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Renal Physiology


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Renal Physiology

  2. 2. Basic Principles of RenalPhysiology
  3. 3. THE STRUCTURE OF THE MAMMALIAN KIDNEYThe kidneys are a pair of bean-shaped organs foundin the lower back region behind the intestines. Theyare 7-10cm long and are the major excretory andosmoregulatory organs. Along with the ureter, bladderand urethra, they make up the urinary system. It is inthis system that urine is produced and excreted by thebody via urination (micturition).
  5. 5. The renal artery brings blood with waste products tothe kidney to be cleansed. After the blood iscleansed, it returns to the heart via the renal vein.Wastes flow through the ureter as urine to the bladderto be stored. When the bladder is full, stretchreceptors in its wall trigger a response, the muscles inthe wall contract and the sphincter muscles relax,allowing the urine to be excreted through the urethra.The kidneys are enclosed with a protective fibrouscapsule that shows distinct regions.
  6. 6. THE INTERNAL STRUCTURE OF THE KIDNEYCortex: The outer region. It has a more uneven texture than the medulla. The Renalcapsule, proximal convoluted tubule and distal convoluted tubule of the nephron arelocated here.Medulla: The inner region, consisting of zones known as „pyramids‟ which surroundthe pelvis. The Loop of Henle and collecting ducts of the nephron are located here.Pelvis: The central cavity. Urine formed after blood is cleansed is deposited here. Thiscavity is continuous with the ureter so the urine goes directly to the bladder.
  8. 8. THE NEPHRONThe nephron is the functional unit found withinthe kidneys. Each kidney is made up of millionsof microscopic nephrons, each with a rich bloodsupply. To fully understand the function of thekidney, the function of the nephron must bestudied and understood since it is this structurethat carries out excretion and osmoregulation.
  11. 11. Each nephron has the following structures:•Bowman‟s capsule (renal capsule)•Proximal convoluted tubule•Loop of Henle•Distal convoluted tubule•Collecting duct
  13. 13. Glomerulus: A mass of capillaries enclosed by theBowman‟s capsule.Afferent arteriole: A branch of the renal artery thatsupplies the glomerulus with blood.Efferent arteriole: Takes blood away from theglomerulus.Malpighian body: The structure consisting of theBowman‟s capsule and the glomerulus.
  14. 14. There is a hydrostatic pressure in the glomerulus due to thestrong contraction of the left ventricle of the heart and the factthat the diameter of the afferent arteriole is larger than that ofthe efferent arteriole. The difference in diameters between thetwo vessels raise the hydrostatic blood pressure. This causesblood to filter into the Bowman‟s capsule under pressure in aprocess called ultrafiltration. As a result, only molecules withRMM less than 68,000 can enter the capsule (water, glucose,amino acids, hormones, salt, urea), while the larger moleculeslike plasma proteins and blood cells remain in the blood andexit the Malpighian body via the efferent arteriole. The bloodmust pass several filtrating barriers before it can enter thecapsule.
  15. 15. Endothelium of the capillary: these have small pores between thesqamous cells that makes it more permeable than normal capillaries.All the constituents of the blood plasma but blood cells can passthrough.Basement membrane of the endothelium: this is a continuous layerof organic material to which the endothelial cells are attached. Onlymolecules with RMM less than 68,000 can pass through as thismembrane acts as a dialysing membrane. All constituents of the bloodplasma but the plasma proteins can pass through.Podocytes: these are found on the inner wall of the Bowman‟s capsuleand are foot-like cells with many processes that wrap around thecapillary. There are gaps between the branches of the cell whichenables the free flow of substances that have passed through thebasement membrane, into the Bowman‟s capsule.
  16. 16. Diagrams of the podocytes and basement membrane Podocyte:
  18. 18. THE PROXIMAL CONVOLUTED TUBULEThis is the longest part of the nephron and is located inthe cortex of the kidney. It is surrounded by manycapillaries that are very close to the walls. Approximately80% of the glomerular filtrate is reabsorbed here viaselective reabsorption. Cubical epithelial cells line thetubule walls and have many microvilli on their freesurfaces which increase the surface area of the wallexposed to the filtrate.Fact: The total surface area of the Human proximal tubulecells is 50m2!!!
  19. 19. There is a rich blood supply surrounding eachnephron, which is important for thereabsorption process. The cubical epithelialcells lining the tubule invaginates to formintercellular and subcellular spaces next to thebasement membrane of the capillaries. Glucoseand amino acids are absorbed into the blood byactive transport across the infolded membranesand subcellular spaces. These solutes diffusefrom the filtrate into the cells, then through tothe subcellular spaces and then into thebloodstream. This sets up a concentrationgradient which is maintained as the reabsorbedsolutes are carried away by the flowing blood.
  20. 20. Other mineral ions are also actively reabsorbed the wayglucose and amino acids are. As so many of the solutes areremoved, the filtrate becomes hypotonic (lowerconcentration of solute molecules) than the surroundingblood, stimulating water to move via osmosis from thefiltrate to the blood. This leads to the filtrate and the bloodbeing isotonic (same solute concentrations) by the time thefiltrate reaches the end of the tubule. However, since urea isnot actively reabsorbed, its concentration in the filtrate ismuch higher than in the blood and some of the ureaunavoidably diffuses back into the bloodstream and is takenaway.
  21. 21. THE LOOP OF HENLEThis hairpin-bend structure has a descending limband an ascending limb and is found in themedulla of the kidney. The descending limb hasthin walls permeable to water and penetrates deepinto the medulla but the ascending limb hasthicker, relatively impermeable walls that returnsto the cortex. Surrounding the loop is a networkof capillaries, one part of which has the samehairpin structure and is called the vasa recta.
  22. 22. Terminology:Solution with greater Solution with lowerconcentration of solute concentration of solutemolecules moleculesLower concentration of water Higher concentration ofmolecules water moleculesLower solute potential Higher solute potentialLower water potential Higher water potentialhypertonic hypotonic
  23. 23. Need to know:The loop of Henle works by making the concentration of the interstitial tissues of the medulla hypertonic (greater solute concentration) to the filtrate by actively transporting chloride ions out of the filtrate into the surroundings. Sodium ions passively follow. This occurs in the thick part of the ascending limb.The deeper part of the medulla near the pelvis is the most concentrated and therefore has the lowest water potential.
  24. 24. The filtrate at the end of the proximal convoluted tubule,entering the loop of Henle is isotonic. As it descends the loop,it is carried through tissues of increasing solute concentrationand the permeable walls of the descending limb enables waterto leave the filtrate by osmosis and enter the surroundingtissues. This water passes into the vasa recta and is carriedaway in the blood, and this is possible because blood in thevasa recta is flowing from deeper more concentrated regionsof the medulla so its water potential is lower than the filtrateof the adjacent descending limb. The continuous loss of water in the descending limbcauses the filtrate to have the same water potential as thesurrounding tissues by the time it reaches the hairpin bend,both of which are hypertonic to the blood. The active removalof sodium chloride in the ascending limb leaves the filtratehypotonic to the blood as it enters the distal convolutedtubule.
  25. 25. The tissues then become more concentrated than the filtrate which would normally lead to osmosis but water is prohibited from leaving because of the impermeable walls of the ascending limb.The mode of action of the loop of Henle is also called a countercurrent multiplier system since the filtrate flows in opposite directions in the two limbs. The pumping of sodium chloride in the ascending limb and the withdrawal from water in the descending limb can be multiplied if the loop is longer and this is important in water conservation as more water can be withdrawn and a more concentrated urine produced. This works since the concentration of solutes in the medulla causes the water in the collecting duct to exit the filtrate and be reabsorbed into the blood.
  27. 27. The cells of the wall of the distal convoluted tubule are similar to those of the proximal convoluted tubule, having numerous microvilli and mitochondria and carries out active transport. However, this tubule reabsorbs varying quantities of inorganic ions in accordance with the bodys needs.It can also secrete substances into the filtrate to maintain a particular condition (example: control of pH). The walls of the distal convoluted tubule are permeable to water only if the ADH (anti-diuretic hormone), otherwise, it is impermeable to water. If it is permeable, water exits the filtrate and enters the bloodstream and an isotonic filtrate enters the ducts. If it is not permeable, a hypotonic filtrate enters the collecting ducts.
  29. 29. The distal convoluted tubule ends in the collecting duct. (Several nephrons can share one collecting duct.) Final modifications are made to the filtrate which is then emptied into the pelvis of the kideny as urine.Like the walls of the distal convoluted tubule, the walls of the collecting ducts are only permeable to water if ADH is present, otherwise, it is impermeable to water.
  30. 30. BASIC RENAL PROCESSESThere are three basic Renal processes:  Glomerular filtration.  Tubular reabsorption  Tubular secretion
  31. 31. BASIC RENAL PROCESSUrine formation: Filtration from of plasma from the glomerular capillaries into the Bowman‟s space. Movement from the tubular lumen to the peritubular capillaries is the process called tubular reabsorption Movement from the peritubular capillaries to the tubular lumen is the process known as tubular secretion
  32. 32.  Once in the tubule the substance need not be excreted , it can be reabsorbed. These processes do not apply to all substances. E.g.- Glucose (completely reabsorbed.)- Toxins ( Secreted and not reabsorbed)
  33. 33.  A specific combination of glomerular filtration , tubular reabsorption and tubular secretion applies to different substances found in the plasma. It is important to note that the rates of these processes are subject to physiological control. The rates of these processes will therefore be changed in order to ensure homeostatic regulation. A forth process is also important to some substances, this is known as metabolism by the tubular cells.
  34. 34. Glomerular Filtration The filtration of plasma from the glomerular capillaries into the Bowman‟s space is termed glomerular filtration. The filtrate is termed glomerular filtrate or ultrafiltrate Glomerular filtration is a bulk flow process Filtrate contains all plasma substances except protein. Table 1 : Constituents of the Glomerular filtrate Filtered Not filtered Low molecular weight Most plasma proteins ie. substances (including Albumins & Globulins. smaller peptides) water Plasma calcium and fatty acids Collected in the Bowman‟s space of the Bowman‟s capsule.
  35. 35.  Fenestrations found in the glomerular capillary walls are not large enough to allow the passage of large proteins from the plasma, smaller proteins however are allowed to pass. RECALL : Basement membrane is a gelatinous layer composed of collagen and glycoproteins . Glycoproteins in the basement membrane discourage the filtration of small plasma proteins. Glycoproteins are negatively charged and therefore they repel small molecular weight proteins such as albumin which is also negatively charged. Less than 1 % of albumin molecules escape the Bowman‟s capsule. Those that do are removed by exocytosis in the proximal tubule
  36. 36. Forces involved in filtrationTable 2 : Forces involved in the Glomerular filtration Favouring filtration Opposing filtration Glomerular capillary blood Fluid pressure in Bowman‟s pressure space Osmotic force due to protein in plasma- Net glomerular filtration pressure = P GC - P BS - ∏ GC- Net filtration pressure is normally always positive.
  37. 37. Forces involvedin glomerularfiltration( Widmaier E. et al,2008)
  38. 38. RATE OF GLOMERULARFILTRATION ( GFR ) GFR : the volume of fluid filtered from the glomeruliinto the Bowman‟s space per unit time Determined by :1. Net filtration pressure 2. Permeability of the corpuscular membranes 3. Surface area available for filtrationGFR is not fixed but is subject to physiologicalregulation , which causes a change in the net filtrationpressure due to neural and hormonal input to theafferent and efferent arterioles.
  39. 39. Decreased GFR Increased GFR Constriction if afferent  Constriction of the efferent arteriole causes a decrease in arteriole results in an hydrostatic pressure in the increase in hydrostatic glomerular capillaries, this pressure in the glomerular results in decreased GFR capilleries. Results in Dilation of the efferent increased GFR arteriole results in a  Dilation of afferent arteriole reduction in hydrostatic causes an increase in pressure in the glomerular hydrostatic pressure in the capillaries resulting in a glomerular capilleries. This decreased GFR results in an increase in GFR
  40. 40. Tubular Reabsorption Movement of substances from the tubular lumen to the interstitial fluid does not occur by bulk flow due to inadequate pressure differences and permeability of the tubular membranes Tubular reabsorption involves the reabsorption of certain substances out of filtrate by either diffusion or mediated transport Substances are then returned to capillary blood which surround the kidney tubules. Tubular reabsorbtion mainly occurs in the Proximal tubule and the Loop of Henele
  41. 41. Data for a fewplasma componentsthat undergofiltration andreabsorption .(Widmaire E. et al ,2008)
  42. 42.  Diffusion usually occurs across the tight junctions connecting the epithelial cells Mediated transport requires the participation of transport protiens in the membranes of the tubular cells.Table 3 : Methods of Tubular reabsorptionDiffusion Mediated TransportWater reabsorption creates Reabsorption coupled with theconcentration gradient across reabsorption of sodium.tubular epithelium. Requires the use of transporters.Example: Urea , variety of Example : glucose , aminolipid soluble organic acidssubstances
  43. 43. Reabsorption by Mediated Transport Substances which are reabsorbed by mediated transport must cross the luminal membrane followed by the diffusion across the cytosol of the cell and finally across the basolateral membrane. The substance is usually transported across the basolateral membrane by mediated transport, that is it is usually coupled with the reabosorption of sodium. This occurs via secondary active transport.
  44. 44. Diagramaticrepresentation oftubularepithelium.(Widmaier E. et al,2008)
  45. 45. Tubular secretion Involves the transport of substances from peritubular capillaries into the tubular lumen. Secretion occurs via diffusion and transcellular mediated transport. Organic anions and cations are taken up by the tubular epithelium from the blood surrounding the tubules and added to the tubular fluid. Hydrogen ions and potassium are the most important substances secreted in the tubules. Other noteworthy substances secreted are metabolites such as choline and creatinine and chemicals such as penicillin.
  46. 46.  Active transport is required for the movement of the substances from the blood to the cell or out of the cell and into the tubular lumen. Usually coupled with the reabsorption of sodium
  47. 47. Metabolism by Tubules The cells of the renal tubules synthesize glucose and add it to the blood. Cells also catabolize substances such as peptides which are taken from the tubular lumen or peritubular capillaries. Catabolism eliminates these substances from the body.
  48. 48. REGULATION OF MEMBRANECHANNELS Tubular reabsorption and secretion of many substances in the nephrons are subjected to regulation by hormones and paracrine/ autocrine factors. Control of these substances is done by regulating the activity and the concentrations of the membrane channel and transporter proteins which are involved.
  49. 49. Division of labour in the tubules The primary role of the proximal tubule is to reabsorb most of the filtered water and filtered plasma solutes after the filtration in the Bowman‟s capsule. Proximal tubule is a major site for solute secretion. Henle‟s loop also reabsorbs relatively large quantities of major ions and to a lesser extent water. It therefore ensures that the mass of water and solute is smaller as it enters the following segments of the nephron The distal segments determine the final amount of substances excreted in the urine. Homeostatic controls act more on the distal segments of the tubule.
  50. 50. Renal ClearanceRenal clearance of any substance is the volume of plasmafrom which that substance is completely cleared per unittime.Clearance of S=mass of S secreted per unit time/ plasmaconcentration of SAny substance filtered ,but not reabsorbed, secreted ormetabolized by the kidneys is equal to the GlomerularFiltration Rate. How ever no substance completely meetsthis criteria and therefore creatinine clearance is used toapproximate the GFRGeneralization that any substance clearance is greater thanGFR that substance undergoes secreation.
  51. 51. Micturition Remaining fluid containing excretory substances is called urine. Urine is stored in the bladder and periodically ejected during urination. This is termed Micturition. The bladder is a balloon like chamber with walls of smooth muscle collectively termed the detrusor muscle. The contraction of this muscle squeezes on the urine to produce urination.
  52. 52. Control of Bladder.
  53. 53. Micturition Contraction of the external urethral sphincter can prevent urination Contraction of the detrusor muscle causes the internal urethral sphincter to change shape As the bladder fills, stretch receptors are stimulated. The afferent fibers from these receptors enter the spinal chord and stimulate the parasympathetic neurons which leads to the contraction of the detrusor muscle. Input from the stretch receptors also inhibits the sympathetic neurons to the internal urethral sphincter muscle.
  54. 54.  Descending pathways from the brain can influence this reflex. These pathways stimulate both sympathetic and somatic motor nerves therefore preventing urination.
  55. 55. Table 3 : Sources of water gain and loss in the body Water Gain in the Body Water loss in the body Ingested in liquids and food Skin Produced from oxidation of Respiratory Airways organic nutrients Gastrointestinal Tract Urinary Tract Menstrual Flow
  56. 56. Fig : Average Daily Water Gain and Loss inAdults( Widmaier E. , 2008)
  57. 57.  Water loss from skin and lining of respiratory tract is known as insensible water loss Water loss from gastrointestinal tract can be made severe in diarrhoea. Small quantities of Sodium and Chloride are excreted from skin and gastrointestinal tract. During severe sweating , diarrhoea ,vomiting and hemorrhage increased amounts of sodium and chloride are excreted.
  58. 58. Fig: Daily Sodium Chloride Intake and Loss(Widmaier , E. , 2008)
  59. 59.  From Figure 1 and 2 it is seen that salt and water losses equal salt and water gains. This is as a result of regulation of urinary loss. Healthy normal kidneys can readily alter the excretion of salt and water to ensure loss is balanced with gain
  60. 60.  Sodium and water are filtered from the glomerular capillaries and into the Bowman‟s space As a result of the low molecular weights of Sodium and water and how they are circulated in the plasma in their free form
  61. 61.  Reabsorption occurs in the proximal tubule Major hormonal control of reabsorption occurs in the DCT and CD The mechanism of Sodium reabsorption is an ACTIVE process which occurs in all tubular segments but not in the descending limb of the loop of Henle Water reabsorption occurs through diffusion but is highly dependant on Sodium reabsorption
  62. 62. Primary Active Transport of Sodium Sodium is removed from the cell and into the interstital fluid via Primary Active Transport via the Sodium and Potassium ATPase pumps located in the basolateral memebrane. Intracellular conc of Na to be lower than in the tubular lumen
  63. 63.  There is downhill movement of Na out of the lumen and into the tubular epithelial cells Varies from segment to segment in the tubule depending on the channels or transport proteins found in the luminal membrane In the basolateral membrane step the active transport process lowers intracellular Na conc thus allows for the downhill luminal entry step
  64. 64.  In the proximal tubule luminal entry occurs via cotransport molecules like glucose while countertransport with hydrogen ions Reabsorption of cotransport molecules and secrection of hydrogen ions are driven by Na reabsorption. In the CCD sodium enters from the tubular lumen and into the cell via diffusion through sodium channels
  65. 65. Coupling of Water Reabsorption toSodium Reabsorption Sodium is transported from the tubular lumen to the intersitial fluid across the epithelial cells The removal of solutes from the tubular lumen local osmolarity of tubular fluid adjacent to the cell*while the removal of solutes from the interstital fluid outside of the cell local osmolarity
  66. 66.  Difference in water conc between the lumen and interstital fluid causes a net diffusion of water from the lumen across the tubular cells or the tight junctions and into the interstital fluid Water, Na and other solutes are dissolved in the interstital fluid and move into the peritubular capillaries by bulk flow- Final step of reabsorption
  67. 67.  Aquaporins are integral porin proteins found on the plasma membrane of the tubular epithelium commonly known as water channels. Movement of water depends on the permeability of the epithelium. The proximal tubule has a high water permeability hence it reabsorbs water at a similar rate to sodium ions
  68. 68. Critical- Water permability varies in the cortical and the medullary collectingf ducts due to physiogical control (discussed later on)
  69. 69. Vasopressin/ Antidiuretic Hormone(ADH) Stimulates the insertion into the luminal membrane of certain aquaporin water channels by exocytosis As plasma conc increases water permeability of the CD becomes greater Water diuresis occurs when there are low levels of the hormone. Little water is reabsorbed and is excreted in the urine
  70. 70.  Diabetes Insipidus- Occurs as there is a deficiency of or the kidney‟s inability to respond ADH Signs and Symptoms: Excessive Thirst, Excretion of large amounts of severely diluted urine, Blurred Vision and DehyrationOsmotic diuresis- Increased urine flow results from the increase in solute excretion.
  71. 71. Urine Concentration: TheCountercurrent Multiplier System Obligatory water loss- The minimal amount of fluid loss from the body which can occur. Takes place as tubular fluid flows through the medullary CDs ADH causes water to diffuse out of MCD and into the interstital fluid of the medulla to be carried by the blood vessels.
  72. 72. How does medullary fluid becomehyperosmotic? The countercurrent anatomy of the loop of Henle of juxtamedullary nephrons Reabsorption of NaCl in the ascending limb of those loops of Henle Impermeablilty of those ascending limbs to water Trapping of urea in the medulla Hairpin loops of vasa recta to minimize wash out of the hyperosmotic medulla
  73. 73. Ascending limb: In the ascending limb Sodium and Chloride are reabsorbed from the lumen to the medullary interstitial fluid The upper thick area reabsorption occurs via transporters which actively transports sodium and chloride. It is a passive process It is imperable to water therefore resulting in the interstitial fluid of the medullary to be hyperosmmotic to that of the fluid in the ascending limb
  74. 74.  Descending limb Diffusion of water occurs from the descending limb and into the interstital fluid The fluid hyperosmolarity is maintained by the ascending limb The loop of Henle countercurrent multipler- Causes interstitial fluid of the medulla to become concentrated hence water will draw out from the collecting ducts and thus concentrates the urine with solutes.
  75. 75.  Osmolarity increases as tubular fluid goes deeper into the medulla. NB: Active Sodium Chloride transport mechanism in the ascending limb is an essential component to the system because without it the countercurrent flow would have no effect on the loop and its medullary interstitial osmolarity
  76. 76.  In the DCT the fluid becomes more hyperosmotic because it actively transports sodium and chloride out of the tubule and is reletaviely imperable to water. Fluid now enters CCD High levels of Vasopressin causes water reabsorption to occur by diffusion from the hyperosmotic fluid in CCD until the fluid becomes isoosmotic to the interstitial fluid and peritubular plasma of the cortex Along the lengths of the MCD water diffuses out of the collecting ducts and into the interstitial fluid.
  77. 77.  The water which is reabsorbed enters the medullary capillaries and is carried out of the kidneys via the venous blood. Final urine is hyperosmotic When plasma ADH is low the CCD and MCD are imperable to water thus resulting in a large volume of hypoosmotic urine is excreted which would remove excess water in the body
  78. 78. Medullary Circulation
  79. 79.  Blood Vessels(Vasa recta) in the medulla form hairpin loops which run in a parallel position to the loops of Henle and MCD Blood enters the vessel loop and flows down deeper and deeper while sodium and chloride diffuse into the blood while water diffuses out Bulk Flow- maintains the steady state countercurrent gradient set up by the loops of Henle
  80. 80. Recycling of Urea Urea is reabsorbed and secreted into the tubule and then reabsorbed again Urea is then trapped in the medullary interstitium hence increasing its osmolarity Half of the urea is reabsorbed in the proximal tubule and the remainder enters the loop of Henle Urea is secreted back into the tubular lumen via facilitated diffusion
  81. 81.  Urea is reabsorbed from the distal tubule and the CCD Half of the urea is then reabsorbed from the MCD and 5% in the vasa recta The remainder is secreted into the loop of Henle NB: Only 15% of the urea which was filtered remains in the Collecting Duct and the remaining excreted as urine
  82. 82. Renal Regulation of pHAn important function of kidney is to regulate the function by excreting either acidic [H+] or basic [OH-] urine.The pH of urine ranges from 4.5 to 9.5, because the renal system plays a significant role in long term pH maintenance of the blood at 7.4 0.05.This is possible by its capacity of reabsorption, secretion and excretion of the non-volatile acids like lactic acid, pyruvic acid, HCl, phosphoric acid and H2SO4 which are produced in the body cannot be excreted by lungs.The first mechanism for removal of acids (H+) from the body is by renal excretion.
  83. 83. Regulation of H+ Ions
  84. 84. Regulation of H+ Through Ammonia The kidney is to buffer acids and thus to conserve fixed base through the production of NH3 from amino acids with the help of an enzyme glutaminase. Whenever there is excess acid production the NH3 production is also which combines with H+ to form NH4+ which is excreted as NH4Cl. This occurs in the event of acidosis. When alkali is in excess, the H+ is reabsorbed into the cell in exchange to Na+/K+.
  85. 85. Regulation of H+ Through Bicarbonate System The filtered HCO3– combined with H+ H2CO3, carbonic anhydrase present in the brush border of the cell wall dissociate H2CO3 H2O + CO2. The CO2 diffuses into the cell. The CO2 combines with H2O to form H2CO3 again. This H2CO3 again ionizes to HCO3– + H+ with the help of carbonic anhydrase of acid-base balance.
  86. 86. Regulation of H+ Through Bicarbonate System The H+ diffuses into the lumen in exchange for Na+ and HCO3– is reabsorbed into plasma along with Na+. There is no net excretion of H+ or generation of new HCO3– . So this mechanism helps to maintain a steady state
  87. 87.  Calcium and phosphate are controlled mainly by parathyroid hormone. The parathyroid hormone (PTH) is a protein hormone produced in the parathyroid glands. The PTH controls the kidneys. A decline in plasma calcium concentration causes PTH to be secreted and an increase in plasma calcium concentration does the opposite.
  88. 88.  The kidney filters 60% of plasma calcium. Calcium is essential for the functioning of the majority of the body‟s functions Therefore the kidney reabsorbs calcium from tubular fluid. More than 60% of calcium reabsorption occurs in the proximal tubule and is not under the control of any hormones.
  89. 89.  The distal convoluted tubule and in the beginning of cortical collecting duct are mainly involved in the hormonal control of calcium reabsorption. PTH stimulates calcium channels to open. This causes an increase in calcium reabsorption. PTH increases 1-hydroxylase enzyme activity which in turn stimulates 25(OH)-D to 1,25 (OH)2 D. This causes an increase in calcium and phosphate absorption in the gastrointestinal tract.
  90. 90.  The majority if the phosphate that is filtered is reabsorbed in the proximal tubule. Conversely PTH decreases phosphate reabsorption Thus the excretion of phosphate is increased. In conclusion when the plasma calcium concentration declines and PTH and calcium reabsorption increases, the excretion of phosphate is increased.
  91. 91. HORMONES AND THEKIDNEY Renin increases the production of angiotensin II which is released when there is a fall in intravascular volume e.g haemorrhage and dehydration. This leads to:  Constriction of the efferent arteriole to maintain GFR, by increasing the filtration pressure in the glomerulus.  Release of aldosterone from the adrenal cortex  Increased release of ADH from the posterior pituitary  Thirst  Inotropic myocardial stimulation and systemic arterial constriction The opposite occurs when fluid overload occurs.
  92. 92. HORMONES AND THEKIDNEY(cont’d) Aldosterone (secreted by the adrenal gland) promotes sodium ion and water reabsorption in the distal tubule and collecting duct where Na+ is exchanged for potassium (K+) and hydrogen ions by a specific cellular pump. It is also released when there is a decrease in serum sodium ion concentration.  E.g. This can occur, when there are large losses of gastric juice. Gastric juice contains significant concentrations of sodium, chloride, hydrogen and potassium ions. Therefore it is impossible to correct the resulting alkalosis and hypokalaemia without first replacing the sodium ions using 0.9% saline solutions.
  93. 93. HORMONES AND THE KIDNEY(cont’d)  Atrial Natruretic Peptide(ANP) is released when atrial pressure is increased e.g. in heart failure or fluid overload. It promotes loss of sodium and chloride ions and water chiefly by increasing GFR.  Antidiuretic Hormone (ADH or vasopressin) is synthesized by the cells in the supraoptic and paraventricular nuclei of the hypothalmus, transported along a neural pathway (i.e., hypothalamohypophysial tract) to the neurohypophysis (i.e., posterior pituitary); and then released into the circulation.  It increases the water permeability of the distal tubule and collecting duct, thus increasing the concentration of urine.  In contrast, when secretion of ADH is inhibited, it allows dilute urine to be formed. This occurs mainly when plasma sodium concentration falls such as following drinking large quantities of water. This fall is detected by the osmoreceptors.
  94. 94. HORMONES AND THE KIDNEY(cont‟d)  Stretch receptors (baroreceptors) that are sensitive to changes in blood pressure and central blood volume aid in the regulation of ADH release.  The hormones interact when blood loss or dehydration occurs to maintain intravascular volume.FIGURE 20
  95. 95. FIGURE 21
  96. 96. Sodium Regulation The kidney monitors arterial pressure and retains sodium when the arterial pressure is decreased and eliminates it when the arterial pressure is increased Sodium reabsorption is an active process occurring in all tubular segments except the descending limb of the loop of Henle. Water reabsorption is by diffusion and is dependent upon sodium reabsorption. The primary mechanism driving all transport in the proximal tubule is the Na-K ATPhase mechanism located on the basolateral membrane of the tubular cells.
  97. 97. Sodium Regulation(cont’d) The rate at which the kidney excretes or conserves sodium is coordinated by the sympathetic nervous system and the renin-angiotensin-aldosterone system. When Na + concentration falls, blood pressure and volume falls because water is lost with the Na +. The fall in blood pressure causes renin to be released into the bloodstream where it catalyses the conversion of the plasma proteins into angiotensin. The angiotensin stimulates the adrenal cortex to secrete aldosterone. Reabsorption of Na + is accompanied by the loss of K + (Na + - K + balance).
  98. 98. Sodium Regulation(cont’d) The sympathetic nervous system responds to changes in arterial pressure and blood volume by adjusting the GFR and the rate at which sodium is filtered from the blood. Sympathetic activity also regulates tubular reabsorption of sodium and renin release. The reninangiotensin- aldosterone system exerts its action through angiotensin II and aldosterone . Angiotensin II acts directly on the renal tubules to increase sodium reabsorption. It also acts to constrict renal blood vessels, thereby decreasing the glomerular filtration rate and slowing renal blood flow so that less sodium is filtered and more is reabsorbed. Angiotensin II is also a powerful regulator of aldosterone, a hormone secreted by the adrenal cortex.
  99. 99. FIGURE 22
  100. 100. Sodium Regulation(cont’d) Aldosterone acts at the level of the cortical collecting tubules of the kidneys to increase sodium reabsorption while increasing potassium elimination. It increases the uptake of Na by the and reabsorption in the kidneys which causes the concentration of Na+ in the blood to rise. This method of control depends on a feedback. If the concentrations of Na + is too high, the adrenal cortex becomes inhibited and secretes less aldosterone and vice verse. Feedback involves the co-factor renin which is released in the afferent glomerular arerioles.
  101. 101. Sodium Regulation(cont’d) Na + is transported out of the cell into the paracellular space and K + into the cell. This reduces the cell Na + concen. and the raises the K + concen. This causes a concentration gradient in which the presence of K conductance renders the cell electrically negative wrt its surroundings. In a steady state the pump operates below saturation point for Na + and an increase in Na + entry across the apical membrane increases the pump rate. The proximal tubule sodium reabsorption drives the reabsorption of the cotransported substances (glucose and the secretion of hydrogen ions.
  102. 102. Renal water regulation Water excretion is the difference between the volume of water filtered (the GFR) and the volume reabsorbed Two mechanisms which assist in the regulation of body water are: thirst and antidiuretic hormone (ADH). Thirst is the primary regulator of water intake and ADH is a regulator of water output. The both respond to changes in extracellular osmolarity and volume. Thirst is an emergency response which is controlled by the hypothlamus. An important stimulus for thirst is angiotensin II, which becomes increased in response to low blood volume and low blood pressure. ADH acts throught two receptors (V1) and (V2) of which the (V2) are located on the tubular cells of the cortical collecting duct.
  103. 103. Renal water regulation (cont’d) They control water reabsorption by the kidneys. ADH binds to the V2 receptors which increase the permeability of the collecting duct to water (antidiuretic effect). The receptor is coupled via a GTP-requiring stimulatory protein (Gs protein) to the enzyme adenylyl cyclase. The enzyme stimulates the production of cyclic AMP which activates protein kinase A. This kinase induces the insertion (exocytosis) of water channels, aquaporin 2. Aquaporin 2 (from the V2 receptors) move from the cytoplasm of the cells of the collecting duct to the huminal surface of these cells.
  104. 104. Renal water regulation (cont’d) Aquaporins 3 and 4 form the water channels in the basolateral membrane of the principal cells. These are not regulated by ADH (they are constitutively active). These channels then allow free movement of water from the tubular lumen into the cells along a concentration gradient. When ADH is not stimulated, the aquaporin 2 channels readily move out f the apical membrane so that water is no longer transferred out of the collecting duct. Without ADH, the permeability of the collecting duct to water is very low; this results in polyuria.
  105. 105.  The mechanism of action of ADH on principle cells, V2= vasopressin2 receptor, AQ2= aquaporin 2
  106. 106. Potassium Regulation Increases or decreases in extracellular potassium concentration can cause abnormal rhythms of the heart (arrhythmias) and abnormalities of skeletal- muscle contraction. Potassium levels are largely regulated by renal mechanisms that conserve or eliminate potassium. Major route for elimination is the kidney. Regulation is controlled by secretion from the blood into the tubular filtrate rather than vice versa.
  107. 107. Potassium Regulation (cont’d) Potassium is filtered in the glomerulus, reabsorbed along with sodium and water in the proximal tubule and with sodium and chloride in the thick ascending loop of Henle, and then secreted into the late distal and cortical collecting tubules for elimination in the urine. Aldosterone plays an essential role in regulating potassium elimination by the kidney. In the presence of aldosterone, sodium is transported back into the blood and potassium is secreted into the tubular filtrate for elimination in the urine (N+- K+ shift).
  108. 108. Potassium Regulation (cont’d) When body potassium is increased, extracellular potassium concentration increases. This increase acts directly on the cortical collecting ducts to increase potassium secretion and also stimulates aldosterone secretion, the increased plasma aldosterone then also stimulating potassium secretion. There is also a (K+- H+)exchange system in the collecting tubules of the kidney. When serum potassium levels are increased, potassium is secreted into the urine and hydrogen is reabsorbed into the blood, producing a decrease in pH and metabolic acidosis. Conversely, when potassium levels are low, potassium is reabsorbed and hydrogen is secreted into the urine, leading to metabolic alkalosis.
  109. 109. Bibliography
  110. 110. Outline What are diuretics? How do they work and what are some examples of diuretics? What are some clinical situations in which diuretics are used?
  111. 111. Diuretics These are agents which increase the mobilization of extra cellular fluid(ECF) this usually involves the loss of ions and water Diuretics are drugs that are utilized clinically to increase the volume of urine excretion.
  112. 112. Diuretics1. Loop diruetics Example: eg Furosemide( Lasix) Loop diuretics act on the ascending limb of the Loop of Henle, it inhibits the transport of protein which mediates the first step in sodium reabsorption.
  113. 113. Diuretics1. Loop diruetics eg furosemide( Lasix)
  114. 114. Diuretics2. Potassium sparing agents There are two types  Aldosternone Antagonist (i.e. block action of aldoesterone)  Na channel inhibtor {i.e. block the epithelial sodium channel (in the cortical collecting duct)
  115. 115. Diuretics
  116. 116. Diuretics There are many clinical situations in which the use of diuretic therapy can provide advantageous These include  Heart Failure with Edema  Hypertension
  117. 117. DiureticsHeart Failure with Edema Decrease cardiac output causes the kidney to respond as if there is decreased blood volume Retention of more salt and water Increase in blood volume to heart increase vascular volume resulting in edema Loop diuretics are use to reduce the volume
  118. 118. DiureticsHypertension. Hypertension (usually too much salt) Diuretic-induced excretion decreases Na+ and H2O in the body, which results in  Reduce blood volume which reduces the blood pressure  arteriolar dilation and further more lowers the pressure of the blood.
  119. 119. Kidney diseases There are many types of diseases that can affects the kidney These can be divided into  Congenital  Acquired  allergies,  bacteria,  tumors,  toxic chemicals  kidney stones (accumulation of mineral deposits in nephron tubules).
  120. 120. Kidney diseasesclassified as Kidney disease can also be  Acute  Low blood volume  Exposure to kidney toxic substances  Obstruction of urinary tract  Chronic  Diabetes  Hypertension  Glomeruloneprhritis ( inflammation of glomeruli )
  121. 121. Acute kidney injury Pre renal  Usually caused by decreased blood flow to the kidney Intrinsic  Damage to the kidney itself predominantly affecting the glomerulus or tubule Post renal  Usually occurs due to urinary tract obstruction
  122. 122. Acute kidney injurySigns There will be decrease in urine output. Substances normally eliminated by the kidney tend to increase  Urea  Creatine Sodium and potassium, electrolytes that are commonly deranged due to impaired excretion and re absorption
  123. 123. Chronic Kidney disease There are approximately 1 million nephrons are present in each kidney,. The summation of all the nephrons contribute to the Glomerular filtration Rate(GFR) The kidney has the ability when renal injury occurs, the GFR is maintained This is ability allows the clearance of harmful substance to continue largely unaffected till the GFR has decreased to 50 percent of it normal value.
  124. 124. Chronic Kidney diseaseCauses include: Vascular disease  Hypertension Glomerular disease (primary or secondary)  Diabetes mellitus Tubulointerstitial disease  Drugs (eg, sulfa, allopurinol) Urinary tract obstruction  Tumors
  125. 125. Chronic Kidney disease Clinical problems associated with chronic kidney disease include  Hyperkalemia  Metabolic acidosis  Anemia  Bone disease
  126. 126. Chronic Kidney diseaseHyperkalemia The ability to maintain potassium (K) excretion at near-normal levels is generally maintained in chronic kidney disease. However when the GFR falls to less than 20-25 mL/min there is decreased ability of the kidneys to excrete potassium. Resulting in Hyperkalemia
  127. 127. Chronic Kidney diseaseSalt and water handling abnormalities As kidney function declines, there is excessive sodium retention which will cause extracellular volume expansion leading to peripheral edema
  128. 128. Kidney Disease
  129. 129. Chronic Kidney diseaseAnemia This develops from decreased renal synthesis of erythropoietin, the hormone responsible for bone marrow stimulation for red blood cell (RBC) production.
  130. 130. Chronic Kidney disease
  131. 131. Chronic Kidney diseaseBone disease Renal bone disease is a common complication of chronic kidney disease. Decreased renal synthesis of 1,25- dihydroxycholecalciferol (calcitriol) Hypocalcaemia develops primarily from decreased intestinal calcium absorption because of low plasma calcitriol levels
  132. 132. Kidney Disease
  133. 133. Kidney DiseaseReferences:Vander‟s Human Physiology 10th Edition, Eric P. Widmaier, Hersel Raff, Kevin T. Strang,r:9,s:0,r:4,s:0
  134. 134. Kidney Disease GBTT437TT437&biw=1024&bih=456&tbm=isch&tbnid=9gXIjDjjaMJvqM:&imgrefurl = cn/lectures/urinary_physiology.html&docid=0v09nrgwAWVXNM&w=707&h=515&ei= YPt8TtvxMKTv0gHF- LDaDw&zoom=1&iact=hc&vpx=91&vpy=167&dur=109&hovh=192&hovw=263&tx=1 27&ty=199&page=1&tbnh=120&tbnw=165&start=0&ndsp=11&ved=1t:429,r:5,s:0 GBTT437TT437&biw=1024&bih=456&tbm=isch&tbnid=boI10CF6dX0OVM:&imgref url= 020%2520Exam%2520Reviews/Exam%25204/CH25%2520Nephron%2520I%2520- %2520Renal%2520Corpuscle.htm&docid=RdYeUelnc4_AbM&w=699&h=383&ei=YPt 8TtvxMKTv0gHF- LDaDw&zoom=1&iact=hc&vpx=77&vpy=144&dur=94&hovh=166&hovw=303&tx=18 2&ty=95&page=1&tbnh=97&tbnw=177&start=0&ndsp=11&ved=1t:429,r:0,s:0
  135. 135. DIABETES MELLITUS A common cause of renal failure is uncontrolled diabetes mellitus Diabetes meaning “running through” denotes increased urinary volume excreted by the persons suffering with this disease. Diabetes can be due to:1. Deficiency of insulin2. Decreased responsiveness to insulin This abnormality in carbohydrate metabolism leads to high levels of blood glucose which can lead to considerable damage to many parts of the body. These include kidneys, heart ,eyes and blood vessels.
  136. 136. How does Diabetes affect theKidneys Recall : 1. Osmotic diuresis , this is the increased urine flow as a result of a primary increase in the solute excretion. 2. Glucose is reabsorped by the proximal tubule via sodium- glucose transport proteins. The increase in blood glucose causes an increase in the rate filtration. This increase in rate of filtration causes increased amounts of protein to be filtered across the glomerular membranes. Small amounts of protein eventually appear in the urine. The filtered protein leads to increased damage to the membranes of the renal corpuscle .
  137. 137. How does Diabetes affect theKidneys As the kidneys become more compromised larger amounts of protein is allowed to pass from the blood and be excreted in the urine. Leads to proteinuria Kidney function begins to deteriorate. Irreversible damage to the kidneys leads to toxic waste not being able to be filtered out of blood and dialysis is required. This is the usual course of diabetic necropathy which results in end stage kidney disease.
  138. 138. How Diabetes affect the Kidneys Diabetic necropathy is the disease of the capillaries in the kidney glomeruli. That is they show glomerulosclerosis , which is the hardening of the of the glomerulus of the kidney due to scarring. Diabetic necropathy is progressive and results in death 2 – 3 years after diagnosis. It is also the leading cause of premature death in young diabetics.
  139. 139. How does Diabetes affect theKidneys When the blood sugar level of a person rises the glucose is detected in the urine. That is there is an increased glucose load in the proximal tubule. Some glucose therefore escapes reaborption and causes a retention of water in the lumen. This water is excreted along with the glucose. Persons with diabetes usually excrete large amounts of urine.
  140. 140. Diabetes insipidus Diabetes insipidus is caused by the failure of the posterior pituitary to release the hormone vasopressin or the inability of the kidney to respond to vasopressin. RECALL: Water reabsorption in the last portions of the tubules and coritcal collecting ducts can vary greatly due to physiological control. The major control is the peptide hormone vasopressin or antiduretic hormone (ADH)- [vasopressin] results in an in water permeability- [vasopressin] results in an in water permeability In patients with diabetes insipidus the kidneys are therefore unable to conserve water
  141. 141. Diabetes insipidus Therefore large quantities of dilute urine is produced. Persons who have diabetes insipidus will consume more water May also suffer from dehydration
  142. 142. Kidney StonesKidney stones may form in the pelvis or calyces of the kidneyor in the ureter.
  143. 143. Kidney Stones A kidney stone is an accumulation of mineral deposits in the nephron. Kidney stones may also be due to an infection Stones can be calcium, struvite, uric acid or cystine . Calcium stones are the most common type. Calcium which is not used by the bones or muscles goes to the kidneys. Extra calcium is usually removed by the kidneys with the rest of the urine. Persons therefore with calcium stones keep the extra calcium in their kidneys. The acidity or alkalinity of the urine also affects the ability of stone forming substances to remain dissolved.
  144. 144. Kidney Stones Extracorporeal shock wave lithotripsy (ESWL) is a procedure used to shatter simple stones in the kidney or upper urinary tract.
  145. 145. Hyperaldosteronism Emcompasses a number of different chronic diseases all of which involve excess adrenal hormone aldosterone. Conn‟s syndrome – growth of the zona glomerulosa of the adrenal gland , these tumors release aldosterone in the absence of stimulation by angiotensin II RECALL: Aldosterone is released by the adrenal cortex which stimulates the sodium reabsorption by the distal convoluted tubule and the cortical collecting ducts. - High [ aldosterone] increased sodium reabsorption - Low [ aldosterone] deareased sodium reabsorption ( 2% sodium lost in urine)
  146. 146.  In Conn‟s syndrome, there are high levels of aldesterone , which leads to an increase in sodium absorption in the nephron and potassium excretion Leads to an increase in blood pressure, due to increased blood volume which leads to hypertension. Renin release is greatly reduced.
  147. 147.  This is one of the most common causes of endocrine hypertension Endocrine hypertension is a secondary type of hypertension which is usually due to a hormone imbalance.
  148. 148. Hypokalemia This is a lower than normal amount of potassium in the blood. Potassium is obtained from food and is required by the body for proper nerve function Changes in the potassium level therefore can cause abnormal rhythms in the heart and in the skeletal muscle contraction Recall: Due to an increase in plasma aldosterone there is an increase in sodium reabsorption and potassium secretion. Hypokalemia is espcially seen in patients with Conn‟s syndrome
  149. 149. Decrease in Plasma Increase in Plasma volume PotassiumIncrease plasma angiotensin II Adrenal cortex Increase aldosterone secretion Increase plasma aldosterone Cortical collecting ducts Increased Na + Increased K+ reabsorption secretion Increased Decreased sodium Potassium excretion excretion
  150. 150. Hypertension Commonly known as high blood pressure. Normal blood pressure should be 120/80, any persons with a systolic pressure over 140 or a diastolic pressure over 90 is considered to have high blood pressure.
  151. 151. How does hypertension affect thekidneys  Hypertension causes an increase in the work done by the heart.  Over time blood vessels in the body become damaged.  The damage of the blood vessels of the kidney will lead to the deterioration of kidney function, that is they stop removing waste and extra fluid.
  152. 152. How does hypertension affect thekidneys The extra fluid in the fluid in the blood vessels may further raise the blood pressure , resulting in a dangerous cycle. High blood pressure is one of the leading causes of kidney failure, also known as end stage renal disease.
  153. 153. References rogramsandDiseaseTreatment/EndocrineHypertension.htm and-its-effect-kidney-and-liver