Structure of Kidney Kidney is separated into cortical and medullary regions The medulla is further divided into medullary segments called renal or medullary pyramids The functional unit of the kidney is the nephron. It can be divided up into the Glomerular Capsule OR Bowmans Capsule. Proximal Convoluted Tubule, Loop of Henle, Distal Convoluted Tubule and Collecting Duct Renal blood flow is approximately 20% of C.O. The vast majority (90%) of this is filtered in the cortex layer at the Bowmans Capsule Structure of Bowmans Capsule that allows for filtration: Glomerular capillaries have fenestrations which act as pores for small molecules to pass through. A basement membrane exists past this and prevents large molecules from passing through. Podocytes are specialized cells which sit beyond the Basement membrane and their „feet‟ provide another level of filtration. Basic Renal Processes The three basic renal processes are glomerular filtration, tubular reabsorption and tubular secretion. Glomerular Filtration: The filtration of plasma from the glomerular capillaries into Bowmans space Tubular Reabsorption: The movement of fluid from the tubule lumen (proximal tubule, loop of Henle, distal tubule, collecting ducts) to the peritubular capillary plasma Tubular secretion: The movement of fluid in the peritubular capillary plasma to the tubule lumen. As a consequence, the amount of any substance excreted in the urine is equal to Amount excreted = amount filtered + amount secreted (– amount reabsorbed) The degree to which a compound is reabsorbed or secreted following glomerular filtration depends on the nature of the compound and the homeostatic mechanisms to control it. Most of the tubular reabsorption and secretion occurs in the proximal tubule, the Loop of Henle reabsorbs large amounts of ions. The distal tubule act as a „fine tuning‟ mechanism and are under neural and hormonal control. Glomerular Filtration The glomerular filtrate is identical to blood plasma except there are no cells and no large molecular weight proteins (the albumin‟s and globulin‟s). Compounds that are bound to these large proteins (Ca2+ and fatty acids) are also absent from the glomerular filtrate. The pressures involved in the bulk flow of fluid between capillaries and the ISF also exist between the glomerular capillaries and the Bowmans Space. These are as follows: The glomerular capillary hydrostatic pressure (PGC) 60 mmHg Bowmans space hydrostatic pressure (PBS) 15 mmHg The osmotic pressure of the glomerular capillary plasma (GC) 29 mmHg NOTE: These forces are identical to the Starling forces that exist between the capillaries and ISF. The magnitude of GC is larger than ISF. The net glomerular filtration pressure is a function of the above forces Net glomerular filtration pressure = PGC PBS GC As a result of the above forces there is a NETglomerular filtration pressure of 16 mmHg forcing fluid out of the glomerular capillary and into Bowmans space The volume of fluid filtered per unit time across the glomerular capillary is called the Glomerular Filtration Rate (GFR) GFR is related to filtration pressure, glomerular capillary permeability and glomerular capillary surface area. GFR is normally 180 litres per day. Recall that plasma volume is 3 litres. As a consequence the blood plasma is filtered 60 times a day through the kidneys GFR can be regulated by neural and hormonal input to the afferent and efferent arterioles thus changing glomerular filtration pressure. Regulation of GFR GFR is kept relatively constant under most conditions through three mechanisms. First two of which are intrinsic to the kidneys themselves (Renal Autoregulation) 1. Myogenic response of the smooth muscle in the afferent arterioles. Changes in blood pressure induce contraction or dilation of smooth muscle in afferent arterioles to keep GFR constant 2. Juxtaglomerular Feedback. Involves the Juxtaglomerular apparatus. Macula Densa cells which sense osmolarity and flow of urine in distal collecting duct. GFR is modulated depending on urine osmolarity and flow. 3. Sympathetic Nervous system. More concerned with regulating blood volume and pressure. This is achived by changing GFR. Sympathetic nervous system through baroreceptor reflex tends to decrease GFR by causing vasocontriction of afferent and efferent arterioles Tubular Reabsorption Organic nutrients such as glucose are completely reabsorbed into the peritubular capillaries and are not subject to homeostatic mechanisms that regulate their reabsorption rates. Although most of the water and electrolytes are reabsorbed they are regulated by neural and hormonal homeostatic mechanisms. Waste metabolites are only partially reabsorbed Tubular reabsorption occurs via two process‟. 1. Diffusion: Substances (urea and lipid soluble compounds) in the proximal tubule move down their respective concentration gradients into the pertitubular capillary. The concentration gradients are established by the movement of water into the proximal tubule. The movement of fluid from the ISF into the pertibular capillaries occurs via Starling Forces. 2. Mediated transport Substances moving from the tubular lumen to the peritubular capillaries against their electrochemical gradient move via transcellular epithelial transport. Transcellular Epithelial Transport Transcellular epithelial transport involves the movement of molecules through two membranes: The luminal membrane (lumen side) and the basolateral membrane (plasma side). The characteristics of these two membranes are different in terms of their complement of ion channels and transport proteins. The electrochemical gradients for the molecules which are moved are also different with respect to the concentrations in the lumen, epithelial cell and plasma side. The movement of Na+ ion from the lumen to the epithelial cell occurs via diffusion through a Na+ channel in the luminal membrane of the epithelial cell. The movement of Na+ out of the epithelial cell and into the ISF and hence the plasma occurs through the Na+ / K+ ATPase transporter (ie active transport of Na+) located in the basolateral membrane The movement of glucose and amino acids against their concentration gradient from the lumen into the epithelial cell is coupled to the movement of Na+ ions down their concentration gradient. Movement of glucose and amino acids out of the epithelial cell, across the basolateral membrane and into the ISF and hence the plasma occurs via facilitated diffusion. Again, the movement of Na+ ions out of the cell across the basolateral membrane occurs via the Na+ / K+ ATPase transporter. As with any carrier mediated transport mechanisms there is a maximal rate at which a substance can be transported (Transport maximum, Tm). This is dependent on the concentration of the molecule and number of transport protein molecules available to transport it. People with diabetes mellitus have a high plasma glucose concentration and often exceed the Tm for glucose and have glucose appearing in their urine (glucosuria). The net movement of water across the luminal and basolateral membranes and across the tight junctions between epithelial cells occurs via osmosis. However, it should be noted that osmosis is made possible by the active movement of electrolytes (particularly of Na+ ions) out of the epithelial cell across the basolateral membrane. This is called the „solvent drag‟ phenomena and is the basis for the Golden Rule “Water follows Sodium” Tubular Secretion Tubular secretion like tubular reabsorption occurs via diffusion and mediated diffusion (transcellular epithelial transport). Ions such as H+, K+ organic anions and drugs are actively secreted. The epithelial cells also metabolise a variety of compounds and secrete them into the tubular lumen (eg. ammonium ion) The number of transport proteins in the luminal or basolateral membranes for tubular reabsorption or secretion is regulated by neural and hormonal factors. This provides a means by which the tubular reabsorption and secretion of a molecule is controlled. Sodium and Water Reabsorption Normally, Na+ and water losses are exactly equal to sodium and water gains. This matching of inputs with outputs is achieved through the regulation of urinary loss. Na+ and water are reabsorbed via two process‟: 1. Na+ reabsorption is an active process in all tubules except in the descending limb of the Loop of Henle. The mechanism by which Na+ diffuses across the luminal membrane of the epithelial cell differs along the tubule. In some areas Na+ diffuses through Na+ channels, Na+ / glucose co-transporter, or Na+ / H+ counter transporter. The mechanism by which Na+ is moved out of the epithelial cell across the basolateral membrane is always via the Na+ / K+ ATPase. 2. Water reabsorption is always via diffusion but is dependent on Na+ reabsorption. The net movement of water across the luminal and basolateral membranes (through aquaporins) and across the tight junctions between epithelial cells occurs via osmosis. However, it should be noted that osmosis is made possible by the active movement of Na+ out of the epithelial cell across the basolateral membrane. The electrochemical gradient created by the movement of Na+ establishes a gradient by which osmosis can occur. The water permeability of the proximal tubule is the highest as a consequence most of the Na+ is reabsorbed here. The water permeability of the cortical and medullary collecting ducts is controlled by antidiuretic hormone (ADH) also known as vassopressin. ADH stimulates the insertion of an aquaporin into the luminal membrane of epithelial cells lining the cortical and medullary collecting ducts and enhances water reabsorption. Deficiencies in ADH lead to a water diuresis and is the underlying cause of diabetes insipidus The Counter Current Multiplier The kidneys can produce urine with an osmolarity of up to 1400mOsm/litre. This is five times the osmolarity of plasma. This concentrated urine is achieved through the interaction of the counter current multiplier system (Loop of Henle), the action of ADH on medullary and cortical collecting ducts and the unique anatomy of the blood vessels within the medulla (vasa recta) Fluid entering the Loop of Henle from the proximal tubule is isoosmotic with the plasma. The descending Loop of Henle is permeable to water. The ascending Loop is impermeable to water while it pumps out Na and Cl ions. The whole point is to create an osmolarity gradient in the ISF down through medulla region of the kidney. As a consequence of this osmotic gradient, water can move out into the ISF (if ADH is present) and be reabsorbed. This creates hyperosmotic urine. If ADH is not present all the water stays in the collecting ducts and is lost in the urine. This urine is hypoosmotic. The vasa recta (blood vessels within the medulla) runs in parallel to the Loop of Henle and ensures that the osmotic gradient in the medullary ISF is maintained. Renal Sodium Regulation The regulation of total body Na+ is achieved through the baroreceptors and osmoreceptors. As Na+ is the major electrolyte in plasma, any change in Na+ ion concentration will affect plasma volume and hence blood pressure. Low Na+ concentration will ultimately lead to low blood pressure. Low blood pressure activates the baroreceptor reflex. An increase in the activity of sympathetic nerves causes a constriction of the renal arterioles that lowers GFR and increases Na+ reabsorption. The renin-angiotensin system acts to stimulate the secretion of aldosterone from the adrenal cortex. Aldosterone increases the reabsorption of Na+ ions by the collecting ducts by promoting the expression and synthesis of the transport proteins involved in moving Na+ ions. That is, aldosterone promotes the expression and synthesis of Na+ channels and the Na+ / K+ ATPase on the luminal and basolateral membranes respectively. Stimulation of the renal sympathetic nerves (as a result of the initiation of the baroreceptor reflex) stimulate the juxtaglomerular cells to release renin. The juxtaglomerular cells are sensitive to pressure and constitute intrarenal baroreceptors. A reduction in renal blood pressure (as a result of low Na+) stimulates the juxtaglomerular cells to release renin Renal Water Regulation ADH is the major hormone controlling water reabsorption. NOTE: The baroreceptor reflexes and renin-angiotensin system will also regulate water reabsorption as a the movements of water are associated with Na+ ADH release from the posterior pituitary is stimulated by osmoreceptors located in the hypothalamus. An increase in total body water leads to a reduction in body fluid osmolarity. This causes a decreased firing of the hypothalamic osmoreceptors and a decreased release of ADH from the posterior pituitary. Hydrogen Ion Regulation / Acid Base Enzyme mediated reactions are highly sensitive to changes in pH. As a consequence the concentration of H+ ions is closely regulated. H+ ions are continually added to the plasma. These sources include: 1. Carbonic acid formation 2. Acids produced from the metabolism of proteins and other organic molecules 3. Loss of bicarbonate ions (HCO3-) from GI tract and urine (the loss of one bicarbonate ion is effectively equal to the gain of one H+ ion) H+ ions are continually lost from the plasma. These sources include: 1. Utilisation of H+ ions in metabolism if organic anions 2. Loss of H+ from vomiting and urine 3. Hyperventilation Large changes in the plasma pH are prevented by buffer systems. A buffer system is composed of two compounds that minimize pH when an acid or base is added or removed from the plasma.. There are four buffer systems in the body: 1. The carbonic acid/bicarbonate system 2. The protein buffer system 3. The hemoglobin buffer system 4. The phosphate buffer system The regulation of plasma pH by the kidneys is achieved through the interaction of tubular secretion of H+ ions and ISF secretion of bicarbonate ions. If there are excess H+ ions in the lumen after all of the bicarbonate ions have been used a non bicarbonate (phosphate buffer system) buffer combines with the H+ ions. When non bicarbonate buffer combines with secreted H+ ions in the lumen a net gain of bicarbonate ions results. Bicarbonate ions are also produced by tubular epithelial cells from glutamine. Glutamine is absorbed from the glomerular filtrate in the tubular lumen or from the ISF and is converted to ammonium ions and bicarbonate ions. The ammonium ions are secreted across the luminal membrane and into the lumen via Na+ / ammonium counter transport and the bicarbonate ions diffuse across the basolateral membrane and into the ISF through a transport protein. The renal responses to metabolic / respiratory alkalosis / acidosis will involve changes in the rates of the above mechanisms to compensate for an increase / decrease in blood pH.
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