renal physiology

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RENAL PHYSIOLOGY

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  • 1.RENAL PHYSIOLOGY

2. Basic Principles of RenalPhysiology 3. THE STRUCTURE OF THEMAMMALIAN 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). 4. DIAGRAM OF THE URINARY SYSTEM 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. 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. 7. A DIAGRAM OF THE INTERNAL STRUCTURE OF THE KIDNEY 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. 9. DIAGRAM OF A NEPHRON 10. DIAGRAM OF A NEPHRON 11. Each nephron has the following structures:Bowmans capsule (renal capsule)Proximal convoluted tubuleLoop of HenleDistal convoluted tubuleCollecting duct 12. BOWMANS CAPSULE 13. Glomerulus: A mass of capillaries enclosed by theBowmans 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 theBowmans capsule and the glomerulus. 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 Bowmans 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. 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 Bowmans 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 Bowmans capsule. 16. Diagrams of the podocytes and basement membrane Podocyte: 17. BASEMENT MEMBRANE 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. 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. 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. 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. Terminology:Solution with greaterSolution with lowerconcentration of soluteconcentration of solutemoleculesmoleculesLower concentration of water Higher concentration ofmoleculeswater moleculesLower solute potential Higher solute potentialLower water potentialHigher water potentialhypertonic hypotonic 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. 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. 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. 26. DISTAL CONVOLUTED TUBULE 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. 28. THE COLLECTING DUCT 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. BASIC RENAL PROCESSESThere are three basic Renal processes: Glomerular filtration. Tubular reabsorption Tubular secretion 31. BASIC RENAL PROCESSUrine formation: Filtration from of plasmafrom the glomerularcapillaries into theBowmans space. Movement from the tubularlumen to the peritubularcapillaries is the processcalled tubular reabsorption Movement from theperitubular capillaries to thetubular lumen is the processknown as tubular secretion 32. Once in the tubule thesubstance need not beexcreted , it can bereabsorbed. These processes do notapply to all substances.E.g.- Glucose (completelyreabsorbed.)- Toxins ( Secreted and notreabsorbed) 33. A specific combination of glomerular filtration ,tubular reabsorption and tubular secretion applies todifferent substances found in the plasma. It is important to note that the rates of these processesare subject to physiological control. The rates of these processes will therefore be changedin order to ensure homeostatic regulation. A forth process is also important to some substances,this is known as metabolism by the tubular cells. 34. Glomerular Filtration The filtration of plasma from the glomerular capillaries into theBowmans 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 (includingAlbumins & Globulins. smaller peptides) waterPlasma calcium and fatty acids Collected in the Bowmans space of the Bowmans capsule. 35. Fenestrations found in the glomerular capillary walls arenot large enough to allow the passage of large proteinsfrom the plasma, smaller proteins however are allowed topass. RECALL : Basement membrane is a gelatinous layercomposed of collagen and glycoproteins . Glycoproteins in the basement membrane discourage thefiltration of small plasma proteins. Glycoproteins are negatively charged and therefore theyrepel small molecular weight proteins such as albuminwhich is also negatively charged. Less than 1 % of albumin molecules escape the Bowmanscapsule. Those that do are removed by exocytosis in theproximal tubule 36. Forces involved in filtrationTable 2 : Forces involved in the Glomerular filtration Favouring filtration Opposing filtration Glomerular capillary blood Fluid pressure in Bowmans pressure spaceOsmotic force due toprotein in plasma- Net glomerular filtration pressure = P GC - P BS - GC- Net filtration pressure is normally always positive. 37. Forces involvedin glomerularfiltration( Widmaier E. et al,2008) 38. RATE OF GLOMERULARFILTRATION ( GFR ) GFR : the volume of fluid filtered from the glomeruliinto the Bowmans space per unit time Determined by :1. Net filtration pressure 2. Permeability of the corpuscularmembranes 3. Surface area available for filtrationGFR 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. Decreased GFRIncreased GFR Constriction if afferent Constriction of the efferentarteriole causes a decrease in arteriole results in anhydrostatic pressure in theincrease in hydrostaticglomerular capillaries, this pressure in the glomerularresults in decreased GFR capilleries. Results in Dilation of the efferent increased GFRarteriole results in a Dilation of afferent arteriolereduction in hydrostatic causes an increase inpressure in the glomerular hydrostatic pressure in thecapillaries resulting in a glomerular capilleries. Thisdecreased GFRresults in an increase in GFR 40. Tubular Reabsorption Movement of substances from the tubular lumen to theinterstitial fluid does not occur by bulk flow due toinadequate pressure differences and permeability of thetubular membranes Tubular reabsorption involves the reabsorption of certainsubstances out of filtrate by either diffusion or mediatedtransport Substances are then returned to capillary blood whichsurround the kidney tubules. Tubular reabsorbtion mainly occurs in the Proximal tubuleand the Loop of Henele 41. Data for a fewplasma componentsthat undergofiltration andreabsorption .(Widmaire E. et al ,2008) 42. Diffusion usually occurs across the tight junctions connectingthe epithelial cells Mediated transport requires the participation of transportprotiens in the membranes of the tubular cells.Table 3 : Methods of Tubular reabsorptionDiffusion Mediated TransportWater reabsorption createsReabsorption coupled with theconcentration gradient across reabsorption of sodium.tubular epithelium. Requires the use oftransporters.Example: Urea , variety ofExample : glucose , aminolipid soluble organic acidssubstances 43. Reabsorption by Mediated Transport Substances which are reabsorbed by mediated transportmust cross the luminal membrane followed by thediffusion across the cytosol of the cell and finally acrossthe basolateral membrane. The substance is usually transported across the basolateralmembrane by mediated transport, that is it is usuallycoupled with the reabosorption of sodium. This occurs via secondary active transport. 44. Diagramaticrepresentation oftubularepithelium.(Widmaier E. et al,2008) 45. Tubular secretion Involves the transport of substances from peritubular capillariesinto the tubular lumen. Secretion occurs via diffusion and transcellular mediatedtransport. Organic anions and cations are taken up by the tubular epitheliumfrom the blood surrounding the tubules and added to the tubularfluid. Hydrogen ions and potassium are the most important substancessecreted in the tubules. Other noteworthy substances secreted are metabolites such ascholine and creatinine and chemicals such as penicillin. 46. Active transport is required for the movement of thesubstances from the blood to the cell or out of the cell andinto the tubular lumen. Usually coupled with the reabsorption of sodium 47. Metabolism by Tubules The cells of the renal tubules synthesize glucose and addit to the blood. Cells also catabolize substances such as peptides whichare taken from the tubular lumen or peritubular capillaries. Catabolism eliminates these substances from the body. 48. REGULATION OF MEMBRANECHANNELS Tubular reabsorption and secretion of many substances inthe nephrons are subjected to regulation by hormones andparacrine/ autocrine factors. Control of these substances is done by regulating theactivity and the concentrations of the membrane channeland transporter proteins which are involved. 49. Division of labour in the tubules The primary role of the proximal tubule is to reabsorb most ofthe filtered water and filtered plasma solutes after the filtrationin the Bowmans capsule. Proximal tubule is a major site for solute secretion. Henles loop also reabsorbs relatively large quantities of majorions and to a lesser extent water. It therefore ensures that themass of water and solute is smaller as it enters the followingsegments of the nephron The distal segments determine the final amount of substancesexcreted in the urine. Homeostatic controls act more on the distal segments of thetubule. 50. Renal ClearanceRenal 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 SAny 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 GFRGeneralization that any substance clearance is greater thanGFR that substance undergoes secreation. 51. Micturition Remaining fluid containing excretory substances iscalled urine. Urine is stored in the bladder and periodically ejectedduring urination. This is termed Micturition. The bladder is a balloon like chamber with walls ofsmooth muscle collectively termed the detrusormuscle. The contraction of this muscle squeezes on the urine to produce urination. 52. Control of Bladder. 53. Micturition Contraction of the external urethral sphincter can preventurination Contraction of the detrusor muscle causes the internalurethral sphincter to change shape As the bladder fills, stretch receptors are stimulated. Theafferent fibers from these receptors enter the spinal chordand stimulate the parasympathetic neurons which leads tothe contraction of the detrusor muscle. Input from the stretch receptors also inhibits thesympathetic neurons to the internal urethral sphinctermuscle. 54. Descending pathways from the brain can influencethis reflex. These pathways stimulate both sympathetic andsomatic motor nerves therefore preventing urination. 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 nutrientsGastrointestinal TractUrinary TractMenstrual Flow 56. Fig : Average Daily Water Gain and Loss inAdults( Widmaier E. , 2008) 57. Water loss from skin and lining of respiratory tract isknown as insensible water loss Water loss from gastrointestinal tract can be made severein diarrhoea. Small quantities of Sodium and Chloride are excretedfrom skin and gastrointestinal tract. During severe sweating , diarrhoea ,vomiting andhemorrhage increased amounts of sodium and chloride areexcreted. 58. Fig: Daily Sodium Chloride Intake and Loss(Widmaier , E. , 2008) 59. From Figure 1 and 2 it is seen that salt and water lossesequal salt and water gains. This is as a result of regulation of urinary loss. Healthy normal kidneys can readily alter the excretion ofsalt and water to ensure loss is balanced with gain 60. Sodium and water are filtered from the glomerular capillaries and into the Bowmans 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. Reabsorption occurs in the proximal tubule Major hormonal control of reabsorption occurs in theDCT and CD The mechanism of Sodium reabsorption is anACTIVE 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. 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. There is downhill movement of Naout of thelumen and into the tubular epithelial cells Varies from segment to segment in the tubule depending onthe channels or transport proteins found in the luminalmembrane In the basolateral membrane step the active transport processlowers intracellular Na conc thus allows for the downhillluminal entry step 64. In the proximal tubule luminal entry occurs via cotransportmolecules likeglucosewhile countertransport withhydrogen ions Reabsorption of cotransport molecules and secrection ofhydrogen ions are driven by Na reabsorption. In the CCD sodium enters from the tubular lumen and intothe cell via diffusion through sodium channels 65. Coupling of Water Reabsorption toSodium Reabsorption Sodium is transported from the tubular lumen to theintersitial fluid across the epithelial cells The removal of solutes from the tubular lumenlocal osmolarity of tubular fluid adjacent to the cell*while the removal of solutes from the interstital fluid outside of the cell local osmolarity 66. Difference in water conc between the lumen and interstitalfluid causes a net diffusion of water from the lumen acrossthe tubular cells or the tight junctions and into the interstitalfluid Water, Na and other solutes are dissolved in the interstitalfluid and move into the peritubular capillaries by bulk flow-Final step of reabsorption 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. Critical- Water permability varies in the cortical and the medullary collectingf ducts due to physiogical control (discussed later on) 69. Vasopressin/ Antidiuretic Hormone(ADH) Stimulates the insertion into the luminal membrane ofcertain aquaporin water channels by exocytosis As plasma conc increases water permeability of the CDbecomes greater Water diuresis occurs when there are low levels of thehormone. Little water is reabsorbed and is excreted in theurine 70. Diabetes Insipidus- Occurs as there is a deficiency of orthe kidneys 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. Urine Concentration: TheCountercurrent Multiplier System Obligatory water loss- The minimal amount of fluid lossfrom the body which can occur. Takes place as tubular fluid flows through the medullaryCDs ADH causes water to diffuse out of MCD and into theinterstital fluid of the medulla to be carried by the bloodvessels. 72. How does medullary fluid becomehyperosmotic? The countercurrent anatomy of the loop of Henle ofjuxtamedullary nephrons Reabsorption of NaCl in the ascending limb of those loopsof Henle Impermeablilty of those ascending limbs to water Trapping of urea in the medulla Hairpin loops of vasa recta to minimize wash out of thehyperosmotic medulla 73. Ascending limb: In the ascending limb Sodium and Chloride arereabsorbed from the lumen to the medullary interstitialfluid The upper thick area reabsorption occurs via transporterswhich actively transports sodium and chloride. It is apassive process It is imperable to water therefore resulting in theinterstitial fluid of the medullary to be hyperosmmotic tothat of the fluid in the ascending limb 74. Descending limb Diffusion of water occurs from the descending limb andinto the interstital fluid The fluid hyperosmolarity is maintained by the ascendinglimb The loop of Henle countercurrent multipler- Causesinterstitial fluid of the medulla to become concentratedhence water will draw out from the collecting ducts andthus concentrates the urine with solutes. 75. Osmolarity increases as tubular fluid goes deeper into themedulla. NB: Active Sodium Chloride transport mechanism in theascending limb is an essential component to the systembecause without it the countercurrent flow would have noeffect on the loop and its medullary interstitial osmolarity 76. In the DCT the fluid becomes more hyperosmoticbecause it actively transports sodium and chloride out ofthe tubule and is reletaviely imperable to water. Fluidnow enters CCD High levels of Vasopressin causes water reabsorptionto 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 thecollecting ducts and into the interstitial fluid. 77. The water which is reabsorbed enters the medullarycapillaries and is carried out of the kidneys via thevenous blood. Final urine is hyperosmotic When plasma ADH is low the CCD and MCD areimperable to water thus resulting in a large volume ofhypoosmotic urine is excreted which would removeexcess water in the body 78. Medullary Circulation 79. Blood Vessels(Vasa recta) in the medulla form hairpinloops which run in a parallel position to the loops of Henleand MCD Blood enters the vessel loop and flows down deeper anddeeper while sodium and chloride diffuse into the bloodwhile water diffuses out Bulk Flow- maintains the steady state countercurrentgradient set up by the loops of Henle 80. Recycling of Urea Urea is reabsorbed and secreted into the tubule and thenreabsorbed again Urea is then trapped in the medullary interstitium henceincreasing its osmolarity Half of the urea is reabsorbed in the proximal tubule andthe remainder enters the loop of Henle Urea is secreted back into the tubular lumen via facilitateddiffusion 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 remainsin the Collecting Duct and the remaining excreted asurine 82. Renal Regulation of pHAn 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. Regulation of H+ Ions 84. Regulation of H+ ThroughAmmonia The kidney is to buffer acids andthus to conserve fixed basethrough the production of NH3from amino acids with the helpof an enzyme glutaminase. Whenever there is excess acidproduction the NH3 productionis also which combines withH+ to form NH4+ which isexcreted as NH4Cl. This occursin the event of acidosis. Whenalkali is in excess, the H+ isreabsorbed into the cell inexchange to Na+/K+. 85. Regulation of H+ ThroughBicarbonate System The filtered HCO3 combinedwith H+ H2CO3, carbonicanhydrase present in the brushborder of the cell wall dissociateH2CO3 H2O + CO2. The CO2 diffuses into the cell.The CO2 combines with H2O toform H2CO3 again. This H2CO3again ionizes to HCO3 + H+with the help of carbonicanhydrase of acid-base balance. 86. Regulation of H+ ThroughBicarbonate System The H+ diffuses into thelumen in exchange forNa+ and HCO3 isreabsorbed into plasmaalong with Na+. There is no netexcretion of H+ orgeneration of newHCO3 . So thismechanism helps tomaintain a steady state 87. Calcium and phosphate are controlled mainly byparathyroid hormone. The parathyroid hormone (PTH) is a protein hormoneproduced in the parathyroid glands. The PTH controls the kidneys. A decline in plasma calcium concentration causes PTH tobe secreted and an increase in plasma calciumconcentration does the opposite. 88. The kidney filters 60% of plasma calcium. Calcium is essential for the functioning of the majority ofthe bodys functions Therefore the kidney reabsorbs calcium from tubular fluid. More than 60% of calcium reabsorption occurs in theproximal tubule and is not under the control of anyhormones. 89. The distal convoluted tubule and in the beginning ofcortical collecting duct are mainly involved in thehormonal control of calcium reabsorption. PTH stimulates calcium channels to open. This causes an increase in calcium reabsorption. PTH increases 1-hydroxylase enzyme activity which inturn stimulates 25(OH)-D to 1,25 (OH)2 D. This causes an increase in calcium and phosphateabsorption in the gastrointestinal tract. 90. The majority if the phosphate that is filtered is reabsorbedin the proximal tubule. Conversely PTH decreases phosphate reabsorption Thus the excretion of phosphate is increased. In conclusion when the plasma calcium concentrationdeclines and PTH and calcium reabsorption increases, theexcretion of phosphate is increased. 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, byincreasing 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 arterialconstriction The opposite occurs when fluid overload occurs. 92. HORMONES AND THEKIDNEY(contd) Aldosterone (secreted by the adrenal gland) promotessodium ion and water reabsorption in the distal tubule andcollecting 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 serumsodium 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. HORMONES AND THE KIDNEY(contd) 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 andcollecting duct, thus increasing the concentration of urine. In contrast, when secretion of ADH is inhibited, it allows diluteurine to be formed. This occurs mainly when plasma sodiumconcentration falls such as following drinking large quantities ofwater. This fall is detected by the osmoreceptors. 94. HORMONES AND THE KIDNEY(contd) Stretch receptors(baroreceptors) that aresensitive to changes in bloodpressure and central bloodvolume aid in the regulationof ADH release. The hormones interact whenblood loss or dehydrationoccurs to maintainintravascular volume.FIGURE 20 95. FIGURE 21 96. Sodium Regulation The kidney monitors arterial pressure and retains sodiumwhen the arterial pressure is decreased and eliminates itwhen the arterial pressure is increased Sodium reabsorption is an active process occurring in alltubular segments except the descending limb of the loopof Henle. Water reabsorption is by diffusion and is dependent uponsodium reabsorption. The primary mechanism driving all transport in theproximal tubule is the Na-K ATPhase mechanism locatedon the basolateral membrane of the tubular cells. 97. Sodium Regulation(contd) The rate at which the kidney excretes or conserves sodiumis coordinated by the sympathetic nervous system and therenin-angiotensin-aldosterone system. When Na + concentration falls, blood pressure and volumefalls because water is lost with the Na +. The fall in blood pressure causes renin to be released intothe bloodstream where it catalyses the conversion of theplasma proteins into angiotensin. The angiotensin stimulates the adrenal cortex to secretealdosterone. Reabsorption of Na + is accompanied by the loss of K +(Na + - K + balance). 98. Sodium Regulation(contd) The sympathetic nervous system responds to changes inarterial pressure and blood volume by adjusting the GFRand the rate at which sodium is filtered from the blood. Sympathetic activity also regulates tubular reabsorption ofsodium and renin release. The reninangiotensin- aldosterone system exerts itsaction through angiotensin II and aldosterone . Angiotensin II acts directly on the renal tubules to increasesodium reabsorption. It also acts to constrict renal bloodvessels, thereby decreasing the glomerular filtration rateand slowing renal blood flow so that less sodium is filteredand more is reabsorbed. Angiotensin II is also a powerfulregulator of aldosterone, a hormone secreted by the adrenalcortex. 99. FIGURE 22 100. Sodium Regulation(contd) Aldosterone acts at the level of the cortical collectingtubules of the kidneys to increase sodium reabsorptionwhile increasing potassium elimination. It increases the uptake of Na by the and reabsorption inthe kidneys which causes the concentration of Na+ in theblood to rise. This method of control depends on afeedback. If the concentrations of Na + is too high, the adrenalcortex becomes inhibited and secretes less aldosteroneand vice verse. Feedback involves the co-factor renin which is released inthe afferent glomerular arerioles. 101. Sodium Regulation(contd) Na + is transported out of the cell into the paracellularspace 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 presenceof K conductance renders the cell electrically negative wrtits surroundings. In a steady state the pump operates below saturation pointfor Na + and an increase in Na + entry across the apicalmembrane increases the pump rate. The proximal tubule sodium reabsorption drives thereabsorption of the cotransported substances (glucose andthe secretion of hydrogen ions. 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 bodywater are: thirst and antidiuretic hormone (ADH). Thirst is the primary regulator of water intake and ADH isa regulator of water output. The both respond to changesin extracellular osmolarity and volume. Thirst is an emergency response which is controlled by thehypothlamus. An important stimulus for thirst isangiotensin II, which becomes increased in response tolow blood volume and low blood pressure. ADH acts throught two receptors (V1) and (V2) of whichthe (V2) are located on the tubular cells of the corticalcollecting duct. 103. Renal water regulation (contd) They control water reabsorption by the kidneys. ADH binds to the V2 receptors which increase thepermeability of the collecting duct to water (antidiureticeffect). The receptor is coupled via a GTP-requiringstimulatory protein (Gs protein) to the enzyme adenylylcyclase. The enzyme stimulates the production of cyclic AMPwhich activates protein kinase A. This kinase induces theinsertion (exocytosis) of water channels, aquaporin 2.Aquaporin 2 (from the V2 receptors) move from thecytoplasm of the cells of the collecting duct to the huminalsurface of these cells. 104. Renal water regulation (contd) Aquaporins 3 and 4 form the water channels in thebasolateral membrane of the principal cells. These are notregulated by ADH (they are constitutively active). These channels then allow free movement of water fromthe tubular lumen into the cells along a concentrationgradient. When ADH is not stimulated, the aquaporin 2 channelsreadily move out f the apical membrane so that water is nolonger transferred out of the collecting duct. Without ADH, the permeability of the collecting duct towater is very low; this results in polyuria. 105. The mechanism of action of ADH on principle cells, V2= vasopressin2 receptor, AQ2= aquaporin 2 106. Potassium Regulation Increases or decreases in extracellular potassiumconcentration can cause abnormal rhythms of theheart (arrhythmias) and abnormalities of skeletal-muscle contraction. Potassium levels are largely regulated by renalmechanisms that conserve or eliminate potassium. Major route for elimination is the kidney. Regulation is controlled by secretion from the bloodinto the tubular filtrate rather than vice versa. 107. Potassium Regulation (contd) Potassium is filtered in the glomerulus, reabsorbedalong with sodium and water in the proximaltubule and with sodium and chloride in the thickascending loop of Henle, and then secreted intothe late distal and cortical collecting tubules forelimination in the urine. Aldosterone plays an essential role in regulatingpotassium elimination by the kidney. In the presenceof aldosterone, sodium is transported back into theblood and potassium is secreted into the tubularfiltrate for elimination in the urine (N+- K+ shift). 108. Potassium Regulation (contd) When body potassium is increased, extracellular potassiumconcentration increases. This increase acts directly on thecortical collecting ducts to increase potassium secretion andalso stimulates aldosterone secretion, the increased plasmaaldosterone then also stimulating potassium secretion. There is also a (K+- H+)exchange system in the collectingtubules of the kidney. When serum potassium levels areincreased, potassium is secreted into the urine and hydrogen isreabsorbed into the blood, producing a decrease in pH andmetabolic acidosis. Conversely, when potassium levels are low,potassium is reabsorbed and hydrogen is secreted into theurine, leading to metabolic alkalosis. 109. Bibliography cikgurozaini.blogspot.com apbrwww5.apsu.edu http://www.nda.ox.ac.uk/wfsa/html/u09/u09_017.htm 110. Outline What are diuretics? How do they work and what are some examples ofdiuretics? What are some clinical situations in which diuretics areused? 111. Diuretics These are agents which increase the mobilization of extracellular fluid(ECF) this usually involves the loss of ionsand water Diuretics are drugs that are utilized clinically to increasethe volume of urine excretion. 112. Diuretics1. Loop diruetics Example: eg Furosemide( Lasix) Loop diuretics act on the ascending limb of the Loop ofHenle, it inhibits the transport of protein which mediatesthe first step in sodium reabsorption. 113. Diuretics1. Loop diruetics eg furosemide( Lasix) 114. Diuretics2. Potassium sparing agents There are two types Aldosternone Antagonist (i.e. block actionof aldoesterone) Na channel inhibtor {i.e. block theepithelial sodium channel (in the corticalcollecting duct) 115. Diuretics 116. Diuretics There are many clinical situations in which the use ofdiuretic therapy can provide advantageous These include Heart Failure with Edema Hypertension 117. DiureticsHeart Failure with Edema Decrease cardiac output causes the kidney torespond 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. DiureticsHypertension. Hypertension (usually too much salt) Diuretic-induced excretion decreases Na+ and H2O in thebody, which results in Reduce blood volume which reduces the blood pressure arteriolar dilation and further more lowers the pressure ofthe blood. 119. Kidney diseases There are many types of diseases that can affects thekidney These can be divided into Congenital Acquired allergies, bacteria, tumors, toxic chemicals kidney stones (accumulation of mineral deposits in nephron tubules). 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. 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. Acute kidney injurySigns There will be decrease in urine output. Substances normally eliminated by the kidney tend toincrease Urea Creatine Sodium and potassium, electrolytes that are commonlyderanged due to impaired excretion and re absorption 123. Chronic Kidney disease There are approximately 1 million nephrons are present ineach kidney,. The summation of all the nephronscontribute to the Glomerular filtration Rate(GFR) The kidney has the ability when renal injury occurs, theGFR is maintained This is ability allows the clearance of harmful substance tocontinue largely unaffected till the GFR has decreased to50 percent of it normal value. 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. Chronic Kidney disease Clinical problems associated with chronic kidney diseaseinclude Hyperkalemia Metabolic acidosis Anemia Bone disease 126. Chronic Kidney diseaseHyperkalemia The ability to maintain potassium (K) excretion at near-normallevels is generally maintained in chronic kidney disease. However when the GFR falls to less than 20-25 mL/min thereis decreased ability of the kidneys to excrete potassium. Resulting in Hyperkalemia 127. Chronic Kidney diseaseSalt and water handling abnormalities As kidney function declines, there is excessive sodiumretention which will cause extracellular volumeexpansion leading to peripheral edema 128. Kidney Disease 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. Chronic Kidney disease 131. Chronic Kidney diseaseBone disease Renal bone disease is a common complication of chronickidney disease. Decreased renal synthesis of 1,25-dihydroxycholecalciferol (calcitriol) Hypocalcaemia develops primarily from decreasedintestinal calcium absorption because of low plasmacalcitriol levels 132. Kidney Disease 133. Kidney DiseaseReferences:Vanders Human Physiology 10th Edition, Eric P. Widmaier, Hersel Raff, Kevin T. Stranghttp://emedicine.medscape.com/article/238798-overview#a0104http://en.wikipedia.org/wiki/File:Gray1128.pnghttp://kidney.niddk.nih.gov/kudiseases/pubs/proteinuria/http://3.bp.blogspot.com/_kaQ5P19FVgk/SwWAH4PM9kI/AAAAAAAAETw/hkXpMi1NQGQ/s400/ProximalConvolutedTubule.JPGhttp://www.google.tt/imgres?q=cortical+collecting+duct&hl=en&rlz=1C1_____en-GBTT437TT437&biw=1024&bih=456&tbm=isch&tbnid=8V5ptLll587HQM:&imgrefurl=http://open.jorum.ac.uk/xmlui/bitstream/handle/123456789/947/Items/S324_1_section8.html&docid=FptccfGU81hJJM&w=510&h=588&ei=W3R6TsXKI8Xc0QGH1byoAg&zoom=1&iact=hc&vpx=670&vpy=111&dur=944&hovh=239&hovw=208&tx=113&ty=155&page=1&tbnh=115&tbnw=100&start=0&ndsp=11&ved=1t:429,r:9,s:0 http://www.google.tt/imgres?q=proximal+tubule+cells&hl=en&sa=X&rlz=1C1_____en-GBTT437TT437&biw=1024&bih=499&tbm=isch&prmd=imvns&tbnid=eKM4E-R07hFL1M:&imgrefurl=http://www.uic.edu/classes/bios/bios100/lecturesf04am/lect21.htm&docid=1qQumxeqTWij_M&w=360&h=440&ei=q_p8TqijIafj0QHm7-znDw&zoom=1&iact=hc&vpx=106&vpy=139&dur=1451&hovh=248&hovw=203&tx=113&ty=189&page=1&tbnh=144&tbnw=118&start=0&ndsp=8&ved=1t:429,r:4,s:0 134. Kidney Disease http://www.google.tt/imgres?q=renal+corpuscle+diagram&hl=en&rlz=1C1_____en-GBTT437TT437&biw=1024&bih=456&tbm=isch&tbnid=9gXIjDjjaMJvqM:&imgrefurl=http://www.profelis.org/webpages-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=127&ty=199&page=1&tbnh=120&tbnw=165&start=0&ndsp=11&ved=1t:429,r:5,s:0 http://www.google.tt/imgres?q=renal+corpuscle+diagram&hl=en&rlz=1C1_____en-GBTT437TT437&biw=1024&bih=456&tbm=isch&tbnid=boI10CF6dX0OVM:&imgrefurl=http://apbrwww5.apsu.edu/thompsonj/Anatomy%2520%26%2520Physiology/2020/2020%2520Exam%2520Reviews/Exam%25204/CH25%2520Nephron%2520I%2520-%2520Renal%2520Corpuscle.htm&docid=RdYeUelnc4_AbM&w=699&h=383&ei=YPt8TtvxMKTv0gHF-LDaDw&zoom=1&iact=hc&vpx=77&vpy=144&dur=94&hovh=166&hovw=303&tx=182&ty=95&page=1&tbnh=97&tbnw=177&start=0&ndsp=11&ved=1t:429,r:0,s:0 135. DIABETES MELLITUS A common cause of renal failure is uncontrolled diabetesmellitus Diabetes meaning running through denotes increased urinaryvolume 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 highlevels of blood glucose which can lead to considerable damageto many parts of the body. These include kidneys, heart ,eyes and blood vessels. 136. How does Diabetes affect theKidneys Recall : 1. Osmotic diuresis , this is the increased urineflow as a result of a primary increase in the soluteexcretion.2. Glucose is reabsorped by the proximal tubulevia sodium- glucose transport proteins. The increase in blood glucose causes an increase in therate filtration. This increase in rate of filtration causes increased amountsof 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 themembranes of the renal corpuscle . 137. How does Diabetes affect theKidneys As the kidneys become more compromised largeramounts of protein is allowed to pass from the bloodand be excreted in the urine. Leads to proteinuria Kidney function begins to deteriorate. Irreversible damage to the kidneys leads to toxicwaste not being able to be filtered out of blood anddialysis is required. This is the usual course of diabetic necropathy whichresults in end stage kidney disease. 138. How Diabetes affect the Kidneys Diabetic necropathy is the disease of the capillaries inthe kidney glomeruli. That is they showglomerulosclerosis , which is the hardening of the ofthe glomerulus of the kidney due to scarring. Diabetic necropathy is progressive and results in death2 3 years after diagnosis. It is also the leading causeof premature death in young diabetics. 139. How does Diabetes affect theKidneys When the blood sugar level of a person rises theglucose is detected in the urine. That is there is an increased glucose load in theproximal tubule. Some glucose therefore escapesreaborption and causes a retention of water in thelumen. This water is excreted along with the glucose. Persons with diabetes usually excrete large amountsof urine. 140. Diabetes insipidus Diabetes insipidus is caused by the failure of the posteriorpituitary to release the hormone vasopressin or theinability of the kidney to respond to vasopressin. RECALL: Water reabsorption in the last portions of thetubules and coritcal collecting ducts can vary greatly dueto physiological control. The major control is the peptidehormone 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 aretherefore unable to conserve water 141. Diabetes insipidus Therefore large quantities of dilute urine is produced. Persons who have diabetes insipidus will consumemore water May also suffer from dehydration 142. Kidney StonesKidney stones may form in the pelvis or calyces of the kidneyor in the ureter. 143. Kidney Stones A kidney stone is an accumulation of mineral depositsin 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. Calciumwhich is not used by the bones or muscles goes to thekidneys. Extra calcium is usually removed by the kidneys withthe rest of the urine. Persons therefore with calciumstones keep the extra calcium in their kidneys. The acidity or alkalinity of the urine also affects theability of stone forming substances to remaindissolved. 144. Kidney StonesExtracorporeal shockwave lithotripsy(ESWL) is a procedureused to shatter simplestones in the kidney orupper urinary tract. 145. Hyperaldosteronism Emcompasses a number of different chronic diseasesall of which involve excess adrenal hormonealdosterone. Conns syndrome growth of the zona glomerulosa ofthe adrenal gland , these tumors release aldosterone inthe absence of stimulation by angiotensin II RECALL: Aldosterone is released by the adrenalcortex which stimulates the sodium reabsorption bythe distal convoluted tubule and the cortical collectingducts. - High [ aldosterone] increased sodium reabsorption - Low [ aldosterone] deareased sodium reabsorption ( 2% sodium lost in urine) 146. In Conns syndrome, there are high levels of aldesterone ,which leads to an increase in sodium absorption in thenephron and potassium excretion Leads to an increase in blood pressure, due to increasedblood volume which leads to hypertension. Renin release is greatly reduced. 147. This is one of the most common causes of endocrinehypertension Endocrine hypertension is a secondary type ofhypertension which is usually due to a hormoneimbalance. 148. Hypokalemia This is a lower than normal amount of potassium in theblood. Potassium is obtained from food and is required by thebody for proper nerve function Changes in the potassium level therefore can causeabnormal rhythms in the heart and in the skeletal musclecontraction Recall: Due to an increase in plasma aldosterone there isan increase in sodium reabsorption and potassiumsecretion. Hypokalemia is espcially seen in patients with Connssyndrome 149. Decrease in Plasma Increase in Plasma volumePotassiumIncrease plasma angiotensin II Adrenal cortexIncrease aldosterone secretion Increase plasma aldosterone Cortical collecting ducts Increased Na +Increased K+ reabsorption secretionIncreased Decreased sodium Potassium excretionexcretion 150. Hypertension Commonly known as high blood pressure. Normal blood pressure should be 120/80, anypersons with a systolic pressure over 140 or a diastolic pressure over 90 is considered to have high blood pressure. 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. How does hypertension affect thekidneys The extra fluid in the fluid in the blood vessels may furtherraise the blood pressure , resulting in a dangerous cycle. High blood pressure is one of the leading causes of kidneyfailure, also known as end stage renal disease. 153. References http://www.froedtert.com/SpecialtyAreas/Endocrinology/ProgramsandDiseaseTreatment/EndocrineHypertension.htm http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001493/ http://ehealthmd.com/content/how-do-kidney-stones-form http://www.biotecnika.org/blog/vishtiw/diabetes-mellitus-and-its-effect-kidney-and-liver