Acid-Base Physiology

2.4 Renal Regulation of Acid-Base Balance

2.4.1 Role of the Kidneys

The organs involved in regulation of external acid-base balance are the lungs are the kidneys.

The lungs are important for excretion of carbon dioxide (the respiratory acid) and there is a huge amount of this to be excreted: at least 12,000 to 13,000 mmols/day.

In contrast the kidneys are responsible for excretion of the fixed acids and this is also a critical role even though the amounts involved (70-100 mmols/day) are much smaller. The main reason for this renal importance is because there is no other way to excrete these acids and it should be appreciated that the amounts involved are still very large when compared to the plasma [H+] of only 40 nanomoles/litre.

There is a second extremely important role that the kidneys play in acid-base balance, namely the reabsorption of the filtered bicarbonate. Bicarbonate is the predominant extracellular buffer against the fixed acids and it important that its plasma concentration should be defended against renal loss.

In acid-base balance, the kidney is responsible for 2 major activities:

Both these processes involve secretion of H+ into the lumen by the renal tubule cells but only the second leads to excretion of H+ from the body.

The renal mechanisms involved in acid-base balance can be difficult to understand so as a simplification we will consider the processes occurring in the kidney as involving 2 aspects:

2.4.2 Proximal Tubular Mechanism

The contributions of the proximal tubules to acid-base balance are:

The next 2 sections explain these roles in more detail.

2.4.3 Bicarbonate Reabsorption

Daily filtered bicarbonate equals the product of the daily glomerular filtration rate (180 l/day) and the plasma bicarbonate concentration (24 mmol/l). This is 180 x 24 = 4320 mmols/day (or usually quoted as between 4000 to 5000 mmols/day).

About 85 to 90% of the filtered bicarbonate is reabsorbed in the proximal tubule and the rest is reabsorbed by the intercalated cells of the distal tubule and collecting ducts.

The reactions that occur are outlined in the diagram. Effectively, H+ and HCO3- are formed from CO2 and H2O in a reaction catalysed by carbonic anhydrase. The actual reaction involved is probably formation of H+ and OH- from water, then reaction of OH- with CO2 (catalysed by carbonic anhydrase) to produce HCO3-. Either way, the end result is the same.

The H+ leaves the proximal tubule cell and enters the PCT lumen by 2 mechanisms:

Filtered HCO3- cannot cross the apical membrane of the PCT cell. Instead it combines with the secreted H+ (under the influence of brush border carbonic anhydrase) to produce CO2 and H2O. The CO2 is lipid soluble and easily crosses into the cytoplasm of the PCT cell. In the cell, it combines with OH- to produce bicarbonate. The HCO3- crosses the basolateral membrane via a Na+-HCO3- symporter. This symporter is electrogenic as it transfers three HCO3- for every one Na+. In comparison, the Na+-H+ antiporter in the apical membrane is not electrogenic because an equal amount of charge is transferred in both directions.

The basolateral membrane also has an active Na+-K+ ATPase (sodium pump) which transports 3 Na+ out per 2 K+ in. This pump is electrogenic in a direction opposite to that of the Na+-HCO3- symporter. Also the sodium pump keeps intracellular Na+ low which sets up the Na+ concentration gradient required for the H+-Na+ antiport at the apical membrane. The H+-Na+ antiport is an example of secondary active transport.

The net effect is the reabsorption of one molecule of HCO3 and one molecule of Na+ from the tubular lumen into the blood stream for each molecule of H+ secreted. This mechanism does not lead to the net excretion of any H+ from the body as the H+ is consumed in the reaction with the filtered bicarbonate in the tubular lumen.

[Note: The differences in functional properties of the apical membrane from that of the basolateral membranes should be noted. This difference is maintained by the tight junctions which link adjacent proximal tubule cells. These tight junctions have two extremely important functions:

Gate function: They limit access of luminal solutes to the intercellular space. This resistance can be altered and this paracellular pathway can be more open under some circumstances (ie the ‘gate’ can be opened a little).

Fence function: The junctions maintain different distributions of some of the integral membrane proteins. For example they act as a ‘fence’ to keep the Na+-H+ antiporter limited to the apical membrane, and keep the Na+-K+ ATPase limited to the basolateral membrane. The different distribution of such proteins is absolutely essential for cell function.]

The 4 major factors which control bicarbonate reabsorption are:

An increase in any of these four factors causes an increase in bicarbonate reabsorption. Parathyroid hormone also has an effect: an increase in hormone level increases cAMP and decreases bicarbonate reabsorption.

Outline of Reactions in Proximal Tubule Lumen & Cells

Diagram to be added

The mechanism for H+ secretion in the proximal tubule is described as a high capacity, low gradient system:

The high capacity refers to the large amount (4000 to 5000 mmols) of H+ that is secreted per day. (The actual amount of H+ secretion is 85% of the filtered load of HCO3-).

The low gradient refers to the low pH gradient as tubular pH can be decreased from 7.4 down to 6.7-7.0 only.

Though no net excretion of H+ from the body occurs, this proximal mechanism is extremely important in acid-base balance. Loss of bicarbonate is equivalent to an acidifying effect and the potential amounts of bicarbonate lost if this mechanism fails are very large.

2.4.4 Ammonium Production

Ammonium (NH4) is produced predominantly within the proximal tubular cells. The major source is from glutamine which enters the cell from the peritubular capillaries (80%) and the filtrate (20%). Ammonium is produced from glutamine by the action of the enzyme glutaminase. Further ammonium is produced when the glutamate is metabolised to produce alpha-ketoglutarate. This molecule contains 2 negatively-charged carboxylate groups so further metabolism of it in the cell results in the production of 2 HCO3- anions. This occurs if it is oxidised to CO2 or if it is metabolised to glucose.

The pKa for ammonium is so high (about 9.2) that both at extracellular and at intracellular pH, it is present entirely in the acid form NH4+. The previous idea that lipid soluble NH3 is produced in the tubular cell, diffuses into the tubular fluid where it is converted to water soluble NH4+ which is now trapped in the tubule fluid is incorrect.

The subsequent situation with ammonium is complex. Most of the ammonium is involved in cycling within the medulla. About 75% of the proximally produced ammonium is removed from the tubular fluid in the medulla so that the amount of ammonium entering the distal tubule is small. The thick ascending limb of the loop of Henle is the important segment for removing ammonium. Some of the interstitial ammonium returns to the late proximal tubule and enters the medulla again (ie recycling occurs).

An overview of the situation so far is that:

If H+ secretion continues into the medullary collecting duct this would reduce the pH of the luminal fluid further. A low pH greatly augments transfer of ammonium from the medullary interstitium into the luminal fluid as it passes through the medulla. The lower the urine pH, the higher the ammonium excretion and this ammonium excretion is augmented further if an acidosis is present. This augmentation with acidosis is 'regulatory' as the increased ammonium excretion by the kidney tends to increase extracellular pH towards normal.

If the ammonium returns to the blood stream it is metabolised in the liver to urea (Krebs-Henseleit cycle) with net production of one hydrogen ion per ammonium molecule.

(Note: Section 2.4.7 discusses the role of urinary ammonium excretion.)

'Renal regulation of Acid-Base Balance' is continued on the next page.