A Practical Approach, Second Edition=Ronald D. Ho.pdf

1016 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONHumansThe role of ACE inhibitors in infant renal failure has been well documented in the literature (35,36, 37, 38). Udwadia-Hegde et al. (38) present a review of case histories of mothers taking ACEinhibitors during the second and third trimesters of pregnancy. Oligohydramnios was observedwhich resulted in preterm delivery of neonates with intrauterine growth retardation, severe hypotension,and anuria. Biopsy of the kidneys generally showed renal tubular dysplaisia. Major anomaliesinduced by ACE inhibitors in humans include oligohydramnios, neonatal anuria/renal tubulardysgenesis, pulmonary hypoplasia, intrauterine growth retardation, persistent patent ductus arteriosus,calvarial hypoplasia/acalvaria, fetal or neonatal death (35). Since 1992, ACE inhibitorsmarketed in the United States carry a black box warning in the label regarding the use of this drugclass during pregnancy, as in the following label for Lotrel.When used in pregnancy during the second and third trimesters, angiotensin converting enzymeinhibitors can cause injury and even death to the developing fetus. When pregnancy is detected,Lotrel should be discontinued as soon as possible (Physician’s Desk Reference, 2000).Comparative SpeciesMice — Renin angiotensin is essential for the development of the mammalian kidney and urinarytract (19). Using mutant mice carrying a targeted null mutation of the angiotensin I or II receptor,Miyazaki and Ichikawa (19) demonstrated that both mutants have distinct phenotype in the kidneyand urinary tract system. Angiotensin II is involved in multiple aspects of the early morphogenesisof the kidney and urinary tract. Angiotensin I receptor induces the development of the renal pelvis,which promotes the removal of urine from the renal parenchyma. Failure of the angiotensin receptorsto operate properly during specific developmental stages results in congenital anomalies of thekidney and urinary tract in utero and hydronephrosis ex utero (19).Other investigators have noted the important role of renin-angiotensin in nephrogenesis, vascularization,and architectural and functional development of the kidney (39). Renal developmentwas studied using ACE inhibitors in neonatal rats and ACE mutant mice and similar renal pathologywas observed in both cases. The authors hypothesized that the primary lesion was a disturbance inrenal vessel development, with tubular pathology due to the close temporal and spatial relationshipof the tubules to the vessels during late stages of development (39).Rats — Rat studies illustrate the importance of the timing of exposure to ACE inhibitors as acritical factor in the development of altered renal morphology. The rat is susceptible to altered renalmorphology mainly during the last 5 days of pregnancy and the first two weeks of life (2, 39).Treatment of newborn rats with an ACE inhibitor for the first 12 days of postnatal life resulted inmarked renal abnormalities (2). Microscopic findings included relatively few and immature glomeruli,distorted and dilated tubules, relatively few and short thick arterioles that resulted in lessbranching and arrested maturation. The changes did not resolve after termination of treatment after23 days of age (2). Similarly, when rats were treated with enalapril on postnatal days 3 – 13,abnormalities in renal morphology were correlated with functional abnormalities (16). Functionalabnormalities included impairment of urinary concentrating ability, which correlated with the degreeof papillary atrophy. When losartan treatment began in 21-day-old rats or enalapril treatment beganin 14-day-old rats, no changes in renal morphology were observed (16, 36, 39). The timeframe inwhich rats are susceptible to renal injury induced by ACE inhibitor exposure correlates with thecritical period for nephrogenesis and marked tubular growth and differentiation.The human kidney is more mature than the rat kidney at birth, and therefore the adverse effectsof renin-angiotensin blockers on human kidneys are more likely to occur when exposure occursduring the last few weeks of pregnancy (39).© 2006 by Taylor & Francis Group, LLC