1.1.1 Kidney and urinary tract anatomy
The urinary system is a multi-component organ system, whose primary function is to produce, transport, store, and eliminate urine in order to maintain body homoeostasis by controlling the water and ionic balance of the blood (Rasouly and Lu, 2013). The kidney eliminates nitrogenous waste, maintains the volume, composition, and pressure of the blood, and the density of the bones (Bover and Cozzolino, 2011). Anatomically, the urinary system can be subdivided into an upper unit, the kidney, which filters and modifies the blood to produce urine, and a lower unit consisting of the ureter, the bladder, and the urethra, which transports, stores and eliminates the urine from the body (Rasouly and Lu, 2013). The nephron is the major component of the kidney, which filters the blood and maintains body homeostasis. A human kidney contains average 1 million nephrons (ranging between 200,000 and 1.8 million), which comprise intricately patterned and functionally compartmentalized epithelial structures (Hughson et al., 2003). The nephron can be further divided into the glomerulus, the proximal tubule, the loop of Henle, and the distal tubule.
1.1.2 Kidney and urinary tract development.
The kidney and ureter originate from the intermediate mesoderm in early embryos when an epithelial outpouching called the ureteric bud (UB) sprouts from the caudal region of the Wolffian duct (also called the nephric duct) and invades adjacent metanephric mesenchyme (MM) (Illustration 1.1A) (Davidson, 2008). After the UB invasion into the MM, a reciprocal induction between the tip of the UB and the MM results in multiple rounds of UB branching morphogenesis to form the collecting system (the collecting duct), while mesenchymal-to-epithelial transition (MET) of the MM leads to the formation of the nephron (Saxen, 1987). These developmental processes ultimately give rise to a functional kidney that starts to produce urine at ~10 weeks of gestation in human and ~E16.5 in mice. At the same time, the trunk of the UB (i.e. the UB portion remaining outside of the MM) elongates without branching to form the ureter, a muscular tube structure transporting urine from the kidney to the bladder (Illustration 1.1C) (Airik and Kispert, 2007). Together with the differential growth in the caudal part of the body during fetal development, the elongation of the ureter leads to the ascent of the kidney to its final position in the retroperitoneal space behind the abdominal cavity.
At each round of ureteric branching, the MM becomes compacted and forms aggregates that undergo mesenchymal-to-epithelial transition. The aggregates of MM first form spheres of polarized epithelia with de novo generation of a central lumen, called renal vesicles. Each sphere then elongates to form the comma-shaped body (C-shaped body), and then the S-(C-shaped body during nephrogenesis. The proximal end of the
S-shaped body forms the glomerulus, which connects to the proximal tubule that is derived from the mid-region of the S-shaped body, and the distal tubule that is derived from the distal-region of the S-shaped body. The distal tubule ultimately fuses with the tip of the adjacent ureteric bud to complete the connection of developing nephron to the collecting duct.
Illustration 1.1: Urinary tract development and Structure
(A) Early development of the urinary tract (4th week of gestation in human and E10.5 in mice). An epithelial diverticulum called ureteric bud (UB) emanates from the Wolffian duct and grows into an adjacent group of mesenchymal cells (metanephric mesenchyme).
(B) Elongation of the ureter and formation of the kidney (metanephros) during development. The common nephric ducts shorten, expand and integrate into the urogenital sinus (the future bladder) close to the region where the future bladder neck is located. (C) Structure of mature urinary tract in human and mice. Urine flows from the renal pelvis in the kidney through the ureter to the bladder for storage and eliminates to the outside through the urethra. The ureter is connected to the kidney at the ureteropelvic junction (UPJ) and connected to the bladder at the ureterovesical junction (UVJ). Inside the bladder, two ureteric orifices and the internal urethral orifice form the trigone. The urethral sphincter complex includes the lissosphincter which is a continuation of the bladder smooth muscle and the rhabdosphincter which consists of striated muscles. (D)
Transverse section of the mature ureter depicts four layers of cells: urothelium, stromal cells, smooth muscle cells and adventitial fibroblasts (Rasouly and Lu, 2013).
1.1.3 The renal corpuscle structure
The glomerular filtration barrier is the major structure that filters the blood to produce the primary urine. The glomerulus receives the blood from an afferent arteriole and drains into an efferent arteriole. The high pressure in the glomerulus capillaries enables blood filtration. The interior surface of the capillaries comprises the fenestrated endothelial cells. Numerous endothelial cell fenestrae of 60-80nm diameter enable the first filtration of plasma solutes and small molecular weight proteins. The endothelial cells sit on a thick (250-350nm) glomerular basement membrane (GBM) that also filters the blood. The podocytes line the other side of the GBM. The podocytes extend their cell bodies to form long filopodia structures called foot processes that interdigitate and wrap around the capillaries. The foot processes of neighboring podocytes are separated by filtration slits that are bridged by a cell adhesion structure called the slit diaphragm through which the blood is filtered to form the primary urine in the Bowman’s space. The Bowman’s space is enclosed by the Bowman’s capsule that is lined by parietal epithelial cells. The capsule has two poles: the vascular pole, where the afferent and the efferent arterioles enter into and exist from the sphere, and the urinary pole which is connected to the proximal tubule and enable the drainage of the urine. The glomerular filtrate (i.e.
primary urine) then passes through the renal tubules where it is modified and partially reabsorbed into the blood stream and ultimately enters into the collecting ducts to form the final concentrated urine.