Farid Boubred

Effects Of Maternally Administered Drugs On The Fetal And Neonatal Kidney

The number of pregnant women and women of childbearing age who are receiving drugs is increasing. A variety of drugs are prescribed for either complications of pregnancy or maternal diseases that existed prior to the pregnancy. Such drugs cross the placental barrier, enter the fetal circulation and potentially alter fetal development, particularly the development of the kidneys. Increased incidences of intrauterine growth retardation and adverse renal effects have been reported. The fetus and the newborn infant may thus experience renal failure, varying from transient oligohydramnios to severe neonatal renal insufficiency leading to death. Such adverse effects may particularly occur when fetuses are exposed to NSAIDs, ACE inhibitors and specific angiotensin II receptor type 1 antagonists. In addition to functional adverse effects, in utero exposure to drugs may affect renal structure itself and produce renal congenital abnormalities, including cystic dysplasia, tubular dysgenesis, ischaemic damage and a reduced nephron number. Experimental studies raise the question of potential long-term adverse effects, including renal dysfunction and arterial hypertension in adulthood. Although neonatal data for many drugs are reassuring, such findings stress the importance of long-term follow-up of infants exposed in utero to certain drugs that have been administered to the mother.

Adverse consequences of accelerated neonatal growth: cardiovascular and renal issues

Epidemiological and experimental studies show that the risk of cardiovascular and metabolic diseases at adulthood is inversely related to the weight at birth. Although with less evidence, low birth weight has been suggested to increase the risk of chronic kidney disease (CKD). It is well established that the developmental programming of arterial hypertension and of renal disease involves in particular renal factors, especially nephron endowment, which is reduced in low birth weight and maternal diabetes situations. Experimental studies, especially in rodents, have demonstrated the long-term influence of postnatal nutrition and/or postnatal growth on cardiovascular, metabolic and renal functions, while human data are scarce on this issue. Vascular and renal diseases appear to have a “multihits” origin, with reduced nephron number the initial hit and rapid postnatal growth the second hit. This review addresses the current understanding of the role of the kidney, both as a mechanism and as a target, in the developmental origins of adult disease theory, with a particular focus on the long-term effects of postnatal growth and nutrition.

The Intensity of IUGR-Induced Transcriptome Deregulations Is Inversely Correlated with the Onset of Organ Function in a Rat Model

A low-protein diet applied during pregnancy in the rat results in intrauterine growth restricted (IUGR) fetuses. In humans, IUGR is associated with increased perinatal morbidity, higher incidence of neuro-developmental defects and increased risk of adult metabolic anomalies, such as diabetes and cardiovascular disease. Development and function of many organs are affected by environmental conditions such as those inducing fetal and early postnatal growth restriction. This phenomenon, termed “fetal programming” has been studied unconnectedly in some organs, but very few studies (if any) have investigated at the same time several organs, on a more comparative basis. However, it is quite probable that IUGR affects differentially most organ systems, with possible persistent changes in gene expression. In this study we address transcriptional alterations induced by IUGR in a multi-organ perspective, by systematic analysis of 20-days rat fetuses. We show that (1) expressional alterations are apparently stronger in organs functioning late in foetal or postnatal life than in organs that are functioning early (2) hierarchical classification of the deregulations put together kidney and placenta in one cluster, liver, lungs and heart in another; (3) the epigenetic machinery is set up especially in the placenta, while its alterations are rather mild in other organs; (4) the genes appear deregulated in chromosome clusters; (5) the altered expression cascades varies from organ to organ, with noticeably a very significant modification of the complement and coagulation cascades in the kidney; (6) we found a significant increase in TF binding site for HNF4 proteins specifically for liver genes that are down-regulated in IUGR, suggesting that this decrease is achieved through the action of HNF transcription factors, that are themselves transcriptionnally induced in the liver by IUGR (x 1.84 fold). Altogether, our study suggests that a combination of tissue-specific mechanisms contributes to bring about tissue-driven modifications of gene cascades. The question of these cascades being activated to adapt the organ to harsh environmental condition, or as an endpoint consequence is still raised.

Fetal and neonatal consequences of antenatal exposure to type 1 angiotensin II receptor-antagonists

Sartans are selective type 1 angiotensin II receptor-antagonists that are used in the treatment of arterial hypertension. Few reports are available concerning the use of sartans during pregnancy. We report two cases of adverse fetal outcome in hypertensive pregnancies exposed to sartans. In the first case, anamnios and fetal renal failure due to severe tubular dysgenesia led to termination of pregnancy in the 27th week. The second patient presented with hypocalvaria and developed fetal renal failure. The use of sartans during the two last trimesters of pregnancy should be strictly avoided.

Therapeutic closure of the ductus arteriosus: Benefits and limitations

Patency of the ductus arteriosus (PDA), a common complication of preterm birth, has been associated to increased risk for intraventricular cerebral hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia and death. Consequently, prophylactic or curative treatment has been advocated before the critical left-to-right shunting occurs. A host of studies has shown that both pharmacological agents and surgical closure are effective in closing the ducutus arteriosus in premature infants. Indomethacin has long been the drug of choice. However, renal and cerebral haemodynamic side effects have been frequently reported. Strategies to minimise adverse effects of indomethacin, such as the association with frusemide, dopamine or the use of low-dose prolonged treatment with indomethacin have failed or shown partial benefit. Other NSAIDs have been investigated. But either the profile of adverse effects was unfavourable, as in the case of mefenamic acid, or their efficacy was less than that of indomethacin for PDA closure. More recently, ibuprofen has been proposed for the treatment of PDA as it was shown to induce less adverse effects on cerebral blood flow, intestinal and renal hemodynamics, while retaining similar efficacy to indomethacin. However, since renal perfusion, GFR and diuresis in early neonatal life strongly depend on the vasodilator effects of PGs on the afferent glomerular arterioles, ibuprofen, as other COX-inhibitors may not be exempt of some renal undesirable effects.  While numerous studies have shown that PDA is a risk factor associated with immaturity and with increased incidence of complications of preterm birth, including broncho-pulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis and death, there is little evidence that such association is causative. Moreover, still little evidence exists from even recent randomized controlled trials that the pharmacological closure of PDA benefits to premature infants in terms of clinically significant short-term or medium-term outcomes, beyond a positive effect on DA patency. The use of COX-inhibitors for the prophylaxis or closure of PDA during the first hours or days of life should thus be cautious and based on an individual evaluation of benefit and risk. There is need of a randomized, placebo-controlled trials designed to assess the benefits in terms of mortality and morbidity outcomes of an early, or even very early pharmacological closure of PDA in extremely low gestational age infants.

Clinical research in newborn infants: difficulties and specificity

BackgroundClinical trials are essential in neonates to evaluate scientifically the efficacy and safety of drugs. However, major specificities condition clinical research in human neonates.ObjectiveTo review specific constraints to be taken into account in neonatal research studies.MethodsA review of the literature and contribution of authors’ opinions was carried out.Results and conclusionNeonatal specificities that induce obstacles in neonatal studies and proposals are detailed. This review also looks at recommendations recently developed by the European Commission to promote safe and ethical research in neonatology.

High protein intake in neonatal period induces glomerular hypertrophy and sclerosis in adulthood in rats born with IUGR

Background:Intrauterine growth restriction (IUGR) and postnatal nutrition are risk factors for cardiovascular and renal diseases in both humans and animals. The long-term renal effects of protein intake early in life remain unknown. The objective was to evaluate the effects of a neonatal feeding with high protein (HP) milk on renal functions and structure in IUGR male rats.Methods:Maternal gestational low protein diet was used to produce IUGR. At day 5, IUGR pups were gastrostomized in the “pup-in-the cup” model and received either normal protein (NP) milk or HP (+50% protein content) milk until day 21. After weaning, the animals were fed the same standard diet. Renal functions and structure were assessed at postnatal day 18 (D18) and in adult offspring.Results:During the preweaning period, the postnatal weight gain between the two groups was unaffected. On D18, kidneys from HP offspring were heavier with significant glomerular hypertrophy (+40%, P < 0.05). HP diet was associated with significant proteinuria and glomerulosclerosis (+49%, P < 0.05). Glomerular number was unaltered.Conclusion:Neonatal HP feeding following IUGR affects renal functions and structure at adulthood. These alterations may result from a single nephron glomerular hyperfiltration.

Ibubrofen in the Treatment of Patent Ductus Arteriosus in Preterm Infants: What We Know, What We Still Do Not Know

The patency of the ductus arteriosus has ever been considered as a pathological situation in preterm infants and one likely cause of mortality and morbidity, including broncho-pulmonary dysplasia, necrotizing enterocolitis, intraventricular haemorrhage, retinopathy of prematurity. The incidence of patent ductus arteriosus is inversely proportional to gestational age and infants with the lowest gestational ages are the most exposed to the complications of prematurity. So, associations between patent ductus arteriosus and the other morbidities may not be causative and patent ductus arteriosus could be more a sign of immaturity and severity of disease than the cause of these problems. Non-steroidal anti-inflammatory agents, such as indomethacin or ibuprofen, have been shown to be effective in closing or preventing patent ductus arteriosus, with differences in side effects. However nearly all randomized controlled trials have been designed with the closure of the ductus arteriosus, not mortality or morbidity, as the main endpoint. Thus, evidence is still lacking on the eventual benefits for the patient of pharmacological or surgical intervention on PDA. Moreover, both ibuprofen and indomethacin efficacy seems markedly reduced in extremely low gestational age infants, who are the most likely to benefit from such intervention. The explanation of the reduced pharmacodymanic effect in such population is unclear; so far, studies using increased dosing of ibuprofen have failed to show a clear benefit. Prophylaxis with indomethacin or ibuprofen has failed to show sustained benefits on neurodevelopment at 2 years of age in low gestational age infants. New curative trials may aim at investigating the effects of early curative administration of ibuprofen, which has reduced side effects compared to indomethacin, on immature kidney function, on mortality and morbidity in very low gestational age infants, ideally with a combined endpoint such as survival in the absence of severe neurodevelopmental alteration at 2 years age. Despite an understandable reluctance given the historical background of systematic, therapeutic closure of ductus arteriosus in preterm infants, there are no definite ethical obstacles to a placebo-controlled design.

Stress oxydant chez l’enfant prématuré : causes, biomarqueurs et possibilités thérapeutiques

The survival of preterm babies has increased over the last few decades. However, disorders associated with preterm birth, known as oxygen radical diseases of neonatology, such as retinopathy, bronchopulmonary dysplasia, periventricular leukomalacia, and necrotizing enterocolitis are severe complications related to oxidative stress, which can be defined by an imbalance between oxidative reactive species production and antioxidant defenses. Oxidative stress causes lipid, protein, and DNA damage. Preterm infants have decreased antioxidant defenses in response to oxidative challenges, because the physiologic increase of antioxidant capacity occurs at the end of gestation in preparation for the transition to extrauterine life. Therefore, preterm infants are more sensitive to neonatal oxidative stress, notably when supplemental oxygen is being delivered. Furthermore, despite recent advances in the management of neonatal respiratory distress syndrome, controversies persist concerning the oxygenation saturation targets that should be used in caring for preterm babies. Identification of adequate biomarkers of oxidative stress in preterm infants such as 8-iso-prostaglandin F2α, and adduction of malondialdehyde to hemoglobin is important to promote specific therapeutic approaches. At present, no therapeutic strategy has been validated as prevention or treatment against oxidative stress. Breastfeeding should be considered as the main measure to improve the antioxidant status of preterm infants. In the last few years, melatonin has emerged as a protective molecule against oxidative stress, with antioxidant and free-radical scavenger roles, in experimental and preliminary human studies, giving hope that it can be used in preterm infants in the near future.

Pathophysiology of Fetal and Neonatal Kidneys

The definitive kidney, the methanephros, is formed by two processes, nephrogenesis (the formation of glomerulus and tubules) and branching morphogenesis (the formation of collecting ducts, calyces, pelvis and ureters). The metanephric kidney takes place after the formation and involution of two embryonic kidneys, the pronephros (non functional organ) and the mesonephros (first functional kidney), that in turn evolves into the ureteric bud (UB). The metanephros appears during the fifth gestational week, and develops from the specific interaction between the epithelial ureteric bud and the undifferentiated metanephric mesenchyme (MM). This interaction is crucial for the differentiation of the mesenchyme and the induction of UB branching division (Fig. 124.1). The UB arises in response to signals elaborated by the mesenchyme and then undergoes branching morphogenesis following the invasion of the MM by the UB. This process gives a 15 branch generation. At 20–22 weeks of gestation, branching morphogenesis is completed and results in the collecting system. Mesenchymal cells that are in close contact with the invading UB undergo an epithelial transformation. The induced metanephric mesenchyme (MM) gives the nephrons, through the consecutive stages of condensation, renal vesicule, vascular cleft, and S-shaped body. The glomerular capillary tuft is formed via recruitment and proliferation of endothelial and mesangial cells precursors. The nephrons develop in successive stages from the inner to the outer area of the fetal kidney in parallel with the vascular system. In the human, the primitive glomerulus appears at approximately 9–10 weeks of gestation. The nephrogenesis is completed by 34–36th weeks of gestation [1]. About 60% of the nephrons develop during the third trimester of gestation, while nephrogenesis may continue ex-utero in preterm infants [2]. Once nephrogenesis is complete, stroma cells differentiate into fibroblasts, pericytes and lymphocytes-like cells. At birth the final nephron number varies from 800,000 and 1 million per kidney. Such variation in nephron number is due to genetic factors and to the fetal environment [3]. Several genes and molecular pathways control the formation of the renal collecting system and nephrogenesis, such as transcriptional factors (PAX-2, WT1), growth factors (IGF, EGF, TGF), oncogenes, the extracellular matrix, and vascular factors (Table 124.1) [4]. These factors act at a specific time of kidney development especially when the UB interacts with the adjacent MM. Blockade of vascular endothelial growth factor receptor (VEGF-R), inhibition of the renin angiotensin system (RAS) and knock-out for cyclooxigenase (COX)-2 gene expression are associated with impaired nephrogenesis including glomerular cysts, dysplasic tubules and tubular dysgenesis [5, 6, 7].