The functional unit of the kidney is the nephron (Fig. 6-2 ), which is comprised of the glom- erulus (Fig. 6-3 and Fig. 6-4 ) and the tubule. The tubule can be further divided into the proximal tubule, the loop of Henle, the distal tubule and the collecting duct. The glomeru- lus functions as a fi lter. Blood enters via the afferent arterioles in the vascular pole of the glomeruli, which drain into a capillary bed within Bowman’s capsule. The capillary wall acts as a barrier, as an ultrafi ltrate is formed by movement of fl uid out of the capillaries into Bowman’s space. There are three layers of the capillary wall – the fenestrated endothelial cell (which lines the lumen of the capillary), the glomerular basement membrane and the epithelial cell. These three layers form a barrier for both size and charge to prevent the loss of large, negatively charged molecules. The epithelial cells are connected to the glomerular basement membrane by foot processes. In nephrotic syndrome (Fig. 6-4 ), loss of the foot processes can lead to leaking of albumin, which normally remains in the capillary due to its large size and negative charge. Once the ultrafi ltrate is formed in Bowman’s space, it leaves the glomerulus through the urinary pole and travels into the tubule. The blood remaining in the glomerular capillary bed is drained by the efferent arterioles and returned to the systemic circulation. Within the tubule, the ultrafi ltrate is modifi ed in a highly regu- lated process to produce urine that varies to maintain the extracellular environment within the body.
The urine can be modifi ed within the tubule in a number of ways, with each segment mak- ing a distinctive contribution. At the beginning of the tubule, the urine is an ultrafi ltrate which is similar to plasma in electrolyte composition and osmolality. The removal of a sub- stance from the ultrafi ltrate within the tubule is known as reabsorption, while secretion is the addition of a substance to the ultrafi ltrate. Excretion is the elimination of water and solutes from the body through removal in the formed urine. In order for a substance to be reab- sorbed, it must either travel through the cells which line the tubule or pass between cells.
With intracellular transport, transport must occur across the luminal membrane of the cell.
FIGURE 6-2
Structure of the nephron, the smallest unit of the kidney, demonstrating the contiguous segments
Glomerulus Proximal
Tubule
Distal Tube
Collecting Duct Loop of
Henle
FIGURE 6-3
The glomerular apparatus is a network of capillaries originating from the afferent arteriole and surrounded by an extension of a basement membrane from the proximal tubule called Bowman’s capsule. The rate of urine forma- tion, ie, glomerular fi ltration rate (GFR) or ultrafi ltration, depends on hydraulic permeability of the glomerular capillaries and net ultrafi ltration pressure across the capillary wall. These Starling forces govern glomerular fi ltration. In addition to being dependent on hydraulic and oncotic pressures within the glomerular capillary, urine formation is also infl uenced by local and systemic neurohumoral infl uences, exogenous adminis- tration of diuretics, and an intact kidney-ureter-bladder feedback loop
Efferent renal arteriole
Glomerulus Bowman’s capsule
Renal tube
Afferent renal arteriole
Filtration permeability factor
Colloid osmotic pressure or plasma protein
Glomerular filtration rate [GRF]
Introcapillary hydrostatic pressure
Introcapsular hydrostatic pressure
− −
x =
Capillary hydrostatic pressure
FIGURE 6-4
The renal pathologic fi ndings of minimal-change nephrotic syndrome. The fi rst biopsy performed at age 4 years revealed a normal-looking glomerulus (light microscope, upper left panel, PAS stain, ×400) and wide foot process effacement (electron microscope, upper middle panel, ×2,500). The second biopsy performed at age 11 years revealed segmental mesangial cell proliferation (light microscope, lower left panel, PAS stain,
×400), mesangial electron-dense deposits and widely effaced foot processes (electron microscope, lower middle panel, ×4,000), and mesangial IgA deposition (immunofl uores- cent microscope, lower right panel, ×400)
In order to exit the cell, the substance must then pass through the basolateral membrane in order to reach the interstitium. From there, it can be reabsorbed into the peritubular capillar- ies and returned to the circulation. Each section of the tubule plays a distinctive role in modi- fi cation of the urine, with varying permeability to water and a variety of channels and transporters to facilitate movement of solutes.
The major roles of each segment of the tubule are outlined in Table 6-1 . The proximal tubule is responsible for reabsorption of the bulk of the fi ltered sodium and water, in addition to much of the fi ltered bicarbonate, protein, glucose and electrolytes. In the next segment of the nephron (Fig. 6-3 ), the loop of Henle, sodium is reabsorbed in excess of water, generat- ing a hypotonic urine and a hypertonic interstitium which is necessary for urinary concentra- tion. The distal tubule is a major site of regulated calcium excretion, under the infl uence of parathyroid hormone and possibly calcitriol, and is the site of the thiazide sensitive NaCl transporter. The collecting tubule is responsible for the fi nal adjustments to the urine, with multiple important roles including ADH-mediated water reabsorption and aldosterone medi- ated regulation of proton and potassium secretion and sodium reabsorption.
In a normal adult, 130–150 L of ultrafi ltrate are formed daily in the glomeruli. The proxi- mal tubule is able to reduce this ultrafi ltrate volume signifi cantly and is responsible for the recovery of a number of solutes, including about 65% of the fi ltered sodium and 55–60%
NEPHRON SEGMENT FUNCTION
Glomerulus Formation of ultrafi ltrate
Proximal tubule 65% of fi ltered sodium and 55–60% of water reabsorbed 90% of fi ltered bicarbonate recovered
Almost all glucose and amino acids reabsorbed
Potassium, phosphorus, calcium, magnesium, urea, uric acid reabsorbed
Loop of Henle NaCl absorbed in excess of water
Generates hypertonic interstitium necessary for countercurrent multiplication
Distal tubule Regulates urinary calcium excretion 5% of fi ltered NaCl reabsorbed
Collecting duct Presence or absence of ADH-induced water channels determines urine concentration
Sodium reabsorbed through luminal channel
Aldosterone mediated potassium and proton secretion Acidifi cation through titration of urinary ammonia
TABLE 6-1
PRIMARY FUNCTIONS OF EACH SEGMENT OF THE NEPHRON
FIGURE 6-5
Proximal tubule cell, simplifi ed diagram demonstrating sodium- dependent cotransport of solutes, paracellular cation fl ow, and basolateral Na + -K + -ATPase
Solutes
K+
2K+
Na+, K+
Proximal Tubule Cell
3Na+
Na+
Na+–K+–ATPase
Lumen -
of the water. Sodium is reabsorbed by active transporst via Na + -K + -ATPase (Fig. 6-5 ).
Other solutes, such as glucose and amino acids, are reabsorbed almost completely through co-transporters that are linked to sodium reabsorption. This is called secondary active trans- port, because the solute reabsorption cannot occur without the sodium being extruded across the basolateral membrane by the Na + -K + -ATPase. Water follows passively due to the cre- ation of an osmotic gradient from solute absorption. The proximal tubule is also the major site for bicarbonate recovery, with reabsorption of about 90% of fi ltered bicarbonate. In addition, although urinary acidifi cation occurs in the collecting tubule, the process is depen- dent on ammonium which is produced in the proximal tubule cells. The proximal tubule also plays an important role in the reabsorption of potassium, phosphorus, calcium, magnesium, urea, and uric acid. The importance of the proximal tubule is evident in Fanconi syndrome, a clinical state in which there is generalized proximal tubular dysfunction. Fanconi syn- drome can be due to inherited conditions, or can be acquired, such as due to chemotherapy with cisplatin or ifosfamide. The clinical manifestations of Fanconi syndrome – acidosis, polyuria, hypophosphatemia, hypokalemia, glucosuria and aminoaciduria, highlight some of the major functions of the proximal tubule.
Iso-osmotic fl uid leaving the proximal tubule enters the loop of Henle. The loop of Henle is divided into three segments: the thin descending limb, the thin ascending limb, and the thick ascending limb. In the loop of Henle, 15–25% of the fi ltered sodium chloride is reabsorbed and active calcium and magnesium regulation occurs. The main function, however, is to generate a hyperosmolar interstitium through reabsorption of sodium in excess of water in the thick ascending limb, which is impermeable to water. This is pow- ered by the Na + -K + ATPase in the basolateral surface and is facilitated by passive entry of sodium, chloride and potassium through the bumetanide-sensitive Na + -K + -2Cl - carrier in the luminal membrane. Loop diuretics compete for the chloride channel in the Na + -K + -2Cl - carrier, resulting in inhibition of sodium and potassium reabsorption (Fig. 6-6 ). The removal of sodium, chloride and potassium leads to a hypertonic interstitium and results in hypotonic urine leaving the loop of Henle (Fig. 6-7 ). As a result of the hypertonic inter- stitium, the descending limb of the loop of Henle, which is permeable to water, is able to passively reabsorb water. This is known as countercurrent multiplication. The major site of countercurrent multiplication, however, occurs after the ultrafi ltrate leaves the loop of Henle and enters the collecting duct. Although the urine entering the collecting duct is hypotonic, the ultimate concentration of the urine is dependent on the permeability of the collecting duct to water. This is regulated by antidiuretic hormone (ADH), which controls
The clinical manifestations of Fanconi syndrome, generalized proximal tubule dysfunction, include acidosis, polyuria, hypophosphatemia,
hypokalemia, glucosuria and aminoaciduria.
FIGURE 6-6
Thick ascending limb cell, simplifi ed diagram, demonstrat- ing apical Na + -K + -2Cl - cotrans- porter, ion channels, and basolateral Na + -K + -ATPase
2Cl–
Cl– K+
K+
2K+
Na+
Thick Ascending Limb Cell
3Na+
Na+
Na+–K+–ATPase
Lumen +
the insertion of aquaporin-2 water channels into the luminal membrane of the collecting duct. In a state of high ADH, the collecting duct will be highly permeable to water. Through the countercurrent mechanism, with a hypertonic interstitium generated by the loop of Henle, water diffuses into the interstitium and is reabsorbed, resulting in a concentrated urine. In humans, this process is so effi cient that a urinary concentration of 1,000–
1,200 mOsm/kg can be achieved. If serum ADH levels are low, such as in states of high water intake, the collecting tubule will be relatively impermeable to water, resulting in a dilute urine with osmolality as low as 30–50 mOsm/kg. Again, the effi ciency of the pro- cess is highlighted by the fact that an individual can drink more than 10 L of fl uid a day and still maintain a normal serum osmolality. Thus, the generation of concentrated urine requires a hypertonic interstitium and ADH-induced water channels (Table 6-2 ). In order for dilute urine to be generated, there must be a state of low water permeability in the col- lecting tubule and adequate NaCl reabsorption in the loop of Henle. The collecting tubule, in addition to the role it plays in urinary concentration, is also the main site for the regula- tion of potassium.
1. Factors required for the formation of a concentrated urine:
(a) Hypertonic interstitium, generated by the loop of Henle
(b) Presence of ADH-induced water channels in the collecting tubule 2. Factors required for the formation of a dilute urine:
(a) NaCl in excess of water reabsorption in the loop of Henle (b) Absence of ADH-induced water channels in the collecting tubule.
(c) Normal glomerular formation rate
TABLE 6-2
FACTORS NECESSARY TO GENERATE A CONCENTRATED OR DILUTE URINE
FIGURE 6-7
Drawing depicting countercurrent multiplication by the kidney, illustrating the relative tonicity along the nephron as gradients are generated by the thick ascending limb cells
Hypertonic Interstitium Proximal Tubule Isoosmotic
Urine
Active Nacl Transport
Hypotonic Urine
Hypertonic Interstitium
Passive Nacl Passive
H2O Diffusion
ADH Contr-
olled H2O Absor-
ption
Distal Tubule
Collecting Duct
Urine Tonicity ADH-Dependent Loop of Henle
Trans- port
The removal of sodium in excess of water in the loop of Henle allows for generation of a hypertonic interstitium which is necessary for urinary concentra- tion by countercurrent
multiplication.