**4.2.3 Extrauterine growth / nutrition**

In general, postnatal growth of the preterm infant is markedly attenuated when compared to the term infant and when compared to the normal rate of growth *in utero* for the same post-conceptional age (Ehrenkranz, 2000; Clark et al., 2003). Extrauterine growth restriction in premature neonates (defined as growth below the 10th percentile of intrauterine growth expectation) is likely to directly influence nephrogenesis. In support of this concept, Bacchetta et al (2009) reported lower GFRs (albeit in the normal range) in 7 year old children who had been born very preterm (< 30 weeks gestation) and who were either IUGR or extrauterine growth restricted. However, it is important to note that in some preterm infants there can be a disproportional increase in kidney size (relative to body weight) after birth (Huang et al., 2007; Sutherland et al., 2011b) most probably due to the increased functional demands on the kidney. Importantly we have shown in our preterm baboon studies that under these circumstances, there remains a significant correlation between kidney size and nephron number (Gubhaju et al., 2009).

Taken together, these studies highlight the importance that neonatal nutrition can potentially have on kidney development in the preterm infant. Since nephrogenesis is

Effects of Preterm Birth on the Kidney 77

eliminated (Nagai and Takano, 2004). In experimental studies antibiotics are also linked with impairment of nephrogenesis (Gilbert et al., 1990; Gilbert et al., 1994; Cullen et al., 2000; Nathanson et al., 2000). For instance, it has been shown that incubation of metanephroi in culture with gentamicin leads to decreased branching morphogenesis of the ureteric tree; this is a likely mediator of the reduction in the number of nephrons formed (Cullen et al., 2000). Given that antibiotics can readily cross the placenta, plus their wide use in the neonatal care of the preterm infant, it is imperative in future studies to gain a more precise understanding of the dose, duration and class of antibiotic treatment that leads to adverse effects in the neonatal kidney; such information would likely influence the care in the

NSAIDs, such as ibuprofen and indomethacin are usually administered to preterm neonates to stimulate closure of a patent ductus arteriosus; this can occur in up to 80% of extremely preterm infants (Ellison et al., 1983). Importantly, there have been a number of studies that have reported adverse effects on both the structure and function of the preterm kidney following treatment with NSAIDs. For example, renal insufficiency, demonstrated by a significant increase in serum creatinine has been reported in infants following either antenatal or postnatal exposure to NSAIDs (Kang et al., 1999; Butler-O'Hara and D'Angio, 2002). Of concern, in a case-controlled study where renal impairment was reported in preterm neonates that had received indomethacin treatment for a patent ductus arteriosus, 24% of the babies suffered acute renal failure (Akima et al., 2004). In addition, in the rat model where, similar to the preterm infant, nephrogenesis is ongoing after birth, exposure to indomethacin, ibuprofen and gentamicin have all been shown to lead to renal injury in the immature kidneys. There was evidence of vacuolization of epithelium and loss of microvilli in proximal tubules, effacement of podocyte foot processes and irregularities of the basement membrane in the

At birth, there is a marked change in hemodynamics, with a subsequent rise in blood pressure and heart rate (Teitel et al., 1987; Louey et al., 2000). Preterm birth causes an abrupt and premature shift in the circulation from the fetal to postnatal configuration at a time when the cardiovascular system is still relatively immature; as a result, it is often necessary for inotropes to be administered to preterm neonates when blood pressure remains abnormally low after birth (Kluckow and Evans, 2001; Osborn et al., 2002). Given the importance of renal blood flow to growth of the kidney it is important that future research examines how the hemodyamic transition at birth affects the development of the immature renal vasculature and/or nephrogenesis and what effect the administration of inotropes

Over the past decade, considerable advances have been made in our understanding of the effects of preterm birth on the developing kidney. Encouragingly, it has clearly been demonstrated that nephrogenesis continues after birth in the preterm neonate, however, glomerular abnormalities are commonly observed. Future research should be directed into the causes of these abnormalities, so that strategies can be implemented to maximise the

neonatal intensive care unit.

**4.3.4 Inotropes** 

**5. Conclusion** 

have on the developing kidney.

**4.3.3 Non steroidal anti-inflammatory drugs** 

glomeruli and edema within the interstitium (Kent et al., 2007).

ongoing after birth in the preterm infant, this provides a window of opportunity whereby early postnatal nutrition in the intensive care unit may be able to directly influence the number of nephrons formed within the kidney. Hence optimising nutrition in the neonatal period, with an aim to maximising nephron endowment in the preterm newborn, is an important area for future research. At this stage, there is no known maternal nutrient supplementation that can improve renal outcomes in the fetus; it is critical to investigate this.
