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

https://doi.org/10.1016/j.etap.2020.103510Get rights and content

Highlights

  • Moderate to severe AKI occur after poisoning of KMnO4/H2C2O4, paraquat, and GPSH.

  • Normalized urinary Cytochrome C is high in all three poisonings.

  • Normalized urinary Cytochrome C strongly predicts moderate to severe AKI in paraquat poisoning.

  • High serum creatinine to creatine ratio observes in KMnO4/H2C2O4 poisoning.

Abstract

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.

Introduction

A laundry detergent consisting of two sachets each of 1.2 g of potassium permanganate (KMnO4) and 12.5 g of oxalic acid (H2C2O4) has become a common self-poisoning agent since 2006. Ingestion of H2C2O4 had a 25 % case fatality, ingestion of both compounds had 10 % case fatality, while no deaths occurred following ingestion of only KMnO4 (Gawarammana et al., 2009). The reported lethal dose in humans for H2C2O4 is 5−30 g (Dassanayake and Gnanathasan, 2012) and 10 g for KMnO4 (Korkut et al., 2013). Both paraquat and glyphosate surfactant herbicide (GPSH) are extensively used in agriculture as herbicides (Roberts et al., 2010; Seok et al., 2009). Self-poisoning with paraquat has a 60–70 % case fatality (Seok et al., 2009) and GPSH has a 8 % case-fatality (Roberts et al., 2010).

We previously studied the renal injury caused by these three poisonings using several serum and urinary renal biomarkers (Wijerathna et al., 2017; Wijerathna et al., 2018; Mohamed et al., 2015a; Mohamed et al., 2016; Mohamed et al., 2015b). A very early rapid rise of serum creatinine (sCr) is often seen in severe poisonings with H2C2O4 and KMnO4/H2C2O4 (Wijerathna et al., 2017b), paraquat (Mohamed et al., 2015a), and glyphosate surfactant herbicide (GPSH) (Mohamed et al., 2016). Serum creatinine is a functional biomarker used to diagnose acute kidney injury (AKI), however, the rise in sCr in these poisoning was too rapid to be consistent with the delayed rise seen after AKI (Waikar et al., 2012). These patients often develop AKI and we postulated that oxidative stress is a likely factor in the pathogenesis of toxic-AKI (Wijerathna et al., 2018; Mohamed et al., 2016; Mohamed et al., 2015b).

Systemic toxicity of both H2C2O4 and KMnO4 is postulated to be due to oxidative injury (Young et al., 1996) and H2C2O4 is known to cause mitochondrial dysfunction (Dassanayake and Gnanathasan, 2012). Severe AKI (AKIN2/3) was common in patients who ingested H2C2O4 irrespective of coingestion of KMnO4 (H2C2O4 - 58 %, KMnO4/H2C2O4 – 50 %, KMnO4 – 17 %) (Wijerathna et al., 2018). However, the extent to which oxidative stress depends on the ratio of the two compounds has not been studied. Paraquat (McCarthy et al., 2004) and GPSH (Chaufan et al., 2014) also cause oxidative stress.

Oxidative stress could be both a cause and a consequence of change in renal function since the primary function of redox regulation is to maintain a balance in the electrolytes and homeostasis (Pellegrino et al., 2019). Increased reactive oxygen species (ROS) and decreased endogenous antioxidants are observed in oxidative stress related AKI pathogenesis (Palipoch, 2013). Excessive amounts of superoxide and ROS induce the accumulation of uncoupling protein-2 (UCP-2) in mitochondria (Robey and Hay, 2006). Increased UCP-2 leads to inward proton leak and reduces adenosine tri-phosphate (ATP) synthesis (Noiri and Goligorsky, 2011). Renal reabsorption in tubular epithelial cells is energy dependent, and energy depletion can initiate renal tubular injury (Mohamed et al., 2015a; Pushpa-Rekha et al., 1995; Ratliff et al., 2016; Molck and Friis, 1997). Hence, we hypothesised that oxidative stress was the most likely cause of the early and rapid rise of sCr in KMnO4/H2C2O4 and paraquat poisonings (Mohamed et al., 2015a; Wijerathna et al., 2017b). Uncoupling of oxidative phosphorylation is also a factor in GPSH poisoning (Bradberry et al., 2004; Goldstein et al., 2002), but the link to oxidative stress has not been explored.

Therefore, in this study we explored patterns of commonly used biomarkers of oxidative stress that might give insights into cellular injury and consequent early and rapid rise of sCr in humans with these three poisonings.

Section snippets

Study design

Patients were from a multicenter cohort study of AKI following poisoning in Sri Lanka. We randomly selected a sub-group of patients (N = 105) who had been investigated in our previous studies (Patients with KMnO4/H2C2O4 (N = 57), paraquat (N = 21) and GPSH poisoning (N = 27)) (Wijerathna et al., 2018; Mohamed et al., 2015a; Mohamed et al., 2016; Wijerathna et al., 2017). Full details of the patient recruitment and many other biomarker assays are described elsewhere (Mohamed et al., 2016).

Results

Baseline demographic and clinical variables of patients included are presented in Table 1. There were no major differences in most demographic or clinical variables of the three poison groups. Paraquat poisonings were more commonly by males (81 %) and had more fatal outcomes (9/21) compared to KMnO4/H2C2O4 and GPSH (Table 1).

There were no important differences in the demographic and clinical data between the patients who were included (n = 105) and other patients with these poisonings (n = 482)

Discussion

This study shows that urinary CytoC (normalized to uCr) increases many-fold and rapidly in patients who later develop moderate to severe toxic-AKI after three different poisonings with KMnO4/H2C2O4, paraquat and GPSH. These increases were significantly greater than that seen in those with minor or NoAKI (Figs. 1, 3A–C). This mitochondrial damage biomarker predicted AKI as well as the best biomarker(s) in our previous studies (Mohamed et al., 2016). In contrast, normalized urinary 8-IsoPs, a

Conclusions

Mitochondrial damage is the likely dominant toxic response in toxic AKI following acute KMnO4/H2C2O4, paraquat and GPSH poisonings. The early rapid increase in sCr is likely the consequence of ATP generation under reduced energy production following oxidative stress.

CRediT authorship contribution statement

Thilini Madushanka Wijerathna: Conceptualization, Formal analysis, Investigation, Writing - original draft. Fahim Mohamed: Conceptualization, Writing - review & editing. Indika Bandara Gawarammana: Conceptualization, Writing - review & editing, Supervision. Klintean Wunnapuk: Investigation, Writing - review & editing. Dhammika Menike Dissanayake: Writing - review & editing, Supervision. Fathima Shihana: Investigation. Nicholas Allan Buckley: Conceptualization, Writing - review & editing,

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have happened to influence the work reported in this paper.

Acknowledgements

We would like to thank the physicians, directors, medical staff of the study hospitals, and SACTRC staff for their support. A special thanks goes to Mr. Chathura Palangasinghe and Mr. Umesh Chathuraga for their great support in coordinating sample collection. We also thank patients who participated in the study.

Funding

The study was funded by the Australian National Health and Medical Research Council (NHMRC grants: 1011772 and 1055176).

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