4th Pathophysiology Lecture

AB Balance-Pathophysiology:
Buffering systems and ventilation: both systems are active elements & they are emergency
mechanisms that can restore the AB balance in a short time BUT they dont eliminate H ions or
Bases in excess!
We have also other regulatory mechanisms like the chloride shift!

Carbonic acid and the equation of Henderson Hasselbalch for the pH- the bicarbonate system is
the most important buffering system- and this is in relation with all the other mechanisms of
regulation in AB balance!

Chloride Shift:

The phenomena in the erythrocytes are possible because of some particularities of the
erythrocytes. the erythrocyte have Carbonic anhydrase and that carbonic anhydrase stimulates
the reaction of carbonic acid and the equilibrium of this reaction could be moved to the right

with dissociation of the carbonic acid if the pressure of CO2 is increased because it will stimulate
the carbonic anhydrase.

Other particularity for the erythrocytes are related to their membrane permeability, their
membrane are permeable for Chloride and Bicarbonate and is not permeable for K and Na.
We know about erythrocytes that they are transporting O2 because of their Hemoglobin content
and they are moving from the lungs (where we have a hyper-ventilated tissue with high O2
pressure and low CO2 pressure) to the tissues and in the inverse way.
In the tissues we have low O2 pressure because in the tissues the O2 is consumed and high CO2
pressure because of the production of CO2 from the metabolism.

Whats happening with Hemoglobin transporting O2 from the lungs to the tissues?
The erythrocytes are charged with potassium oxyhemoglobinate which is the form of
oxygenated hemoglobin.
At the level of the tissues where the pressure of the O2 is decreased the erythrocyte will leave the
O2 and the K remains because hemoglobin will be combined with H ions from the carbonic acid
formed here in the cytoplasm of the erythrocytes.
We can have CO2 dissociated here because at the same time at the tissues level we have high
pressure of CO2 and CO2 is a diffuse-able gas classic to the membrane, arriving to the
cytoplasm of the erythrocytes, from CO2 in the water according to increase activity of the CO2
because this elevated pressure of CO2 carbonic acid is formed, and carbonic acid dissociates and
now H is available for reduced hemoglobin and bicarbonate can get out from the cell because

chloride is attracted by K and bicarbonate will arrive in the plasma re-establishing the
electrostatic equilibrium.
The same erythrocytes with reduced hemoglobin will go from the tissue coming to the lungswhere theres a high partial pressure of O2 and low partial pressure of CO2- now the equilibrium
of this reaction is not moved to the right now it will be moved to the left.
So here because of O2, Oxyhemoglonated potassium will be formed, again delivering the
chloride out of the cell exchanging with bicarbonate and the bicarbonate with H ions resulted
from the hemoglobin will form CO2- , the equilibrium of this reaction will be shifted to the left,
so we will have H2O and CO2, CO2 is a diffuse-able gas-will arrive out of the cell being exhaled
into the expiration so we can have an elimination of CO2.
As we see from this mechanism again we have the participation of the bicarbonate system and
we can notice an important feature of this regulatory mechanism we can notice that in fact the
erythrocytes could be considered as a producer of bicarbonate if there is enough CO2 pressure,
producer of the bicarbonate from plasma.

Another important regulatory mechanism in the AB balance is cellular, we know if there

is a high concentration of H ions in the extracellular space and this is happening in
acidosis so there is an exchange between H ions and K at the cellular level, the H ions
tends to enter in the cell and the K tends to go out, so usually the acidosis associate a
hyperkalemia and inverse when H ions concentration decrease we will have alkalosis.
There is a tendency of H ions to get out from the cell entering the K, so alkalosis usually
associates hypokalemia.

Another tissue do very important AB balance will be the bone, because of the exchanges
of K, Phosphate and carbonate release. Phosphate is an important buffer system in the
intracellular space and this is found especially in bone tissue and in the tubular-renal
tissue.

Discussing about the bone, we know that in acidosis condition there is an important delivery of
the calcium bicarbonate from the bone structure; because of this status of acidosis it takes a long
time so happen a di-mineralization of the bones.
-

And another important regulatory mechanism is the renal mechanism. Renal excretion
of H ions, but here in fact we have 3 mechanisms, the nephrocytes has this particularity
very important contains Carbonic Anhydrase.
And the regulation of AB in the nephrocytes is done by 3 processes:
1. Bicarbonate reabsorption

2. excretion of H ions as an ammonium salts

3. Excretion of H ions as titratable acid or as a conjugated phosphate.
These last 2 processes are the dominant at the distal tubules.

The active secretion of the H ions is also coupled with reabsorption of Na.
These 3 processes are dominant at the proximal tubules so we have a bicarbonate reabsorption
without excretion of salts or acids and in the distal tubules we have the other processes which are
predominant, the excretion of H ions as an ammonium salts and as a titratable acid acidity or as
Phosphates.
The nephrocytes have the anhydrase CO2 diffuses through the membrane arriving in the
nephrocytes; here we have capillary membrane of the nephrocytes / the tubular membrane / the
tubular liquid and the blood.
So CO2 and H2O combine with activity of Carbonic Anhydrase we have carbonic acid
formation with dissociation and this dissociation is more important if we have a high pressure of
CO2,.
So dissociation results in bicarbonate and H ions! H ions will be excreted in parallel with the
reabsorption of salts.
In the tubular fluid we have Na and this Na can be absorbed attracting this bicarbonate so this
bicarbonate is not lost, its reabsorbed in the tubular lumen, the H ions cannot remain alone so
with bicarbonate will form carbonic acid, here we dont have carbonic acid pressure elevated so
from carbonic acid the equilibrium of the reaction is moved to the left- we have H2O and CO2.
H2O will be eliminated into the urine and CO2 can enter back into the cell participating to
these processes.

So as we see in the proximal tubules excretion of H ions is under this form of water, the pH of
the urine is not acid yet because we have no acidification of the urine.
In the distal tubule the nephrocytes have anhydrase but they have also an enzyme they have
Glutaminase and from glutamine Glutaminase will deliver the ammonia, ammonia is a liposoluble molecule and could pass through the cellular membrane, so ammonia will arrive on the
other side of the cellular membrane, what could happen into the cell from CO2 and H2O because
we have carbonic anhydrase we will have carbonic acid which dissociates and H ions will be
excreted in parallel with reabsorption of Na because in the tubular fluid we have Na, chloride
and other ions which are filtered, so Na will be absorbed-economizing the bicarbonate- and H
ions is excreted but H ions on this site of the membrane could be combined with the ammonia
forming the ammonium ions, ammonium ions is not lip-soluble anymore and cannot go back into
the cell so ammonium ions with an anions which were combined with chloride can form an
ammonium salt like ammonium-chloride for instance.
So at this level of distal tubule we have H ions excretion as ammonium salts.

Another process which is predominant to the distal tubules is the excretion of H ions as
titratable acid! We have the buffer system of the phosphate / Na/ basic phosphates/ Bisodium-phosphate.
Again in the cell has the carbonic anhydrase and carbonic acid formation dissociation and
H ions will be excreted in parallel with 1 Na is reabsorbed attracting the bicarbonate.
**By definition, titratable acid is H+ excreted with urinary buffers. Inorganic phosphate
is the most important of these buffers because of its relatively high concentration in urine
and its ideal pK.

Now, whats happening in the tubular fluid?

H ions will be combined with the sodium phosphate- resulting sodium-acid-phosphate as we see
we have 1 H but because of this 1 we will have 2 H ions and 1 Na because: 1 Na is actually
absorbed and this is an acid which is titratable thats why the pH of the urine will be decreased
arriving to 5 for instance and this pH is measurable and is done because of this acid especially
because of ammonium salts.
So thats why we say that H ions excretion in the distal tubule is done especially by ammonium
salts formation and titratable acidity and thats why we say that because of the H ions excretion
in the distal tubules we have the acidification of the urine according to this titratable acidity.

Classification of the AB disturbances:

According to the pH value we classify the AB disturbance into 2 big groups:
Acidosis & Alkalosis
Acidosis is when the pH has the tendency to decrease and alkalosis when the pH has the
tendency to increase, if they are compensated the pH is steel in normal range.
If they compensated the pH is modified over the physiological ranges. Acidosis and Alkalosis
both of them could be metabolic and respiratory. We have to take a look at the equation of
Henderson hasselbalch.
Metabolic acidosis alkalosis is done by the primary modification to the bicarbonate which
modifies the ph.
A respiratory acidosis alkalosis is done because of the primary modification of the CO2modifying the ph. So lets take for instance metabolic acidosis means low pH or tendency for
lowering pH, this modification will be done decreased carbonate, carbonate could be decreased
by lost or by consumption in buffering in the referent process of H ions, because of the
compensatory mechanisms we can have also the CO2 modified the most important compensatory
mechanism in metabolic acidosis could be hyperventilation, CO2 pressure will have the tendency
to decrease in this way this ratio could be maintained in normal ranges and pH could maintained
in normal ranges so the metabolic acidosis will be compensated with hypocapnia, cannot say that
the metabolic acidosis compensated by respiratory alkalosis this is a non-sense, a disturbance
cannot be compensated by another disturbance, if we have different and opposite disturbances
we will have a mixed AB imbalance so we can have a simple AB disturbance like a metabolic
acidosis associating each compensatory mechanism it means compensatory hypocalcaemia or
we can have another situation to opposite disturbances, metabolic acidosis and respiratory
alkalosis, the differential diagnosis between these 2 situations metabolic acidosis with its
compensatory mechanism and 2 opposite metabolic acidosis and respiratory alkalosis is a bit
difficult to be done but is not impossible, so taking in account the investigation of AB balance
and other laboratory data we can establish if there are difference between those 2 situations and
the difference is very important for the therapy because if we dont make these differences we
can cut the physiological compensation or we can aggravate the next opposite AB balance if we
dont take in account that it is not an compensatory mechanism.
** Hypercapnia (a high concentration of carbon dioxide in the blood)
Metabolic alkalosis means increase recombinant primary modification with increase pH the CO2
because of the ventilatory compensation can be not efficient.
in metabolic alkalosis the compensation is very limited because hypoventilation will produce
compensatory hypercapnia, with hypercapnia over 55mmhg will see invader respiratory center

this is one of the reasons, and the other one is hypoventilation in metabolic alkalosis,
hypercapnia, hypercapnia means stimulation of carbonic anhydrase in the kidney and stimulation
excretion in fact of H ions so loss of acidity in condition of metabolic alkalosis, so these limit of
compensation is very important.
We discussed about buffering we discussed about ventilation modulation as compensatory
mechanism, they are rapid mechanisms in AB imbalances and they are efficient in short time
this advantage through this mechanism has no elimination of acid or basic excess, buffering,
elimination of CO2, cellular mechanisms can make some another repartition but they dont
eliminate H ions or basics. The kidney is the most efficient regulatory mechanism for the
elimination of H ions or economization of bicarbonate, the kidneys has also a disadvantage, the
efficacy of this mechanism occurs with a big latency 2-3 days, so this mechanism is not rapid is
efficient in long time.
The respiratory acidosis, will be done by the increase of CO2 in the tissue, for instance because
of the CO2 production or by the CO2 accumulation because of the hypoventilation, so we will
have a cellular mechanism for regulation, renal regulation, in the respiratory disturbance between
acute and chronic we can distinguish because the kidney is not efficient in acute the kidney will
be efficient in chronic respiratory disturbance so the bicarbonate will be modified, will be
increase for instance as a compensatory mechanism in a respiratory acidosis with increased CO2
in chronic respiratory acidosis. When the respiratory acidosis is in acute the bicarbonate will not
have time to be ingredit! because the kidney is not efficiently, in respiratory alkalosis we will
have decreased CO2 value because of hyperventilation and in acute the kidney is not efficient, in
chronic the respiratory alkalosis we will have a compensatory decreased bicarbonate. The simple
acid base imbalance is associating or not compensatory mechanisms and we can distinguish
between done and combined acid balance 2 of the opposite AB imbalance or they could be in the
same sense, for instance metabolic acidosis and respiratory acidosis or 2, 3 different metabolic
acidosis with 2, 3 different pathogenic mechanisms.
Metabolic acidosis, we distinguish 4 important mechanisms for metabolic acidosis, means
tendency for decreasing pH because of the decreased bicarbonate.
The 4 important mechanisms for decreasing pH:
1. Excessive production of acids- endogenous/exogenous- will over pass the capacity of
the excretion and metabolization and utilization of that. For instance lactic acidosis,
ketoacidosis and the complications of exogenous accumulation of acids could be done
by various intoxications, so we will have an acids in excess by endogenous
productions or by exogenous input, so if we have a high concentration of H ions this
situation will consume bicarbonate in buffering so thats why we have decreased
bicarbonate and metabolic acidosis,

2. Another situation with accumulation of H ions, decreased excretion of H ions, and

here we will discuss different 2 types of tubular acidosis, proximal and distal tubular
acidosis, and diuretic acidosis.
A decrease excretion of H ions so we will have an accumulation of H ions in internal
medium, and this high concentration of H ions will consume the bicarbonate in buffering.
3. The 3rd mechanism for metabolic acidosis will be done by renal loss of bicarbonate
and renal loss of bicarbonate is characterized for the proximal tubular acidosis, so the
bicarbonate is not consumed anymore because it is lost. Another pathway of loss is
the GI intestinal loss of bicarbonate, especially by diarrhea or by fistula. An example
of H ions accumulation, excessive production of H ions.
Lactic acidosis, (scheme about concerning the lactic acidosis), the tissues producing lactic acids
the most important are: skin, enteral tissue, brain, erythrocytes, the liver and the kidneys.
In the hepatic cells, we have the transformation in the cytoplasm, the transformation from
pyruvate to lactic and inverse according to the LDH-Lactic dehydrogenic ions- at this reaction
needs co-substrate functions in parallel with the reaction between NADH and NAD, and the
lactic acid production depends on the ratio of NADH/NAD and on the concentration of the
pyruvate. Pyruvate comes from the glucose oxidation, glycogenolysis, dissemination of iodine,
this reaction is reversible it is also mate the formation of iodine from pyruvate by animation!,
one pathway for pyruvate usage is transforming in lactic into the cytoplasm, but pyruvate also
can enter into the mitochondria and in the mitochondria there are 2 metabolic pathways, one is
the pathway of pyruvate carboxylation because of an enzyme pyruvate carboxylase using CO2
and another pathway is pyruvate dehydrogenation because of pyruvate dehydrogenase this is an
oxidation reaction needing O2, the result from the carboxylation is Oxaloacetate entering in
krebs cycle, and the result from pyruvate dehydrogenation is the Acetyl-CoA forming citrate and
from this entering in krebs cycle or generating ATP and the reaction of energy generation in
mitochondria are also in parallel with NADPH and NAD and the most important acceptor of
protons from NADPH is the O2, so we can make a relation with our last theme about postaggression status-shock status, and we always said that because of vasoconstriction we have
ischemia, we have hypoxia, and because of that we have lactigemia, and in the irreversible shock
status we have decompensated lactic acidosis. And lactic acid will be increased first because of
the increase of pyruvate, 2nd because of the increase of NADH/NAD ratio, both of them are
related to the O2, Pyruvate concentration is increased because it is not used any more in the
mitochondria, is decreased the dehydrogenation, is decreased the ATP formation because of the
lack of O2 NADPH,NAD also can be not transferred protons on O2 because there are no O2.
And in this case NADH/NAD ratio is increased-other reason for lactic increase, so we can make
a relation between the AB balance and the hypoxia-ischemia.
4. Another type of H ions accumulation consuming the bicarbonate, this accumulation is
done by a deficiency in H ions excretion, so its about tubular acidosis. So we can

discuss about proximal tubular acidosis we can describe some mechanisms affecting
the H ions excretion in the proximal tubule, this is the 2nd type because the tubular
acidosis could be classified into 4 types, the proximal tubular acidosis is in the 2nd
part, and the 1,3,4 are distal tubular acidosis with pathogenic mechanisms in these
processes in distal tubules concern the H ions excretion and a particular form of
tubular acidosis is the so called uretic acidosis occurring in the final stage of chronic
renal failure!.
Proximal tubular acidosis 2nd type, in proximal tubule the reabsorption of the bicarbonate is
mediated by the exchange H ions/Na, so the excretion of H ions in exchange with Na will attract
finally the reabsorption of bicarbonate-the economization of the bicarbonate- because in fact we
dont reabsorb anything from the tubule, we economize this bicarbonate not letting it to be lost.
The reabsorption of bicarbonate is attracted by the reabsorption of Na, the reabsorption of Na is
coupled in exchange with the excretion of H ions, and in the same time the reabsorption of Na is
related to the excretion of K according to the K/Na ATPase.
The types of mechanisms could be disturbed at this level of the proximal tubule which could
affect the H ions excretion and consequently H ions accumulation and lose of bicarbonate, so at
this level we cannot preserve anymore the bicarbonate.
The incubation of Na/k ATPase will impair the Na reabsorption, in this way the exchange with H
ions is not possible anymore, and in the same time the bicarbonate preservation, the bicarbonate
reabsorption cannot be attractive anymore because the Na is not reabsorbed, so the bicarbonate
will be lost, thats why we have metabolic acidosis with bicarbonatoneia and the pH of the urine
is not acid.
Another possibility that can affect the bicarbonate reabsorption is the hydrogenase proton trans
locating ATPase, so the H ions can be excreted because of the proton trans locating ATPase, if
there is a dysfunction of this pump the reabsorption of Na will be impaired and consecutively the
reabsorption of bicarbonate- so we will have bicarbonate lost.
Another possibility is the deficiency of the carbon anhydrase activity, so we will have no
bicarbonate and H ions exchanger so we have no excretion of H ions and we have no
reabsorption of bicarbonate. Usually this type of proximal tubular acidosis is always with
hypokalemia so we have also K lost because bicarbonate lost and Na lost at that level, so Na and
bicarbonate in the tubular fluid will stimulate the K secretion in the distal tubules so this type of
acidosis will be an exception from that rule which says that acidosis associates usually
hyperkalemia, and alkalosis usually associate hypokalemia here we have metabolic acidosis
bicarbonate lost without acid urine and hypokalemia because at the distal level there is a
stimulation of kalemia K secretion. So we can describe a proximal tubular acidosis by metabolic
acidosis with low bicarbonate because bicarbonate will buffer will be consumed with buffer of
the excess H ions but also we have bicarbonate lost in the urine in a bicarbotenia, and the pH of

the urine not acid, and this acidosis is associated usually with hypokalemia. This titricular
acidosis we can have different mechanisms for instance we can have a defect in the membrane
permeability and at this level the H ions excreted against the concentration gradient and because
of this defect of permeability the H ions excreted could come back to the cell and also into the
internal medium because of this gradient and this defect of permeability.
Another possibility is another defect of the proton trans locating ATPase at this level at the distal
level, so this proton trans locating ATPase will affect the H ions excretion and will affect the
ammonium salt formation and the titratable acidity formation, we had no bicarbonate lost, the K
secretion at the distal tubule is not affected, we have a decrease of the acid excretion and the
ammonium salt excretion but the pH of the urine is not so acid as we expect but the bicarbonate!
Expression is preserved.
The consequently of these tubular acidosis proximal or distal
In the proximal we have a loss of bicarbonate, this loss of bicarbonate will associate other
disturbances of reabsorption, will associate a many defects in reabsorption of glucose, phosphate,
aa. So the defect will be more complicated we have glucogneia!, aminosegnia!, phosphatemia, so
the patient lost more other important molecules and ions. Another characteristic is the
hypokalemia. There could be also other important consequences for both of proximal and distal
tubular acidosis, and these consequences are related to the bone possibility of AB regulation, in
this situation of H ions accumulation we will have a utilization! Of ca-carbonate in the bone, so
the consequence will be a tendency to buffer the acidosis but at the bone level we have
dimenralization resulting in the so called renal osterodystrophy!, this disturbance in the
dimenralization of the bone we have also associated a deficiency in vitamin D!, which related to
the dimenralization because of the hypophosphatemia and so we will have a hypocalcemia in this
context.
So the .. are not remaining at the level of the renal disturbances, the importance of these acidosis
are more extended.
The etiology of these acidosis
The 1st group is the group of Unknown causes they are idiopathic primary tubular acidosis
proximal or distal, in some cases they could be hereditary acidosis, and plasmids with inherited
defect for instance carbonic anhydrase deficiency, down.. syndrome, hereditary intolerance to
poptosis! With other defects of reabsorptions.
Secondary tubular acidosis which are associated with some diseases, Autoimmune diseases like
systemic erythematous, nephrotic syndrome, pulmonary fibrosis, some cases of chronic hepatitis
with autoimmune components, multiple myeloma which is not an autoimmune disease which
this associates with tubular acidosis or interstitial nephropathic which associate their evolution
with one type or more of tubular acidosis.

Diuretic acidosis, is the particular form of tubular acidosis, is the metabolic acidosis of urine in
the final stage of renal failure, it is but is not related with the diurea, in the final stage of
chronic renal failure we have also accumulation of urea and other types of azor-toxic! Products,
but the metabolic acidosis in this stage of chronic renal failure is related to the pathogenic
mechanism of chronic renal failure and it is related to the destruction of the nephrons, in the
early stages the destruction of the nephrons could be compensated by the remain nephrons which
will become hypertrophic and will become hyper-functional, every nephron will be over load
filtering more, secreting more, excreting more than normal but in the final stage of chronic renal
failure when the number of the remaining nephrons is very small, this small number of the
remaining nephrons cannot compensate anymore and the homeostasis will be disturbed, among
them-the disturbances- we have accumulation of toxic products from the metabolisms including
, urea, but we will have also metabolic acidosis but metabolic acidosis is not done by the urea
, the metabolic acidosis is done by this 3 processes which are impaired because of the nephrons
lost, nephrons destruction, so the bicarbonate reabsorption will be very decreased, the
ammonium salts production will be depressed and also the titratable acidity elimination could be
depressed, it was noticed that from these 3 processes, the most important affected which produce
in fact metabolic acidosis is ammonium salts production. In fact ammonium salts production is
the most effective regulatory mechanism in the kidneys for AB balance and in chronic renal
failure because of the nephrons destruction, this ammonium salts production and elimination is
very affected. So we will have decrease in H ions secretions, accumulation of H ions, metabolic
acidosis with consumption of bicarbonate buffers so the name of the urinic acidosis is related to
the last stage of chronic renal failure, the acidosis is not related to the urea.

The pathophysiological effects of the urinic acidosis will be discussed in the final stage of
chronic renal failure-renal osterodystrophy- , we have also pulmonary effect, metabolic effect,
protein metabolism and hemodynamic effects because of the acidosis, for instance in the protein
metabolism the accumulation of the acids, the H ions, will stimulate the endogenous protein
consumption will stimulate the protein metabolism, because of the protein catabolism we have
also relation with the lipids metabolism, the lipoproteins could be effected, associated to the
chronic renal failure we will have different sorts of disliproteinemia, hemodynamic effects
because of the metabolic acidosis we have depression of myocardial contractility, vasodilation
arterial territory so decreased arterial tension-hypotension, in the same time we have venule
constriction with non-repartition! Of the circulating blood, with tissue hypo-perfusion, in this
condition we have high sensitivity of the myocardium with a possibility of arrhythmia and
related to acidosis we have a disturbance in the electrolytes metabolism concerning the Ca,
concerning the bone which will be demineralized and we meet again the renal osteosim!, in the
chronic renal failure we have very clear the deficiency of vitamin D, because in the kidney we
have the last transformation of the vitamin D, so the vitamin D cannot become active and is not
effective/ed! In the Ca metabolism.