Anatomy and Physiology

The kidney consists of over a million individual filtering units called nephrons. Each nephron consists of a filtering body, the renal corpuscle, and a urine‐collecting and concentrating tube, the renal tubule. The renal corpuscle is an assemblage of two structures, the glomerular capillaries and the glomerular capsule, shown in Figure 1.

• The glomerulus is a dense ball of capillaries (glomerular capillaries) that branches from the afferent arteriole that enters the nephron. Because blood in the glomerular capillaries is under high pressure, substances in the blood that are small enough to pass through the pores (fenestrae, or endothelial fenestrations) in the capillary walls are forced out and into the encircling glomerular capsule. The glomerular capillaries merge, and the remaining blood exits the glomerular capsule through the efferent arteriole.

• The glomerular capsule is a cup‐shaped body that encircles the glomerular capillaries and collects the material (filtrate) that is forced out of the glomerular capillaries. The filtrate collects in the interior of the glomerular capsule, the capsular space, which is an area bounded by an inner visceral layer (that faces the glomerular capillaries) and an outer parietal layer. The visceral layer consists of modified simple squamous epithelial cells called podocytes, which project branches that bear fine processes called pedicels. The pedicels' adjacent podocytes mesh to form a dense network that envelops the glomerular capillaries. Spaces between the pedicels, called filtration slits, are openings into the capsular space that allow filtrate to enter the glomerular capsule.

• The renal tubule consists of three sections:
  • The first section, the proximal convoluted tubule (PCT), exits the glomerular capsule as a winding tube in the renal cortex. The wall of the PCT consists of cuboidal cells containing numerous mitochondria and bearing a brush border of dense microvilli that face the lumen (interior cavity). The high‐energy yield and large surface area of these cells support their functions of reabsorption and secretion.
  • The middle of the tubule, the nephron loop, is shaped like a hairpin and consists of a descending limb that drops into the renal medulla and an ascending limb that rises back into the renal cortex. As the loop descends, the tubule suddenly narrows, forming the thin segment of the loop. The loop subsequently widens in the ascending limb, forming the thick segment of the loop. Cells of the nephron loop vary from simple squamous epithelium (descending limb and thin segment of ascending limb) to cuboidal and low columnar epithelium (thick segment of ascending limb) and almost entirely lack microvilli.
  • The final section, the distal convoluted tubule (DCT), coils within the renal cortex and empties into the collecting duct. Cells here are cuboidal with few microvilli.

Renal tubules of neighboring nephrons empty urine into a single collecting duct. Here and in the final portions of the DCT, there are cells that respond to the hormones aldosterone and antidiuretic hormone (ADH), and there are cells that secrete H ⁺ in an effort to maintain proper pH.

Various collecting ducts within the medullary pyramids merge to form papillary ducts, which drain eventually into the renal pelvis through the medullary papillae. Urine collects in the renal pelvis and drains out of the kidney through the ureter.

The efferent arteriole carries blood away from the glomerular capillaries to form peritubular capillaries. These capillaries weave around the portions of the renal tubule that lie in the renal cortex. In portions of the nephron loop that descend deep into the renal medulla, the capillaries form loops, called vasa recta, that cross between the ascending and descending limbs. The peritubular capillaries collect water and nutrients from the filtrate in the tubule. They also release substances that are secreted into the tubule to combine with the filtrate in the formation of urine. The capillaries ultimately merge into an interlobular vein, which transports blood away from the nephron region.

There are two kinds of nephrons:

• Cortical nephrons, representing 85 percent of the nephrons in the kidney, have nephron loops that descend only slightly into the renal medulla (refer to Figure 1).

• Juxtamedullary nephrons have long nephron loops that descend deep into the renal medulla. Only juxtamedullary nephrons have vasa recta that traverse their nephron loops (refer to Figure 1).

The juxtaglomerular apparatus (JGA) is an area of the nephron where the afferent arteriole and the initial portion of the distal convoluted tubule are in close contact. Here, specialized smooth muscle cells of the afferent arteriole, called granular juxtaglomerular (JG) cells, act as mechanoreceptors that monitor blood pressure in the afferent arteriole. In the adjacent distal convoluted tubule, specialized cells, called macula densa, act as chemoreceptors that monitor the concentration of Na ⁺ and Cl ^– in the urine inside the tubule. Together, these cells help regulate blood pressure and the production of urine in the nephron.

The operation of the human nephron consists of three processes:

• Glomerular filtration

• Tubular reabsorption

• Tubular secretion

These three processes, which determine the quantity and quality of the urine, are discussed in the following sections.

Glomerular filtration

When blood enters the glomerular capillaries, water and solutes are forced into the glomerular capsule. Passage of cells and certain molecules are restricted as follows:

• The fenestrae (pores) of the capillary endothelium are large, permitting all components of blood plasma to pass except blood cells.

• A basement membrane (consisting of extracellular material) that lies between the capillary endothelium and the visceral layer of the glomerular capsule blocks the entrance of large proteins into the glomerular capsule.

• The filtration slits between the pedicels of the podocytes prevent the passage of medium‐sized proteins into the glomerular capsule.

The net filtration pressure (NFP) determines the quantity of filtrate that is forced into the glomerular capsule. The NFP, estimated at about 10 mm Hg, is the sum of pressures that promote filtration less the sum of those that oppose filtration. The following contribute to the NFP:

• The glomerular hydrostatic pressure (blood pressure in the glomerulus) promotes filtration.

• The glomerular osmotic pressure inhibits filtration. This pressure is created as a result of the movement of water and solutes out of the glomerular capillaries, while proteins and blood cells remain. This increases the concentration of solutes (thus decreasing the concentration of water) in the glomerular capillaries and therefore promotes the return of water to the glomerular capillaries by osmosis.

• The capsular hydrostatic pressure inhibits filtration. This pressure develops as water collects in the glomerular capsule. The more water in the capsule, the greater the pressure.

The glomerular filtration rate (GFR) is the rate at which filtrate collectively accumulates in the glomerulus of each nephron. The GFR, about 125 mL/min (180 liters/day), is regulated by the following:

• Renal autoregulation is the ability of the kidney to maintain a constant GFR even when the body's blood pressure fluctuates. Autoregulation is accomplished by cells in the juxtaglomerular apparatus that decrease or increase secretion of a vasoconstrictor substance that dilates or constricts, respectively, the afferent arteriole.

• Neural regulation of GFR occurs when vasoconstrictor fibers of the sympathetic nervous system constrict afferent arterioles. Such stimulation may occur during exercise, stress, or other fight‐or‐flight conditions and results in a decrease in urine production.

• Hormonal control of GFR is accomplished by the renin/angiotensinogen mechanism. When cells of the juxtaglomerular apparatus detect a decrease in blood pressure in the afferent arteriole or a decrease in solute (Na ⁺ and Cl ^–) concentrations in the distal tubule, they secrete the enzyme renin. Renin converts angiotensinogen (a plasma protein produced by the liver) to angiotensin I. Angiotensin I in turn is converted to angiotensin II by the angiotensin‐converting enzyme (ACE), an enzyme produced principally by capillary endothelium in the lungs. Angiotensin II circulates in the blood and increases GFR by doing the following:

• Constricting blood vessels throughout the body, causing the blood pressure to rise

• Stimulating the adrenal cortex to secrete aldosterone, a hormone that increases blood pressure by decreasing water output by the kidneys

Tubular reabsorption

In healthy kidneys, nearly all of the desirable organic substances (proteins, amino acids, glucose) are reabsorbed by the cells that line the renal tube. These substances then move into the peritubular capillaries that surround the tubule. Most of the water (usually more than 99 percent of it) and many ions are reabsorbed as well, but the amounts are regulated so that blood volume, pressure, and ion concentration are maintained within required levels for homeostasis.

Reabsorbed substances move from the lumen of the renal tubule to the lumen of a peritubular capillary. Three membranes are traversed:

• The luminal membrane, or the side of the tubule cells facing the tubule lumen

• The basolateral membrane, or the side of the tubule cells facing the interstitial fluids

• The endothelium of the capillaries

Tight junctions between tubule cells prevent substances from leaking out between the cells. Movement of substances out of the tubule, then, must occur through the cells, either by active transport (requiring ATP) or by passive transport processes. Once outside of the tubule and in the interstitial fluids, substances move into the peritubular capillaries or vasa recta by passive processes.

The reabsorption of most substances from the tubule to the interstitial fluids requires a membrane‐bound transport protein that carries these substances across the tubule cell membrane by active transport. When all of the available transport proteins are being used, the rate of reabsorption reaches a transport maximum (Tm), and substances that cannot be transported are lost in the urine.

The following mechanisms direct tubular reabsorption in the indicated regions:

• Active transport of Na ⁺ (in the PCT, DCT, and collecting duct). Because Na ⁺ concentration is low inside tubular cells, Na ⁺ enters the tubular cells (across the luminal membrane) by passive diffusion. At the other side of the tubule cells, the basolateral membrane bears proteins that function as sodium‐potassium (Na ⁺‐K ⁺) pumps. These pumps use ATP to simultaneously export Na ⁺ while importing K ⁺. Thus, Na ⁺ in the tubule cells is transported out of the cells and into the interstitial fluid by active transport. The Na ⁺ in the interstitial fluid then enters the capillaries by passive diffusion. (The K ⁺ that is transported into the cell leaks back passively into the interstitial fluid.)

• Symporter transport (secondary active transport) of nutrients and ions (in the PCT and nephron loop). Various nutrients, such as glucose and amino acids, and certain ions (K ⁺ and Cl ^–) in the thick ascending limb of the nephron loop are transported into the tubule cells by the action of Na ⁺ symporters. A Na ⁺ symporter is a transport protein that carries both Na ⁺ and another molecule, such as glucose, across a membrane in the same direction. Movement of glucose and other nutrients from the tubular lumen into the tubule cells occurs in this fashion. The process requires a low concentration of Na ⁺ inside the cells, a condition maintained by the Na ⁺‐K ⁺ pump operating on the basolateral membranes of the tubule cells. The movement of nutrients into cells by this mechanism is referred to as secondary active transport, because the ATP‐requiring mechanism is the Na ⁺‐K ⁺ pump and not the symporter itself. Once inside the tubular cells, nutrients move into the interstitial fluid and into the capillaries by passive processes.

• Passive transport of H ₂ O by osmosis (in the PCT and DCT). The buildup of Na ⁺ in the peritubular capillaries creates a concentration gradient across which water passively moves, from tubule to capillaries, by osmosis. Thus, the reabsorption of Na ⁺ by active transport generates the subsequent reabsorption of H ₂O by passive transport, a process called obligatory H ₂O reabsorption.

• Passive transport of various solutes by diffusion (in the PCT and DCT, and collecting duct). As H ₂O moves from the tubule to the capillaries, various solutes such as K ⁺, Cl ^–, HCO ₃ ^–, and urea become more concentrated in the tubule. As a result, these solutes follow the water, moving by diffusion out of the tubule and into capillaries where their concentrations are lower, a process called solvent drag. Also, the accumulation of the positively charged Na ⁺ in the capillaries creates an electrical gradient that attracts (by diffusion) negatively charged ions (Cl ^–, HCO ₃ ^–).

• H ₂ O and solute transport regulated by hormones (in the DCT and collecting duct). The permeability of the DCT and collecting duct and the resultant reabsorption of H ₂O and Na ⁺ are controlled by two hormones:
• Aldosterone increases the reabsorption of Na ⁺ and H ₂O by stimulating an increase in the number of Na ⁺‐K ⁺ pump proteins in the principal cells that line the DCT and collecting duct.
• Antidiuretic hormone (ADH) increases H ₂O reabsorption by stimulating an increase in the number of H ₂O‐channel proteins in the principal cells of the collecting duct.

Tubular secretion

In contrast to tubular reabsorption, which returns substances to the blood, tubular secretion removes substances from the blood and secretes them into the filtrate. Secreted substances include H ⁺, K ⁺, NH ₄ ⁺ (ammonium ion), creatinine (a waste product of muscle contraction), and various other substances (including penicillin and other drugs). Secretion occurs in portions of the PCT, DCT, and collecting duct.

Secretion of H ⁺. Because a decrease in H ⁺ causes a rise in pH (a decrease in acidity), H ⁺ secretion into the renal tubule is a mechanism for raising blood pH. Various acids produced by cellular metabolism accumulate in the blood and require that their presence be neutralized by removing H ⁺. In addition, CO ₂, also a metabolic byproduct, combines with water (catalyzed by the enzyme carbonic anhydrase) to produce carbonic acid (H ₂CO ₃), which dissociates to produce H ⁺, as follows:

CO ₂ + H ₂O ← → H ₂CO ₃ ← → H ⁺ + HCO ₃ ^–

This chemical reaction occurs in either direction (it is reversible) depending on the concentration of the various reactants. As a result, if HCO ₃ ^– increases in the blood, it acts as a buffer of H ⁺, combining with it (and effectively removing it) to produce CO ₂ and H ₂O. CO ₂ in tubular cells of the collecting duct combines with H ₂O to form H ⁺ and HCO ₃ ^–. The CO ₂ may originate in the tubular cells or it may enter these cells by diffusion from the renal tubule, interstitial fluids, or peritubular capillaries. In the tubule cell, Na ⁺/H ⁺ antiporters, enzymes that move transported substances in opposite directions, transport H ⁺ across the luminal membrane into the tubule while importing Na ⁺. Inside the tubule, H ⁺ may combine with any of several buffers that entered the tubule as filtrate (HCO ₃ ^–, NH ₃, or HPO ₄ ^2–). If HCO ₃ ^– is the buffer, then H ₂CO ₃ is formed, producing H ₂O and CO ₂. The CO ₂ then enters the tubular cell, where it can combine with H ₂O again. If H ⁺ combines with another buffer, it is excreted in the urine. Regardless of the fate of the H+ in the tubule, the HCO ₃ ^– produced in the first step is transported across the basolateral membrane by an HCO ₃ ^–/Cl ^– antiporter. The HCO ₃ ^– enters the peritubular capillaries, where it combines with the H ⁺ in the blood and increases the blood pH. Note that the blood pH is increased by adding HCO ₃ ^– to the blood, not by removing H ⁺.

• Secretion of NH ₃. When amino acids are broken down, they produce toxic NH ₃. The liver converts most NH ₃ to urea, a less toxic substance. Both enter the filtrate during glomerular filtration and are excreted in the urine. However, when the blood is very acidic, the tubule cells break down the amino acid glutamate, producing NH ₃ and HCO ₃ ^–. The NH ₃ combines with H ⁺, forming NH ₄ ⁺, which is transported across the luminal membrane by a Na ⁺ antiporter and excreted in the urine. The HCO ₃ ^– moves to the blood (as discussed earlier for H ⁺ secretion) and increases blood pH.

• Secretion of K ⁺. Nearly all of the K ⁺ in filtrate is reabsorbed during tubular reabsorption. When reabsorbed quantities exceed body requirements, excess K ⁺ is secreted back into the filtrate in the collecting duct and final regions of the DCT. Because aldosterone stimulates an increase in Na ⁺/K ⁺ pumps, K ⁺ secretion (as well as Na ⁺ reabsorption) increases with aldosterone.