1. Lecture7 RENAL HANDLING OF ACID-BASE BALANCE

2. Acid-Base Background Information Traditionally Confusing SEVEN GENERAL GUIDLINES One ► One ►Balance principle applies …. acid/base input = acid/base output Two► Two►Acidity is measured in terms of pH …. pH is the negative log of [H + ] pH = 4 means [H] is0.0001 10 -4 moles/L pH = 7 0.0000001 10 -7 pH = 7.40.0000000410 -7.4 pH = 110.0000000000110 -11 *Remember …. when free [H + ]  the pH  Three► Three►Body fluids are buffered …. buffers are substances that bind H + ions If you add H + to a buffered solution, then the buffer binds the added H + so that free H + does not rise much. If you add H + to unbuffered solution, then free H + rises by amount added.

3. Five ► Five ►C0 2 is a volatile acid …. it generates a H + by reacting with H 2 0 Volatile because it can escape from solution as a gas Fixed acids (like lactic acid) can not simply blow off as a gas Six ► Six ►Gain/Loss of fixed acids alters body’s HC0 3 levels  Fixed Acid ….  HC0 3 level ( always ! )  Fixed Acid ….  HC0 3 level ( always ! ) Four ► Four ►Most important pH buffer system in body is …. C0 2 -bicarbonate system C0 2 + H 2 0 H 2 C0 3 HC0 3 + H + ca ( Note: ca = carbonic anhydrase ) Usually consider only …. C0 2 + H 2 0 HC0 3 + H + Seven ► Seven ► Plasma pH is defined by ratio of C0 2 and HC0 3 levels Henderson-Hasselbach Equation The 0.03 is solubility factor. Normal [HC0 3 ] = 24 mM Normal P CO2 = 40 mmHg 24/(0.03x40) = 20 ( Log 20 = 1.3 ) Important Point: Keeping H + balance is essentially same as keeping HC0 3 balance.

4. Renal Handling of Bicarbonate Bicarbonate (HC0 3 ) is freely filtered. Normal plasma HC0 3 is 24 mM. Most filtered HC0 3 is reabsorbed. Reabsorption is transcellular. Most reabsorbed from proximal tubule. Reabsorption always involves a H + secretion step.

5. Bicarbonate Reabsorption from Proximal Tubule 1.Powered by Na + gradient. 2.Apical H + secretion by the Na-H-antiporter 3.Secreted H + binds to filtered HC0 3 4.Complex dissociates to C0 2 and H 2 0 5.C0 2 and H 2 0 re-associate inside cell 6.Reformed HC0 3 transported into interstitium H The H crank ca Electrogenic Pump 3HC0 3 & 1 Na powered by Vm

6. Bicarbonate Reabsorption from Collecting Duct Type A Intercalated Cells 1.Not powered by Na + gradient. 2.Powered by apical H + pumps. K-H-ATPase H-ATPase 3.As before, secreted H + binds to filtered HC0 3 4.Complex dissociates to C0 2 and H 2 0 5.C0 2 and H 2 0 re-associate inside cell 6.Reformed HC0 3 transported into interstitium A Common Theme: HC0 3 reabsorption always involves a H + secretion step. H The H crank

7. Secreting of Excess Base ( HC0 3 Secretion ) There are 2 ways to clear excess base: - reabsorb less HC0 3 - secrete HC0 3 1.Powered by basolateral H + pumps. K-H-ATPase H-ATPase 2.As H + recycles across basolateral membrane, a HC0 3 is reformed in cell and a HC0 3 disappears from the interstitium. 3.Reformed HC0 3 is transported into the tubular lumen. Collecting Duct Type B Intercalated Cell “looks like a flipped-around type A cell” H The H crank

8. Secreting Excess Acid ( H + excretion via phosphate ) 1.Secreted H + binds to phosphate not filtered HC0 3 2.Bound H + is excreted in urine. 3.The H + secretion still results in HC0 3 formation inside the tubular cell. 4.The new HC0 3 is transported into the interstitium. Collecting Duct Type A Intercalated Cell “same that reabsorb HC0 3 earlier” Important Note: Excreted H + and simultaneous net HC0 3 gain act to alkalinize plasma. H

9. Phosphate is “Titratable Acid”: Titrate …. act of carefully and slowly adding a measured amounts of acid/base to a buffer solution. In essence, the collecting duct has titrated HP0 4 2- to H 2 P0 4 - by adding H + Remember, one new HC0 3 was made for each H + added to phosphate. The added H + can easily come off if urine pH is raised to 7.4 (in the lab). Thus, phosphate is called a titratable acid. Phosphate is most important & abundant titratable acid in urine. There are other ones (urate, creatinine) but these are less important.

10. Secreting Excess Acid ( H + excretion via ammonium ) Very complicated process summarized only very simply here. Ammonium (NH 4 + ) is produce by H + binding to ammonia (NH 3 ). Proximal tubule produces ammonia for this purpose only “on demand” When there is a need to get rid of acid, → NH 3 & HCO 3 are produced from the amino acid glutamine → The new HC0 3 is transported into the interstitium. → the NH 3 diffused into tubular lumen and binds to a secreted H + A General Concept: When ever a secreted H + binds to something other than filtered HC0 3 it results in formation of new HC0 3.

11. Ammonium (NH 4 + ) is not a “Titratable Acid” Any H + bound will not dissociate (you can not reverse titrate) by titrating the urine back to pH to 7.4. Once H + binds it stays bound over the whole pH range of normal urine. Remember, one new HC0 3 was made for each H + added to NH 4 +

12. “Running the Numbers” Maintaining acid/base balance is equivalent to maintaining HCO 3 balance Body’s net HC0 3 gain/loss = new HC0 3 gained in plasma - HC0 3 lost in urine The HC0 3 gain comes from H + binding to phosphate and ammonium Normally, body needs to get rid of 60 mEq/day acid Some Typical HCO 3 Gain/Loss Numbers: Note: During acidosis, NH 4 + plays much larger role than Phosphate.

13. Acid-Base Disturbances C0 2 + H 2 0 HC0 3 + H + Respiration Controls Kidney Controls Respiratory Acidosis Respiratory Alkalosis Metabolic Acidosis Metabolic Alkalosis General Categories: Important Reminder: Plasma pH depends on both HC0 3 & C0 2

14. Acid-Base Disturbances & Compensation

15. Metabolic Disturbances may be of renal or non-renal in origin. Renal …. is when the problem is with kidney’s H + or HC0 3 handling. Non-renal …. examples include vomiting, diarrhea, large acid consumption.

16. The Diagnostic Table Simply a Summary of Previous Diagrams For Example Metabolic Acidosis:

17. The Diagnostic Table Simply a Summary of Previous Diagrams For Example Metabolic Alkalosis:

18. The Diagnostic Table Simply a Summary of Previous Diagrams For Example Respiratory Alkalosis: but… you need more info in order to distinguishbetweenthese

19. The Diagnostic Table [HC0 3 ] urine Metabolic Acidosis: Renal … excreting to much HC0 3  [HC0 3 ] urine high low Metabolic Alkalosis: Renal … reabsorbing too much HC0 3  [HC0 3 ] urine low Non-Renal… HC0 3 lost in diarrhea  [HC0 3 ] urine high Non-Renal… acid lost by vomiting  [HC0 3 ] urine ( low H +  less HC0 3 reabsorbed … so more in urine)

21. Renal Physiology Quiz for Lecture 7: Note that this and other Renal Physiology quizzes are simply provided to you to help you self- test your understanding of each lecture. They are not a substitute for studying the other learning materials presented to you. These questions are not intended to reflect the style or level of difficulty of questions on the Final Exam.

22. True/False Questions: 1.Metabolic production of acid is typically about 60 mEq/day. F 2.Bicarbonate (HC03) is the most important pH buffer in the plasma. T 3.Most hydrogen excreted in the urine is in its free ionic form (H+). F 4.NH4 is a titratable acid. F 5.Ammonium (NH3) enters the tubular lumen primarily in the collecting duct. F 6.The pH of urine is always less than 4.5. F 7. Most filtered bicarbonate is reabsorbed from the proximal tubule. T 8.New bicarbonate is formed when secreted H+ ions bind to something other than filtered bicarbonate. T

23. Multiple Choice Questions : 9.Which of the following is true during an acidosis caused by a respiratory problem? a. higher than normal PCO 2 b. lower than normal plasma concentration of HCO 3 c. the patient could be hyperventilating d. a and b are both correct e. b and c are both correct 10.Which of the following statements does not accurately describe the HCO 3 handling by intercalated cells of the collecting duct? a. during HCO 3 reabsorption, apical antiporters transport H+ and Na+ b. during HCO 3 reabsorption, the H+ ion is actively transported by an ATPase c. during HCO 3 secretion, the H+ ion is actively transported by an ATPase d. during HCO 3 secretion, the HCO 3 -Cl antiporters moveHCO 3 across the apical membrane into the tubular lumen e. if secreted H+ binds to filtered HC0 3, then the filtered HCO3 disappears and a new HCO 3 reforms inside the cell 11.Given the following values: NH 4 + excretion: 40 mEq/day HCO 3 excretion: 10 mEq/day Titratable acid excretion: 15 mEq/day Urine formation rate: 1 ml/min Calculate the daily amount of net bicarbonate added to the blood per day: a. 15 mEq b. 35 mEq c. 45 mEq d. 55 mEq e. 75 mEq 12.Vomiting (loss of gastic acid) may result in which of the following? a. immediate loss of HC0 3 from the body b. acidosis c. decreased plasma HCO 3 level d. metabolic alkalosis of renal origin e. compensation by kidney and lung