H+ Homeostasis by the Kidney

H+ Homeostasis

Goal: To maintain a plasma (ECF) pH of approximately 7.4

(equivalent to [H+] = 40 nmol/L

Action needed: The body generates excess H+

Requirement is to excrete H+

Occasionally there is a need to excrete excess alkali

H+ Homeostasis

OUTPUTINPUT

Body Fluids

Buffers

Oral intake,food, drink

Metabolism

Kidney

Lungs

H+ Homeostasis

Excreted byH+ in the form of

BuffersNon CO2(Volatile H+)

Kidney

LungsCO2

(Volatile H+)

HCO3-

H2O + CO2

Other buffers

Fate of Buffers

LungsHCO3- + H+ H2O + CO2H2CO3

HPO42- + H+ H2PO4

-

Hb- + H+ HbH

If CO2 is washed out through the lungs HCO3 is lost

Buffering power is lost if not converted to original form

Determinants of [H+]

[HCO3- ]

[H+]PCO2

-

= k

[HCO3-] changes will result in changes in [H+]

Role of Kidney in H+ Homeostasis

Role of kidney Excrete excess H+

Reabsorb filtered HCO3-

Generate new HCO3-

H+ Secretion into the Tubule

H+ can not be left as it is in the tubule, need to be buffered Prevent high acidity of urine, and prevent tissue injury Keep H+ concentration relatively low so that more can be

easily secreted

Role of Kidney in H+ Homeostasis

Parts of the nephron involved Proximal tubule Thick ascending limb of loop of Henle Distal tubule Collecting duct

Proximal Tubule in H+ Homeostasis

The proximal tubule Secretes the major part of the excess H+

Reabsorbs about 80% of filtered HCO3-

Proximal Tubule in H+ Homeostasis

The proximal tubule Secretes the major part of the excess H+

Reabsorbs about 80% of filtered HCO3-

These processes are interdependent

Proximal Tubule in H+ Homeostasis

Na+

Capillary

H+H+HCO3

-+

H2CO3 HCO3-H+ +

H2O + CO2

CO2 + H2O

H2CO3

HCO3-

Na+

K+

Na+

Carbonic anhydrase

Proximal Tubule in H+ Homeostasis

Secretion of H+ by proximal tubular cells Secondary active, energy derived from sodium-potassium

pump in the basolateral membrane H+ is generated from CO2 and water by the action of carbonic

anhydrase Is secreted by an antiport mechanism on the luminal surface Secreted combines with HCO3

- in tubular fluid

Proximal Tubule in H+ Homeostasis

The overall effect of secretion of H+

H+ moves from the cell to tubular fluid- But comes back in the form of CO2, no excretion of H+

HCO3- produced in the cell enters the interstitial fluid and

then the capillary HCO3

- in the tubular fluid disappears

- Reabsorption of HCO3-

Proximal Tubule in H+ Homeostasis

Significance of secreted H+ combining with HCO3- in the

tubular fluid

Enables ‘reabsorption’ of HCO3-

No significant increase in acidity in the tubular fluid

Proximal Tubule in H+ Homeostasis

Na+

Capillary

H+H+HPO4

2- +

H2PO4- HCO3

-H+ +

CO2 + H2O

H2CO3

HCO3-

Na+

K+

Na+

Carbonic anhydrase

Proximal Tubule in H+ Homeostasis

Secretion of H+ by proximal tubule with buffering in urine by HPO4

2-

Some of the H+ secreted is buffered by HPO42-

There is net H+ excretion New HCO3

- is generated Only small amounts buffered in this manner in proximal

tubule as much HCO3 is available

Proximal Tubule in H+ Homeostasis

Secretion of NH4+ by proximal tubular cells

Na+

Capillary

NH4+

HCO3-

H+

+

glutamine

NH3

HCO3-

Na+ Na+

Glutaminase

+ ἀ ketoglutarate

NH4+

Na+

K+

Proximal Tubule in H+ Homeostasis

Secretion of NH4+ by proximal tubular cells

Dependent on sodium potassium pump NH3 derived from glutamine (catalysed by glutaminase) NH4

+ formed and secreted by antiport mechanism in the luminal surface

Net H+ excretion occurs HCO3

- is transported to the capillaries

New generation of HCO3-

Thick Ascending Limb of Loop of Henle in H+ Homeostasis

Functions of thick ascending limb Reabsorb HCO3

-

About 15% of filtered HCO3- is reabsorbed

• Mechanism similar to that in the proximal tubule

Distal Tubule in H+ Homeostasis

Functions Reabsorb HCO3

-

About 5% if filtered HCO3- is reabsorbed

Mechanism similar to that in the proximal tubule Secrete H+ to be buffered by HPO4

2- and other minor buffers

Secrete NH4+

Distal Tubule in H+ Homeostasis

H+ secretion is by intercalated cells

K+

Capillary

H+H+HCO3

-+

H2CO3 HCO3-H+ +

H2O + CO2

CO2 + H2O

H2CO3

HCO3-

Na+

K+

Na+

Carbonic anhydrase

H+

Distal Tubule in H+ Homeostasis

H+ secretion is by intercalated cells

K+

Capillary

H+H+HPO4

2- +

H2PO4- HCO3

-H+ +

CO2 + H2O

H2CO3

HCO3-

Na+

K+

Na+

Carbonic anhydrase

H+

Distal Tubule in H+ Homeostasis

Secretion of NH4+ by distal tubular cells

Na+

Capillary

NH4+

HCO3-

H+

+

glutamine

NH3

HCO3-

Na+ Na+

Glutaminase

+ ἀ ketoglutarate

NH4+

Na+

K+

Distal Tubule in H+ Homeostasis

H+ secretion Two luminal mechanisms in intercalated cells

K+ H+ antiport H+ ATPase

Fate of secreted H+

Used for reabsorption of HCO3- but only small amounts as

most of the HCO3- is reabsorbed in proximal tubule

Buffered by HPO42-, urate, creatinine, ketone bodies, which

generates new HCO3-

Distal Tubule in H+ Homeostasis

NH4+ secretion

Similar to proximal tubule

Regulation of H+ Homeostatic Mechanisms

Stimuli Extracellular fluid [H+]

Influences intracellular [H+] which directly activates H+

secreting mechanisms pCO2 in blood

Diffuses into the cells and activates H+ secreting mechanisms

Extracellular & Intracellular H+ and K+

H+ H+

K+ K+

Intracellular and extracellularH+ are in equilibrium

Intracellular and extracellularK+ are in equilibrium

Intracellular and extracellularH+ and K+ are in equilibrium

Extracellular & Intracellular H+

H+ H+

H+ H+

K+ K+

K+ K+

Extracellular & Intracellular H+

H+ H+

H+ H+

K+ K+

K+ K+

Extracellular & Intracellular H+

H+ H+

H+ H+

K+ K+

K+ K+

Extracellular & Intracellular H+

H+ H+

H+ H+

K+ K+

K+ K+

Effect of PCO2

Capillary

HCO3-H++

CO2+H2O

H2CO3

Na+

K+

Carbonic anhydrase

CO2

Regulation of H+ Homeostatic Mechanisms

Processes enhanced by the main stimuli Enhanced luminal Na+H+ exchange Enhanced activity of the luminal H+ATPase Increased activity of the Na:3HCO3

- cotransporter in the basolateral membrane

Increased NH+4 production from glutamine

Other Factors that Increase H+ Excretion

H+ secretion is increased when there is Increased Na+ reabsorption (e.g. hypovolaemia)

More H+ exchanged for Na+ Hypochloraemia

Less Cl- available in tubular fluid, more HCO3- is reabsorbed with Na+

Hypokalemia Increases intracellular H+

Increased aldosterone Increases H+ secretion in exchange for Na+ reabsorption

Modes of H+ Secretion and Urinary pH

1. Buffer with HCO3-

No net H+ secretion, does not make urine acidic, HCO3 reabsorption

2. Buffer with HPO42- (and other similar buffers)Net H+ secretion, makes urine acidic, new HCO3 generation

3. NH4+ secretion

Net H+ secretion, does not make urine acidic, new HCO3 generation

Titrable Acid

H+ Excretion by Kidney

Alkalosis Normal Acidosis

HCO3 Excretion 80 1 0

Titrable acid 0 20 40

NH4+ 0 40 160

Total H+ excreted (HCO3 added to body) - 80 59 200

Urine pH 8.0 6.0 4.6

H+ excretion in mmol/day

pH of Urine

Range 4.5 – 8 Further acidification is not possible, H+ transport

mechanisms do not function when a critical gradient is established

Most often in acidic range ? Normal urine pH / ? Appropriate urine pH

Renal Disease and H+ Excretion

Renal diseases are associated with acidosis – metabolic acidosis Reduced glomerular filtrate, unavailability of buffers

acute renal failure chronic renal failure

Tubular defects, proximal / distal, general / specific defects Renal tubular acidosis