Effect of preterm birth on renal outcomes

Introduction

Preterm birth is estimated to impact 15 million births worldwide annually. Due to advancements in the treatment of preterm infants, survival of these infants has improved, albeit with increased morbidity due to the development of chronic diseases, especially in those born extremely preterm. ^, The renal consequences of preterm birth are relevant in the short term, during the neonatal intensive care unit (NICU) course, as well as in the long term over the life span. ^, Preterm birth has been repeatedly shown in large epidemiologic studies to be associated with an increased risk of chronic kidney disease (CKD) and hypertension in adulthood as part of the developmental origins of cardiovascular and renal disease model. This phenomenon was initially described by Barker several decades ago after his observation that individuals in specific regions during periods of famine or high infant mortality rates were born of lower birth weight and developed cardiovascular disease and metabolic syndrome in late adulthood disproportionately to those not exposed in utero to harsh environmental stressors. ^, This paradigm has now spawned both clinical and experimental studies looking at various exposures from the womb, including preterm birth and low birth weight (LBW), and the impact on how adaptive responses in utero to various stressors becomes maladaptive in early life and can lead to various chronic disease phenotypes, coined the “thrifty phenotype.” In this chapter, we will highlight the unique impact of preterm birth on the developing kidney as well as summarize important tools available to monitor renal health after preterm birth.

Nephrogenesis interrupted by preterm birth and physiologic adaptations

Nephrogenesis in humans, as opposed to other species, is ongoing through 36 weeks’ gestation, with most of the nephron development occurring in the second and third trimesters. ^, Thus preterm infants are born with an incomplete complement of nephrons—oligonephronia—which is proportional to the degree of prematurity. ^, Autopsy studies of infants born preterm have shown that more advanced nephrogenesis correlated with gestational age (GA), that preterm infants had a lower radial glomerular count than term infants and that preterm infants had a greater percentage of morphologically abnormal glomeruli and evidence of renal hyperfiltration ( Fig. 10.1 ). In fact, the number of nephrons has been shown to increase by 25,743 for each additional 100 g of birth weight. Additionally, among all humans, there is a wide normal distribution in congenital nephron endowment, with a 10-fold variance in nephron numbers ranging from approximately 200,000 to over 2 million per kidney, which is likely reflective of evolutionary developmental plasticity and epigenetic processes that alter phenotype in response to environmental stimuli. Similarly, infants born preterm have a high interindividual variability in radial glomerular counts and glomerular morphology, which implies that some infants born preterm have more resilience in nephron mass and function at birth than others.

In addition, postnatal nephrogenesis in preterm infants has been noted to occur aberrantly in the first 40 days of life. Unsurprisingly, even outside this initial period, postnatal nephrogenesis is negatively impacted by the presence of acute kidney injury (AKI) ( Fig. 10.2 ). Various extrauterine stressors encountered frequently by the preterm neonate including nephrotoxin exposures, hemodynamic instability, sepsis, and oxidative stress from hyper- and hypoxic insults are cumulatively detrimental during the limited 4- to 6-week period of ongoing nephron formation after birth. Once nephrogenesis ceases, only tubular and interstitial tissue expansion and vascular growth continue to occur.

At the time of birth, the kidneys undergo a significant hemodynamic transition from the fetal to extrauterine environment that is heralded by an abrupt increase in renal perfusion pressure mediated by a larger proportion of the cardiac output (3% fetal → 20% postnatal) directed toward the kidneys. This transition characterizes the increase in glomerular filtration rate (GFR) seen during the switch from fetal to extrauterine life given that the mean arterial pressure increases while the renal vascular resistance decreases allowing for improved renal blood flow. This phenomenon is further orchestrated by several intrarenal vasoconstrictive (i.e., renin-angiotensin-aldosterone system [RAAS], endothelin) and vasodilator (i.e., atrial natriuretic peptide, bradykinin, prostaglandins, nitric oxide) forces that are essential in maintaining an appropriate balance in renal perfusion and avoiding vasomotor nephropathy. There is also a gradual decrease in filtration fraction (filtration fraction = GFR/renal plasma flow), which is the proportion of the plasma reaching the kidneys that ultimately passes into the renal tubules, from 50% after birth to a mature level of 20% once renal vascular resistance decreases and tubular expansion occurs. However, in preterm infants the filtration fraction is higher and takes longer to mature. The urinary flow rate is positively correlated with increasing GFR during the first few days of life in both term and preterm infants. Of note, the rate of increase of GFR is less in preterm than in term infants and continues to be discrepant during the early childhood years. ^{, ,} Significant debate still exists as to how to best calculate GFR and define AKI in the neonatal period given the limitations of current biomarkers. ^{, ,} At birth, immature renal tubules result in a limited urinary concentrating ability and increased fractional excretion of sodium, which gradually matures with time.

One important consequence of having a congenital nephron deficit and hence reduced glomerular filtration surface area is the development of hyperfiltration known as the Brenner hypothesis . This phenomenon describes the adaptation to a reduction in the number of nephrons by increasing the single nephron GFR. Although this compensation helps to maintain GFR initially, over time the rise in intraglomerular pressure related in part to activation of the RAAS leads to albuminuria, glomerulosclerosis, and clinically significant CKD ( Fig. 10.3 ). ^,