Pathophysiology of Fetal and Neonatal Kidneys

Abstract

The definitive kidney, the methanephros, is formed by two processes, nephrogenesis (the formation of glomerulus and tubules) and branching morphogenesis (the formation of collecting ducts, calyces, pelvis and ureters). The metanephric kidney takes place after the formation and involution of two embryonic kidneys, the pronephros (non functional organ) and the mesonephros (first functional kidney), that in turn evolves into the ureteric bud (UB). The metanephros appears during the fifth gestational week, and develops from the specific interaction between the epithelial ureteric bud and the undifferentiated metanephric mesenchyme (MM). This interaction is crucial for the differentiation of the mesenchyme and the induction of UB branching division (Fig. 124.1). The UB arises in response to signals elaborated by the mesenchyme and then undergoes branching morphogenesis following the invasion of the MM by the UB. This process gives a 15 branch generation. At 20–22 weeks of gestation, branching morphogenesis is completed and results in the collecting system. Mesenchymal cells that are in close contact with the invading UB undergo an epithelial transformation. The induced metanephric mesenchyme (MM) gives the nephrons, through the consecutive stages of condensation, renal vesicule, vascular cleft, and S-shaped body. The glomerular capillary tuft is formed via recruitment and proliferation of endothelial and mesangial cells precursors. The nephrons develop in successive stages from the inner to the outer area of the fetal kidney in parallel with the vascular system. In the human, the primitive glomerulus appears at approximately 9–10 weeks of gestation. The nephrogenesis is completed by 34–36th weeks of gestation [1]. About 60% of the nephrons develop during the third trimester of gestation, while nephrogenesis may continue ex-utero in preterm infants [2]. Once nephrogenesis is complete, stroma cells differentiate into fibroblasts, pericytes and lymphocytes-like cells. At birth the final nephron number varies from 800,000 and 1 million per kidney. Such variation in nephron number is due to genetic factors and to the fetal environment [3]. Several genes and molecular pathways control the formation of the renal collecting system and nephrogenesis, such as transcriptional factors (PAX-2, WT1), growth factors (IGF, EGF, TGF), oncogenes, the extracellular matrix, and vascular factors (Table 124.1) [4]. These factors act at a specific time of kidney development especially when the UB interacts with the adjacent MM. Blockade of vascular endothelial growth factor receptor (VEGF-R), inhibition of the renin angiotensin system (RAS) and knock-out for cyclooxigenase (COX)-2 gene expression are associated with impaired nephrogenesis including glomerular cysts, dysplasic tubules and tubular dysgenesis [5, 6, 7].