Human nephrotoxicity assessment using novel renal biomarkers following herbicide self-poisoning in less developed countries

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Copyright: Abdul Cader, Mohamed Fahim
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Abstract
Acute kidney injury (AKI) following self-poisoning with herbicides is common and an important predictor of mortality. Early diagnosis may reduce mortality if successful treatments are developed. AKI is diagnosed by changes in serum creatinine (sCr), a surrogate of glomerular filtration rate (GFR). This delays diagnosis and underestimates extent of injury, so use of sCr to diagnose nephrotoxicity is suboptimal. We prospectively studied Sri Lankan subjects admitted to hospitals following deliberate drug/chemical ingestion and after snake envenomation. This thesis focuses on two herbicides, paraquat and glyphosate. Firstly, we hypothesised that the abrupt increase in sCr following paraquat poisoning was so rapid and was unlikely to be due solely to nephrotoxicity. We assessed this by comparing kinetics of sCr and serum cystatin C, and influences of non-renal factors. The increase in creatinine greatly exceeded that predicted or even possible with maximal decreases in GFR. We speculated this represents increased production of creatine and creatinine to meet energy demands following paraquat-induced oxidative stress. Creatinine was not a good marker of GFR and paraquat nephrotoxicity should be evaluated using more specific renal biomarkers. The utility of 10 structural injury biomarkers was then evaluated. Three (urinary cystatin C, NGAL and clusterin) of 10 showed a modest performance in detecting AKI. Most patients with AKI died due to multi-organ failure within 2 days and sCr predicted mortality independently of GFR. Therefore, any additional clinical utility of injury biomarkers to sCr was limited in paraquat poisoning. We assessed the influence of proteinuria on biomarker excretion. Albuminuria was associated with increased excretion of most biomarkers and biomarker cutoffs for prediction of death were higher. Diagnostic cutoffs for outcome prediction and stratification must be modified if albuminuria is due to comorbid conditions. Finally, the role of biomarkers in detecting nephrotoxicity and their added value to sCr was evaluated in 90 patients following glyphosate-surfactant herbicide (GPSH) poisoning. GPSH-induced nephrotoxicity was common but generally mild and reversible. It can be diagnosed within 8-16 hours by cytochrome C (uCytoC). The early increases in uCytoC and interleukin-18 support a primary mechanism of GPSH-induced nephrotoxicity involving mitochondrial toxicity and apoptosis and use of these biomarkers may identify mechanism-specific targets for treatments.
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Author(s)
Abdul Cader, Mohamed Fahim
Supervisor(s)
Buckley, Nicholas Allan
Endre, Zoltan Huba
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Publication Year
2015
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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