1. Lecture 6 Renal Handling of Potassium, Calcium & Phosphate

2. Background Information The normal plasma K + level is ……. 3.6 - 5.2 mEq/L (a very narrow range) Deviation outside this range is cause for alarm. Reason: resting potential of excitable cells depends on extracellular K + level. Also, its important to realize that most of the body’s K + is inside cells. Thus, shifting K + in/out of cells can substantially change extracellular K + levels without substantially changing in the intracellular level. This fact is used by the body as a short-term means to normalize and control plasma K + levels.

3. K + Balance

4. Epinephrine/Insulin modulate K + shifting in/out of cells. Aldosterone modulates renal K + handling. Epinephrine Epinephrine quickly deals with big K + loads arising from exercise or trauma. Insulin Insulin quickly deals with big K + loads arising from a meal. Aldosterone Aldosterone action is slower and works to maintain the body’s long-term K + balance. K + Balance

5. K + Shifting Following a K + Load Plasma K + level (always within normal range) 100% K + load initially moves into cells Several hours later, 100% K + load is excreted in urine So….How do the kidney’s handle K + ?

6. Summary of Renal Handling of K + ► The filtered K + load is relatively small. Na load = GFR x P Na = 18 mEq/min K load = GFR x P K = 0.6 mEq/min ► 80% reabsorbed from proximal tubule Passive, paracellular, like urea or Cl - ► 10% reabsorbed from ascending limb Remember, the Na-K-2Cl symporter ► Only 10% filtered K + load reaches the distal nephron, but this is where all the K + handling action is. There may be little K + excreted or huge amounts of K + excreted

7. Renal Handling Varies with Dietary K + Intake Low K + Diet Normal or High K + Diet The distal K + reabsorption has a relatively small influence overall. The distal K + secretion can have a huge influence !!!

9. Focus on Cortical Collecting Duct Distal tubule contribution is minor compared to collecting duct. So…. Our focus here will be only on the cortical collecting duct. A Logical Question: How can this region of the nephron secrete and reabsorb K + ? The Answer is: Different cells do the different things? → K + is reabsorbed by type-A intercalated cells. Small in magnitude (~2% of filtered K + ). → K + is secreted by principal cells. Large in magnitude (20-160% of filtered K + )  Important Point: Usually, the body needs to excrete excess K +. Thus, distal K + secretion is generally the key process that controls the body’s K + balance.

10. K + Secretion by the Principle Cell The K + secretion process 1.Basolateral active Na-K transport 2.Apical passive diffusion through a K + channel. K+K+ Why have a basolateral K + channel? 1.When apical K + channel is closed, it allows K + to recycle keeping the Na-K pump going. 2.If both apical and basolateral K + channels are open, then almost no K + goes out basolateral channel because of the trans-epithelium membrane potential.

11. The Collecting Duct Principle Cell What alters K + secretion rate? 1.Closing apical K + channel. - forces K + to recycle back across basolateral membrane Note: The opposite is also true. Opening more apical K + channels would increase K + secretion.

12. The Collecting Duct Principle Cell What alters K + secretion rate? 2.Closing apical Na + channels. - this slows Na-K-ATPase because less intracellular Na + is available - less pumping means less K + entry which leads to less K + secretion - less Na reabsorption also makes trans-epithelial potential smaller reducing K + secretion Note : The opposite is also true.  open Na + channels   K + secretion Note : Also, simply lowering or raising tubular Na + level may change K + secretion rate.  apical Na + entry   K + secretion

13. The Collecting Duct Principle Cell What alters K + secretion rate? 3.Changes in local K + concentration. ( flow dependence ) - fast flow….keeps local tubular K + level low steeper K + gradient  secretion - slow flow….allows some local K + accumulation shallower gradient  secretion

14. Aldosterone Regulation of K + Secretion Is doing both a problem? - Na + regulation inputs generally dominate. - Seems like this should be a problem for K + control ( e.g.  BP   ald  unintended  K + secretion ) Aldosterone: Steroid, released from adrenal cortex Activates Na + channels in collecting duct -  Na + reabsorption when  BP - ang. II triggers aldosterone release Activates K + channels in collecting duct -  K + secretion when plasma K + high - high plasma K + directly triggers aldosterone release  plasma K + ….  aldosterone  plasma K + ….  aldosterone

15. Flow-Dependence of K Secretion “Saves the Day”  Tubular flow always  K + Secretion  Remember … Na + input dominates. … also the body has big K + reservoir it can tap should need be.  K secretion + Classic Renal Response to  BP Volume Contraction Low Blood Pressure 1) Baroreceptors 2) Renal pressure receptors 3) Tubuloglomerular feedback Renin Release Angiotensin II Aldosterone  Na reaborption corrects  TPR - flow dependence  Tubular Flow

16. Diuretics Increase Tubular Flow …. and consequently most  K + secretion K + Wasting Diuretics: K + Wasting Diuretics: - are diuretics that act upstream of collecting duct - they increase flow through the collecting duct - these are very effective at reducing blood volume K + Sparing Diuretics: K + Sparing Diuretics: - these have their actions on the collecting duct - block Na + entry or inhibit aldosterone action - these actions also tend to reduce K + secretion - caveat is that these are relatively weak diuretics Spironolactone Amiloride Furosemide Hydrochlorothiazide Acetazolamide (*A diuretic is an agent that increases urine volume and reduced extracellular fluid volume)

17. Calcium Background Information Renal excretion …. balances dietary intake Body has standing reservoir …. bones Calcium is important …. regulates many phenomena Plasma Ca 2+ levels are controlled by two factors: 1. Balance between GI Ca 2+ uptake renal Ca 2+ excretion (slow) 2. Relative Ca 2+ distribution between bone and ECF (relatively fast) Key regulators are Vitamin D and Parathyroid Hormone

18. Calcium Handling by the Nephron In the plasma, ~40% Ca 2+ is bound to proteins and not filtered. ~10% is complexed with anions. Remaining Ca 2+ (50%) is freely filtered. What happens to filtered Ca 2+ : 60% reabsorbed in proximal tubule passive paracellular route In distal tubule, reabsorption is transcellular and regulated Normally, only 1 to 3% of filtered Ca 2+ is excreted in the urine Note: Proximal Ca 2+ reabsorption is coupled to Na + & H 2 0 reabsorption. (diuretics & high salt diet   Ca reabsorption)

19. Vitamin D : - acts on GI track, bone & kidney - but … GI action is most important … it promotes Ca uptake Parathyroid Hormone: - released from parathyroid gland - release triggered by low plasma Ca levels PTH #1 : promotes formation of vitamin D (  plasma Ca   GI Ca) PTH #2 : promotes Ca release from bone (fast) (  plasma Ca   bone Ca) PTH #3 : promotes reabsorption of Ca from distal tubule (  plasma Ca   Ca reabsorbed)

20. Phosphate Background Information ~ 10% Phosphate in plasma is bound to proteins and is not filtered. The remainder is freely filtered and ~75% reabsorbed (in proximal tubule). Phosphate reaborption is transcellular (Na-Phosphate-symport) Phosphate left inside tubule may complex with H + (it’s the main titratable acid) Rise in plasma phosphate stimulates PTH release (but usually plasma Ca is primary release signal) PTH acts on proximal tubule to inhibit phosphate reabsorption PTH #4 : inhibits renal phosphate reabsorption