Age-related differences in susceptibility to cisplatin-induced renal toxicity.
Limited experimental models exist to assess drug toxicity in pediatric populations. We recently reported how a multi-age rat model could be used for pre-clinical studies of comparative drug toxicity in pediatric populations. The objective of this study was to expand the utility of this animal model, which previously demonstrated an age-dependent sensitivity to the classic nephrotoxic compound, gentamicin, to another nephrotoxicant, namely cisplatin (Cis). Sprague-Dawley rats (10, 25, 40 and 80 days old) were injected with a single dose of Cis (0, 1, 3 or 6 mg kg(-1) i.p.). Urine samples were collected prior and up to 72 h after treatment in animals that were >or= 25 days old. Several serum, urinary and 'omic' injury biomarkers as well as renal histopathology lesions were evaluated. Statistically significant changes were noted with different injury biomarkers in different age groups. The order of age-related Cis-induced nephrotoxicity was different than our previous study with gentamicin: 80 > 40 > 10 > 25 day-old vs 10 >or= 80 > 40 > 25-day-old rats, respectively. The increased levels of kidney injury molecule-1 (Kim-1: urinary protein/tissue mRNA) provided evidence of early Cis-induced nephrotoxicity in the most sensitive age group (80 days old). Levels of Kim-1 tissue mRNA and urinary protein were significantly correlated to each other and to the severity of renal histopathology lesions. These data indicate that the multi-age rat model can be used to demonstrate different age-related sensitivities to renal injury using mechanistically distinct nephrotoxicants, which is reflected in measurements of a variety of metabolite, gene transcript and protein biomarkers.
Espandiari
P
P
Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, USA. parvaneh.espandiari@fda.hhs.gov
Rosenzweig
B
B
Zhang
J
J
Zhou
Y
Y
Schnackenberg
L
L
Vaidya
V S
VS
Goering
P L
PL
Brown
R P
RP
Bonventre
J V
JV
Mahjoob
K
K
Holland
R D
RD
Beger
R D
RD
Thompson
K
K
Hanig
J
J
Sadrieh
N
N
D000367:Age Factors; D000375:Aging / Q000502:physiology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism / Q000652:urine; D002648:Child; D002945:Cisplatin / Q000633:toxicity*; D004198:Disease Susceptibility / Q000378:metabolism / Q000473:pathology; D005839:Gentamicins / Q000633:toxicity; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000652:urine; D023421:Models, Animal; D010372:Pediatrics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity
D015415:Biomarkers; D005839:Gentamicins; D002945:Cisplatin