Regulation of Electrolyte and Fluid Balance in the Renal Tubules

1. Maintenance of Electrolyte and Fluid Balance A.A.J.Rajaratne

2. The loop of Henle: In the loop of Henle about 20% of filtered Na+, Cl-, and K+ are reabsorbed. Ca++, Mg++, and HCO3- are also reabsorbed. About 17% of filtered water is reabsorbed in Henle's loop. Water is reabsorbed from the descending limb; the ascending limb is impermeable to water.

3. The loop of Henle - contd: 1. Transport processes in thick ascending limb. Na+ enters the TAL epithelial cells across the luminal membrane via the Na/K/2Cl transporter, which transports Cl- and K+ into the cell against their electrochemical potential gradients. The energy of the Na+ gradient is used for this process.

4. There is also a luminal Na/H exchanger, which exports H+ into the lumen and causes reabsorption of HCO3-. K+, Cl-, and HCO3- are transported across the basolateral membrane by other transport proteins. The luminal fluid in the TAL is electrically positive to the extracellular fluid of the basolateral membrane. This powers the reabsorption of Na+, K+, Ca++, and Mg++, partly via transcellular and partly via paracellular pathways.

5. Transport processes in the thick ascending limb + K+ C A K+ Na+ H2O+CO2H2CO3 H+ Cl- H+ + HCO3 HCO3- Na+ 2Cl- K+ 2 K+ K+, Ca2+, Na+, Mg2+ 3 Na+

6. Significant absorption of solute occurs in the TAL, but water cannot follow due to the impermeability of the TAL to water. Thus the osmolarity of TAL fluid falls below isotonicity, reaching less than 150 milliosmolar.

7. The extrusion of Na+ and Cl- by the TAL contributes to an osmotic gradient in the medullary interstitium. The osmotic pressure is highest near the renal papillae and lowest near the corticomedullary junction. Since the descending limb is permeable to water (the ascending limb is not), water is reabsorbed from the descending limbas it descends through the osmoticgradient.

8. The distal tubule and the collecting tubule Reabsorb about 10% of filtered Na+ and Cl- Secrete K+ and H+. Reabsorb a variable amount of water.

9. The first part of the distal tubule reabsorbs Na+, Cl-. and Ca2+. Since this segment of the distal tubule is impermeable to water, the luminal fluid becomes still more dilute, approaching 100 mOsm. The luminal membrane has electrogenic Na+ channels (blocked by amiloride and triamterine diuretics) and a coupled Na+/Cl- transporter (blocked by thiazide diuretics).

10. Na+ Cl- Na+ Cl- 2 K+ 3 Na+ H2O Transport mechanisms in Distal Tubule Amiloride Thiazides

11. Last part of distal tubule and collecting tubule: Contain two types of epithelial cells: 1. Principal cells 2. Intercalated cells a. Principal cells in the last part of the distal tubule and in the cortical collecting tubule reabsorb Na+, Cl-, and water and usually secrete K+.

12. Transport processes in Principal Cells K+ K+ 2 K+ Na+ 3 Na+

13. Intercalated cells Secrete H+ and reabsorb K+ and HCO3-. The H+ and HCO3- is derived from CO2 produced by cellular metabolism. Carbonic anhydrase catalyzes formation of carbonic acid which dissociates into H+ and HCO3. H+ is extruded across the luminal membrane by an H+-ATPase. HCO3- is absorbed into the blood across the basolateral membrane.

14. Transport mechanisms in the Intercalated cells HCO3- Cl- H+ 2 K+ 3 Na+

15. Collecting ducts have two portions, 1. Cortical portion 2. Medullary portion The water permeability is increased by antidiuretic hormone (ADH), also known as vasopressin. ADH from the posterior pituitary increases the permeability to H2O by causing the rapid insertion of aquaporin-2 water channels to the luminal surface of principal cells. When vasopressin is absent, the collecting duct epithelium is relatively impermeable to water.

16. Control of ECF osmolality and volume

17. MAIN DIFFERENCES BETWEEN ICF AND ECF • More Na+ in ECF • More K+ in ICF • More Cl- in ECF • More PO4, HCO3, and Pr- in ICF These differences are maintained by transport processes in the cell membrane

18. Distribution of Na+ and K+ in the body

19. ECF volume • 20% of body weight • 14 L (in a 70 kg man) • 3.5 L plasma; 10.5 L interstitial fluid • Measured by using inulin, mannitol or sucrose

20. Osmolar concentration of plasma: • 290 mosm/L - 142 mEq/L • 0.9% saline is isotonic • 270 mosm/L is contributed by Na+, Cl- and HCO3- • Plasma proteins contribute less than 2 mosm/L (28 mm Hg oncotic pressure)

21. Ranges of salt and water intake and excretion: a. Salt intake from 50 mg to 25 g/day b. Water excretion from 400 ml to 25 l/day

22. Total body sodium is relatively constant. • Freely filtered • Reabsorbed but not secreted • Therefore, • Na+ excretion = Na+ filtered – Na+ reabsorbed • = (GFR X PNa) - Na+ reabsorbed • PNa is relatively constant • Therefore control is exerted by • GFR • Na+ reabsorption

23. Sensors: • Extrarenal baroreceptors • Carotid sinuses • Arteries • Great veins • Atria • 2. Renal juxtaglomerular apparatus • Efferents: • Renal sympathetic nerves • Macula densa renin angiotensin II  aldosterone

24. Control of GFR: • Angiotensin II efferent arteriolar constriction  PGC • Renal sympathetic nerves Na+  adrenergic receptors Constriction of afferent and efferent arterioles  PGC

25. Osmoreceptor -ADH mechanisms

26. Renal handling of NaCl and water: NaCl & H2O are freely filterable at the glomerulus. There is extensive tubular reabsorption but no tubular secretion. Na+ reabsorption is driven by the basolateral Na+/K+-ATPase and is responsible for the major energy expenditure in kidney.

27. H2O permeability of the late DT: Water permeability of distal tubule and initial collecting tubule, is also extremely low. However under the influence of ADH it becomes highly water permeable. Further removal of solute in the EARLY DT presents the LATE DT with markedly hypotonic urine containing even less Na+ Removal of Na+ continues in the LDT and collecting system, so that the final urine may contain virtually no Na+.

28. Anti-diuretic hormone: ADH (antidiuretic hormone), vasopressin or arginine vasopressin (AVP) is the major regulator of urine osmolality and urine volume. ADH is a nonapeptide produced by neurons in the supraoptic and paraventricular nuclei of the hypothalamus. The axon terminals of these neurons reside in the posterior pituitary. ADH is stored in these axon terminals.

29. When ADH is released from the posterior pituitary it causes the kidney to produce urine that is high in osmolality and low in volume. In the absence of ADH the kidney tends to produce a large volume of urine with low osmolality. Total solute excretion is relatively constant over a wide range of urine flow rates and osmolalities.

31. Control of ADH release: 1. Increased osmolality of ECF is a powerful stimulus for ADH release: a 1% change in osmolality induces significant increase in ADH release. Hypothalamic supra-optic and paraventricular nuclei respond to increased osmolality of ECF by producing ADH. As a result of this high sensitivity, responses to increased osmolality occurrapidly.

32. Control of ADH release: 2. Volume: In a volume-depleted individual, the release of ADH is more sensitive to increased osmolality. In a volume-expanded state, ADH release is less sensitive to increases in osmolality. 3. Decreased blood pressure or blood volume also enhance ADH release, but not with such high sensitivity: 5 to 10% changes are required to alter ADH secretion.

34. Effects of ADH on the kidney: ADH increases the water permeability of the epithelial cells of late distal tubules and the collecting tubules May also increase NaCl absorption in the thick ascending limb of the loop of Henle. ADH also increases the urea permeability of the inner medullary collecting tubules.

35. Action of ADH: Binds to receptors in the basolateral membrane, causing increased cAMP. This results in rapid insertion of aquaporin-2 protein channels into the luminal membrane of principal cells. The water channel proteins are present in preformed intracellular vesicles, so this up regulation of water permeability can occur quickly. The water channels can be rapidly re-internalized when ADH is no longer present.

36. H2O A D H Adenyl cyclase cAMP Effect of ADH on collecting tubule cells Aquaporin-2

37. Summary: Stimulation of osmoreceptors in anterior hypothalamus  osmolality Supraoptic & paraventricular Nuclei Posterior pituitary ADH permeability of LDT, CCD, MCD to H2O

38. Summary of handling of Na+ by the kidney

39. Thirst (conscious desire for water): • Under hypothalamic osmoreceptor control • Water intake is regulated by - increased plasma osmolality - decreased ECF volume - psychological factors

40. Stimulus: Intracellular dehydration due to increased osmolar concentration of ECF Excessive K+ loss  Low intracellular K+ in osmoreceptors

41. Mechanism is activated by • The arterial baroreceptor reflex  BP • The volume receptors - low pressure receptors in atria;  CVP • Angiotensin II • Increased Na+ in CSF

42. Hypertonicity Hypovolaemia Baroreceptors Angiotensin II Osmoreceptors Hyp Thirst

43. Other factors regulating water intake: • Psycho-social • Dryness of pharyngeal mucous membrane • ? Gastrointestinal pharyngeal metering

44. Renin-angiotensin –aldosterone system

45. Renin: Produced by Juxtaglomerular cells – located in media of afferent arterioles Lacis cells – junction between afferent and efferent arterioles

46. Factors affecting renin secretion: • Stimulatory • Increased sympathetic activity via renal nerves • Increased circulating catecholamines • Prostaglandins • Inhibitory • Increased Na+ and Cl- reabsorption in macula densa • Angiotensin II • Vasopressin

47. Renin  Angiotensinogen Angiotensin I  Angiotensin-converting enzyme Angiotensin I Angiotensin II  Adrenal cortex Aldosterone

48. Actions of angiotensin II • Arteriolar vasoconstriction and rise in SBP and DBP • On adrenal cortex to produce aldosterone • Facilitates release of noradrenaline • Contraction of mesangeal cells - GFR • Brain -  sensitivity of baroreflex

49. Actions of aldosterone: Increased reabsorption of Na+ from urine, sweat, saliva and GIT – ECF volume expansion Kidney Principal cells – increased amounts of Na+ are exchanged for K+ and H+

50. Salt appetite