Renal Lecture 2 PDF

Autoregulation of GFR and Renal Blood Flow It is the ability of the kidney to keep GFR & RBF relatively constant, despite marked changes in arterial blood pressure. For instance, a decrease in arterial pressure to as low as 75 mm Hg or an increase to as high as 160 mm Hg usually cause...

Autoregulation of GFR and Renal Blood Flow It is the ability of the kidney to keep GFR & RBF relatively constant, despite marked changes in arterial blood pressure. For instance, a decrease in arterial pressure to as low as 75 mm Hg or an increase to as high as 160 mm Hg usually cause very little change in GFR (less than 10 percent). Importance of autoregulation: -Renal autoregulation minimizes the impact of changes in arterial blood pressure on Na+ excretion. Without renal autoregulation, increases in arterial blood pressure would lead to dramatic increases in GFR and potentially serious losses of NaCl and water from the ECF. There are two mechanisms trying to explain autoregulation of GFR and RBF. 1. Tubuloglomerular Feedback mechanism has two components (1) An afferent arteriolar feedback mechanism and (2) an efferent arteriolar feedback mechanism. These feedback mechanisms depend on special anatomical arrangements of the juxtaglomerular complex (Figure10). The juxtaglomerular complex: is structure located at the areas of contact between the DCT and the glomeruli of nephron consists of A. Macula densa cells is a specialized group of epithelial cells in the distal tubules that comes in close contact with the afferent and efferent arterioles, sense changes in volume delivery to the distal tubule. B. juxtaglomerular cells in the walls of the afferent and efferent arterioles, which are the major storage sites for renin. Fig. 10 Structure of the juxtaglomerular apparatus, demonstrating its possible feedback role in the control of nephron function These two components of the tubuloglomerular feedback mechanism, operating together, provide feedback signals to both the afferent and the efferent arterioles for efficient autoregulation of GFR during changes in arterial pressure. In case of hypotension: Decreased GFR, slows the flow rate in the loop of Henle, causing increased reabsorption of sodium and chloride ions in the ascending loop of Henle, thereby reducing the concentration of sodium chloride at the macula densa cells. This decrease in sodium chloride concentration initiates a signal from the macula densa that has two effects: (1) It decreases resistance to blood flow in the afferent arterioles, which raises glomerular hydrostatic pressure and helps return GFR toward normal, and (2) it increases renin release from the juxtaglomerular cells. Renin released from these cells then functions as an enzyme to increase the formation of angiotensin I, which is converted to angiotensin II. Finally, the angiotensin II constricts the efferent arterioles, thereby increasing glomerular hydrostatic pressure and helping to return GFR toward normal. (Figure11) Fig. 11 Macula densa feedback mechanism for autoregulation of glomerular hydrostatic pressure and glomerular filtration rate (GFR) during decreased renal arterial pressure. In case of Hypertension: In case of hypertension the GFR increases, this in turn increases the concentration of sodium and chloride ions at the macula densa; this causes afferent arteriole constriction which decrease the glomerular filtration. The decrease in glomerular filtration rate reduces the entry of sodium and chloride ions in to the tubular lumen and the macula densa cells. (figure12)  Fig. 12 Afferent arteriolar feedback mechanism. 2. Myogenic mechanism It is the ability of individual blood vessels to resist stretching during increased arterial pressure, small arterioles throughout respond to increased wall tension or wall stretch by contraction of the vascular smooth muscle. Stretch of the vascular wall allows increased movement of calcium ions from the extracellular fluid into the cells, causing them to contract.This contraction prevents excessive stretch of the vessel and at the same time, by raising vascular resistance, helps prevent excessive increases in renal blood flow and GFR when arterial pressure increases, the myogenic constrictor response in afferent arterioles occurs within seconds and therefore attenuates transmission of increased arterial pressure to the glomerular capillaries.  Formation of urine B. Tubular Reabsorption Tubular reabsorption is a selective transepithelial process by which water and other substances are transported by renal tubules back to blood.it begins as soon as the filtrate enters the proximal tubules. To reach the blood, transported substances move through three barriers: the luminal and basolateral membranes of the tubular cells and the endothelium of the peritubular capillaries. C. Tubular Secretion Tubular secretion is the opposite process, where the kidneys secrete substances from peritubular capillary blood into tubular fluid, occurs primarily in the distal and collecting tubules of the nephron. Tubular secretion is important for; 1.Disposing of substance, such as certain drugs and metabolites, which are tightly bound to plasma proteins. Such substances are not readily filtered, and so must be secreted. 2. Eliminating undesirable substance or end product that have reabsorbed by passive processes (urea and uric acid). 3. Ridding the body of excess K+. Because all virtually K+ present in the filtrate is reabsorbed in the PCT and ascending loop of Henle, nearly all K+ in urine is from aldosterone driven active tubular secretion in to the late DCT and collecting ducts. 4. Controlling blood pH. When blood pH drops toward the acidic end of the homoeostatic range, the renal tubular cells actively secrete more H+ in to the filtrate and retain more HCO3- (as a base). As a result, the blood pH rises and the urine drains off the excess H+. Conversely, when blood PH approaches the alkaline end of its range, Cl − are reabsorbed instead of HCO3- which are allowed to leave the body in urine. Urine Formation results from glomerular Filtration, tubular reabsorption, and tubular Secretion The rates at which different substances are excreted in the urine represent the sum of three renal processes, (1) glomerular filtration, (2) reabsorption of substances from the renal tubules into the blood, and (3) secretion of substances from the blood into the renal tubules. Renal handling of four hypothetical substances: A, The substance is freely filtered but not reabsorbed. B, The substance is freely filtered, but part of the filtered load is reabsorbed back in the blood. This is typical for many of the electrolytes such as sodium and chloride ions. C, The substance is freely filtered but is not excreted in the urine because all the filtered substance is reabsorbed from the tubules into the blood. This pattern occurs for some of the nutritional substances in the blood, such as amino acids and glucose. D. The substance is freely filtered at the glomerular capillaries and is not reabsorbed, but additional quantities of this substance are secreted from the peritubular capillary blood into the renal tubules. This pattern often occurs for organic acids and bases, permitting them to be rapidly cleared from the blood and excreted in large amounts in the urine. Fig.13 Renal handling of four hypothetical substances  Transport through the renal tubules Water and solutes can be transported through the cell membranes themselves (transcellular route) or through the spaces between the cell junctions (paracellular route). Then, after absorption across the tubular epithelial cells into the interstitial fluid, water and solutes are transported through the peritubular capillary walls into the blood by ultrafiltration (bulk flow). (Figure14) The basic mechanisms for transport through the tubular membrane are essentially the same as those for transport through other membranes of the body. These can be divided into Active transport and passive transport or diffusion. Fig.14 Solutes are transported through the cells (transcellular path) by passive diffusion or active transport, or between the cells (paracellular path) by diffusion. Water is transported through the cells and between the tubular cells by osmosis. Transport of water and solutes from the interstitial fluid into the peritubular capillaries occurs by ultrafiltration (bulk flow).  1. Active transport Active transport can move a solute against an electrochemical gradient and requires energy. Primary active transport: Transport that is coupled directly to an energy source, such as the hydrolysis of adenosine triphosphate (ATP). It includes sodium-potassium ATPase, hydrogen ATPase, hydrogen-potassium ATPase, and calcium ATPase. A good example of a primary active transport system is the reabsorption of sodium ions across the proximal tubular membrane, as shown in Figure15. On the basolateral sides of the tubular epithelial cell, the cell membrane has an extensive Na+/K+ -ATPase that hydrolyzes ATP, and the released energy transport Na+ ions out of the cell into the interstitium. At the same time, K+ is transported from the interstitium to the inside of the cell. The basolateral sides of tubular epithelial cell are highly permeable to K+ that all the K+ diffuse back out of the cell in to the interstitium. The Na+ transport outward from the cell diminished Na+ concentrations and creates a net negative charge of about −70 millivolts within the cell. This favors passive diffusion of Na+ from the tubular lumen in to the cell, for two reasons: (1) There is a concentration gradient favoring Na+ diffusion into the cell because intracellular Na+ concentration is low (12 mEq/L) and tubular fluid Na+ concentration is high (140 mEq/L) and (2) the negative, −70-millivolt, intracellular potential attracts the positive Na+ ions from the tubular lumen into the cell. Fig 15. Basic mechanism for active transport of sodium through the tubular epithelial cell. Secondary active transport: In secondary active transport, two or more substances interact with a specific membrane protein (a carrier molecule) and are transported together across the membrane. As one of the substances (for instance, sodium) diffuses down its electrochemical gradient, the energy released is used to drive another substance (for instance, glucose) against its electrochemical gradient. Thus, secondary active transport does not require energy directly from ATP or from other high-energy phosphate sources. Figure 16 shows secondary active transport of glucose and amino acids in the proximal tubule. In both instances, specific carrier proteins in the brush border combine with a sodium ion and an amino acid or a glucose molecule at the same time (Na+ co-transporter). Then, as the Na+ diffuse inward through the membrane it pulls the glucose and amino acid with it. After entry into the cell, glucose and amino acids exit across the basolateral membranes and thence in to peritubular capillaries by diffusion, driven by the high glucose and amino acid concentrations in the cell facilitated by specific transport proteins. (Facilitated diffusion). Fig. 16 Mechanisms of secondary active transport. SGLT, sodium-glucose co-transporter, GLUT, glucose transporter; NHE, sodium-hydrogen exchanger. Pinocytosis: an active transport mechanism for reabsorption of large molecules. Some parts of the tubule, especially the proximal tubule, reabsorb large molecules such as proteins by pinocytosis. In this process the protein attaches to the brush border of the luminal membrane, and this portion of the membrane then invaginates to the interior of the cell until it is completely pinched off and a vesicle is formed containing the protein. Once inside the cell, the protein is digested into its constituent amino acids, which are reabsorbed through the basolateral membrane into the interstitial fluid. Because pinocytosis requires energy, it is considered a form of active transport. Active secretion Active secretion occurs in the same way as active absorption except that the membrane transports the secreted substance in the opposite direction, from the brush border not from the sides of the cells e.g. hydrogen ions. Primary active secretion: Primary active secretion of potassium: potassium secretion by the principal cells depends on the activity of a sodium-potassium ATPase pump in each cell’s basolateral membrane (Figure 17). This pump maintains a low sodium concentration inside the cell and, therefore, favors sodium diffusion into the cell through special channels. The secretion of potassium by these cells from the blood into the tubular lumen involves two steps: (1) Potassium enters the cell because of the sodium-potassium ATPase pump, which maintains a high intracellular potassium concentration, and then (2) once in the cell, potassium diffuses down its concentration gradient across the luminal membrane into the tubular fluid. Fig.17 Mechanism of potassium secretion in the late distal tubules and cortical collecting tubules. Primary active secretion of hydrogen: hydrogen ion secretion by the intercalated cells is mediated by a hydrogen-ATPase transporter. Hydrogen is generated in this cell by the action of carbonic anhydrase on water and carbon dioxide to form carbonic acid, which then dissociates into hydrogen ions and bicarbonate ions. The hydrogen ions are then secreted into the tubular lumen, and for each hydrogen ion secreted, a bicarbonate ion becomes available for reabsorption across the basolateral membrane. (figure18) Fig.18 Primary active secretion of hydrogen Secondary active secretion: Some substances are secreted into the tubules by secondary active transport. This often involves counter-transport of the substance with sodium ions. In counter-transport, the energy liberated from the downhill movement of one of the substances (e.g., sodium ions) enables uphill movement of a second substance in the opposite direction. One example of counter-transport, shown in 16, is the active secretion of hydrogen ions coupled to sodium reabsorption in the luminal membrane of the proximal tubule. In this case, sodium entry into the cell is coupled with hydrogen extrusion from the cell by sodium- hydrogen counter-transport. This transport is mediated by a specific protein (sodium- hydrogen exchanger) in the brush border of the luminal membrane. As sodium is carried to the interior of the cell, hydrogen ions are forced outward in the opposite direction into the tubular lumen.  2. Passive transport Passive transport, or diffusion, means free movement of a substance by a concentration gradient, chemical, electrical or both, electrochemical gradient. Passive reabsorption of water by osmosis when solutes are transported out of the tubule by either primary or secondary active transport, their concentrations tend to decrease inside the tubule while increasing in the renal interstitium. This creates a concentration difference that causes osmosis of water in the same direction that the solutes are transported, from the tubular lumen to the renal interstitium. The different potions of the tubules have different permeabilities to water, some parts of the renal tubule, especially the proximal tubule, are highly permeable to water. (Figure 19) Fig.19 Water reabsorption by osmosis Reabsorption of chloride, urea, and other solutes by passive diffusion when sodium is reabsorbed through the tubular epithelial cell, negative ions such as chloride are transported along with sodium because of electrical potentials. That is, transport of positively charged sodium ions out of the lumen leaves the inside of the lumen negatively charged, compared with the interstitial fluid. This causes chloride ions to diffuse passively through the paracellular pathway. Additional reabsorption of chloride ions occurs because of a chloride concentration gradient that develops when water is reabsorbed from the tubule by osmosis, thereby concentrating the chloride ions in the tubular lumen (Figure20). Thus, the active reabsorption of sodium is closely coupled to the passive reabsorption of chloride by way of an electrical potential and a chloride concentration gradient. Urea is also passively reabsorbed from the tubule. As water is reabsorbed from the tubules (by osmosis coupled to sodium reabsorption), urea concentration in the tubular lumen increases (Figure20). This creates a concentration gradient favoring the reabsorption of urea. However, urea does not permeate the tubule as readily as water. In some parts of the nephron, especially the inner medullary collecting duct, passive urea reabsorption is facilitated by specific urea transporters. Yet, only about one half of the urea that is filtered by the glomerular capillaries is reabsorbed from the tubules. The remainder of the urea passes into the urine, allowing the kidneys to excrete large amounts of this waste product of metabolism. Another waste product of metabolism, creatinine, is an even larger molecule than urea and is essentially impermeant to the tubular membrane. Therefore, almost none of the creatinine that is filtered is reabsorbed, so that virtually all the creatinine filtered by the glomerulus is excreted in the urine. Passive secretion: Ammonia is synthesized inside tubular cells and then diffuses into tubular lumen by a concentration gradient. Fig. 20 Mechanisms by which water, chloride, and urea reabsorption are coupled with sodium reabsorption.