title: Nephrotoxicity-induced proteinuria increases biomarker diagnostic thresholds in acute kidney injury.
abstract: 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.
  
  
  
  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.
  
  
  
  Albuminuria was detected in 34 of 50 patients, and increased with functional-AKI severity. The concentrations of uNGAL, uCysC, uClusterin, uβ2M, 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.
  
  
  
  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.
authors.affiliation: South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka. fahim.cader@gmail.com.|Department of Pharmacy, Faculty of Allied Health Sciences, University of Peradeniya, Peradeniya, Sri Lanka. fahim.cader@gmail.com.|Department of Nephrology, Prince Of Wales Hospital and Clinical School, University of New South Wales, Sydney, Australia. fahim.cader@gmail.com.|TACT Research Group, Department of Pharmacology, SOMS, Sydney Medical School, University of Sydney NSW, Sydney, Australia. fahim.cader@gmail.com.|SACTRC, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka. fahim.cader@gmail.com.
authors.forename: Fahim
authors.initials: F
authors.lastname: Mohamed
authors.affiliation: South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.|TACT Research Group, Department of Pharmacology, SOMS, Sydney Medical School, University of Sydney NSW, Sydney, Australia.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Buckley
authors.affiliation: Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.|Emergency Department, Christchurch Hospital, Christchurch, New Zealand.
authors.forename: John W
authors.initials: JW
authors.lastname: Pickering
authors.affiliation: Department of Forensic Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Klintean
authors.initials: K
authors.lastname: Wunnapuk
authors.affiliation: South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.
authors.forename: Sandamali
authors.initials: S
authors.lastname: Dissanayake
authors.affiliation: South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.
authors.forename: Umesh
authors.initials: U
authors.lastname: Chathuranga
authors.affiliation: South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.
authors.forename: Indika
authors.initials: I
authors.lastname: Gawarammana
authors.affiliation: South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.
authors.forename: Shaluka
authors.initials: S
authors.lastname: Jayamanne
authors.affiliation: Department of Nephrology, Prince Of Wales Hospital and Clinical School, University of New South Wales, Sydney, Australia.|Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Zoltan H
authors.initials: ZH
authors.lastname: Endre
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism; D000328:Adult; D000419:Albuminuria / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D051152:Clusterin / Q000652:urine; D003404:Creatinine / Q000378:metabolism; D055316:Cystatin C / Q000378:metabolism; D005260:Female; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000378:metabolism; D006540:Herbicides / Q000506:poisoning*; D006801:Humans; D000071068:Lipocalin-2 / Q000652:urine; D008297:Male; D009517:New South Wales; D010269:Paraquat / Q000506:poisoning*; D011379:Prognosis; D011446:Prospective Studies; D011507:Proteinuria / Q000139:chemically induced* / Q000378:metabolism; D012189:Retrospective Studies; D013188:Sri Lanka; D055815:Young Adult; D001613:beta 2-Microglobulin / Q000378:metabolism
chemical_list: D015415:Biomarkers; C495242:CLU protein, human; D051152:Clusterin; D055316:Cystatin C; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D006540:Herbicides; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D001613:beta 2-Microglobulin; D003404:Creatinine; D010269:Paraquat
keywords: Albuminuria; Biomarkers; Nephrotoxicity; Paraquat; Poisoning