Morphologic Development of the Kidney
Laura S. Finn
The development of the kidney is a complex and well-coordinated process relying on the integration of cellular proliferation, programmed cell death, migration, morphogenesis, and differentiation. Through the regulated expression of various transcription factors, adhesion molecules, and growth factors, nephrogenesis proceeds in an orderly fashion; aberration of the systematic progression can lead to a wide spectrum of renal disorders that manifest in children and adults.
The mature human kidney and ureters are the third set of renal organs derived sequentially from intermediate mesoderm. The first paired organs, the most cranially oriented pronephroi (singular, pronephros), appear early in the fourth week of gestation and consist of primitive tubules that attach to a ductal system that empties into the cloaca. These temporary organs do not function in the human embryo, and they degenerate as soon as they are formed, being replaced late in the fourth week of gestation by the second kidney, the mesonephros. The mesonephroi develop primitive glomeruli and tubules that connect to the excretory ducts of the pronephroi. These ducts, renamed mesonephric or Wolffian ducts, connect with the cloaca. The mesonephroi are known to function in some lower animals and may do so transiently in humans. They slowly degenerate as the third set of paired organs, the metanephroi, evolve.
The development of the metanephros, the definitive kidney in mammals, begins during the fifth week of gestation. Signals from the nephrogenic mesenchyme (metanephric blastema), a specialized region of the intermediate mesoderm, induce outgrowth of the ureteric bud from the caudal mesonephric duct. The glial-derived neurotrophic factor (GDNF)–RET signaling pathway is a crucial initiator, as targeted Gdnf deletions can result in bilateral renal agenesis with failure of ureteric bud development. Early stages of development also are dependent on the activity of WT1 that is expressed in metanephric blastema but not in the Wolffian duct or ureteric bud. Upon invasion of the blastema, reciprocal inductive signals promote the elongation and branching of the tip (ampulla) of the ureteric bud to form the collecting system, as well as proliferation of the metanephric blastema, which acquires a stem-cell phenotype and will differentiate into nephrons. The caudal portion of the ureteric bud will lengthen eventually to form the ureter.
The advancing ampulla of the ureteric bud undergoes a rapid sequence of dichotomous divisions, with each branch forming a new ampulla. This branching is under the control of a host of growth factors that induce (e.g., epidermal growth factor) or inhibit (e.g., transforming growth factor–beta) the process. Remodelling of the first three to five generations, by a process of distension and coalescence, forms the major calyces. Subsequent generations of branches form the minor calyces, into which 10 to 20 papillary collecting ducts will drain. The development of the pelvicaliceal system is complete by the tenth to twelfth week of gestation.
Further divisions of the ampullae are dedicated to nephrogenesis. A stimulus from the advancing ampulla induces metanephric blastema to condense, migrate, and proliferate. PAX2 activation and subsequent WNT4 signaling derived from the aggregating mesenchyme are required for the epithelial conversion that results in the formation of the renal vesicle. Changes in the expression patterns of various other transcription factors, protooncogenes, growth factors, and adhesion molecules occur at all steps of nephron formation.