Tubular secretion and renal handling of potassium

1. Tubular secretion and renal handling of potassium Stephen P. DiBartola, DVM Department of Veterinary Clinical Sciences College of Veterinary Medicine Ohio State University Columbus OH 43210

2. Terminology Transepithelial versus transmembrane potential difference Luminal versus basolateral membranes Transcellular versus paracellular transport

3. Just think of it as a six-pack Luminal surface Epithelial tight junctions Basolateral surface

4. Substances secreted by the renal tubules • Weak acids (organic anions) or weak bases (organic cations) • Foreign substances (e.g. drugs, PAH, PSP) • Substances that are not metabolized and excreted unchanged in the urine (e.g., PAH, PSP) • Substances that are slowly metabolized (e.g. thiamine)

5. Evidence for tubular secretion: PSP • 70% of a dose of PSP is excreted after a single circulation through the kidneys • 75% of PSP is bound to plasma proteins (25% is free and available for filtration) • If FF = 20%, only 5% of dose can be filtered in one circulation through the kidneys (20% of 25%) • 65% of dose must have gotten into the urine by secretion (70% - 5%)

6. Normal plasma constituents that undergo secretion at specific sites in the renal tubule • Hydrogen ions • Ammonium • Potassium • Urate

7. Renal handling of potassium • Kidneys are the primary regulator of potassium balance • Potassium is the only plasma electrolyte that is both reabsorbed and secreted by the tubules

8. Renal handling of potassium • Independent of state of balance • 60% reabsorbed passively in proximal tubule • 20% reabsorbed in thick ascending limb of Henle’s loop via Na+-K+-2Cl- carrier • Dependent on state of balance • Secretion by principal cells in cortical collecting duct and outer medullary collecting duct • Reabsorption by H+-K+ ATPase in Type A () intercalated cells in inner medullary collecting duct

9. Renal potassium handling: Proximal tubule • Early proximal tubule • TEPD lumen negative • K+ reabsorbed with water by solvent drag • Late proximal tubule • TEPD lumen positive • Paracellular route important

10. Renal potassium handling: thick ascending limb of Henle’s loop • TEPD lumen positive • Paracellular route important • Basolateral exit via K+ channels and K+-Cl- cotransporter

11. Renal potassium handling: Late distal tubule and collecting duct • Principal cells responsible for K+ secretion • TEPD lumen negative

12. Renal potassium handling: Late distal tubule and collecting duct • Type A () intercalated cells reabsorb K+ and secrete H+ • K+ enters at luminal membrane by H+-K+ ATPase • K+ exits at basolateral membrane by K+ channel

13. Think of it like a river Major factors affecting K+ movement across cortical collecting duct epithelium • Chemical concentration gradient for K+ across luminal membrane • Distal tubular flow rate • Transmembrane PD across luminal membrane

14. Factors influencing renal excretion of potassium • Sodium intake • Potassium intake • Mineralocorticoids (i.e. aldosterone) • Hydrogen ion balance • Diuretics

15. Increased sodium intake • More Na+ reaches distal tubules and enters cells across luminal membranes stimulating Na+-K+ ATPase in basolateral membranes and increasing intracellular K+ concentration • Increased distal delivery of Na+ increases tubular flow rate and moves secreted potassium downstream

16. Increased potassium intake • Increased numbers and activity of Na+-K+ ATPase and amplification of basolateral membranes secondary to aldosterone secretion • Increased Na+-K+ ATPase activity increases intracellular K+ concentration favoring secretion

17. AldosteroneStimuli for release • Volume depletion RAS activation Angiotensin II stimulates zona glomerulosa of adrenal gland to release aldosterone • Hyperkalemia also stimulates zona glomerulosa • Other (minor) stimuli • ACTH • Hyponatremia • Decreased extracellular pH (acidosis)

18. AldosteroneEffects • Main effect is to increase the number of open Na+ channels in luminal membranes of principal cells • Also stimulates H+ ATPase in luminal membranes of Type A () intercalated cells

19. AldosteroneInhibition of release • Dopamine (released in response to increased ECF volume) • Atrial natriuretic peptide (released in response to increased ECF volume)

20. Nephron segments affected by aldosterone • Connecting segment (late distal tubule) • Cortical collecting duct • Outer medullary collecting duct

21. Could you remind me again … what are the parts of the nephron? … What a bozo … Glomerulus… Proximal tubule… Thin descending LH… Thin ascending LH… Thick ascending LH… Distal convoluted tubule… Connecting segment… Cortical collecting duct… Outer medullary collecting duct… Inner medullary collecting duct…

22. Hydrogen ion balance • Alkalosis increases urinary excretion of potassium • ACUTE MINERAL METABOLIC acidosis decreases urinary excretion of potassium • ORGANIC METABOLIC acidosis does not • CHRONIC METABOLIC acidosis may increase urinary excretion of potassium

23. Effects of acid base balance on translocation of potassium H+ K+ K+ H+ ACIDOSIS ALKALOSIS An oversimplification in acidosis

24. pH effects on translocation of potassium Cl- H+ K+ H+ Org-

25. Diuretics • Many diuretics increase urinary excretion of potassium (e.g. furosemide, thiazides, mannitol) • They do so by increasing distal delivery of sodium and distal tubular flow rate

26. Renal handling of urate • In veterinary medicine, primarily important in Dalmatian dogs • Urate is both reabsorbed and secreted in the renal tubule • Secretion resembles that of PAH • Co-transported into cell with Na+ at basolateral membrane • Exits cell at luminal membrane by facilitated diffusion down its concentration gradient