Renal Physiology Questions and Answers

I. David Weiner, M.D.

Professor of Medicine and Physiology

University of Florida and NF/SGVHS

Hello Dr. Weiner,

I have a question/comment I would like to address with you from your lecture to us this past week. You mentioned that chloride is the ion needed to combat alkalemia and the reason for that is the Cl/HCO3 antiporter on the luminal border of the Type B intercalated cells of the collecting duct, which definitely makes sense because you want to lower HCO3 conc. I came across something that I think runs along the same lines of this idea. It seems to me that the presence of the Cl/HCO3 antiporter on the membrane of the RBC is also very responsible for the relief of alkalemia. So if H+ goes down then the RBC is going to try to kick more HCO3 to the outside via the Cl/HCO3 antiporter so the C.A enzyme within the RBC will be able to convert more CO2+H2O to HCO3- and H+ thus increasing the concentration of H+ in plasma. And therefore, if a person is choride deficient (don't know scientific name for that) then the Cl/HCO3 antiporter on RBC membrane won't work well, thus retarding the rest of the process. I'm not really sure which method (the RBC or the nephron) has better control over the alkalemia issue. What would be your input on that.
I very much appreciate your concern...

• Very interesting thought, but the RBC probably does not play a major role in recovery from metabolic alkalosis (HCO3- excess).  In order to recover, the body has to get the HCO3- out of the body.  The kidney does this, predominantly through changes in HCO3- secretion by the Type B intercalated cells. 
• Sequestering HCO3- inside the RBC does not contribute to acid-base regulation to to any significant extent.  The affinity of the RBC Cl-/HCO3- exchanger for Cl- is high enough that changes in extracellular Cl- concentration that might occur with chloride-depletion metabolic alkalosis do not alter the rate of Cl- and HCO3- exchange. 

 

I. David Weiner, M.D.

Associate Professor of Medicine and Physiology

Hi Dr. Weiner,

I asked you this in class yesterday, but I was reading over the information in our packet and thought I might ask again to confirm in case I wrote down the wrong answer in my notes. Figure 2 in the packet shows a Bicarb./Cl- exchanger on the basolateral membrane of the proximal tubule cells, but when I asked you in class yesterday, you said those only exist on the intercalated cells. Should I go by the packet or by my class notes?

Please let me know.

Thanks,

• The handout is correct, and the proximal tubule does have a basolateral Cl-/HCO3- exchanger, at least in some portions of the proximal tubule.  However, the amount of bicarbonate exit via this transporter is substantially less than exits by the Na⁺(HCO₃^-)₃ cotransporter.  In intercalated cells, however, almost all basolateral bicarbonate transport occurs via Cl-/HCO3- exchange.  Thus, the Cl-/HCO3- exchanger plays a major role in acid-base transport in the collecting duct, and not in the proximal tubule.

Dr. Weiner,

I have a question about the regulation of bicarbonate. I heard you talk about regulation by acidosis, hypokalemia, and volume depletion. I am not sure how hypokalemia acts to increase bicarbonate besides activating the break down of glutamine-but how does hypokalemia do this? Also your notes mention aldosterone regulates as well, but how? Lastly, I recall you mentioning Angiotensin II as a regulator, how does this regulate bicarbonate as well? Thanks for your help and I apologize if I missed these explanations during lecture.
 

• Hypokalemia stimulates proximal tubule new bicarbonate formation by stimulating glutamine's conversion to bicarbonate and ammonium.  The mechanism is now completely understood.  Many people think that hypokalemia induces intracellular acidification, which then stimulates this process.
• Aldosterone stimulates bicarbonate reabsorption by increasing expression of H+-ATPase, and probably H+-K+-ATPase in the collecting duct.  It also stimulates proximal tubule ammonium production.
• Angiotensin II (AII) stimulates proximal tubule bicarbonate reabsorption by increasing the activity of apical Na+/H+ exchange and basolateral Na+(HCO3-)3 cotransport.  It may also, in work done by the Dean at UF, H+-ATPase in the collecting duct.
• Hope this helps!

HI Dr. Weiner,

The apical border CA is critical for the reabsorption of bicarb in the proximal tubule (80%). The book says that the TALH reabsorbs an additional 15% of the filtered load. It also says that the TALH has the same reabsorption mechanisms as the proximal tubule EXCEPT that it lacks the brush border CA (pg137-8). How is the TALH able to reabsorbed bicarb without CA? It seems that lacking the CA would produce the same effect in the TALH that an acetazolamide diuretic would produce in the proximal tubule, decreasing the reabsorption and increasing the excretion of bicarb.

Thank you.

• Carbonic anhydrase is important because it speeds up the conversion of H₂CO₃, carbonic acid, to H₂O and CO₂.  This reaction continues, just slower, if carbonic anhydrase is not present.  In the TALH, the rate of proton secretion and, thus, luminal carbonic acid formation is slower than in the proximal tubule.  As a result, the conversion rate of carbonic acid to water and carbon dioxide, even in the absence of apical CA, is fast enough to keep up with proton secretion and bicarbonate reabsorption.

Hello, I was wondering if you could clarify how hyperkalemia and hypokalemia affect acid secretion/excretion. Thanks!

• Hypokalemia and hyperkalemia have opposite effects on renal acid excretion.  First, hypokalemia increases and hyperkalemia decreases proximal tubule ammonium production, loop of Henle ammonium reabsorption and ammonia secretion across the collecting duct into the luminal fluid.  
• This results in increased urinary ammonia excretion in hypokalemia, which can, and frequently does, lead to metabolic alkalosis.  Hyperkalemia can lead to decreased ammonia excretion, which can, and does, frequently lead to metabolic acidosis.

Subject: Late Proximal tubule Bicarb question

Dr. Weiner,

Hi, XXX from the 1st year med class. You said that in the basolateral part of a LATE Proximal Tubule cell that 3HCO3’s are symported with ONE Na’s. In Dr. G’s notes, his diagram (which I thought came from the same place) shows the exact opposite, with only one HCO3 and 3Na’s. What is it?

Also, I’m sure you’ve already gotten a barrage of emails about which part of the nephron is the true diluting portion…is it the TALH or the DCT??? Which ones do we need to know for the course. I realize that teachers will disagree, but I was wondering if you knew what the deal was.

Thank you,

• The proximal tubule basolateral sodium bicarbonate cotransporter transports the equivalent of 1 Na and 3 HCO3- molecules.  

  I believe that Dr. Gerencser's notes were based on a  handout I originally prepared that was incorrect.  

   

• Regarding the term, "diluting segment," I have looked at multiple resources, and it is clear that different people use the term quite differently. Some people use it to refer to both the thick ascending limb of the loop of Henle and the distal convoluted tubule. Others use it to refer only to the distal convoluted tubule.

  The important fact to know, in my opinion, is that the thick ascending limb of the loop of Henle is involved in generation of the hypertonic medullary interstitium, and that the distal convoluted tubule is involved in generation of a dilute urine.

  Because of the differences in how people use the term, "diluting segment," and that it does not appear to refer strictly to a strictly defined anatomic site, I propose that the students should be told that this is a loosely defined term, and that they should refer to the different regions of the nephron/tubule by their anatomic name, and that the term "diluting segment" should not be used.

Subject: Renal ???

Hi there, I have a question about the notes vs. the handout.

In class all you mentioned that HCO3 transport in the PT was a sodium Bicarbonate exchanger but in the handout it also shows a Cl-/ HCO3- transporter as well. Is this important?????

Also, would a low pH (high H+), a low HCO3 and a high CO2 be metabolic acidosis or would it be combined or strictly respiratory? I understand (I think) w/ normal levels of HCO3 and respiratory acidosis or alkalosis but I'm getting lost w/ changing levels of HCO3

Ie... is high pH, normal HCO3 and low CO2 acute respiratory alkalosis?

Clearly I am getting myself all confused.

Thanks

• There is a Cl-/HCO3- exchanger present in certain parts of the proximal tubule. Specifically, this is the proximal straight tubule. More important, though, is that the primary mechanism of basolateral bicarbonate transport in the proximal tubule is via sodium-bicarbonate cotransporter.

  Regarding the acid-base conditions, I think that you understand it better than you think. A low pH means that there must be either metabolic acidosis, respiratory acidosis or both. In this case, the low bicarbonate means that there is metabolic acidosis. The high pCO2 means that there is respiratory acidosis. Since there is both metabolic and respiratory acidosis, this is an example of a 'combined' metabolic and respiratory acidosis. This produces the most severe type of acidosis.

  In the second case, the high pH means that there must be either a metabolic or reparatory alkalosis. The normal hco3 means that there is not metabolic alkalosis. The low pCO2 means that there is a respiratory alkalosis. Because there is no renal compensation, i.e., no metabolic acidosis, there must not have been time for the metabolic (renal) compensation to develop. That means that this is an example of acute respiratory alkalosis.

  Hope this helps,

  I. David Weiner, M.D. 
  Associate Professor of Medicine and Physiology
  University of Florida College of Medicine
  Chief, Renal Section NF/SGVHS

Question,

What is the mechanism of basolateral ammonia/ammonium exit in the medullary thick ascending limb of the loop of Henle.

• The exact mechanism is not known.  This is why I didn't discuss it in class.
• I think that the most likely mechanism is that intracellular NH4+ dissociates to H+ and NH3.  The proton probably exits across the basolateral membrane via a basolateral Na+/H+ exchanger.  The NH3 probably diffuses across the basolateral membrane.  Once in the peritubular space, the proton and NH3 recombine to form NH4+.  There are other possible mechanisms, however.

I'll post more questions and their answers as they come in.

Last modified:  Saturday, March 07, 2009