**4.2.1 Hyperoxia**

74 Basic Nephrology and Acute Kidney Injury

Two potential factors in the *in utero* environment that may render the preterm kidney

IUGR (growth below the 10th percentile for gestational age) is often a co-morbidity of preterm birth. Certainly, it is well described in both human and experimental models that IUGR leads to a reduced nephron endowment at birth (Hinchliffe et al., 1992a; Merlet-Benichou et al., 1994; Manalich et al., 2000; Zimanyi et al., 2004; Zohdi et al., 2007). This is likely due to the reduced growth of the fetal kidney (with the number of nephrons directly proportional to kidney size). In this regard, there is often redistribution of blood flow in the growth-restricted fetus, leading to preferential blood flow to the brain (termed brain sparing) and reduced blood flow to organs such as the kidneys (Behrman et al., 1970; Gunnarsson et al., 1998). To our knowledge the impact of reduced blood flow to the formation of nephrons in the IUGR fetal kidney has not been investigated. Given the dramatic change in hemodynamics at the time of birth (elevation in blood pressure and increased renal blood flow) it is conceivable that the recently formed glomeruli in the IUGR kidney (with a reduced renal blood flow prenatally) may be particularly vulnerable to the haemodynamic transition at birth. This is an important area of research that needs to be

Chorioamnionitis (a bacterial infection of the chorion and amnion) is a common antecedent of preterm birth (Romero et al., 2006; Goldenberg et al., 2008), especially in births prior to 30 weeks of gestation (Lahra and Jeffery, 2004); it is often complicated by IUGR. Chorioamnionitis may manifest as either a clinical or subclinical condition. When severe, it can ultimately give rise to the fetal inflammatory response syndrome which is characterised by funisitis, fetal vasculitis and an increase in of pro-inflammatory cytokines in fetal blood and amniotic fluid (Romero et al., 1998; Romero et al., 2003; Gotsch et al., 2007). It is likely that the fetal systemic inflammatory response will lead to renal inflammation in chorioamnionitis-exposed infants; conceivably if present *in utero* this will have deleterious effects on nephrogenesis, and if present at the time of delivery, it will adversely impact on renal function. In this regard, we have recent evidence in fetal sheep to demonstrate that exposure to chorioamnionitis late in gestation does adversely affect nephrogenesis, leading to a 23% and 18% reduction in nephron endowment in singleton and twin-exposed fetuses, respectively (Galinsky et al., 2011). It is important to note that we did not observe any morphological abnormalities in the glomeruli of these fetal kidneys. However, it is conceivable, that if renal inflammation is present at the time of birth, that this will further compromise postnatal nephrogenesis and renal function in the neonate. Following the hemodynamic transition at birth, it may be then that glomerular morphological abnormalities develop in these already compromised kidneys. Importantly in this regard, a multiple logistic regression analysis of 2508 preterm neonates, treated with indomethacin, showed a significant correlation between intrauterine inflammation and prevalence of renal and electrolyte abnormalities (Itabashi et al., 2003), thus suggesting that intrauterine inflammation in concert with postnatal indomethacin treatment can lead to renal dysfunction. Certainly our results support the idea that prematurity, when complicated with

**4.1 Adverse factors in the** *in utero* **environment** 

**4.1.1 Intrauterine growth restriction** 

thoroughly investigated.

**4.1.2 Chorioamnionitis** 

vulnerable are IUGR and/or exposure to chorioamnionitis.

The administration of supplemental oxygen to preterm infants experiencing respiratory distress is standard therapy, however, the effects of high levels of oxygen in the bloodstream on the development of organs is not well understood. Although the levels of supplemental oxygen administered to the preterm infant have been substantially reduced in recent years, the levels of oxygen in the bloodstream remain elevated above normal; hence it is important that research is conducted into the effects of hyperoxia on nephrogenesis in the preterm infant. Certainly, experimental studies in the lung have shown that hyperoxia can lead to the generation of oxygen free radicals, infiltration of inflammatory cells, collagen deposition, cellular apoptosis and subsequent tissue injury (McGrath-Morrow and Stahl, 2001; Dieperink et al., 2006; Alejandre-Alcazar et al., 2007; Chen et al., 2007; Chetty et al., 2008). Whether this is also the case in other tissues has not been examined.
