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.
South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka; Department of Pharmacy, Faculty of Allied Health Sciences, University of Peradeniya, Sri Lanka; Department of Nephrology, Prince Of Wales Hospital and Clinical School, University of New South Wales, Sydney, Australia; TACT Research Group, Department of Pharmacology, SOMS, Sydney Medical School, University of Sydney, NSW, Australia. Electronic address: fahim.cader@gmail.com.
Fahim
F
Mohamed
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.
Zoltan H
ZH
Endre
Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand; Emergency Department, Christchurch Hospital, Christchurch, New Zealand.
John W
JW
Pickering
South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.
Shaluka
S
Jayamanne
South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.
Chathura
C
Palangasinghe
South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.
Seyed
S
Shahmy
South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.
Umesh
U
Chathuranga
South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.
Thilini
T
Wijerathna
South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.
Fathima
F
Shihana
South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.
Indika
I
Gawarammana
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, Australia.
Nicholas A
NA
Buckley
D058186:Acute Kidney Injury / Q000175:diagnosis* / Q000209:etiology / Q000503:physiopathology; D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood; D045304:Cytochromes c / Q000652:urine; D042241:Early Diagnosis; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000633:toxicity; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D020382:Interleukin-18 / Q000652:urine; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D062025:Organophosphate Poisoning / Q000097:blood / Q000401:mortality / Q000503:physiopathology* / Q000652:urine; D011237:Predictive Value of Tests; D011446:Prospective Studies; D018570:Risk Assessment; D016728:Self-Injurious Behavior / Q000401:mortality / Q000503:physiopathology; D012720:Severity of Illness Index; D013188:Sri Lanka; D013501:Surface-Active Agents / Q000633:toxicity*; D000097797:Glyphosate
D015415:Biomarkers; D003404:Creatinine; D045304:Cytochromes c; D005998:Glycine; D006540:Herbicides; D020382:Interleukin-18; D013501:Surface-Active Agents; D000097797:Glyphosate; C000589760:IL18 protein, human
AKI; Apoptosis; Biomarkers; Cytochrome C; Glyphosate; IL-18; Poisoning; Renal injury; Surfactant