❖ CASE 27

A 21-year-old man with insulin-dependent diabetes presents to the emergency

center with mental status changes, nausea, vomiting, abdominal pain, and
rapid respirations. On examination, the patient is noted to be hypotensive,
breathing rapidly (tachypneic), and febrile. A fruity odor is detected on his
breath. A random blood sugar is significantly elevated at 600 mg/dL. The
patient also has hyperkalemia, hypomagnesemia, and elevated serum ketones.
An arterial blood gas reveals a metabolic acidosis. The patient is diagnosed
with diabetic ketoacidosis (DKA) and is admitted to the intensive care unit for
intravenous (IV) hydration, glucose control, and correction of metabolic
abnormalities.

◆ What is the response of the kidney to metabolic acidosis?

◆ What is the response of the kidney to a respiratory alkalosis?

◆ What is the predicted compensatory response to metabolic acidosis?

224 CASE FILES: PHYSIOLOGY

ANSWERS TO CASE 27: ACID–BASE PHYSIOLOGY

Summary: A 21-year-old man with type I diabetes develops DKA and meta-
bolic acidosis.

◆ Response of the kidney to metabolic acidosis: Increased excretion of

the excess fixed hydrogen as ammonia and increased reabsorption of
bicarbonate

◆ Response of the kidney to respiratory alkalosis: Decreased hydrogen

excretion and decreased bicarbonate absorption

◆ Compensatory response to metabolic acidosis: Decrease in

bicarbonate and in PCO2

CLINICAL CORRELATION
This 21-year-old man with type I diabetes (insulin deficiency) has the clinical
manifestations of DKA. The first priorities are always the ABCs: Because the
airways and breathing are normal, the focus in this case is on the circulation.
Two large-bore IV lines should be placed, and the patient should receive 2 L
of isotonic solution. The cornerstones of therapy are insulin in an IV drip, cor-
rection of metabolic abnormalities, and detection of the underlying etiology of
the DKA (such as an infection).
Understanding how the body manages acid–base changes is critical to make
the correct diagnosis, develop a treatment plan, and monitor the effectiveness
of the treatment. Respiratory acidosis and alkalosis primarily begin in the
lungs, whereas metabolic acidosis and alkalosis begin with abnormalities of
bicarbonate in the blood. An arterial blood gas can be done to help determine
which type of acid–base abnormality may be present. Metabolic acidosis can
be differentiated into two groups: anion gap and non-anion gap. Examples of
normal anion gap acidosis include renal tubular acidosis and gastrointestinal
(GI) bicarbonate losses (diarrhea). Examples of increased anion gap acidosis
include ingestion of methanol, ethanol or ethylene glycol (antifreeze), salicy-
lates, cyanide, or paraldehyde; uremia or renal failure; lactic acidosis; and dia-
betic or alcoholic ketoacidosis. The serum anion gap can be calculated by
determining the concentration of sodium minus the sum of the chloride and
bicarbonate concentrations. The serum anion gap is increased if the concen-
tration of an unmeasured anion is present and is normal if the concentration of
chloride is increased to replace the bicarbonate. Treatment is based on diag-
nosing and treating the underlying disease process.
In this example of DKA, the patient will be started on IV fluids, insulin to
correct the DKA, and supportive care, depending on the severity of the symp-
toms. The potassium level will be monitored closely as the hyperkalemia will
resolve with treatment of the acidosis and the addition of insulin.
CLINICAL CASES 225

APPROACH TO ACID–BASE PHYSIOLOGY

Objectives
1. Understand the role of the kidney in acid–base balance.
2. Know how to calculate the anion gap and be able to list examples of
disorders that cause anion gap acidosis.
3. Understand volatile and nonvolatile acids and buffers.
4. Understand the significance of the Henderson-Hasselbalch equation.

Definitions
1. Hydrogen ion homeostasis: The process of maintaining the pH of the
plasma at a constant value of 7.4.
2. Acid-base balance: Matching the daily intake or production of acids
and bases with an equivalent daily excretion.
3. Carbonic acids: Substances such as fatty acids or carbohydrates whose
end products of metabolism are CO2 and H2O.
4. Noncarbonic acids: Also known as fixed acids are substances such as
phospholipids or sulfur containing amino acids whose end product of
metabolism is a nonvolatile acid.

DISCUSSION
Acid–base physiology includes H+ ion homeostasis (maintaining the arterial pH
at 7.4) and acid–base balance: the ability to match the daily production of acids
and bases with an equivalent excretion. A disturbance or change in the rates of
ingestion, production, and excretion of acids or bases can alter the balance and
cause a change in pH. The body has four lines of defense against an acid or
base challenge to minimize the change in pH and restore acid–base balance:
1. Simple chemical buffers in the blood (eg, the CO2-bicarbonate buffer
system, proteins such as hemoglobin and albumen) minimize a change
in pH by reacting with an acid or base upon contact.
2. Intracellular buffering is afforded by the protein mass contained
within the cells. This process requires the movement of protons (H+)
into the cell largely in exchange for potassium ions and is slower react-
ing than is the extracellular buffer pool.
3. Pulmonary compensation for a change in arterial pH or CO2 is
effected by a neural feedback loop involving central and peripheral
chemoreceptors that control the rate of ventilation. The CO2-bicarbon-
ate buffer system is unique in that one of its components, CO2, is
gaseous and is controlled by pulmonary ventilation. Changes in the
rate of ventilation can increase or decrease the alveolar and thus the
arterial CO2 concentration, compensating for changes in bicarbonate in
response to a metabolic acidosis or alkalosis. The pulmonary response
to changes in arterial pH or PCO2 is almost immediate.
226 CASE FILES: PHYSIOLOGY

4. The kidney responds to an acidosis or alkalosis by excreting non-

volatile acids or bases and controlling the rate of bicarbonate reab-
sorption. Unlike pulmonary ventilation, which is under the control of a
neural feedback loop involving chemoreceptors that are sensitive to H+,
CO2, and O2, renal function is controlled by mass action and the rela-
tive rates of H+ secretion and bicarbonate filtration. Because the renal
response is dependent on glomerular filtration and the transport of
large amounts of electrolytes, it is somewhat slower responding than
are the other buffer systems. It is worth noting that renal and pul-
monary functions are coupled to each other because one of the main
factors determining the rate of renal bicarbonate reabsorption is the
arterial PCO2.
Many substances in the blood can serve as effective buffers; however,
identifying each chemically distinct component is a monumental task. The
task is simplified by the use of the isohydric principle, which states that in a
mixed solution all acid–base pairs are in equilibrium with each other.
Thus, to assess the acid–base status of a patient, it is not necessary to measure
a hundred different species, but simply one representative pair. The most
convenient and informative representative is the CO2-HCO3- -buffer system.
The dissociation of an acid is governed by the physical chemical properties of
acids and bases, and their behavior can be predicted from the Henderson-
Hasselbalch equation:

[base]
pH = pK a + log
[acid]

The pKa or dissociation constant is characteristic for a specific acid–base

pair; thus, knowing any two of the three variables allows the calculation of the
third. Physiologically, the most important pair is the CO2 and HCO3−:
CO2 + H2O → H2CO3 → H+ + HCO3−
This expression can be simplified by assuming that CO2 represents the free
acid pool and HCO3− is the conjugate base. The Henderson-Hasselbalch
expression for the CO2-HCO3− buffer is

[HCO 3− ]
pH = pK a + log
[CO 2 ]dis

where the pKa = 6.1 and the [CO2]dis= 0.03 mmol/L_mm Hg CO2. Under nor-
mal physiologic conditions,

[24 mEq / L]
pH = pK a + log
[1.2 mEq / L]
CLINICAL CASES 227

Perhaps one of the most important features of this expression is that the pH is
not determined by the absolute concentration of either component, but is deter-
mined solely by the ratio [HCO3-]/[CO2]. If the ratio gets larger (more HCO3- or
less CO2), the pH is more alkaline. If the ratio gets smaller (less HCO3- or more
CO2), the pH is more acidic. This greatly simplifies the understanding of the phys-
iologic response to an acid–base disturbance. For example, if the disturbance is
of metabolic origin, there will be an initial change in [HCO3−]. A metabolic aci-
dosis will decrease [HCO3−], and the ratio [HCO3−]/[CO2] will shrink. To com-
pensate for the change, there are two options: The [HCO3−] could be restored to
normal, or the [CO2] could be reduced. The pulmonary response to an acid–base
disturbance is mediated by central and peripheral chemoreceptors and is almost
immediate. The initial response to a metabolic acidosis (fall in [HCO3-]) would
be an increase in pulmonary ventilation (hyperventilation) to lower the PCO2,
thereby restoring the ratio [HCO3−]/[CO2] more closely to normal. In this instance,
the pH has been corrected, yet the acid–base balance has been disturbed. To restore
balance, the [HCO3−] must be restored to normal. The kidney will excrete the acid
that caused the disturbance and generate bicarbonate at the same time to restore
[HCO3−]. Because the lungs control the [CO2] and the kidney controls the [HCO3−],
one may view the Henderson-Hasselbalch equation metaphorically as follows:

[kidney]
pH = pK a + log
[lung]

Physiologically, acids can be divided into two groups. The distinction is

made on the basis of their routes of production, the rates of production, and the
routes of excretion. Carbonic acids often are referred to as volatile acids:
1. Carbonic acids are substances whose end product of metabolism is
CO2 and water. CO2 is a volatile gas that is excreted by the lungs.
Substances such as fats and carbohydrates are not acids or bases per se,
but their metabolism yields CO2 and water. They are considered to be
acids because the end product of their metabolism, CO2, reacts with
water to form carbonic acid:
CO2 + H2O → H2CO3 → H+ + HCO3−
2. Noncarbonic or fixed acids are substances whose end products of
metabolism are nonvolatile acids. For example, metabolism of phos-
pholipids or proteins results in the production of H3PO4 and H2SO4.
These are strong acids that readily dissociate in the blood and are non-
volatile substances that have to be excreted by the kidney.
To understand the role of the kidney in acid–base disturbances, it is neces-
sary to understand the mechanism of bicarbonate reabsorption. In the tubular
cells, secreted H+ is formed by the dissociation of carbonic acid as follows:
CO2 + H2O → H2CO3 → H+ + HCO3−
228 CASE FILES: PHYSIOLOGY

For each H+ that is formed and secreted, a bicarbonate ion is formed and
transported into the blood. The secreted H+ has several available fates. If it
reacts with filtered bicarbonate, it is neutralized and there is no net gain or loss
of bicarbonate. The secreted H+ also can react with a titratable acid or NH3. A
bicarbonate is added to the blood, but the H+ is excreted in the urine as titrat-
able acidity (TA) or ammonium ion. In either case, there is a net gain of one
bicarbonate and the excretion of one fixed acid. Titratable acids are weak acids
in the glomerular filtrate, such as uric acid, which can react with secreted H+.
They are formed at a steady rate and are of limited availability during an
acid–base disturbance. However, the primary adaptive response of the kid-
ney to a chronic acidosis is ammoniagenesis, the increased production of
NH3 from glutamine. The maximal adaptive response may take several days
and can augment the daily excretion of H+ by twofold to threefold.
In the case of an alkalosis, the situation is reversed. If the rate of bicarbon-
ate filtration exceeds the rate of H+ secretion, excess bicarbonate is not reab-
sorbed but simply is excreted in an alkaline urine.
What factors control the rate of H+ secretion? The bulk (~90%) of bicar-
bonate reabsorption and H+ secretion occurs in the proximal tubule. The
mechanism of H+ secretion is via a Na+-H+ exchanger in the apical membrane
of the tubular cells. This exchanger is regulated by the intracellular pH, with
activation occurring at more acidic cytosolic pH. In the present discussion, the
key factors that will influence the intracellular pH are the arterial H+ and the
arterial PCO2. An increase in either of those two factors will cause an increase
in intracellular H+ and activation of the Na+-H+ exchanger.
In the present case, there was an uncontrolled overproduction of
ketoacids as a consequence of the insulin insufficiency. Normally, ketoacids
are oxidized to CO2 and water and eliminated as CO2 through pulmonary ven-
tilation. In a DKA, their production exceeds the oxidative capacity, with
their accumulation in the blood. These ketoacids dissociate in the blood,
yielding the carboxylate anion and H+ that were buffered by the chemical
buffers in the blood and the intracellular compartment. The H+ reacted with
bicarbonate, reducing its concentration with the production of CO2, which was
eliminated through pulmonary ventilation. This reaction created the anion
gap. The fall in bicarbonate also resulted in a fall in the arterial pH that would
stimulate peripheral chemoreceptors. Increased peripheral chemoreceptor
activity would stimulate ventilation to initiate a compensatory fall in PCO2.
The function of the kidney in this circumstance is to restore acid–base bal-
ance by eliminating all the excess fixed (or noncarbonic) acid that was gen-
erated in the episode and at the same time restore bicarbonate back to normal
levels. Although the PCO2 is reduced, the arterial H+ is elevated, and this will
lead to a parallel rise in the intracellular H+ concentration to ensure the activ-
ity of the Na+-H+ exchanger. The plasma [HCO3−] is reduced; therefore, the fil-
tered load of HCO3− is reduced, and thus all filtered HCO3− will be reabsorbed.
The generation of additional HCO3− requires that H+ be excreted. In fact, under
these conditions the rate-limiting factor for HCO3− reabsorption is not H+
CLINICAL CASES 229

secretion but H+ excretion. The availability of TA and NH3 is limiting for bind-
ing to the secreted H+. In a chronic state, the kidney will increase production
of NH3, but this may take several days. Over a period of days, the fixed acid
generated during the acidosis will be excreted with the addition of an equiva-
lent amount of HCO3− to the blood. As the HCO3− levels in the blood are
restored, there will be a gradual rise in the pH toward a normal 7.4, and as the
pH rises, the hyperventilation will abate. When the entire acid load is excreted,
HCO3− will be restored to normal and acid–base balance will be restored.

COMPREHENSION QUESTIONS
[27.1] Recovery from a severe metabolic acidosis is most dependent on
which of the following?
A. The rate of ventilation to blow off excess CO2
B. The rate of H+ secretion by the kidney
C. The rate of H+ excretion by the kidney
D. The arterial pH
E. The arterial PCO2
[27.2] After a rapid ascent to very high altitude, one begins to hyperventilate
because of hypoxic drive. The hyperventilation will cause a decrease
in the arterial PCO2. What is the renal response to this condition?
A. Increased rate of acid excretion
B. Decreased rate of acid excretion
C. Increased rate of bicarbonate reabsorption
D. Diuresis to eliminate excess fluid
E. Increased ammoniagenesis
[27.3] A 21-year-old man with gastroenteritis developed severe vomiting
with a loss of stomach acids. A metabolic alkalosis is present. Which
of the following is most likely to occur?
A. The plasma bicarbonate concentration will decrease.
B. H+ will move from the plasma into the cells.
C. Peripheral chemoreceptors will stimulate pulmonary ventilation.
D. Renal H+ excretion will decrease.

Answers
[27.1] C. The rate of recovery from a severe metabolic acidosis is most
dependent on the rate of H+ excretion. Pulmonary compensation
occurs rapidly; however, it can only minimize the change in pH.
Pulmonary compensation cannot restore the balance after a metabolic
disturbance. Recovery necessitates the excretion of the entire acid
load to the system. Renal acid excretion is limited by the availability
of titratable acids and ammonia for ammonium ion formation from
230 CASE FILES: PHYSIOLOGY

secreted H+. The primary adaptive response of the kidney to an aci-

dosis is ammoniagenesis. Ammoniagenesis can augment the daily
excretion of acids as much as threefold. When an equivalent amount
of acid is excreted, acid–base balance will be restored.
[27.2] B. The two most important drivers of renal bicarbonate reabsorption
are CO2 and H+. The hyperventilation experienced at high altitude
decreases the PCO2, which generates a respiratory alkalosis.
Reducing both CO2 and H+ will decrease renal H+ secretion and thus
bicarbonate reabsorption. The filtered bicarbonate load will exceed
the rate of H+ secretion with a loss of excess bicarbonate in the urine.
[27.3] D. The loss of gastric (hydrochloric) acid leads to an increase in the
plasma bicarbonate concentration and a metabolic alkalosis. The
increase in the pH will depress peripheral chemoreceptors to slow ven-
tilation and increase the PCO2 to compensate for the increased bicar-
bonate. The increase in PCO2 will bring the pH nearer to 7.4 and at the
same time increase renal H+ secretion. Because there is an increased
level of bicarbonate in the glomerular filtrate, there will be an increase
in bicarbonate reabsorption. The rate of filtration will exceed the rate
of H+ secretion, and there will be a continuous loss of bicarbonate. As
the plasma bicarbonate falls, the pH will continue to approach the nor-
mal of 7.4 and the ventilatory rate will increase gradually. When all the
excess bicarbonate has been excreted, the plasma bicarbonate and pH
will have returned to normal with a normal respiratory rate.

PHYSIOLOGY PEARLS
❖ Carbonic acids are substances whose end products of metabolism
are CO2 and water, such as triglycerides and carbohydrates.
❖ Noncarbonic or fixed acids are substances whose end products of
metabolism are nonvolatile, such as phosphoric acid and sulfuric
acid produced from phospholipids and protein breakdown.
❖ The rate of bicarbonate reabsorption is dependent on the relative
rates of bicarbonate filtration and H+ secretion.
❖ The rate of urinary acid excretion is limited by the availability of
titratable acids and NH3.
❖ Ammoniagenesis is the primary adaptive response of the kidney to a
chronic acidosis.
❖ The isohydric principle states that in a mixed solution all the
acid–base pairs are in equilibrium with each other.
❖ The Henderson-Hasselbalch equation relates the pH of the plasma to
the concentrations of HCO3− and CO2. The ratio [HCO3−]/[CO2]
determines the pH. Respiratory function controls CO2, and renal
function controls [HCO3−].
CLINICAL CASES 231

REFERENCES

Goodman HM. The pancreatic islets. In: Johnson LR, ed. Essential Medical
Physiology. 3rd ed. San Diego, CA: Elsevier Academic Press; 2003:637-658.
Rose BD, Post TW. Clinical Physiology of Acid-Base Disorders. 5th ed. New York:
McGraw-Hill; 2001:578-646.
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