Renal Physiology

Questions and Answers

I. David Weiner, M.D.

Professor of Medicine and Physiology

University of Florida and NF/SGVHS

June 2, 2007

Dr. Weiner,

Could you explain the mechanisms of high phosphate excretion for the following stimuli:
a)  ECV expansion
b)  Acidosis
c)  Glucocorticoids

These were referenced on third page of your notes entitled "Calcium and Phosphate Homeostasis".

Thank you in advance.

• All three decrease phosphate reabsorption in the proximal tubule due to decreased expression of the apical sodium-phosphate cotransporter.

  For ECV expansion, you might think of this as being teleologically linked to the need to decrease sodium absorption.

  For acidosis, you might think of it as being related to stimulation of bone resorption, with a resulting need to excrete the "bone phosphate" in the urine. This also helps to increase, a little, net acid excretion by increasing titratable acid excretion in the form of phosphate.

  Since glucocorticoids induce a catabolic state, there is a need to increase renal phosphate excretion of the phosphate released from protein/cellular catabolism.

I. David Weiner, M.D.

May 30, 2007

Dear Dr. Weiner,

I have a couple of questions listed below concerning topics that I do not understand or just want to clarify. Thank you for your help in advance.

1. Ca++ Handling in Proximal Tubule: I understand the concept that Ca is driven via a paracellular path because of the positive luminal charge (generated from Cl- reabsorption). I also wrote down another driving mechanism during lecture, which entails a low [Na] in the lumen and an effective high [H20] and this contributes to an increased [Ca] gradient. I am slightly confused regarding this mechanism and was hoping you could clarify it. Do both mechanisms contribute equally toward the reabsorption of Ca?

• Both mechanisms contribute to calcium reabsorption in the proximal tubule. The exact proportion which each contributes is not known, since the two mechanisms are related to each other. Specifically, greater rates of sodium chloride reabsorption result in a greater degree of luminal positive charge. It also results in a slightly greater decrease in luminal sodium concentration, which increases luminal water reabsorption, which concentrates luminal calcium and results in an increased calcium gradient for paracellular calcium reabsorption.

2. In states of hypokalemia, there is a risk for metabolic alkalosis. I realize that this state can stimulate NH4+ production (and also new bicarbonate generation), however, how does the potassium level specifically trigger this stimulation?

• The current theory that most people use to explain this observation is that hypokalemia increases intracellular electronegativity in the proximal tubule cell by altering the intracellular to extracellular potassium gradient. This increased intracellular electronegativity results in increased rates of HCO3 exit through the electrogenic basolateral sodium bicarbonate cotransporter. This increased rate of HCO3 exit results in intracellular acidification. Enzymes involved in ammoniagenesis in the proximal tubule are pH-sensitive, and increased intracellular acidification results in increased expression of these enzymes, and therefore in increased rates of ammoniagenesis and bicarbonate production.

3. When NH4+ is secreted into the CD tubule; does this occur via the principle cells, intercalated cells, or both? It is my understanding that bicarbonate secretion in the CD (during states of metabolic alkalosis) occurs via the intercalated cells only, is this correct? I know that the intercalated cells are usually the ones involved in acid base balance, but I was not sure since the principle cells are more numerous. Also, could you clarify for me the difference between the type A and B intercalated cells?

• Ammonium secretion in the collecting duct probably occurs via both principal and intercalated cells.

  Bicarbonate secretion occurs in the collecting duct only the intercalated cells. Specifically it is the B-type intercalated cell in the cortical portion of the collecting duct that mediates bicarbonate secretion.

  The difference between the A-type and the B-type intercalated cell is whether they are designed for acid or bicarbonate secretion. The A-type intercalated cell has an apical H-ATPase and H-K-ATPase and a basolateral chloride-bicarbonate exchanger, and is designed for acid (proton) secretion. The B-type intercalated cell has an apical chloride-bicarbonate exchanger and basolateral H-ATPase, and is designed for bicarbonate secretion.

I. David Weiner, M.D.

May 29, 2007

Hello Dr. Weiner,

I just have a few questions that I want to ask you.

1. When we talk about cases in which someone is eating a diet high in a certain mineral/ion and talk about their excretion and reabsorption, do we take into account the body's regulatory mechanisms in which FE of that ion is changing in response or do we assume that with a high ___ diet, we excrete AND reabsorb more of that mineral since there's more of it in the filtrate?

2. On the other hand, when we talk about someone who is deficient in a certain mineral, is the transport rate of the ion transporters increasing to reabsorb more of that ion from the filtrate or decreasing because there's not much in the filtrate TO reabsorb?

3. Does potassium deficiency cause an increase in Na reabsorption because it's movement out into the ECF, making the cell more electronegative and attracting more Na into the cell/duct cell from the lumen?

4. Also, how does potassium deficiency cause an increase in lumenal ammonium and increased bicarb production? In our notes, it just says that this happens but doesn't explain why.

5. Does high Na diet lead to higher Ca excretion because our body is signalling to the kidneys to not reabsorb Na, therefore increasing FE and therefore Ca is being excreted with the Na as well?

I'm sorry for bombarding you with questions [which are probably worded really badly], but these questions are causing me MUCH frustration.

• 1.  The kidneys adaptive mechanisms to maintain electrolyte homeostasis result in rather small changes in the serum concentration of most minerals over wide ranges of changes in dietary intake.  As a result, for most questions on this topic, one can assume that the filtered load, while possibly changing, does not change to a dramatic extent.  For example, with a high sodium diet, serum sodium concentrations do not change to a significant extent, the filtered load of sodium does not change to a significant extent, but the tubular reabsorption decreases, resulting in increased fractional excretion of sodium.

  2.  The answer to this is just the converse of the answer to #1.

  3.  It is probably more complicated than that.  Potassium deficiency actually increases sodium absorption in the loop of Henle (!).  The exact mechanism by which this occurs is not completely understood presently.

  4.  The current theory that most people use to explain this observation is that hypokalemia causes increased intracellular electronegativity in the proximal tubule cell by altering the intracellular to extracellular potassium gradient.  This increased intracellular electronegativity results in increased rates of HCO3 exit through the electrogenic basolateral sodium bicarbonate cotransporter.  This increased rate of HCO3 exit results in intracellular acidification.  Enzymes involved in ammoniagenesis in the proximal tubule are pH-sensitive, and increased intracellular acidification results in increased expression of these enzymes, and therefore in increased rates of ammoniagenesis and bicarbonate production.

  5.  Exactly.  The high sodium diet inhibits sodium absorption in the thick ascending limb of the loop of Henle.  Decreased sodium absorption in the thick ascending limb of the loop of Henle decreases calcium absorption in this segment.  This is because sodium absorption results in generation of positive charge in the tubule lumen in this segment.  The positive charge then drives paracellular calcium absorption.  Decreased sodium absorption rates to decreased positive charge which leads to decreased calcium absorption.

   I hope this helps.

I. David Weiner, M.D.

May 29, 2007

Dr. Weiner,

This is more for personal interest than anything else, but I'm curious about potassium's effects on blood pressure. You told us that a high potassium diet effectively lowers blood pressure, however, I'm having trouble thinking of how this might work. You also told us that high levels of plasma potassium stimulate aldosterone release to cause the excretion of this excess by activation of the Na/K ATPase and ENaC. In addition, aldosterone should increase Na reabsorption, leading to an increase in plasma volume and thus an increase in BP. Of course, you also told us that potassium acts as a local vasodilator, which would lower BP. Those are my thoughts, any clarification or additional information you could provide would be appreciated. Thanks!

• You actually raise a very good question about the mechanism by which potassium supplementation lowers blood pressure. Your surmise that is probably not due to changes in aldosterone is probably correct.

The first mechanism through which potassium works is by functioning, indirectly, as a diuretic. Potassium supplementation decreases sodium transport by the apical Na-K-2Cl cotransporter in the loop of Henle. These effects are subtle, but results in decreased sodium absorption in proximal segments, which results in net diuresis, decrease in plasma volume and a decrease in blood pressure.

Why, you might ask, does this occur? Teleologically, this appears to be related to the need to have adequate sodium delivery to the collecting duct to enable adequate potassium secretion by the collecting duct principal cell.

Second, potassium supplementation probably decreases oxygen free radical mediated vasoconstriction of resistance blood vessels. The exact mechanism by which this occurs has not been completely identified.

Third, potassium supplementation decreases cardiovascular reactivity to circulating vasopressors, such as norepinephrine and angiotensin II.

I hope this helps.

I. David Weiner, M.D.

May 24, 2007

Hello, I was wondering if you could clarify a concept for me that I am a bit confused about. Regarding Ca++ resorption in the loop of Henle, I have in my notes that it occurs via a paracellular mechanism as a result of Na+ reabsorption leaving a positive luminal charge. What I am confused about is how this positive luminal charge is generated. Is it generated as a result of the K+ being secreted into the lumen? I am not sure if my logic is correct about how the charges are distributed. Thank you for your help. :)  

• Your logic is perfect. Yes, the positive luminal charge is due to potassium that is secreted ("recycled") across the apical membrane in order to allow continued function of the apical Na-K-2Cl cotransporter.

I. David Weiner, M.D.

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

Last modified:  Saturday, March 07, 2009