Cisplatin-induced Nephrotoxicity Research Articles

Sinapic acid alleviates cisplatin-induced acute kidney injury by mitigating oxidative stress and apoptosis.

Cisplatin is an anticancer agent with many side effects such as nephrotoxicity, as well as being widely used in the treatment of many tumor types. Sinapic acid has antioxidant, anti-inflammatory, antihyperglycemic, and antiapoptotic effects. This study aimed to investigate the possible beneficial effects of sinapic acid against cisplatin-induced nephrotoxicity. Twenty-eight Wistar albino male rats were used. The groups are as follows: control, cisplatin, cisplatin + sinapic acid, and sinapic acid groups (n = 7). The control group received 1ml of single-dose intraperitoneal saline on the first day of the study. The cisplatin group was given a single dose of 7mg/kg cisplatin intraperitoneal. Animals in the cisplatin + sinapic acid group were given sinapic acid for 7days 25mg/kg, 3days after oral gavage administration of 7mg/kg cisplatin intraperitoneal. The sinapic acid group was given 25mg/kg/day of sinapic acid by oral gavage for 7days after the 3rd day of the study. The kidney of the rats was examined by stereological, immunohistochemical, histopathological, and biochemical methods. According to the stereological findings of the study, while the volume of the glomerulus cortex and filtration gap increased, the volume of the medulla decreased, and there was no significant difference in tubular volume in the CP group compared to the control group. The volume of the glomerulus, cortex, and filtration gap of the cisplatin + sinapic acid group was significantly reduced compared to the cisplatin group (p˂0.05). Histopathologically, it was observed the enlargement of the filtration gap, tubular dilatation, atrophy, renal fibrosis, deterioration of the microvilli, and necrosis in the tubular epithelial cells in the cisplatin group. In the cisplatin + sinapic acid group, these pathologies decreased compared to the cisplatin group. Compared to the control group, caspase-3 expression, urea, creatine, and malondialdehyde increased, while Bcl-2 and catalase decreased in the cisplatin group. However, caspase-3 expression, urea, creatine, and malondialdehyde were decreased, while Bcl-2 and catalase increased in the cisplatin + sinapic acid group compared to the cisplatin group. The results of our study showed that sinapic acid reduced the nephrotoxicity induced by cisplatin.

Mechanistic Approach for Protective Effect of ARA290, a Specific Ligand for the Erythropoietin/CD131 Heteroreceptor, against Cisplatin-Induced Nephrotoxicity, the Involvement of Apoptosis and Inflammation Pathways.

ARA 290, an 11-amino acid linear nonhematopoietic peptide derived from the three-dimensional structure of helix B of the erythropoietin (EPO), interacts selectively with the innate repair receptor (IRR) that arbitrates tissue protection. The aim of this study was to investigate the protective effects of ARA290 against cisplatin-induced nephrotoxicity. For this purpose, HEK-293 and ACHN cells were treated with ARA290 (50-400nM) and cisplatin (2.5μM) in pretreatment condition. Then, cytotoxicity, genotoxicity, oxidative stress parameters (ROS, GPx, SOD, and MDA), and inflammatory markers (TNFα, IL6, and IL1β) were evaluated. Furthermore, apoptotic cell death was assessed via caspase-3 activity and tunnel assay. To determine the molecular mechanisms of the possible nephroprotective effects of ARA290, gene and protein expressions of TNFα, IL1β, IL6, Caspase-3, Bax, and Bcl2 were evaluated by real-time PCR and western blot assay, respectively. The findings indicated that ARA290 significantly reduced the DNA damage parameters of comet assay and the frequency of micronuclei induced by cisplatin. Besides, ARA290 improved cisplatin-inducedoxidative stressby reducing MDA/ROS levels and enhancing antioxidant enzyme levels. In addition, reduced levels of pro-inflammatory cytokines indicated that cisplatin-induced renal inflammation was mitigated upon the treatment with ARA290.Besides, ARA290ameliorates cisplatin-inducedcellinjury by antagonizingapoptosis. Furthermore, the molecular findings indicated that gene and protein levels of TNFα, IL1β, IL6, Caspase-3, and Bax were significantly decreased and gene and protein levels of Bcl2 significantly increased in the ARA290 plus cisplatin group compared with the cisplatin group. These findings revealed that ARA290 as a potent chemo-preventive agent exerted a protective effect on cisplatin-induced nephrotoxicity mostly through its anti-apoptotic, anti-inflammatory, and antioxidant potentials and also suggested that ARA290 might be a new therapeutic approach for patients with acute kidney injury.

The Cannabinoid-2 receptor agonist, 1-phenylisatin, protects against cisplatin-induced nephrotoxicity in mice

AimThe present study investigated the potential protective effect of a selective Cannabinoid-2 (CB2) receptor agonist, 1-phenylisatin, in acute nephrotoxicity induced by cisplatin. Materials and methodsAnimals were arranged into 5 groups. Group I; normal saline, group II; 1-phenylisatin for 7 days, group III: received a single injection of cisplatin (20 mg/kg, i.p.) on day 5, group IV: 1-phenylisatin for 7 days and cisplatin on day 5 and group V: AM630, CB2 antagonist, 15 min before 1-phenylisatin for 7 days and a single injection of cisplatin on day 5. Mice were sacrificed 72 h after cisplatin injection. Kidneys were isolated for histopathological and biochemical analyses. Nephrotoxicity parameters including serum creatinine and urea were assessed as well as histopathological examination was done. Also, Oxidative stress markers; MDA and GSH, inflammatory markers; TNF-α, NF-κB (p65), MCP-1, MIP-2, and ICAM-1, along with apoptotic markers, Bax, Bcl2, and caspase-3 were studied. Further, CB2 receptor expression was investigated. Key findingsCisplatin injection increased serum creatinine and urea levels, and increased lipid peroxidation, decreased glutathione level and increased the renal expression of pro-inflammatory markers, TNF-α, NF-κB, MCP-1, MIP-2, and ICAM-1, along with increased apoptotic markers and significantly reduced the expression of the anti-apoptotic Bcl2. Pretreatment with 1-phenylisatin significantly counteracted these effects. The CB2 receptor antagonist; AM630, increased the renal expression of caspase-3 and Bax whereas Bcl2 expression decreased. Significance1-Phenylisatin protected against cisplatin-induced nephrotoxicity owing to its anti-apoptotic, anti-inflammatory, and antioxidant effects. These actions were mostly mediated through CB2 receptor.

MicroRNAs Involved in Intrinsic Apoptotic Pathway during Cisplatin-Induced Nephrotoxicity: Potential Use of Natural Products against DDP-Induced Apoptosis.

Cisplatin (cis-diamminedichloroplatinum (II), DDP) is an antineoplastic agent widely used in the treatment of solid tumors because of its extensive cytotoxic activity. However, the main limiting side effect of DDP use is nephrotoxicity, a rapid deterioration in kidney function due to toxic chemicals. Several studies have shown that epigenetic processes are involved in DDP-induced nephrotoxicity. Noncoding RNAs (ncRNAs), a class of epigenetic processes, are molecules that regulate gene expression under physiological and pathological conditions. MicroRNAs (miRNAs) are the most characterized class of ncRNAs and are engaged in many cellular processes. In this review, we describe how different miRNAs regulate some pathways leading to cell death by apoptosis, specifically the intrinsic apoptosis pathway. Accordingly, many classes of natural products have been tested for their ability to prevent DDP-induced apoptosis. The study of epigenetic regulation for underlying cell death is still being studied, which will allow new strategies for the diagnosis and therapy of this unwanted disease, which is presented as a side effect of antineoplastic treatment.

Metabolic Profiling of Jasminum grandiflorum L. Flowers and Protective Role against Cisplatin-Induced Nephrotoxicity: Network Pharmacology and In Vivo Validation.

Cisplatin (CP) is a powerful chemotherapeutic agent; however, its therapeutic use is restricted due to its nephrotoxicity. In this work, we profiled the phytoconstituents of Jasminum grandiflorum flower extract (JGF) using LC-MS/MS and explored the possible molecular mechanisms against acute renal failure through pharmacological network analysis. Furthermore, the possible molecular mechanisms of JGF against acute renal failure were verified in an in vivo nephrotoxicity model caused by cisplatin. LC-MS analysis furnished 26 secondary metabolites. Altogether, there were 112 total hit targets for the identified metabolites, among which 55 were potential consensus targets related to nephrotoxicity based on the network pharmacology approach. Upon narrowing the scope to acute renal failure, using the DisGeNET database, only 30 potential targets were determined. The computational pathway analysis illustrated that JGF might inhibit renal failure through PI3K-Akt, MAPK signaling pathway, and EGFR tyrosine kinase inhibitor resistance. This study was confirmed by in vivo experiment in which kidneys were collected for histopathology and gene expression of mitogen-activated protein kinase 4 (MKK4), MKK7, I-CAM 1, IL-6, and TNF receptor-associated factor 2 (TRAF2). The animal-administered cisplatin exhibited a substantial rise in the expression levels of the MMK4, MKK7, I CAM 1, and TRFA2 genes compared to the control group. To summarize, J. grandiflorum could be a potential source for new reno-protective agents. Further experiments are needed to confirm the obtained activities and determine the therapeutic dose and time.

Preventive effects of garlic powder on cisplatin-induced nephrotoxicity in male wister rats

Cisplatin is cancer chemotherapeutic agent that used in treatment of many types of solid cancers. However, cisplatin administration showed adverse effects including multi-organs toxicity including nephrotoxicity. Garlic is an anti-carcinogenic, antioxidant, anti-diabetic, Reno protective, anti-atherosclerotic, antibacterial, antifungal, and antihypertensive agent. Therefore, present study was conducted to investigate preventive effect of garlic powder on Cisplatin induced nephrotoxicity in male Wister rats. Twenty-one male Wister rats were assigned into three groups namely, C (as control negative group), CP (control positive) received two i.p injection of cisplatin at dose of 8 mg/kg and G-CP received two i.p injection of cisplatin at dose of 8 mg/kg and fed with 10% garlic powder diet. Serum samples were collected and kidney function parameters including creatinine, urea and uric acid levels were measured using colorimetric kits for these parameters. creatinine results showed a significant increasing in CP group rats compared with G-CP group. Urea results showed a significant increasing in CP group rats compared with G-CP group. Also, uric acid results showed a significant increasing in CP group rats compared with G-CP group. In conclusion, rats that fed with 10% garlic powder diet reduced nephrotoxicity that induced by Cisplatin.

Rosinidin Protects against Cisplatin-Induced Nephrotoxicity via Subsiding Proinflammatory and Oxidative Stress Biomarkers in Rats.

Background: Rosinidin is a flavonoid anthocyanin pigmentation found in shrub flowers such as Catharanthus roseus and Primula rosea. The molecular docking studies predicted that rosinidin has adequate structural competency, making it a viable medicinal candidate for the treatment of a wide range of disorders. The current study intends to assess rosinidin nephroprotective efficacy against nephrotoxicity induced by cisplatin in rats. Materials and Methods: Oral acute toxicity tests of rosinidin were conducted to assess potential toxicity in animals, and it was shown to be safe. The nephroprotective effect of rosinidin 10, and 20 mg/kg were tested in rats for 25 days with concurrent administration of cisplatin. Several biochemical parameters were measured to support enzymatic and non-enzymatic oxidative stress such as superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH). Likewise, changes in several non-protein-nitrogenous components and blood chemistry parameters were made to support the theory linked with the pathogenesis of chemical-induced nephrotoxicity. Results: Cisplatin caused significant changes in biochemical, enzymatic, and blood chemistry, which rosinidin efficiently controlled. Conclusions: The present investigation linked rosinidin with nephroprotective efficacy in experimental models.

Assessment of cisplatin-induced nephrotoxicity and its associated factors among cervical cancer patients in the leading tertiary hospital in Kenya.

Cisplatin is the widely used antineoplastic agent in managing cervical cancer despite nephrotoxicity being a major concern. In addition, there was a paucity of data about the degree of nephrotoxicity due to cisplatin in the study setting. Therefore, this study aimed to investigate the prevalence of cisplatin nephrotoxicity among cervical patients. A retrospective cross-sectional study was conducted at the Cancer Treatment Centre of Kenyatta National Hospital among 100 cervical cancer patients treated with a cisplatin regimen. Simple random sampling was employed to the recruit medical record of patients. This study used a data abstraction tool to extract the patients' relevant socio-demographic and clinical characteristics. The data were analysed using Statistical Package for Social Sciences version 25.0 software. Frequency tables and figures were used to present the findings of the study. Binary logistic regression analysis was used to determine factors associated with cisplatin nephrotoxicity. The study showed a mean age of 52.09 ± 10.44 years. The prevalence rate of cisplatin-induced nephrotoxicity in cervical cancer patients was 45%. Of these patients, 36% and 9% patients had grade 1 and 2 nephrotoxicities, respectively. Comorbidities (crude odd's ratio (COR) = 3.05, 95% confidence interval [CI] = 1.3-7.02, p = 0.011), hypertension (COR = 3.0, 95% CI = 1.1-7.8, p = 0.03), and more than three cycles of cisplatin treatment (adjusted odd's ratio = 4.5, 95% CI = 1.19-17.0, p = 0.027) were significant factors of nephrotoxicity. The prevalence of cisplatin-induced nephrotoxicity among cervical cancer patients was high in the study setting. Comorbidities, number of cycles and types of comorbidities were significant factors associated with cisplatin nephrotoxicity.

Concomitant palonosetron ameliorates cisplatin-induced nephrotoxicity, nausea, and vomiting: a retrospective cohort study and pharmacovigilance analysis

BackgroundCisplatin (CDDP)-induced nephrotoxicity is the most important complication of CDDP treatment. 5-Hydroxytryptamine type 3 receptor antagonists (5-HT3RAs) are widely used to prevent chemotherapy-induced nausea and vomiting (CINV). However, in patients with the triple antiemetic (neurokinin-1 receptor antagonist, 5-HT3RA, and dexamethasone) therapy, the advantage of palonosetron in comparison with other 5-HT3RAs on CDDP-induced nephrotoxicity and CINV remains unclear. In the present study, we investigated the effect of palonosetron on CDDP-induced nephrotoxicity and CINV in patients with the triple antiemetic therapy by a retrospective cohort study and a pharmacovigilance analysis.MethodsWe retrospectively analyzed the effect of 5-HT3RAs on the development of nephrotoxicity and CINV in 110 patients who received CDDP, fluorouracil, and triple antiemetic therapy for the treatment of esophageal cancer. Moreover, the effect of 5-HT3RAs on CDDP-induced nephrotoxicity was validated in patients with the triple antiemetic therapy using the Japanese Adverse Drug Event Report (JADER) database.ResultsIn a retrospective study, the incidence of nephrotoxicity (≥ grade 1) in patients receiving palonosetron (18%) was significantly lower than that in patients receiving ramosetron (another 5-HT3RA) (36%, p = 0.044). Moreover, severe nephrotoxicity ≥ grade 3 was observed in one patient treated with ramosetron, whereas hematological toxicity was comparable between the two groups (p = 0.553). Furthermore, the incidence rate of CINV within 120 h following CDDP administration in patients treated with palonosetron (18%) was significantly lower than that in patients receiving ramosetron (39%, p = 0.026). JADER database analyses revealed that the reporting odds ratio of palonosetron for CDDP-induced acute kidney injury was 0.282 (95% confidence interval: 0.169–0.472).ConclusionsThe findings of the present study suggested a greater potential of palonosetron against CDDP-induced nephrotoxicity and CINV than other 5-HT3RAs in patients with the triple antiemetic therapy.

Nephroprotective effect of polyphenol-rich extract of Costus spicatus in cisplatin-induced nephrotoxicity in Wistar albino rats.

The online version contains supplementary material available at 10.1007/s13205-022-03233-z.

Loss of sphingosine kinase 2 protects against cisplatin-induced kidney injury.

Cisplatin is an established chemotherapeutic drug for treatment of solid-organ cancers and is the primary drug used in the treatment of head and neck cancer; however, cisplatin-induced nephrotoxicity largely limits its clinical use. Inhibition of sphingosine kinase 2 (SphK2) has been demonstrated to alleviate various kidney diseases. Therefore, we hypothesized that inhibition of SphK2 could also protect against cisplatin-induced nephrotoxicity. Results from the present study showed that the SphK2 inhibitor ABC294640 or knockdown of SphK2 by siRNA blocked the cisplatin-induced increase of cellular injury markers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and cleaved caspase-3) by Western blot analysis in HK-2 cells, a human renal tubular cell line. In addition, SphK2 inhibition blocked cisplatin-induced activation of NF-κB by Western blot analysis and immunostaining analysis. Furthermore, SphK2 inhibition suppressed cisplatin-induced increases of proinflammatory markers (NLR family pyrin domain containing 3, interleukin-1β, and interleukin-6). Genetic deletion of the SphK2 gene in mice further confirmed that inhibition of SphK2 protected against cisplatin-induced kidney damage in vivo. Compared with wild-type mice, SphK2 knockout mice exhibited less renal dysfunction and reduced promotion of kidney injury markers, inflammatory factors, tubular morphology damage, and fibrotic staining. At the same time, the SphK2 inhibitor ABC294640 failed to interfere with the activity of cisplatin or radiation in two cell culture models of head and neck cancer. It is concluded that inhibition of Sphk2 protects against cisplatin-induced kidney injury. SphK2 may be used as a potential therapeutic target for the prevention or treatment of cisplatin-induced kidney injury.NEW & NOTEWORTHY The present study provides new findings that sphingosine kinase 2 (SphK2) is highly expressed in renal tubules, cisplatin treatment increases the expression of SphK2 in proximal tubular cells and kidneys, and inhibition of SphK2 alleviates cisplatin-induced kidney injury by suppressing the activation of NF-κB, production of inflammatory factors, and apoptosis. SphK2 may serve as a potential therapeutic target for the prevention or treatment of cisplatin-induced nephrotoxicity.

Renoprotective Effect of Pediococcus acidilactici GKA4 on Cisplatin-Induced Acute Kidney Injury by Mitigating Inflammation and Oxidative Stress and Regulating the MAPK, AMPK/SIRT1/NF-κB, and PI3K/AKT Pathways.

Acute kidney injury (AKI) describes a sudden loss of kidney function and is associated with a high mortality. Pediococcus acidilactici is a potent producer of bacteriocin and inhibits the growth of pathogens during fermentation and food storage; it has been used in the food industry for many years. In this study, the potential of P. acidilactici GKA4 (GKA4) to ameliorate AKI was investigated using a cisplatin-induced animal model. First, mice were given oral GKA4 for ten days and intraperitoneally injected with cisplatin on the seventh day to create an AKI mode. GKA4 attenuated renal histopathological alterations, serum biomarkers, the levels of inflammatory mediators, and lipid oxidation in cisplatin-induced nephrotoxicity. Moreover, GKA4 significantly decreased the expression of inflammation-related proteins and mitogen-activated protein kinase (MAPK) in kidney tissues. Eventually, GKA4 also increased the levels of related antioxidant enzymes and pathways. Consistently, sirtuin 1 (SIRT1) upregulated the level of autophagy-related proteins (LC3B, p62, and Beclin1). Further studies are needed to check our results and advance our knowledge of the mechanism whereby PI3K inhibition (wortmannin) reverses the effect of GKA4 on cisplatin-treated AKI. Taken together, GKA4 provides a therapeutic target with promising clinical potential after cisplatin treatment by reducing oxidative stress and inflammation via the MAPK, AMP-activated protein kinase (AMPK)/SIRT1/nuclear factor kappa B (NF-κB), and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) axes.

Alleviation of cisplatin-induced hepatotoxicity and nephrotoxicity by L-carnitine.

Objective(s):To assess the protective effect of L-carnitine in reducing cisplatin toxicity via estimating biochemical tests, histomorphometric, and immunohistochemistry (IHC) of β-catenin and cyclin D.Materials and Methods: Fifteen adult male rabbits were used in this study and allocated into 3 groups; Group 1 (Control negative), rabbits of this group were not given any treatment. In group 2, the animals were injected with cisplatin single-dose/per week. Group 3 rabbits were treated with Cisplatin+L-carnitine orally by gavage tube for 29 days. At the end of the experiments, blood samples from all rabbits were taken from the earlobe, and then the biochemical test was done, the kidney and tissue sections were prepared for both H& E and IHC for both β-catenin and cyclin D genes.Results:Treatment with L-carnitine reduced the injury effect of cisplatin via a decline in serum creatinine, urea, bilirubin, GPT, GOP, and ALP significantly (P<0.05). Also, administration of LC attenuates the histopathologic abnormality in the kidney (15.71% vs 85.18%) and liver (score 3 vs 15 ) induced by cisplatin. L-carnitine elevates the expression of β-catenin and cyclin D in renal and hepatic parenchyma by diffuse, moderate-strong positivity vs cisplatin that showed local-weak staining.Conclusion:These findings imply that L-carnitine, by its pleiotropic actions in activating Wnt signaling, alleviates cisplatin-induced renal and hepatic destruction. It might be a method of preventing cisplatin-related nephrotoxicity and hepatotoxicity.

O2-2 The effect of mannitol versus intravenous diuretics in preventing cisplatin-induced nephrotoxicity: A meta-analysis

Cisplatin is one of the most widely used chemotherapeutic agents in the treatment of a majority of malignancies. However, it is associated with nephrotoxicity despite adequate hydration prior to cisplatin administration. We aimed to determine the efficacy and safety of diuretics versus mannitol in preventing cisplatin-induced nephrotoxicity among adult patients with cancer receiving cisplatin chemotherapy.

High-throughput "read-on-ski" automated imaging and label-free detection system for toxicity screening of compounds using personalised human kidney organoids.

Organoid models are used to study kidney physiology, such as the assessment of nephrotoxicity and underlying disease processes. Personalized human pluripotent stem cell-derived kidney organoids are ideal models for compound toxicity studies, but there is a need to accelerate basic and translational research in the field. Here, we developed an automated continuous imaging setup with the "read-on-ski" law of control to maximize temporal resolution with minimum culture plate vibration. High-accuracy performance was achieved: organoid screening and imaging were performed at a spatial resolution of 1.1 μm for the entire multi-well plate under 3 min. We used the in-house developed multi-well spinning device and cisplatin-induced nephrotoxicity model to evaluate the toxicity in kidney organoids using this system. The acquired images were processed via machine learning-based classification and segmentation algorithms, and the toxicity in kidney organoids was determined with 95% accuracy. The results obtained by the automated "read-on-ski" imaging device, combined with label-free and non-invasive algorithms for detection, were verified using conventional biological procedures. Taking advantage of the close-to-in vivo-kidney organoid model, this new development opens the door for further application of scaled-up screening using organoids in basic research and drug discovery.

The evaluation of urinary calprotectin levels for prediction of acute cisplatin-induced nephrotoxicity.

Calprotectin is a protein molecule that is released from inflammatory cells. Measurement of calprotectin in various body fluids has recently gained significant importance for differentiating inflammatory and noninflammatory events. The subject has aroused interest in the field of nephrology and some renal pathologies in which urinary calprotectin levels have been studied. In this study, the measurement of urinary calprotectin level and its use for determining acute cisplatin nephrotoxicity in a group of patients with non-small cell lung cancer who received cisplatin-based oncological treatments have been investigated.The study included 41 patients who received cisplatin-based treatments for non-small cell lung cancer between January 2019 and January 2020. The patients were excluded from this study who were with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, serum creatinine (sCr) >1.5 mg/dL, a history of urinary tract infection, and nephrotoxic drug use in the past month. Baseline and 48-hour sCr values and baseline, 6-hour, 12-hour, 24-hour, and 48-hour urinary calprotectin levels of all patients were measured.Four of the 41 patients who received cisplatin treatment were excluded because their 48-hour sCr values could not be accessed. The control group included 29 patients. While there was no difference between the cisplatin group and the control group in terms of baseline sCr and eGFR values, the cisplatin group had significantly higher urinary calprotectin values. Of the 37 patients treated with cisplatin, 7 (18.9%) developed cisplatin-induced nephrotoxicity. The comparison of groups with (group 1) and without cisplatin nephrotoxicity (group 2) showed comparable mean age and male sex ratio. Baseline sCr and eGFR values were similar in both groups. The cisplatin-induced nephrotoxicity group had significantly higher 48-hour sCr and significantly lower 48-hour eGFR values. Baseline, 12-hour, 24-hour, and 48-hour urinary calprotectin levels were similar in groups with and without cisplatin nephrotoxicity.Recent studies have demonstrated that urinary calprotectin level measurement can be used to distinguish intrinsic acute kidney disease from prerenal kidney disease. However, the comparison of groups with and without cisplatin nephrotoxicity in our study showed no difference in urinary calprotectin levels. However, there is a need for large-scale studies using combined urinary biomarkers.

Antioxidant Properties of Protein Extracted from the Brown Seaweed (Sargassum ilicifolium) against Cisplatin-induced Nephrotoxicity in Rats

Antioxidant Properties of Protein Extracted from the Brown Seaweed (Sargassum ilicifolium) against Cisplatin-induced Nephrotoxicity in Rats

Pro-Inflammatory Signalling PRRopels Cisplatin-Induced Toxicity.

Cisplatin is a platinum-based chemotherapeutic that has long since been effective against a variety of solid-cancers, substantially improving the five-year survival rates for cancer patients. Its use has also historically been limited by its adverse drug reactions, or cisplatin-induced toxicities (CITs). Of these reactions, cisplatin-induced nephrotoxicity (CIN), cisplatin-induced peripheral neuropathy (CIPN), and cisplatin-induced ototoxicity (CIO) are the three most common of several CITs recognised thus far. While the anti-cancer activity of cisplatin is well understood, the mechanisms driving its toxicities have only begun to be defined. Most of the literature pertains to damage caused by oxidative stress that occurs downstream of cisplatin treatment, but recent evidence suggests that the instigator of CIT development is inflammation. Cisplatin has been shown to induce pro-inflammatory signalling in CIN, CIPN, and CIO, all of which are associated with persisting markers of inflammation, particularly from the innate immune system. This review covered the hallmarks of inflammation common and distinct between different CITs, the role of innate immune components in development of CITs, as well as current treatments targeting pro-inflammatory signalling pathways to conserve the use of cisplatin in chemotherapy and improve long-term health outcomes of cancer patients.

Costus spiralis extract restores kidney function in cisplatin-induced nephrotoxicity model: Ethnopharmacological use, chemical and toxicological investigation

Ethnopharmacological relevanceCostus spiralis (Jacq.). Roscoe (Costaceae) is traditionally used in Brazil for the treatment of kidney diseases such as pyelonephritis, urethra inflammation, kidney stones, and inflammatory conditions. There are reports of its use by Brazilian Indians since the 17th century when it was known as “pacocatinga.” Currently, the use of the Costus species in Brazil is widespread, which was evidenced by the inclusion of the genus in the Brazilian National List of Medicinal Plants of Interest to the Unified Health System (RENISUS). Aim of the studyThis study aimed to confirm the ethnopharmacological use of Costus spiralis in the treatment of kidney diseases, toxicity study using animal models, and the phytochemistry of the species. Materials and methodsThe chemical profile of Costus spiralis leaves extract (CSLE) was obtained for the hydroethanolic extract by ultra-performance liquid chromatography coupled to a mass spectrometer and ultraviolet detector with diode array (UPLC-UV/DAD-ESI-MS). The acute oral toxicity of the extract was predicted using the neutral red uptake cytotoxicity assay. Wistar rats were used in a model in vivo for confirmation of acute oral toxicity (2000 mg/kg p.o. for 14 days.) and determination of the effect on a cisplatin-induced nephrotoxicity model. ResultsThe analysis by UPLC-UV/DAD-ESI-MS showed that the chemical composition of the extract is mostly di-glycosylated flavones of apigenin. In the extract were identified the flavones vicenin II and schaftoside. The quantification of total flavonoids by spectrometry showed 0.880%. CSLE proved to be safe for acute oral administration (2000 mg/kg) with an IC50 value of 222.9 μg/mL and predicted oral toxic dose of 523.82 μg/mL in a neutral red uptake cytotoxicity assay. The absence of death allows the classification of the extract in class 5 according to OECD 423 guidelines and therefore it can be considered as a high acute safety product, which is highly relevant, considering the wide popular use of the species. In the cisplatin-induced nephrotoxicity model, C. spiralis extract (5, 15, and 30 mg/kg) significantly improved renal function, reversing almost completely the effects on plasma creatinine levels and creatinine clearance (p < 0.001). ConclusionsThis study demonstrates that oral administration of Costus spiralis extract leaves is safe and effective in restoring the renal function in rats in a cisplatin-induced nephrotoxicity. It is suggested that the observed activity is related to the flavonoids present. This hypothesis should be confirmed, and the participation of other secondary metabolites should be investigated in the future.

Cisplatin-induced nephrotoxicity in childhood cancer: comparison between two countries.

Various definitions used to describe cisplatin nephrotoxicity potentially lead to differences in determination of risk factors. This study evaluated incidence of kidney injury according to commonly used and alternative definitions in two cohorts of children who received cisplatin. This retrospective cohort study included children from Vancouver, Canada (one center), and Mexico City, Mexico (two centers), treated with cisplatin for a variety of solid tumors. Serum creatinine-based definitions (KDIGO and Pediatric RIFLE (pRIFLE)), electrolyte abnormalities consisted of hypokalemia, hypophosphatemia and hypomagnesemia (based on NCI-CTCAE v5), and an alternative definition (Alt-AKI) were used to describe nephrotoxicity. Incidence with different definitions, definitional overlap, and inter-definition reliability was analyzed. In total, 173 children (100 from Vancouver, 73 from Mexico) were included. In the combined cohort, Alt-AKI criteria detected more patients with cisplatin nephrotoxicity compared to pRIFLE and KDIGO criteria (82.7 vs. 63.6 vs. 44.5%, respectively). Nephrotoxicity and all electrolyte abnormalities were significantly more common in Vancouver cohort than in Mexico City cohort except when using KDIGO definition. The most common electrolyte abnormalities were hypomagnesemia (88.9%, Vancouver) and hypophosphatemia (24.2%, Mexico City). The KDIGO definition provided highest overlap of cases in Vancouver (100%), Mexico (98.6%), and the combined cohort (99.4%). Moderate overall agreement was found among Alt-AKI, KDIGO, and pRIFLE definitions (κ = 0.18, 95% CI 0.1-0.27) in which KDIGO and pRIFLE showed moderate agreement (κ = 0.48, 95% CI 0.36-0.60). Compared to pRIFLE and KDIGO criteria, Alt-AKI criteria detected more patients with cisplatin nephrotoxicity. pRIFLE is more sensitive to detect not only actual kidney injury but also patients at risk of cisplatin nephrotoxicity, while KDIGO seems more useful to detect clinically significant kidney injury. A higher resolution version of the Graphical abstract is available as Supplementary information.