Daily Acid Load

The daily acid load is constituted by ones diet, and is comprised primarily of foods
containing acid, and the production of acid as a result of metabolism. The intake of alkali
containing foods and the production of alkali as a result of metabolism offsets the daily acid
load but the net effect is daily addition of acid to the body that must
be buffered and excreted to maintain acid base balance.
There are 2 types of acids that can potentially contribute to the daily acid load;
carbonic or volatile acid(H2CO3) and noncarbonic or nonvolatile acids.
Carbonic acids
Metabolism of fats and carbohydrates result in the production of 15-20 mol of CO 2 per day.
Before elimination by the lungs, most of the CO2 is taken up by red blood cells, reacting with
H2O to form carbonic acid as shown below:
CO2 + H2O H2CO3(CA) H+ + HCO3where (CA) is the very important enzyme carbonic anhydrase.
Intracellularly, carbonic acid dissociates to form hydrogen and bicarbonate ions. The latter is
pumped out of the cell into plasma. At the alveoli, bicarbonate ions re-enter the RBC and
the above equation is driven to the left, re-producing CO 2 which is then eliminated by the
lung.
Under normal circumstances, CO2 produced via metabolism is primarily eliminated via
alveoli ventilation. Any increases in CO2 production is matched by an increase in alveolar
ventilation leading to a stable PCO2 level.

Nonvolatile Acids
Metabolism of amino acids,
producing HCL and H2SO4
Intake of acid containing foodssulphates, phosphates
Daily loss of alkali in feces
(minimal unless diarrhea)

Volatile Acids (H2CO3)

Metabolism of fats and
carbohydrates producing CO2

Noncarbonic acids
Noncarbonic acids on the other hand are primarily derived from the metabolism of proteins
and dietary intake of foods containing sulphates (H 2SO4) and phosphates (H2PO4-) and are
primarily responsible for the daily acid load that requires excretion by the kidneys.
A normal diet results in the generation of 50 -100 meq of H+ per day. Most of this comes
from the metabolism of sulphur containing amino acids such as cysteine and methionine
which yield sulphuric acid and from metabolism of lysine, arginine and histidine which yield
hydrochloric acid.
Ingestion of alkali containing foods (e.g. citrate), and metabolism of amino acids such as
aspartate and glutamate that lead to alkali production offset the daily acid load but the net
effect is daily acid addition.

Acid Buffering
One of the major ways in which large changes in H+ concentration are prevented is by
buffering. The body buffers which are primarily weak acids, are able to take up or release
H+ so that changes in the free H+ concentration are minimized. Buffers are located in the
extracellular fluid (ECF), intracellular fluid and bone.

Extracellular Buffers
The most important buffer in the ECF and the body is HCO3- (bicarbonate) which combines
with excess H+ ions to form carbonic acid.
Take for instance an acid load of H2SO4 produced via metabolism of methionine:
H2SO4 + 2NaHCO3 NA2SO4 + 2H2CO3 2CO2 + 2H2O + NA2SO4.
Note in this buffering reaction that bicarbonate reacts with a strong acid to form a weaker
acid(H2CO3) which then dissociates into CO2 and H2O. The CO2 produced here does not
reform H2CO3 because it is then excreted by the lungs. Note that HCO3- is used up in this
reaction. So that pH is not affected, the HCO3- used up in this process must be regenerated
and the NA2SO4 must be excreted by the kidneys.
The CO2/HCO3- buffer system is considered very effective because of the vast quantity of
bicarbonate in the body and the ability to excrete the CO2 formed via ventilation.
Other less important buffers in the ECF are plasma proteins and inorganic phosphates.

Intracellular Buffers
The primary intracellular buffers are proteins, organic and inorganic phosphates and in the
RBC, hemoglobin (HB-). Whereas buffering by plasma HCO3- occur almost immediately,
approximately 2-4 hours is required for buffering by cell buffers due to slow cell entry.
Hemoglobin is a very important buffer in RBCs, particularly in the role of carbonic acid
buffering.
It should also be noted that transcellular uptake of hydrogen ions by cells result in the
passage of Na+ and K+ ions out of cells to maintain electroneutrality. This process can
substantially affect potassium balance as will be discussed later.

Bone
Bone represents an important site of buffering acid load. An acid load, is associated with the
uptake of excess H+ ions by bone which occurs in exchange for surface Na+ and K+ and by
the dissolution of bone mineral, resulting in the release of buffer compounds, such as
NaHCO3, CaHCO3, and CaHPO4.

It has been estimated that at least 40% of the buffering of an acute acid load
takes place in bone. Chronic acidosis can have very adverse effects on bone
mineralization due to this process and can result in bone diseases such as rickets,
osteomalacia and osteopenia.

Renal Acid Excretion

The process of renal acid excretion is complex. In order to conceptualize this process, lets
consider the follow equation:
HCl + NaHCO3 NaCl + H2CO3 CO2 + H2O + NACl.
The above equation represents the process of buffering of the daily nonvolatile acid load.
Buffering minimizes the effect that strong acids such as HCl would have on the pH.
Nonetheless the pH will be affected if the bicarbonate lost in this process is not
regenerated, because as we will learn; loss of bicarbonate from the ECF lowers the
extracellular pH, leading to acidosis. One way to regenerate the lost bicarbonate would be
for the kidney to reverse the above equation, and excrete HCl in the urine as free H+ ions.
Unfortunately this would require a urine pH of 1.0, an impossible task since the minimum
attainable urine pH is 4.0 to 4.5.

In order to maintain acid base balance, the kidney must accomplish two tasks:
1) Reabsorption of all filtered bicarbonate
2) Excrete the daily acid load
The kidney achieves these three tasks effectively via the processes of hydrogen
secretion, bicarbonate reabsorption and excretion of hydrogen ions with urinary
buffers( titratable acids and ammonium) .

Hydrogen Ion Secretion

The kidney is responsible for excreting the nonvolatile acid load, which as previously
mentioned, is equivalent to about 50-100meq/L of hydrogen ions per day. Hydrogen ions
are buffered in the blood and are not filtered by the kidney as free ions. Hydrogen ions are
instead excreted in the urine via the process of hydrogen ion secretion. In the tubular
fluid, the secreted hydrogen ions combine with urinary buffers to be excreted astitratable
acids and ammonium or combine with filtered bicarbonate leading to bicarbonate
reabsorption.

Bicarbonate Reabsorption
The kidney filters approximately 4320 meq/day of HCO3- (24 meq/L 180L/day).
Under normal circumstances, the kidney is able to completely reabsorb all the
filtered bicarbonate. This is vitally important, since any loss of bicarbonate in the
urine would disturb acid base balance.
The process of bicarbonate reabsorption occur predominantly in the proximal tubule
(about 90%). The rest occur in the thick ascending limb and in the collecting tubule.
All involve hydrogen ion secretionas shown in the diagram below. To completely
reabsorb bicarbonate,the kidney must secrete 4320 meq/day of hydrogen ions in
addition to the amount required to exrete the daily acid load.

 The primary step in proximal hydrogen secretion is the secretion of H+ by the Na+ H+ antiporter in the luminal membrane. Hydrogen ions are generated by the
intracellular breakdown of H20 to OH- and H+.
Hydrogen ions secreted combine with filtered HCO3- ions to form carbonic acid and
then CO2 + H2O, which are then passively reabsorbed.
Technically, HCO3- ions reabsorbed in this process are not the same as the ones
filtered. Note that a new HCO3- ion is generated from the intracellular breakdown
of H20 to OH- and H+ and subsequent reaction of OH- with CO2 to form HCO3- .
This new bicarbonate then crosses the basolateral membrane via a Na+ - 3HCO3cotransporter.
The net effect is one mol of bicarbonate ion returned to systemic circulation for every
H+ ion that is secreted and reabsorption of virtually all filtered bicarbonate.
Similar processes occur in the thick ascending loop of Henle and intercalating cells
of the collecting duct. In contrast to the proximal tubule, hydrogen ion secretion in
the collecting tubule is mediated by aH+ ATPase pump in the luminal membrane
and a Cl-HCO3- exchanger in the basolateral membrane as shown in the diagram
above. The H+ ATPase pump is influenced by aldosterone, which stimulates
increased H+ secretion. Hydrogen ion secretion in the collecting tubule is the
process primarily responsible for acidification of the urine, particularly during
states of acidosis. The urine pH may fall as low as 4.0.
Proximal reabsorption of bicarbonate can be affected by many factors, in
particular, potassium balance, volume status and renin/angiotensin levels.

Therefore these factors can have very significant effects on acid base balance.
Their specific effects will be discussed later.

Urinary Buffering
The role of urinary buffering serves two purposes; to a) excrete the daily acid load and b)
regenerate bicarbonate lost during extracellular buffering. It is a process whereby seceted
hydrogen ions are buffered in the urine by combining with weak acids (titratable acidity) or
with NH3 (ammonia) to be excreted. It is a necessary process because the kidney cannot
easily excrete free hydrogen ions.

Titratable Acidity
The major titratable acid buffer is HPO42- . Other less important buffers are
creatinine and uric acid. In DKA, ketoanions also serve as a source of titratable acids.

Below is a diagram outlining this process.

Excretion of titratable acids is dependent on the quantity of phosphate filtered and

excreted by the kidneys, which is dependent on one's diet,and also PTH levels. As
such, the excretion of titratable acids is not regulated by acid base balance and
cannot be easily increased to excrete the daily acid load.Ammonium
production can however be regulated to respond to acid base status, as will be
discussed next.

Ammonium Excretion
With increased acid load, there is increased hydrogen ion secretion, causing the urine pH to
fall below 5.5. At this point, virtually all the urinary phosphate exist as H2PO4- and further
buffering cannot occur unless there is an increase in urinary phosphate excretion. As
mentioned previously, phosphate excretion is mainly dependent on dietary phosphate intake
and PTH levels and is not regulated in response to the need to maintain acid base balance.
Without further urinary buffering, adequate acid excretion cannot take place. The major
adaptation to an increased acid load is increased ammonium production and
excretion. The ability to excrete H+ ions as ammonium adds an important degree of
flexibility to renal acid base regulation, because the rate of NH4+ production and excretion
can be regulated in response to the acid base requirements of the body. Also of
importance is the role of ammonium production in the further generation of
bicarbonate ions.
The process of ammonium excretion takes place in 3 steps.
Ammonium Formation (ammoniagenesis) (proximal tubule)
Ammonium Reabsorption (Medullary Recycling)(thick ascending loop)
Ammonium Trapping (collecting tubule)

Ammoniagenesis
The process of ammoniagenesis occurs within proximal tubular cells. Glutamine made in
the liver, is received from peritubular capillaries and is metabolized into alpha-keto glutarate
and NH4+, in a reaction that involves the enzyme glutaminase.
The ammonium is secreted into the tubular lumen by substituting for H+ on the Na+ - H+
exchanger. In the tubular fluid, NH4+ circulates partly in equilibrium with NH3.
The alpha-ketoglutarate is metabolized further into two HCO3- ions, which then leave the
cell and enter systemic circulation by crossing the basolateral membrane.
Please note that the generation of new HCO3- ions is probably the most important
feature of this process.
This will be explained next.

Below is a diagram outlining Ammonium formation .

The Role of Ammonium Excretion

What happens next to ammonium is somewhat complex. So before continuing , let us reexamine the rational behind ammonium excretion.
Now remember; free hydrogen ions are not filtered by the kidney. Instead, they are secreted
into the tublar fluid. Because free hydrogens cannot be excreted in the urine easily, there
are excreted with weak acids such as H2PO4- which function as urinary buffers. Now in the
presence of an increased acid load, the phospate ions are used up and the kidney then
increases its production of ammonium .
Notice that ammonium, not ammonia is produced in the proximal tubule. Therefore you
might ask yourself, how does ammonium production increase hydrogen excretion if it
cannot bind to hydrogen ions secreted in the proximal tubular lumen?
The answer to this is somewhat controversial in the literature. Below is one school of
thought that has gained popularity.
As was mentioned previously, new bicarbonate ions are produced during ammoniagenesis.
The generation of new bicarbonate ions conceptually is akin to inceased hydrogen
excretion. Therefore the real function of ammoniagenesis is not as a urinary buffer of
hydrogen ions as is commonly inaccurately described. The real function of
ammoniagensis is to increase the generation of new bicarbonate ions.

For simplicity, this rational will be the basis of the remaining discussion on ammonium
excretion.
Ammonium before it is excreted is first re-absorbed in the thick ascending limb, circulated in
the medullary interstitium and then pumped back in the collected tubule as ammonia. In the
collecting tubule, ammonia then takes up hydrogen ions secreted into the lumen by
intercalated cells, to form ammonium.
Now the second question you might ask is why so many steps leading to the same result?
In order for ammoniagenesis to be effective in the generation of new HCO3-, the
NH4+ produced must be excreted in the urine. If NH4+ were to enter the circulation, it
would end up in the liver where metabolism would lead to the formation of urea as showed
in the following equation:
NH4+ + 2 HCO3- => urea + CO2 + 3 H2O
Notice that the formation of urea consumes 2 molecules of bicarbonate. Therefore, in
essence, the bicarbonate generated in the proximal tubule would be negated or cancelled
out, and ammoniagenesis would not increase net acid excretion.
As mentioned previously, NH4+ secreted in the proximal tubule is in equilibrium with a small
quantity of NH3. This NH3 is capable of diffusing out of the lumen into the peritubular
capillaries. If this were allowed to continually happen, a large quantity of ammonium would
be lost to the circulation and its metabolism in the liver would consume the HCO3generated.
This effect is minimized by having an acidic urine ph which keeps NH4+ in its protonated
form. However, the urine does not become maximally acidified until the collecting tubule
where secretion of hydrogen ions by intercalated cells significantly reduce the urine pH.
Therefore the kidney prevents loss of ammonium by reabsorbing NH4+ in the thick
ascending limb and pumping it into the collecting duct where the urine pH is very low,
facilitating ammonia in its protonated form. This process is enhanced during periods of
acidosis when hydrogen secretion by the intercalated cells is significantly increased .

Medullary Recycling and Ammonium Trapping.

After ammoniagenesis, ammonium is taken up into the medullary interstitium via a process called
medullary recycling. It is then pumped back into the tubular fluid at the level of the collecting duct,
where it undergoes what is called ammonium trapping after which it is excreted.
Below is an outline of this process.

1. Ammonium is first reabsorbed at the level of the thick ascending limb by substituting for K+
on the Na+ -K+ -2Cl- carrier.
2. The less acidic tubular cell then causes NH4+ to dissociate into NH3 and H+.
3. The luminal membrane in the thick ascending limb is impermeable to NH3 and thus NH3
cannot diffuse back into the lumen. It instead diffuses out into the medullary interstitium into
those compartments which have the lowest NH3 concentration, i.e. the S3 segment of the
proximal tubule and the medullary interstitium of the collecting tubule.
4. At the S3 segment of the proximal tubule, NH3 re-enters the lumen where it is protonated
back to NH4 and is again recycled back into the medullary interstitium via reabsorption at
the thick ascending limb. This leads to a high concentration of NH3 in the medullary
interstitium.
5. Because of the very low NH3 concentration in the collecting tubular fluid (as a result of
removal in the loop of Henle), and a maximally acidic urine pH in the collecting duct that
further reduces tubular NH3, there is a large gradient for NH3 secretion into the collecting
tubular lumen.
6. In contrast to the thick ascending limb, the tubular lumen is permeable to NH3 but not to
NH4. As a result, NH3 secretion into the collecting duct lumen leads to ammonium
trapping as NH4+ formed from the very acidic urine is unable to diffuse back into the cell.

7. NH4 is then excreted in the urine, usually with a Cl- anion.

Note that this process is primarily dependent on acidification of the urine in the
collecting tubule as a result of hydrogen secretion by intercalated cells.
In states of acidosis, where hydrogen secretion is significantly increased in the collecting
tubule, this process is greatly enhanced.
In states of alkalosis, the process is appropriately hindered as a result of the alkalemic urine.

Pumonary Acid Excretion

The main physiologic stimuli to respiration are an elevation in the PCO2 and a reduction in
the PO2 (hypoxemia). The CO2 stimulus to ventilation occurs in the chemosensitive areas
in the respiratory center in the brain stem, which responds to CO2 induced changes in the
cerebral interstitial pH. This effect is important in removing the 15 mol of CO2 produced
daily from metabolism of fats and carbohydrates, via alveolar ventilation. In acid base
disorders, the initial rise or fall in alveolar ventilation is mediated primarily by the peripheral
chemoreceptors in the carotid or aortic bodies, which immediately sense the change in pH.
Changes in PCO2 are sensed via central chemo-receptors as CSF ph is altered. In general,
PCO2 is regulated by alveolar ventilation. Hyperventilation (increase in alveolar ventilation)
enhances CO2 excretion and lowers the PCO2 while hypoventilation (reduction in
ventilation) reduces CO2 excretion and raises the PCO2.
The effects of acid base balance on alveolar ventilation and vice versa will be discussed in
more detail when specific acid base disorders are described.