Embryonic development of the kidney and urinary tract

Because of the complex nature of renal development, there are multiple opportunities for interference, through mutations in crucial genes or environtmental stresses, affecting various stages in the ontogeny of the kidney, which unfortunately lead to the outcome of a congenital anomalies of the kidneys and urinary tract disorders. In humans, the kidneys develop through a multistep process, progressing from an anterior to posterior tract. To produce mature kidneys, 2 transient phases must be navigated. These are characterized by partial development, followed by regression of primitive kidney, and then a third and final phase that results in a pair of functioning kidneys that serve to filter blood, excrete metabolic waste products, and regulate plasma electrolyte concentration and osmolality.

The process begins with formation of the nephritic duct (day 22 in humans) in the intermediate mesoderm at an anterior position. The duct induces nearby intermediate mesoderm cells to form the primitive tubules of the first kidney, known as the pronephros. In humans, the pronephros quickly degenerates, never forming a functioning renal organ. As the tubules of the pronephros dissapear, the nephritic duct grows caudally, following parallel to the tract of intermediate  mesoderm.  At a location caudal to the pronephros, the signals of the nephric duct transform the intermediate mesoderm into the next  primitive kidney, the mesonephros. Like the pronephros, the mesonephros forms a series of tubules (day 25 in humans),  but degenerates after a short time.  However, in the case of mesonephros, parts of tubules remain, becoming components of the male reproductive tracts (vas deferens), but do not contribute to the final kidney.

Still further caudal, near the level of the developing hind limb, is the metanephric mesenchyme, which will eventually develop into the final kidneys if the proper signaling  cascade is achieved. The metanephric mesenchyme cells produce and secrete glial cell line-derived neurotrophic factor, once the nephric duct reaches the level of the metanephric mesenchyme and is exposed to the chemical gradient of glial cell line-derived neurotrophic factor, it responds by producing a diverticula that homes in on, and invades, the metanephric mesenchyme tissue. This diverticula coming of the nephric duct is known as the ureteric bud, and it reciprocates the chemical communication with the  metanephric mesenchyme by secreting a number of transcription factors, including Fgf2 and BMP7, which are necessary to prevent the cells of the metanephric mesenchyme from undergoing apoptosis, as occured with the pronephros and mesonephros. The metanephric mesenchyme is the only tissue that can respond to ureteric bud signaling because of expression in this tissue.

As  the ureteric bud invades the metanephric mesenchyme, it will begin a series of branching events influenced by glial cell line-derived neurotrophic factor. Cells from the metanephric mesenchyme that condense onto the tips of the ureteric bud (known as cap mesenchyme) will eventually form the nephron. The proper number of branching events by ureteric bud is critical to achieve the appropriate number of nephrons in the final kidney (with normal variation ranging from 300.000 to 1.000.000).
The branches of the ureteric bud eventually form the collecting ducts, renal pelvis and the ureters. The cap mesenchyme that condensed onto the branches of the ureteric bud go on to become  the glomerulus, proximal tubule, loop of Henle and distal tubule. The bladder itself originates from a portion of the cloaca, and the nephric duct empties into the bladder, under the direction of Hox genes. All these events need to be precise in both time and space in order for the kidneys, ureters, and bladder to form properly.