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The kidney is one of the most highly differentiated organs in the body. At the conclusion of embryologic development, nearly 30 different cell types form a multitude of filtering capillaries and segmented nephrons enveloped by a dynamic interstitium. This cellular diversity modulates a variety of complex physiologic processes. Endocrine functions, the regulation of blood pressure and intraglomerular hemodynamics, solute and water transport, acid-base balance, and removal of drug metabolites are all accomplished by intricate mechanisms of renal response. This breadth of physiology hinges on the clever ingenuity of nephron architecture that evolved as complex organisms came out of water to live on land.

Kidneys develop from intermediate mesoderm under the timed or sequential control of a growing number of genes, described in Fig. 277-1. The transcription of these genes is guided by morphogenic cues that invite two ureteric buds to each penetrate bilateral metanephric blastema, where they induce primary mesenchymal cells to form early nephrons. This induction involves a number of complex signaling pathways mediated by Pax2, Six2, WT-1, Wnt9b, c-Met, fibroblast growth factor, transforming growth factor β, glial cell-derived neurotrophic factor, hepatocyte growth factor, and epidermal growth factor. The two ureteric buds emerge from posterior nephric ducts and mature into separate collecting systems that eventually form a renal pelvis and ureter. Induced mesenchyme undergoes mesenchymal epithelial transitions to form comma-shaped bodies at the proximal end of each ureteric bud leading to the formation of S-shaped nephrons that cleft and enjoin with penetrating endothelial cells derived from sprouting angioblasts. Under the influence of vascular endothelial growth factor A (VEGF-A), these penetrating cells form capillaries with surrounding mesangial cells that differentiate into a glomerular filter for plasma water and solute. The ureteric buds branch, and each branch produces a new set of nephrons. The number of branching events ultimately determines the total number of nephrons in each kidney. There are approximately 900,000 glomeruli in each kidney in normal birth weight adults and as few as 225,000 in low birth weight adults—producing the latter in numerous comorbid risks.

Figure 277-1

Genes controlling renal nephrogenesis. A growing number of genes have been identified at various stages of glomerulotubular development in the mammalian kidney. The genes listed have been tested in various genetically modified mice, and their location corresponds to the classical stages of kidney development postulated by Saxen in 1987. GDNF, giant cell line-derived neutrophilic factor; FGFR2, fibroblast growth factor receptor 2; WT-1, Wilms' tumor gene 1; FGF-8, fibroblast growth factor 8; VEGF–A/Flk-1, vascular endothelial growth factor–A/fetal liver kinase-1; PDGFβ, platelet-derived growth factor β; PDGFβR, PDGFβ receptor; SDF-1, stromal-derived factor 1; NPHS1, nephrin; NCK1/2, NCK-adaptor protein; CD2AP, CD2-associated protein; NPHS2, podocin; LAMB2, laminin beta-2.

Glomeruli evolve as complex capillary filters with fenestrated endothelia under the guiding influence of VEGF-A and angiopoietin-1 secreted by adjacently developing podocytes. Epithelial podocytes facing the urinary space envelop the exterior basement membrane supporting ...

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