Preterm birth: effects on renal development and function
thesisposted on 17.02.2017 by Sutherland, Megan
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Worldwide, approximately 10% of all births are preterm (defined as delivery prior to 37 completed weeks of gestation). Preterm birth is the leading cause of perinatal mortality and morbidity, which may be attributed to the structural and functional immaturity of a number of organ systems after birth. In the kidney, nephrogenesis (the development of nephrons) is ongoing in late gestation, with the final complement of nephrons normally only formed by 32-36 weeks gestation. Therefore, in infants born preterm, the development of the kidney is often still ongoing at the time of birth; it is unknown, however, what effect this may have on renal development. In addition, the preterm infant may be exposed to a number of factors in the extrauterine environment (such as supplemental oxygen therapy and exposure to nephrotoxic medications) that may further influence renal development, and may also lead to renal injury. It was therefore hypothesised that preterm birth (and/or related factors in the postnatal care of the preterm neonate after birth) would adversely affect renal development and function in the neonatal period. To address this hypothesis, studies of structural and functional renal development in human preterm neonates, as well as in preterm baboon, preterm lamb and neonatal mouse models, were undertaken. The aims of the first two experimental studies reported in this thesis were to determine the effects of preterm birth on renal function (Chapter 2) and renal morphology (Chapter 3) in human neonates. The preterm neonatal kidney was shown to be functionally immature during the first month of life, with a lower rate of creatinine clearance and higher sodium and protein excretion than neonates born at term. Renal maturity was the major determinant of renal functional capacity; however, pathological proteinuria and high urinary neutrophil gelatinase associated lipocalin (NGAL) levels suggested that postnatal renal injury had also occurred in some neonates. The results of Chapter 3 demonstrated that nephrogenesis was ongoing in the extrauterine environment following preterm birth. Evidence of accelerated renal maturation, glomerular hypertrophy, and abnormal glomerular morphology suggest, however, that the ongoing nephrogenesis may have been impaired. Dilation of glomerular capillaries was also observed in the lamb kidney following preterm birth (Chapter 4); if this persists, it is probable that glomerular hypertrophy may in the long term result in glomerulosclerosis and subsequent nephron loss. In Chapters 5 and 6 of this thesis, specific factors commonly involved in the postnatal care of the preterm neonate were investigated as possible causes of impaired renal development. As reported in Chapter 5, exposure to moderate hyperoxia (65% O2) did not appear to have any effect on postnatal nephrogenesis in a neonatal mouse model; there was no change in the maturation of glomeruli, and nephron endowment was within the normal range. In early adulthood, however, glomerular hypertrophy was evident in the hyperoxia-exposed animals, which suggests the possibility of an underlying impairment in vascular development and/or injury. As shown in Chapter 6, early postnatal treatment with the nephrotoxic medication ibuprofen (commonly used in the treatment of a patent ductus arteriosus in preterm neonates) resulted in a significant reduction in nephrogenic zone width; this may imply the early cessation of nephrogenesis. Overall, the findings of this series of studies suggest that the nephrogenic potential of the preterm neonate is not being reached after birth. Ultimately, this may result in a deficit of functional nephrons in the preterm kidney, which is likely to have an adverse effect on both the short and long-term renal health of individuals born preterm. It is essential that future research be focused on the identification of factors that adversely influence development of the preterm kidney, in order to develop strategies that can be implemented in the neonatal intensive care setting to optimise postnatal renal development.