changes were evident in I/R, EPO-treated, or allopurinol-treated groups ([Figure 2] and [Table 4]).
Figure 2 Photomicrograph of regenerative changes of the OSOM in the kidney of rats treated with erythropoietin (a, c) or allopurinol (b, d) and killed 3 days after I/R. Regeneration was evident in the form hyperplastic interstitial solid sheets of epithelial cells with mitotic figures (a, b). Intratubular proliferation and papillary projections of regenerating cells (c, d). Magnification, ×400 (a, b), ×200 (c, d). I/R, ischemia/reperfusion; OSOM, outer stripe of the outer medulla.

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Table 4 Regenerative changes in the renal cortex, OSOM, ISOM, and IM of sham-operated, renal I/R, EPO-treated, and allopurinol-treated renal I/R groups at 24 h, 3 days, and 7 days post reperfusion (n=6 in each group for each time point)

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Chronic changes

In all three groups of renal I/R, chronic changes were not evident.

Of note, only the EPO-treated group showed a fluffy material in the Bowman’s capsule and brownish red necrotic materials with excess hyaline casts in the tubules in almost all samples. This feature was constant in the 24-h and 3-day group but disappeared in the 7-day group.

  Discussion Top

I/R injury is a serious cause of AKI [2]. I/R of the kidney may result from shock, acute myocardial infarction, renal vascular surgery, renal transplantation, or surgery of an aortic aneurysm related to the renal artery [3],[29],[30]. Several complex interrelated events have been incriminated to explain the harmful effect of renal I/R. These events include microvascular dysfunctions, depletion of ATP, the buildup of intracellular Ca+2, disturbed vasoactive substances, high intracellular ROS and reactive nitrogen species, endothelial cell injury, confined inflammation, and unstable mitochondrial respiration [4],[31],[32]. In fact, even the tubular epithelium actively participates in the pathogenesis of I/R [33]. Furthermore, the formation of ROS in I/R models may be derived from different pathways. Examples include mitochondrial electron transport chain that generates superoxide, xanthine oxidase, prostaglandin H synthase, or lipoxygenase [6]. Thus, an ideal agent to prevent or treat renal I/R injury must work by multiple mechanisms. In addition, not all antioxidants are expected to produce equal results.

In the current study, we demonstrated that either EPO or allopurinol effectively ameliorated the kidney damage induced by I/R. They are well-known antioxidants, but each one acts by totally different mechanisms. EPO showed superiority to allopurinol regarding its effect on AST and MDA but not on sCr. However, sCr has been long considered as a marker of kidney injury that lacks a sufficient sensitivity [34]. In fact, we have demonstrated that different oxidative stress markers might be more sensitive markers for AKI than sCr. In a parallel way, we believe that lack of significant difference between EPO and allopurinol at the level of histopathological scoring of injury or regeneration could be attributed to the fact that the nonparametric data evaluated were not sensitive enough to reveal minor differences.

EPO is a kidney-derived hormone that has been usually employed in the management of anemia of renal failure [35]. In the past few years, EPO has also demonstrated the ability to attenuate cell damage [36]. As reviewed elsewhere [37], evidence has been provided that EPO protected against I/R-induced kidney injury by several mechanisms. Generally, EPO has been proven as an antiapoptotic [15], antioxidant [16], and immunomodulatory agent [17],[18],[38]. In this study, we focused on the antioxidant property of EPO.

The current study demonstrated the ability of EPO to exert an antioxidant effect and reduce the injury induced by renal I/R. Our findings are in consistence with the results of earlier studies [17],[18],[19],[20]. Speaking of the mechanism, it was suggested that EPO may have direct antioxidative effects by provoking intracellular antioxidative enzymes such as hemeoxygenase-1 [16],[39] and glutathione peroxidase [40],[41]. Patel et al. [17] found that the degree of protection and antioxidant effect afforded by EPO against I/R-induced renal injury was greater when EPO was given as pretreatment before ischemia induction compared with EPO administration upon reperfusion. Among the other explanations, they suggested that 3 days pretreatment with EPO may result in the induction of protective genes and antioxidant enzymes. Dissimilar from therapy at reperfusion, preconditioning with such pretreatment permits stimulation of protein synthesis and not just the activation of standing proteins. However, Ates et al. [18] stated a significant reduction of MDA level in a rat model of I/R-induced renal damage, although they used EPO only 2 h before the injury. It was suggested that EPO may act as an antioxidant both directly and indirectly [41]. The indirect antioxidant property of EPO has been linked to its ability to induce iron depletion leading to inhibition of iron-dependent oxidative damage [42]. In another way, EPO treatment leads to increased red blood cells that are laden with antioxidant enzymes; thus, EPO may be thus indirectly reducing cellular oxidative stress [43]. Still, both mechanisms require a time to develop, and none of these two mechanisms were capable of explaining the results of Ates et al. [18]. In the present study, EPO was administered 24 h before I/R and then it was given daily until the day of sacrifice. Although EPO significantly reduced both renal damage and MDA level at day 1, the value of using EPO daily after I/R was difficult to evaluate in this study. Many cellular mechanisms that mediate the action of EPO require a lag-time. Thus, it was difficult to include a suitable control in the design of this experiment to help in judging the benefits of using EPO daily after I/R.

In a parallel way, the antioxidant and, subsequently, its renoprotective effect of allopurinol were evident in fewer studies [21],[22]. Authors found that allopurinol significantly protected against I/R-induced renal injury in rats with a significant decline of sCr and the rise of creatinine clearance at 24 and 96 h of reperfusion. However, we used a dose of allopurinol that is more comparable to the human therapeutic dose used in gout. Allopurinol is a xanthine oxidase inhibitor that is thought to diminish oxidative tissue damage in a dose-dependent way. The conversion of xanthine dehydrogenase to xanthine oxide surges during ischemia, and, in addition to the degradation products of hypoxanthine/xanthine, results in the production of injurious ROS, particularly with the reperfusion [44]. Unlike EPO, the antioxidant effect of allopurinol depends on blocking only one pathway. In addition, allopurinol does not have other actions that might be beneficial in I/R in comparison with EPO. We believe that these two reasons explain why some of the results of EPO were superior to those of allopurinol. Although the antioxidant effect of EPO alone in this model outweighed that of allopurinol, we could not say that EPO is a more potent antioxidant. Reduction of oxidative stress may be partly due to the decrease of tissue damage by other mechanisms.

The limitations of the current study include, first, the need to include new markers of kidney injury in future studies as a sensitive method for evaluating the degree of kidney injury. Second, renal tissue proliferative capacity is not adequately tested by specific markers such as bromouridine or Ki-67 immunostaining; also, more specific oxidative stress markers should be investigated in future studies. Last, although testing the protective effect of these drugs could be useful in clinical setting of renal ischemia as predicted during surgery or transplantation, an additional evaluation of the ‘curative’ effects of these drugs is required to find out their ability to reduce an already developed damage.

In conclusion, the present study demonstrated that, in renal injury associated with I/R, EPO is a better choice than allopurinol. Unlike allopurinol, EPO has multiple beneficial effects beyond the antioxidant effect and counteract many aspects in the complex process of renal damage after I/R. EPO appears to be promising in the treatment of ischemic renal failure.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4]


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