Kidney biomarkers in MCPA-induced acute kidney injury in rats: reduced clearance enhances early biomarker performance.
For improved early detection and assessment of severe acute kidney damage following accidental or intentional ingestion of the herbicide MCPA, we compared a panel of 14 novel kidney injury biomarkers with plasma creatinine. Male Wistar rats received four different oral doses of MCPA and plasma and urine biomarker levels were measured at 8, 24 and 48 h after MCPA exposure. Diagnostic performances using absolute levels, urine levels normalized to urine creatinine or urinary excretion rate were determined by ROC analysis. Plasma creatinine remained the best early biomarker for predicting histological changes at 48 h. The performance of plasma cystatin C in mirroring kidney function was similar to that of plasma creatinine. While urine concentrations were generally less predictive, normalization by urine creatinine greatly improved the performance of several biomarkers. This may be due to an apparent amplification of the biomarker signal on normalizing to creatinine, in the presence of a declining glomerular filtration rate prior to reaching steady state. Normalized 8 h osteopontin and albumin concentrations outperformed other normalized biomarkers in predicting histological changes at later times. Normalized urinary kidney injury molecule-1 at 48 h also correlated well with the degree of kidney damage.
Therapeutics Research Centre, School of Medicine, The University of Queensland, Brisbane, QLD, Australia; Department of Forensic Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Klintean
K
Wunnapuk
Therapeutics Research Centre, School of Medicine, The University of Queensland, Brisbane, QLD, Australia.
Xin
X
Liu
Centre for Kidney Disease Research, School of Medicine, The University of Queensland, Brisbane, QLD, Australia.
Glenda C
GC
Gobe
Centre for Kidney Disease Research, School of Medicine, The University of Queensland, Brisbane, QLD, Australia; Department of Nephrology, Prince of Wales Clinical School and Prince of Wales Hospital, Sydney, NSW, Australia.
Zoltan H
ZH
Endre
Department of Nephrology, Prince of Wales Clinical School and Prince of Wales Hospital, Sydney, NSW, Australia.
Philip W
PW
Peake
Therapeutics Research Centre, School of Medicine, The University of Queensland, Brisbane, QLD, Australia. Electronic address: jeff.grice@uq.edu.au.
Jeffrey E
JE
Grice
Therapeutics Research Centre, School of Medicine, The University of Queensland, Brisbane, QLD, Australia; School of Pharmacy & Medical Sciences, University of South Australia, Adelaide, SA, Australia.
Michael S
MS
Roberts
South Asian Clinical Toxicology Research Collaboration, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka; Professorial Medicine Unit, University of New South Wales, Sydney, NSW, Australia.
Nicholas A
NA
Buckley
D008456:2-Methyl-4-chlorophenoxyacetic Acid / Q000008:administration & dosage / Q000633:toxicity*; D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism* / Q000652:urine; D000418:Albumins / Q000032:analysis; D000818:Animals; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood / Q000652:urine; D015815:Cell Adhesion Molecules / Q000097:blood; D003404:Creatinine / Q000097:blood* / Q000652:urine; D055316:Cystatin C / Q000097:blood; D006651:Histocytochemistry; D008297:Male; D053495:Osteopontin / Q000097:blood; D012372:ROC Curve; D051381:Rats; D017208:Rats, Wistar
D008456:2-Methyl-4-chlorophenoxyacetic Acid; D000418:Albumins; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D003404:Creatinine; D055316:Cystatin C; D053495:Osteopontin; C110936:Havcr1 protein, rat
4-Chloro-2-methylphenoxyacetic acid; Acute kidney injury; Biomarkers; Creatinine; Kidney injury molecule-1; MCPA