case 7 - acid base balance and the kidney Flashcards
what is the regulation of plasma pH dominated by
Regulation is dominated by the HCO3-/CO2 buffering system
what happens to H+ and CO3- in the kidney
H+ is excreted by the kidney and CO3- is retained by the kidney
what decides the pH
CO2
what is the Henderson Hasselbach equation
pH= pK+ (log)10 ([〖HCO〗_3^-]) / ([〖CO〗_2])
what happens if there is respiratory acidosis
increased CO2
what happens if there is metabolic acidosis
decreased HCO3-
what happens if there is respiratory alkalosis
there is decreased CO2
what happens if there is metabolic alkalosis
increased HCO3-
what are the bicarbonate and carbon dioxide regulated by
Bicarbonate part of the equation regulated by the kidney and the carbon dioxide bit regulated by the respiratory system.
what does the kidney have to do to maintain whole body acid base balance
a) excrete ~70 mmol H+ per day
b) reabsorb all the filtered HCO3- (equivalent to ~4,000 mmol H+ per day!!)
renal epithelial can only secrete H+ to a concentration of what
*And, renal epithelia can only secrete H+ to a concentration of about pH 4.4 (i.e. a 1000-fold concentration gradient)
what needs to happen to excreted H+
needs to be buffered
where is H+ secreted
at the apical membrane
what does this H+ do
it joins on to HC03- to form the CO2 and H20 and then that is brought into the cell
where is HCO3- extruded
at the basolateral membrane
what does the net transfer and extrusion of HCO3- involve
*Involves carbonic anhydrases II (intracellular) and IV (apical membrane)
what are carbonic anhydrases
Zn-containing enzymes
At least 16 isoforms
what do the carbonic anhydrases do
catalyse the reactions:
H20 <-> H+ + OH-
and
CO2 + OH- <-> HCO3-
what are the two important isoforms of the kidney and where are they
CAII - soluble cytoplasmic
CAIV - extracellular, linked to the membrane (by GPI anchor)
what is secreted H+ mostly buffered by
filtered phosphate in the lumen
what is NH4+ synthesised by
the kidney
what does NH4+ come from
glutamine metabolism
what does the new HCO3- do
enters circulation and neutralises acidity
what does the ammonium do
can also break down into hydrogen and ammonia and they are secreted and join back together to form ammonium
where is most of the HCO3- reabsorbed
in the proximal convoluted tubule
where is most of the NH4+ secreted
in the proximal tubule
what happens to some of the NH4+
recycles in the medulla - Loop of Henle and contributes to hyperosmotic concentration that allows for water reabsorption
where is NH4+ resecreted
in the collecting duct
what is the summary of this part of the lecutre
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
when does renal tubule acidosis occur
when there are defects in HCO3- reabsorption and H+ excretion
what are the four types of RTA
Type 1 - distal RTA
Type 2 - proximal RTA
Type 3 RTA (combination of type 1 and 2)
Type 4 - hyperkalaemia RTA (hypoaldosteronsim)
what happens in HCO3- reabsorption in the early PCT
in exchange for sodium via the NHE3 transporter and via the H+-ATPase transporter
what transporter dominates in more acidic environments
H+ ATPase
what does the HCO3- leave via
the kNBCe1 transporter
what transporter is dominant in the proximal tubule
the NHE3
what is the difference between H+ ATPase and NHE3 transporters
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)
what makes kNBCe1 electrogenic
1:3 stoichiometry
what does this allows for
Allows HCO3- efflux from the cell because of extra drive from membrane potential;
Unusual to have Na+ leaving the cell on a cotransporter
what happens in the thick ascending limb and distal tubule
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
where is the main site of V-type H+ATPase activity
the alpha-intercalated cells of collecting tubule and duct cells
what does it use
Uses H+, K+-ATPase as well (mainly to reabsorb K+)
where in the alpha intercalated cells is V-type H+ATPase found
in the apical membrane of alpha intercalated cells
absent form principal cells
what is the method of NH4+ secretion in the proximal tubule
leaves as NH3
And H+
NH4+ produced by glutamine metabolism
Makes new HCO3- as well
what is NH4+ reabsorption via in the TAL
via ROMK2 chanel. And NKCC1 accepts NH4+ in place of K+
Low NH3 permeability at apical membrane, so it leaves across the basolateral membrane
what is the NH4+ re secretion in the collecting duct
most crosses epithelium as NH3
Maybe some NH4+ is carried by Na+K+ATPase
what is type one - distal renal tubular acidosis
*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)
what is used to treat type one
HCO3- supplementation
what does the several transporter mutations mainly affect
the alpha intercalated cells:
kAE1
V-type H+-ATPase
CAII (proximal effects too)
what is type 2 - proximal renal tubular acidosis
*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)
what is type 2 attributed to
*Attributed to mutations in kNBCe1
*Ocular abnormalities too because of kNBCe1 and pNBCe1 expression there too
what is respiratory and metabolic acidosis
*increased PCO2 (resp.) or decreased [HCO3-] (metab.)
what do both of these directly stimulate
*both directly stimulate increased H+ secretion and increased NH4+ synthesis by proximal tubule
what can chronic acidosis lead to
*chronic leads to increased expression of NHE3 and kNBCe1
what is respiratory/metabolic alkalosis
opposite changes in proximal tubule
*chronic leads to more β-intercalated cells (HCO3- secreting) in collecting tubule
what is the summary for this part of the lecture
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
