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.

Multiple regression analysis, using body size and cardiac cycle length, in predicting echocardiographic variables in dogs.

A significant (P less than 0.0001) positive correlation was demonstrated between left ventricular internal chamber dimension in diastole or systole and body weight, body surface area, cycle length, and the square root of cycle length. On the basis of adjusted coefficients of determination, multiple regression analysis, using body weight or body surface area and cycle length or the square root of cycle length, was superior to separate simple regression with these variables in accounting for variations in left ventricular internal chamber dimensions. Shortening fraction had a significant (P less than 0.0001) negative correlation and left ventricular free wall measurements had a significant (P less than 0.0001) positive correlation to body weight and body surface area. For these echocardiographic variables, correlation to the square root of cycle length was insignificant (P greater than 0.05), and a multiple regression model was not helpful in developing confidence intervals. Septal wall measurements were not correlated with body weight, body surface area, cycle length, or the square root of cycle length.

Influence of alterations in heart rate on echocardiographic measurements in the dog.

M-mode echocardiograms were recorded from 10 conscious, clinically normal dogs at various heart rates during atrial pacing. Heart rate was recorded as cycle length (seconds), and measurements were made only during sustained 1:1 atrial-to-ventricular conduction. In all dogs studied, there was a significant (P less than 0.01) positive correlation of left ventricular internal chamber dimension in diastole and systole to cycle length. Also, there was positive correlation between these left ventricular dimensions and the square root of cycle length, which predicted a plateau in dimensional changes as cycle length increased. Echocardiographic shortening fraction and left ventricular and septal wall thickness measurements did not change consistently during pacing. We concluded that left ventricular chamber dimensions in the dog may be significantly affected by alterations in heart rate.