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Renal Week 1 > Lecture 14: Acid-Base Buffering and Urinary Acidification > Flashcards

Lecture 14: Acid-Base Buffering and Urinary Acidification Flashcards

1
Q

What are the two sources of proton intake one get per day?

A
  1. Through the diet = 30 mmole of H+
    -absorb 20 mmole of H+ from food
    -secrete 10 mmole of OH- in gut
    -therefore, net 30 mmole of H+ in ECF
  2. Through metabolism (oxidation of carbs, fats and amino acids) = 40 mmole of H+ of nonvolatile acids
    Diet + nonvolatile acids = 70 mmole of H+ generated per day
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2
Q

How does one neutralize the H+ generated per day? Two methods:

A
  1. Kidney reabsorbs a net 70 mmole of HCO3- (filters 4320 mmole of HCO3-/day but reabsorbs 4390 mmole of HCO3- in the same day)
    Kidney also excretes 70 mmole of H+ per day
    -this compensates for the non-volatile acid production per day
  2. lungs expel CO2
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3
Q

What is a buffer?

A

A substance that reversibly accepts or release H+
Buffer minimizes the changes in free [H+] concentration (pH) upon addition of a strong acid or base

HA + B-  HBuffer + A-
Strong acid + Buffer = weak acid

Buffers = conjugate weak bases
Examples: HCO3-, NH3, HPO4^2-

When strong acid is added to a solution with one or more weak bases, the buffers accept almost all of the solution

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4
Q

What is total CO2?

A

HCO3- + dissolved CO2

Normal dissolved CO2 = 0.03 PCO2 (partial pressure of CO2)

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5
Q

What is the normal ECF pH?

A

7.38-7.42

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6
Q

What is the Henderson-hasselbalch equation?

A

pH = pKa + log (A-/HA) = 6.1 (pKa of HCO3-) + log (bicarb/pCO2*0.03)
0.03 is the dissociation constant

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7
Q

What types of buffers do we have in our body to ensure our ECF remains at narrow pH range?

A
  1. ECF buffers
  2. ICF buffers
  3. Bone
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8
Q

What are the types of ECF buffers?

A 
1. Bicarb/carbonic acid/CO2
H + HCO3-  H2CO3  H2O + CO2
And the scrubs
2. Plasma proteins
3. inorganic phosphate
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9
Q

In the H2O + CO2  H2CO3  H + HCO3-, what is the rate limitng step?

A

Hydration of CO2…H2O + CO2  H2CO3

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10
Q

Why is CO2 an acid in Bern’s opinion?

A

Because it turns into H2CO3 when it is hydrated

Although we already know CO2 is a Lewis Acid from an ochem point of view

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11
Q

What are types of ICF buffers?

A
  1. Hemoglobin (a buffer for RBCs)
  2. Proteins
  3. Inorganic phosphate
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12
Q

What are types of bone buffers?

A

Bone releases NaHCO3, KHCO3, CaCO3 and CaHPO4 in response to acid load
Accounts for up to 40% of acute acid/base buffering

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13
Q

What is the relationship between acidosis and bone?

A

When body is in a state of acute acidosis, the bone releases a shitload of buffers into the system to maintain body pH within normal range
Including NaHCO3, KHCO3, CaCO3 and CaHPO4
Leads to osteopenia because bone is dissolving

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14
Q

How do we apply the Henderson-hasselbalch equation to the body?

A

Use the equation:
H2O + CO2  H + HCO3

Thus, pH of body = pKa + log [HCO3]/[CO2]*0.03
Where [CO2] is determined by pCO2

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15
Q

What is the pKa of effective buffer systems?

A

Buffer pKa must be +/- 1 of system pKa

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16
Q

Why does HCO3- work as a buffer if its pka is not within range?

A

Because the independent regulation of pCO2 makes system able to buffer effectively

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17
Q

What is the value of an open system?

A

Allows body to expel more acid and maintain pH range within acceptable level
If in a closed system and too much acid was added to the body, your body would be fucked if you ran out of buffer. That’s why we can use our lungs to compensate for lack of buffer in our bodies in those types of situations

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18
Q

What is respiratory compensation?

A

When one hyperventilates to expel more CO2 and raise body pH back up to 7.4

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19
Q

What is the value of having multiple buffers and an open system for HCO3-/CO2?

A

Because a buffer has maximum buffering power at the pH that equals its pKA
-thus if you only have one buffer, you are only effective at one pH range
However if you have multiple buffers, you can have a constant buffering power if you include buffers with all different types of pKa’s

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20
Q

What are the volatile acids?

A

Example: CO2 because it evaporates at normal temperatures
End product of carb, fat, amino acid metabolism
200-300 mmole/kg is produced daily

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21
Q

What does volatility mean?

A

Volatile = substance that is easily evaporated at normal temperatures

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22
Q

What are the non-volatile (fixed) acids?

A

End products of metabolism:
i. inorganic acids (sulphuric acid and phosphoric acid)
ii. cationic amino acids
iii. organic acids from incomplete oxidation of CHO, fat
-lactic acid
-ketoacids (alpha hydroxylbutyric acid and acetoacetic acid)
iv. GI base loss
v. Oxidation of anionic amino acids and organic anions  base
Things that can’t escape into the atmosphere

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23
Q

What are the types of acid the body produces everyday?

A
  1. volatile acid = CO2

2. non-volatile acid = metabolic products like lactic acid and ketoacids

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24
Q

How does one defend against increased H+ input?

A
  1. Acidosis leads to suppression of endogenous organic acid production
    • less lactic acid and keto acids are produced
  2. Buffering
    • extracellular buffering = 1-2 hours
    • intracellular buffering = 6-8 hours
  3. Increased CO2 excretion (pulmonary hyperventilation)
  4. Renal H+ excretion (and new HCO3- generation)
    • occurs slowly, taking up 72 hours for full adaptation
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25
Q

How long does kidney take to adapt to acidosis?

A

Up to 72 hours for commensurate renal H+ excretion

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26
Q

What is the body’s fastest response mechanism to acidosis?

A

Distribution and buffering in the ECF

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27
Q

What’s the body’s slowest response mechanism to acidosis?

A

Renal acid excretion

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28
Q

Order in which body responds to acidosis:

A
  1. distribution and buffering in ECf
  2. intracellular buffering processes
  3. respiratory compensation (12 hours to complete)
  4. renal base excretion
  5. renal acid excretion
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29
Q

What is the difference between respiratory acidosis and metabolic acidosis?

A

Respiratory acidosis = addition of volatile acids = body will compensate through H+ excretion in kidney (metabolic compensation)
Metabolic acidosis = caused by addition of nonvolatile acids = body will compensate through pulmonary ventilation (respiratory compensation)

30
Q

What is the kidney’s role in acid-base regulation?

A

Kidney’s job to excrete protons, the anions of nonvolatile acids, and reabsorb filtered HCO3- and generate new HCO3-

31
Q

What is the fractional excretion of HCO3-?

A

<0.01%
Significant because kidney needs to reabsorb nearly ALL of the filtered HCO3-
Proximal tubule reabsorbs 80
TAL reabsorbs 10-15%
Remainder is absorbed in DCT and collecting duct

32
Q

Where does the generation of new HCO3 occur in nephron?

A

Both proximal and distal nephron

Moreso in proximal tubule

33
Q

What are the mechanisms of HCO3- generation in kidney?

A
  1. Hydroxylation of CO2, catalyzed by intracellular carbonic anhydrase-II
  2. H+ secretion
  3. HCO3- reabsorption
34
Q

What is the equation for urinary net acid excretion (NAE)?

A 
NAE = H + TA + NH4 – HCO3
H = negligible amount of acid excretion but is significant because that’s how we determine pH of urine
TA = present to make sure urine doesn’t drop to pH of 4
35
Q

What does TA stand for?

A

Titratable acid
Example: phosphate
HPO4 + H  H2PO4-

36
Q

What is an acceptable pH level for urine?

A

4.5

If urine is more acidic than 4-4.5, kidneys will not excrete it

37
Q

What is the relationship between ammonia/ammonium synthesis/excretion?

A

Under conditions of acidosis, body will upregulate ammonia synthesis and ammonium excretio

38
Q

How is HCO3- reabsorbed at the level of the proximal tubule?

A

It combines with H+ and turns into H2O and CO2 (by brush border carbonic anhydrase-4)
H2O and CO2 then diffuse across the lumen, where it is converted back to HCO3- by intracellular carbonic anhydrase

39
Q

Thus, is HCO3- absorbed directly in the kidney?

A

No it is not
It depends on the secretion of H+
More H+ secretion = more production of H2O and CO2 which will then diffuse into the cell and make HCO3-
To absorb 4320 mmol of bicarb, you need to secrete 4320 mmol of H+

40
Q

What are the channels in the proximal tubule that secrete H+?

A
  1. Na/H antiport

2. H+ ATPase

41
Q

What transports the HCO3- intracellularly into the blood, ie located on the basolateral membrane?

A
  1. Na:3HCO3- symporter

2. HCO3-/Cl- antiport

42
Q

How is bicarb reabsorbed in the distal tubule, particularly in the TAL?

A

Distal tubule has basolateral Cl/HCO3 exchanger (Cl going into cell, bicarb going into blood)
Distal tubule has K/bicarb symporter
Thus, bicarb is transported directly into the cell and then transported out by Cl/HCO3 exchanger

43
Q

What are factors that affect proximal tubule HCO3- reabsorption?

A
  1. Delivery of HCO3 = greater bicarb concentration = greater the reabsorption
    • even though this depends on H+ secretion, if you have high bicarb in filtrate, you react all the H+ in the lumen, thereby creating a gradient down which H+ can be secreted
    • depends on GFR and tubular flow rate
    • depends on plasma HCO3- concentration
  2. Blood pH and HCO3- concentration
    • high bicarb blood concentration = less active HCO3-/Cl antiport on proximal tubule basolateral membrane = higher intracellular pH = downregulation of Na/H exchanger and H+-ATPase
    • high pH = more active HCO3-/Cl antiport activity on basolateral membrane = lower intracellular pH = upregulation of Na/H exchanger and H+ ATPase (this was implied but not explicitly stated)
  3. Blood pCO2
    • increase in pCO2 = upregulation of basolateral membrane Na/HCO3 cotransport and apical membrane H+ secretion
  4. Carbonic anhydrase activity
  5. ECF volume status
    • angio II and catecholamines stimulate apical membrane Na/H exchanger
  6. Endothelin/catecholamines (alpha)
    • increased with acidosis
    • stimulates apical membrane Na/H exchange
  7. PTH
    • inhibits apical membrane Na/H exchanger
  8. Serum K
    • affects intracellular pH and proximal tubule ammoniagenesis
44
Q

What happens at the proximal tubule if there is low ECF K+, hypokalemia?

A

Low ECF K+ = more K efflux from inside of cells = cation void inside of the cells = more intake of H+ = lower intracellular pH
Lowering intracellular pH stimulates Na/H exchange and ammoniagenesis

45
Q

What happens at proximal tubule if there is high ECF K+, hyperkalemia?

A

Hyperkalemia = influx of K into cells (or leave at slower rate) = protons move out of the cell to balance K influx = higher intracellular pH
High intracellular pH downregulates ammoniagenesis

46
Q

What does intracellular acidosis do to ammonia production?

A

Upregulates it

47
Q

What does intracellular alkalosis do to ammonia production?

A

Downregulates it

48
Q

How does the proximal tubule generate new HCO3-?

A

Whenever one H+ is secreted into lumen, one bicarb is secreted into the blood
For generation of new bicarb for the blood, H+ is secreted in the lumen where it is taken up by a buffer that is NOT bicarb
-for instance, HPO42- as shown below
-the other buffer will complex with H+ and therefore drive more H’s to flow into the lumen
-for every H that flows into the lumen, there is one bicarb that flows into the blood

49
Q

How does the collecting duct reabsorb bicarb?

A

Does so through the Alpha-intercalated cells
Same process as in proximal tubule: H+ is secreted by the alpha-intercalated cells of collecting duct and bicarb is absorbed via H2O and CO2 diffusing into the cell
Remember, alpha absorbs acid (H+)

50
Q

How is H+ secreted in the alpha-intercalated cells of collecting tubule?

A
  1. H/K antiport

2. H+ ATPase

51
Q

How is HCO3- reabsorbed?

A

Through HCO3-/Cl- symporters on basolateral membrane

52
Q

How does the collecting duct generate HCO3-?

A

Does so in the alpha intercalating cells (because bicarb is reabsorbed)
Same way as proximal cells (proton secreted to lumen and bicarb absorbed in blood)

53
Q

What are the major factors affecting distal H+ secretion?

A
  1. Aldosterone
    • aldosterone stimulates Na reabsorption which hyperpolarizes apical membrane, thereby creating a greater gradient for H+ secretion by intercalated cells
    • aldosterone also directly stimulates intercalated cell H+ secretion via H+ATPase
    • also upregulates conductance of apical K channels (more potassium secretion) in principal cells
  2. Transepithelial voltage
    • lumen becomes more negative when aldosterone stimulates uptake of Na at principal cell because principal is impermeable to Cl-, leaving Cl- in the lumen
  3. Buffer availability
    • more buffer in the lumen = more H+ gets secreted
  4. Endothelin
    • activated during metabolic acidosis
    • increases aldosterone synthesis, stimulates Na/H exchange, H+ATPase activity and renal ammoniagenesis
54
Q

How is ammonia generated in the proximal tubule?

A
  1. Na/Glutamine symporter on both the apical and basolateral membranes brings glutamine into the proximal tubule cell
  2. glutamine is then converted into glutamate in the mitochondria
    -enzyme = glutaminase
    -produces one NH4+
  3. Glutamate is the converted into alpha ketoglutarate
    -enzyme = glutamate dehydrogenase
    -produces one NH4+
  4. NH4+ get secreted out to lumen, while the two HCO3- produced at the end are secreted into the blood
    Some of the NH4+ may leave as NH3 and a H+, though it will recombine to two NH4+ in lumen
    Most NH4+ go through via H+ transporters
55
Q

What is the net effect of glutamine metabolism in the proximal tubule?

A

2 NH4+ and 2 HCO3-

56
Q

What happens if NH4+ is not excreted into the urine and remains in the circulation?

A

NH4+ gets delivered to the liver where it is neutralized by HCO3-, thereby negating the HCO3- formed in ammoniagenesis

57
Q

What are the three sites of action for renal handling of ammonia?

A
  1. proximal tubule
  2. thick ascending limb
  3. collecting duct
58
Q

How does proximal tubule contribute to the renal handling of ammonia?

A

Ammonium/ammonia is secreted into the lumen of the proximal tubule by way of glutamine metabolism in the mitochondria (process described above)
2 NH4+ and 2 HCO3- are produced as a result

59
Q

How does the thick ascending limb contribute to the renal handling of ammonia?

A

It is here where the majority of NH4+ is reabsorbed into the interstitial fluid (medulla)
NH4+ flows to the medullary interstitium by way of the NKCC2…replaces K+ in the NKCC2
Significance: forms high concentration of NH3 and NH4+ in medullary interstitium
-this high concentration sets the stage for diffusion back into the lumen at a location downstream

60
Q

How does the collecting duct contribute to the renal handling of ammonia?

A

It is here where the high concentration of NH3 and H+ in the medullary interstitium is secreted into the lumen, thereby forming NH4+
NH3 and H+ are both permeable to collecting duct lumen
-once NH3 and H+ combine to form NH4+, it becomes trapped inside the lumen
Thus, the collecting duct is IMPERMEABLE to NH4+ outright, so it takes in H+ and NH3 instead

61
Q

What happens if collecting duct H+ secretion is impaired for any reason?

A

Then NH4+ excretion will be impaired because there will be no H+ to combine with NH3

62
Q

What happens if the NH4+ is not excreted?

A

It will go into the peritubular capillaries and travel to the liver, where it is converted to urea and consumes a bicarb in process

63
Q

What are the transporters in the collecting duct that allow the passage of NH3?

A

Rhesus glycoproteins:
i. Rhbg
ii. Rhcg
Located basolaterally

64
Q

What are Rhbg and Rhcg?

A

Rhesus glycoproteins
Function as ammonia transporters
Located basolaterally

65
Q

Can NH4+ be taken into the cells of the collecting ducts directly?

A

Yes through the Na/K ATPase (substituting for K)…

66
Q

What type of collecting duct cell has the rhesus glycoprotein transporters?

A

Alpha intercalated because these are the guys secreting acid

67
Q

How is NH3 pumped out from inside of collecting duct to lumen?

A

Can go through diffusion (thin grey lines)
Or
Through Rhcg

68
Q

How is H+ secreted into the lumen of the collecting ducts?

A
  1. H+ ATPase

2. H/K ATPase antiport

69
Q

What is the effect of urinary pH and acidosis on ammonia excretion?

A

The lower the pH, the higher the urinary excretion of NH4+

In chronic metabolic acidosis, the urines ability to excrete NH4+ goes up almost 10 fold

70
Q

What is the significance of ammoniagenesis?

A

Since the titratable acids (TA) remains pretty much constant even in the setting of a metabolic acidosis, the only thing that can be increased is the amount of NH4+ secreted
Thus, without ammoniagenesis, body has no way to secrete excess H+ in the setting of metabolic acidosis

Renal Week 1 (15 decks)

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