case 7 - acid base balance and the kidney

Question 1

what is the regulation of plasma pH dominated by

Answer 1

Regulation is dominated by the HCO3-/CO2 buffering system

Question 2

what happens to H+ and CO3- in the kidney

Answer 2

H+ is excreted by the kidney and CO3- is retained by the kidney

Question 3

what decides the pH

Answer 3

CO2

Question 4

what is the Henderson Hasselbach equation

Answer 4

pH= pK+ (log)10 ([〖HCO〗_3^-]) / ([〖CO〗_2])

Question 5

what happens if there is respiratory acidosis

Answer 5

increased CO2

Question 6

what happens if there is metabolic acidosis

Answer 6

decreased HCO3-

Question 7

what happens if there is respiratory alkalosis

Answer 7

there is decreased CO2

Question 8

what happens if there is metabolic alkalosis

Answer 8

increased HCO3-

Question 9

what are the bicarbonate and carbon dioxide regulated by

Answer 9

Bicarbonate part of the equation regulated by the kidney and the carbon dioxide bit regulated by the respiratory system.

Question 10

what does the kidney have to do to maintain whole body acid base balance

Answer 10

a) excrete ~70 mmol H+ per day
b) reabsorb all the filtered HCO3- (equivalent to ~4,000 mmol H+ per day!!)

Question 11

renal epithelial can only secrete H+ to a concentration of what

Answer 11

*And, renal epithelia can only secrete H+ to a concentration of about pH 4.4 (i.e. a 1000-fold concentration gradient)

Question 12

what needs to happen to excreted H+

Answer 12

needs to be buffered

Question 13

where is H+ secreted

Answer 13

at the apical membrane

Question 14

what does this H+ do

Answer 14

it joins on to HC03- to form the CO2 and H20 and then that is brought into the cell

Question 15

where is HCO3- extruded

Answer 15

at the basolateral membrane

Question 16

what does the net transfer and extrusion of HCO3- involve

Answer 16

*Involves carbonic anhydrases II (intracellular) and IV (apical membrane)

Question 17

what are carbonic anhydrases

Answer 17

Zn-containing enzymes
At least 16 isoforms

Question 18

what do the carbonic anhydrases do

Answer 18

catalyse the reactions:
H20 <-> H+ + OH-
and
CO2 + OH- <-> HCO3-

Question 19

what are the two important isoforms of the kidney and where are they

Answer 19

CAII - soluble cytoplasmic
CAIV - extracellular, linked to the membrane (by GPI anchor)

Question 20

what is secreted H+ mostly buffered by

Answer 20

filtered phosphate in the lumen

Question 21

what is NH4+ synthesised by

Answer 21

the kidney

Question 22

what does NH4+ come from

Answer 22

glutamine metabolism

Question 23

what does the new HCO3- do

Answer 23

enters circulation and neutralises acidity

Question 24

what does the ammonium do

Answer 24

can also break down into hydrogen and ammonia and they are secreted and join back together to form ammonium

Question 25

where is most of the HCO3- reabsorbed

Answer 25

in the proximal convoluted tubule

Question 26

where is most of the NH4+ secreted

Answer 26

in the proximal tubule

Question 27

what happens to some of the NH4+

Answer 27

recycles in the medulla - Loop of Henle and contributes to hyperosmotic concentration that allows for water reabsorption

Question 28

where is NH4+ resecreted

Answer 28

in the collecting duct

Question 29

what is the summary of this part of the lecutre

Answer 29

Kidney reabsorbs all of the filtered HCO3-
*Excretes additional H+ as titratable acid (using filtered buffers) and NH4+ (synthesized)
*All achieved by apical H+ secretion via NHE3, V-type H+-ATPase and H+,K+-ATPase
*Basolateral HCO3- exit via kNBCe1 and AE2 replenishes plasma HCO3-
*Dependent on carbonic anhydrases II & IV

Question 30

when does renal tubule acidosis occur

Answer 30

when there are defects in HCO3- reabsorption and H+ excretion

Question 31

what are the four types of RTA

Answer 31

Type 1 - distal RTA
Type 2 - proximal RTA
Type 3 RTA (combination of type 1 and 2)
Type 4 - hyperkalaemia RTA (hypoaldosteronsim)

Question 32

what happens in HCO3- reabsorption in the early PCT

Answer 32

in exchange for sodium via the NHE3 transporter and via the H+-ATPase transporter

Question 33

what transporter dominates in more acidic environments

Answer 33

H+ ATPase

Question 34

what does the HCO3- leave via

Answer 34

the kNBCe1 transporter

Question 35

what transporter is dominant in the proximal tubule

Answer 35

the NHE3

Question 36

what is the difference between H+ ATPase and NHE3 transporters

Answer 36

Large capacity but limited gradient generation (down to pH 6-ish in the lumen)
V-type (vacuolar) H+ ATPase can generate a bigger gradient down to pH 4 or 5)

Question 37

what makes kNBCe1 electrogenic

Answer 37

1:3 stoichiometry

Question 38

what does this allows for

Answer 38

Allows HCO3- efflux from the cell because of extra drive from membrane potential;

Unusual to have Na+ leaving the cell on a cotransporter

Question 39

what happens in the thick ascending limb and distal tubule

Answer 39

H+ generated from Co2 + H20 (as usual)

Luminal CAIV less important (slower here)

No kNBe1 here, just AE2 for HCO3- exit at the basolateral membrane

Question 40

where is the main site of V-type H+ATPase activity

Answer 40

the alpha-intercalated cells of collecting tubule and duct cells

Question 41

what does it use

Answer 41

Uses H+, K+-ATPase as well (mainly to reabsorb K+)

Question 42

where in the alpha intercalated cells is V-type H+ATPase found

Answer 42

in the apical membrane of alpha intercalated cells

absent form principal cells

Question 43

what is the method of NH4+ secretion in the proximal tubule

Answer 43

leaves as NH3
And H+
NH4+ produced by glutamine metabolism
Makes new HCO3- as well

Question 44

what is NH4+ reabsorption via in the TAL

Answer 44

via ROMK2 chanel. And NKCC1 accepts NH4+ in place of K+
Low NH3 permeability at apical membrane, so it leaves across the basolateral membrane

Question 45

what is the NH4+ re secretion in the collecting duct

Answer 45

most crosses epithelium as NH3
Maybe some NH4+ is carried by Na+K+ATPase

Question 46

what is type one - distal renal tubular acidosis

Answer 46

*Defective H+ excretion by distal segment of nephron
*Inability to acidify urine – serious systemic consequences (Metabolic acidosis)
*May be incomplete (compensatory mechanisms of proximal tubule)

Question 47

what is used to treat type one

Answer 47

HCO3- supplementation

Question 48

what does the several transporter mutations mainly affect

Answer 48

the alpha intercalated cells:

kAE1
V-type H+-ATPase
CAII (proximal effects too)

Question 49

what is type 2 - proximal renal tubular acidosis

Answer 49

*Rare autosomal-recessive disease
*Impaired HCO3- reabsorption in proximal tubule
*Severe metabolic acidosis
*Not treatable by HCO3- supplementation (80% of bicarbonate is reabsorbed in PCT)

Question 50

what is type 2 attributed to

Answer 50

*Attributed to mutations in kNBCe1
*Ocular abnormalities too because of kNBCe1 and pNBCe1 expression there too

Question 51

what is respiratory and metabolic acidosis

Answer 51

*increased PCO2 (resp.) or decreased [HCO3-] (metab.)

Question 52

what do both of these directly stimulate

Answer 52

*both directly stimulate increased H+ secretion and increased NH4+ synthesis by proximal tubule

Question 53

what can chronic acidosis lead to

Answer 53

*chronic leads to increased expression of NHE3 and kNBCe1

Question 54

what is respiratory/metabolic alkalosis

Answer 54

opposite changes in proximal tubule
*chronic leads to more β-intercalated cells (HCO3- secreting) in collecting tubule

Question 55

what is the summary for this part of the lecture

Answer 55

kidney reabsorbs all of the filtered HCO3-
Excretes additional H+ as titratable acid (using filtered buffers) and NH4+ (synthesised)
All achieved by apical H+ secretion via NHE3, V-type H+ATPase and H+,K+ATPase
Basolateral HCO3- exit via kNBCe1 and AE2 replenishes plasma HC03-
Dependent on carbonic anhydrases II and IV