Renal Function: Acid Base Regulation

What three main systems does the body use to achieve acid base balance?

1) Intra- and extra-cellular buffers - RAPID

2) Lungs/respiratory system (volatile acids)

3) Kidneys (SLOW - relatively speaking)

• Only system for removal of non-volatile acids formed during metabolism

How do we regulate acid / base production in the kidney?

production/reabsorption of HCO_3^- (Combatting acidosis)

excretion of H+ (Combatting acidosis)

excretion of HCO_3^- (Combatting alkalosis)

What is the typical urinary pH?

4.5 - 8.5

Where is the majority of tubular HCO_3^- reabsorbed?

• Where else is it absorbed?

• In the PCT

• Restores HCO₃ to plasma, NO net change in H+ (cycles between tubular lumen and cell) Tm/saturable, excess excreted

  • TAL reabsorbs ~15% of filtered using a similar mechanism

In conditions of acidosis, the body might need to produce more HCO_3^-, how is this done?

Where plasma HCO_3^- is low…

• Production of HCO_3^-, by tubular walls in the DCT and CD

• Intercalated cells of CD

  • Can secrete HCO_3^- into the capillaries and absorb Cl- into the tubular cells

  • H+ also actively pumped into filtrate to be excreted

  • K+ / H+ ATPase pump also actively pumps H+ into filtrate

    • Both serve to decrease pH, net gain of HCO₃

The active transport of H+ at the level of the collecting duct can increase luminal H+ by how much?

900 fold

• Renal Net Acid Excretion (NAE)

Under acid conditions H+ is excreted into the filtrate, however H+ is low because most is buffered. What is the predominant buffer and what happens when the body needs to reabsorb this specific compound?

Predominant buffer in the filtrate is HCO_3^-, but as most HCO_3^-, is reabsorbed........

Two additional tubular buffers…

Titratable Acids:

1. Phosphate

   1. (НРО4^2- - H₂РО_4^-) (dietary source, tubular concentration determined by filtration / reabsorption)

   2. Limited amount of phosphate in tubular fluid

1. Ammonia (NH₃ → NH4⁺ (Ammonium)) - regulated production in kidney allows for control of H+

What are titratable acids?

Filtered solutes, in base form, that therefore can bind protons

Excreted titratable acids are formed from secreted protons.

• Where are these hydrogen ions mainly secreted?

• What transporters allow them to be secreted?

• PCT

  • Via the Na+ / H+ exchanger (Secondary Active Transport)

  • H+ ATPase (Active transport of intracellular H+ across apical membrane) (Small Amount)

• TAL

  • Via the Na+ / H+ exchanger

• CD

  • H+ ATPase (Active transport of intracellular H+ across apical membrane)

  • K+ / H+ ATPase pump

Once H+ is inside the tubular filtrate, it can be weak bases such as phosphate to form…

• Why is this done and what does it prevent?

H⁺ in the tubule fluid…

• Combines with filtered weak bases e.g. HPO₄^2- (Which is lipid soluble, and permeable), to form H₂PO₄ (Which is impermeable)

• H₂PO_4^- is lipid insoluble, SO bound protons are excreted

H+ can also be excreted bound to creatinine and/or citrate (urates in birds).

Once H+ is inside the tubular filtrate, it can join weak bases such as ammonia to form…

• Where does this occur?

• What is it formed froM?

• H+ can join ammonia (NH₃) - (lipid soluble) which is a weak base to form NH_4⁺ (A weak acid → Transported) (not lipid soluble)

Main sites

• PCT (Production and secretion), CD regulation of excretion

• Most NH_4⁺ is formed from amino acids (particularly glutamine).

During acidosis, how much does NH₄⁺ excretion increase?

Up to 10 fold

• Ammoniagenesis and ammonium excretion, account for 60-90% of net acid excretion in mice, rats, dogs, chickens and humans (not, cats, rabbits).

How is ammonia produced?

• In the proximal tubule → Glutamine broken into NH₃ + H⁺ and HCO_3^-

  • HCO_3^- absorbed with Na⁺ into the capillaries (Cotransporter)

  • NH₃ joins with H⁺ forming NH₄⁺

  • NH₄⁺ enters filtrate, Na+ enters tubular cell (Counter transporter)

Describe what happens once NH_4⁺ is produced in the PCT.

Passes through the descending loop, to the ascending loop of henle.

• Na⁺ / K⁺ / 2 Cl^- channel (Originally all into the tubular cell) can be used to transport NH₄⁺ (Substitutes K⁺)

• NH₄⁺ and Na⁺ transported into the tubular cell, 2 Cl^- can be transported into the filtrate

• NH₄⁺ transported into interstitial space

  • Can break down into ammonia and hydrogen ions again

  • High medullary [NH4+] maintained by counter current multiplication

  • Some of which is absorbed by the collection duct as H⁺ and NH₃

Describe how ammonium and ammonia enter the collecting duct to be excreted.

Basolateral Membrane

• NH₄⁺ and Na⁺ Cotransporter

  • Transports NH₄⁺ into tubule cells

  • NH₄⁺ can break down into ammonia and H+

• NH₃ Channels

  • Transports NH₃ into the tubule cells

Apical Membrane

• NH₃ Channel

  • Transports NH₃ into the filtrate

• H+ and K+ Channel

  • H+ joins with NH₃ to form NH₄⁺

During acidosis, how can ammonia channels be regulated?

• During acidosis, NH₃ and NH₄⁺ channels are up-regulated

• Promoting NH₄⁺ formation in the collecting duct to be excreted

What effect does angiotensin II have on acid/base regulation?

• Stimulates absorption of bicarbonate into capillaries

  • Via Na+ and HCO₃^- Cotransporter

What effect does corticosteroids / endothelin have on acid/base regulation?

• Increases H+ secretion into filtrate via Na+ and H+ Cotransporter

What effect does PTH have on acid/base regulation?

• Inhibits angiotensin II and corticosteroid/endothelin effects

How does the collecting duct determine final urine pH?

• By H+ and HCO₃^- secretion

What is the pH of initial CD filtrate?

7.4

What purpose do the type A intercalated cells have and where are they found?

Found in CD - Most active under conditions of acidosis

• Type A intercalated Cells produce HCO₃- and H+

• Can directly secrete hydrogen ions using H+ ATPase pump or H+ / K+ ATPase channel (On Apical Surface)

  • H+ in filtrate, K+ in tubule cell

• Basolaminar surface has HCO₃- / Cl- channels to move bicarbonate back into interstitial space

• Apical surface also has NH₃ channels to move ammonia into filtrate

How are the Type A Intercalated Cells regulated during acidodis?

• Increased NH₃ channels

• Up-regulate K+ / H+ and H+ channels

What purpose do the type B and C intercalated cells have and where are they found?

Found in CD, most active under alkalosis-conditions

• Mirror image of acid secreting cells

• Move bicarbonate out into filtrate (HCO₃- and Cl- transporter)

  • HCO₃- into filtrate

  • Cl- into tubular cell

• Move hydrogen ions into interstitial space

• Activity increased by alkalosis and inhibited by acidosis

• Increased by aldosterone and angiotensin II

If there is an increased production/consumption of H+, results in a reduction in…

If there is an excess amount of bases, results in..

Will use and result in a reduction in buffers, including HCO₃-

• Reabsorb HCO₃-, (matched by 1:1 H+ excretion)

  Produce HCO₃- (matched by 1:1 H+ excretion)

Kidney excretes HCO₃-

What hormones will chronic metabolic acidosis activate and what effects will it have?

• Angiotensin II, Endothelin, PTH

  • Level of PCT

  • Reabsorb HCO₃-

    H+ Secretion

    Generation of NH₄⁺

    Generation of HCO₃-

  • Level of CD

  • AND H+ Secretion, NH₄⁺ entry/H+ secretion

• Glucocorticoids

  • Reabsorb HCO₃-

    H+ Secretion

    Generation of NH₄⁺

    Generation of HCO₃-

What are possible causes of chronic metabolic acidosis?

• Increase non-volatile acids e.g. lactic acid

• Ketosis

• Increased B-hydroxybutyric acid

• Increased Acetoacetic acid

• Increased loss of HCO3-

• Prolonged starvation

• Diabetes mellitus

• Rumen acidosis

• Renal failure

• Faecal HCO3- loss

• Diarrhoea

• Respiratory acidosis (severe)

Describe the renal acid base regulation occuring in concert with the respiratory system. For each describe…

• 1⁰ Change

• Respiratory Compensation

• Renal Compensation

Metabolic acidosis

Metabolic alkalosis

Respiratory acidosis

Respiratory alkalosis

What is proteinuria or albuminuria caused by?

alteration in filtration barrier (Glomerulus)

What is haemoglobinuria caused by?

Exceeding binding capacity of haptoglobulin to Hb present in filtrate

What is glucosuria caused by?

exceeded Tm for glucose, secondary increase in water loss due to osmotic potential of the filtrate

What is water diuresis caused by?

increased volume of excreted urine due to low concentrations of ADH in plasma

What is polyuria caused by?

abnormally large volume of urine, could be water diuresis or osmotic challenge, e.g. secondary to glucosuria

Reminder, where do the following drugs act and how do they affect renal function?

• Loop Diuretics

• Potassium sparing diuretics

• Osmotic Diuretics

Loop diuretics - act on ascending limb of LOH to inhibit transport proteins that mediate cotransport of Na+ (Cl- and K+).

Potassium sparing diuretics - act in cortical CD to inhibit Na+ reabsorption and K+ secretion, by either inhibition of aldosterone or epithelial Na+ channel

Osmotic diuretics - filtered but not reabsorbed.