Kidney and acid base physiology : part 3

Distal tubule (DT) and collecting duct (CD)

Distal tubule and the collecting duct are the chief sites of K⁺ secretion. Along with that about 7% of filtered NaCl and about 10-15 % of water (in principal cells only in the presence of ADH hormone) is also absorbed here. As for the details, let us just go through the following points and then compare with the previous two sections:

1.      The key player is Na⁺-Cl^- symporter in the early Distal tubule which moves NaCl inside the cell.

2.      This segment is totally impermeable to water hence its name ‘cortical diluting segment.

3.      Thiazide diuretics also act here and inhibit NaCl transport inside the cell.

4.      Principal cells are involved in the potassium secretion where it reaches a high concentration via Na⁺/K⁺ ATPase.

5.      Na⁺ also gets absorbed here through epithelial sodium channels (ENaC) channel present on the apical surface.

6.      The inward movement of Na results in a relatively low voltage in the lumen as compared to the voltage across the basolateral surface. This lumen negative transepithelial voltage acts as a driving force for K⁺ from blood to the lumen via voltage gated K⁺ channels on the apical surface (which are inhibited by high cytosolic Ca⁺⁺ or H^+.

7.      Sensitivity of the K channels in the principal cells can explain stimulation of K⁺ excretion during metabolic alkalosis or increased bicarbonate excretion.

8.      Intercalated cells have very less Na/K ATPase activity and absolutely no conductance channel on the apical surface for ions; all they possess is gastric parietal type H⁺/K⁺ ATPases which are active constitutively and Colonic type H⁺/K⁺ ATPases which get activated only during dietary NaCl depletion, potassium depletion and acidotic condition.

9.      In the intercalated cells of the CD and late DT, H⁺-ATPase and H⁺/K⁺ ATPase are present on the apical membrane to facilitate the H⁺ ion exit from the cell into the lumen.

10.  The HCO₃^- leave the cell via AE1 (as described previously). Aldosterone increase the H⁺ secretion by stimulating H⁺-ATPase.

11.  Resorption of K⁺ ions occurs only when there is a need for K⁺ conservation. On dietary loading , area of basolateral surface and activity of Na⁺/K⁺ ATPase increases.

12.  Stimulation of K transport by mineralocorticoids

a.       Activate Na/K pump

b.      Increased rate of electrogenic cationic exchange

c.       Hyperpolarisation of cell negative basolateral membrane voltage

13.  There are two types of K⁺ channels on the apical membrane: the secretory type ( with a small conductance and a high open probability; inhibited by increased cytosolic H⁺ and Ca⁺⁺ concentration) and maxi-K⁺ type (large conductance and low open probability; high cytosolic Ca⁺⁺ concentration activate this channel).

14.  Amiloride inhibits K⁺ secretion by reducing the lumen - negative transepithelial voltage by blocking the Na⁺ channels from the luminal side.

15.  Aldosterone penetrates the cell from the interstitial side and combines with the mineralocorticoid receptor MR. This complex enters the nucleus and promotes mRNA synthesis which then directs the synthesis of Aldosterone-induced-proteins (AIP).

16.  The AIPs include Na+ channels and Na/K-ATPase and increase ATP production by mitochondria. All these act to promote sodium absorption and increase K+ and H+ secretion.

17.  Spironolactone binds to MR and prevents aldosterone effects.

Kidney and acid base physiology:part 2

Transport of ions at the loop of Henle

Water is absorbed passively at the thin descending limb of the loop of Henle and is (?) accompanied by diffusion of sodium ions in the loop of Henle.

Limited absorption of NaCl can occur through the thin ascending limb passively.

Key players at The Thick Ascending limb

As in the previous post, the accompanying diagram is self explanatory and the steps involved in the H⁺/ HCO₃^- transport and Na⁺/K⁺ movement are more or less same barring a few exceptions which can be summarized as follows:

 i.                    About 15% of the filtered HCO₃^- can be reabsorbed here at the basolateral  (BL) surface.

ii.                  The Na⁺-HCO₃- cotransporter at the BL surface is NBCn1.

iii.            The HCO₃- can exit the cell in exchange for Cl^- (Anion Exchanger2, AE2) or by a K⁺-HCO₃ symporter.

iv.                There is no Carbonic anhydrase in the brush border (luminal side).

v.        The most remarkable difference is the presence of Na⁺-K⁺-2Cl^- cotransporter here which is responsible for the downhill transport of Na⁺ and Cl^- and uphill transport of K⁺ inside the cell.

vi.                K⁺ and Cl^- ions exit at the basolateral surface through separate channels whereas Na⁺ leaves the cell primarily through the Na⁺/K⁺ ATPase.

vii.              Some K+ is able to leak through the apical surface into the lumen and results in a slightly positive (+6 mV) inside the lumen. This acts as a driving force for cations like Na⁺, Mg⁺⁺, Ca⁺⁺ and even K⁺ to pass through a paracellular route to capillaries.

viii.            This segment is totally impermeable to water so known as the ‘diluting segment’.

ix.           Thus 20% Na⁺ and K⁺ are reabsorbed in this segment where half of that Na⁺ absorption is passive (paracellular) and the rest is active.

x.                  The site of action of Furosemide is the Na⁺-K⁺-2Cl⁺ cotransporter to which it reaches through the luminal side after being secreted in the PT by organic anion transport (shown in the diagram in the previous post).

Kidney and acid- base physiology:part 1

As we move up the ladder, I feel that it is the right time to discuss the role of kidney in maintaining the acid base balance. Just as the gut is important for HCO₃^-  secretion , kidney plays a role in hydrogen ion removal from the body. Each day the bicarbonate loss in the faeces imparts an acid load (Net endogenous acid production, NEAP) to the body which is in a way made up for by the kidney’s acid secretion (Renal net acid excretion, RNAE).

Thus a balance is reached in normal physiological conditions when NEAP equals the RNAE.

As I was about to start with this topic, I found that sodium-potassium transport is invariably linked to and coexists with the H⁺/HCO₃^- movement in/out of the tubular cells. I felt that this is the right time when I highlight the site of action of various diuretics too.

The normal HCO₃^- in plasma is about 24 meq/l and GFR is 180 l/day, so the filtered load of the bicarbonate is about (180*24=4300 meq/day). Approximately 80 % of the HCO₃^- is reabsorbed in the proximal tubule (PT) with the thick ascending limb (ThAL) and distal convoluted tubule (DT) contributing to additional 16 % reabsorption. The remaining bicarbonate is reabsorbed by the collecting duct (CD).

The following diagram depicting the reabsorption of the various ions at basolateral surface and secretion at the apical luminal surface is self -explanatory.

The salient features of the events at (proximal tubule) PT are as follows:

1. Main transporter for H⁺ ion secretion at the PT are H⁺ - ATPase and Na⁺/H⁺ antiporter (exchanger; NHE3).

2. The NHE3  is responsible for driving approximately 2/3 of HCO₃^-  reabsorption at the corresponding basolateral surface; rest 1/3 is contributed by the H⁺ - ATPase.

3.      The H+ are generated inside the cell by the activity of Carbonic anhydrase (II).

4.    Carbonic anhydrase (IV) is present in the brushborder at the apical surface also where it catalyses the production of H₂O and CO₂ from the luminal carbonic acid.

5.      Thus the bicarbonate in the tubular fluid are neutralized by the H⁺ secreted at the apical surface inside the lumen and there is actually no change in the pH of the tubular fluid.

6.      The HCO₃^- which is reabsorbed at the basolateral surface is actually a new molecule; for one H⁺ secreted from the cell, one molecule of HCO₃^- is reabsorbed in the blood.

7.      The HCO₃^- transporters at the basolateral surface are 3HCO₃^--Na⁺ symporter (NBCe1) mainly and HCO₃^-/Cl^- exchanger (to some extent).

8.      The Na⁺ entering the cell by NHE3 at the apical surface is extruded out by Na⁺-K⁺ ATPase athe basolateral surface.

9.      The Na⁺ movement inside the cell at the apical surface is also coupled with glucose cotransport (SGLT-1, SGLT-2 at late and early PT respectively). At the basolateral surface, the carrier for the facilitated diffusion of glucose are  GLUT-2,GLUT-1 at early and late PT respectively).

10.  The glucose, lactate, phosphates and amino acids are completely reabsorbed in the PT.

11.     The K⁺ and Cl^- entering the cell are extruded or reabsorbed at the basolateral surface by separate K⁺-Cl^- cotransporter.

12.     Na⁺, K⁺, Cl^- are also reabsorbed through paracellular pathways and the lateral surface of the PT cells have selective K⁺ channels for the K⁺ ion movement into the cells.

13.     More water is reabsorbed in the early PT as compared to Cl^- so Cl^- concentration goes on increasing and is reltively higher in the late PT. This creates a concentration gradient for the Cl^- ions which diffuse to the interior through paracellular pathway leaving the lumen slightly positive. This positivity then drags the Na⁺ to diffuse in the blood.

14.     Thus about 67% of filtered Na⁺, K⁺, Cl^- are reabsorbed at the PT along with water.