Renal handling of acid-base balance

By segments

Proximal tubule

• Resorb 80% of filtered bicarbonate
  * By secretion of hydrogen
• Produces and secrete ammonium

Thick ascending limb of loop of Henle

• Resorb about 10-15% of filtered bicarbonate
  * By secretion of hydrogen

Distal convoluted tubues and collecting duct system

• Produces titratable acid
  * by type A intercalated cells
• Secretes bicarbonate
  * by type B intercalated cells
• Resorbs virtually all bicarbonates

Proximal tubule

(High capacity, low gradient system)

For every hydrogen ion secreted

--> 1 bicarbonate ion is generated

--> bicarbonate diffuses into peritubular capillaries

Secretion of hydrogen

By luminal Na-H antiporter

• Responsible for majority of Na+ uptake
• Secondary active transport

In the lumen, H+ combines with filtered HCO3 to form water and CO2

--> CO2 diffuses into the cell

NB:

• Carbonic anhydrase is found on the luminal surface of the tubule cells (????on the brush border)
• In addition to the intracellular carbonic anhydrase found in H+ secreting tubular cells

Overall effect

• Does not contribute to urinary excretion of H+
• Serves only to conserve HCO3

Transport of bicarbonate

By basolateral Na-HCO3 symporter

• 3 HCO3 is transported for every Na+
• HCO3 is out of cell into peritubular capillary
• Na+ into the cell from interstitial space

NB:

• Na+ transport is UP the gradient passively (which is very unusual case)
• HCO3 moves down its electrochemical gradient

DCT and CD

(Low capacity, high gradient system)

All H+ secreting cells have primary active H-ATPase pump in the luminal membrane

Type A intercalated cells

Has

• Primary active H-ATPase pump
• Primary active H-K ATPase pump
  * Transports H+ into lumen and K+ into cell
• HCO3 moves out of cell into interstitium
  * via Cl-HCO3 antiporter
• ????Cl moves from interstitium into cell by the antiporter
  --> Secreted into tubule by Cl- channel
  * [AV6:p160] is not very clear on this

Type B intercalated cells

• Basically type A flipped around
• Secrete bicarbonate
  * via Cl-HCO3 antiporter

Buffering and H+ excretion

Neither filtered H+ or excretion of free H+ makes significant contribution to H+ secretion

At minimum urinary pH (4.4)
--> [H+] = 0.06mmol/day
--> Much less than the 50-100mmol ingested or produced everyday
* KB: 70+ mmol/day

Also,

H+ combining with HCO3 in lumen

--> Formation of CO2 and water in the tubule

--> Diffusion of CO2 back

Thus,

Effective for resorption of HCO3 but not for net excretion of H+

Therefore,

Excretion of H+ must involve non-bicarbonate urinary buffer

Phosphate

pKa of phosphate

pKa = 6.8

Filtered phosphate is normally the most important non-bicarbonate urinary buffer

At normal pH 7.4,

• 80% is in divalent form (HPO₄^2-)
• 20% is in monovalent form (H₂PO₄^-)

 

Phosphate handling

Plasma level of phosphate = About 1mmol/L

90% free (not bound to protein)

--> about 160mmol/day filtered

Resorption about 75-90%

--> Kidney can use phosphate to excrete about 40mmol of H+ per day.

 

Ketones

Beta-hydroxybutyrate and acetoacetate

--> pKa of the bases are low (4.5)

--> Only about half of the respective filtered bases can be used as buffers

Thus,

Not effective buffers

 

Amino acids

Processing of amino acids

Processing of the carboxyl group of the amino acid produces HCO3

Processing of the amino group produces ammonium

Ammonium is further processed by liver to urea or glutamine
* The process consumes a HCO3
* No net production of HCO3

Ammonium and glutamine

2 amino acids + O2
--> 2NH4+ + 2HCO3-
--> Urea or glutamine (+CO2 and some H2O)

Step 1

Glutamine released from the liver is taken up by proximal tubule cells
* Both from lumen (20%) and from interstitium (80%)

Step 2

--> Glutamine converted to bicarbonate and NH4+
* Basically reverse of what liver does

Step 3

--> NH4+ is secreted into lumen by Na-H antiporter and HCO3 diffuses into peritubular capillaries

Thus,

• New bicarbonate is produced

Other notes on ammonium

• pKa of ammonium ~ 9.2
• [AV6:p167] Additional reabsorption and secretion of ammonium do happen and eventually NH3 is secreted into medullary collecting duct and binds with H+, forming NH4+ and trapping it in the lumen
• Ammonium level in DCT tubule is low
• Ammonium level in medullary interstitium is high
• Ammonium can masquerade as hydrogen ions or potassium ions and be transported by their transport proteins
• 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.

 

Quantitative measurement of acid secretion

Titratable acid

The amount of NaOH (i.e. base) needed to be added to increase urine pH to 7.4

--> Presumably equivalent to amount of H+ added to the tubular fluid that combined with phosphate and organic buffers.

NB:

• Does not include H+ excreted in the form of ammonium (due to the high pKa of 9.2)
• Titration with alkali to pH 7.4 will not remove hydrogen ion from NH4+

Contributions

Phosphate (pKa~6.8) is the most imporant and significant of the titratable acids
* Limited by the amount of phosphate filtered

Creatinine (pKa ~ 5.0) may also contribute when urinary pH is low

In severe diabetic ketoacidosis, beta-hydroxybutyrate (pKa 4.8) is the major component of TA
* [KB: online text acid and base]

 

Total acid excretion

Total acid excretion
= [Titratable acid] + [NH4+] - [HCO3]

In acidosis

In response to acidosis, increased production and excretion of NH4+ is quantitatively much more important than increased formaton of titratable acid

 

Regulation of renal acid excretion

Stimulation for acid excretion

PaCO2 and arterial pH act directly on kidney to increase acid excretion

PaCO2 acts by

--> Diffusion into tubular cells

--> Increasing pCO2 intracellularly

--> Decreasing intracelluar pH

Extracellular pH action is unrelated to PaCO2.

Other factors

[KB: online text on acid and base]

• ECF volume
• K+ deficiency
  --> Increase HCO3 resorption
  --> Increased acid excretion
• Cl- deficiency (in alkalosis)
  --> HCO3 is transported with Na+ to maintain electric neutrality (normally it's Cl-)
  --> Prevents excretion of excess HCO3
  --> Maintains alkalosis
• Aldosterone
  --> Increase Na+ resorption
  --> Increase H+ secretion (via antiporter)
• Decreased GFR
  --> Decreased filtration of HCO3
  --> Alkalosis

Regulation of NH4+ excretion

Decreased extracellular pH

--> Liver preferentially converts ammonium to glutamine (instead of to urea)

--> More glutamine available

Also,

Decreased extracellular pH

--> Increased renal glutamine oxidation by proximal tubule

--> Increased excretion of NH4+

NB:

[KB: online text] There is a lag period between an acid load and NH4+ excretion reaching a maximum level

 

Regulation of HCO3 resorption in proximal tubule

Normally all HCO3 are reabsorbed

[KB online text on acid and base]

The 4 major factors which control bicarbonate reabsorption are

• Luminal HCO3- concentration
• Luminal flow rate
• Arterial pCO2
• Angiotensin II
  * via decrease in cyclic AMP

An increase in any of these four factors causes an increase in bicarbonate reabsorption.

NB:

• Increase in PTH level increases cAMP and decreases bicarbonate reabsorption
  * ???? Minor contribution

Factors causing kidneys to maintain or generate metabolic alkalosis

Over-excretion of H+ can be due to

1. Volume contraction
2. Chloride depletion
3. Combination of aldosterone excess and K+ depletion

--> All three causes metabolic alkalosis

Volume contraction

Decreased ECF volume

--> Elevated angiotensin

--> Elevated aldosterone

--> Increased sodium resorption in exchange for acid
* i.e. Na-H antiporter

--> Increased HCO3 resorption

--> Increase urinary acid excretion

Thus,

Urinary acidity is high despite metabolic alkalosis

Chloride depletion

[AV6:p176] Chloride depletion stimulate hydrogen ion secretion
--> Reasons not explained.

Related: large volume of normal saline infusion causes hyperchloraemic acidosis
--> mechanism unknown
* Possibly due to a combination of factors [http://www.frca.co.uk/article.aspx?articleid=100924]

???? I wonder if it is related to the Cl-HCO3 antiporter in the basolateral membrane of type A intercalated cells
---> This actually does NOT make sense... If the antiporter is the reason, then it should be acidosis

Combination of aldosterone excess and K+ depletion

Aldosterone stimulates hydrogen ion secretion

Potassium depletion also weakly stimulate tubular hydrogen ion secretion and NH4+ production

Combination of both stimulates tubular H+ secretion significantly

Thus,

Excessive use of diuretics

--> Hypovolemia and hypokalemia

--> Increase H+ excretion

--> Metabolic acidosis

Chloride depletion may also be involved and may compound the problem

 

Other notes

• When [HCO3] exceeds 27-28 mmol/L
  --> Renal threshold exceed
  --> Bicarbonates start to appear in urine
  * [KB2:p164]