Methotrexate-induced Nephrotoxicity Research Articles

Empagliflozin mitigates methotrexate-induced nephrotoxicity in male albino rats: insights on the crosstalk of AMPK/Nrf2 signaling pathway

BackgroundThe anti-diabetic drug, empagliflozin (EMPA), has many pleiotropic actions and is challenged recently to possess renoprotective properties. This renoprotective potential is proposed to be mediated via the activation of AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways. This research investigated the renoprotective potential and the mechanistic pathway of EMPA against methotrexate (MTX)-induced nephrotoxicity and evaluated the role of AMPK by utilizing an AMPK inhibitor, dorsomorphin (Dorso).MethodsThirty male Wistar rats, weighing 180–200 g, were divided equally into five groups. Group I represented the control group. Nephrotoxicity was induced in the remaining rats through the administration of a single intraperitoneal injection of MTX (20 mg/kg). Rats were then randomly assigned to: Group 2 (received MTX injection only); Group 3 (received MTX and EMPA 30 mg/kg/day); Group 4 (received MTX and Dorso 0.2 mg/kg/day), Group 5 (received MTX, Dorso, EMPA). After one week, blood samples were collected, the rats were euthanized, and renal tissues were harvested for biochemical and histomorphometric assessments.ResultsMTX produced a significant rise in serum creatinine and tissue MDA levels; an increase in BAX, p53, cytochrome-c expression; a reduction in Bcl2 level; and disruption of renal microarchitecture. In contrast, EMPA therapy in group 3, resulted in a significant improvement of all these parameters, correlated with significant increase in AMPK phosphorylation and Nrf2 expression. Importantly, the co-administration of Dorso, in group 5, prevented EMPA’s beneficial effects.ConclusionEMPA has a potential protective effect against MTX-induced toxicity through the activation of the AMPK/Nrf2 signaling pathway.

The Effect of Dextrose Hypotonic vs Saline Hydration on Methotrexate-Induced Nephrotoxicity in Male and Female Rats.

High-dose methotrexate (HDMTX) as a cytotoxic agent might cause various side effects. Hyperhydration has been implemented as the major strategy to decrease the potential risk of toxicities induced by HDMTX. This study aims to assess the renoprotective effect of hydration with dextrose water (DW) 5% versus normal saline (N/S) 0.9% against methotrexate (MTX) induced nephrotoxicity. This experimental animal study has been conducted on 36 Wistar rats (200-250 g) categorized into six groups, including male (n = 6) and female (n = 6) rats receiving sodium chloride 0.9% saline plus MTX, DW 5% plus MTX, or MTX alone. By the fifth day after the MTX injection, biochemical indexes were measured. The rats were also sacrificed and renal specimens were evaluated microscopically to determine kidney tissue damage (KTD). The groups were not significantly different with regard to blood urea nitrogen (BUN) (P = 0.5), creatinine (Cr) (P = 0.24), kidney weight (P = 0.34), and urine flow (UF) (P = 0.5), while KTD score was remarkably less in the hydrated groups (P < 0.001). Weight loss in DW-treated rats was significantly more than N/S-treated ones, and creatinine clearance (CrCl) and urine load (UL) of Cr were statistically similar between males and females in the control group, but significantly lower among the DW5% treated males. Based on the findings of this study, hydration with N/S was superior to DW5% for the prevention from HDMTX-induced nephrotoxicity. Besides, we found insignificant differences between male versus female rats in response to the hydration for HDMTX-induced renoprotection; however, females probably benefit more.

Effect of morin hydrate on oxidative stress and renal function in methotrexate-induced nephrotoxicity

Effect of morin hydrate on oxidative stress and renal function in methotrexate-induced nephrotoxicity

Dose-dependent renoprotective effect of vanillic acid on methotrexate-induced nephrotoxicity via its anti-apoptosis, antioxidant, and anti-inflammatory properties.

Methotrexate-induced nephrotoxicity is a medical emergency which is associated with a variety of side effects. Vanillic acid (VA), as an antioxidant, removes free radical oxygen to protect cell defense. Therefore, this study investigated VA's beneficial effects on nephrotoxicity induced by methotrexate through its anti-apoptosis, antioxidant, and anti-inflammatory properties. Our study included five groups of male Wistar rats (n = 8): sham, MTX (Methotrexate) group: rats receiving methotrexate (20 mg/kg, intraperitoneally) on Day 2. Moreover, the remaining groups consisted of animals that received vanillic acid (25, 50, and 100 mg/kg, orally for seven days) plus MTX on the 2nd day. The rats were deeply anesthetized on the eighth day to obtain blood and renal tissue samples. The results showed that MTX can increase blood urea nitrogen and creatinine. However, VA (50 and 100 mg/kg) improved renal function as approved by histological findings. Compared with MTX-treated rats, VA enhanced the contents of total antioxidant capacity (TAC) and reduced renal malondialdehyde (MDA). Moreover, VA reduced mRNA expressions of caspase-3 and Bcl-2-associated x protein (Bax) and caused mRNA overexpression of the renal B-cell lymphoma-2 (Bcl-2), and Nrf-2 (Nuclear factor erythroid 2-related factor 2) compared to the MTX group. Also, VA administration significantly reduced inflammatory agents. Overall, VA protects the kidneys against methotrexate-induced nephrotoxicity via anti-apoptosis, antioxidant, and anti-inflammatory properties. Our results revealed that the most effective dose of VA was 100 mg/kg.

Alpha-linolenic acid protects against methotrexate-induced nephrotoxicity in mouse kidney cells.

Methotrexate (MTX) is a folic acid antagonist used in chronic inflammatory diseases and various cancer treatments. Although the main mechanism of the toxic effect of MTX is not known, it is stated that it causes oxidative stress and inflammation. Alpha-linolenic acid (ALA) protects against oxidative stress, apoptosis, and inflammation. For this reason, we aimed to find out the useful effect of ALA on MTX-induced nephrotoxicity MATERIALS AND METHODS: The mice were divided into 4 groups randomly. The control group was treated with physiological saline solution; the ALA group was treated with ALA (200 mg/kg) by gavage; MTX-treated group received 20 mg/kg i.p. (intraperitoneal) MTX; and MTX+ALA treated group received 20 mg/kg i.p. MTX and ALA 200 mg/kg by gavage. All of the drugs were performed once a day for 9 days. Alpha-linolenic acid significantly decreased oxidative stress parameters and MTX-induced inflammatory and apoptotic mediators. Furthermore, histopathological examination showed that MTX induced significant edematous damage, and ALA treatment attenuated this damage in renal tissue. Our results revealed that ALA may be helpful against MTX-induced nephrotoxicity in mice via its antioxidant and anti-inflammatory properties.

The potential protectivity of honey and olive oil in methotrexate induced renal damage in rats

Methotrexate (MTX) is an antimetabolite used to treat inflammatory diseases, autoimmune disorders and some malignancies. However, it has some life-threatening side effects such as nephrotoxicity which limit its clinical applications. That motivated the attention to seek for a defensive material to improve the outcomes of methotrexate while minimizing both renal and non-renal toxicity. Both honey (H) and olive oil (OO) are bioactive substances widely used as nutraceuticals that exhibited a potent therapeutic and antioxidant properties. This study aimed to assess the possible protective effect of H and OO intake either singly or together against the biochemical and structural Methotrexate-induced nephrotoxicity in rats. The study was conducted on 56 adult albino rats, they were divided into seven groups (n = 8): group 1 received only distelled water (negative control), group 2 received H (1.2 g/kg/day), group 3 received OO (1.25 ml/kg/day), group 4 received a single intraperitoneal injection of MTX (20 mg/kg), group 5 received MTX and H, group 6 received MTX and OO, group 7 received MTX, H and OO together. At the end of the experiment (2 weeks), all rats were sacrificed, and blood samples were assessed for kidney function tests. Kidney tissues were evaluated for several antioxidant parameters including Malondialdehyde (MDA), Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities. Tissues were also processed for histological and immunohistochemical assessments. Results revealed that both H and OO improved the kidney function markers, histopathological and immunohistological changes due to Methotrexate-induced renal damage. Additionally, both substances also redeemed the oxidative damage of the kidney by decreasing MDA and increasing anti-oxidant enzymatic activities. Such effects were more apparent when the two substances were given together. Ultimately, our results proof that H and OO amiolerate the Methotrexate-induced nephrotoxicity in rats, thus they can be used as an adjuvant supplements for patients requiring methotrexate therapy.

Inhibitory interaction of flavonoids with organic anion transporter 3 and their structure-activity relationships for predicting nephroprotective effects

The organic anion transporter 3 (OAT3), an important renal uptake transporter, is associated with drug-induced acute kidney injury (AKI). Screening and identifying potent OAT3 inhibitors with little toxicity in natural products, especially flavonoids, in reducing OAT3-mediated AKI is of great value. The five strongest OAT3 inhibitors from the 97 flavonoids markedly decreased aristolochic acid I-induced cytotoxicity and alleviated methotrexate-induced nephrotoxicity. The pharmacophore model clarified hydrogen bond acceptors and hydrophobic groups are the critical pharmacophores. These findings would provide valuable information in predicting the potential risks of flavonoid-containing food/herb-drug interactions and optimizing flavonoid structure to alleviate OAT3-related AKI.

Metabolomic profiling reveals the mechanisms underlying the nephrotoxicity of methotrexate in children with acute lymphoblastic leukemia.

Methotrexate is widely recommended as a first-line treatment for the intensive systemic and consolidation phases of childhood acute lymphoblastic leukemia. However, methotrexate-induced nephrotoxicity is a severe adverse reaction, of which the mechanisms remain unclear. An untargeted metabolomics analysis of serum from childhood acute lymphoblastic leukemia patients with delayed methotrexate excretion, with or without acute kidney injury, was performed to identify altered metabolites and metabolic pathways. An independent external validation cohort and in vitro HK-2 cell assays further verified the candidate metabolites, and explored the mechanisms underlying the nephrotoxicity of methotrexate. Four metabolites showed significant differences between normal excretion and delayed excretion, seven metabolites reflected the differences between groups with or without acute kidney injury, and six pathways were finally enriched. In particular, oxidized glutathione was confirmed as a candidate metabolite involved in the toxicity of methotrexate. We further explored the role of glutathione deprivation-induced ferroptosis on methotrexate cytotoxicity, and it was found that methotrexate overload significantly reduced cell viability, triggered reactive oxygen species and intracellular Fe2+ accumulation, and altered the expression of ferroptosis-related proteins in HK-2 cells. These methotrexate-induced changes were alleviated or reversed by the administration of a ferroptosis inhibitor, further suggesting that ferroptosis promoted methotrexate-induced cytotoxicity in HK-2 cells. Our findings revealed complex metabolomic profiles and provided novel insights into the mechanism by which ferroptosis contributes to the nephrotoxic effects of methotrexate.

Protective effects of sitagliptin on methotrexate-induced nephrotoxicity in rats

Methotrexate (MTX), a cytotoxic chemotherapeutic and immunosuppressant agent, is widely used in the treatment of autoimmune diseases and different types of cancers. However, its use has been limited by its life-threatening side effects, including nephrotoxicity and hepatotoxicity. The purpose of this study was to investigate the protective effect of sitagliptin on methotrexate (MTX)-induced nephrotoxicity in rats. Twenty-four rats were divided into four groups: control group, which received the vehicle for 6 days; MTX group, which received a single dose of MTX, followed by five daily doses of vehicle dosing; MTX + sitagliptin group, which received a single dose of MTX 1 h after the first sitagliptin treatment and six daily doses of sitagliptin; and sitagliptin group, which received sitagliptin for 6 days. Both MTX and sitagliptin were given as intraperitoneal injections at a dose of 20 mg/kg body weight. All rats were euthanized on the seventh day of the study. Kidney tissues were harvested and blood samples were collected. Serum levels of blood urea nitrogen (BUN) and creatinine were evaluated. Furthermore, catalase, glutathione peroxidase, superoxide dismutase activities, and malondialdehyde (MDA) levels were determined in kidney tissue. In addition, histopathological analysis was conducted. Histopathological evaluation showed that MTX-induced marked kidney injury. Biochemical analysis revealed a significant increase of BUN and creatinine in the serum of the MTX group. Furthermore, oxidative stress and depressed antioxidant system of the kidney tissues were evident in the MTX group. Sitagliptin did not affect these endpoints when administered alone, but it significantly attenuated the observed MTX-induced effects. These results suggest that sitagliptin exhibits potent anti-oxidant properties against the nephrotoxicity induced by MTX in rats.

Alamandine alleviates methotrexate-induced nephrotoxicity in rats by targeting oxidative stress and inflammation

Aim: Nephrotoxicity due to the use of methotrexate (Mtx) is one of the most important problems associated with chemotherapy. Oxidative stress and inflammation are the major pathomechanisms of Mtx-induced nephrotoxicity. Alamandine (Ala), a new member of the renin-angiotensin system (RAS), is an important peptide with antioxidant and anti-inflammatory capacities. In this study, it was investigated whether Ala ameliorates Mtx-induced kidney damage by reducing oxidative stress and inflammation. Materials and Methods: Male Wistar albino rats were assigned into three groups: control group, Mtx group, and Mtx+Ala group. At the end of the experiment, kidney tissues were quickly removed. Glutathione (GSH) and malondialdehyde (MDA) levels were measured to determine the oxidative state in kidney tissues. In addition, tissue samples were assessed as histopathological and immunohistochemical for heat shock protein 60 (HSP60), caspase-3, tumor necrosis factor-α (TNF-α), and receptor-interacting protein kinase-3 (RIPK3). Results: Mtx treatment resulted in reduced GSH content, elevated MDA level, increased heat shock protein 60 (HSP60), and caspase-3 expression. These changes in kidney tissues of rats treated with Mtx triggered oxidative stress characterized by apoptosis and kidney damage. Mtx also markedly increased the expression of TNF-α, an inflammation marker, and RIPK3, a marker of necroptosis. However, Ala administration significantly alleviated Mtx-induced kidney damage by reducing apoptosis and necroptosis by suppressing oxidative stress and inflammation. Conclusion: Taken together, our results support that Ala treatment can serve as a new and promising therapeutic strategy against Mtx-induced nephrotoxicity. Keywords: Alamandine; methotrexate; oxidative stress; inflammation; apoptosis; necroptosis; nephrotoxicity

Possible ameliorative effect of human placental extract on methotrexate-induced nephrotoxicity in albino rats

BackgroundMethotrexate (MTX) is one of chemotherapeutic drugs that induce several side effects. The present study aimed to investigate the ameliorative effect of human placental extract (HPE) against MTX-induced nephrotoxicity in rats. In this study, forty adult male albino rats were equally divided into four groups. Control group: rats were daily injected intraperitoneally with physiological saline (0.5 ml for each rat) for 5 days, HPE group: rats were subcutaneously injected with HPE at a dose level of 10.08 mg/Kg b.w/day for 2 weeks, MTX group: rats were intraperitoneally injected with MTX at a dose level of 5 mg/Kg b.w/day for 5 consecutive days, MTX and HPE group: rats were intraperitoneally injected with MTX (at the same dosage of MTX group) for 5 days and at the same time they were subcutaneously injected with HPE (at an exact dosage of HPE group), daily for 2 weeks. Twenty-four hours after the last dose for each treatment, rats were killed and blood samples were collected for determination of urea, creatinine, sodium (Na+) and potassium (K+) levels. Kidney tissues were taken for histological examination and immunohistochemical staining of both cysteine-aspartic protease-3 (caspase-3) and proliferating antigen Ki-67 (Ki-67) expressions.ResultsFrom the obtained data, MTX induced nephrotoxicity through a highly significant increase in urea, creatinine, Na+ and K+ levels compared with the control group. In addition to massive histological alterations, a highly significant increase in caspase-3 expression and a significant decrease in Ki-67 expression were observed. On the other hand, injection with HPE ameliorated urea, creatinine, Na+ and K+ levels comparing to MTX group. Moreover, HPE markedly improved the histological and immunohistochemical changes resulted from MTX treatment.ConclusionsIt is concluded that HPE ameliorated the nephrotoxicity induced by MTX.

Effects of Co-administration of Pyridoxine in Two Different Doses with Methotrexate-induced Nephrotoxicity in Rats

Nephrotoxicity is defined as rapid deterioration in kidney functions that arises from direct exposure to a drug or its metabolite. Methotrexate is an anti-metabolite used in low doses for autoimmune and inflammatory disorders and high doses for different malignancies. Pyridoxine is the usual form of vitamin B6 included in pharmaceutical products. This study is designed to examine the effect of pyridoxine in two different doses, each co-administered with methotrexate at 20 mg/kg made renal toxicity in rats through the involvement of Nrf2/HO-1 molecular mechanism in this respect. The animals used in this research were allocated to four distinct groups (each group with 10 rats) of both sexes; as control, MTX, pyridoxine 33 mg/kg and MTX, Pyridoxine 100 mg/kg, and MTX. Serum creatinine, neutrophil gelatinase-associated lipocalin (NGAL), and NrF2/HO-1 signaling pathway were determined. Administration of Pyridoxine (33 mg/kg intraperitoneally) in combination with MTX showed no significant differences (p &gt;0.05) as compared to the MTX group. At the same time, administration of pyridoxine (100 mg/kg intraperitoneally) in combination with methotrexate showed a significant reduction in serum activities of both neutrophil gelatinase associated lipocalin (NGAL) and creatinine (p is less than 0.05) and significant upregulation in Nrf2/HO-1 signaling pathway each compared to corresponding levels in MTX-only group. In conclusion, this study demonstrated that when pyridoxine (100 mg/kg IP) was administered in combination with methotrexate, the renal toxicity was reduced as a result.

The Ameliorative Effect of Fimasartan against Methotrexate-Induced Nephrotoxicity in Rats

Drug-induced acute kidney injury is a serious disorder. Oxidative stress has a key role in its initiation and progression. In this study, the possible ameliorative effect of fimasartan against methotrexate-induced nephrotoxicity was investigated in comparison with α-tocopherol in rats. Wistar rats were allocated into six groups and treated as follows: group Ӏ received water on a daily basis for 8 successive days; group ӀӀ received methotrexate (20 mg/kg) on day 1, followed by water for 7 successive days; group ӀӀӀ received fimasartan (3 mg/kg/day) for 7 successive days; group IV received α-tocopherol (1 g/kg/day) for 7 successive days; group V received methotrexate (20 mg/kg) on day 1, followed by fimasartan (3 mg/kg/day) for 7 successive days; and group VI received methotrexate (20 mg/kg) on day 1, followed by α-tocopherol (1 g/kg/day) for 7 successive days. Finally, after euthanization of each animal by diethyl ether, the samples were collected for analysis. Administration of fimasartan and α-tocopherol resulted in a significant decline in serum creatinine and urea, a significant reduction of renal malondialdehyde, and a significant elevation of renal superoxide dismutase-1 compared to the methotrexate-treated rats. In conclusion, fimasartan has ameliorative effects, comparable to those of α-tocopherol, on methotrexate-induced nephrotoxicity in rats.

Hypoalbuminemia and not undernutrition predicts high-dose methotrexate-induced nephrotoxicity in children with acute lymphoblastic leukemia in resource-constrained centers.

The standard practice to mitigate high-dose methotrexate (HD-MTX)-induced nephrotoxicity (HMN) in acute lymphoblastic leukemia (ALL) is to monitor levels until serum MTX falls below a predefined threshold. It is not feasible in most resource-constrained centers. Literature on the various factors affecting HMN in these centers is limited, retrospective, and heterogeneous. Though hypoalbuminemia has been postulated as a risk factor for HMN, the relationship of undernutrition with HMN has not been studied. This prospective observational study consecutively enrolled children<12 years old with ALL receiving HD-MTX. Children with preexisting renal disease and exposed to nephrotoxic drugs two weeks preceding HD-MTX infusion were excluded. HD-MTX was administered over 24 hours (BFM-2009 protocol) with 12 hours of prehydration. Solitary MTX levels at 36 hours (MTX36) were outsourced, and 6-8 doses of leucovorin were given six-hourly. Hydration was continued till last dose of leucovorin. Various factors affecting HMN (rise in creatinine to 1.5 times baseline) were recorded: age, sex, type of ALL, risk group of ALL, first dose of MTX, dose of MTX, undernourishment, serum protein, and albumin along with C-reactive protein and MTX36 levels. Forty-four children who received 150 HD-MTX cycles were analyzed. HMN was seen in 14% of cycles. On univariate analysis, undernourishment, MTX36 levels, hypoproteinemia, and hypoalbuminemia were significantly associated with HMN. On multivariate analysis, hypoalbuminemia and MTX36 levels significantly predicted the development of HMN with odds ratios of 4.71 and 1.45. Hypoalbuminemia and solitary serum MTX levels predict HMN in centers where serial MTX level monitoring is not feasible.

Protective effect of green tea in methotrexate-induced nephrotoxicity

Protective effect of green tea in methotrexate-induced nephrotoxicity

Paeonol Protects Against Methotrexate-Induced Nephrotoxicity via Upregulation of P-gp Expression and Inhibition of TLR4/NF-κB Pathway.

Methotrexate (MTX) is a well-known anticancer drug that causes nephrotoxicity as a side effect. To investigate the mechanisms by which paeonol, a natural phenolic compound, can protect against MTX-induced nephrotoxicity, paeonol (100 mg/kg/day orally) was given to rats for 10 days, with or without MTX (20 mg/kg once i.p. at day 5). Compared to control, MTX caused nephrotoxic effects manifested by increased serum urea and creatinine and distortion in renal histological architecture, with a significant increase in the mean glomerular diameter and upregulation of kidney injury molecule-1. MTX caused oxidative stress manifested by decreasing reduced glutathione and superoxide dismutase while increasing malondialdehyde and nitric oxide. MTX also induced renal inflammation by upregulating TLR4, NF-κB, and IL-1β and caused apoptosis by induction of caspase 3. Administering paeonol with MTX improved kidney functional and structural parameters, as well as all oxidative, inflammatory, and apoptotic markers tested. Interestingly, both MTX and paeonol increased the expression of the renal efflux transporter P-glycoprotein (P-gp) that helps in MTX elimination, and their drug combination further upregulated renal P-gp. In silico, paeonol was neither a substrate nor an inhibitor of P-gp, suggesting that its effect on P-gp is not on functional but on the expression level. In vitro, paeonol and MTX were administered to colon cancer cells and their combination caused a progressive cellular cytotoxic effect, which was dose-dependent with the increase of paeonol concentration. In conclusion, paeonol protects against MTX-induced nephrotoxicity through antioxidant, anti-inflammatory, and antiapoptotic mechanisms and might potentiate MTX chemotherapeutic efficacy.

Ameliorative Potential of Lactoferrin on Methotrexate-Induced Nephrotoxicity in Rat: A Histological and Immunohistochemical Study

Ameliorative Potential of Lactoferrin on Methotrexate-Induced Nephrotoxicity in Rat: A Histological and Immunohistochemical Study

Harmine Has Nephroprotective Effect Against Methotrexate-Induced Injury in Mice via Inhibition of Oxidative Stress

Background and objectives: Despite clinical use, the efficacy of methotrexate is often limited by some adverse effects, mainly nephrotoxicity. The most common mechanism of methotrexate-induced kidney damages is oxidative stress. Harmine as a plant-derived compound has antioxidant and anti-inflammatory properties, The aim of this study was to evaluate the therapeutic effect of harmine, against methotrexate -induced nephrotoxicity. Methods: The mice were divided into six groups: control (saline only); 20 mg/kg methotrexate; 20 mg/kg harmine, and 20 mg/kg methotrexate + harmine at three doses of 5, 10, or 20 mg/kg. Administrations were intraperitoneally and the treatment period was a 14-days. After this time, the sera and kidneys were collected from each group for the following analyses. Samples were analyzed by hematoxylin-eosin (H&E) staining, qRT-PCR, and biochemical assays. Results: The mice that received methotrexate showed significant increase in creatinine and blood urea nitrogen levels, and 10, or 20 mg/kg harmine mitigated these results. The number and diameter of glomeruli were improved by harmine in methotrexate -treated groups. Moreover, malondialdehyde and nitric oxide levels showed significant increase in the kidney of the mice that received methotrexate, while total antioxidant capacity and superoxide dismutase were diminished. Harmine treatment suppressed oxidative stress markers and also enhanced antioxidant defense parameters. Harmine inhibited methotrexate-induced oxidative stress as shown by the decreased expression of Nqo1, Ho-1, Trx1 and Nrf2 at mRNA level. Harmine also ameliorated histological alterations induced by methotrexate. Conclusion: Our results suggested that harmine has the potential to protect against methotrexate-induced nephrotoxicity.

Risk factors for high-dose methotrexate-induced nephrotoxicity.

High-dose methotrexate (MTX) is widely used for the treatment of hematological malignancies. Despite the application of routine supportive care measures, such as intensive fluid hydration and urine alkalinization, nephrotoxicity is still a problem. The present study aimed to evaluate the risk factors for MTX-induced nephrotoxicity. We retrospectively reviewed 88 patients who received a regimen consisting of high-dose MTX (1000mg/m2) and cytosine arabinoside between 2006 and 2018. Nephrotoxicity (≥ grade 2) was observed in 11 patients. Nephrotoxicity was observed only in patients with a high MTX concentration. Other than the MTX concentration, the serum uric acid level and urine pH at day 1 were associated with nephrotoxicity. A multivariate analysis revealed that urine pH was an independent risk factor for MTX-induced nephrotoxicity. Urine pH < 7.0 at day 1 was a significant risk factor for nephrotoxicity (odds ratio, 8.05; 95% confidence interval 1.95-33.3) and was also a predictor of delayed MTX elimination at 72h after injection. Among pre-treatment factors, a low serum calcium level predicted urine pH < 7.0 at day 1. In conclusion, the present study suggests that low urine pH at day 1 is an independent risk factor for MTX-induced nephrotoxicity.

Punicalagin Reverses Methotrexate-Induced Nephrotoxicity by Attenuating Oxidative Stress, Inflammation and Apoptosis

Methotrexate (MTX) is a trusted anticancer agent; however, its multi-organ toxicity limits its clinical application, including nephrotoxicity. Punicalagin (PUN) is an ellagitannin found in the fruit peel of Punicagranatum with anti-inflammatory and antioxidant properties. The present study aimed to investigate the renoprotective effects of PUN in a well-established rat model of MTX-induced nephrotoxicity. Rats were divided randomly into four groups (six animals per group) as follows: the first group (control) was a normal control group. The second group (PUN) received PUN (30 mg kg- 1 day- 1) daily through oral gavage for 10 consecutive days. The third group (MTX) a single i.p. injection of MTX (20 mg/kg) on day 7. The fourth group (PUN + MTX) received PUN (30 mg kg- 1 day- 1) via oral gavage for 10 consecutive days and a single i.p. injection of MTX (20 mg/kg) on day 7. MTX-induced nephrotoxicity was associated with increased creatinine and urea in the serum. MTX also resulted in increased oxidative stress as evidenced by elevated malondialdehyde and protein carbonyl levels along with decreased glutathione content and superoxide dismutase and catalase activities in the kidney. Moreover, renal tissues were characterized by increased proinflammatory cytokines, cytochrome c and caspases-3, indicating increased inflammation and apoptosis in the kidney. PUN pretreatment prevented kidney injury, oxidative stress, inflammation and apoptosis, and enhanced antioxidant defenses in the kidney. Collectively, these findings indicate that PUN may represent a novel renoprotective strategy against MTX-induced oxidative stress, inflammation and apoptosis in the kidney, which deserves further exploration in future studies.