Distal nephron, diuretics and transport disorders

1. Distal nephron, diuretics and transport disorders Linda. Peterson@ubc.ca PHY 423 Session 3

2. Three disorders causing low plasma [K] • Group 1 Bartter’s Syndrome/Disease Group 2 Gitelman’s Syndrome/Disease Group 3 Liddle’s Syndrome/Disease • What specific nephron segment, cell type and transport molecule- how is function changed (loss or gain of function) • What is the effect on transport in the specific segment where the affected molecule is located

3. What are the changes in potassium excretion and BP in these three disorders? * vs normal

4. Inherited transport disorders causing hypokalemia (low plasma [K]) and metabolic alkalosis i.e. elevated pH due to increased [HCO3]. Are they the same or different disorders? * vs normal

5. CCD DCT ENaC Chromosome 16 TAL Linda Peterson@ubc.ca

6. DCT Linda Peterson@ubc.ca

7. Transport in the TALNo Water is Reabsorbed Here The NKCC Transporter* Sodium Potassium 2 Chloride Cotransporter +10 mV 3Na+ Na+ Na+ K+ 2Cl- ATPase K+ 2K+ 2Cl- Cl- K K+ Na+ Ca++ Mg++ K+ Adapted from: Diagram in Molecular Biology of the Cell (Garland Science 2008)

8. Bartter’s +10mV

9. Transport in the Distal Convoluted Tubule (DCT) No water is reabsorbed Here Na+ Ca++ Ca++ 3Na+ Na+ ATPase 2K+ Cl- Cl- Mg++ Diagram in Molecular Biology of the Cell (Garland Science 2008)

10. Gitelman’s X Mg++

11. Inherited transport disorders causing hypokalemia (low plasma [K]), and metabolic alkalosis i.e. elevated plasma pH due to an increase in [HCO3]. * vs normal

12. What is the underlying defect in Liddle’s Disorder?

13. K-sparing diuretics Liddle’s

15. Inherited transport disorders causing hypokalemia (low plasma [K]) and metabolic alkalosis i.e. an increase in plasma pH due to an increase in [HCO3]. * vs normal

16. Potassium loss in patients with Liddle’s Disorder occurs in the CCD-due to increased K secretion by Principal cells as a direct consequence of the mutation in ENaC. Why is potassium lost in patients with Bartter’s and Gitelman’s syndromes?

17. Cortical Collecting Duct is the site of regulated K transport

18. Increased Na delivery in Bartter’s and Gitelman’s patients stimulates K secretion Increased K excretion is an indirect effect of the two disorders K loss in Bartter’s is >>> Gitelman’s consistent with the difference in Na delivery Na+ ENaC -20mV Na+ -70mV K+

19. Na entry through apical Na channels depolarizes the apical membrane Apical membrane depolarization creates a favourable electrical gradient for K exit via apical K channels Na+ ENaC -20mV Na+ -70mV K+

20. Apical Na Channels • Na entry through apical ENaC channels drives K secretion • If ENaCs close K secretion ceases X ENaC -70mV X -20mV K- sparing diuretics – one class (Amiloride)

21. Factors affecting K secretion 1. Aldosterone * 2. Sodium delivery * • Responsible for PHYL 423 Aldosterone is the most important regulator of K secretion- it must be present for normal rates of K secretion (excretion). However to answer our question, we will look at sodium delivery first.

22. How does Na delivery affect K secretion? • The rate of apical Na entry depends on the Na gradient across the apical membrane

23. Na entry through apical Na channels depolarizes the apical membrane Apical membrane depolarization creates a favourable electrical gradient for K exit via apical K channels Na+ ENaC -20mV Na+ -70mV K+

24. How does Na delivery affect K secretion? • The rate of apical Na entry depends on the Na gradient across the apical membrane • At low flow rates, [Na] in the lumen decreases as Na is reabsorbed • At high flow rates, [Na] in the lumen does not decrease as Na is reabsorbed despite maximal rates of Na transport out of the lumen. Na is replaced as quickly as it is reabsorbed.

25. Diabetes Mellitus Loop diuretics & Bartter’s Thiazide diuretics & Gitelman’s Cortical Collecting Duct

26. Normal Range Excess Aldosterone Normal Absence Aldosterone Effect of Na delivery and aldosterone on K secretion

27. Aldosterone stimulates K secretion Adrenal Gland Aldo K+ K+

28. Principal cells of the CCD Aldosterone

29. Effects of Aldosterone • Primary Acute Effect • Increases the number of ENaC in the apical membrane

30. Longterm Effects of Aldosterone • Stimulates synthesis of Na-K-ATPase • Stimulates synthesis of ROMK- potassium channels

31. Normal or High Aldo + High Na Delivery is Pathophysiological Urinary K losses will occur

32. High Aldo + High Na DeliveryPathophysiological • Increased Aldosterone + normal or increased Na delivery to the cortical collecting duct will dramatically stimulate K secretion • K depletion (a reduction in total body K) will occur • The effect on plasma [K] will depend on other factors that may affect K distribution

33. Changes in potassium excretion and [Aldo] in these three disorders * vs normal

34. What are the changes in potassium excretion and [Aldo] in these three disorders? * vs normal

35. Diuretics- mechanism of action * vs normal

36. What are the changes in NaCl, water, K , Ca and Mg excretion, and BP caused by these diuretics relative to Normal and to each other? * vs normal

37. Can you answer the questions in the course objectives handout? • Can you draw a TAL cell, explain how it reabsorbs NaCl, K, Mg and Ca? Why doesn’t water follow? Can you identify the primary active step, carriers, and channels? • Where is the defect in Gitelman’s syndrome?Can you describe the changes in ion transport in the segment and explain the underlying problem? • If a patient is given furosemide can you describe the changes in electrolyte and water excretion and explain what causes them (direct and indirect effects)?