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CVR > Kidney Function V: Regulation of Acid-Base Status > Flashcards

Kidney Function V: Regulation of Acid-Base Status Flashcards

1
Q

Why is it important to tightly regulate plasma pH?

A

Metabolic reactions are highly sensitive to free hydrogen ion concentration in the solution in which they occur.

Metabolic reactions are catalysed by enzymes which are proteins.

Enzymes CHANGE THEIR SHAPE depending on surrounding hydrogen ion concentration.

Changing their shape changes their ability to function.

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2
Q

Over what pH range do enzymes function?

A

Enzymes function optimally over a narrow range of [H+]

Optimum pH= 7.35-7.45 (pH of ECF)

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3
Q

Equation for acid excretion?

A

Acid excretion= metabolic acid production + H+ intake

Any acid ingested should be balanced by acid excretion in order to maintain pH of ECF

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4
Q

List the 4 sources of Hydrogen ion GAIN

A

1) Generation of hydrogen ions from CO2
2) Production of non-volatiel acids from the metabolism of proteins and other organic molecules
3) Gain of H+ from loss of bicarbonate in diarrhoea and other non-gastric GI fluids
4) Gain of H+ from loss of bicarbonate in urine

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5
Q

List the 4 sources of hydrogen ion LOSS

A

1) Utilisation of various hydrogen ions in the metabolism of organic ions
2) Loss of hydrogen ions in vomitus
3) Loss of hydrogen ions in urine
4) Hyperventilation

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6
Q

Equation for production of bicarbonate ions and hydrogen ions

A

CO2 + H2O <> H2CO3 <> HCO3- + H+

In the lungs, reaction will go to the left so carbon dioxide can be breathed off.

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7
Q

How much carbon dioxide is generated by oxidative metabolism?

A

20,000 mmol

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8
Q

What occurs in hypoventilation and hyperventilation?

A

Hypoventilation- body will gain hydrogen ions

Hyperventilation- body will lose hydrogen ions

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9
Q

What are non-volatile and non-respiratory acids and how are they produced?

A

sulfuric acid, phosphoric acid and lactic acid

Carbonic acid is a respiratory acid which can be breathed off.

From the metabolism of proteins and other organic molecules which is balanced by the utilisation of hydrogen ions.

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10
Q

How much H+ do western diets contain?

A

It is a protein rich diet.

So gain 40-80 mmol/day of H+.

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11
Q

How are hydrogen ions gained in diarrhoea?

A

Through the loss of bicarbonate.

CO2 + H2O <> H2CO3 > H+

Diarrhoea involves the loss of an alkaline fluid so the reaction cannot go to the left. Hydrogen cannot be breathed off so it is like the body has gained a hydrogen ion.

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12
Q

How are hydrogen ions lost in vomitus?

A

CO2 + H2O <> H2CO3 > HCO3-

  • Vomit consists of the contents of the stomach which contains mainly HCL
  • Hydrogen ion has been lost via vomit so like the body has gained a bicarbonate ion
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13
Q

At what acid levels are plasma acid levels regulated and acid production produced?

A

Regulated at nM range

Produced in mM range

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14
Q

How are respiratory and non-respiratory acids excreted?

A

Respiratory acids are excreted via the lungs through CO2 production and oxidative metabolism.

Non-respiratory acids such as phosphoric acid are excreted through the kidneys.

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15
Q

What is the equation for pH and the normal plasma pH and in nM range?

A
  • pH= -log[H+] (pH only refers to hydrogen ions not bound to another molecule)
  • normal plasma pH is 7.35-7.45 or 35-45nM H+
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16
Q

How do buffers work?

What is the most important buffer?

A

Prevent large changes in pH or free hydrogen ion concentration.

Buffer + H+= HBuffer

HCO3- + H+ <> H2CO3 <> CO2 + H2O

Increase in [H+], reaction goes to right

Decrease in [H+]. reaction goes to left

Bicarbonate system
HCO3- + H+ <> H2CO3

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17
Q

What are the different buffers for H+ within blood, interstitial fluid, intracellular fluid?

A

Blood: H+ is buffered by plasma proteins, Hb, bicarbonates and phosphates

Interstitial fluid: some proteins, bicarbonates and phosphates

Intracellular fluid: intracellular proteins, bicarbonates and phosphates

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18
Q

What are the main buffers in urine?

A

Phosphate and ammonia

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19
Q

What is the pH of

  • mitochondria
  • nucelus
  • cytosol
  • ECF
  • Interstitial fluid
  • ER
  • lysosome
A

Mitochondria- 8

Nucleus- 7.2

Cytosol- 7.2

ECF- 7.35-7.45

Interstitial fluid- <7.35

lysosome- 4.7

All of the organelles have a lower pH than the cytosol apart from mitochondria.

pH of intracellular fluid < ECF

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20
Q

How can the pH of a buffer solution be determined?

A

By the Henderson- Hasselbach equation

HCO3- + H+ = H2CO3

pH= pK + (log [HCO3-]/[H2CO3]

Allows calculation of pH, pCO2 and [HCO3-] if the other two variables are known

21
Q

What is pK?

A

The log of dissociation constant of HBuffer.

pK= pH when the acid is half dissociated.

22
Q

What is H2CO3 and body pH proportional to?

A

H2CO3 is proportional to pCO2 because CO2 + H2O <> H2CO3

Qualitatively body pH is proportional to [HCO3-]/pCO2

23
Q

At what pH/pK will proteins (His residues), ammonia, phophates, bicarbonate, urate and citrate accept or donate hydrogens?

A 
Protein= 6
Ammonia= 9.2
Phosphate= 6.8
Bicarbonate= 6.1
Urate= 5.8
Citrate= 5.5
24
Q

What are the advantages of a bicarbonate buffer?

A
  • the addition of acid causes pCO2 to rise
  • this drives respiration which increases elimination of CO2 from the body
  • this makes the bicarbonate buffer very effective but it is still a short term measure because sooner or later it will run out of bicarbonate
25
Q

How is the total body pH controlled?

A
  • the kidney can reabsorb bicarbonate, the kidney can rid of the body of excess H+
  • normally urine pH is acid but can range from 4-4.8
  • pH of urine is reflected in the diet of an individual- alkaline urine if the person is vegetarian
  • total body pH is controlled by the kidney and lungs
  • kidneys deals with the bicarbonate ions and the lungs with pCO2
26
Q

Where in the kidney is bicarbonate reabsorbed?

A
  • bicarbonate does not bind to protein, it is freely filtered at the level of the renal corpuscle
  • it is reabsorbed at 3 segments: 80% in PCT, 10-15% in ascending loop of Henle and corticol collecting ducts (intercalated cells type A)

Reabsorbed by transporters present on the basolateral membrane which then passes into the interstitial fluid and then into the peritubular fluid.

27
Q

What does carbonic anhydrase isoform 2 do?

A

Is present in the tubular epithelial cells.

Speeds up formation of carbonic acid from carbon dioxide and water. These can dissociate to form bicarbonate and hydrogen ions.

28
Q

How are H+ secreted into the tubular lumen filtrate?

A

NaH+ countertransporters (NH3)
H+ATPase pumps, H+K+ATPase pumps

o If bicarbonate is in the tubular lumen filtrate and meets with hydrogen ion- will form carbonic acid- will form carbon dioxide which will passively diffuse into the membrane
o Water may use aquaporin channels
o Once inside the cell, water and CO2 can react- cascade of events- repeat

29
Q

Why secreted hydrogen is not excreted if HCO3- is in the lumen?

A

Body wants to reabsorb bicarbonate.

30
Q

What would happen if the pH of urine wasn’t buffered?

A

• If we didn’t buffer is the pH of urine would decrease to below 4 and transporters expressed on the luminal membrane would not be able to function

31
Q

How is hydrogen excreted?

A

• Occurs in combination with non-bicarbonate buffer e.g. monohydrogen phosphate (HPO42-)

  • Once all the bicarbonate in the filtrate has been reabsorbed, H+ will enter the filtrate and combine with monohydrogen phosphate forming dihydrogen phosphate which can be excreted
  • ‘hydrogen secretion- excretion’
  • Hydrogen excretion results in the addition of a new bicarbonate to the blood
32
Q

What additional mechanism adds new HCO3- to the plasma?

A
  • Involves the metabolism of glutamine- glutamine is freely filtered at the level of the renal corpuscle and is present in the filtrate and in peritubular blood
  • Glutamine enters inside cells either through glutamine amino acid exchanger LAT2 or Na-dependent co-transporters
  • Glutamine is metabolised in the tubule epithelial cells forming ammonium ions (NH4+) and HCO3- (goes to blood)
  • Ammonium ions can enter the filtrate due to the presence of Na-countertransporter and then gets excreted into the urine
  • NH4+ can be considered as NH3+ and H+
  • Free hydrogen has been buffered by the presence of ammonia
  • Ammonium can be excreted in the urine
33
Q

What are normal plasma values for PCO2 and arterial and venous HCO3?

A
  • Arterial pH= 7.4 (7.35-7.45)
  • Parterial CO2= 5.3 kPa (4.0-6.0kPa)
  • Arterial [HCO3]= 25Mm (19-24Mm)
  • Venous [HCO3]= 25Mm (22-28Mm)
  • Concentration of bicarbonate in venous blood is higher than arterial
34
Q

What types of acid-base disorders are there?

A
  • Acidosis pH <7.35
  • Alkalosis pH >7.45
  • Two forms of acid base disorders are respiratory and metabolic
  • Respiratory acidosis or alkalosis caused by a respiratory problem
  • Metabolic acidosis or alkalosis is caused by a non-respiratory problem
35
Q

How is acid-base status regulated?

A 
•	Chemical buffers 
o	Works in seconds
o	Bicarbonate in ECF
o	Phosphate in ICF
o	Phosphate or ammonia in urine
•	Brainstem respiratory centre
o	Works in minutes
o	Adjust ventilation to retain or expel CO2
•	Renal mechanisms
o	Works in hours to days
o	For each H+ secreted, HCO3 reabsorbed
36
Q

What is respiratory acidosis caused by?

A

Caused by insufficient CO2 excretion by the lungs (alveolar hypoventilation)

37
Q

What is acute respiratory acidosis?

A

ACUTE (PaCO2 > 5.3pKa; ph < 7.35)
o abrupt failure in ventilation
o bicarbonate concentrations are elevated but still within normal range
o Is a recent occurrence
o Caused by drug-induced respiratory depression e.g. narcotics, barbiturates
o Or Airway obstruction e.g asthma

38
Q

What is chronic respiratory acidosis?

A

CHRONIC (PaCO2 > 5.3kPa; ph < 7.35; HCO3 > 30Mm.
o Increase in bicarbonate concentration becomes detectable
o Secondary to many disorders- may be restrictive (small lungs) or obstructive (reduced airflow) respiratory disorders
o Airway obstruction e.g. chronic obstructive pulmonary disease
o Lung damage e.g. fibrosis- restrictive
o Chest wall disorders e.g. pectus carinatum- restrictive
o Neuromuscular disorder e.g. amyotrophic lateral sclerosis- restrictive
o NOTE- patient likely to be hypoxic (low PaO2) as well. Correction cannot come from a respiratory change.

39
Q

How is respiratory acidosis compensated for?

A
  1. Chemical buffers (works in seconds)
    • As we have alveolar hypoventilation- cannot expel the CO2
    • Action of physiochemical buffers as follows:
    • Some of the retained CO2 is converted to HCO3- by the reaction
    • CO2 + H2O = H2CO3 = H+ + HCO3-
    • Therefore plasma [HCO3-] increases
    • Overall result buffer attenuates arterial PCO2 increases (> 5.3kPa) and attenuates pH decreases
    • Decrease in PH and increase in bicarbonate
  2. Brainstem respiratory centre (works in minutes)
    • Adjust ventilation to expel CO2
    • However, ventilation an issue therefore correction cannot come from a respiratory change
  3. Renal mechanisms (works in hours to days)
    • For each H+ excreted, HCO3 reabsorbed
40
Q

What is the renal compensation for respiratory acidosis?

A
  • Body also gets rid of acid by metabolising glutamine and by combining acid with non-bicarbonate buffers
  • Overall generating an acidic urine pH=4.4
  • High plasma bicarbonate concentrations
  • Is called RENAL COMPENSATION FOR RESPIRATORY ACIDOSIS
41
Q

What is metabolic acidosis?

A

Metabolic acidosis pH < 7.35 characterised by a fall in plasma bicarbonate concentration.

42
Q

What are the general mechanisms for metabolic acidosis?

A
  • true HCO3 deficit
  • kidney- due to problems with bicarbonate reabsorption to damage of tubules (renal tubular acidosis)
  • gastrointestinal- bicarbonate
  • H+ gain
  • exogenous acid- NH4CL admin, toxins
  • abnormal lipid metabolism- diabetic ketoacidosis
  • abnormal carbohydrate metabolism- lactic acidosis
  • normal protein metabolism- uremic acidosis
43
Q

What are the compensations for metabolic acidosis?

A

1) Chemical buffer- in all cases the initial increase in blood H+ will cause [HCO3-] to fall and pCO2 to rise because of the reaction H+ + HCO3- = H2CO3 = H2O + CO2
Blood H= increases so pH decreases and this will lead to a reduction in [HCO3-]
2) Respiratory- increase in pCo2 increases ventilation
3) Renal compensation for (non-renal) metabolic acidosis- hydrogen ions secreted and as much bicarbonate reabsorbed as possible. More bicarbonate synthesised by glutamine metabolism.

44
Q

What is respiratory alkalosis caused by?

A
  • Caused by: excessive central respiratory drive (e.g. aspirin overdose, fever, brainstem damage) or hypoxic stimulation (e.g. response to altitude, hysterical hyperventilation, pulmonary embolism).
  • Excess CO2 is lost in lungs, PCO2 falls (<5.3 kPa; hypocapnia).
45
Q

What are the compensation mechanisms for low PCO2?

A

1) Chemical buffers:
[HCO3¯ ] decreases as some of it reacts with H+ to produce CO2 so both HCO3- and H+ decrease (pH rises).
H+ + HCO3¯ = H2CO3 = H2O + CO2
2) Respiratory compensation: (if possible) reduce ventilation.
3) Renal compensation:
• Kidneys respond to fall in pCO2 with reduction in H+ secretion into tubules.
• There is now insufficient H+ to ensure the reabsorption of all the HCO3¯ in filtrate, and HCO3¯ is excreted in the urine, which is alkaline (pH.7.4). The end result is pCO2 is still low, pH high and [HCO3¯ ] low, but changes smaller than they would otherwise be.
• Aspirin acidosis will cause respiratory acidosis and then cause metabolic acidosis

46
Q

Causes of metabolic alkalosis?

A

• Metabolic alkalosis characterised by pH>7.45 with high plasma [HCO3¯ ].
caused by:
i) repeated vomiting-loss of gastric acid or
ii) excess aldosterone –hyperaldosteronism stimulates tubule H+-ATPase pump (stimulate hydrogen secretion/ excretion) or
iii) excess alkali ingestion- bicarbonate or citrate/lactate which are metabolised to bicarbonate:

47
Q

Compensation mechanisms for metabolic alkalosis?

A
  1. Chemical buffers: There is an increase in plasma [HCO3¯ ], and an increase in pH, but there will not be a significant direct rise in PCO2 because the reaction below only needs to change the [H+] by a few nM….
    H+ + HCO3 = H2CO3 = H2O + CO2
  2. Ventilation: …before the rise in pH should inhibit respiration, causing CO2 to be retained in the body. However, the resulting hypoxia will continue to stimulate respiration.
  3. Renal: The kidneys should excrete excess bicarbonate.
    Either of these correction mechanisms should help to reduce the increase in pH.
  4. Renal compensation: type B intercalated cells of collecting duct function in metabolic alkalosis
    • Pendrin
48
Q

Responses to acidosis

A

1) Sufficient hydrogen ions are secreted to reabsorb all the filtered bicarbonate
2) Still more hydrogen ions are secreted, and this contributes new bicarbonate to the plasma as these hydrogen ions are excreted bound to non-bicarbonate buffers such as HPO42-
3) Tubular glutamine metabolism and ammonium excretion are enhanced, which also contributes new bicarbonate to the plasma
Net result- more new bicarbonate ions than usual are added to the blood, and plasma bicarbonate is increased, thereby compensating for the acidosis. The urine is highly acidic (lowest attainable pH= 4.4)

49
Q

Responses to alkalosis

A

1) Rate of hydrogen ion secretion is inadequate to reabsorb all the filtered bicarbonate, so significant amounts of bicarbonate are excreted in the urine and there is little or no excretion of hydrogen ions on nonbicarbonate urinary buffers
2) Tubular glutamine metabolism and ammonium excretion are decreased so that little or no new bicarbonate is contributed to the plasma from this source
Net result- plasma bicarbonate concentration is decreased, thereby compensating for the alkalosis. The urine is alkaline (pH >7.4)

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