Prevention Of Cisplatin-induced Nephrotoxicity Research Articles

2113P Efficacy and effectiveness of prophylactic magnesium supplementation on prevention of cisplatin-induced nephrotoxicity: A systematic review and meta-analysis

2113P Efficacy and effectiveness of prophylactic magnesium supplementation on prevention of cisplatin-induced nephrotoxicity: A systematic review and meta-analysis

Prevention of cisplatin-induced nephrotoxicity by kidney-targeted siRNA delivery

Cisplatin is a potent and widely used chemotherapy agent, however, nephrotoxicity limits its use. Many patients need to pause or withdraw from chemotherapy to prevent acute kidney injury.To prevent cisplatin damage, we designed chitosan/siRNA nanoparticleswhich are nontoxic and are readily taken up by HEK293 cells. The nanoparticlescontainedsiRNA against cationic membrane transport (OCT1&2) and apoptosis related proteins (p53, PKCδ, and γGT). In mice treated with cisplatin, serum creatinine levels increased from 15 to 88 mg/dL andblood urea nitrogenlevels increased from 0.25 to 1.7 mg/dL, however, siRNA nanoparticles significantly limited these levels to 30 mg/dL and 0.55 mg/dL, respectively.Western and IHC analyses showed lower p53, PKCδ, and γGT expressions in siRNA treated mice. Histomorphological evaluation revealed high-level protection of kidney proximal tubules from cisplatin damage. Protein expressions and extent of kidney protection were directly correlated with number of siRNA applications. Our results suggest that this novel approach for kidney-targeted delivery of select siRNAs may represent a promising therapy for preventing cisplatin-induced nephrotoxicity. Furthermore, this or other similarly sized nanocarriers could potentially be utilized to passively target kidneys for diagnostic, protective, or treatment purposes.

Melatonin in the prevention of cisplatin-induced acute nephrotoxicity: a randomized, controlled clinical trial.

Background and purpose:Cisplatin-induced nephrotoxicity (CisIN) remains the most dose-limiting adverse effect of its clinical use. The protective effects of melatonin on CisIN have been addressed in several non- clinical and animal studies. This study aimed at investigating the potential effects of melatonin on the prevention of CisIN in human.Experimental approach:Our study was a randomized controlled clinical trial, performed on 66 eligible patients in two groups of melatonin or control (no intervention). Melatonin was administrated daily at a dose of 20 mg for 5 days to the patients receiving cisplatin-containing regimens along with the standard protocol of CisIN prevention. Patient demographic information, blood and urinary indices of nitrogen, creatinine, and electrolytes such as sodium, potassium, magnesium as well as neutrophil gelatinase-associated lipocalin were measured in both groups at the baseline, 24 h and five days after melatonin administration.Findings/Results:Cisplatin administration resulted in significant magnesium and potassium loss in patients with cancer. In comparison with the control group, the prevalence of acute renal injury and the rate of urinary magnesium and potassium loss improved with melatonin administration; however, the results were not statistically significant. Tolerable side effects such as daytime drowsiness, nausea, and vomiting were reported in the melatonin group.Conclusion and implications:Although pretreatment with melatonin led to amelioration in urinary electrolyte loss due to CisIN, it failed to show a positive result on acute renal injury prevention. Future well-designed studies with a longer duration of follow-up, larger sample sizes, and higher doses of melatonin are warranted.

The Prevention of Cisplatin-Induced Nephrotoxicity: A General Consensus Statement of a Group of Oncologist-Hematologists, Adult and Pediatric Nephrologists, Radiation Oncologists, Clinical Pathologists, Clinical Pharmacologists, and Renal Physiologists on Cisplatin Therapy in Cancer Patients.

Backgrounds:Most of the cancer patients with solid tumor are subjected to chemotherapy with cisplatin (CP) in clinic. However, the most side effect of CP is nephrotoxicity, which limits the treatment. The aim of study was to develop a general consensus statement for CP therapy in clinic to limit the drug-induced nephrotoxicity.Methods:A total of 30 oncologist-hematologists, adult and pediatric nephrologists, radiation oncologists, clinical pathologist clinical pharmacologist, and renal physiologist participated in a workshop, and in order to reduce the incidence of CP-induced nephrotoxicity, a general consensus was developed.Results:The developed general consensus was focused on some items such as age, sex, female hormone, nonsteroidal anti-inflammatory drugs (NSAID), renin–angiotensin system inhibitor drugs, glomerular filtration rate, hydration methods, contrasts, antioxidants, dextrose, and magnesium.Conclusion:The agreement between participants for CP therapy in clinic was achieved, and this general consensus was announced to be implemented in the hospitals.

O6-4 The effect of intravenous mannitol in combination with normal saline on the prevention of cisplatin-induced nephrotoxicity: A randomized, double-blind, placebo-controlled trial

O6-4 The effect of intravenous mannitol in combination with normal saline on the prevention of cisplatin-induced nephrotoxicity: A randomized, double-blind, placebo-controlled trial

The flavonoid 6-hydroxyflavone prevention of cisplatin-induced nephrotoxicity.

In this study, the flavonoid, 6-hydroxyflavone was investigated for its renal protective activity in the cisplatin rat model of nephrotoxicity. Male Sprague-Dawley rats weighing 200-250 g were included in the study. 6-Hydroxyflavone was daily administered at 25 and 50 mg/kg (i.p.), while ascorbic acid was used as a positive control and injected (i.p.) at 50 mg/kg for 15 days. The nephrotoxicity was evoked with a single cisplatin injection at 7.5 mg/kg on the tenth day of treatment. The renal function and levels of oxidative stress markers were assessed. Each tissue slide of different groups was observed under a compound microscope attached with a digital camera. Cisplatin significantly decreased the overall body weight with an increase in serum creatinine and urea and production of severe histopathological and oxidative stress in the kidneys. The daily treatment with 6-hydroxyflavone significantly attenuated the cisplatin associated detrimental changes in the body weight, and serum levels of creatinine and urea at both 25 mg/kg (P<0.05) and 50 mg/kg (P<0.01). The 6-hydroxyflavone treatment also preserved the renal histoarchitecture from the toxicological influence of cisplatin as evident from a significant reduction in the severity of histopathological changes in the renal tissues. Moreover, 6-hydroxyflavone also reduced the cisplatin-induced lipid peroxidation and corrected the renal antioxidant status. A similar protective effect was observed with the positive control, ascorbic acid (50 mg/kg). These findings show that the flavonoid 6-hydroxyflavone has potential nephroprotective properties and can be used for the management of chemotherapy associated renal disturbances.

The Effect of Intravenous Mannitol Plus Saline on the Prevention of Cisplatin-induced Nephrotoxicity: A Randomized, Double-blind, Placebo Controlled Trial

The Effect of Intravenous Mannitol Plus Saline on the Prevention of Cisplatin-induced Nephrotoxicity: A Randomized, Double-blind, Placebo Controlled Trial

Efficacy of Antioxidant Supplements on Prevention and Amelioration of Cisplatin-Induced Nephrotoxicity: A Systematic Review and Meta-analysis of Randomized Controlled Trials

ContextCisplatin is a widely used antineoplastic agent in the treatment of a wide range of malignancies although it is associated with nephrotoxicity. Much clinical evidence supports the use of antioxidant supplements in the prevention of cisplatin-induced nephrotoxicity (CIN). However, conflicting evidence makes us unable to provide any robust results for antioxidants use against CIN.ObjectivesThe study aimed to investigate the efficacy of antioxidant supplements on CIN through a comprehensive meta-analysis of randomized controlled trials. Data Sources: A systematic literature search was conducted in PubMed, EMBASE, Cochrane Library, CPCI-S (Conference Proceedings Citation Index-Science), ICTRP (International Clinical Trials Registry Platform), and Google Scholar until February 2017 by two independent researchers. Various outcomes such as serum creatinine, estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), creatinine clearance, and incidence of CIN were assessed. All statistical analyses were performed using RevMan V.5.3ResultsOverall, 672 patients were identified from 10 studies of whom 330 (49.10%) patients received antioxidant treatment. Antioxidant treatment showed a significant reduction in serum creatinine (SMD: -3.40, 95% CI: -5.47 to -1.33, P = 0.001), BUN (SMD = -5.96, 95% CI: -10.07 to -1.86, P = 0.004), and eGFR (SMD = -3.77, 95% CI: -6.16 to -1.38; P = 0.002) when compared to the control group.ConclusionsAntioxidant treatment is associated with a reduced risk of CIN. It also has important clinical implications for CIN patients who are not responding to other therapies such as hydration, diuresis, or magnesium supplementation.

Urolithin A Mitigates Cisplatin-Induced Nephrotoxicity by Inhibiting Renal Inflammation and Apoptosis in an Experimental Rat Model.

Cumulative kidney toxicity associated with cisplatin is severe and there is no clear consensus on the therapeutic management of the same. The pathogenesis involves activation of inflammatory and apoptotic pathways; therefore, regulating these pathways offers protection. Given the anti-inflammatory and antioxidant effects of urolithin A, a gut microbial metabolite of ellagic acid, our aim was to explore the potential use of urolithin A in the prevention of cisplatin-induced nephrotoxicity in an experimental rat model. For this purpose, animals received a single intraperitoneal dose of cisplatin (5 mg/kg body weight). Six hours prior to cisplatin administration, rats were orally treated with either ellagic acid or urolithin A (50 mg/kg body weight), followed by a daily dose of these compounds during the next 5 days. At the end, plasma and kidneys were collected for analysis. Cisplatin-induced kidney damage was revealed by a significant rise in the plasma creatinine levels accompanied by significant morphologic changes in tubules, T cell Ig and mucin domain-containing protein-1, ionized calcium-binding adapter molecule 1, as well as a marked increase in the number of apoptotic cells localized in tubules. Cisplatin also reduced nitric oxide synthase 3 and nuclear factor kappa-light-chain-enhancer of activated B cells resulting in regulation of various inflammatory cytokines. Urolithin A effectively attenuated cisplatin-induced kidney damage and showed significantly greater effect than its precursor ellagic acid on preserving the normal kidney architecture by downregulating the proinflammatory cytokines. In summary, urolithin A mitigates cisplatin-induced nephrotoxicity in rats by modulation of the inflammatory cascade and inhibition of the proapoptotic pathway.

Should mannitol be reinstated in prevention of cisplatin-induced nephrotoxicity?

Should mannitol be reinstated in prevention of cisplatin-induced nephrotoxicity?

Potential of morin and hesperidin in the prevention of cisplatin-induced nephrotoxicity

Oxidative stress is one of the important mechanisms of cisplatin-induced nephrotoxicity. Therefore, this study was designed to explore the potential protective effects of morin and/or hesperidin on oxidative stress in cisplatin-induced nephrotoxicity. This study was performed on 42 Wistar rats. Rats were divided into seven groups: control, morin, hesperidin, cisplatin, cisplatin + morin, cisplatin + hesperidin, and cisplatin + morin + hesperidin. Morin and/or hesperidin were given for 10 consecutive days by oral gavage and on the 4th day a single dose of cisplatin (7 mg/kg) was injected intraperitoneally. After administrations, on the 11th day of the experiment the animals were killed, and malondialdehyde (MDA), nitric oxide (NOx), glutathione (GSH) levels and myeloperoxidase (MPO), catalase (CAT), superoxide dismutase (SOD) activity were measured. Cisplatin-treated rats showed increased levels of MDA, and decreased levels of NOx also activity of CAT. Morin and/or hesperidin pretreatment prevent oxidative stress in kidney tissue, while they increase the NOx level, CAT activity, and decrease MPO activity. In conclusion, morin + hesperidin pretreatment may have a significant potential for protection of cisplatin-induced nephrotoxicity.

Mannitol for the prevention of cisplatin-induced nephrotoxicity: A retrospective comparison of hydration plus mannitol versus hydration alone in inpatient and outpatient regimens at a large academic medical center

Background Cisplatin-induced nephrotoxicity is a dose limiting adverse effect that occurs in nearly one-third of patients. Mannitol administration has been used as a means to negate this toxicity. Data regarding the efficacy of mannitol use in this context are conflicting and limited. Objective The aim of this study is to evaluate the effect of mannitol on renal function and describe the incidence of cisplatin-induced nephrotoxicity. Methods This study is a quasi-experimental retrospective analysis approved by the Institutional Review Board of inpatient and outpatient adults receiving cisplatin doses ≥40 mg/m2. The primary outcome was mean change in serum creatinine from baseline. Secondary outcomes included incidences of various grades of nephrotoxicity. Results A total of 313 patients (95 treated with mannitol and 218 without) were evaluated. The average increase in serum creatinine (mg/dL) was lower in patients who received mannitol versus those who did not (0.30 vs. 0.47; 95% confidence interval for difference, 0.03 to 0.31; P = 0.02). Grade 2 or higher nephrotoxicity occurred less frequently in patients who received mannitol versus those who did not (8% vs. 17%; P = 0.04). Non-gynecologic regimens and those who received doses ≥70 mg/m2 of cisplatin had lower rates of grade 2 or higher nephrotoxicity with mannitol (6% vs. 23%; P = 0.001, and 7% vs. 22%; P = 0.03, respectively). Conclusion The use of mannitol reduces the incidence and severity of nephrotoxicity in patients treated with cisplatin. The results of the study suggest mannitol may be most effective when used with non-gynecologic regimens and with cisplatin doses ≥70 mg/m2.

12. Prevention of cisplatin-induced nephrotoxicity by dichloroacetate

Background There is a continuing need to improve the efficacy of anticancer agents and to reduce the toxicity associated with them. Recently, reversal of the glycolytic phenotype of cancer cells with novel agents such as DCA (dichloroacetate) has been recognised as an important new target for cancer therapy. DCA is currently being assessed as a novel chemotherapeutic in clinical trials. It is anticipated that DCA will be used in combination with other well-established chemotherapeutic drugs. It is therefore critically important to determine the effects of DCA on therapeutic efficacy, and off-target effects of existing frontline anti-cancer drugs. We have recently discovered that DCA induces glutamate cysteine ligase, the rate-limiting step in glutathione (GSH) synthesis, a major cellular antioxidant. We hypothesised that the ability of DCA to stimulate GSH-synthesising capacity could reduce cisplatin-induced nephrotoxicity, which is thought to be mediated in part by oxidative stress. Aims To determine whether DCA can attenuate cisplatin-induced nephrotoxicity, and to determine if DCA influences the anti-cancer properties of cisplatin. Methods 120 Balb/c mice were injected subcutaneously with the syngeneic 4T1 breast cancer cell line and then co-treated with DCA and cisplatin weekly for 1 month. Controls included treatment with cisplatin alone, DCA alone, or normal saline injections. Serum blood urea nitrogen (BUN) and creatinine were measured and kidney damage was assessed histologically. Tumour size was monitored throughout. Results and conclusions DCA prevented increases in serum creatinine, BUN, and renal proximal tubule apoptosis evident in cisplatin-only treated mice. The tumour size in mice in the co-treated group decreased at the same rate as the cisplatin-only treated mice. We have thus concluded that DCA largely prevents the development of cisplatin-induced nephrotoxicity, and does not attenuate its anti-cancer properties.

The protective effect of theophyline in cisplatin nephrotoxicity

Cisplatin is a potent and a major anti-neoplastic drug in the treatment of a broad spectrum of malignancies. However, its clinical use is limited by renal tubular dysfunction that occurs in a significant percent of patients. The aim of the present study was to evaluate the possible protective effect of theophyline in the prevention of cisplatin-induced nephrotoxicity. The trial design was prospective, randomized, double-blinded and placebo controlled. Chemotherapeutic patients who received cisplatin at a dosage of at least 50 mg/m 2 alone or in combination with other chemotherapy agent(s) were included in the study. There were a total of 76 patients who were randomly divided into two groups. In group 1 (n = 38), placebo was advised; in group 2 (n = 38), patients received 4 mg/kg aminophyline as an intravenous loading dose, followed by theophyline in a dose of 200 mg three times daily orally for four consecutive days. The placebo group had 22 males and 16 females and the theophyline group had 26 males and 12 females. The mean age was 51 ± 17.6 years and the mean dose of cisplatin was 86.71 ± 43.18 mg. The prevalence of cisplatin nephrotoxicity in groups 1 and 2 was 7.9 and 5.3%, respectively, and the difference was not significant (P = 1). In addition, there was no significant association of cisplatin nephrotoxicity with age (P = 0.1), gender (P = 0.64) and mean dose of cisplatin (P = 0.8). These results indicate that prophy-lactic application of aminophyline and theophyline does not have a protective effect against cisplatin nephrotoxicity.

Cyanidin reverses cisplatin-induced apoptosis in HK-2 proximal tubular cells through inhibition of ROS-mediated DNA damage and modulation of the ERK and AKT pathways

Cyanidin is an anthocyanin widely distributed in food diet with novel antioxidant activity. Herein, we investigated the protective effects of cyanidin on HK-2 proximal tubular cells against cisplatin-induced apoptosis and elucidated the underlying mechanisms. The results showed that cisplatin-induced apoptosis in HK-2 cells was significantly attenuated by cyanidin. The cleavage of caspases and PARP, activation of p53 and mitochondrial-mediated apoptosis pathways induced by cisplatin were effectively blocked by cyanidin. Moreover, cyanidin significantly suppressed the overproduction of ROS, and activation of ERK and AKT pathways triggered by cisplatin. Our results indicate that cyanidin exhibits therapeutic potential in prevention of cisplatin-induced nephrotoxicity.

Comparison between the Effect of Melatonin and Zinc sulfate in Prevention of cisplatin induced Nephrotoxicity in Rats

Cisplatin is an inorganic complex; the therapeutic effects of it are significantly improved by dose escalation. However high-dose therapy with cisplatin is limited by its cumulative nephrotoxicity and neurotoxicity. The aim of study was to compare between the effect of melatonin and zinc sulfate in prevention of cisplatin induced-nephrotoxicity in rats. Forty male albino rats weighing (200-250gm) were equally divided into four groups: normal group (0.2 ml isotonic saline group), control group "cisplatin group" (12 mg/kg cisplatin, single dose I.P.), melatonin group (15 mg/kg I.P.)prophylactically one day prior to cisplatin administration and continued for further 3 days, and zinc sulfate group (50 mg/ kg I.P.) prophylactically one day prior to cisplatin administration and continued for further 3 days.There was significant difference (p&lt;0.05) between zinc sulfate and melatonin in reducing serum creatinine and BUN (melatonin more effective in reducing these parameters), and there was no significant difference (p&gt;0.05) between them in reducing serum malondialdhyde (MDA) and increasing serum glutathione (GSH).As a conclusion, melatonin (15 mg/ kg I.P.) and zinc sulfate (50 mg/ kg I.P.) had protective effects against cisplatin- induced nephrotoxicity in rats. Melatoninwas found to be more effective than zinc sulfate in its ability to reverse the abnormal renal function and preventing histopathological changes

Prevention of Cisplatin-Induced Nephrotoxicity by Ethanolic Extract of Embelia ribes Fruits and ?-Tocopherol in Experimental Animals

Oxidative stress due to abnormal production of reactive oxygen species (ROS) is believed to be involved in the etiology of toxicity of many xenobiotics. Evidence suggests that in cisplatin-induced nephrotoxicity, ROS is involved. We studied the nephroprotective effects of ethanol extract of Embelia ribes fruits alone and in combination with vitamin E (?-tocopherol) in cisplatin (12mg/kg i.p)-induced nephrotoxicity in mice. The results of the study indicated that Embelia ribes fruits significantly and dose dependently protected the cisplatin-induced nephrotoxicity. The serum urea, creatinine and blood urea nitrogen levels in cisplatin alone treated groups were significantly elevated (P &lt; 0.01) with respect to control group. The serum urea, creatinine and blood urea nitrogen levels were reduced in the Embelia ribes fruits extract treated (200 and 400 mg/kg, p.o), vitamin E (200 mg/kg, p.o), and Embelia ribes fruits (200 mg/kg) with vitamin E (200 mg/kg, p.o) treated groups. The renal levels of reduced glutathione (GSH) were declined in cisplatin alone treated groups. The level of GSH was elevated significantly (P &lt; 0.01) in the Embelia ribes fruits (200 and 400 mg/kg) and Embelia ribes fruits (200 mg/kg) with vitamin E (200 mg/kg) treated groups. The results also demonstrated that combination of Embelia ribes fruits (200 mg/kg) with vitamin E (200 mg/kg) showed a better protection compared to their 200 mg/kg alone treated groups.

A comparison of the rates of cisplatin (cDDP) - induced nephrotoxicity associated with sodium loading or sodium loading with forced diuresis as a preventative measure

To determine whether forced diuresis and sodium loading or sodium loading alone is better at preventing cisplatin-induced nephrotoxicity. Records of 92 patients receiving cisplatin >40 mg/m(2) and sodium loading with or without mannitol were reviewed to determine the incidence of nephrotoxicity, average decline in creatinine clearance, degree of nephrotoxicity, time to resolution, rates of hospitalization, and electrolyte abnormalities among patients receiving sodium loading or sodium loading with forced diuresis. The mean cisplatin dose was 64.5 mg/m(2) with a majority of the subjects receiving treatment for lung cancer. The patients who received sodium loading experienced an average decline in creatinine clearance of 33.9 mL/min versus a decline of 38.9 mL/min in the group receiving forced diuresis and sodium loading (p = 0.09). Incidence of nephrotoxicity, rate of hospitalization and rates of hypokalemia or hypomagnesemia were similar between the groups. Time to resolution of nephrotoxicity was significantly different between the groups, although there were limitations in evaluating this outcome. Majority of the subjects in the sodium loading group experienced NCIC-TC Grade 0 nephrotoxicity, whereas half of the patients in the forced diuresis group experienced Grade 2 nephrotoxicity. We detected no difference in the prevention of cisplatin-induced nephrotoxicity when patients were treated with sodium loading alone or with sodium loading with mannitol. No differences were detected in average decrease in creatinine clearance, incidence of nephrotoxicity, or rates of hypomagnesemia and hypokalemia. The difference in time to resolution of toxicity appeared to be significant, however there were limitations in evaluating this outcome.

Prevention of cisplatin-induced nephrotoxicity by glucosides of ascorbic acid and α-tocopherol

Background Cisplatin is one of the most widely used cytotoxic therapeutic agents for the treatment of cancer. This drug, at effective higher doses, causes many physiological adverse effects such as nephrotoxicity and genotoxicity. The toxicity of the drug has been attributed to the induction of oxidative free radicals. Methods Following intraperitoneal administration of cisplatin and ascorbic acid monoglucoside (AsAG) or α-tocopherol monoglucoside (TMG), investigations were conducted on levels of serum urea and creatinine, peroxidation of lipids in renal tissues, renal antioxidants and histopathology of renal tissue. Results Administration of cisplatin to mice induced a marked renal failure, characterized by significant increase in serum urea and creatinine levels in addition to severe alterations in renal tissue architecture. Cisplatin also induced oxidative stress as indicated by increased lipid peroxidation and decreased levels of reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase in renal tissues. Administration of AsAG or TMG markedly reduced the cisplatin-induced higher plasma creatinine and urea levels and counteracted the deleterious effects of cisplatin on oxidative stress markers and protected the tissues from the cisplatin-induced lipid peroxidation. Conclusion These results indicated that AsAG or TMG has a protective effect against cisplatin-induced renal damage in mice. The protection is mediated by preventing the decline of antioxidant status. The results have implications in use of AsAG or TMG in human application for protecting against drug-induced nephrotoxicity.