Development and Regulation of Renal Blood Flow in the Neonate

Characteristics of Renal Blood Flow in the Immature Kidney

Total Renal Blood Flow

In most mammalian species, with the horse as one exception, renal blood flow in the neonate is lower than in the adult compared on the basis of body weight, kidney weight, or surface area. ^, In human newborns and infants, total renal blood flow has been determined by the clearance of p -aminohippurate (PAH), which measures effective renal plasma flow (ERPF) and by Doppler ultrasonography. ^, Renal blood flow measured by Doppler and ERPF by clearance of PAH is lowest in newborns, and it correlates with gestational age. The increase in renal blood low, measured by pulsed Doppler ultrasonography, is related to an increase in vessel diameter and flow velocity. ^, After birth, following the short-term occlusion of the umbilical cord, renal blood flow does not change immediately, but there is redistribution of blood to the renal outer cortex (see below). There are also no significant changes in renal blood flow velocity or in renal vascular resistance during the transition from fetal to newborn life, rather renal blood flow increases after 24 hours of postnatal life. ^, After birth, the increase in renal blood flow is most likely related in part to an overall increase in blood pressure, cardiac output, as well as a decrease in renal vascular resistance. ^, In humans, the proportion of cardiac output distributed in the kidney in fetal life is 2% to 3%, ^, 4% to 6% in the first 12 hours of life, 10% at one day of age, and 16% at 2 days of age, which are less than the 20% to 25% observed in adults. ^, A decreased proportion of cardiac output to non-human fetuses has also been reported. ^, Using 3D-power Doppler ultrasonography, renal blood flow/index was reported to increase linearly from 23 to 40 weeks of gestational age. By contrast, in fetuses with intrauterine growth retardation, the renal blood flow index plateaued at 34 weeks of gestational age. Renovascular reactivity index, which can detect changes in renal blood flow, can be monitored by reflectance near-infrared spectroscopy. ^, However, renal oxygen saturation may slightly increase, not change, or even decrease over the first few weeks of life of preterm infants instead of the expected increase in renal blood flow after birth. ^,

The increase in renal blood flow after birth in preterm infants is influenced by postconceptional rather than postnatal age. ERPF increases from 20 mL/min/1.73 m ² at 30 weeks gestation to 50 mL/min/1.73 m ² by 35 weeks gestation and 80 mL/min/1.73 m ² at term gestation. During the first 3 months of human postnatal life, ERPF increases rapidly to 300 mL/min/1.73 m ² . Thereafter, ERPF increases gradually, reaching values of 650 mL/min/1.73 m ² by 12 to 24 months of age ( Fig. 95.2 ). ^, However, the clearance of PAH underestimates ERPF in the neonatal period because the renal extraction of PAH is only 60% during the first 3 months of age compared with 94% by 5 months of age. The low renal extraction of PAH in the neonate ^, has been attributed to shunting of blood to non-PAH-extracting tissues (e.g., relatively greater medullary blood flow and intracortical efferent arteriovenous shunting). PAH clearance also increases postnatally in the mouse. However, PAH is also transported by OAT1 (SLC22a6) in renal proximal tubules and increases with maturation. Thus, the PAH clearance, as an index of renal plasma flow, may be overestimated by renal proximal tubular secretion. ^, Increasing blood pH with use of bicarbonate or maternal use of antihypertensive drugs does not affect fetal renal oxygen saturation, which may be related to autoregulation of renal blood flow. ^,

Intrarenal Blood Flow

The renal vasculature is characterized by two capillary networks (the glomerular and peritubular capillary system) linked in series with each other. The major sites of renal vascular resistance are the glomerular arterioles. Blood enters the glomerulus via the afferent arteriole that arises from the interlobular artery, and it exits via the efferent arteriole. Vasoconstriction or vasodilation at these sites regulates blood flow to the glomerulus (hence, glomerular filtration rate) and the intrarenal distribution between the cortex, which contains all the glomeruli, and the medulla, which contains vasa recta and tubules but not glomeruli. In the mature kidney, the afferent arteriole of inner cortical nephrons accounts for the entire preglomerular resistance to blood flow, whereas in superficial cortical nephrons, the interlobular arteries offer the largest resistance to blood flow. Blood flow to each region of the kidney (cortical, medullary, and papillary) increases with maturation. ^{, , ,} The distribution of intrarenal blood flow in the young, however, is different from that reported in adults. The neonatal kidney has a greater percentage of blood flow to the inner cortical and medullary areas than the adult kidney. ^, In newborn lambs, clamping the umbilical cord increases renal outer cortical blood flow. The low extraction ratio of PAH in infants younger than 3 months of age may be related to a relatively greater perfusion of juxtamedullary nephrons. As total renal blood flow reaches adult levels with maturation, a greater fraction of renal blood flow is received by the outer cortical nephrons. The duration of this maturational period varies from species to species. ^{, ,}

Autoregulation of Renal Blood Flow in the Young

The mature kidney exhibits autoregulation; that is, renal blood flow remains constant even though renal perfusion pressure (determined by mean arterial pressure) varies throughout a range from low to high. Autoregulation depends on intrarenal mechanisms which is modulated by intrarenal factors. The myogenic response and macula-densa-tubuloglomerular feedback mediate the autoregulation of renal blood flow. In the newborn, the range of autoregulation is set at lower perfusion pressures than seen in the adult, and the renal pressure-flow relationship changes with renal growth. ^{, ,} Autoregulation of renal blood flow has been claimed to be negligible at birth and less efficient in the young than in the adult. Furthermore, uninephrectomy impairs the autoregulatory response in young rats but does not affect this response in adult rats. This reduced autoregulatory efficiency in the neonate is apparently the result of prostaglandin-dependent renin release, which causes vasoconstriction at lower levels of perfusion pressure. In pigs, the reduced autoregulatory efficiency in the neonate is not due to impaired myogenic responses. ^, The genetics and epigenetics of autoregulation have to be taken into consideration. For example, TRPV4 channels and γ-adducin are involved in myogenic autoregulation. TRPV4 channels in preglomerular arteriolar smooth muscles contribute to renal myogenic autoregulation in neonatal pigs. In the fetal lamb kidney, the sensitivity of the tubuloglomerular feedback is increased and decreases after birth; this is believed to be important in the postnatal increase in glomerular filtration rate. In human infants, the frequency of a negative sodium balance is inversely proportional to gestational age and suggests immaturity of glomerulotubular feedback.

Maturational relationships between tubular flow and glomerular filtration rate (tubuloglomerular feedback) occur with postnatal growth. The tubuloglomerular feedback mechanism is maximally sensitive at a tubular flow range that corresponds to the normal operating range. As the glomerular filtration rate increases with maturation, the maximal response and flow range also increase, so the relative sensitivity of the tubuloglomerular feedback mechanism is unaltered during growth. However, gestational exposure to glucocorticoids increases the sensitivity of the tubuloglomerular feedback. The relative roles of endothelial cell and smooth muscle in tubuloglomerular feedback have not been fully defined in the developing animal.

Regulation of Postnatal Renal Hemodynamics

The low renal blood flow of the preterm and full-term neonate and the increase that occurs with maturation are the result of a combination of effects, including alterations in cardiac output, perfusion pressure, and renal vascular resistance. ^, Lower cardiac output and perfusion pressure may partially account for the decreased renal blood flow noted in the newborn infant. In the dog, however, cardiac output corrected for body weight is highest in the youngest puppies, which also have the lowest renal blood flow per body weight. ^, As aforementioned, the proportion of cardiac output distributed in the kidney in fetal life is 2% to 3%. The proportion of cardiac output distributed to the kidneys is 4% to 6% in the first 12 hours of life and increases to about 10% at one day of age, 16% at two days of age. These are in contrast to the 20% to 25% of cardiac output distributed to the kidneys in the normal adult. ^, As noted earlier, a decreased proportion of cardiac output to non-human fetuses has also been reported. ^, Systemic vascular resistance decreases markedly after birth. This may cause a redistribution of blood flow to organs other than the kidney and may immediately contribute to the low neonatal renal blood flow. Systemic vascular resistance gradually increases with maturation and therefore is not a factor in the increase in renal blood flow with age. However, in most species, renal vascular resistance is the most important component contributing to postnatal renal hemodynamics. Gruskin and colleagues demonstrated that, in the developing piglet, the major factor influencing the maturational increase in renal blood flow was an 86% decrease in renal vascular resistance. Renal vascular resistance in the developing kidney is influenced by structural factors, the number and size of vascular channels, as well as by functional vasoactive factors, the modulators of the resistance offered by the glomerular arterioles ( Fig. 95.3 ). ^,