C H A P T E R

Acid-Base Balance

25 George A. Tanner, Ph.D.

CHAPTER OUTLINE

■ A REVIEW OF ACID-BASE CHEMISTRY ■ RESPIRATORY REGULATION OF PH

■ PRODUCTION AND REGULATION OF HYDROGEN ■ RENAL REGULATION OF PH
IONS IN THE BODY ■ REGULATION OF INTRACELLULAR PH
■ CHEMICAL REGULATION OF PH ■ DISTURBANCES OF ACID-BASE BALANCE

KEY CONCEPTS

1. The body is constantly threatened by acid resulting from (mainly proteins and organic phosphates), and by meta-
diet and metabolism. The stability of blood pH is main- bolic reactions.
tained by the concerted action of chemical buffers, the 7. Respiratory acidosis is an abnormal process characterized
lungs, and the kidneys. by an accumulation of CO2 and a fall in arterial blood pH.
2. Numerous chemical buffers (e.g., HCO3⫺/CO2, phosphates, The kidneys compensate by increasing the excretion of H⫹
proteins) work together to minimize pH changes in the in the urine and adding new HCO3⫺ to the blood, thereby,
body. The concentration ratio (base/acid) of any buffer diminishing the severity of the acidemia.
pair, together with the pK of the acid, automatically defines 8. Respiratory alkalosis is an abnormal process characterized
the pH. by an excessive loss of CO2 and a rise in pH. The kidneys
3. The bicarbonate/CO2 buffer pair is effective in buffering in compensate by increasing the excretion of filtered HCO3⫺,
the body because its components are present in large thereby, diminishing the alkalemia.
amounts and the system is open. 9. Metabolic acidosis is an abnormal process characterized
4. The respiratory system influences plasma pH by regulating by a gain of acid (other than H2CO3) or a loss of HCO3⫺.
the PCO2 by changing the level of alveolar ventilation. The Respiratory compensation is hyperventilation, and renal
kidneys influence plasma pH by getting rid of acid or base compensation is an increased excretion of H⫹ bound to uri-
in the urine. nary buffers (ammonia, phosphate).
5. Renal acidification involves three processes: reabsorp- 10. Metabolic alkalosis is an abnormal process characterized
tion of filtered HCO3⫺, excretion of titratable acid, and by a gain of strong base or HCO3⫺ or a loss of acid (other
excretion of ammonia. New HCO3⫺ is added to the than H2CO3). Respiratory compensation is hypoventilation,
plasma and replenishes depleted HCO3⫺ when titratable and renal compensation is an increased excretion of
acid (normally mainly H2PO4⫺) and ammonia (as NH4⫹) HCO3⫺.
are excreted. 11. The plasma anion gap is equal to the plasma [Na⫹] ⫺ [Cl⫺]
6. The stability of intracellular pH is ensured by membrane ⫺ [HCO3⫺] and is most useful in narrowing down possible
transport of H⫹ and HCO3⫺, by intracellular buffers causes of metabolic acidosis.

very day, metabolic reactions in the body produce and that [H⫹] stays relatively constant both outside and inside
E consume many moles of hydrogen ions (H⫹s). Yet, the
⫹
[H ] of most body fluids is very low (in the nanomolar
cells.
Most of this chapter discusses the regulation of [H⫹]
range) and is kept within narrow limits. For example, the in extracellular fluid because ECF is easier to analyze than
[H⫹] of arterial blood is normally 35 to 45 nmol/L (pH intracellular fluid and is the fluid used in the clinical eval-
7.45 to 7.35). Normally the body maintains acid-base bal- uation of acid-base balance. In practice, systemic arterial
ance; inputs and outputs of acids and bases are matched so blood is used as the reference for this purpose. Measure-

426
 CHAPTER 25 Acid-Base Balance 427

ments on whole blood with a pH meter give values for strength of the solution. Note that pKa is inversely propor-
the [H⫹] of plasma and, therefore, provide an ECF pH tional to acid strength. A strong acid has a high Ka and a
measurement. low pKa. A weak acid has a low Ka and a high pKa.

A REVIEW OF ACID-BASE CHEMISTRY pH Is Inversely Related to [H⫹]

In this section, we briefly review some principles of acid- [H⫹] is often expressed in pH units. The following equa-
base chemistry. We define acid, base, acid dissociation tion defines pH:
constant, weak and strong acids, pKa, pH, and the Hender-
son-Hasselbalch equation and explain buffering. Students pH ⫽ log10 (1/[H⫹]) ⫽ ⫺log10 [H⫹] (3)
who already feel comfortable with these concepts can skip ⫹
where [H ] is in mol/L. Note that pH is inversely related to
this section. [H⫹]. Each whole number on the pH scale represents a 10-
fold (logarithmic) change in acidity. A solution with a pH
Acids Dissociate to Release Hydrogen Ions of 5 has 10 times the [H⫹] of a solution with a pH of 6.
in Solution
An acid is a substance that can release or donate H⫹; a base The Henderson-Hasselbalch Equation Relates
is a substance that can combine with or accept H⫹. When pH to the Ratio of the Concentrations of
an acid (generically written as HA) is added to water, it dis- Conjugate Base and Acid
sociates reversibly according to the reaction, HA H⫹ ⫹
A⫺. The species A⫺ is a base because it can combine with a For a solution containing an acid and its conjugate base, we
H⫹ to form HA. In other words, when an acid dissociates, can rearrange the equilibrium expression (equation 1) as
it yields a free H⫹ and its conjugate (meaning “joined in a
pair”) base. Ka ⫻ [HA]
[H⫹] ⫽ ᎏᎏ (4)
[A⫺]
The Acid Dissociation Constant Ka Shows the
Strength of an Acid If we take the negative logarithms of both sides,

At equilibrium, the rate of dissociation of an acid to form [A⫺]

H⫹ ⫹ A⫺, and the rate of association of H⫹ and base A⫺ –log [H⫹] ⫽ ⫺log Ka ⫹ log ᎏ (5)
[HA]
to form HA, are equal. The equilibrium constant (Ka),
which is also called the ionization constant or acid dissoci- Substituting pH for ⫺log [H⫹] and pKa for ⫺log Ka, we
ation constant, is given by the expression get

[H⫹] ⫻ [A⫺] [A⫺]

Ka ⫽ ᎏᎏ (1) pH ⫽ pKa ⫹ log ᎏ (6)
[HA] [A]

The higher the acid dissociation constant, the more an This equation is known as the Henderson-Hasselbalch
acid is ionized and the greater is its strength. Hydrochloric equation. It shows that the pH of a solution is determined
acid (HCl) is an example of a strong acid. It has a high Ka by the pKa of the acid and the ratio of the concentration of
and is almost completely ionized in aqueous solutions. conjugate base to acid.
Other strong acids include sulfuric acid (H2SO4), phos-
phoric acid (H3PO4), and nitric acid (HNO3).
An acid with a low Ka is a weak acid. For example, in a Buffers Promote the Stability of pH
0.1 mol solution of acetic acid (Ka ⫽ 1.8 ⫻ 10⫺5) in water, The stability of pH is protected by the action of buffers. A
most (99%) of the acid is nonionized and little (1%) is pres- pH buffer is defined as something that minimizes the change
ent as acetate⫺ and H⫹. The acidity (concentration of free in pH produced when an acid or base is added. Note that a
H⫹) of this solution is low. Other weak acids are lactic acid, buffer does not prevent a pH change. A chemical pH buffer is
carbonic acid (H2CO3), ammonium ion (NH4⫹), and dihy- a mixture of a weak acid and its conjugate base (or a weak
drogen phosphate (H2PO4⫺). base and its conjugate acid). Following are examples of
buffers:
pKa Is a Logarithmic Expression of Ka
Weak Acid Conjugate Base
Acid dissociation constants vary widely and often are small H2CᎏO3 HCO3⫺ ⫹ H⫹
ᎏ ᎏᎏ (7)
numbers. It is convenient to convert Ka to a logarithmic (carbonic acid) (bicarbonate)
form, defining pKa as
H2PO4⫺ HPO42– ⫹ H⫹
ᎏᎏᎏ ᎏᎏᎏ (8)
pKa ⫽ log10(1/Ka) ⫽ ⫺log10Ka (2) (dihydrogen phosphate) (monohydrogen phosphate)
In aqueous solution, each acid has a characteristic pKa, NH4⫹ NH3 ⫹ H⫹
ᎏᎏ ᎏᎏ (9)
which varies slightly with temperature and the ionic (ammonium ion) (ammonia)
428 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

Generally, the equilibrium expression for a buffer pair basic form of phosphate: H⫹ ⫹ HPO42– H2PO4⫺. Go-
can be written in terms of the Henderson-Hasselbalch ing from left to right as strong base is added, OH⫺ com-
equation: bines with H⫹ released from the acid form of the phos-
phate buffer: OH⫺ ⫹ H2PO4⫺ HPO42– ⫹ H2O. These
[conjugate base] reactions lessen the fall or rise in pH.
pH ⫽ pKa ⫹ log ᎏᎏ (10)
[acid] At the pKa of the phosphate buffer, the ratio
[HPO42–]/[H2PO4⫺] is 1 and the titration curve is flattest
For example, for H2PO40/HPO42– (the change in pH for a given amount of an added acid or
base is at a minimum). In most cases, pH buffering is effec-
[HPO42–] tive when the solution pH is within plus or minus one pH
pH ⫽ 6.8 ⫹ log ᎏᎏ (11)
[HPO4⫺] unit of the buffer pKa. Beyond that range, the pH shift that
a given amount of acid or base produces may be large, so
The effectiveness of a buffer—how well it reduces pH the buffer becomes relatively ineffective.
changes when an acid or base is added—depends on its
concentration and its pKa. A good buffer is present in high
concentrations and has a pKa close to the desired pH. PRODUCTION AND REGULATION OF
Figure 25.1 shows a titration curve for the phosphate HYDROGEN IONS IN THE BODY
buffer system. As a strong acid or strong base is progres-
sively added to the solution (shown on the x-axis), the re- Acids are continuously produced in the body and threaten
sulting pH is recorded (shown on the y-axis). Going from the normal pH of the extracellular and intracellular fluids.
right to left as strong acid is added, H⫹ combines with the Physiologically speaking, acids fall into two groups: (1)
H2CO3 (carbonic acid), and (2) all other acids (noncar-
bonic; also called “nonvolatile” or “fixed” acids). The dis-
tinction between these groups occurs because H2CO3 is in
equilibrium with the volatile gas CO2, which can leave the
body via the lungs. The concentration of H2CO3 in arterial
blood is, therefore, set by respiratory activity. By contrast,
9 HPO42⫺ noncarbonic acids in the body are not directly affected by
breathing. Noncarbonic acids are buffered in the body and
excreted by the kidneys.

Metabolism Is a Constant Source

8 of Carbon Dioxide
A normal adult produces about 300 L of CO2 daily from
metabolism. CO2 from tissues enters the capillary blood,
where it reacts with water to form H2CO3, which dissoci-
ates instantly to yield H⫹ and HCO3⫺: CO2 ⫹ H2O
pH

7
H2CO3 H⫹ ⫹ HCO3⫺. Blood pH would rapidly fall to
pKa⫽6.8 lethal levels if the H2CO3 formed from CO2 were allowed
to accumulate in the body.
Fortunately, H2CO3 produced from metabolic CO2 is
only formed transiently in the transport of CO2 by the
6 blood and does not normally accumulate. Instead, it is con-
verted to CO2 and water in the pulmonary capillaries and
the CO2 is expired. In the lungs, the reactions reverse:
H⫹ ⫹ HCO3⫺ H2CO3 H2O ⫹ CO2 (12)
5 H2PO4⫺ As long as CO2 is expired as fast as it is produced, arte-
rial blood CO2 tension, H2CO3 concentration, and pH do
not change.
Amount of HCl added (mEq)
Amount of NaOH added (mEq)
Incomplete Carbohydrate and Fat Metabolism
A titration curve for a phosphate buffer. Produces Nonvolatile Acids
FIGURE 25.1
The pKa for H2PO4⫺ is 6.8. A strong acid
(HCl) (right to left) or strong base (NaOH) (left to right) was
Normally, carbohydrates and fats are completely oxidized
added and the resulting solution pH recorded (y-axis). Notice to CO2 and water. If carbohydrates and fats are incompletely
that buffering is best (i.e., the change in pH upon the addition of oxidized, nonvolatile acids are produced. Incomplete oxi-
a given amount of acid or base is least) when the solution pH is dation of carbohydrates occurs when the tissues do not re-
equal to the pKa of the buffer. ceive enough oxygen, as during strenuous exercise or hem-
 CHAPTER 25 Acid-Base Balance 429

orrhagic or cardiogenic shock. In such states, glucose me- Food intake

tabolism yields lactic acid (pKa ⫽ 3.9), which dissociates
into lactate and H⫹, lowering the blood pH. Incomplete Digestion
fatty acid oxidation occurs in uncontrolled diabetes melli-
tus, starvation, and alcoholism and produces ketone body Absorption
acids (acetoacetic and ␤-hydroxybutyric acids). These Chemical Respiratory Renal
acids have pKa values around 4 to 5. At blood pH, they Cell metabolism buffering response response
mostly dissociate into their anions and H⫹, making the of food
H+ H+
blood more acidic.
Bound by
Sulfate body buffer CO2
Phosphate bases
Protein Metabolism Generates Strong Acids Chloride CO2
The metabolism of dietary proteins is a major source of
H⫹. The oxidation of proteins and amino acids produces Extracellular New
strong acids such as H2SO4, HCl, and H3PO4. The oxi- fluid HCO3-
[HCO3-]
dation of sulfur-containing amino acids (methionine, cys-
teine, cystine) produces H2SO4, and the oxidation of
cationic amino acids (arginine, lysine, and some histidine Extracellular
residues) produces HCl. H3PO4 is produced by the oxi- fluid
dation of phosphorus-containing proteins and phospho- [HCO3-]
CO2
esters in nucleic acids. H+ Excreted
(combined with
urinary
On a Mixed Diet, Net Acid Gain Threatens pH buffer bases)
A diet containing both meat and vegetables results in a net Excreted
production of acids, largely from protein oxidation. To Sulfate Sulfate
some extent, acid-consuming metabolic reactions balance Phosphate Phosphate
Chloride
H⫹ production. Food also contains basic anions, such as Chloride
citrate, lactate, and acetate. When these are oxidized to
CO2 and water, H⫹ ions are consumed (or, amounting to The maintenance of normal blood pH by
the same thing, HCO3⫺ is produced). The balance of acid- FIGURE 25.2
chemical buffers, the respiratory system,
forming and acid-consuming metabolic reactions results in and the kidneys. On a mixed diet, pH is threatened by the pro-
a net production of about 1 mEq H⫹/kg body weight/day duction of strong acids (sulfuric, hydrochloric, and phosphoric)
in an adult person who eats a mixed diet. Persons who are mainly as a result of protein metabolism. These strong acids are
vegetarians generally have less of a dietary acid burden and buffered in the body by chemical buffer bases, such as ECF
a more alkaline urine pH than nonvegetarians because most HCO3⫺. The kidneys eliminate hydrogen ions (combined with
fruits and vegetables contain large amounts of organic an- urinary buffers) and anions in the urine. At the same time, they
add new HCO3⫺ to the ECF, to replace the HCO3⫺ consumed
ions that are metabolized to HCO3⫺. The body generally in buffering strong acids. The respiratory system disposes of CO2.
has to dispose of more or less nonvolatile acid, a function
performed by the kidneys.
Whether a particular food has an acidifying or an alka-
linizing effect depends on if and how its constituents are mizes a change in pH but does not remove acid or base
metabolized. Cranberry juice has an acidifying effect be- from the body.
cause of its content of benzoic acid, an acid that cannot be 2) Respiratory response. The respiratory system is
broken down in the body. Orange juice has an alkalinizing the second line of defense of blood pH. Normally, breath-
effect, despite its acidic pH of about 3.7, because it contains ing removes CO2 as fast as it forms. Large loads of acid
citrate, which is metabolized to HCO3⫺. The citric acid in stimulate breathing (respiratory compensation), which re-
orange juice is converted to CO2 and water and has only a moves CO2 from the body and lowers the [H2CO3] in ar-
transient effect on blood pH and no effect on urine pH. terial blood, reducing the acidic shift in blood pH.
3) Renal response. The kidneys are the third line of
Many Buffering Mechanisms Protect defense of blood pH. Although chemical buffers in the
and Stabilize Blood pH
body can bind H⫹ and the lungs can change [H2CO3] of
blood, the burden of removing excess H⫹ falls directly on
Despite constant threats to acid-base homeostasis, a healthy the kidneys. Hydrogen ions are excreted in combination
person maintains a normal blood pH. Figure 25.2 shows with urinary buffers. At the same time, the kidneys add new
some of the ways in which blood pH is kept at normal lev- HCO3⫺ to the ECF to replace HCO3⫺ used to buffer
els despite the daily net acid gain. The key buffering agents strong acids. The kidneys also excrete the anions (phos-
are chemical buffers, along with the lungs and kidneys. phate, chloride, sulfate) that are liberated from strong
1) Chemical buffering. Chemical buffers in extra- acids. The kidneys affect blood pH more slowly than other
cellular and intracellular fluids and in bone are the first buffering mechanisms in the body; full renal compensation
line of defense of blood pH. Chemical buffering mini- may take 1 to 3 days.
430 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

CHEMICAL REGULATION OF PH Proteins Are Excellent Buffers

The body contains many conjugate acid-base pairs that act Proteins are the largest buffer pool in the body and are ex-
as chemical buffers (Table 25.1). In the ECF, the main cellent buffers. Proteins can function as both acids and
chemical buffer pair is HCO3⫺/CO2. Plasma proteins and bases, so they are amphoteric. They contain many ioniz-
inorganic phosphate are also ECF buffers. Cells have large able groups, which can release or bind H⫹. Serum albumin
buffer stores, particularly proteins and organic phosphate and plasma globulins are the major extracellular protein
compounds. HCO3⫺ is present in cells, although at a lower buffers, present mainly in the blood plasma. Cells also have
concentration than in ECF. Bone contains large buffer large protein stores. Recall that the buffering properties of
stores, specifically phosphate and carbonate salts. hemoglobin play an important role in the transport of CO2
and O2 by the blood (see Chapter 21).
Chemical Buffers Are the First to Defend pH
The Bicarbonate/Carbon Dioxide Buffer Pair
When an acid or base is added to the body, the buffers just
Is Crucial in pH Regulation
mentioned bind or release H⫹, minimizing the change in
pH. Buffering in ECF occurs rapidly, in minutes. Acids or For several reasons, the HCO3⫺/CO2 buffer pair is espe-
bases also enter cells and bone, but this generally occurs cially important in acid-base physiology:
more slowly, over hours, allowing cell buffers and bone to 1) Its components are abundant; the concentration of
share in buffering. HCO3⫺ in plasma or ECF normally averages 24 mmol/L.
Although the concentration of dissolved CO2 is lower (1.2
mmol/L), metabolism provides a nearly limitless supply.
A pKa of 6.8 Makes Phosphate a Good Buffer 2) Despite a pK of 6.10, a little far from the desired
The pKa for phosphate, H2PO4⫺ H⫹ ⫹ HPO42–, is 6.8, plasma pH of 7.40, it is effective because the system is
close to the desired blood pH of 7.4, so phosphate is a good “open.”
buffer. In the ECF, phosphate is present as inorganic phos- 3) It is controlled by the lungs and kidneys.
phate. Its concentration, however, is low (about 1 mmol/L),
so it plays a minor role in extracellular buffering. Forms of Carbon Dioxide. CO2 exists in the body in sev-
Phosphate is an important intracellular buffer, how- eral different forms: as gaseous CO2 in the lung alveoli, and
ever, for two reasons. First, cells contain large amounts of as dissolved CO2, H2CO3, HCO3⫺, carbonate (CO32–),
phosphate in such organic compounds as adenosine and carbamino compounds in the body fluids.
triphosphate (ATP), adenosine diphosphate (ADP), and CO32– is present at appreciable concentrations only in
creatine phosphate. Although these compounds primarily rather alkaline solutions, and so we will ignore it. We will
function in energy metabolism, they also act as pH also ignore any CO2 that is bound to proteins in the car-
buffers. Second, intracellular pH is generally lower than bamino form. The most important forms are gaseous CO2,
the pH of ECF and is closer to the pKa of phosphate. (The dissolved CO2, H2CO3, and HCO3⫺.
cytosol of skeletal muscle, for example, has a pH of 6.9.)
Phosphate is, thus, more effective in this environment The CO2/H2CO3/HCO3⫺ Equilibria. Dissolved CO2 in
than in one with a pH of 7.4. Bone has large phosphate pulmonary capillary blood equilibrates with gaseous CO2
salt stores, which also help in buffering. in the lung alveoli. Consequently, the partial pressures of
CO2 (PCO2) in alveolar air and systemic arterial blood are
normally identical. The concentration of dissolved CO2
([CO2(d)]) is related to the PCO2 by Henry’s law (see Chap-
ter 21). The solubility coefficient for CO2 in plasma at
37⬚C is 0.03 mmol CO2/L per mm Hg PCO2. Therefore,
TABLE 25.1 Major Chemical pH Buffers in the Body [CO2(d)] ⫽ 0.03 ⫻ PCO2. If PCO2 is 40 mm Hg, then
[CO2(d)] is 1.2 mmol/L.
Buffer Reaction In aqueous solutions, CO2(d) reacts with water to form
Extracellular fluid
H2CO3: CO2(d) ⫹ H2O H2CO3. The reaction to the
Bicarbonate/CO2 CO2 ⫹ H2O→←H2CO3→←H⫹ right is called the hydration reaction, and the reaction to
⫹ HCO3⫺ the left is called the dehydration reaction. These reactions
Inorganic phosphate H2PO4⫺→←H⫹ ⫹ HPO42⫺ are slow if uncatalyzed. In many cells and tissues, such as
Plasma proteins (Pr) HPr→←H⫹ ⫹ Pr⫺ the kidneys, pancreas, stomach, and red blood cells, the re-
Intracellular fluid actions are catalyzed by carbonic anhydrase, a zinc-con-
Cell proteins (e.g., HHb→←H⫹ ⫹ Hb⫺ taining enzyme. At equilibrium, CO2(d) is greatly favored;
hemoglobin, Hb) at body temperature, the ratio of [CO2(d)] to [H2CO3] is
Organic phosphates Organic-HPO4⫺→←H⫹ ⫹ about 400:1. If [CO2(d)] is 1.2 mmol/L, then [H2CO3]
organic-PO42⫺ equals 3 ␮mol/L. H2CO3 dissociates instantaneously into
Bicarbonate/CO2 CO2 ⫹ H2O→←H2CO3→←H⫹ H⫹ and HCO3⫺: H2CO3 H⫹ ⫹ HCO3⫺. The Hender-
⫹ HCO3⫺ son-Hasselbalch expression for this reaction is
Bone
Mineral phosphates H2PO4⫺→←H⫹ ⫹ HPO42⫺
[HCO3⫺]
Mineral carbonates HCO3⫺→←H⫹ ⫹ CO32⫺ pH ⫽ 3.5 ⫹ log ᎏᎏ (13)
[H2CO3]
 CHAPTER 25 Acid-Base Balance 431

Note that H2CO3 is a fairly strong acid (pKa ⫽ 3.5). Its mmol of dissolved CO2(d) (PCO2 ⫽ 40 mm Hg). Using the
low concentration in body fluids lessens its impact on acidity. special form of the Henderson-Hasselbalch equation de-
scribed above, we find that the pH of the blood is 7.40:
The Henderson-Hasselbalch Equation for HCO3⫺/CO2..
Because [H2CO3] is so low and hard to measure and be- [HCO3⫺]
pH ⫽ 6.10 ⫹ log ᎏᎏ
cause [H2CO3] ⫽ [CO2(d)]/400, we can use [CO2(d)] to 0.03 PCO2
represent the acid in the Henderson-Hasselbalch equation: (17)
[24]
[HCO3⫺] ⫽ 6.10 ⫹ log ᎏ ⫽ 7.40
pH ⫽ 3.5 ⫹ log ᎏᎏ [1.2]
[CO2(d)] /400
Suppose we now add 10 mmol of HCl, a strong acid.
[HCO3⫺] HCO3⫺ is the major buffer base in the blood plasma (we
⫽ 3.5 ⫹ log 400 ⫹ log ᎏᎏ (14)
[CO2(d)] will neglect the contributions of other buffers). From the
reaction H⫹ ⫹ HCO3⫺ H2CO3 H2O ⫹ CO2, we
[HCO3⫺] predict that the [HCO3⫺] will fall by 10 mmol, and that 10
⫽ 6.1 ⫹ log ᎏᎏ
[CO2(d)] mmol of CO2(d) will form. If the system were closed and no
CO2 could escape, the new pH would be
We can also use 0.03 ⫻ PCO2 in place of [CO2(d)]:
[24 ⫺ 10]
pH ⫽ 6.10 ⫹ log ᎏᎏ
[1.2 ⫹ 10] ⫽ 6.20 (18)
[HCO3⫺]
pH ⫽ 6.1 ⫹ log ᎏᎏ (15)
0.03 PCO2
This is an intolerably low—indeed a fatal—pH.
This form of the Henderson-Hasselbalch equation is Fortunately, however, the system is open and CO2 can
useful in understanding acid-base problems. Note that the escape via the lungs. If all of the extra CO2 is expired and
“acid” in this equation appears to be CO2(d), but is really the [CO2(d)] is kept at 1.2 mmol/L, the pH would be
H2CO3 “represented” by CO2. Therefore, this equation is
valid only if CO2(d) and H2CO3 are in equilibrium with [24 ⫺ 10]
pH ⫽ 6.10 ⫹ log ᎏᎏ ⫽ 7.17 (19)
each other, which is usually (but not always) the case. [1.2]
Many clinicians prefer to work with [H⫹] rather than
pH. The following expression results if we take antiloga- Although this pH is low, it is compatible with life.
rithms of the Henderson-Hasselbalch equation: Still another mechanism promotes the escape of CO2. In
the body, an acidic blood pH stimulates breathing, which
[H⫹] ⫽ 24 PCO2/[HCO3⫺] (16) can make the PCO2 lower than 40 mm Hg. If PCO2 falls to
⫹
In this expression, [H ] is expressed in nmol/L, 30 mm Hg ([CO2(d)] ⫽ 0.9 mmol/L) the pH would be
[HCO3⫺] in mmol/L or mEq/L, and PCO2 in mm Hg. If PCO
[24 ⫺ 10]
is 40 mm Hg and plasma [HCO3⫺] is 24 mmol/L, [H⫹] is pH ⫽ 6.10 ⫹ log ᎏᎏ ⫽ 7.29 (20)
40 nmol/L. [0.9]

An “Open” Buffer System. As previously noted, the pK The system is also open at the kidneys and new HCO3⫺
of the HCO3⫺/CO2 system (6.10) is far from 7.40, the nor- can be added to the plasma to correct the plasma
mal pH of arterial blood. From this, one might view this as [HCO3⫺]. Once the pH of the blood is normal, the stimu-
a rather poor buffer pair. On the contrary, it is remarkably lus for hyperventilation disappears.
effective because it operates in an open system; that is, the
two buffer components can be added to or removed from Changes in Acid Production May
the body at controlled rates. Help Protect Blood pH
The HCO3⫺/CO2 system is open in several ways:
1) Metabolism provides an endless source of CO2, Another way in which blood pH may be protected is by
which can replace any H2CO3 consumed by a base added changes in endogenous acid production (Fig. 25.4). An in-
to the body. crease in blood pH caused by the addition of base to the
2) The respiratory system can change the amount of body results in increased production of lactic acid and ke-
CO2 in body fluids by hyperventilation or hypoventilation. tone body acids, which then reduces the alkaline shift in
3) The kidneys can change the amount of HCO3⫺ in pH. A decrease in blood pH results in decreased produc-
the ECF by forming new HCO3⫺ when excess acid has tion of lactic acid and ketone body acids, which opposes
been added to the body or excreting HCO3⫺ when excess the acidic shift in pH.
base has been added. This scenario is especially important when the endoge-
How the kidneys and respiratory system influence blood nous production of these acids is high, as occurs during stren-
pH by operating on the HCO3⫺/CO2 system is described uous exercise or other conditions of circulatory inadequacy
below. For now, the advantages of an open buffer system (lactic acidosis) or during ketosis as a result of uncontrolled
are best explained by an example (Fig. 25.3). Suppose we diabetes, starvation, or alcoholism. These effects of pH on
have 1 L of blood containing 24 mmol of HCO3⫺ and 1.2 endogenous acid production result from changes in enzyme
432 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

Closed Open
system system
response response

[HCO3-]
14

Kidneys
[HCO3-] add new [HCO3-]
24 Lose
Add Remove CO2 HCO3- 24
10 mmol/L extra because of to blood
strong acid CO2 [HCO3-] hyperventilation [HCO3-] (excrete H+)
14 14

[CO2(d)] 11.2

[CO2(d)] 1.2 [CO2(d)] 1.2 [CO2(d)] 0.9 [CO2(d)] 1.2

pH = 7.40 pH = 6.20 pH = 7.17 pH = 7.29 pH = 7.40

Normal Normal
condition condition

FIGURE 25.3 The HCO32/CO2 system. This system is re- in mmol/L. See text for details. (Adapted from Pitts RF. Physiol-
markably effective in buffering added strong ogy of the Kidney and Body Fluids. 3rd Ed. Chicago: Year
acid in the body because it is open. [HCO3⫺] and [CO2(d)] are Book, 1974.)

activities brought about by the pH changes, and they are idea is known as the isohydric principle (isohydric meaning
part of a negative-feedback mechanism regulating blood pH. “same H⫹”). For plasma, for example, we can write

[HPO42–]
All Buffers Are in Equilibrium With the Same [H⫹] pH ⫽ 6.80 ⫹ log ᎏᎏ
[H2PO4⫺]
We have discussed the various buffers separately but, in the
body, they all work together. In a solution containing mul- [HCO3⫺]
tiple buffers, all are in equilibrium with the same [H⫹]. This ⫽ 6.10 ⫹ log ᎏᎏ
0.03 PCO2

Acid load Base load [proteinate⫺]

⫽ pKprotein ⫹ log ᎏᎏ (21)
[H-protein]
Systemic Endogenous acid Systemic
pH production pH
(ketoacidosis, If an acid or a base is added to such a complex mixture of
lactic acidosis) buffers, all buffers take part in buffering and shift from one
form (base or acid) to the other. The relative importance of
each buffer depends on its amount, pK, and availability.
Systemic The isohydric principle underscores the fact that it is the
pH concentration ratio for any buffer pair, together with its pK,
that sets the pH. We can focus on the concentration ratio for
FIGURE 25.4
Negative-feedback control of endogenous one buffer pair and all other buffers will automatically adjust
acid production. The addition of an exoge- their ratios according to the pH and their pK values.
nous acid load or increased endogenous acid production result in The rest of this chapter emphasizes the role of the
a fall in pH, which, in turn, inhibits the production of ketone
HCO3⫺/CO2 buffer pair in setting the blood pH. Other
body acids and lactic acid. A base load, by raising pH, stimulates
the endogenous production of acids. This negative-feedback buffers, however, are present and active. The HCO3⫺/CO2
mechanism attenuates changes in blood pH. (From Hood VL, system is emphasized because physiological mechanisms
Tannen RL. Protection of acid-base balance by pH regulation of (lungs and kidneys) regulate pH by acting on components
acid production. N Engl J Med 1998;339:819–826.) of this buffer system.
 CHAPTER 25 Acid-Base Balance 433

RESPIRATORY REGULATION OF PH loss of acid or base (e.g., gastrointestinal losses) are small
and can be neglected, which normally is the case. The net
Reflex changes in ventilation help to defend blood pH. By
loss of H⫹ in the urine can be calculated from the following
changing the PCO2 and, hence, [H2CO3] of the blood, the
equation, which shows typical values in the parentheses:
respiratory system can rapidly and profoundly affect blood
pH. As discussed in Chapter 22, a fall in blood pH stimu- Renal net acid excretion (70 mEq/day) ⫽
lates ventilation, primarily by acting on peripheral urinary titratable acid (24 mEq/day) ⫹
chemoreceptors. An elevated arterial blood PCO2 is a pow- urinary ammonia (48 mEq/day) ⫺
erful stimulus to increase ventilation; it acts on both periph- urinary HCO3⫺ (2 mEq/day) (22)
eral and central chemoreceptors, but primarily on the latter. Urinary ammonia (as NH4⫹) ordinarily accounts for
CO2 diffuses into brain interstitial and cerebrospinal fluids, about two thirds of the excreted H⫹, and titratable acid for
where it causes a fall in pH that stimulates chemoreceptors about one third. Excretion of HCO3⫺ in the urine repre-
in the medulla oblongata. When ventilation is stimulated, sents a loss of base from the body. Therefore, it must be
the lungs blow off more CO2, making the blood less acidic. subtracted in the calculation of net acid excretion. If the
Conversely, a rise in blood pH inhibits ventilation; the con- urine contains significant amounts of organic anions, such
sequent rise in blood [H2CO3] reduces the alkaline shift in as citrate, that potentially could have yielded HCO3⫺ in
blood pH. Respiratory responses to disturbed blood pH be- the body, these should also be subtracted. Since the
gin within minutes and are maximal in about 12 to 24 hours. amount of free H⫹ excreted is negligible, this is omitted
from the equation.

RENAL REGULATION OF PH Hydrogen Ions Are Added to Urine as

The kidneys play a critical role in maintaining acid-base It Flows Along the Nephron
balance. If there is excess acid in the body, they remove As the urine flows along the tubule, from Bowman’s capsule
H⫹, or if there is excess base, they remove HCO3⫺. The on through the collecting ducts, three processes occur: fil-
usual challenge is to remove excess acid. As we have tered HCO3⫺ is reabsorbed, titratable acid is formed, and
learned, strong acids produced by metabolism are first ammonia is added to the tubular urine. All three processes
buffered by body buffer bases, particularly HCO3⫺. The involve H⫹ secretion (urinary acidification) by the tubular
kidneys then must eliminate H⫹ in the urine and restore the epithelium. The nature and magnitude of these processes
depleted HCO3⫺. vary in different nephron segments. Figure 25.5 summarizes
Little of the H⫹ excreted in the urine is present as free measurements of tubular fluid pH along the nephron and
⫹
H . For example, if the urine has its lowest pH value shows ammonia movements in various nephron segments.
(pH ⫽ 4.5), [H⫹] is only 0.03 mEq/L. With a typical daily
urine output of 1 to 2 L, the amount of acid the body must Acidification in the Proximal Convoluted Tubule. The
dispose of daily (about 70 mEq) obviously is not excreted pH of the glomerular ultrafiltrate, at the beginning of the
in the free form. Most of the H⫹ combines with urinary proximal tubule, is identical to that of the plasma from
buffers to be excreted as titratable acid and as NH4⫹. which it is derived (7.4). H⫹ ions are secreted by the prox-
Titratable acid is measured from the amount of strong imal tubule epithelium into the tubule lumen; about two
base (NaOH) needed to bring the urine pH back to the thirds of this is accomplished by a Na⫹/H⫹ exchanger and
pH of the blood (usually, 7.40). It represents the amount about one third by H⫹-ATPase in the brush border mem-
of H ⫹ ions that are excreted, combined with urinary brane. Tubular fluid pH falls to a value of about 6.7 by the
buffers such as phosphate, creatinine, and other bases. end of the proximal convoluted tubule (see Fig. 25.5).
The largest component of titratable acid is normally The drop in pH is modest for two reasons: buffering of
phosphate, that is, H2PO4⫺. secreted H⫹ and the high permeability of the proximal
Hydrogen ions secreted by the renal tubules also com- tubule epithelium to H⫹. The glomerular filtrate and tubule
bine with the free base NH3 and are excreted as NH4⫹. fluid contain abundant buffer bases, especially HCO3⫺,
Ammonia (a term that collectively includes both NH3 and which soak up secreted H⫹, minimizing a fall in pH. The
NH4⫹) is produced by the kidney tubule cells and is se- proximal tubule epithelium is rather leaky to H⫹, so that
creted into the urine. Because the pKa for NH4⫹ is high any gradient from urine to blood, established by H⫹ secre-
(9.0), most of the ammonia in the urine is present as NH4⫹. tion, is soon limited by the diffusion of H⫹ out of the
For this reason, too, NH4⫹ is not appreciably titrated when tubule lumen into the blood surrounding the tubules
titratable acid is measured. Urinary ammonia is measured Most of the H⫹ ions secreted by the nephron are se-
by a separate, often chemical, method. creted in the proximal convoluted tubule and are used to
bring about the reabsorption of filtered HCO3⫺. Secreted
Renal Net Acid Excretion Equals the H⫹ ions are also buffered by filtered phosphate to form
Sum of Urinary Titratable Acid and titratable acid. Ammonia is produced by proximal tubule
cells, mainly from glutamine. It is secreted into the tubular
Ammonia Minus Urinary Bicarbonate
urine by the diffusion of NH3, which then combines with a
In stable acid-base balance, net acid excretion by the kid- secreted H⫹ to form NH4⫹, or via the brush border mem-
neys equals the net rate of H⫹ addition to the body by me- brane Na⫹/H⫹ exchanger, which can operate in a
tabolism or other processes, assuming that other routes of Na⫹/NH4⫹ exchange mode.
434 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

Acidification in the Distal Nephron. The distal nephron

Glutamine Distal
convoluted (distal convoluted tubule, connecting tubule, and collect-
Collecting ing duct) differs from the proximal portion of the nephron
NH4+ tubule
duct
pH = 6.7 in its H⫹ transport properties. It secretes far fewer H⫹ ions,
H+ NH3
and they are secreted primarily via an electrogenic H⫹-
Na+ ATPase or an electroneutral H⫹/K⫹-ATPase. The distal
nephron is also lined by “tight” epithelia, so little secreted
H++ NH3 NH4+ H⫹ diffuses out of the tubule lumen, making steep urine-to-
blood pH gradients possible (see Fig. 25.5). Final urine pH
2Cl- is typically about 6, but may be as low as 4.5.
Na+ NH4+ The distal nephron usually almost completely reabsorbs
pH = 7.4 Proximal
NH4 + the small quantities of HCO3⫺ that were not reabsorbed by
convoluted
tubule H+ + NH3
more proximal nephron segments. Considerable titratable
Na+
acid forms as the urine is acidified. Ammonia, which was re-
NH3 absorbed by the ascending limb of the Henle loop and has
NH4+ accumulated in the medullary interstitial space, diffuses as
NH4+ NH4+ lipid-soluble NH3 into collecting duct urine and combines
H+ + NH3 with secreted H⫹ to form NH4⫹. The collecting duct ep-
Na+ ithelium is impermeable to the lipid-insoluble NH4⫹, so am-
NH3 monia is trapped in an acidic urine and excreted as NH4⫹
+ (see Fig. 25.5). The intercalated cells of the collecting duct
H+ H+ are involved in acid-base transport and are of two major
types: an acid-secreting ␣-intercalated cell and a bicarbon-
ate-secreting ␤-intercalated cell. The ␣-intercalated cell has
a vacuolar type of H⫹-ATPase (the same kind as is found in
NH4+ lysosomes, endosomes, and secretory vesicles) and an
pH = 7.4 H⫹/K⫹-ATPase (similar to that found in stomach and colon
epithelial cells) in the luminal plasma membrane and a
Cl⫺/HCO3⫺ exchanger in the basolateral plasma membrane
(Fig. 25.6). The ␤-intercalated cell has the opposite polarity.
A more acidic blood pH results in the insertion of cyto-
pH ~ 6
plasmic H⫹ pumps into the luminal plasma membrane of ␣-
FIGURE 25.5 Acidification along the nephron. The pH of intercalated cells and enhanced H⫹ secretion. If the blood
tubular urine decreases along the proximal con- is made alkaline, HCO3⫺ secretion by ␤-intercalated cells
voluted tubule, rises along the descending limb of the Henle is increased. Because the amounts of HCO3⫺ secreted are
loop, falls along the ascending limb, and reaches its lowest values ordinarily small compared to the amounts filtered and re-
in the collecting ducts. Ammonia (⫽NH3 ⫹ NH4⫹) is chiefly absorbed, HCO3⫺ secretion will not be included in the re-
produced in proximal tubule cells and is secreted into the tubular maining discussion.
urine. NH4⫹ is reabsorbed in the thick ascending limb and accu-
mulates in the kidney medulla. NH3 diffuses into acidic collecting
duct urine, where it is trapped as NH4⫹. The Reabsorption of Filtered HCO3⫺ Restores Lost
HCO3⫺ to the Blood
Acidification in the Henle Loop. Along the descending HCO3⫺ is freely filtered at the glomerulus, about 4,320
limb of the Henle loop, the pH of tubular fluid rises (from mEq/day (180 L/day ⫻ 24 mEq/L). Urinary loss of even a
6.7 to 7.4). This rise is explained by an increase in intralu- small portion of this HCO3⫺ would lead to acidic blood
minal [HCO3⫺] caused by water reabsorption. Ammonia is and impair the body’s ability to buffer its daily load of meta-
secreted along the descending limb. bolically produced H⫹. The kidney tubules have the im-
The tubular fluid is acidified by secretion of H⫹ along portant task of recovering the filtered HCO3⫺ and return-
the ascending limb via a Na⫹/H⫹ exchanger. Along the ing it to the blood.
thin ascending limb, ammonia is passively reabsorbed. Figure 25.7 shows how HCO3⫺ filtration, reabsorption,
Along the thick ascending limb, NH4⫹ is mostly actively and excretion normally vary with plasma [HCO3⫺]. This
reabsorbed by the Na-K-2Cl cotransporter in the luminal type of graph should be familiar (Fig. 23.8). The y-axis of
plasma membrane (NH4⫹ substitutes for K⫹). Some NH4⫹ the graph is unusual, however, because amounts of HCO3⫺
can be reabsorbed via a luminal plasma membrane K⫹ per minute are factored by the GFR. The data are expressed
channel. Also, some NH4⫹ can be passively reabsorbed be- in this way because the maximal rate of tubular reabsorp-
tween cells in this segment; the driving force is the lumen tion of HCO3⫺ varies with GFR. The amount of HCO3⫺
positive transepithelial electrical potential difference. Am- excreted in the urine per unit time is calculated as the dif-
monia may undergo countercurrent multiplication in the ference between filtered and reabsorbed amounts. At low
Henle loop, leading to an ammonia concentration gradient plasma concentrations of HCO3⫺ (below about 26 mEq/L),
in the kidney medulla. The highest concentrations are at all of the filtered HCO3⫺ is reabsorbed. Because the plasma
the tip of the papilla. [HCO3⫺] and pH were decreased by ingestion of an acid-
 CHAPTER 25 Acid-Base Balance 435

Blood α-Intercalated cell Collecting

duct urine
HCO3-
ATP H+
Cl- ADP + Pi
H+
Cl-
ATP
ADP + Pi
K+

Blood β-Intercalated cell Collecting

duct urine

H+ ATP
H+ ADP + Pi
ATP HCO3-
ADP + Pi The filtration, reabsorption, and excretion
Cl- FIGURE 25.7
K+ of HCO3⫺. Decreases in plasma [HCO3⫺]
Cl- were produced by ingestion of NH4Cl and increases were pro-
duced by intravenous infusion of a solution of NaHCO3. All the
filtered HCO3⫺ was reabsorbed below a plasma concentration of
Collecting duct intercalated cells. The ␣- about 26 mEq/L. Above this value (“threshold”), appreciable
FIGURE 25.6
intercalated cell secretes H⫹ via an electro- quantities of filtered HCO3⫺ were excreted in the urine.
genic, vacuolar H⫹-ATPase and electroneutral H⫹/K⫹-ATPase (Adapted from Pitts RF, Ayer JL, Schiess WA. The renal regula-
and adds HCO3⫺ to the blood via a basolateral plasma mem- tion of acid-base balance in man. III. The reabsorption and excre-
brane Cl⫺/HCO3⫺ exchanger. The ␤-intercalated cell, which is tion of bicarbonate. J Clin Invest 1949;28:35–44.)
located in cortical collecting ducts, has the opposite polarity
and secretes HCO3⫺.

an electrogenic cotransporter in the basolateral membrane

that simultaneously transports three HCO3⫺ and one Na⫹.
ifying salt (NH4Cl), it makes good sense that the kidneys
The reabsorption of filtered HCO3⫺ does not result in
conserve filtered HCO3⫺ in this situation. ⫹
H excretion or the formation of any “new” HCO3⫺. The
If the plasma [HCO3⫺] is raised to high levels because of
secreted H⫹ is not excreted because it combines with fil-
intravenous infusion of solutions containing NaHCO3 for
tered HCO3⫺ that is, indirectly, reabsorbed. There is no
example, filtered HCO3⫺ exceeds the reabsorptive capacity
net addition of HCO3⫺ to the body in this operation. It is
of the tubules and some HCO3⫺ will be excreted in the urine
simply a recovery or reclamation process.
(see Fig. 25.7). This also makes good sense. If the blood is too
alkaline, the kidneys excrete HCO3⫺. This loss of base
would return the pH of the blood to its normal value. Excretion of Titratable Acid and Ammonia
At the cellular level (see Fig. 25.8), filtered HCO3⫺ is Generates New Bicarbonate
not reabsorbed directly across the tubule’s luminal plasma
membrane as, for example, is glucose. Instead, filtered When H⫹ is excreted as titratable acid and ammonia, new
HCO3⫺ is reabsorbed indirectly via H⫹ secretion in the HCO3⫺ is formed and added to the blood. New HCO3⫺
following way. About 90% of the filtered HCO3⫺ is reab- replaces the HCO3⫺ used to buffer the strong acids pro-
sorbed in the proximal convoluted tubule, and we will em- duced by metabolism.
phasize events at this site. H⫹ is secreted into the tubule lu- The formation of new HCO3⫺ and the excretion of H⫹
men mainly via the Na⫹/H⫹ exchanger in the luminal are like two sides of the same coin. This fact is apparent if
membrane. It combines with filtered HCO3⫺ to form we assume that H2CO3 is the source of H⫹:
H2CO3. Carbonic anhydrase (CA) in the luminal mem- H⫹ (urine)
brane (brush border) of the proximal tubule catalyzes the z
dehydration of H2CO3 to CO2 and water in the lumen. CO2 ⫹ H2O H2CO3 (23)
x
The CO2 diffuses back into the cell.
HCO3⫺ (blood)
Inside the cell, the hydration of CO2 (catalyzed by in-
tracellular CA) yields H2CO3, which instantaneously forms A loss of H⫹ in the urine is equivalent to adding new HCO3⫺ to the
H⫹ and HCO3⫺. The H⫹ is secreted into the lumen, and blood. The same is true if H⫹ is lost from the body via an-
the HCO3⫺ ion moves into the blood surrounding the other route, such as by vomiting of acidic gastric juice. This
tubules. In proximal tubule cells, this movement is favored process leads to a rise in plasma [HCO3⫺]. Conversely, a loss
by the inside negative membrane potential of the cell and by of HCO3⫺ from the body is equivalent to adding H⫹ to the blood.
436 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

the urine pH is lowered, more titratable acid can form. The

supply of phosphate and other buffers is usually limited. To
Peritubular Tubular Tubular excrete large amounts of acid, the kidneys must rely on in-
blood epithelium urine creased ammonia excretion.

Na+ Ammonia Excretion. Figure 25.10 shows a cell model for

Na+ the excretion of ammonia. Most ammonia is synthesized in
HCO3- HCO3-
proximal tubule cells by deamidation and deamination of
H+ HCO3- the amino acid glutamine:
(reclaimed) H+
CO2 CO2 + H2O H2CO3
(filtered) NH4⫹ NH4⫹
CA H2CO3
z z
Glutamine → Glutamate⫺ → ␣-Ketoglutarate2 (24)
CA
Glutaminase Glutamate dehydrogenase
CO2 H2O
As discussed earlier, ammonia is secreted into the urine
by two mechanisms. As NH3, it diffuses into the tubular
urine; as NH4⫹, it substitutes for H⫹ on the Na⫹/H⫹ ex-
changer. In the lumen, NH3 combines with secreted H⫹ to
form NH4⫹, which is excreted.
FIGURE 25.8 A cell model for HCO32 reabsorption. Fil- For each mEq of H⫹ excreted as NH4⫹, one mEq of new
tered HCO3⫺ combines with secreted H⫹ and HCO3⫺ is added to the blood. The hydration of CO2 in the
is reabsorbed indirectly. Carbonic anhydrase (CA) is present in
the cells and in the proximal tubule on the brush border.
tubule cell produces H⫹ and HCO3⫺, as described earlier.
Two H⫹s are consumed when the anion ␣-ketoglutarate2– is
converted into CO2 and water or into glucose in the cell.
Titratable Acid Excretion. Figure 25.9 shows a cell model The new HCO3⫺ returns to the blood along with Na⫹.
for the formation of titratable acid. In this figure, H2PO4⫺ If excess acid is added to the body, urinary ammonia ex-
is the titratable acid formed. H⫹ and HCO3⫺ are produced cretion is increased for two reasons. First, a more acidic
in the cell from H2CO3. The secreted H⫹ combines with urine traps more ammonia (as NH4⫹) in the urine. Second,
the basic form of the phosphate (HPO42–) to form the acid renal ammonia synthesis from glutamine increases over sev-
phosphate (H2PO4⫺). The secreted H⫹ replaces one of the
Na⫹ ions accompanying the basic phosphate. The new
HCO3⫺ generated in the cell moves into the blood, to-
gether with Na⫹. For each mEq of H⫹ excreted in the urine
as titratable acid, a mEq of new HCO3⫺ is added to the
blood. This process eliminates H⫹ in the urine, replaces Peritubular Tubular Tubular
blood urine
ECF HCO3⫺, and restores a normal blood pH. epithelium
The amount of titratable acid excreted depends on two
factors: the pH of the urine and the availability of buffer. If Glutamine
Na+
2 NH4+

NH4+ Cl-
Peritubular Tubular Tubular α-Ketoglutarate2- NH3 NH3
blood epithelium urine +
NH4+ Cl-
Glucose or H+
CO2 + H2O H+
Na+
Na+ +
2 Na
HCO3- HCO3- HPO4 2-2Na+ 2H+
HCO3- 2 HCO3- Na+
(new) H+ H+ (filtered)
(new)
CO2 CO2 + H2O H2CO3
CA CO2 2 CO2 + 2 H2O 2 H2CO3
H2PO4-Na+ CA
(excreted)

FIGURE 25.10
A cell model for renal synthesis and excre-
tion of ammonia. Ammonium ions are formed
FIGURE 25.9
A cell model for the formation of titratable from glutamine in the cell and are secreted into the tubular urine
acid. Titratable acid (e.g., H2PO4⫺) is formed (top). H⫹ from H2CO3 (bottom) is consumed when ␣-ketoglu-
when secreted H⫹ is bound to a buffer base (e.g., HPO42–) in the tarate is converted into glucose or CO2 and H2O. New HCO3⫺
tubular urine. For each mEq of titratable acid excreted, a mEq of is added to the peritubular capillary blood—1 mEq for each mEq
new HCO3⫺ is added to the peritubular capillary blood. of NH4⫹ excreted in the urine.
 CHAPTER 25 Acid-Base Balance 437

eral days. Enhanced renal ammonia synthesis and excretion 1) Hydration of CO2 in the cells, forming H2CO3 and
is a lifesaving adaptation because it allows the kidneys to yielding H⫹ for secretion
remove large H⫹ excesses and add more new HCO3⫺ to 2) Dehydration of H2CO3 to H2O and CO2 in the
the blood. Also, the excreted NH4⫹ can substitute in the proximal tubule lumen, an important step in the reabsorp-
urine for Na⫹ and K⫹, diminishing the loss of these cations. tion of filtered HCO3⫺
With severe metabolic acidosis, ammonia excretion may If carbonic anhydrase is inhibited (usually by a drug),
increase almost 10-fold. large amounts of filtered HCO3⫺ may escape reabsorption.
This situation leads to a fall in blood pH.
Several Factors Influence Renal Excretion Sodium Reabsorption. Na⫹ reabsorption is closely
of Hydrogen Ions linked to H⫹ secretion. In the proximal tubule, the two ions
Several factors influence the renal excretion of H⫹, includ- are directly linked, both being transported by the Na⫹/H⫹
ing intracellular pH, arterial blood PCO2, carbonic anhy- exchanger in the luminal plasma membrane. The relation is
drase activity, Na⫹ reabsorption, plasma [K⫹], and aldos- less direct in the collecting ducts. Enhanced Na⫹ reabsorp-
terone (Fig. 25.11). tion in the ducts leads to a more negative intraluminal elec-
trical potential, which favors H⫹ secretion by its electro-
Intracellular pH. The pH in kidney tubule cells is a key genic H⫹-ATPase. The avid renal reabsorption of Na⫹
factor influencing the secretion and, therefore, the excretion observed in states of volume depletion is accompanied by a
of H⫹. A fall in pH (increased [H⫹]) enhances H⫹ secretion. parallel rise in urinary H⫹ excretion.
A rise in pH (decreased [H⫹]) lowers H⫹ secretion.
Plasma Potassium Concentration. Changes in plasma
Arterial Blood PCO2. An increase in PCO2 increases the [K⫹] influence the renal excretion of H⫹. A fall in plasma
formation of H⫹ from H2CO3, leading to enhanced renal [K⫹] favors the movement of K⫹ from body cells into in-
H⫹ secretion and excretion—a useful compensation for any terstitial fluid (or blood plasma) and a reciprocal move-
condition in which the blood contains too much H2CO3. ment of H⫹ into cells. In the kidney tubule cells, these
(This will be discussed later, when we consider respiratory movements lower intracellular pH and increase H⫹ se-
acidosis.) A decrease in PCO2 results in lowered H⫹ secretion cretion. K⫹ depletion also stimulates ammonia synthesis
and, consequently, less complete reabsorption of filtered by the kidneys. The result is the complete reabsorption
HCO3⫺ and a loss of base in the urine (a useful compensa- of filtered HCO3⫺ and the enhanced generation of new
tion for respiratory alkalosis, also discussed later). HCO 3 ⫺ as more titratable acid and ammonia are ex-
creted. Consequently, hypokalemia (or a decrease in
Carbonic Anhydrase Activity. The enzyme carbonic an- body K ⫹ stores) leads to increased plasma [HCO 3 ⫺ ]
hydrase catalyzes two key reactions in urinary acidification: (metabolic alkalosis). Hyperkalemia (or excess K⫹ in the
body) results in the opposite changes: an increase in in-
tracellular pH, decreased H⫹ secretion, incomplete reab-
sorption of filtered HCO 3 ⫺ , and a fall in plasma
[HCO3⫺] (metabolic acidosis).
Peritubular Tubular Tubular
blood epithelium urine Aldosterone. Aldosterone stimulates the collecting ducts
to secrete H⫹ by three actions:
1) It directly stimulates the H⫹-ATPase in collecting
Increased H+
plasma H+-ATPase duct ␣-intercalated cells.
aldosterone 2) It enhances collecting duct Na⫹ reabsorption, which
Decreased
leads to a more negative intraluminal potential and, conse-
intracellular quently, promotes H⫹ secretion by the electrogenic H⫹-
pH Na+ Increased ATPase.
H+ H+ sodium 3) It promotes K⫹ secretion. This response leads to hy-
Na+ reabsorption pokalemia, which increases renal H⫹ secretion.
Decreased
K+
K+ Hyperaldosteronism results in enhanced renal H⫹ ex-
cretion and an alkaline blood pH; the opposite occurs with
H+ hypoaldosteronism.
HCO3- HCO3- H+

CO2 CO2 + H2O H2CO3 pH gradient. The secretion of H⫹ by the kidney tubules
Increased CA and collecting ducts is gradient-limited. The collecting
Carbonic anhydrase
PCO2 activity
ducts cannot lower the urine pH below 4.5, corresponding
to a urine/plasma [H⫹] gradient of 10⫺4.5/10⫺7.4 or 800/1
when the plasma pH is 7.4. If more buffer base (NH3,
HPO42–) is available in the urine, more H⫹ can be secreted
FIGURE 25.11 Factors leading to increased H⫹ secretion before the limiting gradient is reached. In some kidney
by the kidney tubule epithelium. (See text tubule disorders, the secretion of H⫹ is gradient-limited
for details.) (see Clinical Focus Box 25.1).
438 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

CLINICAL FOCUS BOX 25.1

Renal Tubular Acidosis proximal tubule is impaired, leading to excessive losses of

Renal tubular acidosis (RTA) is a group of kidney disor- HCO3⫺ in the urine. As a consequence, the plasma [HCO3⫺]
ders characterized by chronic metabolic acidosis, a normal falls and chronic metabolic acidosis ensues. In the new
plasma anion gap, and the absence of renal failure. The steady state, the tubules are able to reabsorb the filtered
kidneys show inadequate H⫹ secretion by the distal HCO3⫺ load more completely because the filtered load is
nephron, excessive excretion of HCO3⫺, or reduced excre- reduced. The distal nephron is no longer overwhelmed by
tion of NH4⫹. HCO3⫺ and the urine pH is acidic. In type 2 RTA, the ad-
In classic type 1 (distal) RTA, the ability of the col- ministration of an NH4Cl challenge results in a urine pH be-
lecting ducts to lower urine pH is impaired. This condition low 5.5. This disorder may be inherited, may be associated
can be caused by inadequate secretion of H⫹ (defective with several acquired conditions that result in a general-
H⫹-ATPase or H⫹/K⫹-ATPase) or abnormal leakiness of ized disorder of proximal tubule transport, or may result
the collecting duct epithelium so that secreted H⫹ ions from the inhibition of proximal tubule carbonic anhydrase
diffuse back from lumen to blood. Because the urine pH is by drugs such as acetazolamide. Treatment requires the
inappropriately high, titratable acid excretion is dimin- daily administration of large amounts of alkali because
ished and trapping of ammonia in the urine (as NH4⫹) is when the plasma [HCO3⫺] is raised, excessive urinary ex-
decreased. Type 1 RTA may be the result of an inherited cretion of filtered HCO3⫺ occurs.
defect, autoimmune disease, treatment with lithium or Type 4 RTA (there is no type 3 RTA) is also known as
the antibiotic amphotericin B, or the result of diseases of hyperkalemic distal RTA. Collecting duct secretion of
the kidney medulla. A diagnosis of this form of RTA is es- both K⫹ and H⫹ is reduced, explaining the hyperkalemia
tablished by challenging the subject with a standard oral and metabolic acidosis. Hyperkalemia reduces renal am-
dose of NH4Cl and measuring the urine pH for the next monia synthesis, resulting in reduced net acid excretion
several hours. This results in a urine pH below 5.0 in and a fall in plasma [HCO3⫺]. The urine pH can go below
healthy people. In subjects with type 1 RTA, however, 5.5 after an NH4Cl challenge because there is little ammo-
urine pH will not decrease below 5.5. Treatment of type 1 nia in the urine to buffer secreted H⫹. The underlying dis-
RTA involves daily administration of modest amounts of order is a result of inadequate production of aldosterone or
alkali (HCO3⫺, citrate) sufficient to cover daily metabolic impaired aldosterone action. Treatment of type 4 RTA re-
acid production. quires lowering the plasma [K⫹] to normal; if this therapy
In type 2 (proximal) RTA, HCO3⫺ reabsorption by the is successful, alkali may not be needed.

REGULATION OF INTRACELLULAR PH
The intracellular and extracellular fluids are linked by ex-
changes across plasma membranes of H⫹, HCO3⫺, various H+
acids and bases, and CO2. By stabilizing ECF pH, the body
helps to protect intracellular pH.
Metabolism
If H⫹ ions were passively distributed across plasma
H+
membranes, intracellular pH would be lower than what is
seen in most body cells. In skeletal muscle cells, for exam-
- +
CO2 CO2
ple, we can calculate from the Nernst equation (see Chap-
ter 2) and a membrane potential of ⫺90 mV that cytosolic H+
pH should be 5.9 if ECF pH is 7.4; actual measurements,
however, indicate a pH of 6.9. From this discrepancy, two
conclusions are clear: H⫹ ions are not at equilibrium across
the plasma membrane, and the cell must use active mecha- H+
nisms to extrude H⫹.
Cl-
Cells are typically threatened by acidic metabolic end- HCO3- Na+
products and by the tendency for H⫹ to diffuse into the cell
down the electrical gradient (Fig. 25.12). H⫹ is extruded by
Na⫹/H⫹ exchangers, which are present in nearly all body
Na+
cells. Five different isoforms of these exchangers (desig-
nated NHE1, NHE2, etc.), with different tissue distribu-
tions, have been identified. These transporters exchange FIGURE 25.12 Cell acid-base balance. Body cells usually
maintain a constant intracellular pH. The cell is
one H⫹ for one Na⫹ and, therefore, function in an electri- acidified by the production of H⫹ from metabolism and the in-
cally neutral fashion. Active extrusion of H⫹ keeps the in- flux of H⫹ from the ECF (favored by the inside negative plasma
ternal pH within narrow limits. membrane potential). To maintain a stable intracellular pH, the
The activity of the Na⫹/H⫹ exchanger is regulated by cell must extrude hydrogen ions at a rate matching their input.
intracellular pH and a variety of hormones and growth fac- Many cells also possess various HCO3⫺ transporters (not de-
tors (Fig. 25.13). Not surprisingly, an increase in intracellu- picted), which defend against excess acid or base.
 CHAPTER 25 Acid-Base Balance 439

Normal Arterial Blood Plasma

TABLE 25.2
Acid-Base Values

Mean Rangea
pH 7.40 7.35–7.45
[H⫹], nmol/L 40 45–35
Naⴙ/Hⴙ PCO2, mm Hg 40 35–45
exchanger [HCO3⫺], mEq/L 24 22–26
a
The range extends from 2 standard deviations below to 2 standard
deviations above the mean and encompasses 95% of the healthy
population.

bance. Acidosis is an abnormal process that tends to pro-

⫹ ⫹ duce acidemia. Alkalosis is an abnormal process that tends
FIGURE 25.13 The plasma membrane Na /H exchanger.
This exchanger plays a key role in regulating to produce alkalemia. If there is too much or too little CO2,
intracellular pH in most body cells and is activated by a decrease a respiratory disturbance is present. If the problem is too
in cytoplasmic pH. Many hormones and growth factors, acting much or too little HCO3⫺, a metabolic (or nonrespiratory)
via intracellular second messengers and protein kinases, can in- disturbance of acid-base balance is present. Table 25.3
crease (⫹) or decrease (⫺) the activity of the exchange. summarizes the changes in blood pH (or [H⫹]), plasma
[HCO3⫺], and PCO2 that occur in each of the four simple
acid-base disturbances.
lar [H⫹] stimulates the exchanger but not only because of In considering acid-base disturbances, it is helpful to re-
more substrate (H⫹) for the exchanger. H⫹ also stimulates call the Henderson-Hasselbalch equation for
the exchanger by protonating an activator site on the cyto- HCO3⫺/CO2:
plasmic side of the exchanger, making the exchanger more
effective in dealing with the threat of intracellular acidosis. [HCO3⫺]
Many hormones and growth factors, via intracellular sec- pH ⫽ 6.10 ⫹ log ᎏᎏ (25)
0.03 PCO2
ond messengers, activate various protein kinases that stim-
ulate or inhibit the Na⫹/H⫹ exchanger. In this way, they If the primary problem is a change in [HCO3⫺] or PCO2,
produce changes in intracellular pH, which may lead to the pH can be brought closer to normal by changing the
changes in cell activity. other member of the buffer pair in the same direction. For ex-
Besides extruding H⫹, the cell can deal with acids and ample, if PCO2 is primarily decreased, a decrease in plasma
bases in other ways. In some cells, various HCO3⫺ trans- [HCO3⫺] will minimize the change in pH. In various acid-
porting systems (e.g., Na⫹-dependent and Na⫹-independ- base disturbances, the lungs adjust the blood PCO2 and the
ent Cl⫺/HCO3⫺ exchangers) may be present in plasma kidneys adjust the plasma [HCO3⫺] to reduce departures
membranes. These exchangers may be activated by of pH from normal; these adjustments are called compen-
changes in intracellular pH. Cells have large stores of pro- sations (Table 25.4). Compensations generally do not
tein and organic phosphate buffers, which can bind or re- bring about normal blood pH.
lease H⫹. Various chemical reactions in cells can also use
up or release H⫹. For example, the conversion of lactic acid
to CO2 and water to glucose effectively disposes of acid. In Respiratory Acidosis Results From an
addition, various cell organelles may sequester H⫹. For ex- Accumulation of Carbon Dioxide
ample, H⫹-ATPase in endosomes and lysosomes pumps
H⫹ out of the cytosol into these organelles. In summary, Respiratory acidosis is an abnormal process characterized
ion transport, buffering mechanisms, and metabolic reac- by CO2 accumulation. The CO2 build-up pushes the fol-
tions all ensure a relatively stable intracellular pH. lowing reactions to the right:
CO2 ⫹ H2O H2CO3 H⫹ ⫹ HCO3⫺ (26)
Blood [H2CO3] increases, leading to an increase in [H⫹]
DISTURBANCES OF ACID-BASE BALANCE
or a fall in pH. Respiratory acidosis is usually caused by a
Table 25.2 lists the normal values for the pH (or [H⫹]), failure to expire metabolically produced CO2 at an ade-
PCO2, and [HCO3⫺] of arterial blood plasma. A blood pH quate rate, leading to accumulation of CO2 in the blood
of less than 7.35 ([H⫹] ⬎ 45 nmol/L) indicates acidemia. A and a fall in blood pH. This disturbance may be a result of
blood pH above 7.45 ([H⫹] ⬍ 35 nmol/L) indicates alka- a decrease in overall alveolar ventilation (hypoventilation)
lemia. The range of pH values compatible with life is ap- or, as occurs commonly in lung disease, a mismatch be-
proximately 6.8 to 7.8 ([H⫹] ⫽ 160 to 16 nmol/L). tween ventilation and perfusion. Respiratory acidosis also
Four simple acid-base disturbances may lead to an ab- occurs if a person breathes CO2-enriched air.
normal blood pH: respiratory acidosis, respiratory alkalo-
sis, metabolic acidosis, and metabolic alkalosis. The word Chemical Buffering. In respiratory acidosis, more than
“simple” indicates a single primary cause for the distur- 95% of the chemical buffering occurs within cells. The cells
440 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

TABLE 25.3 Directional Changes in Arterial Blood Plasma Values in the Four Simple Acid-Base Disturbancesa

Arterial Plasma

Disturbance pH [H⫹] [HCO3⫺] PCO2 Compensatory Response

Respiratory acidosis ↓ ↑ ↑ ⇑ Kidneys increase H⫹ excretion
Respiratory alkalosis ↑ ↓ ↓ ⇓ Kidneys increase HCO3⫺excretion
Metabolic acidosis ↓ ↑ ⇓ ↓ Alveolar hyperventilation; kidneys increase
H⫹ excretion
Metabolic alkalosis ↑ ↓ ⇑ ↑ Alveolar hypoventilation; kidneys increase
HCO3⫺excretion
a
Heavy arrows indicate the main effect.

contain many proteins and organic phosphates that can Renal Compensation. The kidneys compensate for respi-
bind H⫹. For example, hemoglobin (Hb) in red blood cells ratory acidosis by adding more H⫹ to the urine and adding
combines with H⫹ from H2CO3, minimizing the increase new HCO3⫺ to the blood. The increased PCO2 stimulates
in free H⫹. Recall from Chapter 21 the buffering reaction: renal H⫹ secretion, which allows the reabsorption of all fil-
tered HCO3⫺. Excess H⫹ is excreted as titratable acid and
H2CO3 ⫹ HbO2⫺ HHb ⫹ O2 ⫹ HCO3⫺ (27)
NH4⫹; these processes add new HCO3⫺ to the blood,
This reaction raises the plasma [HCO3⫺]. In acute respira- causing plasma [HCO3⫺] to rise. This compensation takes
tory acidosis, such chemical buffering processes in the body several days to fully develop.
lead to an increase in plasma [HCO3⫺] of about 1 mEq/L for With chronic respiratory acidosis, plasma [HCO3⫺] in-
each 10 mm Hg increase in PCO2 (see Table 25.4). Bicar- creases, on average, by 4 mEq/L for each 10 mm Hg rise in
bonate is not a buffer for H2CO3 because the reaction PCO2 (see Table 25.4). This rise exceeds that seen with
acute respiratory acidosis because of the renal addition of
H2CO3 ⫹ HCO3⫺ HCO3⫺ ⫹ H2CO3 (28)
HCO3⫺ to the blood. One would expect a person with
is simply an exchange reaction and does not affect the pH. chronic respiratory acidosis and a PCO2 of 70 mm Hg to
An example illustrates how chemical buffering reduces a have an increase in plasma HCO3⫺ of 12 mEq/L. The
fall in pH during respiratory acidosis. Suppose PCO2 in- blood pH would be 7.33:
creased from a normal value of 40 mm Hg to 70 mm Hg
([CO2(d)] ⫽ 2.l mmol/L). If there were no body buffer bases [24 ⫹ 12]
that could accept H⫹ from H2CO3 (i.e., if there was no pH ⫽ 6.10 ⫹ log ᎏᎏ ⫽ 7.33 (31)
[2.1]
measurable increase in [HCO3⫺]), the resulting pH would
be 7.16:

[24]
pH ⫽ 6.10 ⫹ log ᎏ ⫽ 7.16 (29) TABLE 25.4 Compensatory Responses in Acid-Base
[2.1] Disturbancesa
Respiratory acidosis
In acute respiratory acidosis, a 3 mEq/L increase in Acute 1 mEq/L increase in plasma [HCO3⫺]
plasma [HCO3⫺] occurs with a 30 mm Hg rise in PCO2 (see for each 10 mm Hg increase in PCO2b
Table 25.4). Therefore, the pH is 7.21: Chronic 4 mEq/L increase in plasma [HCO3⫺]
for each 10 mm Hg increase in PCO2c
[24 ⫹ 3] ⫽ 7.21
pH ⫽ 6.10 ⫹ log ᎏ (30)
Respiratory alkalosis
[2.1] Acute 2 mEq/L decrease in plasma [HCO3⫺]
for each 10 mm Hg decrease in PCO2d
Chronic 4 mEq/L decrease in plasma [HCO3⫺]
The pH of 7.21 is closer to a normal pH because body
for each 10 mm Hg decrease in PCO2d
buffer bases (mainly intracellular buffers) such as proteins Metabolic acidosis 1.3 mm Hg decrease in PCO2 for each
and phosphates combined with H⫹ ions liberated from 1 mEq/L decrease in plasma [HCO3⫺]d
H2CO3. Metabolic alkalosis 0.7 mm Hg increase in PCO2 for each
1 mEq/L increase in plasma [HCO3⫺]d
Respiratory Compensation. Respiratory acidosis pro-
From Valtin H, Gennari FJ. Acid-Base Disorders. Basic Concepts and
duces a rise in PCO2 and a fall in pH and is often associated Clinical Management. Boston: Little, Brown, 1987.
with hypoxia. These changes stimulate breathing (see a
Empirically determined average changes measured in people with
Chapter 22) and diminish the severity of the acidosis. In simple acid-base disorders.
b
other words, a person would be worse off if the respiratory This change is primarily a result of chemical buffering.
c
This change is primarily a result of renal compensation.
system did not reflexively respond to the abnormalities in d
This change is a result of respiratory compensation.
blood PCO2, pH, and PO2.
 CHAPTER 25 Acid-Base Balance 441

With chronic respiratory acidosis, time for renal com- chronic hyperventilation and a PCO2 of 20 mm Hg, the
pensation is allowed, so blood pH (in this example, 7.33) is blood pH is
much closer to normal than is observed during acute respi-
ratory acidosis (pH 7.21). [24 ⫺ 8]
pH ⫽ 6.10 ⫹ log ᎏᎏ ⫽ 7.53 (34)
[0.6]
Respiratory Alkalosis Results From an
Excessive Loss of Carbon Dioxide This pH is closer to normal than the pH of 7.62 of acute
respiratory alkalosis. The difference between the two situ-
Respiratory alkalosis is most easily understood as the ations is largely a result of renal compensation.
opposite of respiratory acidosis; it is an abnormal
process causing the loss of too much CO 2 . This loss
causes blood [H2CO3] and, thus, [H⫹] to fall (pH rises). Metabolic Acidosis Results From a Gain of
Alveolar hyperventilation causes respiratory alkalosis. Noncarbonic Acid or a Loss of Bicarbonate
Metabolically produced CO2 is flushed out of the alveo-
lar spaces more rapidly than it is added by the pul- Metabolic acidosis is an abnormal process characterized
monary capillary blood. This situation causes alveolar by a gain of acid (other than H2CO3) or a loss of HCO3⫺.
and arterial PCO2 to fall. Hyperventilation and respira- Either causes plasma [HCO3⫺] and pH to fall. If a strong
tory alkalosis can be caused by voluntary effort, anxiety, acid is added to the body, the reactions
direct stimulation of the medullary respiratory center by
some abnormality (e.g., meningitis, fever, aspirin intox- H⫹ ⫹ HCO3⫺ H2CO3 H2O ⫹ CO2 (35)
ication), or hypoxia caused by severe anemia or high al-
titude. are pushed to the right. The added H ⫹ consumes
HCO3⫺. If a lot of acid is infused rapidly, PCO2 rises, as
Chemical Buffering. As with respiratory acidosis, dur- the equation predicts. This increase occurs only tran-
ing respiratory alkalosis more than 95% of chemical siently, however, because the body is an open system,
buffering occurs within cells. Cell proteins and organic and the lungs expire CO2 as it is generated. PCO2 actually
phosphates liberate H⫹ ions, which are added to the falls below normal because an acidic blood pH stimulates
ECF and lower the plasma [HCO3⫺], reducing the alka- ventilation (see Fig. 25.3).
line shift in pH. Many conditions can produce metabolic acidosis, in-
With acute respiratory alkalosis, plasma [HCO3⫺] falls cluding renal failure, uncontrolled diabetes mellitus, lac-
by about 2 mEq/L for each 10 mm Hg drop in PCO2 (see tic acidosis, the ingestion of acidifying agents such as
Table 25.4). For example, if PCO2 drops from 40 to 20 mm NH4Cl, abnormal renal excretion of HCO3⫺, and diar-
Hg ([CO2(d)] ⫽ 0.6 mmol/L) plasma [HCO3⫺] falls by 4 rhea. In renal failure, the kidneys cannot excrete H⫹ fast
mEq/L, and the pH will be 7.62: enough to keep up with metabolic acid production and,
in uncontrolled diabetes mellitus, the production of ke-
[24 ⫺ 4] tone body acids increases. Lactic acidosis results from
pH ⫽ 6.10 ⫹ log ᎏᎏ ⫽ 7.62 (32)
[0.6] tissue hypoxia. Ingested NH4Cl is converted into urea
and a strong acid, HCl, in the liver. Diarrhea causes a
If plasma [HCO3⫺] had not changed, the pH would loss of alkaline intestinal fluids. Clinical Focus Box 25.2
have been 7.70: discusses the metabolic acidosis seen in uncontrolled di-
abetes mellitus.
[24]
pH ⫽ 6.10 ⫹ log ᎏᎏ ⫽ 7.70 (33)
[0.6] Chemical Buffering. Excess acid is chemically buffered in
extracellular and intracellular fluids and bone. In metabolic
Respiratory Compensation. Although hyperventilation acidosis, roughly half the buffering occurs in cells and
causes respiratory alkalosis, hyperventilation also causes bone. HCO3⫺ is the principal buffer in the ECF.
changes (a fall in PCO2 and a rise in blood pH) that in-
hibit ventilation and, therefore, limit the extent of hy-
perventilation. Respiratory Compensation. The acidic blood pH stimu-
lates the respiratory system to lower blood PCO2. This action
lowers blood [H2CO3] and tends to alkalinize the blood,
Renal Compensation. The kidneys compensate for respi-
opposing the acidic shift in pH. Metabolic acidosis is ac-
ratory alkalosis by excreting HCO3⫺ in the urine, thereby,
companied on average by a l.3 mm Hg fall in PCO2 for each
getting rid of base. A reduced PCO2 reduces H⫹ secretion
by the kidney tubule epithelium. As a result, some of the fil- l mEq/L drop in plasma [HCO3⫺] (see Table 25.4). Suppose,
tered HCO3⫺ is not reabsorbed. When the urine becomes for example, the infusion of a strong acid causes the plasma
more alkaline, titratable acid excretion vanishes and little [HCO3⫺] to drop from 24 to l2 mEq/L. If there was no res-
ammonia is excreted. The enhanced output of HCO3⫺ piratory compensation and the PCO2 did not change from its
causes plasma [HCO3⫺] to fall. normal value of 40 mm Hg, the pH would be 7.10:
Chronic respiratory alkalosis is accompanied by a 4
mEq/L fall in plasma [HCO3⫺] for each l0 mm Hg drop in [12]
pH ⫽ 6.10 ⫹ log ᎏᎏ ⫽ 7.10 (36)
PCO2 (see Table 25.4). For example, in a person with [1.2]
442 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

CLINICAL FOCUS BOX 25.2

Metabolic Acidosis in Diabetes Mellitus lar and arterial blood PCO2. The consequent reduction in
Diabetes mellitus is a common disorder characterized by blood [H2CO3] acts to move the blood pH back toward nor-
an insufficient secretion of insulin or insulin-resistance by mal. The labored, deep breathing that accompanies severe
the major target tissues (skeletal muscle, liver, and uncontrolled diabetes is called Kussmaul’s respiration.
adipocytes). A severe metabolic acidosis may develop in The kidneys compensate for metabolic acidosis by re-
uncontrolled diabetes mellitus. absorbing all the filtered HCO3⫺. They also increase the ex-
Acidosis occurs because insulin deficiency leads to de- cretion of titratable acid, part of which is comprised of ke-
creased glucose utilization, a diversion of metabolism to- tone body acids. But these acids can only be partially
ward the utilization of fatty acids, and an overproduction of titrated to their acid form in the urine because the urine pH
ketone body acids (acetoacetic acid and ␤-hydroxybutyric cannot go below 4.5. Therefore, ketone body acids are ex-
acids). Ketone body acids are fairly strong acids (pKa 4 to creted mostly in their anionic form; because of the re-
5); they are neutralized in the body by HCO3⫺ and other quirement of electroneutrality in solutions, increased uri-
buffers. Increased production of these acids leads to a fall nary excretion of Na⫹ and K⫹ results.
in plasma [HCO3⫺], an increase in plasma anion gap, and a An important compensation for the acidosis is in-
fall in blood pH (acidemia). creased renal synthesis and excretion of ammonia. This
Severe acidemia, whatever its cause, has many adverse adaptive response takes several days to fully develop, but
effects on the body. It impairs myocardial contractility, re- it allows the kidneys to dispose of large amounts of H⫹ in
sulting in a decrease in cardiac output. It causes arteriolar di- the form NH4⫹. The NH4⫹ in the urine can replace Na⫹ and
lation, which leads to a fall in arterial blood pressure. He- K⫹ ions, resulting in conservation of these valuable
patic and renal blood flows are decreased. Reentrant cations.
arrhythmias and a decreased threshold for ventricular fibril- The severe acidemia, electrolyte disturbances, and vol-
lation can occur. The respiratory muscles show decreased ume depletion that accompany uncontrolled diabetes mel-
strength and fatigue easily. Metabolic demands are in- litus may be fatal. Addressing the underlying cause, rather
creased due, in part, to activation of the sympathetic nerv- than just treating the symptoms best achieves correction
ous system, but at the same time anaerobic glycolysis and of the acid-base disturbance. Therefore, the administration
ATP synthesis are reduced by acidemia. Hyperkalemia is fa- of a suitable dose of insulin is usually the key element of
vored and protein catabolism is enhanced. Severe acidemia therapy. In some patients with marked acidemia (pH ⬍
causes impaired brain metabolism and cell volume regula- 7.10), NaHCO3 solutions may be infused intravenously to
tion, leading to progressive obtundation and coma. speed recovery, but this does not correct the underlying
An increased acidity of the blood stimulates pulmonary metabolic problem. Losses of Na⫹, K⫹, and water should
ventilation, resulting in a compensatory lowering of alveo- be replaced.

With respiratory compensation, the PCO2 falls by 16 The Plasma Anion Gap Is Calculated From
mm Hg (12 ⫻ 1.3) to 24 mm Hg ([CO2(d)] ⫽ 0.72 mmol/L) Na⫹, Cl⫺, and HCO3⫺ Concentrations
and pH is 7.32:
The anion gap is a useful concept, especially when trying to
determine the possible cause of a metabolic acidosis. In any
[12]
pH ⫽ 6.10 ⫹ log ᎏᎏ ⫽ 7.32 (37) body fluid, the sums of the cations and anions are equal be-
[0.72] cause solutions are electrically neutral. For blood plasma,
we can write
This value is closer to normal than a pH of 7.10. The res-
piratory response develops promptly (within minutes) and 兺 cations ⫽ 兺 anions (38)
is maximal after 12 to 24 hours. or
[Na⫹] ⫹ [unmeasured cations] ⫽ [Cl⫺]
Renal Compensation. The kidneys respond to metabolic ⫹ [HCO3⫺] ⫹ [unmeasured anions] (39)
acidosis by adding more H⫹ to the urine. Since the plasma ⫹
The unmeasured cations include K , Ca , and Mg2⫹
2⫹
[HCO3⫺] is primarily lowered, the filtered load of HCO3⫺
ions and, because these are present at relatively low con-
drops, and the kidneys can accomplish the complete reab-
centrations (compared to Na⫹) and are usually fairly con-
sorption of filtered HCO3⫺ (see Fig. 25.7). More H⫹ is ex-
stant, we choose to neglect them. The unmeasured anions
creted as titratable acid and NH4⫹. With chronic meta-
include plasma proteins, sulfate, phosphate, citrate, lactate,
bolic acidosis, the kidneys make more ammonia. The
and other organic anions. If we rearrange the above equa-
kidneys can, therefore, add more new HCO3⫺ to the
tion, we get
blood, to replace lost HCO3⫺. If the underlying cause of
metabolic acidosis is corrected, then healthy kidneys can [unmeasured anions] or anion gap ⫽
correct the blood pH in a few days. [Na⫹] ⫺ [Cl⫺] ⫺ [HCO3⫺] (40)
 CHAPTER 25 Acid-Base Balance 443

In a healthy person, the anion gap falls in the range of 8 titrated in the alkaline direction. About one third of the
to 14 mEq/L. For example, if plasma [Na⫹] is 140 mEq/L, buffering occurs in cells.
[Cl⫺] is 105 mEq/L, and [HCO3⫺] is 24 mEq/L, the anion
gap is 11 mEq/L. If an acid such as lactic acid is added to
Respiratory Compensation. The respiratory compensa-
plasma, the reaction lactic acid ⫹ HCO3⫺ lactate⫺ ⫹
H2O ⫹ CO2 will be pushed to the right. Consequently, the tion for metabolic alkalosis is hypoventilation. An alkaline
plasma [HCO3⫺] will be decreased and because the [Cl⫺] is blood pH inhibits ventilation. Hypoventilation raises the
not changed, the anion gap will be increased. The unmea- blood PCO2 and [H2CO3], reducing the alkaline shift in
sured anion in this case is lactate. In several types of meta- pH. A l mEq/L rise in plasma [HCO3⫺] caused by meta-
bolic acidosis, the low blood pH is accompanied by a high bolic alkalosis is accompanied by a 0.7 mm Hg rise in
anion gap (Table 25.5). (These can be remembered from the PCO 2 (see Table 25.4). If, for example, the plasma
mnemonic MULEPAKS formed from the first letters of this [HCO3⫺] rose to 40 mEq/L, what would the plasma pH
list.) In other types of metabolic acidosis, the low blood pH be with and without respiratory compensation? With res-
is accompanied by a normal anion gap (see Table 25.5). For piratory compensation, the PCO2 should rise by 11.2 mm
example, with diarrhea and a loss of alkaline intestinal fluid, Hg (0.7 ⫻ 16) to 51.2 mm Hg ([CO2(d)] ⫽ 1.54 mmol/L).
plasma [HCO3⫺] falls but plasma [Cl⫺] rises, and the two The pH is 7.51:
changes counterbalance each other so the anion gap is un-
[40]
changed. Again, the chief value of the anion gap concept is pH ⫽ 6.10 ⫹ log ᎏᎏ ⫽ 7.51 (41)
that it allows a clinician to narrow down possible explana- [1.54]
tions for metabolic acidosis in a patient.
Without respiratory compensation, the pH would be
7.62:
Metabolic Alkalosis Results From a Gain
of Strong Base or Bicarbonate or a Loss [40]
pH ⫽ 6.10 ⫹ log ᎏᎏ ⫽ 7.62 (42)
of Noncarbonic Acid [1.2]
Metabolic alkalosis is an abnormal process characterized Respiratory compensation for metabolic alkalosis is lim-
by a gain of a strong base or HCO3⫺ or a loss of an acid ited because hypoventilation leads to hypoxia and CO2 re-
(other than carbonic acid). Plasma [HCO3⫺] and pH rise; tention, and both increase breathing.
PCO2 rises because of respiratory compensation. These
changes are opposite to those seen in metabolic acidosis
(see Table 25.3). A variety of situations can produce meta- Renal Compensation. The kidneys respond to meta-
bolic alkalosis, including the ingestion of antacids, vomit- bolic alkalosis by lowering the plasma [HCO3⫺]. The
ing of gastric acid juice, and enhanced renal H⫹ loss (e.g., plasma [HCO3⫺] is primarily raised and more HCO3⫺ is
as a result of hyperaldosteronism or hypokalemia). Clinical filtered than can be reabsorbed (see Fig. 25.7); in addi-
Focus Box 25.3 discusses the metabolic alkalosis produced tion, HCO3⫺ is secreted in the collecting ducts. Both of
by vomiting of gastric juice. these changes lead to increased urinary [HCO3⫺] excre-
tion. If the cause of the metabolic alkalosis is corrected,
Chemical Buffering. Chemical buffers in the body limit the kidneys can often restore the plasma [HCO3⫺] and
the alkaline shift in blood pH by releasing H⫹ as they are pH to normal in a day or two.

TABLE 25.5 High and Normal Anion Gap Metabolic Acidosis

Condition Explanation
High anion gap metabolicacidosis
Methanol intoxication Methanol metabolized to formic acid
Uremia Sulfuric, phosphoric, uric, and hippuric acids retained due to renal failure
Lactic acid Lactic acid buffered by HCO3⫺ and accumulates as lactate
Ethylene glycol intoxication Ethylene glycol metabolized to glyoxylic, glycolic, and oxalic acids
p-Aldehyde intoxication p-Aldehyde metabolized to acetic and chloroacetic acids
Ketoacidosis Production of ␤-hydroxybutyric and acetoacetic acids
Salicylate intoxication Impaired metabolism leads to production of lactic acid and ketone body acids; accumulation of salicylate
Normal anion gap metabolic acidosis
Diarrhea Loss of HCO3⫺ in stool; kidneys conserve Cl⫺
Renal tubular acidosis Loss of HCO3⫺ in urine or inadequate excretion of H⫹; kidneys conserve Cl⫺
Ammonium chloride ingestion NH4⫹ is converted to urea in liver, a process that consumes HCO3⫺; excess Cl⫺ is ingested
444 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

CLINICAL FOCUS BOX 25.3

Vomiting and Metabolic Alkalosis Renal tubular Na⫹/H⫹ exchange is stimulated by volume
Vomiting of gastric acid juice results in metabolic alka- depletion because the tubules reabsorb Na⫹ more avidly
losis and fluid and electrolyte disturbances. Gastric acid than usual. With more H⫹ secretion, more new HCO3⫺ is
juice contains about 0.1 M HCl. The acid is secreted by added to the blood. The kidneys reabsorb filtered HCO3⫺
stomach parietal cells; these cells have an H⫹/K⫹-ATPase completely, even though plasma HCO3⫺ level is elevated,
in their luminal plasma membrane and a Cl⫺/HCO3⫺ ex- and maintain the metabolic alkalosis.
changer in their basolateral plasma membrane. When HCl Vomiting results in K⫹ depletion because of a loss of K⫹
is secreted into the stomach lumen and lost to the outside, in the vomitus, decreased food intake and, most important
there is a net gain of HCO3⫺ in the blood plasma and no quantitatively, enhanced renal K⫹ excretion. Extracellular
change in the anion gap. The HCO3⫺, in effect, replaces lost alkalosis results in a shift of K⫹ into cells (including renal
plasma Cl⫺. cells) and, thereby, promotes K⫹ secretion and excretion.
Ventilation is inhibited by the alkaline blood pH, result- Elevated plasma aldosterone levels also favor K⫹ loss in
ing in a rise in PCO2. This respiratory compensation for the the urine.
metabolic alkalosis, however, is limited because hypoven- Treatment of metabolic alkalosis primarily depends on
tilation leads to a rise in PCO2 and a fall in PO2, both of which eliminating the cause of vomiting. Correction of the alka-
stimulate breathing. losis by administering an organic acid, such as lactic acid,
The logical renal compensation for metabolic alkalosis does not make sense because this acid would simply be
is enhanced excretion of HCO3⫺. In people with persistent converted to CO2 and H2O; this approach also does not
vomiting, however, the urine is sometimes acidic and renal address the Cl⫺ deficit. The ECF volume depletion and the
HCO3⫺reabsorption is enhanced, maintaining an elevated Cl⫺ and K⫹ deficits can be corrected by administering iso-
plasma [HCO3⫺]. This situation occurs because vomiting is tonic saline and appropriate amounts of KCl. Because re-
accompanied by losses of ECF and K⫹. Fluid loss leads to a placement of Cl⫺ is a key component of therapy, this type
decrease in effective arterial blood volume and engage- of metabolic alkalosis is said to be “chloride-responsive.”
ment of mechanisms that reduce Na⫹ excretion, such as After Na⫹, Cl⫺, water, and K⫹ deficits have been replaced,
decreased GFR and increased plasma renin, angiotensin, excess HCO3⫺ (accompanied by surplus Na⫹) will be ex-
and aldosterone levels (see Chapter 24). Aldosterone stim- creted in the urine, and the kidneys will return blood pH
ulates H⫹ secretion by collecting duct ␣-intercalated cells. to normal.

Clinical Evaluation of Acid-Base Disturbances respiratory acidosis; a low pH and low plasma [HCO3⫺] in-
Requires a Comprehensive Study dicate metabolic acidosis. If alkalosis is present, it could be
either respiratory or metabolic. A high blood pH and low
Acid-base data should always be interpreted in the context plasma PCO2 indicate respiratory alkalosis; a high blood pH
of other information about a patient. A complete history and high plasma [HCO3⫺] indicate metabolic alkalosis.
and physical examination provide important clues to possi- Whether the body is making an appropriate response for
ble reasons for an acid-base disorder. a simple acid-base disorder can be judged from the values
To identify an acid-base disturbance from laboratory in Table 25.4. Inappropriate values suggest that more than
values, it is best to look first at the pH. A low blood pH in- one acid-base disturbance may be present. Patients may
dicates acidosis; a high blood pH indicates alkalosis. If aci- have two or more of the four simple acid-base disturbances
dosis is present, for example, it could be either respiratory at the same time; in which case, they have a mixed acid-
or metabolic. A low blood pH and elevated PCO2 point to base disturbance.

REVIEW QUESTIONS

DIRECTIONS: Each of the numbered (E) 1,000:1 (B) Thin ascending limb
items or incomplete statements in this 2. An arterial blood sample taken from a (C) Thick ascending limb
section is followed by answers or by patient has a pH of 7.32 ([H⫹] ⫽ 48 (D) Distal convoluted tubule
completions of the statement. Select the nmol/L) and PCO2 of 24 mm Hg. What (E) Collecting duct
ONE lettered answer or completion that is is the plasma [HCO3⫺]? 4. Most of the hydrogen ions secreted by
BEST in each case. (A) 6 mEq/L the kidney tubules are
(B) 12 mEq/L (A) Consumed in the reabsorption of
1. If the pKa of NH4⫹ is 9.0, the ratio of (C) 20 mEq/L filtered bicarbonate
NH3 to NH4⫹ in a urine sample with a (D) 24 mEq/L (B) Excreted in the urine as ammonium
pH of 6.0 is (E) 48 mEq/L ions
(A) 1:3 3. Which segment can establish the (C) Excreted in the urine as free
(B) 3:1 steepest pH gradient (tubular fluid-to- hydrogen ions
(C) 3:2 blood)? (D) Excreted in the urine as titratable
(D) 1:1,000 (A) Proximal convoluted tubule acid
(continued)
 CHAPTER 25 Acid-Base Balance 445

Plasma
5. The following measurements were a comatose condition. An arterial Po2 Pco2 [HCO32]
made in a healthy adult: blood sample revealed a pH of 7.10, pH (mm Hg) (mm Hg) (mEq/L)
PCO2 of 20 mm Hg, and plasma (A) 7.25 95 19 8
Filtered bicarbonate 4,320 mEq/day [HCO3⫺] of 6 mEq/L. Plasma glucose (B) 7.29 55 60 28
Excreted bicarbonate 2 mEq/day and blood urea nitrogen (BUN) values (C) 7.40 95 40 24
Urinary titratable acid 30 mEq/day were normal. Plasma [Na⫹] was 140 (D) 7.59 95 16 15
Urinary ammonia 60 mEq/day mEq/L and [Cl⫺] was 105 mEq/L. (E) 7.70 95 16 19
(NH4⫹) Which of the following might explain SUGGESTED READING
Urine pH 5 her condition?
(A) Acute renal failure Abelow B. Understanding Acid-Base. Balti-
Net acid excretion by the kidneys is more: Williams & Wilkins, 1998.
(A) 28 mEq/day (B) Diarrhea as a result of food
Adrogue HJ, Madias NE. Management of
(B) 30 mEq/day poisoning
life-threatening acid base disorders. N
(C) 88 mEq/day (C) Methanol intoxication Engl J Med 1998;338:26–34, 107–111.
(D) 90 mEq/day (D) Overdose with a drug that Alpern RJ, Preisig PA. Renal acid-base trans-
(E) 92 mEq/day produces respiratory depression port. In: Schrier RW, Gottschalk CW,
6. If a patient with uncontrolled diabetes (E) Uncontrolled diabetes mellitus eds. Diseases of the Kidney. 6th Ed.
mellitus has a daily excretion rate of 9. Which of the following arterial blood Boston: Little, Brown, 1997;189–201.
200 mEq of titratable acid and 500 values might be expected in a Bevensee MO, Alper SL, Aronson PS,
mEq of NH4⫹, how many mEq of new mountain climber who has been Boron WF. Control of intracellular pH.
HCO3⫺ have the kidney tubules added residing at a high-altitude base camp In: Seldin DW, Giebisch G, eds. The
to the blood? below the summit of Mt. Everest for Kidney. Physiology and Pathophysiol-
(A) 0 mEq one week? ogy. 3rd Ed. Philadelphia: Lippincott
Plasma Williams & Wilkins, 2000;391–442.
(B) 200 mEq Po2 Pco2 [HCO32]
(C) 300 mEq pH (mm Hg) (mm Hg) (mEq/L)
Hood VL, Tannen RL. Protection of acid-
(D) 500 mEq (A) 7.18 95 25 9 base balance by pH regulation of acid
production. N Engl J Med
(E) 700 mEq (B) 7.35 50 60 32
1998;339:819–826.
7. Which of the following causes (C) 7.53 40 20 16 Knepper MA, Packer R, Good DW. Am-
increased tubular secretion of hydrogen (D) 7.53 95 50 40 monium transport in the kidney. Phys-
ions? (E) 7.62 40 20 20 iol Rev 1989;69:179–249.
(A) A decrease in arterial PCO2 10.A 25-year-old nurse is brought to the Lowenstein J. Acid and basics: A guide to un-
(B) Adrenal cortical insufficiency emergency department shortly before derstanding acid-base disorders. New
(C) Administration of a carbonic midnight. Although somewhat drowsy, York: Oxford University Press, 1993.
anhydrase inhibitor she was able to relate that she had Rose BD. Clinical Physiology of Acid-Base
(D) An increase in intracellular pH attempted to kill herself by swallowing and Electrolyte Disorders. 4th Ed. New
(E) An increase in tubular sodium the contents of a bottle of aspirin York: McGraw-Hill, 1994.
reabsorption tablets a few hours before. Which of Valtin H, Gennari FJ. Acid-Base Disorders.
8. A homeless woman was found on a hot the following set of arterial blood Basic Concepts and Clinical Manage-
summer night lying on a park bench in values is expected? ment. Boston: Little, Brown, 1987.

CASE STUDIES FOR PART IV •••

microscopy, but effacement of podocyte foot processes
CASE STUDY FOR CHAPTER 23 and loss of filtration slits is seen with the electron micro-
Nephrotic Syndrome scope. No immune deposits or complement are seen af-
A 6-year-old boy is brought to the pediatrician by his ter immunostaining. The biopsy indicates minimal
mother because of a puffy face and lethargy. A few change glomerulopathy. The podocyte cell surface and
weeks before, he had an upper respiratory tract infec- glomerular basement membrane show reduced staining
tion, probably caused by a virus. Body temperature is with a cationic dye.
36.8⬚C; blood pressure, 95/65; and heart rate, 90 Questions
beats/min. Puffiness around the eyes, abdominal 1. What features in this case would cause suspicion of
swelling, and pitting edema in the legs are observed. A nephrotic syndrome?
urine sample (dipstick) is negative for glucose but re- 2. What is the explanation for the proteinuria?
veals 3⫹ protein. Microscopic examination of the urine 3. Why does the abnormally high rate of urinary protein excre-
reveals no cellular elements or casts. Plasma [Na⫹] is tion underestimate the rate of renal protein loss?
140 mEq/L; BUN, 10 mg/dL; [glucose], 100 mg/dL; creati- 4. What is the endogenous creatinine clearance, and is it nor-
nine, 0.8 mg/dL; serum albumin, 2.3 g/dL (normal, 3.0 to mal? (The boy’s body surface area is 0.86 m2.)
4.5 g/dL); and cholesterol, 330 mg/dL. A 24-hour urine 5. What is the explanation for the edema?
sample has a volume of 1.10 L and contains 10 mEq/L
Na⫹, 60 mg/dL creatinine, and 0.8 g/dL protein. Answers to Case Study Questions for Chapter 23
The child is treated with the corticosteroid prednisone, 1. The child has the classical feature of nephrotic syndrome:
and the edema and proteinuria disappear in 2 weeks. heavy proteinuria (8.8 g/day), hypoalbuminemia (⬍3 g/dL),
Puffiness and proteinuria recur 4 months later, and a re- generalized edema, and hyperlipidemia (plasma cholesterol
nal biopsy is performed. Glomeruli are normal by light 330 mg/dL).
446 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

2. Proteinuria is a consequence of an abnormally high perme- mm Hg. She is transferred to a general hospital and, dur-
ability of the glomerular filtration barrier to the normal ing transfer, has three grand mal seizures and arrives in
plasma proteins. This condition might be a result of an in- a semiconscious, uncooperative state. A blood sample
creased size of “holes” or pores in the basement membrane reveals a plasma [Na⫹] of 103 mEq/L. Urine osmolality is
and filtration slit diaphragms. The decreased staining with a 362 mOsm/kg H2O and urine [Na⫹] is 57 mEq/L. She is
cationic dye, however, suggests that there was a loss of given an intravenous infusion of hypertonic saline (1.8%
fixed negative charges from the filtration barrier. Recall that NaCl) and placed on water restriction. Several days after
serum albumin bears a net negative charge at physiological she had improved, bronchoscopy is performed.
pH values, and that negative charges associated with the Questions
glomerular filtration barrier impede filtration of this plasma 1. What is the likely cause of the severe hyponatremia?
protein. 2. How much of an increase in plasma [Na⫹] would an infu-
3. Proteins that have leaked across the glomerular filtration sion of 1 L of 1.8% NaCl (308 mEq Na⫹/L) produce? Assume
barrier are not only excreted in the urine but are reabsorbed that her total body water is 25 L (50% of her body weight).
by proximal tubules. The endocytosed proteins are digested Why is the total body water used as the volume of distribu-
in lysosomes to amino acids, which are returned to the cir- tion of Na⫹, even though the administered Na⫹ is limited to
culation. Both increased renal catabolism by tubule cells the ECF compartment?
and increased excretion of serum albumin in the urine con- 3. Why is the brain so profoundly affected by hypoosmolality?
tribute to the hypoalbuminemia. The liver, which synthe- Why should the hypertonic saline be administered slowly?
sizes serum albumin, cannot keep up with the renal losses. 4. Why was the bronchoscopy performed?
4. The endogenous creatinine (CR) clearance (an estimate of
Answers to Case Study Questions for Chapter 24
GFR) equals (UCR ⫻ V)/PCR ⫽ (60 ⫻ 1.10)/0.8 ⫽ 82 L/day. Nor-
1. The problem started with ingestion of excessive amounts of
malized to a standard body surface area of 1.73 m2, CCR is
water. Compulsive water drinking is a common problem in
166 L/day ⫺1.73 m2, which falls within the normal range
psychotic patients. The increased water intake, combined
(150 to 210 L/day ⫺1.73 m2). Note that the permeability of
with an impaired ability to dilute the urine (note the inap-
the glomerular filtration barrier to macromolecules (plasma
propriately high urine osmolality), led to severe hypona-
proteins) was abnormally high, but permeability to fluid
tremia and water intoxication.
was not increased. In some patients, a loss of filtration slits
2. Addition of 1 L of 308 mEq Na⫹/L to 25 L produces an in-
may be significant and may lead to a reduced fluid perme-
crease in plasma [Na⫹] of 12 mEq/L. The total body water is
ability and GFR.
used in this calculation because when hypertonic NaCl is
5. The edema is a result of altered capillary Starling forces and
added to the ECF, it causes the movement of water out of
renal retention of salt and water. The decline in plasma
the cell compartment, diluting the extracellular Na⫹.
[protein] lowers the plasma colloid osmotic pressure, favor-
3. Because the brain is enclosed in a nondistensible cranium,
ing fluid movement out of the capillaries into the interstitial
when water moves into brain cells and causes them to
compartment. The edema is particularly noticeable in the
swell, intracranial pressure can rise to very high values.
soft skin around the eyes (periorbital edema). The abdomi-
This can damage nervous tissue directly or indirectly by im-
nal distension (in the absence of organ enlargement) sug-
pairing cerebral blood flow. The neurological symptoms
gests ascites (an abnormal accumulation of fluid in the ab-
seen in this patient (headache, semiconsciousness, grand
dominal cavity). The kidneys avidly conserve Na⫹ (note the
mal seizures) are consequences of brain swelling. The in-
low urine [Na⫹]) despite an expanded ECF volume. Al-
creased blood pressure and cool and pale skin may be a
though the exact reasons for renal Na⫹ retention are contro-
consequence of sympathetic nervous system discharge re-
versial, a decrease in the effective arterial blood volume
sulting from increased intracranial pressure. Too rapid
may be an important stimulus (see Chapter 24). This leads
restoration of a normal plasma [Na⫹] can produce serious
to activation of the renin-angiotensin-aldosterone system
damage to the brain (central pontine myelinolysis).
and stimulation of the sympathetic nervous system, both of
4. The physicians wanted to exclude the presence of a bron-
which favor renal Na⫹ conservation. In addition, distal seg-
chogenic tumor, which is the most common cause of
ments of the nephron reabsorb more Na⫹ than usual be-
SIADH. No abnormality was detected. Today, a computed
cause of an intrinsic change in the kidneys.
tomography (CT) scan would be performed first.
Reference
References
Orth SR, Ritz E. The nephrotic syndrome. N Engl J Med
Grainger DN. Rapid development of hyponatremic seizures in a
1998;338:1202–1211
psychotic patient. Psychol Med 1992;22:513–517.
Goldman MB, Luchins DJ, Robertson GL Mechanisms of al-
CASE STUDY FOR CHAPTER 24 tered water metabolism in psychotic patients with polydipsia
Water Intoxication and hyponatremia. N Engl J Med 1988;318:397–403.
A 60-year-old woman with a long history of mental ill-
ness was institutionalized after a violent argument with CASE STUDY FOR CHAPTER 25
her son. She experiences visual and auditory hallucina-
tions and, on one occasion, ran naked through the ward Lactic Acidosis and Hemorrhagic Shock
screaming. She refuses to eat anything since admission, During a violent argument over money, a 30-year-old
but maintains a good fluid intake. On the fifth hospital man was stabbed in the stomach. The assailant escaped,
day, she complains of a slight headache and nausea and but friends were able to rush the victim by car to the
has three episodes of vomiting. Later in the day, she is county hospital. The patient is unconscious, with a blood
found on the floor in a semiconscious state, confused pressure (mm Hg) of 55/35 and heart rate of 165
and disoriented. She is pale and had cool extremities. beats/minute. Breathing is rapid and shallow. The sub-
Her pulse rate is 70/min and blood pressure is 150/100 ject is pale, with cool, clammy skin. On admission, about
 CHAPTER 25 Acid-Base Balance 447

an hour after the stabbing, an arterial blood sample is tilation is stimulated by the low blood pH, sensed by the pe-
taken, and the following data were reported: ripheral chemoreceptors.
Patient Normal Range 3. The anion gap is ⫽ [Na⫹] ⫺ [Cl⫺] ⫺ [HCO3⫺] ⫽ 140 ⫺ 103 ⫺
Glucose 125 mg/dL 70–110 mg/dL (3.9–6.1 mmol/L) 4 ⫽ 33 mEq/L, which is abnormally high. Considering the
(fasting values) history and physical findings, the high anion gap is most
Na⫹ 140 mEq/L 136–145 mEq/L likely caused by inadequate tissue perfusion, with resultant
K⫹ 4.8 mEq/L 3.5–5.0 mEq/L anaerobic metabolism and production of lactic acid. The lac-
Cl⫺ 103 mEq/L 95–105 mEq/L tic acid is buffered by HCO3⫺ and lactate accumulates as the
HCO3⫺ 4 mEq/L 22–26 mEq/L unmeasured anion. Note that tissue hypoxia can occur if
BUN 23 mg/dL 7–18 mg/dL blood flow is diminished, even when arterial PO2 is normal.
(1.2–3.0 mmol/L urea nitrogen) 4. The low hematocrit is a result of absorption of interstitial
Creatinine 1.1 mg/dL 0.6–1.2 mg/dL fluid by capillaries, consequent to the hemorrhage, low arte-
(53–106 ␮mol/L) rial blood pressure, and low capillary hydrostatic pressure.
pH 7.08 7.35–7.45 5. In response to the blood loss and low blood pressure, kid-
PaCO2 14 35–45 mm Hg ney blood flow and GFR would be drastically reduced. The
PaO2 97 mm Hg 75–105 mm Hg sympathetic nervous system, combined with increased
Hematocrit 35% 41–53% plasma levels of AVP and angiotensin II, would produce in-
Questions tense renal vasoconstriction. The hydrostatic pressure in the
1. What type of acid-base disturbance is present? glomeruli would be so low that practically no plasma would
2. What is the reason for the low PaCO2? be filtered and little urine (oliguria) or no urine (anuria)
3. Calculate the plasma anion gap and explain why it is high. would be excreted. Because of the short duration of renal
4. Why is the hematocrit low? shutdown, plasma [creatinine] is still in the normal range;
5. Discuss the status of kidney function. the elevated BUN is probably mainly a result of bleeding
6. What is the most appropriate treatment for the acid-base into the gastrointestinal tract, digestion of blood proteins,
disturbance? and increased urea production.
Answers to Case Study Questions for Chapter 25 6. Control of bleeding and administration of whole blood (or
1. The subject has a metabolic acidosis, with an abnormally isotonic saline solutions and packed red blood cells) would
low arterial blood pH and plasma [HCO3⫺]. help restore the circulation. With improved tissue perfusion,
2. The low PaCO2 is a result of respiratory compensation. Ven- the lactate will be oxidized to HCO3⫺.