Epidemiology and renal injury following 2-methyl-4-chlorophenoxyacetic acid (MCPA) poisoning.

2-Methyl-4-chlorophenoxyacetic acid (MCPA) is a widely used chlorophenoxy herbicide. MCPA poisoning causes mitochondrial dysfunction, which can lead to kidney injury and death. The objective of this study is to describe the epidemiology, case fatality and extent of renal injury in a large cohort of MCPA self-poisonings. The study consists of two parts: (1) A report of epidemiological data and clinical outcomes in MCPA poisoned patients in Sri Lanka between 2002 and 2019; (2) Evaluation of acute kidney injury (AKI) using renal biomarkers in a subset from this cohort. Serum creatinine (sCr) and biomarkers were measured soon after hospitalization (2 [IQR 1-3] h) and at different time intervals. We measured serum biomarkers: sCr, cystatin C (sCysC), creatine kinase (CK), and urinary biomarkers: creatinine, kidney injury molecule-1 (KIM-1), clusterin, albumin, beta-2-microglobulin (ß2M), cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), trefoil factor 3 (TFF3) and cytochrome C (CytoC). Kidney Disease Improving Global Outcomes (KDIGO) criteria was used to define acute kidney injury (AKI). There were 1653 patients; 65% were male. The median time from ingestion to examination was 3:54 (IQR 2:19-6:57) h. The overall case-fatality rate was 5.3%. Patients who died were older (42 [IQR 33.5-54] vs 27 [IQR 20-37] for survivors). The median estimated amount of MCPA ingested by patients who died was also greater (88 [IQR 34-200] vs. 30 [IQR 15-63] ml in survivors). Moderate to severe AKI (AKI2/3) was uncommon (6/59 patients in the biomarker study had KDIGO stage 2 or 3). Most patients in AKI2/3 group with increased sCr were older (median age 35 years [IQR 27-41]) compared to No AKI (23 years (19-29) years) or AKI1 (26 years (21-40) years) group who had no or mild increase in sCr. These patients had no pre-existing kidney diseases. In these patients, serum creatinine (maximum medium concentration; 1.12 [IQR 0.93-1.67] mg/dl) and CK (maximum medium concentration; 284 [IQR 94-428] U/l) were increased but sCysC (maximum medium concentration; 0.79 [IQR 0.68-0.81] mg/l) remained in the normal range within 72 h. All urinary biomarkers performed poorly in diagnosing AKI (area under the receiver operating characteristic curve < 0.68). The higher numbers of men with MCPA poisoning likely reflects greater occupational access to pesticides. Fatal outcome and higher ingested dose were more common in the elderly. Significant AKI with tubular injury biomarkers was uncommon. Most people with raised sCr were older and appeared to have no pre-existing kidney disease.

Albuminuria and other renal damage biomarkers detect acute kidney injury soon after acute ingestion of oxalic acid and potassium permanganate.

BACKGROUND: Deliberate self-poisoning with a combination washing powder containing oxalic acid (H2C2O4) and potassium permanganate (KMnO4) is a significant medical problem in the Southern Province of Sri Lanka. Acute kidney injury (AKI) is a frequent consequence. Biomarkers for early diagnosis of nephrotoxicity could guide appropriate supportive therapies. METHODS: We investigated the performance of three serum biomarkers and nine urinary biomarkers in 85 patients in an ongoing multicenter prospective cohort study in Sri Lanka exploring AKI following poisoning. RESULTS: Sixty two (62/85, 73%) patients developed AKI (acute kidney injury network, AKIN, criteria). Early and rapid increases in serum creatinine (sCr) peaking on day 3 were observed in AKIN stage 2 and 3 patients. In these patients, serum cystatin C (sCysC) rose more gradually but also peaked on day 3. Biomarker concentrations (normalized to urinary creatinine) of urinary albumin (uAlbumin), clusterin (uClusterin), beta-2-microglobulin (uB2M), osteopontin (uOPN), neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (uKIM-1) in the AKIN2/3 group increased above the 95th centile concentration of the healthy population. Within 8 h of ingestion, the normalized uAlbumin and sCysC predicted AKIN2/3 with respective area under receiver operating characteristic curve, AUC-ROC values, of 0.94 (95% CI 0.86-1.00) and 0.85 (95% CI 0.76-0.95). CONCLUSIONS: Urinary albumin was the best performing AKI biomarker following ingestion of H2C2O4/KMnO4. This may reflect glomerular injury and/or proximal tubular injury. The urinary albumin concentrations observed in this study could generally be detected using albumin specific dipstick methods, easily available even in resource poor settings.

Mechanism-specific injury biomarkers predict nephrotoxicity early following glyphosate surfactant herbicide (GPSH) poisoning.

Acute kidney injury (AKI) is common following glyphosate surfactant herbicide (GPSH) self-poisoning. Serum creatinine (sCr) is the most widely used renal biomarker for diagnosis of AKI although a recent study in rats suggested that urinary kidney injury molecule-1 predicted AKI earlier and better after GPSH-induced nephrotoxicity. We explored the utility of a panel of biomarkers to diagnose GPSH-induced nephrotoxicity in humans. In a prospective multi-centre observational study, serial urine and blood samples were collected until discharge and at follow-up. The diagnostic performance of each biomarker at various time points was assessed. AKI was diagnosed using the Acute Kidney Injury Network (AKIN) definitions. The added value of each biomarker to sCr to diagnose AKI was assessed by the integrated discrimination improvement (IDI) metric. Of 90 symptomatic patients, 51% developed AKI and 5 patients who developed AKIN≥2 died. Increased sCr at 8 and 16h predicted moderate to severe AKI and death. None of the 10 urinary biomarkers tested increased above normal range in patients who did not develop AKI or had mild AKI (AKIN1); most of these patients also had only minor clinical toxicity. Absolute concentrations of serum and urinary cystatin C, urinary interleukin-18 (IL-18), Cytochrome C (CytoC) and NGAL increased many fold within 8h in patients who developed AKIN≥2. Maximum 8 and 16h concentrations of these biomarkers showed an excellent diagnostic performance (AUC-ROC ≥0.8) to diagnose AKIN≥2. However, of these biomarkers only uCytoC added value to sCr to diagnose AKI when assessed by IDI metrics. GPSH-induced nephrotoxicity can be diagnosed within 24h by sCr. Increases in uCytoC and uIL-18 confirm GPSH-induces apoptosis and causes mitochondrial toxicity. Use of these biomarkers may help to identify mechanism specific targeted therapies for GPSH nephrotoxicity in clinical trials.

Kidney damage biomarkers detect acute kidney injury but only functional markers predict mortality after paraquat ingestion.

Acute kidney injury (AKI) is common following paraquat ingestion. The diagnostic performance of injury biomarkers was investigated in serial blood and urine samples from patients from 5 Sri Lankan hospitals. Functional AKI was diagnosed using serum creatinine (sCr) or serum cystatin C (sCysC). The 95th centile in healthy subjects defined the urinary biomarker cutoffs for diagnosing structural AKI. 50 poisoned patients provided 2 or more specimens, 76% developed functional AKI [AKIN stage 1 (n=12), 2 (n=7) or 3 (n=19)]; 19/26 patients with AKIN stage 2/3 also had functional AKI by sCysC criteria (≥50% increase). Urinary cystatin C (uCysC), clusterin (uClu) and NGAL (uNGAL) increased within 24h of ingestion compared with NoAKI patients and healthy controls. Each biomarker demonstrated moderate diagnostic utility [AUC-ROC: uCysC 0.79, uNGAL 0.79, uClu 0.68] for diagnosis of functional AKI at 16h. Death occurred only in subjects with functional AKI. Structural biomarker-based definitions detected more AKI than did sCr or sCysC, but did not independently predict death. Renal injury biomarkers did not add clinical value to patients who died rapidly due to multi-organ failure. Use of injury biomarkers within 16-24h may guide early intervention for reno-protection in less severe paraquat poisoning.

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.

Acute intentional self-poisoning with a herbicide product containing fenoxaprop-P-ethyl, ethoxysulfuron, and isoxadifen ethyl: a prospective observational study.

BACKGROUND: Herbicides are commonly ingested for self-harm, but relatively little has been published on poisoning with herbicides other than paraquat and glyphosate. We report here a case series of patients with acute exposure to a combination herbicide (brand name Tiller Gold or Whip Super) containing the selective phenoxy herbicide compounds fenoxaprop-P-ethyl and ethoxysulfuron and a safener isoxadifen ethyl. METHOD: Clinical data on all patients presenting with Tiller Gold or Whip Super poisoning to two General Hospitals in Sri Lanka from 2002-2008 were collected prospectively until discharge. RESULTS: Eighty-six patients with a history of Tiller Gold or Whip Super ingestion were included. The main clinical features were an epigastric burning sensation and vomiting; however, most of those who vomited had received gastric lavage or forced emesis. Eight patients had a reduced level of consciousness on admission (Glasgow coma scale 9-14) that resolved without intervention over several hours. Only symptomatic and supportive care was required. The median hospital stay was 1 day (IQR: 1-2) and the case fatality was zero (95% confidence interval: 0-4.2%). This low case fatality compared favorably with the case fatality of other common herbicides in our cohort: paraquat >40%, propanil >10%, 4-chloro-2-methylphenoxyacetic acid > 5%, and glyphosate >2%. CONCLUSION: This combination herbicide product appears to be safe in patients with acute self-poisoning, particularly in comparison with other herbicides, and causing few clinical features.

Acute human self-poisoning with imidacloprid compound: a neonicotinoid insecticide.

BACKGROUND: Deliberate self-poisoning with older pesticides such as organophosphorus compounds are commonly fatal and a serious public health problem in the developing world. The clinical consequences of self-poisoning with newer pesticides are not well described. Such information may help to improve clinical management and inform pesticide regulators of their relative toxicity. This study reports the clinical outcomes and toxicokinetics of the neonicotinoid insecticide imidacloprid following acute self-poisoning in humans. METHODOLOGY/PRINCIPAL FINDINGS: Demographic and clinical data were prospectively recorded in patients with imidacloprid exposure in three hospitals in Sri Lanka. Blood samples were collected when possible for quantification of imidacloprid concentration. There were 68 patients (61 self-ingestions and 7 dermal exposures) with exposure to imidacloprid. Of the self-poisoning patients, the median time to presentation was 4 hours (IQR 2.3-6.0) and median amount ingested was 15 mL (IQR 10-50 mL). Most patients only developed mild symptoms such as nausea, vomiting, headache and diarrhoea. One patient developed respiratory failure needing mechanical ventilation while another was admitted to intensive care due to prolonged sedation. There were no deaths. Median admission imidacloprid concentration was 10.58 ng/L; IQR: 3.84-15.58 ng/L, Range: 0.02-51.25 ng/L. Changes in the concentration of imidacloprid in serial blood samples were consistent with prolonged absorption and/or saturable elimination. CONCLUSIONS: Imidacloprid generally demonstrates low human lethality even in large ingestions. Respiratory failure and reduced level of consciousness were the most serious complications, but these were uncommon. Substitution of imidacloprid for organophosphorus compounds in areas where the incidence of self-poisoning is high may help reduce deaths from self-poisoning.