1. H + Homeostasis by the Kidney

2. H + Homeostasis Goal:  To maintain a plasma (ECF) pH of approximately 7.4 (equivalent to [H + ] = 40 nmol/L Action needed:  The body generates excess H +  Requirement is to excrete H +  Occasionally there is a need to excrete excess alkali

3. H + Homeostasis OUTPUTINPUT Body Fluids Buffers Oral intake, food, drink Metabolism Kidney Lungs

4. H + Homeostasis Excreted byH + in the form of Buffers Non CO2 (Volatile H + ) Kidney Lungs CO2 (Volatile H + ) HCO 3 - H 2 O + CO 2 Other buffers

5. Fate of Buffers LungsHCO 3 - + H + H 2 O + CO 2 H 2 CO 3 HPO 4 2- + H + H 2 PO 4 - Hb - + H + HbH If CO 2 is washed out through the lungs HCO 3 is lost Buffering power is lost if not converted to original form

6. Determinants of [H + ] [HCO 3 - ] [H + ] PCO 2 - = k [HCO 3 - ] changes will result in changes in [H + ]

7. Role of Kidney in H + Homeostasis Role of kidney  Excrete excess H +  Reabsorb filtered HCO 3 -  Generate new HCO 3 -

8. H + Secretion into the Tubule H + can not be left as it is in the tubule, need to be buffered  Prevent high acidity of urine, and prevent tissue injury  Keep H + concentration relatively low so that more can be easily secreted

9. Role of Kidney in H + Homeostasis Parts of the nephron involved  Proximal tubule  Thick ascending limb of loop of Henle  Distal tubule  Collecting duct

10. Proximal Tubule in H + Homeostasis The proximal tubule  Secretes the major part of the excess H +  Reabsorbs about 80% of filtered HCO 3 -

11. Proximal Tubule in H + Homeostasis The proximal tubule  Secretes the major part of the excess H +  Reabsorbs about 80% of filtered HCO 3 - These processes are interdependent

12. Proximal Tubule in H + Homeostasis Na + Capillary H+H+ H+H+ HCO 3 - + H 2 CO 3 HCO 3 - H+H+ + H2OH2O + CO 2 + H2OH2O H 2 CO 3 HCO 3 - Na+ K+ Na+ Carbonic anhydrase

13. Proximal Tubule in H + Homeostasis Secretion of H + by proximal tubular cells  Secondary active, energy derived from sodium-potassium pump in the basolateral membrane  H + is generated from CO2 and water by the action of carbonic anhydrase  Is secreted by an antiport mechanism on the luminal surface  Secreted combines with HCO 3 - in tubular fluid

14. Proximal Tubule in H + Homeostasis The overall effect of secretion of H +  H + moves from the cell to tubular fluid - But comes back in the form of CO2, no excretion of H +  HCO 3 - produced in the cell enters the interstitial fluid and then the capillary  HCO 3 - in the tubular fluid disappears - Reabsorption of HCO 3 -

15. Proximal Tubule in H + Homeostasis Significance of secreted H + combining with HCO 3 - in the tubular fluid  Enables ‘reabsorption’ of HCO 3 -  No significant increase in acidity in the tubular fluid

16. Proximal Tubule in H + Homeostasis Na + Capillary H+H+ H+H+ HPO 4 2- + H 2 PO 4 - HCO 3 - H+H+ + CO 2 + H2OH2O H 2 CO 3 HCO 3 - Na + K+K+ Carbonic anhydrase

17. Proximal Tubule in H + Homeostasis Secretion of H + by proximal tubule with buffering in urine by HPO 4 2-  Some of the H + secreted is buffered by HPO 4 2-  There is net H + excretion  New HCO 3 - is generated  Only small amounts buffered in this manner in proximal tubule as much HCO 3 is available

18. Proximal Tubule in H + Homeostasis Secretion of NH 4 + by proximal tubular cells Na + Capillary NH 4 + HCO 3 - H+H+ + glutamine NH 3 HCO 3 - Na+ Glutaminase + ἀ ketoglutarate NH 4 + Na + K+K+

19. Proximal Tubule in H + Homeostasis Secretion of NH 4 + by proximal tubular cells  Dependent on sodium potassium pump  NH 3 derived from glutamine (catalysed by glutaminase)  NH 4 + formed and secreted by antiport mechanism in the luminal surface  Net H + excretion occurs  HCO 3 - is transported to the capillaries  New generation of HCO 3 -

20. Thick Ascending Limb of Loop of Henle in H + Homeostasis Functions of thick ascending limb  Reabsorb HCO 3 -  About 15% of filtered HCO 3 - is reabsorbed Mechanism similar to that in the proximal tubule

21. Distal Tubule in H + Homeostasis Functions  Reabsorb HCO 3 -  About 5% if filtered HCO 3 - is reabsorbed  Mechanism similar to that in the proximal tubule  Secrete H + to be buffered by HPO 4 2- and other minor buffers  Secrete NH 4 +

22. Distal Tubule in H + Homeostasis H + secretion is by intercalated cells K+K+ Capillary H+H+ H+H+ HCO 3 - + H 2 CO 3 HCO 3 - H+H+ + H2OH2O + CO 2 + H2OH2O H 2 CO 3 HCO 3 - Na + K+K+ Carbonic anhydrase H+H+

23. Distal Tubule in H + Homeostasis H + secretion is by intercalated cells K+K+ Capillary H+H+ H+H+ HPO 4 2- + H 2 PO 4 - HCO 3 - H+H+ + CO 2 + H2OH2O H 2 CO 3 HCO 3 - Na + K+K+ Carbonic anhydrase H+H+

24. Distal Tubule in H + Homeostasis Secretion of NH 4 + by distal tubular cells Na + Capillary NH 4 + HCO 3 - H+H+ + glutamine NH 3 HCO 3 - Na+ Glutaminase + ἀ ketoglutarate NH 4 + Na + K+K+

25. Distal Tubule in H + Homeostasis H + secretion  Two luminal mechanisms in intercalated cells  K + H + antiport  H + ATPase  Fate of secreted H +  Used for reabsorption of HCO 3 - but only small amounts as most of the HCO 3 - is reabsorbed in proximal tubule  Buffered by HPO 4 2-, urate, creatinine, ketone bodies, which generates new HCO 3 -

26. Distal Tubule in H + Homeostasis NH 4 + secretion  Similar to proximal tubule

27. Regulation of H+ Homeostatic Mechanisms Stimuli  Extracellular fluid [H + ]  Influences intracellular [H + ] which directly activates H + secreting mechanisms  pCO 2 in blood  Diffuses into the cells and activates H + secreting mechanisms

28. Extracellular & Intracellular H + and K + H+H+ H+H+ K+K+ K+K+ Intracellular and extracellular H + are in equilibrium Intracellular and extracellular K + are in equilibrium Intracellular and extracellular H + and K + are in equilibrium

29. Extracellular & Intracellular H + H+H+ H+H+ H+H+ H+H+ K+K+ K+K+ K+K+ K+K+

30. H+H+ H+H+ H+H+ H+H+ K+K+ K+K+ K+K+ K+K+

31. H+H+ H+H+ H+H+ H+H+ K+K+ K+K+ K+K+ K+K+

32. H+H+ H+H+ H+H+ H+H+ K+K+ K+K+ K+K+ K+K+

33. Effect of PCO 2 Capillary HCO 3 - H+H+ + CO 2 + H2OH2O H 2 CO 3 Na+ K+ Carbonic anhydrase CO 2

34. Regulation of H+ Homeostatic Mechanisms Processes enhanced by the main stimuli  Enhanced luminal Na + H + exchange  Enhanced activity of the luminal H + ATPase  Increased activity of the Na:3HCO 3 - cotransporter in the basolateral membrane  Increased NH + 4 production from glutamine

35. Other Factors that Increase H+ Excretion H + secretion is increased when there is  Increased Na + reabsorption (e.g. hypovolaemia)  More H + exchanged for Na +  Hypochloraemia  Less Cl - available in tubular fluid, more HCO3 - is reabsorbed with Na +  Hypokalemia  Increases intracellular H +  Increased aldosterone  Increases H + secretion in exchange for Na + reabsorption

36. Modes of H + Secretion and Urinary pH 1. Buffer with HCO 3 - No net H + secretion, does not make urine acidic, HCO 3 reabsorption 2. Buffer with HPO4 2- (and other similar buffers) Net H + secretion, makes urine acidic, new HCO 3 generation 3. NH 4 + secretion Net H + secretion, does not make urine acidic, new HCO 3 generation Titrable Acid

37. H + Excretion by Kidney AlkalosisNormalAcidosis HCO 3 Excretion8010 Titrable acid02040 NH 4 + 040160 Total H + excreted (HCO 3 added to body) - 8059200 Urine pH8.06.04.6 H+ excretion in mmol/day

38. pH of Urine  Range 4.5 – 8  Further acidification is not possible, H+ transport mechanisms do not function when a critical gradient is established  Most often in acidic range  ? Normal urine pH / ? Appropriate urine pH

39. Renal Disease and H + Excretion Renal diseases are associated with acidosis – metabolic acidosis  Reduced glomerular filtrate, unavailability of buffers  acute renal failure  chronic renal failure  Tubular defects, proximal / distal, general / specific defects  Renal tubular acidosis