Pulmonary hypoplasia in the fetus with oligohydramnios: Causes, treatment, and prevention

Kidney development

Human fetal kidneys arise sequentially from the embryonic mesoderm and nephrogenic cord over three distinct stages of overlapping rostral-to-caudal systems: the pronephros, mesonephros, and metanephros. The earliest pronephric ducts are nonfunctional vestigial ducts that form at the cervical region of the nephrogenic cord, appearing at the beginning of the fourth week of gestation then regressing by the end of the same week. In the next stage, the mesonephros emerges in the fourth week of gestation, arising from the upper thoracic to upper lumbar segments of the nephrogenic cord. The mesonephros and mesonephric ducts differentiate in a rostral-to-caudal fashion, developing early renal corpuscles that include a glomerulus, tubules, and collecting ducts. These early nephrons excrete small amounts of “urine” into the amnion during the second month of gestation. However, by the end of the second month of gestation, the majority of the mesonephros degenerates. In males, select structures persist and develop into parts of the reproductive system. ^, The final stage, the metanephros, becomes the definitive mammalian kidney. It appears in the fifth week of gestation and is derived from the sacral region of the nephrogenic duct ( Fig. 4.1 A). The undifferentiated and pluripotent cells or blastema of the metanephros develop into nephrons in a similar fashion as in the mesonephros, leading to the formation of glomeruli, Bowman’s capsules, and the proximal and distal tubules. The collecting ducts of the metanephros, on the other hand, develop from the ureteric bud, which is an extension of the mesonephric duct proximal to the cloaca. Through reciprocal induction with the metanephric blastema, the extending ureteric bud begins branching in the sixth week of gestation and gives rise to the collecting tubules, renal calyces, renal pelvis, and ureters. ^{, ,} The metanephros is functional around the 12th week of gestation. Urine passing into the amnion and eventually comprises approximately 90% of the composition of the amniotic fluid in the third trimester. However, the placenta, not the kidney, serves as the main source of fetal blood filtration and the elimination of fetal waste products until birth.

A detailed description of the regulation of normal nephrogenesis is beyond the scope of this chapter, and excellent reviews can be found elsewhere. However, shared biological pathways in both kidney and lung development may offer a link between congenital kidney anomalies and pulmonary hypoplasia and the potential for therapeutic intervention. The ureteric bud and the surrounding metanephric blastema or cap mesenchyme differentiate though reciprocal signaling. The ligands glial cell–derived neurotropic factor and hepatocyte growth factor from the cap mesenchyme and Rearranged during transfection (RET), the glial cell–derived neurotropic factor receptor in the ureteric bud tip, are fundamental for the growth and branching of the ureteric ducts. Several hierarchical transcription factors, such as Six2, Wnt4, and WT1, guide the differentiation of the blastema into nephrons through regulation of mesenchymal to epithelial differentiation. Later, Notch proteins regulate tubule segment-specific differentiation. Similarly, the ureteric bud secretes signaling factors including fibroblast growth factor (FGF) 2 and bone morphogenetic protein 7, which are involved in normal glomerular, tubule, and collecting duct development. ^{, ,} Renal branching morphogenesis therefore is a crucial process in the formation of fetal kidneys and in the determination of the final number of nephrons, of effective glomerular filtration rate (GFR), and of postnatal renal function. Interestingly, many of the proteins encoded by these genes, such as transforming growth factor-β, FGF, and members of the retinoid signaling pathways, are soluble growth factors that can be recovered in the urine and amniotic fluid. ^, In humans, kidney branching morphogenesis and the acquisition of new nephrons are complete by 36 weeks’ gestation. The average number of nephrons in a human kidney is approximately 1 million, with a wide range between 200,000 up to 2.7 million nephrons. Consequently, a number of factors that disrupt normal kidney development (including genetic mutations, alterations of the normal fetal environment, and preterm birth) have been associated with reduced nephron number.

Lung development

The organogenesis of the human lungs shares some similarities with the kidney, yet with some key differences. Both organs rely on branching morphogenesis to establish the number of functional units (i.e., alveoli in the lung and nephrons in the kidney). Unlike the kidney, the lung continues to develop and mature postnatally; humans acquire their final number of alveoli in the first decade of life. The human lung also develops in multiple stages, namely the embryonic, pseudoglandular, canalicular, saccular, and alveolar stages ( Fig. 4.1 B). These stages occur in chronological sequence and are determined morphologically. The first embryonic stage starts with the appearance of the respiratory diverticulum (lung bud) as an outgrowth from the ventral foregut endoderm at 4 weeks’ gestation. Two bronchial buds emerge and enlarge during the fifth week, determining the right and left main bronchi. ^{, , ,} During the fifth week of gestation, the pseudoglandular stage occurs and is characterized by continued lung growth through dichotomous branching morphogenesis with simultaneous blood vessel branching. At the end of this stage, and by the 16th week of gestation, the airway tree, cartilage, smooth muscle, and mucous glands have branched and differentiated into terminal bronchioles. In the canalicular stage, terminal bronchioles branch into respiratory bronchioles, leading to future alveoli. This canicular stage starts in the 16th week and ends by the 26th week of gestation. By the end of this stage, the most distal epithelial branches start to widen and thin with proximity to the capillary network, leading to the first sign of alveolar epithelial cell differentiation. ^, Between the 24th week and term gestation, the saccular stage occurs during which branching morphogenesis continues. This stage is also characterized by further differentiation of the terminal airspaces into clusters of thin-walled saccules to become alveoli. The alveolar epithelium differentiates into type I and type II alveolar cells, which is surrounded by capillaries and fibroblasts. Surfactant production and recycling starts in this stage. By the end of the saccular stage, the lung is composed of numerous saccules, suitable for gas exchange. The fifth and final alveolar stage occurs postnatally and ends in childhood; however, recent imaging studies suggest that it continues into early adulthood. In the alveolar stage, the saccular walls septate and divide into mature alveoli. The vascular capillary systems also mature around the alveoli, leading to increase surface area for gas exchange. ^,

Similar to the kidneys, the lungs rely on branching morphogenesis for normal development. Lung development also depends on reciprocal signaling between the airway epithelium and the supporting mesenchymal cells. The initial budding of the respiratory diverticulum is induced by increased retinoic acid levels in the surrounding embryonic mesoderm. Retinoic acid upregulates transcription factor TBX4 in the adjacent area of the foregut, leading to the formation of the lung bud. After that, branching is dependent on multiple secretory signals from the mesenchymal cells including FGF10, Sonic Hedgehog (Shh), bone morphogenic protein 4, Wingless-related integration site (WNT), retinoic acid, Notch, transforming growth factor-β, and others. ^, As an example of reciprocal signaling, FGF10 expressed by distal mesenchymal cells drives the expression of Shh in the epithelial cells at the tip of the branch. In turn, Shh signals the smooth muscle at the tip, which splits and bifurcates the growing bud into two branches. Notably there is an overlap of signaling pathways responsible for branching morphogenesis in the lungs and in the kidneys. An alteration in these common branching signaling pathways, either in response to an abnormal intrauterine environment (as seen in lower urinary tract obstruction and associated oligohydramnios) or through genetic mutation, could help explain the association of and relationship between renal dysplasia and lung hypoplasia, particularly in genetic syndromes such as the ciliopathies and nephronophthises.

In addition to signaling pathways, two main mechanical forces, episodic fetal breathing movement and distending pressure of the luminal airway, are unique in and critical to normal fetal lung development. Fetal breathing movements are first noted during the pseudoglandular stage of lung development corresponding to the 10th to 11th week of gestation. Fetal breathing movements lead to repetitive changes in the distal lung surface area and thus lead to mechanical stretching. This stretching promotes epithelial cell differentiation via mechanosensitive channels, the maturation of type II epithelial cells, and the secretion of surfactant. Distending intraluminal fluid is the second mechanical force critical for normal lung development. Lung fluid is secreted into the lumen and creates distending pressure. Peristaltic waves of intraluminal fluid with rhythmic contraction of the airway smooth muscles are thought to promote branching morphogenesis. The amniotic fluid therefore represents a link between kidney and lung development.