Cisplatin-induced Renal Toxicity Research Articles

The Role of Toll-Like Receptor 4 in Cisplatin-Induced Renal Injury

Background Toll-like receptors recognize pattern-associated molecules found in pathogens as well as in endogen cells and in matrix degradation products. Despite the effectiveness of cisplatin against various solid tumors the administered dose is limited by its nephrotoxicity, namely, induction of tubular cell apoptosis. Herein, we investigated whether the cell toxicity of cisplatin was mediated by toll-like receptor 4 signaling. Methods C3H/He J (Toll-like receptor 4 deficient) and C3H/HePas (control) were treated with cisplatin (20 mg/kg). We evaluated renal function as well as expression of (HO-1) heme oxygenase 1 and MCP-1 mRNAs. Results Animals deficient in Toll-like receptor 4 showed less renal dysfunction after cisplatin therapy, which was more evident at later time points. Moreover, MCP-1 mRNA expression in kidneys from these animals were lower than controls, mainly at 96 hours after treatment. No differences were seen in HO-1 mRNA expression. Conclusions These results suggested that cisplatin-induced renal toxicity is mediated in part though toll-like receptor 4.

Cisplatin Nephrotoxicity and Protection by Milk Thistle Extract in Rats

The protective effect of methanolic extract of milk thistle seeds and silymarin against cisplatin-induced renal toxicity in male rats after a single intraperitoneal injection of 3 mg kg−1 cisplatin were studied. Over 5 days, cisplatin-treated rats showed tubular necrosis and elevation in blood urea nitrogen (BUN) and serum creatinine (Scr). Pretreatment of animals with silymarin (50 mg kg−1) or extract (0.6 g kg−1) 2 h before cisplatin prevented the tubular damage. Rats treated with silymarin or extract 2 h after cisplatin had BUN and Scr significantly lower than those receiving cisplatin, but mild to moderate necrosis was observed. These results suggested that milk thistle may protect against cisplatin-induced renal toxicity and might serve as a novel combination agent with cisplatin to limit renal injury.

Low urine osmolarity as a determinant of cisplatin-induced nephrotoxicity.

Cisplatin is widely used in the treatment of human tumors, but it is a nephrotoxic drug. Early pragmatic clinical trials have shown that cisplatin-induced renal toxicity is greatly reduced through the use of high hydration, a large NaCl supply and mannitol infusion, but the precise mechanisms of these nephroprotective measures are not fully understood. We show here an increase in the cisplatin uptake and cytotoxicity on 56/10 A1 human glomerular and HK-2 human tubular cells when the drug incubation was performed in a hypotonic phosphate-buffered saline solution or in human urine ("drag in" transport hypothesis). When 4 mg/kg cisplatin was intraperitoneally injected in rats in 20 ml of a hypotonic 4 g/l NaCl solution, the platinum accumulation increased in both the cortex and papilla but not in the subcutaneously grafted colon tumors when compared to rats injected with cisplatin in normal or hyperosmotic solutions (9 and 14 g/l NaCl, respectively). The urea and creatinine blood levels were significantly increased, and more apoptotic cells were detected by the caspase-3 cleavage and TUNEL assays in the tubular cells of rats treated with cisplatin in a hypotonic solution compared to animals that received normal or hypertonic solutions. Osmolarity was sometimes low in urine from patients receiving an intravenous hydration for a cisplatin treatment or from healthy volunteers who were given an oral hydration with a 50 g/l glucose solution. Our results show that low urine osmolarity could be a major determinant in the increase of cisplatin-induced nephrotoxicity and justify the widely used concurrent infusion of osmotically active substances during intravenous hydration.

Metallothionein as an Adaptive Protein Prevents Diabetes and its Toxicity

Metallothioneins (MTs) are a group of intracellular metal-binding and cysteine-enriched proteins and are highly inducible in many tissues in response to various types of stress. Although it mainly acts as a regulator of metal homeostasis such as zinc and copper in tissues, MT also acts as a potent antioxidant and adaptive (or stress) protein to protect cells and tissues from oxidative stress. Diabetes affects many Americans and other populations, and its development and toxic effect on various organs have been attributed to increased oxidative stress. Studies showed that zinc-induced or genetically enhanced pancreatic MT synthesis prevented diabetes induced by chemicals such as streptozotocin and alloxan, and zinc pretreatment also prevented spontaneously developed diabetes. Since diabetic complications are the consequences of organ damage caused by diabetic hyperglycemia and hyperlipidemia through oxidative stress, whether MT in nonpancreatic organs also provides a preventive effect on diabetic toxicity has been recently investigated. We demonstrated that overexpression of cardiac MT significantly prevented diabetes-induced cardiomyopathy. Likewise, overexpression of renal MT also prevented diabetes-induced renal toxicity. In addition, we also found that MT as an adaptive protein is overexpressed in several organs in response to diabetes. Therefore, the biological importance of diabetes-induced MT in diabetic complications and subsequent other pathogenesis was further explored. We found that diabetes-induced hepatic and renal MT synthesis was accompanied by a significant prevention of endotoxin-induced hepatic toxicity and cisplatin-induced renal toxicity. These studies suggest that MT as an adaptive protein can prevent both diabetes development and its complications or subsequent suffered other pathogenic injury.

Assessment of the Protective Effects of Amifostine against Cisplatin-Induced Toxicity

The goals of this study were to determine whether the toxicity of cisplatin, a chemotherapeutic alkylating agent, could be reduced by the use of amifostine and to determine whether amifostine alone could cause ototoxicity. Prospective, animal study. Auditory brainstem response click threshold, latencies, and blood work were used to measure ototoxicity, nephrotoxicity, and myelotoxicity before and 4 weeks after treatment. Groups of guinea pigs received either cisplatin alone (30 mg/kg), amifostine (1000 mg/kg), cisplatin plus amifostine (1000 mg/kg), or no agent. Amifostine reduced the hearing loss caused by cisplatin for many animals. Amifostine partially protected against cisplatin-induced ototoxicity and renal toxicity. We did not find evidence for myelotoxicity owing to cisplatin in this sample. Amifostine may have a role in reducing toxicity or permitting larger doses of cisplatin to be given, but toxicity can still be significant even with protection.

Protection by a radical scavenger edaravone against cisplatin-induced nephrotoxicity in rats

Acute renal failure is a dose-limiting factor of cisplatin chemotherapy. Here, we show the protective effect of edaravone, a recently developed radical scavenger for clinical use, against cisplatin-induced renal dysfunction in rats. A marked increase in blood urea nitrogen and creatinine in serum, and histological changes including vacuolation, necrosis and protein casts were observed in proximal renal tubules at the fourth day after cisplatin injection (5–10 mg/kg). Repeated injection of edaravone (1–10 mg/kg, i.v. twice a day for 3 days) reversed the cisplatin-induced elevation of blood urea nitrogen and creatinine, and morphological changes in a dose-dependent manner. In particular, the protective effect of edaravone was almost complete at 10 mg/kg. Moreover, the compound was still fully effective, when it was administered only at the second day after cisplatin injection. On the other hand, the glutathione content in renal tissues lowered at the fourth day after cisplatin injection, which was reversed by the late treatment with edaravone. These findings suggest that the clinically available radical scavenger edaravone is potentially useful for the prevention of cisplatin-induced renal toxicity.

N-ACETYLCYSTEINE AS SALVAGE THERAPY IN CISPLATIN NEPHROTOXICITY

N-acetylcysteine (NAC) repletes intracellular stores of reduced glutathione and may be a scavenger of oxygen free radicals. We report a 52-year-old female who developed acute renal insufficiency after administration of one dose of 150 mg of cisplatin for treatment of squamous cell cancer of the esophagus. Her blood urea nitrogen and creatinine rose from 12 and 0.7 mg/dL, respectively, to 24 and 1.8 mg/dL on day 5 after cisplatin. On that day the patient was begun on NAC, starting with a loading dose of 140-mg/kg-body weight followed by 70 mg/kg every 4 h for 4 days. Two days after starting NAC her renal function began to improve, and although she failed to complete a full course of the drug, by day 10 her serum creatinine had fallen to 0.8 mg/dL. A previous report showed that N-acetylcysteine might reverse cisplatin-induced renal toxicity. Our case supports this hypothesis.

Amifostine: an update on its clinical status as a cytoprotectant in patients with cancer receiving chemotherapy or radiotherapy and its potential therapeutic application in myelodysplastic syndrome.

Amifostine (WR-2721) is a cytoprotective agent that protects a broad range of normal tissues from the toxic effects of chemotherapy and radiotherapy without attenuating tumour response. This selective protection is due to the greater conversion and uptake of the active metabolite, WR- 1065, in normal versus neoplastic tissues. In a pivotal phase III trial, 242 patients with advanced ovarian cancer were randomised to receive treatment with cisplatin 100 mg/m2 and cyclophosphamide 1000 mg/m2 every 3 weeks with or without pretreatment with intravenous amifostine 910 mg/m2. Over 6 cycles of therapy, amifostine significantly reduced haematological, renal and neurological toxicities: treatment delays, treatment discontinuation and days in hospital related to these adverse events were also significantly reduced in patients receiving amifostine versus patients receiving chemotherapy alone. In another randomised phase III trial in 303 patients with head and neck cancer undergoing irradiation therapy (total dose 50 to 70Gy), pretreatment with intravenous amifostine 200 mg/m2 significantly reduced the incidence of acute and late grade > or =2 xerostomia. However, mucositis was not significantly reduced in amifostine recipients compared with patients receiving radiotherapy alone, although this has been shown in smaller randomised trials. Amifostine (340 mg/m2) also provided significant protection against pneumonitis and oesophagitis in patients with lung cancer receiving thoracic irradiation in a preliminary report from a phase III trial (n = 144). Other studies have demonstrated protective effects of amifostine in other tumour types and other chemotherapy, radiation and radiochemotherapy regimens; however, evidence is still limited in these indications. No evidence of tumour protection by amifostine has been demonstrated in any clinical trials. Amifostine has also been shown to stimulate haematopoietic stem cells and has been investigated as a therapy for patients with myelodysplastic syndrome in number of small preliminary studies. At the recommended dose and schedule, amifostine is generally well tolerated. Adverse effects are usually reversible and manageable and those most frequently experienced include nausea and vomiting, transient hypotension and somnolence and sneezing. The results of phase III trials have confirmed the safety and efficacy of amifostine as a cytoprotectant to ameliorate cisplatin-induced cumulative renal toxicity, for which it is the only agent proven to be effective, and neutropenia in patients with advanced ovarian cancer, and to reduce xerostomia in patients with head and neck cancer receiving irradiation therapy. Depending on the outcome of numerous ongoing clinical trials, amifostine may eventually find broader clinical applications, both as a cytoprotectant and as a potential therapy in myelodysplastic syndrome.

Role of NK1 receptors on cisplatin-induced nephrotoxicity in the rat.

The role of NK1 receptors on the nephrotoxicity associated with cisplatin treatment was evaluated. Adult Sprague-Dawley male rats (300-400 g) were treated with saline (0.1 ml/100 g, i.p., every 8 h for 72 h) or the selective NK1 receptor antagonist (GR205171; 2 mg/kg, i.p., every 8 h for 72 h). Treatments were started 5 min before cisplatin (7.5 mg/kg, i.p., single dose). All evaluations were made from 72 h to 96 h after cisplatin. An oral load of 10 ml/kg of water was given at time 0 (72 h after cisplatin). Cisplatin reduced the urinary volume (-45%), creatinine clearance (>90%), lithium clearance (-76%) and urinary potassium excretion (-54%). Protein and sodium excretion was not affected by cisplatin. GR205171 prevented the reduction in urine volume induced by cisplatin. In addition, the decreases in creatinine and lithium clearances induced by cisplatin were also attenuated by the NK1 receptor antagonist. The clearance of creatinine averaged 0.57+/-0.2 ml/min in controls, 0.004+/-0.01 ml/min after cisplatin, and 0.09+/-0.02 ml/min after cisplatin + GR205171. The lithium clearance was 0.09+/-0.04 ml/min in controls, 0.02+/-0.01 ml/min after cisplatin and 0.06+/-0.01 ml/min after cisplatin + GR205171. Cisplatin induced marked necrosis, vacuolation and edema of proximal renal tubules; these changes were considerably reduced in GR205171-treated animals. These results indicate that treatment with a selective NK1 receptor antagonist ameliorated cisplatin-induced renal toxicity in rats, as evidenced by improvements in renal function and histology.

Protective effects of cystone, a polyherbal ayurvedic preparation, on cisplatin-induced renal toxicity in rats

Cystone, a polyherbal ayurvedic preparation, was found to protect rats partially but significantly against cisplatin-induced renal toxicity, when given intraperitonially 1 h before cisplatin. At 500 and 1000 μg/ml, it also inhibited lipid peroxidation induced by cisplatin in renal cortical slices by 62.7 and 71.6%, respectively. The rats pretreated with cystone (1000 mg/kg i.p.) had significantly lower blood urea nitrogen (BUN) and serum creatinine (33.8 and 0.92 mg/dl, respectively) compared to cisplatin alone (51.5 and 1.41 mg/dl, respectively). The control animals had 17.1 and 0.63 mg/dl, respectively. The cystone treated animals lost 5.63 g body weight compared to 12.5 g for cisplatin alone treated animals on day 5. Renal functions like urine to serum creatinine ratio and creatinine clearance showed significant improvement when cystone was given 1 h before cisplatin. However, cystone did not protect increased excretion of urinary protein and decreased WBC count caused by cisplatin. The present study suggests that the cystone protects kidney against cisplatin-induced toxicity and the protection may be mediated through its ability to inhibit lipid peroxidation.

Experimental study of the protective effect of glutathione against cisplatin-induced nephrotoxicity

Glutathione (GSH) is the most important intracellular thiol-compound which participates in the detoxification mechanisms of the cell. Its high affinity to react with platinum complexes would give rise to lower or non-toxic metabolites and prevent cisplatin nephrotoxicity. In order to determine if GSH can protect against cisplatin-induced renal toxicity, 120 female Wistar rats received LD-100 or LD-50 of cisplatin with or without GSH, at two different dose levels and by two different routes. Biochemical and histological changes as survival was observed in each group. The administration of GSH did not modify cisplatin LD-100. When cisplatin LD-50 was used, a significant improvement in the survival rate was observed in the group which received GSH as chemoprotector (100% vs 40%). The average values of urea and creatinine were significantly lower in the group treated with GSH (115 vs 370 mg/dl and 1.07 vs 4.02 mg/dl respectively). The degree of the tissue injury was also lower in the GSH group. The administration of GSH prior to cisplatin reduces its nephrotoxicity in this animal model. Further clinical trials are necessary to verify this protective effect when cisplatin is used as a cyclic administration and at different dose levels.

Effect of low-dose prophylactic dopamine on high-dose cisplatin-induced electrolyte wasting, ototoxicity, and epidermal growth factor excretion: a randomized, placebo-controlled, double-blind trial.

To evaluate the protective effect of low-dose dopamine given as continuous infusion in patients who undergo chemotherapy with the nephrotoxin cisplatin. Forty-two patients who received high-dose cisplatin-containing chemotherapy entered a prospective, randomized, double-blind, placebo-controlled trial. Twenty-one patients received dopamine, and 21 received placebo. Patients were to receive either infusional dopamine 2 micrograms/kg/min over 48 hours or placebo. Cisplatin 125 mg/m2 was administered 12 hours after initiating dopamine (group D) or placebo (group P). This schedule was repeated twice, 1 week apart. Measurements of serum creatinine, urinary electrolytes and creatinine, urinary excretion of epidermal growth factor (EGF), ototoxicity, parameters of hematopoietic recovery, and duration of hospitalization were analyzed. We observed an increase in serum creatinine level to a peak of 1.9 mg/dL (range, 0.8 to 7.8) in the dopamine group, in comparison to 1.4 mg/dL (range, 0.9 to 3.3) in the placebo group (P = .04). Urinary magnesium excretion increased and EGF excretion decreased in both groups. Urinary sodium, chloride, and potassium excretion were increased in both groups, but more so in the placebo group. Dopamine had no measurable effect on hearing loss, duration of hospitalization, or hematopoietic recovery. The use of prophylactic dopamine increased peak serum creatinine levels relative to placebo and failed to prevent cisplatin-induced renal toxicity or ototoxicity. Determination of whether dopamine could reverse chemotherapy-induced renal damage would require a randomized prospective trial.

Role of mitochondria in cisplatin-induced oxidative damage exhibited by rat renal cortical slices

The role of mitochondria with regard to cisplatin-induced renal toxicity has been examined in vitro. The mitochondria were prepared from rat renal cortical slices which had been exposed to cisplatin. Incubation of the kidney slices with 2 mM cisplatin for various periods depleted glutathione (GSH) and increased thiobarbituric acid reactive substances (TBARS) in a time-dependent manner, a change which indicates lipid peroxidation in the mitochondria. The content of GSH was significantly depleted within 15 min of incubation, while TBARS formation was increased after 60 min of incubation. Marked depletion (30%) of GSH and increased TBARS formation (2-fold) were observed after 60 min and 120 min of incubation, respectively. Furthermore, cisplatin also depleted GSH and induced TBARS formation in the mitochondria in a concentration-dependent fashion. Cisplatin (0.5 mM) depleted GSH, but did not increase the production of TBARS. In addition, the fluorescence intensity of 8-anilino-1-naphthalenesulphonic acid (ANS)-bound to mitochondrial membranes was decreased after 120 min of incubation with 2 mM cisplatin. Several parameters were measured as indicators of damage to mitochondria and cellular integrity and they showed that cytotoxicity occurred subsequent to both GSH depletion and TBARS formation. Cisplatin-induced depletion of GSH is an early event and a determinant step in oxidative stress to mitochondria in the kidney cortex and may lead to irreversible cell injury.

シスプラチンによる腎障害に対するプロスタグランディンの有効性

シスプラチンによる腎障害に対するプロスタグランディンの有効性

Protective effect of reduced glutathione against cisplatin-induced renal and systemic toxicity and its influence on the therapeutic activity of the antitumor drug

Reduced glutathione has been shown to be an effective protector against cisplatin-induced nephrotoxicity of potential clinical value, since it does not reduce antitumor activity of the cytotoxic drug. This paper extends previous observations on the protective potential of reduced glutathione against cisplatin-induced nephrotoxicity, in different rodent models. Following i.v. administration, glutathione protection against cisplatin-induced nephrotoxicity was found to be critically dependent on timing of thiol administration. Whereas the sulfhydryl compound provided almost complete protection in CD rats, the protective effect against toxic renal damage was only partial in mice of different strains. In spite of the modest protection against kidney toxicity, glutathione reduced lethal toxicity in the mouse. Under the same experimental conditions at protective dose levels, the tripeptide thiol did not interfere with the antitumor effectiveness of cisplatin, in any of the tumor models examined. The kidney content of non-protein sulphydryls of CD rats produced by the effective dose of glutathione was markedly higher than that found in the mouse treated with the same dose. This finding is consistent with a differential protection provided by glutathione against cisplatin-induced renal toxicity in these species.

Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity.

Renal failure in cancer patients is a common problem in oncology; this complication is frequently multifactorial in origin. Several antineoplastic agents are potentially nephrotoxic; previous renal impairment as well as combinations with other nephrotoxic drugs may increase the risk of nephrotoxicity during administration of chemotherapy. Methotrexate-related renal damage most frequently occurs with high-dose therapy and can be avoided by forced alkaline diuresis and administration of folinic acid. Renal dysfunction secondary to semustine (CH3-CCNU) is clearly related to cumulative doses in excess to 1,200 mg/m2; the onset may be delayed and renal failure progress despite drug discontinuation. Streptozotocin is also nephrotoxic and may cause proteinuria and renal tubular acidosis; progressive renal failure can be predicted by a close monitoring of proteinuria and prevented by drug discontinuance. Mitomycin-associated renal failure frequently presents with signs of microangiopathic hemolytic anemia; renal failure is usually delayed but occasionally, it may be rapidly progressive despite drug discontinuance. Cisplatin nephrotoxicity is clearly dose-related and used to be considered dose limiting. Renal insufficiency can be prevented by hydration and forced diuresis; in addition, hyperhydration with mannitol-induced saline diuresis may allow administration of high doses and thus circumvent the dose-limiting effect of cisplatin-induced renal toxicity. Cisplatin-induced renal magnesium wasting occurs frequently and should be supplemented. Other approaches to reduce cisplatin nephrotoxicity are currently under investigation and are discussed.

Renal and hepatic concentrations of platinum: relationship to cisplatin time, dose, and nephrotoxicity.

Autopsy tissues were obtained from 30 patients who had received cisplatin antemortem; the tissues were assayed for platinum by flameless atomic absorption spectrometry. Patients with antemortem evidence of renal toxicity had higher renal cortical platinum concentrations than did patients without evidence of kidney damage. In addition, patients with nephrotoxicity were more likely than patients without toxicity to have renal cortical platinum concentrations that were higher than renal medullary platinum concentrations. Overall, the two variables most closely associated with an increase in serum creatinine with treatment were renal cortical platinum concentration (P less than .02) and cumulative dose of cisplatin (P less than .05). These two variables were important independently of one another. Renal cortex platinum concentrations correlated inversely with time from last treatment until death, whereas hepatic platinum concentrations did not. In contrast, hepatic platinum concentrations correlated with dose of cisplatin while renal platinum concentrations did not. Our results suggest the following: (1) cisplatin-induced renal toxicity is tissue-platinum-concentration dependent and cisplatin-dose dependent; and (2) cisplatin may be handled differently at the molecular level in liver and kidney.

The effects of dimercaptosuccinic acid and other chelating agents on the retention of platinum in the rat kidney after treatment with cisplatin

The ability of three chelating agents, dimercaptopropanesulphonate (DMPS), dimercaptosuccinic acid (DMSA), and diethylenetriaminepentaacetic acid (DPTA), to reduce the retention of platinum in the kidneys was tested in male Sprague-Dawley rats treated 24 h previously with Cisplatin. DMPS and DMSA, when given as four daily doses of 1 mMol/kg, increased the urinary excretion from 10.1% +/- 1.2% to 13.6% +/- 1.3% and 13.5% +/- 2.6%, respectively, but only DMSA caused a small but significant reduction in the kidney platinum content. DTPA was totally ineffective. It is concluded that none of these agents is likely to be useful for the reduction of Cisplatin-induced renal toxicity in the clinical situation.