Pearls
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Development of the definitive human kidney or metanephros begins at 5 weeks’ gestation and is complete by 34 to 36 weeks’ gestation, with an average of 1 million nephrons per kidney.
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While humans are born with a full complement of nephrons, functional maturation of the nephron is not complete until the second year of life.
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As a result of maturational differences in expression of angiotensin II and other vasoactive mediators, infants have a decreased capacity to tightly regulate renal blood flow, with subsequent increased susceptibility to renal ischemia and acute kidney injury, particularly in hypovolemic or hypotensive states.
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The efferent blood supply from a single glomerulus contributes to the capillary vascular supply of tubules from different nephrons. This arrangement of the vascular supply explains the patchy distribution of tubular damage after ischemic injury.
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Combinations of angiotensin-converting enzyme inhibitors and nonsteroidal antiinflammatory drugs inhibit afferent arteriolar vasodilation and efferent arteriolar vasoconstriction. In low-flow states, these agents can cause a precipitous loss of glomerular filtration pressure and kidney function.
Renal anatomy
Normal human kidneys are paired organs that reside in the retroperitoneal space adjacent to the spine. The upper poles of the kidneys typically reside around the level of the T12 vertebrae and extend down to the L3 vertebrae. The liver is superior to the right kidney and thus displaces it lower than the kidney on the left side. The spleen and stomach overlie the superior aspect of the left kidney. Kidneys, however, can be found in a variety of other locations and have altered morphologies as a result of alterations of the normal developmental program (reviewed by Schedl). For example, failure of the kidney to ascend normally results in a pelvic kidney with abnormal vascular supplies from the aorta and/or iliac vessels. Mesenchymal regions of the two kidneys coming in contact during early development likely cause fused kidneys, most commonly seen as a “horseshoe” kidney. Partial or complete renal duplications comprise a variety of abnormalities that may arise from aberrant branching of the ureteric bud into the developing mesenchyme. Unilateral agenesis likely results from failure of ureteric bud development or abnormal mesenchymal induction, leading to regression of the metanephric mesenchyme and failed renal development.
Renal development
Human kidneys develop as three distinct sets beginning in the third week of gestation. The first primitive kidneys, the pronephros and mesonephros, are composed of simple tubules and the pronephric duct. As gestation continues into the fourth week, the pronephros regresses and the second primitive kidney, the mesonephros, forms from parallel strips of mesoderm along the paravertebral axis. The mesonephros contains nephrons and the mesonephric duct. It begins functioning between the sixth and tenth week of gestation before involution in a cranial-caudal direction beginning at 10 weeks’ gestation ( Fig. 70.1 ). The definitive human kidney, or metanephros, begins development at the fifth week of gestation and begins functioning between the 10th and 14th week. The metanephros develops in the pelvis when the branching ureteric bud and undifferentiated metanephric mesenchyme interact in a complex series of reciprocal inductions. These interactions lead to the formation of glomeruli. Vessels and tubules arise from mesenchymal precursors; distal tubules and collecting ducts derive from ureteric bud epithelium. This process occurs in a centrifugal fashion so that deeper corticomedullary nephrons form earliest in organogenesis, whereas the more peripheral cortical nephrons form later. As the metanephros develops, the maturing kidney ascends into the retroperitoneal space to its final location, with the upper poles around the T12 vertebrae. During the ascent, the blood supply is derived from more cranial aspects of the aorta and from the lumbar renal arteries at the final position of the kidney. The ureters elongate and canalize during the ascent to maintain drainage to the bladder. By the time human nephrogenesis is complete, between 34 to 36 weeks’ gestation, repeated cycles of mesenchymal induction, ureteric branching, and morphogenesis result in approximately 1 million nephrons per kidney. While differentiation of new nephrons is complete at the time of term delivery, functional maturation of nephrons continues into the second year of life, and growth of the kidneys completes when somatic growth ceases.
Renal vasculature
Vascular anatomy
Each kidney is typically supplied by a single renal artery traversing from the lateral aorta to the renal hilum, although anatomic variations in the origin and number of renal arteries are found in 25% to 60% of individuals. Upon entering the kidney, the renal artery splits into segmental arteries that further bifurcate into the interlobar arteries. The interlobar vessels travel to the corticomedullary junction and then branch horizontally to run parallel to the surface of the kidney as arcuate arteries. The arcuate arteries run between the cortex and medulla and give rise to the interlobular arteries, which extend to the outer cortex ( Fig. 70.2 ). As the interlobular arteries ascend toward the cortex, the afferent arterioles branch off and enter the Bowman capsule, after which they split to form the glomerular capillary bed. After passing through the glomerular tuft, blood exits the glomerulus via the efferent arterioles, which feed the peritubular capillary beds and the vasa rectae. The efferent arteriole of a single nephron can supply blood to multiple vasa rectae. The postglomerular vasculature of the cortex is supplied by efferent arterioles from midcortical and superficial cortical nephrons, while the blood supply to the medulla is entirely derived from juxtamedullary efferent arterioles. The vasa rectae of the medulla branch as they descend toward the papilla of the kidney and form the complex meshwork of the medullary capillary vascular beds. Only a few vessels of the vasa rectae reach the papillary tip.
Venous drainage of the vasa rectae is divided into two types: the vessels of the deep medulla ascend to join the arcuate veins at the corticomedullary junction, and those of the superficial medulla ascend into the cortex to join the cortical peritubular capillary network and, ultimately, the interlobular and arcuate veins (see Fig. 70.2 ). The arcuate veins join with the interlobar veins via the interlobular veins and finally drain into the main renal vein to join the main circulation.
Vascular function
The kidneys are extraordinarily vascular organs; they receive 15% to 18% of cardiac output in the neonate and up to 20% of cardiac output in the adult. Blood flow to the kidney is tightly regulated to ensure continued renal function over a range of blood pressures. Renal blood flow is regulated by a complex system of sympathetic α 1 -receptors, myogenic contraction, and vasoactive mediators that control vascular resistance and provide regulation of renal blood flow. Maintenance of glomerular filtration rate at the level of the glomerulus occurs by action of vasoactive mediators such as angiotensin II, which induces smooth muscle contraction and prostacyclin, which relaxes afferent arterioles. There are significant developmental variations in the levels of vasoactive mediators and receptor characteristics. Circulating angiotensin II, for example, is elevated in the neonate, as are corresponding vasodilators. The end result of these maturational differences in the infant is a decreased capacity to regulate renal blood flow and subsequent susceptibility to renal ischemia and acute kidney injury, particularly in hypovolemic or hypotensive states.
Vascular development
The development of the kidney vasculature is an area of active investigation. Markers of early vascular development are expressed in undifferentiated metanephric mesenchyme, which suggests that the blood supply to the nephron develops at least partially from precursors inherent to the developing kidney. Migration of committed endothelial cells into the developing glomerulus occurs in response to secreted factors such as vascular endothelial growth factor, which is secreted under the transcriptional regulation of the oxygen-sensitive hypoxic inducible factor. Other factors that have been shown to coordinate and control vascular development in the mammalian kidney include the renin-angiotensin system, transforming growth factor-β, platelet-derived growth factor, angiopoietins, sphingosine-1-phosphate pathway, and Notch signaling.
The nephron
The nephron is the functional unit of the kidney, with structurally and functionally defined areas that refine glomerular filtrate into urine. The nephron consists of a glomerular capillary tuft within the Bowman capsule and the renal tubule, which is divided into anatomically and functionally distinct areas, including the proximal convoluted tubule, loop of Henle, distal tubule, and collecting duct ( Fig. 70.3 ).
Nephron development
Metanephric nephron development occurs through a complex, interactive series of processes beginning at around 5 weeks’ gestation, with cessation of nephrogenesis at around 34 weeks’ gestation. Nephron development begins with the outpouching of ureteric epithelium, the ureteric bud, from the mesonephric duct. This precursor to the collecting duct encroaches on undifferentiated metanephric mesenchyme in the caudal retroperitoneal space and induces the development of an epithelial cell condensate, which is the precursor to the glomerulus and tubule ( Fig. 70.4 ). Simultaneously, factors within the metanephric mesenchyme induce the ureteric bud to continue branching. The epithelial condensate forms a vesicle that convolutes progressively into a comma-shaped body and then an S-shaped body, signifying the development of the urinary space and early tubule segments. The ureteric bud eventually evolves into the collecting ducts, calyces, renal pelvis, and ureters. The mechanisms by which the ureteric bud epithelial derivatives link to the corresponding mesenchymal derivatives in the distal nephron remain unknown but may involve mesenchymal to epithelial cell transitioning under the control of glial cell line–derived neurotrophic factor. The glomerular capillary loops form through the angiogenic processes of committed endothelial cells, and supporting mesangial cells develop from committed metanephric mesenchyme with myoblastic characteristics.
Glomerulus
Glomerular anatomy
The glomerulus is a tuft of capillaries located within the Bowman capsule. It is unique among mammalian vascular beds by having two sets of arterioles, both proximal and distal to the capillary bed. Approximately 80% to 85% of glomeruli are in the cortical region, while the remaining 15% to 20% are juxtamedullary. The location of the glomerulus in either the cortical or juxtamedullary region dictates the tubular length and function of the nephron with regard to salt and water reabsorption capacity and contribution to generation of steep osmotic gradients for production of a concentrated urine, discussed in detail later. The cell types within the glomerulus include extensively fenestrated endothelial cells; podocytes, which are highly specialized epithelial cells; and supporting mesangial cells. Epithelial cells also form the urinary compartment into which ultrafiltrate passes (Bowman space). Endothelial cells and podocytes sit on opposite sides of the glomerular basement membrane, the entirety of which forms the filtration apparatus ( Fig. 70.5 ). Glomerular endothelial cells on the blood side of the filtration barrier are highly fenestrated, promoting efficient solute and fluid transfer across the glomerular basement membrane. The epithelial side is characterized by fingerlike extensions of the podocyte cell membrane that interdigitate to form a mesh on the glomerular basement membrane. Mesangial cells form the supporting network of the glomerular structure, provide some phagocytic function, and participate in control of glomerular filtration.
Glomerular function
Filtration is the primary function of the glomerulus. Filtration requires a gradient across the glomerular basement membrane favoring the movement of water and solute to a low-pressure area. There are generally four factors that contribute to the pressure gradient and determine the quantity of filtrate obtained across the glomerular basement membrane ( Fig. 70.6 ). First, hydrostatic pressure in the glomerular capillary drives filtration of fluid across the glomerular basement membrane. If the blood flow to the glomerulus decreases, the hydrostatic pressure also drops, which necessitates an increase in efferent vascular resistance to maintain glomerular perfusion pressure. Angiotensin II, prostaglandins, and renal sympathetic activity control afferent and efferent vascular tone to carefully regulate glomerular vascular resistance.
The second factor controlling the pressure gradient is the oncotic pressure of the blood entering the glomerulus. As blood is filtered and water leaves the vascular compartment, the oncotic pressure in the blood compartment rises, limiting the passage of additional fluid across the glomerular basement membrane. In situations of low oncotic pressure, such as nephrotic syndrome, the initial rate of ultrafiltrate formation is increased because of low oncotic pressure with preserved hydrostatic pressure. However, over time, low systemic oncotic pressure causes a redistribution of intravascular volume into peripheral tissue spaces, resulting in decreased intravascular hydrostatic pressure and forcing ultrafiltrate production to drop.
The third factor affecting ultrafiltrate formation is tubular hydrostatic pressure, or the resistance within the urinary space. In urinary tract obstruction, tubular hydrostatic pressure limits ultrafiltrate generation as it rises above the hydrostatic pressure of the blood compartment, thereby negatively affecting glomerular filtration rate.
The last factor in the determination of ultrafiltrate formation is the available glomerular basement membrane surface area and related filtration efficiency. Physiologically, the functional size of the glomerular basement membrane can be determined at the whole kidney level or at the glomerular level. At the whole kidney level, the number of nephrons receiving adequate blood supply determines glomerular basement membrane area available for filtration. For example, shunting of blood from the cortex into the medulla, as seen in hepatorenal syndrome, effectively decreases the available glomerular basement membrane area by reducing the number of actively filtering nephrons. Within the glomerulus, glomerular basement membrane area can be altered by mesangial cell function. In hypovolemic states, mesangial cell contraction is thought to decrease glomerular basement membrane area in response to hormonal mediators, resulting in decreased filtration and preservation of intravascular volume. The efficiency of basement membrane filtration is also affected by disease states, including immune complex deposition, fibrosis, or complement activation, which disrupt the integrity and efficiency of the membrane.
Finally, selectivity of the filtration barrier is determined by the ability of the basement membrane to permit water and smaller solutes (such as sodium, chloride, and urea) to pass into the urinary space while restricting others (such as cells and larger proteins) to remain in the blood compartment. The glomerular filtration barrier provides both charge and size selectivity that ultimately involves the compound influences of endothelial fenestrae, glomerular basement membrane structure, and podocyte structure and function. The effects of altered podocyte function on the integrity of filtration are most commonly seen in the various forms of nephrotic syndromes.
Tubular anatomy
Proximal tubule
The proximal tubule consists of polarized epithelia with structurally and functionally defined areas that are key to the primary function of reabsorption of filtered solute and water. The polarity of the cells is maintained by the presence of cell-cell adhesion complexes called tight junctions , which separate apical transport proteins from the gradient-generating basolateral membrane proteins.
The apical surface of the proximal tubular cell has a distinctive brush border that increases the luminal surface area of the cell, maximizing contact with the tubular ultrafiltrate. Increased surface area facilitates reabsorption of solutes and water, which occurs through a wide array of sodium-coupled transporters. The apical brush border membrane also contains numerous ion channels and ion exchange proteins that maintain electrochemical gradients. The basolateral aspects of the proximal tubular cells contain membrane-bound sodium-potassium adenosine triphosphatase (Na + /K + -ATPase) proteins and a high density of intracellular mitochondria along with additional ion channels and ion exchange proteins. It is through the Na + /K + -ATPase that favorable sodium and electrochemical gradients are generated to facilitate transcellular and paracellular transport of solutes and water.
Loop of henle
The loop of Henle, whether cortical or juxtamedullary, is characterized by a long tubule extending from the proximal tubule toward the medulla with a hairpin turn extending back out toward the cortex.
The structural and functional properties of the epithelial cells change throughout the length of the loop of Henle. The proximal portions have cells with prominent microvilli and permeable cell junctions that permit passage of fluid via aquaporin-1 channels. The distal sections of the loop of Henle consist of flat epithelia lacking microvilli and are devoid of aquaporin-1 channels; the thin ascending limb of the loop of Henle is impermeable to water and urea but transports other solutes, particularly chloride, and is important in assisting with the establishment of medullary concentration gradients.
An abrupt transition occurs at the beginning of the thick ascending limb of the loop of Henle (TALH). The TALH is impermeable to water owing to a dense network of tight junctions. The TALH is the site of solute transport in an active, ATP-dependent manner, and these cells have dense localization of mitochondria and Na + /K + -ATPase at the basolateral membrane that generate chemical gradients for solute transport across the luminal surface. Compared with the proximal tubule, the TALH basolateral surface is larger than the luminal surface and accommodates a larger number of Na + /K + -ATPase pumps. , At the distal end of the TALH, the tubule courses back toward its originating glomerulus. Here, a small plaque of tall, narrow tubular epithelial cells, the macula densa , contacts the vascular pole and extraglomerular mesangial cells ( Fig 70.7 ). The primary function of the macula densa cells appears to be the detection of tubular chloride content and the regulation of glomerular filtration via activation of the renin-angiotensin system and additional vasoactive hormones.
