Urinary aminopeptidase activities as early and predictive biomarkers of renal dysfunction in cisplatin-treated rats.
This study analyzes the fluorimetric determination of alanyl- (Ala), glutamyl- (Glu), leucyl-cystinyl- (Cys) and aspartyl-aminopeptidase (AspAp) urinary enzymatic activities as early and predictive biomarkers of renal dysfunction in cisplatin-treated rats. Male Wistar rats (n = 8 each group) received a single subcutaneous injection of either saline or cisplatin 3.5 or 7 mg/kg, and urine samples were taken at 0, 1, 2, 3 and 14 days after treatment. In urine samples we determined Ala, Glu, Cys and AspAp activities, proteinuria, N-acetyl-β-D-glucosaminidase (NAG), albumin, and neutrophil gelatinase-associated lipocalin (NGAL). Plasma creatinine, creatinine clearance and renal morphological variables were measured at the end of the experiment. CysAp, NAG and albumin were increased 48 hours after treatment in the cisplatin 3.5 mg/kg treated group. At 24 hours, all urinary aminopeptidase activities and albuminuria were significantly increased in the cisplatin 7 mg/kg treated group. Aminopeptidase urinary activities correlated (p<0.011; r(2)>0.259) with plasma creatinine, creatinine clearance and/or kidney weight/body weight ratio at the end of the experiment and they could be considered as predictive biomarkers of renal injury severity. ROC-AUC analysis was made to study their sensitivity and specificity to distinguish between treated and untreated rats at day 1. All aminopeptidase activities showed an AUC>0.633. We conclude that Ala, Cys, Glu and AspAp enzymatic activities are early and predictive urinary biomarkers of the renal dysfunction induced by cisplatin. These determinations can be very useful in the prognostic and diagnostic of renal dysfunction in preclinical research and clinical practice.
Área de Fisiología, Departamento de Ciencias de la Salud, Universidad de Jaén, Jaén, Spain.
Andrés
A
Quesada
Félix
F
Vargas
Sebastián
S
Montoro-Molina
Francisco
F
O'Valle
María Dolores
MD
Rodríguez-Martínez
Antonio
A
Osuna
Isabel
I
Prieto
Manuel
M
Ramírez
Rosemary
R
Wangensteen
D000118:Acetylglucosaminidase / Q000652:urine; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000175:diagnosis / Q000652:urine*; D000209:Acute-Phase Proteins / Q000652:urine; D000419:Albuminuria / Q000139:chemically induced / Q000175:diagnosis / Q000652:urine; D000626:Aminopeptidases / Q000652:urine*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D019540:Area Under Curve; D015415:Biomarkers / Q000652:urine; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016014:Linear Models; D000071068:Lipocalin-2; D054834:Lipocalins / Q000652:urine; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000652:urine; D012372:ROC Curve; D051381:Rats; D017208:Rats, Wistar
D000209:Acute-Phase Proteins; D000970:Antineoplastic Agents; D015415:Biomarkers; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D003404:Creatinine; D000118:Acetylglucosaminidase; D000626:Aminopeptidases; D002945:Cisplatin