Abstract
Congenital UTO is the leading cause of childhood renal failure. Although these children receive complex drug therapy, the effects of UTO upon pharmacokinetics have not been adequately studied in immature humans or animals. Pseudomonas infections often complicate congenital UTO and may be treated with CTZ. To study the effects of UTO upon CTZ kinetics, we produced unilateral UTO in 3 fetal sheep at 75d/146d gestation. After spontaneous term birth, catheters were inserted to: drain the obstructed kidney; separately collect urine from the unobstructed kidney; and infuse drug and sample blood separately. Obstructed kidney glomerular filtration rates ranged from 0 to 28% of total by DTPA renal scans. CTZ was infused into 3 lambs for 3 hrs before 3 one hr urine collections to determine each kidney's: CTZ CL, creatinine CL (CR CL), and fractional sodium excretion (FENa). UTO decreased urine flow (0.05 to 0.01 ml/min-kg, p<.05); CR CL (2.16 to 0.44 ml/min-kg, p=.002); and increased FENa (0.35 to 7.94%, p<.05). UTO reduced urine [CTZ] to a low of 74.3±8.6 μg/ml. CTZ CL (y) correlated with CR CL (x) such that y=1.60 x −0.10 (r=.80, p<.001). UTO severely impairs renal function as well as CTZ excretion. Pseudomonas kidney infections in infants with bilateral UTO may require higher CTZ doses to reach therapeutic urine [CTZ] and longer dosing intervals which may be estimated from CR CL.
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