Effects of exposure to glyphosate on oxidative stress, inflammation, and lung function in maize farmers, Northern Thailand.

BACKGROUND: Glyphosate is a herbicide which is commonly used in agricultural areas. However, previous studies on glyphosate exposure in farmers and their health are still scarce. METHODS: A longitudinal pre-post study was performed among maize farmers. Information from questionnaires, urine and blood samples, and lung function were collected a day before and a day after glyphosate application in the morning. The urine samples were analyzed using liquid chromatography-tandem mass spectrometry to detect glyphosate levels. Serum samples were analyzed to detect malondialdehyde (MDA), glutathione (GHS), and C-reactive protein (CRP) levels using thiobarbituric acid, dithiobisnitrobenzoic acid, and nephelometry, respectively. Lung function performances were measured using a spirometer. RESULTS: A total of 180 maize farmers met the study inclusion criteria. After glyphosate application, it was found that increased urinary glyphosate levels contributed to increased serum MDA (ß = 0.024, 95% CI = 0.000, 0.0047) and decreased serum GHS (ß = -0.022, 95% CI = -0.037, -0.007), FEV1 (ß = -0.134, 95% CI = -0.168, -0.100), FEV1/FVC (ß = -0.062, 95% CI = -0.082, -0.042) and PEF (ß = -0.952, 95% CI = -1.169, -0.735). CONCLUSIONS: Exposure to glyphosate during glyphosate application had significant effects on oxidative stress and lung function in maize farmers.

An LC-MS/MS method for creatine and creatinine analysis in paraquat-intoxicated patients.

A sudden increase in serum creatinine after paraquat intoxication has been reported in several clinical studies. However, this dramatic change of creatinine may be possibly due to an interconversion of creatine-creatinine in relation to paraquat toxicity. In order to investigate the creatine-creatinine relationship, a liquid chromatography tandem mass spectrometry in combination with electrospray ionization was developed and validated for simultaneous determination of creatine and creatinine in the serum. The chromatographic separation was achieved on a Gemini® C6-Phenyl column with a gradient elution consisting of 0.1% formic acid in ultrapure water and methanol as the mobile phase. The method yielded suitable levels of specificity and selectivity, and calibration curves of creatine and creatinine in serum were linear over the concentration range of 0.5-200 µg mL-1. The limit of quantification of both compounds was 0.5 µg mL-1, and the method was accurate within the recovery range of 96.23-102.75%, indicating the robustness of the method. The method was successfully applied to toxicological samples from paraquat-intoxicated patients, and the concentrations of creatine and creatinine were quantified. High creatine concentrations in serum samples were observed which may lead to high serum creatinine despite normal kidney function as creatine is converted to creatinine in proportion to its concentration.

Nephrotoxicity-induced proteinuria increases biomarker diagnostic thresholds in acute kidney injury.

BACKGROUND: Paraquat ingestion is frequently fatal. While biomarkers of kidney damage increase during paraquat-induced acute kidney injury (AKI), significant concurrent proteinuria may alter diagnostic thresholds for diagnosis and prognosis to an unknown extent. This study evaluated the effect of albuminuria on biomarker cutoffs for diagnosis and outcome prediction. METHODS: This was a multi-centre prospective clinical study of patients following acute paraquat self-poisoning in 5 Sri Lankan hospitals. Biomarker concentrations were quantified using ELISA and microbead assays and correlated with urinary albumin. Functional-AKI was defined by the Acute Kidney Injury Network serum creatinine definition and alternatively by a ≥50% increase in serum cystatin C. Albuminuria was defined as albumin-creatinine ratio >30 mg/g. The study outcomes were compared with a retrospective analysis of a pre-clinical study of paraquat-induced nephrotoxicity with appropriate controls. RESULTS: Albuminuria was detected in 34 of 50 patients, and increased with functional-AKI severity. The concentrations of uNGAL, uCysC, uClusterin, uß2M, and uKIM-1 were higher in albuminuric compared to non-albuminuric patients (p < 0.001). Albuminuria correlated with biomarker concentration (r > 0.6, p < 0.01) and was associated with death (p = 0.006). Optimal biomarker cutoffs for prediction of death were higher in the albuminuric group. Similar outcomes with more detailed analysis were obtained in experimental paraquat nephrotoxicity. CONCLUSION: Albuminuria was associated with paraquat-induced nephrotoxicity and increased excretion of low-molecular weight protein biomarkers. AKI biomarker cutoffs for diagnosis, outcome prediction and AKI stratification increased in the presence of albuminuria. This may lead to over-diagnosis of AKI in conditions independently associated with proteinuria.

Prediction of paraquat exposure and toxicity in clinically ill poisoned patients: a model based approach.

AIMS: Paraquat poisoning is a medical problem in many parts of Asia and the Pacific. The mortality rate is extremely high as there is no effective treatment. We analyzed data collected during an ongoing cohort study on self-poisoning and from a randomized controlled trial assessing the efficacy of immunosuppressive therapy in hospitalized paraquat-intoxicated patients. The aim of this analysis was to characterize the toxicokinetics and toxicodynamics of paraquat in this population. METHODS: A non-linear mixed effects approach was used to perform a toxicokinetic/toxicodynamic population analysis in a cohort of 78 patients. RESULTS: The paraquat plasma concentrations were best fitted by a two compartment toxicokinetic structural model with first order absorption and first order elimination. Changes in renal function were used for the assessment of paraquat toxicodynamics. The estimates of toxicokinetic parameters for the apparent clearance, the apparent volume of distribution and elimination half-life were 1.17 l h(-1) , 2.4 l kg(-1) and 87 h, respectively. Renal function, namely creatinine clearance, was the most significant covariate to explain between patient variability in paraquat clearance.This model suggested that a reduction in paraquat clearance occurred within 24 to 48 h after poison ingestion, and afterwards the clearance was constant over time. The model estimated that a paraquat concentration of 429 µg l(-1) caused 50% of maximum renal toxicity. The immunosuppressive therapy tested during this study was associated with only 8% improvement of renal function. CONCLUSION: The developed models may be useful as prognostic tools to predict patient outcome based on patient characteristics on admission and to assess drug effectiveness during antidote drug development.

Pathological and toxicological findings in glyphosate-surfactant herbicide fatality: a case report.

Glyphosate herbicide is promoted by the manufacturer as having no risks to human health, with acute toxicity being very low in normal use. In Thailand, however, poisoning from glyphosate agricultural herbicides has been increasing. A case of rapid lethal intoxication from glyphosate-surfactant herbicide involved a 37-year-old woman, who deliberately ingested approximately 500 mL of concentrated Roundup formulation (41% glyphosate as the isopropylamine salt and 15% polyoxyethylene amine; Mosanto Company). The postmortem examination revealed that the stomach contained 550 mL of yellow fluid. The gastric mucosa of anterior fundus revealed hemorrhage and the small intestines had marked dilatation and thin walls. We used the high-performance liquid chromatography method for determination of serum and gastric content levels of glyphosate. The glyphosate levels of serum and gastric content were 3.05 and 59.72 mg/mL, respectively. Toxic effects of polyoxyethylene amine and Roundup were caused by their ability to erode tissues including mucous membranes and linings of the gastrointestinal and respiratory tracts. A mild degree of pulmonary congestion and edema was observed in both lungs. We proposed that the characteristic picture of microvesicular steatosis of the hepatocytes, seen predominantly in centrilobular zones of the liver, resembled drug-induced hepatic toxicity or secondary hypoxic stress.

Factors associated with respiratory symptoms among herbicide applicators and assistant applicators in maize field.

A cross-sectional study was conducted with 3,291 maize farmers enrolled whose main roles were herbicide applicators and assistant applicators. This study aimed to compare the prevalence of respiratory symptoms and the use of personal protective equipment (PPE) between herbicide applicators and assistant applicators, and determine factors associated with respiratory symptoms. Our results suggest that wheeze and dyspnea were associated with the task on the farm (adj. OR = 10.33 for wheeze and 24.13 for dyspnea), amount of herbicide use (adj. OR = 1.95 for wheeze and 1.41 for dyspnea), frequency of herbicide use (adj. OR = 2.87 for wheeze and 4.08 for dyspnea), not always wearing a mask (adj. OR = 1.49 for wheeze and 3.17 for dyspnea), not always wearing gloves (adj. OR = 2.63 for wheeze and 2.44 for dyspnea), and not always wearing goggles (adj.OR = 2.01 for dyspnea) after adjusting for confounding factors.

Urinary Levels of Sirtuin-1, π-Glutathione S-Transferase, and Mitochondrial DNA in Maize Farmer Occupationally Exposed to Herbicide.

Epidemiologic studies have suggested an association between agrochemical exposure and risk of renal injury. Farmers face great risks to developing adverse effects. The most appropriate biomarker related to renal injury needs to be developed to encounter earlier detection. We aim to study the association between early renal biomarker and occupational herbicide exposure in maize farmers, Thailand. Sixty-four farmers were recruited and interviewed concerning demographic data, herbicide usage, and protective behavior. Two spot urines before (pre-work task) and after (post-work task) herbicide spraying were collected. To estimate the intensity of exposure, the cumulative herbicide exposure intensity index (cumulative EII) was also calculated from activities on the farm, type of personal protective equipment (PPE) use, as well as duration and frequency of exposure. Four candidate renal biomarkers including π-GST, sirtuin-1, mitochondrial DNA (mtDNA) were measured. Most subjects were male and mostly sprayed three herbicides including glyphosate-based herbicides (GBH), paraquat, and 2,4-dichlorophenoxyacetic acid (2,4-D). A type of activity in farm was mixing and spraying herbicide. Our finding demonstrated no statistical significance of all biomarker levels between pre- and post-work task urine. To compare between single and cocktail use of herbicide, there was no statistical difference in all biomarker levels between pre- and post-work task urine. However, the urinary mtDNA seems to be increased in post-work task urine. Moreover, the cumulative EII was strongly associated with change in mtDNA content in both ND-1 and COX-3 gene. The possibility of urinary mtDNA as a valuable biomarker was promising as a noninvasive benchmark for early detection of the risk of developing renal injury from herbicide exposure.

Urinary glyphosate kinetics after occupational exposure.

Glyphosate-surfactant herbicides are the most used and imported herbicide in Thailand. Urinary biomonitoring is a very important tool for evaluating glyphosate exposures and its adverse health effects. However, the data for glyphosate toxicokinetics, especially in Asian populations, is relatively limited. The majority of farmers in Thailand have long term experience with glyphosate use, but they generally follow poor safety practices, including insufficient or incorrect use of personal protective equipment during pesticide handling activities. Therefore, this study aimed to determine the toxicokinetics of glyphosate and its metabolite in urine among maize farmers from the northern region of Thailand. The effects of personal protective equipment usage, as well as farmer behavior during work, on urinary glyphosate levels were also studied. Full-voided spot urine samples were collected over the exposure assessment period (0-72 h). Urinary glyphosate levels were determined by liquid chromatography tandem mass spectrometry. The maximum concentration in urine (uCmax), the time of peak glyphosate levels in urine (uTmax), and the urinary elimination half-life (ut1/2) were analyzed using the PKSolver program. The median of uCmax were 27.9, 29.2 and 17.1 µg/g creatinine in a one-time spray group, a two-time spray group Day 1 and a two-time spray group Day 2, respectively. The uTmax was 11.0 h in both study groups. The median of elimination ut1/2 in the one-time and the two-time spray group were 7.0 and 18.1 h, respectively. Although these estimated urinary elimination half-lives may have been impacted by the variation in exposure doses among the participants, it provides the first urinary toxicokinetic data of glyphosate among the Asian population. The toxicokinetic information could be used to increase knowledge and awareness amongst farmers, particularly to minimize the risk of exposure to glyphosate and reduce possible adverse health effects from using pesticide.

Effect of Occupational Exposure to Herbicides on Oxidative Stress in Sprayers.

BACKGROUND: Herbicides such as glyphosate, paraquat, and 2,4-dichlorophenoxyacetic acid have been reported to cause adverse side effects through production of reactive oxygen species. However, there were no data representing the adverse effects of a mixture herbicide usage in farmers, especially the changes in oxidative marker and antioxidant defense. This study aimed to determine the urinary malondialdehyde (MDA) and glutathione (GSH) level in farmers using mixed herbicides. METHODS: Ninety-three farmers were recruited, and two spot urine samples (before and after work) were collected. The urinary MDA level was evaluated by thiobarbituric acid reactive substance assay, and the urinary GSH level was determined using the enzymatic recycling method. RESULTS: Sixty-two percent of the participants were men, and 59% of the participants worked in a farm for 20-40 years. The common combinations of herbicide usage were glyphosate with 2,4-dichlorophenoxyacetic acid (36.5%). There was no significant difference between pre- and post-work urinary MDA and GSH levels among the 3 groups of herbicides. However, the urinary MDA levels in farmers using the combination of glyphosate and paraquat were significantly higher than those found in farmers using glyphosate alone. The associated factors with changes in MDA levels found that the exposure intensity index (B = 0.154), the cumulative exposure intensity index (B = 0.023), and wearing gloves while working (B = -2.347) were found to be significantly associated with MDA level. CONCLUSION: The results suggest that the combined use of glyphosate and paraquat caused a significant increase in urinary MDA levels. Moreover, intensity of exposure to herbicide and wearing gloves were associated with the level of MDA.

Simple Colorimetric Method for Cholinesterase-inhibitor Screening in Gastric Content by Using Phytoesterase Enzyme from Kidney Bean.

BACKGROUND AND OBJECTIVE: Diagnosis of cholinesterase inhibitor insecticide ingestion is based on clinical suspicious and should be confirmed by cholinesterase essay. However, serum cholinesterase activity test requires specific instruments and procedure. This study aimed to develop simple colorimetric test to detect cholinesterase inhibitors in the gastric content, using phytoesterase and alpha naphthyl acetate as a chromogenic substrate. MATERIALS AND METHODS: Methomyl and chlorpyrifos were selected for the phytoesterase enzyme inhibition assay. The experiment was conducted using pooled insecticide-free gastric content sample from ten cadavers. The gastric content samples were prepared by simple filtration procedure or liquid-liquid extraction procedure with dichloromethane or ethyl acetate. The inhibitor concentrations measured by the developed phytoesterase enzyme inhibition assay were compared with those analyzed by the LC-MS/MS and the GC-FPD. RESULTS: Different sample preparation procedures, sensitivity and specificity and specificity of the test were investigated. Sample extracted with dichloromethane reduced the effect of matrix in gastric content as same as ethyl acetate. The developed color test method of detection showed 56.52% sensitivity and 100% specificity for methomyl, 100% sensitivity and 96.30% specificity for chlorpyrifos. The limit of detection of the assay was 422.6 ng mL-1 for methomyl and was 339.8 ng mL-1 for chlorpyrifos. CONCLUSION: This developed method could be used an alternative diagnostic test for methomyl and chlorpyrifos self-ingestion.

Changes in lung function and respiratory symptoms during pesticide spraying season among male sprayers.

Exposure to pesticides via inhalation might impair lung function and develop further severe respiratory symptoms and diseases. Thus, the purpose of the study was to compare lung function between pre- and post-pesticide spraying seasons among male sprayers. The study also evaluated the association of lung function changes and other factors with respiratory symptoms. The follow-up study was conducted on 58 male sprayers. The subjects were interviewed and measured lung function before and after pesticide spraying season. The results found that forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow rate in the post-spraying season were significantly lower than in the pre-spraying season. With regard to respiratory symptoms, cough symptoms were associated with changes in FEV1/FVC [odd ratio (OR) = 1.29, 95% confidence interval (CI) = 1.01-1.67)] and smoking status (OR = 12.95, 95%CI = 1.35-124.34). Phlegm symptoms were also associated with changes in FVC (OR = 2.07, 95%CI = 1.01-4.25) and FEV1 (OR = 0.41, 95%CI = 0.18-0.91). The study provides evidence that pesticide spraying may increase risks for significant alteration of lung function and respiratory symptoms.

Cellular injury leading to oxidative stress in acute poisoning with potassium permanganate/oxalic acid, paraquat, and glyphosate surfactant herbicide.

Previous studies on human acute kidney injury (AKI) following poisoning with potassium permanganate/oxalic acid (KMnO4/H2C2O4), paraquat, and glyphosate surfactant herbicide (GPSH) have shown rapid and large increases in serum creatinine (sCr) that cannot be entirely explained by direct nephrotoxicity. One plausible mechanism for a rapid increase in sCr is oxidative stress. Thus, we aimed to explore biomarkers of oxidative stress, cellular injury, and their relationship with sCr, after acute KMnO4/H2C2O4, paraquat, and GPSH poisonings. Serum biomarkers [sCr, creatine (sCn), cystatin C (sCysC)] and urinary biomarkers [cytochrome C (CytoC), 8-isoprostane (8-IsoPs)] were evaluated in 105 patients [H2C2O4/KMnO4 (N = 57), paraquat, (N = 21), GPSH (N = 27)] recruited to a multicenter cohort study. We used area under the receiver operating characteristics curve (AUC-ROC) to quantify the extent of prediction of moderate to severe AKI (acute kidney injury network stage 2/3 (AKIN2/3)). Patients with AKIN2/3 showed increased levels of CytoC. Early high CytoC predicted AKIN2/3 in poisoning with KMnO4/H2C2O4 (AUC-ROC4-8h: 0.81), paraquat (AUC-ROC4-8h: 1.00), and GPSH (AUC-ROC4-8h: 0.91). 8-Isoprostane levels were not significantly elevated. Reduced sCn and increased sCr/sCn ratios were observed for 48 h post KMnO4/H2C2O4 ingestion. Paraquat exhibited a similar pattern (N = 11), however only 3 were included in our study. Increased CytoC suggests there is mitochondrial injury coupled with energy depletion. The increased sCr within 24 h could be due to increased conversion of cellular creatine to creatinine during the process of adenosine triphosphate (ATP) generation and then efflux from cells. Later increases of sCr are more likely to represent a true decrease in kidney function.

Biological variation in kidney injury and kidney function biomarkers among farmers in Lamphun province, Thailand.

Frequent and long-term exposure to pesticides can induce acute kidney injury and subsequent chronic kidney diseases. In this study, we aimed to investigate the correlation between kidney injury, kidney function biomarkers, and pesticide use in farmers from the Pasang district, Lamphun province, Thailand. A cross-sectional study was performed in 59 farmers occupationally exposed to various types of pesticides. The levels of urinary neutrophil gelatinase-associated lipocalin (uNGAL), serum creatinine (sCr), urinary microalbumin-to-creatinine ratio (ACR), serum cystatin C (sCys-C), estimated glomerular filtration rate (eGFR), and exposure intensity index (EII) were evaluated. Spearman's correlation and a linear regression analysis were carried out to investigate the association between age, pesticide use, EII, kidney injury markers, and kidney function biomarkers. The most common pesticide used in this study area was glyphosate, followed by paraquat and iprodione. Urinary NGAL levels showed a significant correlation with sCys-C levels, EII, and eGFR Cr-Cys. In addition, the sCr levels were associated with glyphosate use (B = 0.08) and EII (B = 0.01). In conclusion, occupation exposure to pesticides is likely to be linked to kidney injury and dysfunction. Pesticide mix status, pesticide application method, equipment repair status, and personal protective equipment (PPE) use are all involved in changes in kidney markers.

PM10-related DNA damage, cytokinetic defects, and cell death in COPD patients from Chiang Dao district, Chiang Mai, Thailand.

Exposure to PM10 generated by biomass burning may reduce lung function and induce cytogenetic effects, especially in chronic obstructive pulmonary disease patients. This study investigated the frequency of DNA-damaged cells, cells with cytokinetic defect, and different types of cell death using a buccal micronucleus cytome assay. The correlations between each biomarker and lung function were investigated. The changes in these biomarkers associated with high pollutant levels (PM10 > 50 µg/m3) and low pollutant levels (PM10 < 50 µg/m3) were evaluated to explore whether PM10 exposure induced genotoxic damages and cytokinetic defects in COPD patients when the daily average PM10 concentration reached above 50 µg/m3. Fifty-eight COPD patients and 26 healthy subjects living in Chiang Dao district, Chiang Mai, Thailand, were recruited in this study. The results revealed that buccal cells with micronuclei (high vs low 1.09 ± 1.95 vs 0.29 ± 0.64 in COPD patients) and binucleated cells (high vs low 11.43 ± 18.68 vs 1.60 ± 1.31 and 7.77 ± 12.76 vs 1.00 ± 1.17 in COPD and healthy subjects, respectively) observed during the high pollutant period were more frequent than in the low pollutant period. Moreover, exposure to PM10 increased the risk of micronucleus induction in COPD patients 295.23-fold.

A longitudinal follow-up study of oxidative stress and DNA damage among farmers exposed to pesticide mixtures.

Exposure to pesticides may have increased risk of oxidative stress and genetic damage and hence of development of chronic diseases. The aim of this longitudinal follow-up study is to compare oxidative stress and DNA damage between the pre- and post-pesticide application seasons among 56 male farmers. The study also investigated the factors associated with changes in oxidative stress, DNA damage, and health symptoms during the pesticide application season. The eligibility criteria for the subjects were men aged between 25 and 55 years, applied pesticide mixtures during May and June 2018, and healthy without current illness. Ten milliliters of venous blood samples was collected twice from each subject in the pre- and post-pesticide application seasons for determination of superoxide dismutase (SOD), 8-hydroxy-2'-deoxyguanosine (8-OHdG), comet tail length, and comet tail moment. The remarkable findings included a statistically significant increase in SOD activity during the pesticide application season (P < 0.001). However, there were no statistical differences in 8-OHdG, comet tail length, and comet tail moment. When we analyzed the factors associated with changes in SOD activity during the pesticide application season by using linear regression analysis, working hours on the farm (B ± SE. = 0.790 ± 0.341, P = 0.025) and planting activities (B ± SE. = 1.217 ± 0.504, P = 0.020) were associated with increase in SOD activity. Therefore, increase in SOD may be a consequence of oxidative damage induced by pesticide exposure and this marker may be used as an early warning for pesticide-induced acute and chronic toxicities.

High-dose immunosuppression to prevent death after paraquat self-poisoning - a randomised controlled trial.

CONTEXT: Intentional self-poisoning with the herbicide paraquat has a very high case-fatality and is a major problem in rural Asia and Pacific. OBJECTIVES: We aimed to determine whether the addition of immunosuppression to supportive care offers benefit in resource poor Asian district hospitals. MATERIALS AND METHODS: We performed a randomised placebo-controlled trial comparing immunosuppression (intravenous cyclophosphamide up to 1 g/day for two days and methylprednisolone 1 g/day for three days, and then oral dexamethasone 8 mg three-times-a-day for 14 days) with saline and placebo tablets, in addition to standard care, in patients with acute paraquat self-poisoning admitted to six Sri Lankan hospitals between 1st March 2007 and 15th November 2010. The primary outcome was in-hospital mortality. RESULTS: 299 patients were randomised to receive immunosuppression (147) or saline/placebo (152). There was no significant difference in in-hospital mortality rates between the groups (immunosuppression 78 [53%] vs. placebo 94 [62%] (Chi squared test 2.4, p = .12). There was no difference in mortality at three months between the immunosuppression (101/147 [69%]) and placebo groups (108/152 [71%]); (mortality reduction 2%, 95% CI: -8 to +12%). A Cox model did not support benefit from high-dose immunosuppression but suggested potential benefit from the subsequent two weeks of dexamethasone. CONCLUSIONS: We found no evidence that high dose immunosuppression improves survival in paraquat-poisoned patients. The continuing high mortality means further research on the use of dexamethasone and other potential treatments is urgently needed.

Differences in the element contents between gunshot entry wounds with full-jacketed bullet and lead bullet.

To elucidate characteristics of gunshot residues in gunshot entry wounds with full-jacketed and lead bullets, element contents in entry gunshot wounds and control skins were analyzed by inductively coupled plasma-atomic emission spectrometry (ICP-AES). It was found that a high content of Fe and Zn was deposited in the gunshot entry wounds with full-jacketed bullet, whereas a high content of Pb was deposited in the gunshot entry wounds with lead (unjacked) bullet. It should be noted that the content of Pb was significantly higher in the gunshot entry wounds with lead bullet than in those with full-jacketed bullet. Regarding the relationships among elements, it was found that there were significant direct correlations between Pb and either Sb or Ba contents in both gunshot entry wounds with full-jacketed and lead bullets. As Pb increased in both gunshot entry wounds, Sb and Ba also increased in the wounds.

Mechanisms underlying early rapid increases in creatinine in paraquat poisoning.

BACKGROUND: Acute kidney injury (AKI) is common after severe paraquat poisoning and usually heralds a fatal outcome. The rapid large increases in serum creatinine (Cr) exceed that which can be explained by creatinine kinetics based on loss of glomerular filtration rate (GFR). METHODS AND FINDINGS: This prospective multi-centre study compared the kinetics of two surrogate markers of GFR, serum creatinine and serum cystatin C (CysC), following paraquat poisoning to understand and assess renal functional loss after paraquat poisoning. Sixty-six acute paraquat poisoning patients admitted to medical units of five hospitals were included. Relative changes in creatinine and CysC were monitored in serial blood and urine samples, and influences of non-renal factors were also studied. RESULTS: Forty-eight of 66 patients developed AKI (AKIN criteria), with 37 (56%) developing moderate to severe AKI (AKIN stage 2 or 3). The 37 patients showed rapid increases in creatinine of >100% within 24 hours, >200% within 48 hours and >300% by 72 hours and 17 of the 37 died. CysC concentration increased by 50% at 24 hours in the same 37 patients and then remained constant. The creatinine/CysC ratio increased 8 fold over 72 hours. There was a modest fall in urinary creatinine and serum/urine creatinine ratios and a moderate increase in urinary paraquat during first three days. CONCLUSION: Loss of renal function contributes modestly to the large increases in creatinine following paraquat poisoning. The rapid rise in serum creatinine most probably represents increased production of creatine and creatinine to meet the energy demand following severe oxidative stress. Minor contributions include increased cyclisation of creatine to creatinine because of acidosis and competitive or non-competitive inhibition of creatinine secretion. Creatinine is not a good marker of renal functional loss after paraquat poisoning and renal injury should be evaluated using more specific biomarkers of renal injury.

Kidney biomarkers in MCPA-induced acute kidney injury in rats: reduced clearance enhances early biomarker performance.

For improved early detection and assessment of severe acute kidney damage following accidental or intentional ingestion of the herbicide MCPA, we compared a panel of 14 novel kidney injury biomarkers with plasma creatinine. Male Wistar rats received four different oral doses of MCPA and plasma and urine biomarker levels were measured at 8, 24 and 48 h after MCPA exposure. Diagnostic performances using absolute levels, urine levels normalized to urine creatinine or urinary excretion rate were determined by ROC analysis. Plasma creatinine remained the best early biomarker for predicting histological changes at 48 h. The performance of plasma cystatin C in mirroring kidney function was similar to that of plasma creatinine. While urine concentrations were generally less predictive, normalization by urine creatinine greatly improved the performance of several biomarkers. This may be due to an apparent amplification of the biomarker signal on normalizing to creatinine, in the presence of a declining glomerular filtration rate prior to reaching steady state. Normalized 8 h osteopontin and albumin concentrations outperformed other normalized biomarkers in predicting histological changes at later times. Normalized urinary kidney injury molecule-1 at 48 h also correlated well with the degree of kidney damage.

Use of a glyphosate-based herbicide-induced nephrotoxicity model to investigate a panel of kidney injury biomarkers.

Accidental or intentional ingestion of glyphosate surfactant-based herbicides, like Roundup(®), leads to nephrotoxicity as well as death. In this study, a panel of kidney injury biomarkers was evaluated in terms of suitability to detect acute kidney injury and dysfunction. The Roundup(®) intoxication model involved oral administration of glyphosate to rats at dose levels of 250, 500, 1200 and 2500 mg/kg. Urinary and plasma biomarker patterns were investigated at 8, 24 and 48 h after dosing. Biomarkers were quantified by absolute concentration; by normalising to urine creatinine; and by calculating the excretion rate. The diagnostic performances of each method in predicting of acute kidney injury were compared. By Receiver Operating Characteristic (ROC) analysis of the selected biomarkers, only urinary kidney injury molecule-1 (KIM-1) best predicted histological changes at 8h (best cut-off point>0.00029 µg/ml). Plasma creatinine performed better than other biomarkers at 24 h (best cut-off point>0.21 mg/dl). Urinary KIM-1 was the best early biomarker of kidney injury in this glyphosate-induced nephrotoxicity model.