Fetal toxic effects and angiotensin-II-receptor antagonists

Martinovic, Jéléna; Benachi, Alexandra; Laurent, Nicole; Daïkha-Dahmane, Farida; Gubler, Marie–Claire

doi:10.1016/s0140-6736(01)05426-5

Cited by 123 publications

(75 citation statements)

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“…Similar morphologic lesions-the so-called "endocrine" kidney-have been described in a rat model of chronic renal hypoperfusion (45). Such lesions also are seen in anuric donor twins in twintwin transfusion syndrome (24,25), in the ipsilateral kidney in renal artery stenosis in children (10,30,46), and in fetuses that are exposed to ACE inhibitors or AT1 antagonists (31)(32)(33)(34). As observed by Marcussen (30) in renal artery stenosis, more proximal than distal tubules are destroyed by the ischemic process.…”

Section: Discussionmentioning

confidence: 61%

“…These situations include the twin-twin transfusion syndrome that is observed in monochorionic twin pregnancies in which the donor fetus presents RTD (23)(24)(25), major cardiac malformations (23,26), severe liver diseases (27)(28)(29), and fetal or infantile renal artery stenosis (30; personal observations). RTD with large fontanels also has been described in fetuses that are exposed in utero to angiotensin-converting enzyme (ACE) inhibitors (31,32) or angiotensin II (AngII) receptor antagonists (33,34). These observations of secondary, drug-induced RTD suggested that dysregulation of the renin-angiotensin system (RAS) could be responsible for the hereditary form of the disorder (17).…”

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confidence: 99%

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Renal Tubular Dysgenesis, a Not Uncommon Autosomal Recessive Disorder Leading to Oligohydramnios

Lacoste

Cai

Guicharnaud

et al. 2006

Journal of the American Society of Nephrology

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Renal tubular dysgenesis is a clinical disorder that is observed in fetuses and characterized by the absence or poor development of proximal tubules, early onset and persistent oligohydramnios that leads to the Potter sequence, and skull ossification defects. It may be acquired during fetal development or inherited as an autosomal recessive disease. It was shown recently that autosomal recessive renal tubular dysgenesis is genetically heterogeneous and linked to mutations in the genes that encode components of the renin-angiotensin system. This study analyzed the clinical expression of the disease in 29 fetus/neonates from 18 unrelated families and evaluated changes in renal morphology and expression of the renin-angiotensin system. The disease was uniformly severe, with perinatal death in all cases as a result of persistent anuria and hypoxia related to pulmonary hypoplasia. Severe defects in proximal tubules were observed in all fetuses from 18 gestational weeks onward, and lesions also involved other tubular segments. They were associated with thickening of the renal arterial vasculature, from the arcuate to the afferent arteries. Renal renin expression was strikingly increased in 19 of 24 patients studied, from 13 families, whereas no renal renin was detected in four patients from three families. Angiotensinogen and angiotensinconverting enzyme were absent or present in only small amounts in the proximal tubule, in correlation with the severity of tubular abnormalities. No specific changes were detected in angiotensin II receptor expression. The severity and the early onset of the clinical and pathologic expression of the disease underline the major importance of this system in fetal kidney function and development in humans. The identification of the disease on the basis of precise histologic analysis and the research of the genetic defect now allow genetic counseling and early prenatal diagnosis. (1) in two stillborn siblings who had developed fetal anuria that resulted in oligohydramnios and the Potter phenotype. Fetal urine is the major constituent of amniotic fluid, especially after 18 to 20 gestational weeks, and estimation of its abundance is the best approach for evaluation of fetal kidney function. Oligohydramnios, whatever the cause, leads to fetal compression and decreased intrauterine motility, resulting in the Potter sequence that includes redundant skin, facial dysmorphia with large and flattened low-set ears, limb positioning

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Section: Discussionmentioning

confidence: 61%

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confidence: 99%

Renal Tubular Dysgenesis, a Not Uncommon Autosomal Recessive Disorder Leading to Oligohydramnios

Lacoste

Cai

Guicharnaud

et al. 2006

Journal of the American Society of Nephrology

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“…25 Inadvertent use of ACE inhibitors or AT 1 receptor blockers during pregnancy causes structural and functional developmental abnormalities of the kidney in the fetus. 25,26 This study showed for the first time that prenatal exposure to LPS resulted in lower renal cortex renin mRNA expression in newborn rats, but higher renal cortex renin mRNA expression in 7-, 16-and 25-week-old rats and higher ACE mRNA expression in 25-week-old rats. This could be explained if prenatal exposure to LPS suppressed the activity of RAS in fetal/newborn rats and in turn impaired renal development during pregnancy; the resulting lower number of glomeruli would result in higher RAS activity in adulthood.…”

Section: Discussionmentioning

confidence: 78%

Prenatal exposure to lipopolysaccharide alters the intrarenal renin–angiotensin system and renal damage in offspring rats

et al. 2009

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Prenatal exposure to inflammation produces offspring that are hypertensive in adulthood. This study explored alterations of the renin-angiotensin system (RAS) during the development of hypertension induced by prenatal exposure to lipopolysaccharide (LPS). In addition, the effects of an inhibitor of the nuclear transcription factor (NF)-jB (pyrrolidine dithiocarbamate, PDTC) on this process were assessed. Pregnant rats were randomly divided into four groups (n¼8): a control group, an LPS group, a PDTC group and an LPS+PDTC group. The rats in these groups were intraperitoneally administered vehicle, 0.79 mg kg À1 LPS, 100 mg kg À1 PDTC or LPS plus PDTC, respectively. LPS was given on the 8th, 10th and 12th days, whereas PDTC was given from the 8th to the 14th day during gestation. At various ages from day 1 to 25 weeks, plasma renin activity, plasma angiotensin II (Ang II) levels, renal function, glomerular number, mRNA expression levels of renal cortex renin and angiotensin-converting enzyme (ACE), the number of Ang II-positive cells and NF-jB activation were determined. The results showed that prenatal exposure to LPS resulted in significantly lower glomerular numbers and creatinine clearance rates and higher urinary protein and renal cortex ACE mRNA expression in adult offspring. Prenatal LPS also decreased the renal cortex renin mRNA expression and the number of Ang II-positive cells in offspring at 1 day of age, but these increased at 7, 16 and 25 weeks, whereas the plasma renin activity and Ang II concentration remained unchanged. Simultaneously, PDTC treatment markedly reversed the action of LPS. In conclusion, prenatal exposure to LPS resulted in alteration of the intrarenal RAS and renal damage in adult offspring rats. INTRODUCTIONThe effects of hypertension on the cardiovascular and renal systems are of major concern due to its morbidity and mortality. Though many efforts have been made to understand the pathophysiology of hypertension, it is still unclear because of its complexity. 1 A growing body of evidence indicates that hypertension is an inflammatory state wherein proinflammatory cytokines, such as tumor necrosis factor-a and interleukin-6, contribute to the hypertensive effect. 2-5 Angiotensin II (Ang II), the major biologically active component of the reninangiotensin system (RAS), not only induces vasoconstriction, aldosterone release and sodium reabsorption by the nephron, but is also intricately interrelated with inflammation. Furthermore, the association of Ang II and inflammation induces an amplification process that involves oxidative stress and proinflammatory transcription factors, leading to progressive vascular injury 6 and having an important role in the development of hypertension and target organ damage. 2 It has been shown in our laboratory that maternal exposure to lipopolysaccharide (LPS) results in hypertension in offspring rats. 7

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“…However, two cases with multiple malformations were identified as oligohydramnios sequences, due to renal defects; these two pregnant women were treated with captopril. Angiotensinconverting enzyme inhibitors [23][24][25] and angiotensin-II receptor inhibitors/antagonists 26,27 are contraindicated in pregnant women because of their fetotoxic effects (mainly renal failure). Captopril is an angiotensin-converting enzyme inhibitor (and therefore contraindicated in pregnant women); nevertheless, 10 pregnant women with CH were treated with captopril during pregnancy, and this drug was Chronic hypertension and congenital abnormalities F Bánhidy et al associated with the oligohydramnios sequence in two multimalformed offspring.…”

Section: Discussionmentioning

confidence: 99%

Chronic hypertension with related drug treatment of pregnant women and congenital abnormalities in their offspring: a population-based study

et al. 2010

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Chronic hypertension (CH) is a common chronic disease and occurs frequently in pregnant women. The teratogenic/fetotoxic effect of certain antihypertensive drugs has been shown. The objective of this study was to investigate the association between pregnant women with CH and the possible risk of congenital abnormalities (CAs) among their offspring. The prevalence of medically recorded CH in the prenatal maternity logbook was compared between 1030 pregnant women who later had offspring with CA (case group) and 1579 pregnant women with CH who later delivered newborn infants without CA (control group). Control newborn infants were matched to cases in the population-based data set of the Hungarian Case-Control Surveillance System of Congenital Abnormalities during 1980-1996. Of 23 different CA groups with informative offspring, esophageal atresia/stenosis was a greater risk in pregnant women with CH (adjusted odds ratios with 95% confidence intervals: 3.1, 1.4-6.8). In conclusion, a higher risk of esophageal atresia/stenosis was found in the offspring of pregnant women with severe CH, which could not be explained by related drug treatments. This finding requires confirmation or lack thereof by future studies.

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Fetal toxic effects and angiotensin-II-receptor antagonists

Cited by 123 publications

References 4 publications

Renal Tubular Dysgenesis, a Not Uncommon Autosomal Recessive Disorder Leading to Oligohydramnios

Renal Tubular Dysgenesis, a Not Uncommon Autosomal Recessive Disorder Leading to Oligohydramnios

Prenatal exposure to lipopolysaccharide alters the intrarenal renin–angiotensin system and renal damage in offspring rats

Chronic hypertension with related drug treatment of pregnant women and congenital abnormalities in their offspring: a population-based study

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