Tubular-functions-of-kidney

First MBBS Renal Physiology Lecture

1. Tubular Functions Renal Physiology 2 Dr Raghuveer Choudhary

2. Q. List different functions of renal tubules - Reabsorption : Transport of substance from lumen of tubule to blood. - Secretion: addition of substance to the glomerular filtrate coming from blood . - Synthesis: addition of new substance to glomerular filtrate e.g ammonia.

3. 3 TUBULAR FUNCTION The glomerular filtrate is formed at a rate of 125 ml/min. or 180 L/day . It passes to the renal tubules. In the tubules, the tubular fluid is subjected to the 2 main tubular functions, reabsorption & secretion . It is finally excreted as urine at a rate of about 1-2 ml/min. or ca. 1.5 L/day .

4. R eabsorption & Secretion Secretion:- refers to the transport of solutes from pritubular capillaries in to the tubular lumen,i.e . it is the addition of substance to the filterate . Reabsorption - denotes the active transport of solutes & passive movement of water from tubular lumen in to the peritubular capillaries ,,i.e . the removal of a substance from the filterate

5. Filtered Load Filtered load (mg/min) =GFR(ml/min) x Plasma Conc. of that solute(mg/ml) Is the amount of solute transported across the glomerular membrane per unit time

6. Renal Tubular Transport Maximum (Tm) Tm=it referes to maximum amount of a given solute that can be transported ( reabsobed or secreted) per minutes by the renal tubules. Tm – pertains to solutes that are actively transported. Substances that are passively transported (urea) do not exhibit a Transport Maximum(Tm)

7. Tubular Reabsorption is a Function of the Epithelial Cells Making up the Tubule Lumen Plasma Cells

8. substance to be reabsorbed must be transported across the tubular epithelial membranes into the renal interstitial fluid through the peritubular capillary membrane back into the blood

9. The transporting pathways of substance through the renal tubular epithelial cells Transcellular pathway: through the cell membranes Paracellular pathway: through the junctional spaces

10. Movement of substances in and out of cell

11. Types of carrier proteins A uniport carrier: transport one substance. A symport carrier: transport two substances in the same direction. An antiport carrier: transport two substances in the opposite directions.

12. Mechanisms of Reabsorption 1. Passive transport 1). Down electrochemical gradient; 2). not require energy; 3). Mode:Diffusion,Osmosis,facilitated diffusion 4). Example:H 2 O

13. 2. Active transport 1). Against an electrochemical gradient; 2). require energy; 3). Depend on carrier proteins that penetrate through the membrane 4). divided into two types: Primary active transport: coupled directly to an energy source(hydrolysis of ATP) Secondary active transport :coupled indirectly to an energy source(an ion gradient)

14. Primary active transport is linked to hydrolysis of ATP Importance: move solutes against an electrochemical gradient energy source: hydrolysis of ATP Example: sodium-potassium ATPase pump

15. Inside Outside Na+ Na+ Na+ K+ K+ K+ K+ Na+ Na+ Na+

16. Inside Outside Na+ Na+ Na+ K+ K+ K+ K+

17. Na + -K + ATPase hydrolysis ATP  release energy  Transport Na + out of the cell into the interstitium Transport K + from the interstitium into the cell The intracellular concentration of sodium is lower (chemical difference) The cell interior is electrically negative than the outside (electrical difference) Favor Na + to diffuse from the tubular lumen into the cell through the brush border   

18. Secondary active transport Co – transport: glucose-sodium transport amino acids -sodium transport phosphate -sodium transport Counter- transport: H + -Na + transport

19. Co – transport of Glucose (or amino Acids) along with Sodium ions through The brush border of The tubular epithelial cells

20. Tubular Reabsorption A) Active transport; against electrochemical gradient. (1) Primary active transport Requires energy directly from ATP. Example ; Na+ reabsorption in PCT (2) Secondary active transport -It does not require energy direct from ATP. a) Co-transport two substances bind to a specific carrier are cotransported in one direction. b) Counter-transport two substances bind to a specific carrier are transported in two directions. B) Passive reabsorption ; (1) Simple diffusion Passive reabsorption of chloride & Osmosis of water (2) Facilitated diffusion Need carrier. C) Pinocytosis It is an active transport mechanism for reabsorption of proteins and peptides in the proximal convoluted tubules.

21. Q. List different Characteristic features of PCT - PCT is about 15 mm long and 55 μm in diameter. - PCT wall is lined by single layer of epithelial cells that are connected by tight junctions at their luminal edges, but there is a space between the cells along the rest of their lateral borders (lateral intercellular spaces) which contains interstitial fluid. - The luminal borders of cells have brush border due to presence of large number of microvilli which increase surface area for reabsorption . - The PCT cells have large numbers of mitochondria (energy supply).

22. Proximal Convoluted Tubule 65% of the nephron function occurs in PCT. The PCT has a single layer of cuboidal cells with millions of microvilli . Increased surface area for reabsorption . PCT's main function is reabsorption . The PCT is full of mitochondria

23. Reabsorption in Proximal Tubule 100% Glucose, protein and Amino Acids 60% Sodium, Cl, and H2O. 80% PH, HCO3, K. 60% Ca. 50% of Filtered Urea.

24. Reabsorption of glucose: Position: proximal tubule. All the filtrated glucose is reabsorbed under normal condition. Secondary active transport, accompanied by the primary active transport of sodium .

25. Renal threshold for glucose: the maximal blood sugar concentration which can not result in glucosuria. Reasons: there is a limit to the amount of transporter proteins and binding site.

26. 33 GLUCOSE : At normal blood glucose levels (~100 mg%), glucose is freely filtered at a rate of 125 mg/min . (= plasma conc. X GFR = 100 mg% x 125 ml/min.). The amount filtered is completely reabsorbed from the upper half of PCT by Na + -glucose cotransport (mechanism: see before). There is, however, a limited number of Na + -glucose carriers: a- At a blood glucose level of less than 180 mg% , all the filtered glucose can be reabsorbed because plenty of carriers are available. b- At a blood glucose level of 180 mg% , glucose starts to appear in urine. This level of blood glucose is called the renal threshold for glucose. It corresponds to a renal tubular load of 220 mg/min . c- At a renal tubular load of glucose of 320 mg/min , all the carriers are saturated, i.e., the transport maximum for glucose, Tm G , is reached. Any further  in filtered glucose is not reabsorbed & is excreted in urine.

27. Glucose reabsorption The transporter for glucose on the basolateral membrane has a limited capacity to carry glucose back into the blood. If blood glucose rises above 180 mg/dl, some of the glucose fails to be reabsorbed and remains in the urine  glucosuria.

28. Tubular maximum for glucose (TmG): The maximum amount of glucose (in mg ) that can be reabsorbed per min. It equals the sum of TmG of all nephrons . Value; 300 mg/min in ♀ , 375 mg/ min in ♂. Renal Threshold for Glucose Is approximately 180 mg/dl If plasma glucose is greater than 180 mg/dl: T m of tubular cells is exceeded glucose appears in urine

29. Plasma Glucose (mg%) Glucose filtered (mg/min) P G x GFR/100 100 125 200 250 300 375 400 500 500 625 600 750

30. 180

31. 180 180

32. GLUCOSE REABSORPTION HAS A TUBULAR MAXIMUM Plasma Concentration of Glucose Glucose Reabsorbed mg/min Filtered Excreted Reabsorbed

33. 3 75mg/min

34. Glucose titration curve Plasma Glucose (mg%) Glucose filtered (mg/min) P G x GFR/100 100 125 200 250 300 375 400 500 500 625 600 750

35. 180

36. Glucosuria presence of glucose in urine 1. Diabetes mellitus blood glucose level > renal threshold. 2. Renal glucosuria It is caused by the defect in the glucose transport mechanism. 3. Phlorhizin A plant glucoside which competes with glucose for the carrier and results in glucosuria ( phloridzin diabetes).

37. Glucose filtration rate = 100 mg/min (P c x GFR) reabsorption rate = 100 mg/min site = early portion of the proximal tubule secretion rate = 0 mg/min excretion rate = 0 mg / min T m = 375 mg/min ideal renal threshold = 300 mg/dL actual renal threshold = 200 mg /dL (arterial) 180 mg/dL (venous) “splay”

38. SGLT 2 PHLORHIZIN

39. GLUCOSE 100 % REABSORBED

40. Amino Acids filtration rate --- small amount reabsorption ---- 100 % site -- early portion of the proximal tubule secretion ---- 0 excretion ----- 0

41. amino acids amino acids amino acids SIMPLE OR FACILITATED DIFFUSION

42. AMINO ACIDS 100 % REABSORBED

43. Proteins peptide hormones, small proteins and small amount of albumin filtration rate = 7.2 g/day (GFR x protein in the ultrafiltrate) reabsorption rate = 7.2 g/day site --- early portion of the proximal tubule secretion rate = 0 excretion rate = 0

44. PROTEINS

45. Endocytosis of Proteins mediated by apical membrane proteins that specifically bind with luminal proteins and peptides. they are multiligand endocytic receptors. Megalin Cubilin

46. PROTEINS 100 % REABSORBED

47. Renal Handling of Inorganic Substances

48. Sodium filtration rate = 25,560 mEq /day (575-580mg/day) reabsorption rate = 25,410 mEq /day (98%) site -- proximal tubule, loop of Henle , distal tubules and collecting duct. secretion rate = 0 mEq /day excretion rate = 150 mEq / day

49. 67% Sodium 25% 5% 1 % 3%

50. Na reabsorption At basolateral side of the tubular epithelial cell there is an extensive Na + -K + ATPase system (= Na + -K + pump). It pumps 3 Na + actively out of the cell into the interstitium , and at the same time carries 2 K + into the cell. But K + will diffuse immediately back into the interstitium due to: (1) high concentration gradient & (2) high permeability of epithelial cells to K + . As a result of this there is: -  intracellular Na + concentration At luminal membrane there will therefore be passive diffusion of Na + into the cell along concentration gradient created by the Na + -K + pump. This diffusion is facilitated by a protein carrier.

51. In the early distal tubule, NaCl reabsorption is coupled via a Na- Cl cotransporter . Na+ exit at the basolateral membrane is via the Na/K- ATPase , and Cl − exit is via the Cl − channel.

52. Late DCT & Cortical CD : (1) Principal Cells : a. They actively reabsorb Na + in exchange for K + secretion. This action is increased by aldosterone . b. Antidiuretic hormone (ADH) causes  reabsorption of H 2 O. In the absence of ADH, the principal cells are impermeable to H 2 O. (2) -Intercalated Cells : - These cells secrete H + . This action is increased by aldosterone .

53. DISTAL TUBULE AND CORTICAL COLLECTING DUCT The distal tubule and the cortical collecting duct are important areas for fi ne regulation of Na+ excretion. The hormone aldosterone increases the activity of the Na+ transport proteins throughout this area to promote renal Na+ conservation and maintain the extracellular fl uid volume.

54. DIURETICS Diuresis is defined as an increase in the urine flow rate; diuretics = agents that induce diuresis .

55. Regulation of sodium excretion Glomerulotubular balance in PT

56. Effect of ECF volume on PT Reabsorption ECFV contraction-increased absorption ECFV expansion-decreased absorption

57. Factors affecting Na reabsoption Na reabsorption increased by Na reabsorption decreased by Peritubular Hydrostatic pressure Peritubular Hydrostatic pressure Peritubular Colloidal osmotic pressure Peritubular Colloidal osmotic pressure ECFV contraction ECFV expansion Aldosterone Glucocorticoids GFR decreased GFR

58. 95 Hormones acting on the kidney 1 . Aldosterone : Stimulus for its secretion :  Blood volume (via renin-angiotentin system). Actions & their site : It stimulates Na + reabsorption in DCT & cortical CD through: 1) In principal cells:  Na + reabsorption in exchange with K + . 2 ) In -intercalated cells:  Na + reabsorption in exchange with H + . 2. Angiotensin II : It is the most powerful Na + retaining hormone. Stimulus for its secretion :  arterial bl. pressure & blood volume, e.g., hemorrhage (via renin ). Actions & their site : 1. It  Na + reabsorption by several mechanisms: a. By stimulating aldosterone secretion. b. In PCT : - By directly stimulating Na + -K + ATPase at basolateral border. - By directly stimulating Na + -H + countertransp . at luminal border. 2. It constricts efferent arterioles.

59. Hormones affecting Na Reabsorption Nacl & water reabsorption by Aldosteron,Angiotensin II water reabsorption - Antidiuretic Hormone ADH Nacl & water reabsorption - ANP,Dopamine,Urodilatin

60. Hormones that influence sodium reabsorption in renal tubules Angiotensin II stimulates sodium reabsorption in the proximal tubule, thick ascending limb, distal tubule and collecting duct. Aldosterone increases sodium reabsorption and potassium secretion in the distal tubule and collecting duct increases sodium reabsorption in the thick ascending limb

61. Hormones that influence sodium reabsorption in renal tubules Atrial Natriuretic Peptide and Brain Natriuretic Peptide inhibits sodium chloride reabsorption in the medullary collecting duct inhibits ADH secretion in the posterior pituitary gland Catecholamines stimulates sodium chloride reabsorption in the PT, thick ascending, DT and CD

62. Hormones that influence sodium reabsorption in renal tubules Dopamine inhibits reabsorption of sodium chloride in the proximal tubule Adrenomedullin, Urodilatin, Uroguanylin and guanylin increases sodium chloride excretion

63. Potassium ECF K + concentration (N = 3.5 - 5.5 meq/L) ICF - 98%, ECF - 2% excretion kidneys - 90 - 95% feces - 5 - 10%

64. ICF K + concentration 140 mEq/L X 28 L 3920 mEq ECF K + concentration 4.2 mEq/L X 14 L 59 mEq K + intake 100 mEq/day K + output Urine = 92 mEq/day Feces = 8 mEq/day NORMAL K + INTAKE, DISTRIBUTION OF K + IN THE BODY FLUIDS AND OUTPUT FROM THE BODY Guyton, Medical Physiology, 2006

65. filtration rate = 756 mEq/day reabsorption rate = 644 mEq/day (87.8%) site -- proximal tubule and ascendong loop of Henle secretion rate = 31 mEq/day excretion rate = 92 mEq/ day

66. 67% POTASSIUM 20 -25% 4% 12% Increased ECF potassium concentration Increased aldosterone Increased tubular flow rate

67. K+ and acid base disorders

68. Bicarbonate Reabsorption Recovery of filtered HCO3 − and net acid excretion is usually required to maintain acid-base balance—almost all the filtered HCO3 − must be recovered. Most HCO3 − reabsorption occurs in the early proximal tubule via the mechanism shown in Figure

69. Mechanisms of H+ excretion and HCO3− generation. B. Titratable acid excretion as H2PO4 − occurs when secreted H+ combines with fi ltered HPO42−. CA, carbonic anhydrase .

70. Mechanisms of H+ excretion and HCO3− generation. A. Renal ammoniagenesis results in the formation of NH4 + within cells because NH3 readily combines with H+ at physiologic pH. NH4 +is secreted via the Na/H exchangers

71. Reabsorption of water: 1. Quantity of reasorption:99% 2. Passive reabsorption: osmotic pressure 3. Position and siginificance: Proximal tubule: 65-70%; Accompanied by the reabsorption of NaCl Has nothing to do with whether the body lack water or not. Not regulated by hormones;

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