Even though the establishment of cisplatin induced nephrotoxicity can be alleviated. The aim of this study was to determine whether the incidence of nephrotoxicity in patients with lung carcinoma is affected by the infusion rate of cisplatin rapid infusion of cisplatin in 1 hour compared to regular infusion in 3 hours. Cisplatininduced nephrotoxicity in porcine proximal. Nlrx1 accelerates cisplatininduced ototoxity in heioc1. Low single nephron glomerular filtration rates sngfr during early cisplatinuminduced acute renal failure is accompanied by reduced renal. Cinnamic acid attenuates cisplatininduced hepatotoxicity and nephrotoxicity amany a. Next, risk groups were constructed by combining categories of those.
Contribution of organic cation transporter 2 oct2 to cisplatin induced nephrotoxicity document type dissertation degree name doctor of philosophy phd program biomedical sciences track molecular therapeutics and cell signaling research advisor alex sparreboom, ph. To investigate the possible protective role of curcumin and. Combining cisplatin with cationized catalase decreases. One of the main therapeutic limitations of cisplatin cp is nephrotoxicity which is timedependent. Cisplatin is a major antineoplastic drug for the treatment of solid tumors, but it has dosedependent renal toxicity. We sought to determine the contributions of renal parenchymal cells and bone marrowderived immune cells to the pathogenesis of cisplatininduced renal injury in vivo. However, its clinical use is limited due to the severe side effects, including nephrotoxicity and acute kidney injury aki which develop due to renal accumulation and biotransformation of cddp. Consistent with this, development of apoptosis has been associated with cisplatininduced acute renal failure zhou et al. Cisplatininduced nephrotoxicity is mediated by mitogenactivated protein kinase mapk intracellular signaling pathways. However, side effects in normal tissues and organs, notably nephrotoxicity in the kidneys, limit the use of cisplatin and related platinumbased therapeutics. Abstract cisplatin is a cancer chemotherapeutic agent whose clinical use is complicated by its dose related kidney toxicity. The cisplatin concentration in proximal tubular epithelial cells is about 5 times the serum concentration. Polyuria and hypomagnesemia, which are commonly associated with cisplatin nephrotoxicity, may be due to defects in deep nephron or collecting duct fluid and solute transport.
Cisplatin has been used as a chemotherapeutic agent to treat many different cancers. Although recovery can occur after one episode of cisplatin induced aki, studies have indicated multiple episodes may lead to the. Risk analysis for cisplatin induced nephrotoxicity 3636 int j clin exp med 2016. Cisplatin is a nephrotoxic chemotherapeutic that causes acute kidney injury aki in 30% of patients. Cinnamic acid attenuates cisplatininduced hepatotoxicity.
In another study, the inhibition of enzymes apn, rdp, and cs lyase did not protect rats given 10 mgkg of cisplatin andor rats treated with 6 mgkg from cisplatin induced nephrotoxicity. Nadph oxidase 4 promotes cisplatininduced acute kidney. Cisplatin is the most widely used antineoplastic agent for most of the tumors like lung cancer, gastric cancers, ovarian cancer, penile cancer, cervical cancer and many other. Cisplatin is a strong cellular toxin and nephrotoxicity is one of the most important. Sixty male and female wistar rats were randomly divided into five groups. Cspm2 hydration protocol for cisplatin chemotherapy. Nigella sativa and cisplatin induced nephrotoxicity ajp, vol. Evidence for interventions to prevent nephrotoxicity. Nephrotoxicity has been identified as the most common and important side effect of cwddp treatment. We focus on the docetaxel, cisplatin, and 5fluorouracil regimen, which is called the tpf regimen, where the standard dose of cisplatin is 60 mgm2. Although cisplatininduced chronic kidney disease ckd in rodent has been reported, the role of.
The chief limit to its greater efficacy is its nephrotoxicity, which has made it necessary both to lower its dosage and actively hydrate. In this study, by conducting different omics data analyses, we demonstrated that cisplatin induces cell death in a proximal tubular cell line by suppressing glycolysis and tricarboxylic acid tcamitochondriarelated genes. Risk analysis for cisplatininduced nephrotoxicity 3636 int j clin exp med 2016. Original article risk analysis for cisplatininduced.
Evaluating dose of cisplatin responsible for causing. The nephrotoxic effect of cisplatin is cumulative and dosedependent and often necessitates dose reduction or withdrawal. Cisplatin has been used for over 40 years in various cancer chemotherapies. To determine the incidence and evaluate the risk factors of cisplatin induced nephrotoxicity. Numerous studies have demonstrated that several mechanisms, including oxidative stress, dna damage, and inflammatory res ponses, are closely associated with cisplatin induced nephrotoxicity. The use of cisplatin in the treatment of lung carcinoma is limited by nephrotoxicity. In the current study, proapoptotic proteins annexin v, bax, and gadd153 were mildly induced in 7day cisplatintreated kidneys table 2, consistent.
Pdf role of curcumin in prevention of cisplatininduced. Cisplatin is a strong cellular toxin and nephrotoxicity is one of the most important complication of this drug in clinical. Low single nephron glomerular filtration rates sngfr during early cisplatinum induced acute renal failure is accompanied by reduced renal. We focus on the docetaxel, cisplatin, and 5fluorouracil regimen, which is. Pdf on jan 1, 2012, dalia abd alkader and others published role of curcumin in prevention of cisplatin induced nephrotoxicity in rat find, read and cite all the research you need on researchgate. Inform patients that cisplatin injection can cause nephrotoxicity and that renal function and electrolyte monitoring during treatment is necessary. Arecent study showed that hydration with saline alone or. Recent studies have improved our understanding of the molecular mechanisms of cisplatin induced nephrotoxicity and ototoxicity. Hydration in conjunction with appropriate diuresis can decrease the incidence of nephrotoxicity. Cisplatin mediates its tumorcidal effects via a number of different cytotoxic mechanisms.
Nephrotoxicity is the doselimiting toxicity of cisplatin. Myelomalike cast nephropathy mlcn has been reported in the literature to occur in various primary renal and nonrenal diseases. May use concomitant amifostine to decrease nephrotoxicity. Nephrotoxicity is the most wellknown and clinically important toxicity. Univariate analysis revealed that cardiac disease and use of nonsteroidal antiinflammatory drugs nsaids were associated with cisplatininduced nephrotoxicity odds ratios or 6 and 3. Patients at highest risk of drug induced nephrotoxicity are those with one or more of the following. Recent progress in the pathophysiology of acute renal failure. Amelioration of cisplatininduced nephrotoxicity in rats. The aim of this study was to identify the risk factors for cin in patients with advanced lung cancer, both nsclc and sclc. Mar, 2017 nlrx1 accelerates cisplatin induced ototoxity in heioc1 cells via promoting generation of ros and activation of jnk signaling pathway. Cisplatin is a chemotherapeutic agent that induces tumor necrosis factor. Pdf prediction of druginduced nephrotoxicity and injury.
Amelioration of cisplatininduced nephrotoxicity in rats by. They regulate cell proliferation, differentiation, and survival. Cisplatincisdichlorodiammineplatinumplatinum coordination complex is an effective chemotherapy against a wide spectrum of tumors such as testicular, head and neck, ovarian, lung, cervical, and bladder cancers. Assessment of cisplatininduced nephrotoxicity by microarray. Caspase1deficient mice are protected against cisplatin induced apoptosis and acute tubular necrosis. If indicated, inform patients about the use of electrolyte supplements see warnings and precautions 5. Dipeptidylpeptidase4 dpp4 inhibitors are well known to improve glucose intolerance by augmentation of endogenous glucagon like peptide glp1 and glucosedependent insulinotropic peptide gip. Prediction of drug induced nephrotoxicity and injury mechanisms with human induced pluripotent stem cellderived cells and machine learning methods article pdf available in scientific reports 5. The features of cisplatininduced peripheral neuropathy were described extensively in the editorial entitled cisplalin neurotoxicity jan. Cisplatin injection infusion concentrate is a clear, colorless, sterile aqueous solution available in amber vials. Nephrotoxicity is the main side effect of cisplatin. Nephrotoxicity evaluation on cisplatin combined with 5ht3.
Although it is best known for dna damage, cisplatin also causes cytoplasmic organelle dysfunction. Protective effect of magnesium preloading on cisplatin. Nephrotoxicity due to a aminoglycosides b cyclophosphamide c cisplatin d. The nephrotoxicity of cisplatin was evaluated in this study using llcpk 1 cells, fetal proximal tubule epithelial cells ptec, and adult ptecs. Although efficacy is limited by cisplatin induced nephrotoxicity cin, little is known about the risk factors for this complication. Cisplatininduced nephrotoxicity results in severe nephropathy involving acute renal failure with histological changes of the renal tubular cells. Cisplatininduced nephrotoxicity was studied in porcine proximal tubular cells, focusing on the relationship between mitochondrial damage, reactive oxygen species ros and cell death. Cisplatininduced nephrotoxicity and the protective effect. Cisplatin nephrotoxicity as a model of chronic kidney disease.
Assessing cisplatininduced nephrotoxicity using both. To do this we created chimeric mice in which the bone marrow was. Pdf mechanisms of cisplatin nephrotoxicity researchgate. Although recovery can occur after one episode of cisplatin induced aki, studies have indicated multiple episodes may lead to the development of chronic kidney disease ckd, an irreversible disease with no current treatments. The protective effect of nigella sativa against cisplatin. Evaluating dose of cisplatin responsible for causing nephrotoxicity.
Mechanism of cisplatininduced cytotoxicity is correlated. Time course of cisplatininduced nephrotoxicity and. It remains an important and effective therapy in many. In this study, we analyzed the effects of three 5ht 3 receptor antagonists i. Each 50 ml or 100 ml amber vial of infusion concentrate contains. Developing a more clinicallyrelevant mouse model of. Risk factors associated with cisplatininduced nephrotoxicity. Combining cisplatin with cationized catalase decreases nephrotoxicity while. Cisplatininduced kidney dysfunction and perspectives on. Cisplatin nephrotoxicity can present in a number of ways including hypomagnesaemia, increased serum creatinine and urea. An integrated view of cisplatininduced nephrotoxicity and.
The disproportionate accumulation of cisplatin in kidney tissue contributes to cisplatin induced nephrotoxicity. All the animals in groups 25 received single dose of cp 10 mgkg. Impairment of renal function has been shown to be a clinical problem in 2535 % of patients treated with cisplatin 5. This article aims to identify best practices in supportive. Cisplatininduced nephrotoxicity is mediated by tumor necrosis factoralpha produced by renal parenchymal cells. Cellular mechanisms of activity, drug resistance and induced side effects. The alleviation or prevention of cddpcaused nephrotoxicity is. Cisplatininduced nephrotoxicity and targets of nephroprotection. Developing a more clinicallyrelevant mouse model of cisplatin nephrotoxicity cierra n.
Human organic cation transporter 2 oct2 and multidrug and toxin extrusion proteins mates work in concert in the elimination of cationic drugs such as cisplatin from the kidney. Klastersky, md renal failure in cancer patients is a common problem in oncology. Evidence for nephrotoxicity prevention with cisplatin. Cisplatin is used as a chemotherapy agent against aggressive cancers. Nephrotoxicity due to a aminoglycosides b cyclophosphamide c cisplatin d radiocontrast e analgesic f amphotericin g crystal. Cisplatin specifically affected mitochondrial functions. Pharmacokinetics of cisplatin and relation to nephrotoxicity. While toxicities include ototoxicity, gastrotoxicity, myelosuppression, and allergic reactions 1,2, the main doselimiting side effect of cisplatin is. Organic cation transporter 2 mediates cisplatin induced oto and nephrotoxicity and. Since carboplatin cbdca, a platinum drug showing less nephrotoxicity than cisplatin, has been developed, it has often replaced cisplatin treatment as the frst line chemotherapy for ovarian cancer. Cisplatininduced aki was observed in 18 patients 21. It remains an important and effective therapy in many forms of cancer today. Mar 31, 2015 evaluation seminar on molecular mechanisms of drug induced nephrotoxicity.
Studies involving furosemide diuresis used to decrease cisplatin induced nephrotoxicity show conflicting results. Cisplatin nephrotoxicity american journal of kidney diseases. Cisplatininduced nephrotoxicity is mediated by tumor. Mesenchymal stem cells therapy in cisplatininduced. Cisplatin cpinduced nephrotoxicity is widely accepted as a model for acute kidney injury aki. Pathophysiology of cisplatininduced acute kidney injury. Nephrotoxicity of cisplatin combination chemotherapy in. Data regarding the efficacy of mannitol use in this context are conflicting and limited. Various regimens have been developed to treat cancer based on the type and severity of the tumor. Cisplatin dosing, indications, interactions, adverse effects. The purpose of this study is to compare the incidence and severity of nephrotoxicity in patients receiving cisplatin with saline hydration vs.
Mannitol to prevent cisplatininduced nephrotoxicity in. Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity f. The protective effects of maltol on cisplatininduced nephrotoxicity. Cisplatin induced nephrotoxicity an assessment based on. Organic cation transporter 2 mediates cisplatininduced oto and nephrotoxicity and. But, cisplatin is very useful in combination with etoposide for the second line chemotherapy. Cisplatin cisdiamminedichloroplatinumii, cddp is an antineoplastic drug used in the treatment of many solidorgan cancers, including those of the head, neck, lung, testis, ovary, and breast. Although the risk factors for cin have been extensively investigated and many factors have been reported,1215. Nephrotoxicity is a wellknown side effect of cisplatin for cancer treatment. Contribution of organic cation transporter 2 oct2 to. Even though the establishment of cisplatininduced nephrotoxicity can be alleviated. Cisplatin induced nephrotoxicity is characterized by renal proximal tubular cell dysfunction.
A histological, ultrastructural and biochemical study in adult albino rats yassa, hanan dawood, gergis, safwat wadie, abdel raheem, hassan on. Cisplatin based regimens have been associated with a wide range of cardiovascular complications. Cisplatin induced nephrotoxicity is mediated by tumor necrosis factoralpha produced by renal parenchymal cells. The nephrotoxicity limits the clinical application of cisplatin. We present a series of three rare cases of cast nephropathy, two of which are hiv patients, and the third patient is receiving cisplatin. The cellular pathways of cisplatin injury to kidney cells have been examined primarily in vitro using freshly isolated or cultured renal tubular epithelial cells. Cisplatin is a potent chemotherapeutic agent, however, its nephrotoxicity manifested by acute kidney injury aki often limits applicability. Cisplatin is one of the most widelyused drugs to treat cancers. It is clear now that during cisplatin nephrotoxicity, the quiescent renal cells enter cell cycle as shown by pcna proliferating cell nuclear antigen staining and brdu incorporation in nucleus. A wellknown side effect of cisplatin is nephrotoxicity, which is the primary doselimiting toxicity. Cisdichlorodiammine platinum ii, or cisplatin, has emerged as a principal chemotherapeutic agent in the treatment of otherwise resistant solid tumors and is currently among the most widely used agents in the chemotherapy of cancer. Cisplatin cisdiamminedichloroplatinum ii is an antineoplastic agent drug, which is used in the treatment of a broad spectrum of malignancies including head and neck, esophagus, bladder, and metastatic testis, ovarian, breast and nonsmall cell lung cancer 1,2. While cisplatin remains as an effective therapeutic for treating cancer, the kidneys remain a primary target for damage.
Since the histopathological profile of cisplatin nephrotoxicity appears similar to that of other heavy metals, it has been commonly presumed that cisplatin nephrotoxicity is related to the platinum moiety. Cisplatin is one of the most widely used and most potent chemotherapy drugs. Recent research has shed significant new lights on the mechanism of cisplatin nephrotoxicity, especially on the signaling pathways leading to tubular cell death. Usage of cisplatin was limited due to its nephrotoxicity during longduration medication and also high dosage causes side effects like nausea, vomiting, etc. Myeloma cast nephropathy is an obstructing disorder of renal tubules, caused by precipitation of bence jones proteins. Molecular mechanisms of cisplatininduced nephrotoxicity.
Cisplatin is a highly effective and frequently used drug in the chemotherapy of solid tumours in children, but only limited data are available on the pharmacokinetics of cisplatin and its associated nephrotoxicity in paediatric patients. Despite these approaches, cisplatininduced nephrotoxicity cin still occurs. Dichloroacetate prevents cisplatininduced nephrotoxicity. Cisplatininduced nephrotoxicity is a dose limiting adverse effect that occurs in nearly onethird of patients. Numerous studies have demonstrated that several mechanisms, including oxidative stress, dna damage, and inflammatory res ponses, are closely associated with cisplatininduced nephrotoxicity. Mannitol administration has been used as a means to negate this toxicity. However, its nephrotoxic and ototoxic sideeffects remain major clinical limitations. The purpose of this study was to determine the optimal timing for initiation of cp toxicity. Pdf cisplatin is a widely used and highly effective cancer chemotherapeutic. Sharp april 25, 2016 cisplatin is a nephrotoxic chemotherapeutic that causes acute kidney injury aki in 30% of patients.
Prevention of cisplatininduced nephrotoxicity with dichloroacetate. However another study showed that hydration with saline and mannitol reduces nephrotoxicity. Assessment of nephrotoxicity associated with combined. The standard mouse model of cisplatin induced aki consists of one. Cisplatin cisdiamminedichloroplatinum ii, cddp is one of the most effective chemotherapeutic agents. Hydration in conjunction with appropriate diuresis can decrease the incidence of.
Mesenchymal stem cells therapy in cisplatininduced nephrotoxicity. Pdf cisplatininduced nephrotoxicity and targets of. Assessment of nephrotoxicity associated with combined cisplatin and mitomycin c usage in laparoscopic hyperthermic intraperitoneal chemotherapy ravish kapoor a, kristen ashlee robinson b, juan pablo cata c, pascal owusuagyemang c, jose miguel soliz c. This study reveals that nox4 is significantly induced in cisplatin treated tubular epithelial cells and in a mouse model of acute kidney injury. Thus, bun values were determined to evaluate the renal toxicity in. Toxicity induced by cisplatin based therapeutic regimens include gastrointestinal toxicity, myelotoxicity, neurotoxicity, ototoxicity and nephrotoxicity. Studies involving furosemide diuresis used to decrease cisplatin. Nephrotoxicity induced by cancer chemotherapy with special. Nephrotoxicity was reported in the initial clinical trials of cisplatin chemotherapy. The role of ctr1 in cisplatin nephrotoxicity in vivo has not been examined. Furthermore, analysis of the urine from cisplatintreated rats revealed the lower.
There are several case reports of adverse cardiac effects of cisplatin due to hydro electrolytic imbalances depleted mg levels owing to nephrotoxicity5. Cisplatin and other platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors. The chemotherapeutic use of cisplatin is limited by its severe side effects. Effects of dpp4 inhibitor on cisplatin induced acute. Oct 26, 2010 the mechanisms of cisplatin induced nephrotoxicity are complex and involve multiple pathways and molecules figure 1 92,93. Cisplatin nephrotoxicity nephrotoxicity was reported in the initial clinical trials of cisplatin chemotherapy. Cisplatin induced apoptosis and atn are reduced in caspase1deficient mice. We present a series of three rare cases of cast nephropathy, two of which are hiv patients, and the third patient is receiving cisplatin based. A known complication of cisplatin administration is acute kidney injury aki. Cisplatin is a platinum containing drug first approved as an antineoplastic agent in 1978. Mar 15, 2016 however, cisplatin can have severe side effectsin particular, cisplatininduced nephrotoxicity, which is dose dependent and is the major side effect that limits the acceptable dose of cisplatin.
Ondansetron can enhance cisplatininduced nephrotoxicity. The mapk pathways are a series of parallel cascades of serinethreonine kinases that are activated by diverse extracellular physical and chemical stresses. Modulation of both cisplatin nephrotoxicity and drug. It has many similarities to human cisplatin nephrotoxicity, which are.
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