RENAL REGULATION OF BICARBONATE
The kidneys regulate the [HC03-] by
1) conserving or excreting the HC03- present in the glomerular ultrafiltrate;
2) producing new HCO3- which enters the body fluids as the kidneys excrete ammonium salts and titratable acids (this sum is called net acid) in the urine
Renal Conservation of HCO3-
If urine pH < 6, the concentration of HC03- in the urine is very low (e.g.< 0.1 mEq/L). The glomerular ultrafiltrate has 24 mM. Thus, most HC03- filtered (4500 mEq/day) is reabsorbed, mostly (90%) along the proximal tubules.
Proximal tubule reabsorption of bicarbonate
Reabsorption: H+ secretion from cells across the luminal membrane is mostly in exchange for Na+ ions, and to a small extent ,through a proton ATPase. Secreted H+ react with filtered HC03- to form H2CO3. In the presence of carbonic anhydrase (type IV), luminal H2CO3 rapidly dehydrates to CO2 + H20. Drugs that inhibit carbonic anhydrase (e.g., acetazolamide) interfere with proximal reabsorption of NaHCO3 and induce a bicarbonate (osmotic) diuresis. Inside the cell, dissociation of H2O into OH- and H+ is promoted by hydroxylation of CO2 (OH- + CO2 => HCO3-) to generate bicarbonate, catalyzed by soluble (type II) carbonic anhydrase. H+ is exchanged for Na+ ions through a high capacity isoform (NHE3) of the Na-H exchange proteins. Bicarbonate exits the cell through the basolateral membrane in a 3:1 cotransport with Na+. The net result is that NaHC03 disappears from the lumen and appears in the blood-side of the proximal tubule cells.
Regulation: Proximal reabsorption HCO3- is stimulated by (1) decreases in cell pH (due to metabolic acidosis, respiratory acidosis or to decreases in cell K). Low cell pH acutely activates Na-H exchange and chronically induces expression of NHE3 and Na-3HCO3 cotransporters and (2) high levels of Angiotensin II stimulate Na-H exchange (e.g., contraction of the extracellular fluid ).
HC03 reabsorption in the collecting ducts
Reabsorption
(1) The amount of HCO3- reabsorbed are much smaller than in the PT.
(2) Reabsorption can be easily saturated by increases in HCO3- load (low Vmax).
(3) Can occur with larger transepithelial pH difference (4.5 -7.4) than in the proximal tubules (6.8 -7.4)
(4) Most is not mediated by luminal carbonic anhydrase.
(5) H+ secretion is mostly by luminal proton (and some by proton-K+) ATPases of alpha-intercalated cells
(6) Basolateral transport of HCO3- is via Cl- exchangers.
(7) Beta-intercalated cells secrete bicarbonate into the lumen and extrude H+ into the ECF.
Regulation: HC03 reabsorption in the CD is stimulated by the following:
(1) High concentration of H+ inside activate the H+ pumps in the cells (as in acidosis or K+ deficiency);
(2) In respiratory or metabolic acidosis, more proton pumps are inserted into the luminal membranes of alpha-intercalated cells.
(3) Low [H+] (i.e. at more alkaline pH) in the tubular fluid.
(4) Increase in the negativity of the tubular lumen (when Na+ reabsorption by principal cells is increased by aldosterone or when the load of slowly reabsorbed PO4-, SO4- or HCO3- increase).
(5) Aldosterone acts directly to increase H+ secreting pumps in alpha-intercalated cells.
Renal Production of HC03
The kidneys can generate (produce) new HC03- through (a) urinary excretion of ammonium (NH4+) salts and (b) urinary excretion of titratable acids.
NH4+ excretion
Renal production of ammonium. Glutamine enters proximal tubule cells from the peritubular capillary blood and from the filtrate. Within the cell, glutamine enters the mitochondria and is deamidated (by glutaminase I enzyme) and deaminated (by glutamic dehydrogenase). There result two molecules of NH4+ and one of divalent alpha-ketoglutarate anion. This anion is oxidized to 2 HCO3- + 4 C02 + H20. NH4+ is secreted into the lumen through the Na+-H+ (or NH4+) exchanger. Bicarbonate exits through basolateral cotransport with Na+. For each NH4+ excreted, one bicarbonate enters the ECF.
Excretion. Ammonium produced and secreted in cortical proximal tubules is transferred to the renal medullary interstitium and from there to the collecting ducts and into the urine. The TAL reabsorbs NH4+ via a luminal NH4+ - Na+ 2Cl- cotransporter, where it replaces some K+. NH4+ dissociates into NH3 (volatile) and H+. The gaseous NH3 diffuses to the medullary interstitium and to the descending limbs where the countercurrent system generates a corticomedullary NH3 (and NH4+) gradient . The NH3 diffuses from the medullary interstitium to the acid fluid in the collecting ducts where it reacts with H+ forming impermeant NH4+ which is excreted in the urine. The more acidic the tubular fluid, the faster and larger the NH3 transfer. Urine NH4+ (mEq/L) may be roughly estimated from the urine cation gap: urine [Na+] + [ K+] - [Cl] in mEq/L.
Regulation
In acute acidosis, increases in renal NH4+ excretion are due to rerouting of NH3 from renal venous blood to the urine due to a more acidic urine pH and sometimes, to increases in urine flow. In addition, an acid intracellular pH activates mitochondrial glutamine transport and metabolism (deamidation ) and oxidation of the resulting alpha-ketoglutarate.
In chronic metabolic acidosis, there is also induction, through genomic effects on an acid pHi, of basolateral and mitochondrial glutamine transporters, of glutaminase, and other enzymes that participate in the oxidation of glutamine. These adaptations to chronic acidosis allow large amounts of ammonium to be excreted at any urine pH, even at pH 7.
Excretion of titratable acid
The major buffer in urine is phosphate. At pH 7.4 as in the glomerular filtrate, only 20% of the phosphate is in the di-acid phosphate form (H2P04-) and 80% is in the monoacid form (HPO4=). In the proximal tubules, H+ secretion progressively decreases pH (to 6.8) and titrates up to 50% of the phosphate in the lumen to the diprotonated form (H2P04-). Luminal Na+ is reabsorbed in exchange for cell H+ and exits, together with HCO3- formed in the cell, across the basolateral membrane. For every proton secreted that titrates the phosphate in the lumen, there is generation of one molecule of bicarbonate that enters the circulation and helps restore the buffering capacity of the body.
H+ secretion in the collecting ducts, through luminal proton ATPases, can acidify the urinary fluid to pH < 6. At this pH practically all phosphate has been converted to the diprotonated form. Again, one HC03- is generated for each H+ secreted due to titration of the phosphate from the mono- to the di-protonated form. Diprotonated phosphates are excreted. Other buffers such as creatinine and b -hydroxybutyrate contribute little to TA excretion except when urine pH is < 5.
Regulation. The rate of urinary excretion of titratable acid depends on: a) the urine pH and b) the rate of excretion of buffers (phosphate, creatinine and b -hydroxyburyrate). In acidosis, titratable acid excretion is enhanced due mostly to the low urine pH and to a small increase in phosphate excretion (due to reduced reabsorption and loss of bone phosphate). b -hydroxybutyrate can contribute significantly (up to 30%) to the high rates (10 fold increment from 30 to 300 mmol/day) of titratable acid excretion observed in severe ketoacidosis when the urine pH reaches values as low as 4.5.
Quantities. The concentration of titratable acid (mEq/L) in the urine can be quantified by direct measurement or roughly estimated (with large probability of error, when urine pH < 6 and no alcohols are present in the urine) from the urinary osmolar anion gap (urine osmolarity minus the sum of urine urea (mM), glucose (mM, if present) and 2x Cl-(mEq/L) concentrations) divided by 2.
Net acid excretion. The sum of the NH4+ excretion and the titratable acids excreted (in milliequivalents) minus the bicarbonate (mEq) that might escape in the urine is called NET ACID EXCRETION and equals the milliequivalents of new bicarbonate produced (generated) by the kidneys to restore the buffer reserves of the body fluids.