Renal Physiology-

Physiology-
Acid Base Balance

Dr Naim
 .
• Understanding by keeping in mind several
fundamental principles always viewing any
complexities of acid-base regulation through the
lens of these fundamentals.

• It is essential for the body to regulate the

concentration of free protons in the extracellular
fluid (ECF) to a value close to 40 nM (pH 7.4) in
order for proteins exposed to the ECF to function
properly. This regulation is called acid-base
balance.
 .
• The essence of acid-base balance comes down to 2
related processes:

• (1) Matching the excretion of acid/base

equivalents to their input, and

• (2) regulating the ratio of weak acids to their

conjugate bases in buffer systems.
 .

• Matching excretion to input keeps the body

content of these substances constant, ie, keeps the
body in balance.

• Regulating the ratio of weak acids to their

conjugate bases clamps the pH to a constant value
that is buffered; ie, is protected against rapid
changes in pH.
 .
• Excretion of “acid
“acid--base equivalents” is the job of
the kidneys.

• (What are acid-base equivalents ???)

• Balancing total-body input and output of acid or

base and

• regulating physiological buffer concentrations are

intimately related.
 1: Acids and Bases Obey the Balance
Principle

• One reason to emphasize the balance concept is

that, unlike substances such as sodium, there are
multiple routes for the entry of acids or bases,
including
• (1) processing of ingested food,
• (2) secretions of the gastrointestinal (GI) tract, and
• (3) de novo generation of acids and bases from
metabolism of stored fat and glycogen.
 .

• Although the body is sometimes transiently out of

balance for acids and bases, acid-base disturbances
DO NOT mean there is a persistent imbalance.

• In a prolonged metabolic acidosis, eg, there may be

a high input of acid and an equally high output.

• There is never a situation in which acid or base

pours into the body for an extended period of time
without being balanced by an equivalent output.
 .

• However, being in acid-base balance (ie, the same

input of acid as output) does not necessarily mean
that there are no changes in body chemistry.

• Input and output of hydrogen ion may be equal (in

balance) during metabolic disorders that produce
excess acid, but the balance comes about only
after there has been a significant change in blood
pH or bicarbonate concentration.
 2: Body Fluids Are Buffered

• Acids and bases that enter the body must be

excreted at the same rate to maintain balance.

• There is often a lag between input and output,

allowing a transient accumulation of acid or base.

• Buffer systems prevent large changes in pH when

these transient accumulations occur.
 .

• A buffer system consists of three substances that

have defined relations to each other according to
the equilibrium constant: a weak acid, its
conjugate base, and free protons.

• In such a system, the free aqueous concentration

of protons is only a trivial fraction of the
concentration of the acid and is determined by the
ratio of acid to its conjugate base.

Acid ↔ conjugate base + H1

 .

• At equilibrium, the concentration of free hydrogen

ions is determined by the ratio of the
concentrations of conjugate base to the weak acid
or in the more familiar pH form (the Henderson-
Hasselbalch equation)

• H2CO3 H+ + HCO3-
 .

• Buffer systems by themselves can only exert a kind

of delaying action and reduce the magnitude of pH
changes upon addition of acid/base equivalents.

• They DO NOT eliminate added acid or base

equivalents, but only AMELIORATE the effect of the
equivalents on blood pH.
 .

• In the face of persistent imbalance between input

and output, the acid form of the buffer or its
conjugate base is gradually consumed.

• Eventually acid or base equivalents added to the

body, even if associated with blood buffers, have
to be excreted by the kidneys to maintain balance.
 .

• For several reasons, the most important buffer

system in the body turns out to be the CO2–
bicarbonate buffer system.

• Fortunately, we can understand acid-base balance

by looking at this single buffer system alone and
ignore the others,
• BECAUSE

• all buffer systems must have ratios of weak acid to

conjugate base that result in the same pH.
• One thing that sets the CO2–bicarbonate buffer
.

system apart from other buffer systems is that the

concentrations of CO2
and bicarbonate are both physiologically
regulated, and they are regulated independently.

• And because their concentrations are regulated,

the ratio of their concentrations is regulated.

• As it is the ratio of weak acid to conjugate base

that sets pH, ----this system therefore regulates pH,
and that is the one of the goals of the regulation.
Derivation of the Henderson-
Henderson-Hasselbalch (H
(H--H)
Equation

• From: Ka = [H+][A ]/[HA],

• Solve for [H+],

[H+] = Ka [HA]/[A ]

• Take Negative log of each side:

–log [H+] = –log Ka – log([HA]/[A ])

• Convert to p scale: pH = pKa – log([HA]/[A ])
.

• Invert log: pH = pKa + log([A ]/[HA])

[proton acceptor]
• pH = pKa + log
[proton donor]
The Henderson-
Henderson-Hasselbalch (H
(H--H) Equation

The pH of a solution, and the concentration of an

acid and its conjugate base are related by the H-H
equation:
[A ]
pH = pKa + log
[HA]
• When the molar concentration of an acid (HA) and
its conjugate base (A ) are equal ([A ] = [HA]),
.

• [A ]/[HA] = 1;

• and log[A ]/[HA] = log 1 = 0

• So the pH of the solution simply equals the

pKa of the acid.

• When [A ] > [HA], pH > pKa.

• When [A ] < [HA], pH < pKa.
• EXAMPLE
.

• ACIDOSIS :

• pH < 7.4

• HCO3- < 20/1

H2CO3-

• ↓ HCO - = metabolic
3

• ↑ H2CO3- = respiratory
 .

• ALKALOSIS:

• pH > 7.4

HCO3- > 20/1

H2CO3-

• ↑ HCO3- = metabolic

↓
• H2CO3- = respiratory
 .

• In the CO2–bicarbonate buffer system, CO2 is not a

weak acid per se, but it acts like a weak acid
because when it combines with water it releases
protons.

• (CO2 is often called a volatile acid because it can

evaporate. All other acids, eg, sulfuric, lactic, are
called fixed acids.)
 .

• H+ + HCO-3 H2CO3 CO2 + H2O

CD CD

• Water is freely available.

 .

• The combination of CO2 with water forms carbonic

acid, which dissociates like any other weak acid
into a proton and its conjugate base, which is
bicarbonate.

• Considered this way, and given the ubiquitous

presence of water in our body, it is clear that
carbon dioxide is effectively an acid.
 .

• The concentration of carbonic acid in our blood is

miniscule (about 3 μmol/L), and at first glance it
appears that this system has little effective
buffering capacity.

• However, the supply of CO2 is effectively infinite,

so that any carbonic acid consumed in a reaction is
replaced by new generation from existing CO2.
 .

• Plasma CO2 level = 1.2 mmol/L

• Plasma HCO3 level = 25 mmol/L
• [HCO3]:[Co2] 20 : 01

• Carbonic acid concentration = 3 μmol/L

• Carbon dioxide production = 9 mmol/min.
• The normal pH range is 7.35 to 7.45
• The normal range of PCo2 is 35 to 45 mm Hg.
• The normal range of HCO3 is 22 to 26 mEq/liter
 .

Base Excess (BE)

• The base excess indicates the amount of excess or

insufficient level of bicarbonate in the system.

• The normal range is –2 to +2 mEq/liter.

• Remember: A negative base excess indicates a

base deficit in the blood.
 3: Input and Output of Acids Alter
Bicarbonate BUT NOT the Partial Pressure
of CO2
• Unlike the other buffer systems in the body,

where addition or loss of hydrogen ions changes

the concentration of the weak acid, in the CO2–
bicarbonate system,

the concentration of the weak acid (CO2) is

essentially constant !
 .

• This is because the partial pressure of arterial CO2

(Paco2) is regulated by our respiratory system to
be about 40 mm Hg.

• This partial pressure corresponds to a CO2

concentration in blood of 1.2 mmol/L.

• Any rise or fall in Pco2 resulting from the addition

or loss of hydrogen ions as depicted in Equation is
sensed by the respiratory centers in the brainstem
that alter the rate of ventilation to restore the
concentration.
 .

• There are times when the Pco2 differs from 40 mm

Hg, but this reflects activity of the respiratory
system, NOT a change in Pco2 in response to
addition or loss of hydrogen ions.

• Although adding or removing hydrogen ions from a

source other than CO2 does not change Pco2, such
changes do change the concentration of
bicarbonate. Eg….
• H+ + HCO-3 H2CO3 .

CO2 + H2O
CD CD

• Water is freely available.

•Adding hydrogen ions drives the reaction to the

right and reduces bicarbonate on a nearly mole-for-
mole basis.

•Removing hydrogen ions drives the reaction to the

left and raises bicarbonate in the same way.
 Any process that puts hydrogen ions into the
.

blood:

• Most of the hydrogen ions, combine with

bicarbonate (and other buffers to some extent).

• When the concentration of carbonic acid rises, the

carbonic acid dissociates into CO2 and water. The
CO2 formed in this manner mixes with metabolic
CO2 and is exhaled, thus restoring the
concentration of CO2 and carbonic acid to their
former values, but some bicarbonate has been
lost.
The Central Role of the Carbonic Acid-Bicarbonate
Buffer System in the Regulation of Plasma pH

Figure 27.11a
 .

• Therefore, when we add hydrogen ions by diet or

some physiological process,

we lose some bicarbonate but we do not change

the Pco2 or concentration of carbonic acid.
 .
Suppose we remove hydrogen ions::

• Example by adding strong base.

• CO2 and water combine to generate a hydrogen

ion (replacing the one lost) and a bicarbonate.

• The CO2 is supplied from the enormous store of

metabolic CO2. The Pco2 remains constant (if it
starts to change, then ventilation adjusts to restore
it).
The Central Role of the Carbonic Acid-Bicarbonate
Buffer System in the Regulation of Plasma pH

Figure 27.11b
 .

• We end up with a gain in bicarbonate and no

change in Pco2.

• Thus, addition or removal of hydrogen ion alters

total-body bicarbonate.

• The problem of maintaining hydrogen ion

balance becomes one of maintaining
bicarbonate balance.
• For every hydrogen ion added to the body,
.

one bicarbonate disappears;

therefore, to maintain balance it is necessary to

generate a new bicarbonate to replace the one
that was lost.

• Generation of new bicarbonate is the responsibility

of the kidneys.
 .

• We have established that CO2 is effectively an

acid. Let us be sure we understand why normal
metabolic production of CO2 does not keep
acidifying the body ???

• An enormous of amount of CO2 is generated from

metabolism each day. It is produced in our body at
a rate of about 9 mmol/min.

• However, it is eliminated at the same rate, so there

is no net addition.
 .

• As arterial blood flows into tissue capillaries the

majority of the CO2 entering the blood
immediately combines with water to form
hydrogen ions and bicarbonate, catalyzed by
carbonic acid in red blood cells.

• Most of the hydrogen ions then combine with non-

bicarbonate buffers (eg, hemoglobin), so the
change in pH is not great, although there is a small
decrease.

• The concentration of bicarbonate rises by about 1

mmol/L (from 24 to 25 mmol/L).
(Rises 1 mmol/L)
 .

• When this blood carrying the newly loaded CO2

(now venous blood) reaches the capillaries of the
lungs, the processes that occurred in the tissue
capillaries are reversed.

• Bicarbonate and hydrogen ions combine to

generate CO2 and water, and the CO2 diffuses into
the air spaces of the lungs.

• The pH rises a little, and the concentration of

bicarbonate falls by about 1 mmol/L (back to 24
mmol/L).
 4: Excretion of CO2 and Bicarbonate
Are Independent of Each Other
• Another situation that CONFUSES students, and
one that needs clarification immediately, is :

• that the input and output of CO2 and bicarbonate

are handled independently: (HOW ??)

• ONE CANNOT BE EXCRETED AS THE OTHER.

 .

• EXAMPLE

• If there is an excess generation of CO2

• eg, if there is a rise in metabolism not matched by

an increase in ventilation, the CO2 cannot be
converted to fixed acid and excreted by the
kidneys.

• Increased CO2 input MUST be BALANCED by

increased CO2 exhalation from the lungs.
 .

• SIMILARLY,

• if there is excess input of fixed acid, the body

CANNOT convert this acid to CO2 and excrete it
through the lungs.

• The reason is that every proton derived from a

fixed acid that combines with bicarbonate to form
CO2 REMOVES that bicarbonate and lowers its
concentration.
 .

• Although the CO2 is simply exhaled, the deficit in

bicarbonate remains.

• A continuous input of fixed acid would soon

reduce the bicarbonate concentration to zero.

• Thus, an input of fixed acid must be

balanced by renal output.
 Sources of Acids and Bases

Metabolism of Dietary Protein

• Although the oxidative metabolism of most

foodstuff is acid-base neutral, protein contains
some amino acids that contribute acid or base.

• When sulfur-(or phosphorus-) containing amino

acids and those with cationic side chains are
metabolized to CO2, water, and urea, the end
result is addition of fixed acid.
 .

• Similarly, the oxidative metabolism of amino acids

with anionic side chains adds base (consumes
hydrogen ions).

• Depending on whether a person’s diet is high in

either meat or fruit and vegetables, the net input
can be acid or base
 .

GI Secretions

• The GI tract, is lined with an epithelium that can

secrete hydrogen ions, bicarbonate, or a
combination.
• The major exocrine secretions of the pancreas and
liver contain large amounts of bicarbonate. The GI
use the CO2–bicarbonate system in an ingenious
way.
• When bicarbonate protons are generated from
CO2 and water in a given medium, the result is
always acidification, because the concentration of
protons rises.
Sodium bicarbonate secretion
by the pancreatic and billiary cells.
 .

• However, cells of the GI tract separate the protons

from the bicarbonate. They transport protons out
of the cell into one medium, and bicarbonate into
another

• Therefore, the lumen becomes acidified and the

surroundings (and the blood leaving the tissue)
becomes alkalinized

• In other regions of the GI tract the cells reverse the

direction of these processes, ie, they transport
bicarbonate into the lumen (alkalinizing it) and
protons into the surroundings.
Acid secretion from stomach.
 .

• Thus, different regions of the GI acidify and

alkalinize the blood.

• Normally, the sum of GI tract secretions is nearly

acid-base neutral (ie, the secretion of acid in one
site, eg, the stomach) is balanced by the secretion
of bicarbonate elsewhere (eg, the pancreas).

• Typically, there is a small net secretion of

bicarbonate into the lumen of the GI tract, resulting
in the addition of protons to the blood.
 Bicarbonate secretion
Parietal cells of • Cells of the gastric
gastric mucosa mucosa secrete H+
H+
ions into the lumen
lumen of
of the stomach in
stomach
exchange for the
HCO3- diffusion of
blood bicarbonate ions into
blood
Pancreatic
epithelial cells
• The direction of the
HCO3- diffusion of these
pancreatic ions is reversed in
H+
juice pancreatic epithelial
blood cells
58
 .

• However, in conditions of vomiting or diarrhea,

one kind of secretion may vastly exceed the other,
resulting in a major loss of acid or base to the
outside world complete with a major retention of
base or acid in the blood.
 .

Anaerobic Metabolism of Carbohydrate and Fat

• The normal oxidative metabolism of carbohydrate

and fat is acid-base neutral.

• Both carbohydrate (glucose) and triglycerides are

oxidized to CO2 and water.

• Although there are intermediates in the

metabolism (eg, pyruvate) that are acids or bases,
the sum of all the reactions is neutral.
 …

• However, the anaerobic metabolism of

carbohydrate produces a fixed acid (lactic acid).

• In conditions of poor tissue perfusion, this can be a

major acidifying factor, and the metabolism of
triglyceride to beta hydroxybutyrate and
acetoacetate also adds fixed acid (ketone bodies).

• These processes normally do not add much of an

acid load BUT can add a huge acid load in unusual
metabolic conditions (eg, diabetes).
 RENAL HANDLING OF ACIDS AND
BASES
• A simplified overview of the renal processing of
acids and bases is as follows:

• In the early part of the nephron (mostly proximal

tubule), the kidneys reabsorb the enormous
filtered load of bicarbonate (thereby resulting in
no addition or loss) from the plasma and,

• Under appropriate conditions, can secrete organic

bases or weak organic acids and acid equivalents.
 .

• Then, in the distal nephron (mostly the collecting

tubules),

the kidneys secrete either protons or bicarbonate

to balance the net input into the body

• THE FIRST TASK IS TO REABSORB FILTERED

BICARBONATE.

• Bicarbonate is freely filtered at the renal

corpuscles.
• How much is normally filtered per day?
.

• Given a typical plasma concentration of 24 mmol/L

and a glomerular filtration rate (GFR) of 180 L/day,
this amounts to 4320 mmol/day.

• Excretion of this bicarbonate would be equivalent

to adding more than 4 L of 1 N acid to the body

• It is essential, therefore, that virtually all the

filtered bicarbonate be reabsorbed or the body
fluids would become profoundly acidic.
FILTERED
BICARBONATE
• Thus, the reabsorption of bicarbonate is an
.

essential conservation process.

• Rather, the mechanism by which bicarbonate is

reabsorbed involves the tubular secretion of
hydrogen ions.

• An enormous amount of hydrogen ion secretion

occurs in the proximal tubule, and TAL of H, CD

• The collecting-duct cells that secrete hydrogen ion

are the Type A intercalated cells, not the principal
cells.
 Normal contributions of tubular segments to renal
.

hydrogen ion balance

• Proximal tubule
Reabsorbs most filtered bicarbonate (normally about
80%)*
• Thick ascending limb of Henle’s loop
Reabsorbs second largest fraction of filtered
bicarbonate (normally about 10–15%)*
• Distal convoluted tubule and collecting-duct system
Reabsorbs virtually all remaining filtered bicarbonate as
well as any secreted bicarbonate (Type A intercalated
cells)*
Produces titratable acid (Type A intercalated cells)*
Secretes bicarbonate (Type B intercalated cells)
 .

• The basic pattern followed in all these tubular

segments

• Within the cells, a hydrogen ion and a bicarbonate

are generated from CO2 and water, catalyzed by
carbonic anhydrase.

• The hydrogen ion is actively secreted into the

tubular lumen. For every hydrogen ion secreted,
one bicarbonate ion remains within the cell. The
cellular bicarbonate is transported across the
basolateral membrane into the interstitial fluid
and then into the peritubular capillary blood.
FILTERED
BICARBONATE
 .

• The net result is that, for every hydrogen ion

secreted into the lumen, a bicarbonate ion enters
the blood in the peritubular capillaries.

• There MUST be a 1-for-1 match between hydrogen

ions secreted and bicarbonate ions transported
into the interstitium.

• Once in the tubular lumen, the secreted hydrogen

ion combines with a filtered bicarbonate to form
water and carbon dioxide, which diffuse into the
cell.
 .

• The hydrogen ion is secreted across the apical

membrane to combine with another luminal
bicarbonate and the cellular bicarbonate leaves
the cell across the basolateral membrane to enter
the plasma.

• The overall result is that the bicarbonate filtered

from the blood at the renal corpuscle has
disappeared, replaced by the bicarbonate that
reenters the plasma from inside the cell.
FILTERED
BICARBONATE
 .

• Thus, no net change in plasma bicarbonate

concentration has occurred as all bicarbonate
filtered has combined with secreted hydrogen ion
and subsequently ended up first inside the cell and
then in plasma.

• It may seem inaccurate to refer to this process as

bicarbonate reabsorption because the bicarbonate
that appears in the peritubular capillary is not the
“SAME” bicarbonate that was filtered.
 .

• It is also important to note that the hydrogen ion

that was secreted into the lumen is Not excreted in
the urine.

• IT HAS BEEN INCORPORATED INTO WATER.

• Any secreted hydrogen ion that combines with

bicarbonate in the lumen to cause bicarbonate
reabsorption does not contribute to the urinary
excretion of hydrogen ions but only to the
conservation of bicarbonate.
 RENAL EXCRETION OF ACID AND BASE

• When base has been added to the body fluids, the

effect is to increase the plasma concentration of
bicarbonate.

• The body fluids contain more bicarbonate. The

renal handling of such base loads is relatively
straightforward:

• ”We excrete enough bicarbonate in the urine to

match the input”.
 .

• The kidneys do this in 2 ways:

• (1) allow some filtered bicarbonate to pass through
to the urine and
• (2) secrete bicarbonate via Type B intercalated cells.

• The Type B intercalated cells, which are found only

in the cortical collecting duct, do indeed secrete
bicarbonate.

• “flipped-around” cells type A and type B

.
.
.
 .

• Thus, the overall process achieves the

disappearance of excess plasma bicarbonate and

• the appearance of bicarbonate in the urine, with

resulting acidification of the plasma and

alkalinization of the urine and---------

maintenance of bicarbonate balance.

 .

• How do the kidneys excrete an acid load?

• For all individuals who ingest animal protein of any

kind, excretion of excess acid is more typical than
the production and removal of excess base.

• This is a more complex process than excretion of

base, but it obeys the principles discussed earlier.

• Recall that the net result of addition of acid to the

body reduces the amount of bicarbonate on an
almost mole-for-mole basis.
 .

• Therefore, the task for the kidney is to replace the

lost bicarbonate by generating NEW bicarbonate
from CO2 and water

• (Being careful to EXCRETE the hydrogen

ion that is created at the same time).
Buffering of Secreted H+ by Filtered phosphate
(NaHPO4-) and Generation of “New” HCO3-

“New” HCO3-
.
 .

• In essence, the process is as follows: Hydrogen

ions and bicarbonate are produced from carbon
dioxide and water within cells.

• Hydrogen ions are secreted and combine with the

conjugate base of buffers in the tubular lumen
other than bicarbonate, thereby generating the
acid form of the buffer.
• The acid form of that buffer is excreted in the
.

urine. The process of producing and secreting

hydrogen ions generated new bicarbonate that
goes into the blood and replaces the bicarbonate
lost when the acid load entered the body.

• The key is generation of new bicarbonate to

replace the bicarbonate that was lost.

• If we just reabsorb filtered bicarbonate, nothing is

changed.

• We must generate “new bicarbonate”.

Buffering of Secreted H+ by Filtered phosphate
(NaHPO4-) and Generation of “New” HCO3-

“New” HCO3-
 .
• Rate of tubular H+ secretion is about
4400mEq/day

• Rate of filtration of Bicarbonate is 4320mEq/day

 HYDROGEN ION EXCRETION ON
URINARY BUFFERS
• The identical transport process of hydrogen ion
secretion can also achieve acid excretion and
addition of new bicarbonate to the blood.

• At first glance, this seems like a contradiction: How

can the same process produce 2 different end
results?

• The answers lies in the fate of the hydrogen ion

once it is in the lumen.
 .

• If the secreted hydrogen ion combines with

bicarbonate, then we are simply replacing
bicarbonate that would have left the body.

• In contrast, if the secreted hydrogen ion combines

with a non-bicarbonate buffer in the lumen (or, to
an extremely small degree, remains free in
solution), the hydrogen ion is excreted.

• The bicarbonate produced in the cell and

transported across the basolateral membrane is
new bicarbonate, not a replacement for existing
bicarbonate.
 .

There are two sources of tubular non-

bicarbonate buffers: filtration and synthesis.

• Normally, the most important of the filtered

buffers is phosphate, while ammonia is the most
important synthesized buffer.

• Ammoniagenesis is crucial to renal acid excretion

because its rate can be greatly increased in the
face of large acid loads, WHEREAS the availability
of filtered buffers, while somewhat variable, is not
regulated for purposes of acid excretion.
Buffering of Secreted H+ by Filtered phosphate
(NaHPO4-) and Generation of “New” HCO3-

“New” HCO3-
 .

• Point of emphasis:

• That the renal contribution of new bicarbonate to

the blood is accompanied by the excretion of an
equivalent amount of buffered hydrogen ion in the
urine.

• In this case, in contrast to the reabsorption of

bicarbonate, the secreted hydrogen ion remains in
the tubular fluid, trapped there by the buffer, and is
excreted in the urine.
 .

• This should reinforce the concept that bicarbonate

can always be generated from CO2 and water, but
to add this new bicarbonate to the blood (and
alkalinize the blood), the kidneys MUST separate
the hydrogen ion from the bicarbonate and excrete
the hydrogen ion that is created at the same time.

• It must be emphasized also that neither filtration

per se nor excretion of free hydrogen ions make a
significant contribution to hydrogen ion excretion.
 .

• First, the filtered load of free hydrogen ions, when

the plasma pH is 7.4 (40 nM/H+), is less than 0.1
mmol/day.

• Second, there is a minimum urinary pH—

approximately 4.4—that can be achieved.

This corresponds to a free hydrogen ion

concentration of 0.04 mmol/L.
 .
• With a typical daily urine output of 1.5 L, the
excretion of free hydrogen ions is only 0.06
mmol/day, a tiny fraction of the normal 50–100
mmol of hydrogen ion ingested or produced every
day.

• To excrete these additional amounts of protons,

they must associate with tubular buffers.
 PHOSPHATE AND ORGANIC ACIDS AS
BUFFERS
• Filtered phosphate is normally the most important
non-bicarbonate urinary buffer. Most free plasma
phosphate exists in a mixture of monovalent and
divalent forms.

• Monovalent dihydrogen phosphate (on the left) is

a weak acid, and divalent monohydrogen
phosphate (on the right) is its conjugate base.

• H2PO4 - H+ + HPO4 --
 .

• At the normal pH of plasma (7.4) and, therefore, of

the glomerular filtrate, about 80% of the
phosphate is in the base (divalent) form and 20% is
in the acid (monovalent) form.

• Thus the ratio 4:1 (base / acid)

• As the tubular fluid is acidified in the collecting

ducts, most of the base form combines with
secreted hydrogen ions.
Buffering of Secreted H+ by Filtered phosphate
(NaHPO4-) and Generation of “New” HCO3-

“New” HCO3-
 .

• By the time the minimum intratubular pH of 4.4 is

reached, virtually all the base (HPO4 --) has been
converted to acid (H2PO4 -).

• Therefore, secreted hydrogen ions that combined

with the base form are excreted, and the
bicarbonate that was generated intracellularly in
the process enters the blood.
 .

• How much phosphate is available for this process?

• The amount is somewhat variable, depending on a

number of factors, but a typical plasma
concentration is about 1 mmol/L, of which about
90% is free (the rest being loosely bound to plasma
proteins).

• At a GFR of 180 L/day, the total filtered load of

phosphate is about 160 mmol/day. The fraction
reabsorbed is also variable: from 75% to 90%.
 .

• Thus, unreabsorbed divalent phosphate available

for buffering is roughly 40 mmol/day.

• In other words, the kidneys can excrete hydrogen

ions, using the phosphate buffer system, at a rate
of about 40 mmol/day. (Normally 50–100 mmol of
hydrogen ion ingested or produced every day).

• However, the availability of phosphate cannot be

easily upregulated to increase acid excretion.

• So what to do with the rest of H+ load ????

Buffering of Secreted H+ by Filtered phosphate
(NaHPO4-) and Generation of “New” HCO3-

40mmol
“New” HCO3- per day
 HYDROGEN ION EXCRETION ON
AMMONIUM

• Ordinarily, hydrogen ion excretion associated with

phosphate and other filtered buffers is no greater
than about 40 mmol/day.

• This amount is not sufficient to balance the normal

hydrogen ion production of 50–100 mmol/day or
take care of any unusually high (usually
pathological) production of acid loads.
 .

• To excrete the rest of the hydrogen ion and achieve

balance, there is a second means of excreting
hydrogen ions that involves ammoniagenesis and
excretion of hydrogen ions as ammonium.

• Quantitatively, far more hydrogen ions can be

excreted by means of ammonium than via organic
buffers.
 .

• The catabolism of protein and oxidation of the

constituent amino acids by the liver generates
CO2, water, urea, and some glutamine.

• Processing of the carboxyl group of the amino acid

produces a bicarbonate, and

• Processing of the amino group produces an

ammonium ion.

• Ammonium is further processed by the liver to

either urea or glutamine due to its toxicity
 .

• Although the production of glutamine by the liver

is acid-base neutral, it is important to recognize
that glutamine can be thought to contain 2
components: a base component (bicarbonate) and
an acid component (ammonium).

• NH4+ ↔ H+ + NH3.. pK of ammonium near 9.2.

• At physiological pH over 98% of the total exists as

ammonium, For renal acid-base purposes, this is a
good because virtually all excreted ammonia is in
the protonated form and takes a hydrogen ion
with it.
 Acidification of urine by excretion of ammonia

108
Production and Secretion of NH4+ and HCO3- by
Proximal, Thick Loop of Henle,
Henle, and Distal
Tubules

H++NH3

“New” HCO3-
ACIDIFICATION OF URINE BY EXCRETION OF AMMONIA
Capillary Distal Tubule Cells

NH2

NH
NH3 3 H+
WHAT
HAPPENS
NEXT?
Tubular urine to
be excreted

110
 ACIDIFICATION OF URINE BY EXCRETION OF AMMONIA
Capillary Distal Tubule Cells Notice the
H+ - Na+
NH3 exchange to
maintain
electrical
neutrality
Dissociation of
carbonic acid
NaNaCl
+ + Cl-
H23CO
HCO - + H+
3

NaHCO3
NH3Cl-
NH4Cl
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111
 ACIDIFICATION OF URINE BY EXCRETION OF AMMONIA
Capillary Distal Tubule Cells Notice the
H+ - Na+
NH3 exchange to
maintain
electrical
neutrality

NaNaCl
+ + Cl-
H23CO
HCO - + H+
3

NaHCO3
NH3Cl-
NH4Cl
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See
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112
Kidney tubules and pH Regulation

Figure 27.10a, b
Control of rate of tubular secretion & H+
reabsorption
 .

• It is interesting to note that while protein

metabolism is a major source of excess total body
hydrogen ions, protein metabolism also produces
excess nitrogen as ammonia.

• By excreting ammonium, the kidney is removing

both the excess ammonia nitrogen and excess
hydrogen ion.
 REGULATION OF THE RENAL
HANDLING OF ACIDS AND BASES

• The regulatory signal that determine the

magnitude of hydrogen ion excretion ( = the
production of new bicarbonate)

is the concentration of free hydrogen ion in the

fluids to which the various transport elements are
exposed, ie the pH of the ECF and cytosol within
renal cells.
 .

• In effect, the kidneys act as “pH meters” and

adjust their transport of hydrogen ion and
ammonium excretion accordingly.

• When we have the more common case of a small

acid load,
- additional hydrogen ions will be secreted that
titrate buffers in the tubular lumen (titratable acid)
- and produce some excreted ammonium,
thereby returning new bicarbonate to the blood.
 .

• During alkalosis, tubular secretion of hydrogen ion

should be too low to completely reabsorb the
filtered bicarbonate.

• Then bicarbonate can be lost in the urine; no

titratable acid is formed because no extra secreted
hydrogen ions are available to combine with non-
bicarbonate buffers, and so no new bicarbonate is
contributed to the blood.
H+
secretion
should be
LOW
 .

• During acidosis, tubular hydrogen ion secretion

should increase to reabsorb all filtered bicarbonate
and have enough hydrogen ions left to convert
most of the base form of titratable buffers to the
acid form.

• Furthermore, glutamine to produce ammonium

should increase in order to excrete as ammonium
the hydrogen ion that is not excreted as titratable
acid.
H+
secretion
should be
HIGH
.
Production and Secretion of NH4+ and HCO3- by
Proximal, Thick Loop of Henle,
Henle, and Distal
Tubules

H++NH3

“New” HCO3-
 .

• A increase in PaCo2, will produce a decrease in

plasma pH and, thereby, signal an increased
tubular hydrogen ion secretion.

• A decrease in PaCo2, as occurs during respiratory

alkalosis (eg, high altitude hyperventilation),
causes a decrease in secretion.

• The effects are not due to the CO2 molecule itself

but to the effects of an altered PaCo2 on renal
intracellular pH.
 .

• We can see that these renal responses are

appropriate.

• If the Paco2 is high (causing a drop in plasma pH),

the increased hydrogen ion secretion raises plasma
bicarbonate, thereby restoring plasma pH to
normal (despite the continued high Paco2).

• Similarly, if the pH is low because of low

bicarbonate, the new bicarbonate restores the
bicarbonate (and, therefore, the pH) to normal.
CONTROL OF RENAL GLUTAMINE METABOLISM
AND NH4+ EXCRETION

• In addition to regulating hydrogen ion secretion

per se, there are several homeostatic controls over
the production and tubular handling of NH4+.

• First,
the generation of glutamine by the liver is
increased by low extracellular pH. In this case, the
liver shifts some of the disposal of ammonium ion
from urea to glutamine.
 .

• Second, the renal metabolism of glutamine is also

subject to physiological control by extracellular pH.

• A decrease in extracellular pH stimulates renal

glutamine oxidation by the proximal tubule,
whereas an increase does just the opposite.

• Thus, an acidosis, by stimulating renal glutamine

oxidation, causes the kidneys to contribute more
new bicarbonate to the blood, thereby
counteracting the acidosis.
 .

• This pH responsiveness increases over the first few

days of an acidosis and allows the glutamine–
NH4+ mechanism for new bicarbonate generation
to become the predominant renal process for
opposing the acidosis.

• Conversely, an alkalosis inhibits glutamine

metabolism, resulting in little or no renal
contribution of new bicarbonate via this route.

• In conclusion, acidosis increases renal NH4+

synthesis and excretion, whereas alkalosis does
the opposite.
• The unifying and, therefore, simplifying
.

principle is that all processes of acid or base

addition boil down to addition or loss of
bicarbonate.

• All processes that

acidify the blood end up removing

bicarbonate, and

all processes that alkalinize the blood end up

adding bicarbonate.
 .

Summary of processes that acidify or alkalinize the

blood –
• Nonrenal mechanisms of acidifying the blood

• Consumption and metabolism of protein (meat)

containing acidic or sulfur-containing amino acids
• Consumption of acidic drugs
• Metabolism of substrate without complete
oxidation (fat to ketones and carbohydrate to lactic
acid)
• GI tract secretion of bicarbonate (puts acid in
blood)
 .

• Nonrenal mechanisms of alkalinizing the blood

• Consumption and metabolism of fruit and

vegetables containing basic amino acids or the
salts of weak acids

• Consumption of antacids

• Infusion of lactated Ringer’s solution

• GI tract secretion of acid (puts bicarbonate in the

blood)
Renal mechanisms of acidifying the blood
.

• Allow some filtered bicarbonate to pass into the

urine
• Secrete bicarbonate (Type B intercalated cells)

Renal means of alkalinizing the blood

• Secrete protons that form urine titratable acidity

(Type A intercalated cells)
• Excrete NH4+ synthesized from glutamine
 INTRAVENOUS SOLUTIONS: LACTATED
RINGER’S

• Physiological saline is iso-osmotic with normal body

fluids (osmolality, 287 mOsm/kg),

• whereas D5W is slightly hypotonic (osmolality, 263

mOsm/kg).

• Neither has any acid-base content.

 .

• Another common solution is lactated Ringer’s

solution, a mixture of salts that contains lactate at a
concentration of 28 mEq/L.

• The pH is about 6.5. However, this is an alkalinizing

solution

• Lactate is the conjugate base of lactic acid. When

lactate is oxidized to CO2 and water, it takes a
hydrogen ion from the body fluids (and leaves a
bicarbonate)
 .
Reference:

• Vander’s Renal Physiology

• Guyton and Hall Medical Physiology
 .
• 1: Acids and Bases Obey the Balance Principle
• 2: Body Fluids Are Buffered
• 3: Input and Output of Acids Alter Bicarbonate BUT
NOT the Partial Pressure of CO2
• 4: Excretion of CO2 and Bicarbonate Are
Independent of Each Other
• RENAL HANDLING OF ACIDS AND BASES
• RENAL EXCRETION OF ACID AND BASE
• PHOSPHATE AND ORGANIC ACIDS AS BUFFERS
• HYDROGEN ION EXCRETION ON URINARY BUFFERS