giáo trình sinh lý dịch và điện giải của NXB elsevier (2017)

F IF T H

ED IT IO N

Fluid, Electrolyte, and
Acid–Base Physiology
A Problem-Based Approach

Kamel S. Kamel, md, frcpc
St. Michael’s Hospital
University of Toronto
Toronto, Ontario, Canada

Mitchell L. Halperin, md, frcpc
St. Michael’s Hospital
University of Toronto
Toronto, Ontario, Canada


1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
FLUID, ELECTROLYTE, AND ACID–BASE PHYSIOLOGY:
A PROBLEM-BASED APPROACH, 5TH EDITION

ISBN: 978-0-323-35515-5

Copyright © 2017 by Elsevier, Inc. All rights reserved.
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Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden
our understanding, changes in research methods, professional practices, or medical treatment may become
necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds, or experiments described herein. In using such information or
methods they should be mindful of their own safety and the safety of others, including parties for whom they
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With respect to any drug or pharmaceutical products identified, readers are advised to check the most
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Previous editions copyright © 2010, 1999, 1994, 1988
Library of Congress Cataloging-in-Publication Data
Names: Halperin, M. L. (Mitchell L.), author. | Kamel, Kamel S., author.
Title: Fluid, electrolyte, and acid-base physiology : a problem-based
  approach / Kamel S. Kamel, Mitchell L. Halperin.
Description: 5th edition. | Philadelphia, PA : Elsevier, [2017] | Author’s
  names reversed on previous edition. | Includes bibliographical references
  and index.
Identifiers: LCCN 2016037933 | ISBN 9780323355155 (hardcover : alk. paper)
Subjects: | MESH: Water-Electrolyte Imbalance--physiopathology | Acid-Base

  Imbalance--physiopathology | Water-Electrolyte Imbalance--diagnosis |
  Acid-Base Imbalance--diagnosis | Potassium--metabolism
Classification: LCC RC630 | NLM WD 220 | DDC 616.3/992--dc23 LC record
available at />
Content Strategist: Maureen Iannuzzi
Senior Content Development Specialist: Joan Ryan
Publishing Services Manager: Catherine Jackson
Project Manager: Kate Mannix
Design Direction: Ryan Cook

Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1


To Marylin and Brenda:
We are indeed extremely
grateful for your patience
and your strong,
unwavering support.


Acknowledgment
We are extremely grateful to our friend and colleague Professor
Martin Schreiber for his critical review of the entire book and the
several insightful comments he provided. Martin, you are truly a
good man.

vii

Preface
About 6 years have passed between this, the fifth edition of Fluid, Electrolyte, and Acid–Base Physiology, and the fourth edition. For this edition, Professor Kamel S. Kamel has taken the role of lead author, while
Professor Marc Goldstein, because of other commitments and time
constraints, has decided not to participate.
Our initial intention with this edition was to provide limited
updates of a few chapters. We ended up, however, extensively revising
the book, so that it is almost entirely rewritten. Although the effort
was substantial and the time commitment was much more than we
anticipated, we could not be more proud of the product. In this fifth
edition of Fluid, Electrolyte, and Acid–Base Physiology, we have tried
to provide a comprehensive, go-to guide to the diagnosis and management of fluid-electrolyte and acid–base disorders. The book aims
to move from basic physiology to pathophysiology to practical clinical guidance, taking into account new discoveries and new insights
into fluid-electrolyte and acid–base physiology, as well as new options
available for treatment. We emphasize principles of metabolic regulation and biochemistry to promote an in-depth understanding of
metabolic acid–base disorders. We also emphasize integrative, wholebody physiology to provide a more in-depth understanding of the
pathophysiology of fluid, electrolyte, and acid–base disorders. The
style of the book, which we believe has been appealing to readers, has
not changed. As in previous editions, we have attempted to provide
information in an easy-to-understand way, with emphasis on how to
apply the information to clinical practice, supported by numerous
diagrams, flow charts, and tables. To engage and challenge the reader,
we have included several clinical cases and questions throughout each
of the chapters in the book.
We believe that this fifth edition of Fluid, Electrolyte, and Acid–Base
Physiology will provide a useful resource to learners at different levels,
from medical students to postgraduate trainees, and to practitioners
such as general internists and specialists with an interest in the area of
fluid-electrolyte and acid–base disorders.

viii

Interconversion of Units
Because some readers will be more familiar with the International
System of Units (SI units) and others will prefer the conventional units
used in the United States, we provide the following conversion table.
To convert units, multiply the reported value by the appropriate conversion factor.

PARAMETER

CONVENTIONAL
TO SI UNITS

SI TO
CONVENTIONAL
UNITS

Sodium
Potassium
Chloride
Bicarbonate
Calcium
Urea
Creatinine
Glucose
Albumin

× 1 = mmol/L
× 1 = mmol/L
× 1 = mmol/L

× 1 = mmol/L
× 0.25 = mmol/L
× 0.36 = mmol/L
× 88.4 = μmol/L
× 0.055 = mmol/L
× 10 = g/L

× 1 = mEq/L
× 1 = mEq/L
× 1 = mEq/L
× 1 = mEq/L
× 4.0 = mg/dL
× 2.8 = mg/dL
× 0.0113 = mg/dL
× 18 = mg/dL
× 0.1 = mg/dL

ix


List of Cases
Chapter 2
Case 2-1
Case 2-2

 ools to Use to Diagnose Acid–Base Disorders
T
Does This Man Really Have Metabolic Acidosis? . . . . . . . 34
Lola Kaye Needs Your Help. . . . . . . . . . . . . . . . . . . . . . . . . 35

Chapter 3
Case 3-1

 etabolic Acidosis: Clinical Approach
M
Stick to the Facts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Chapter 4
Case 4-1
Case 4-2

 etabolic Acidosis Caused by a Deficit of NaHCO3
M
A Man Diagnosed With Type IV Renal Tubular Acidosis. . . . 80
What Is This Woman’s “Basic” Lesion?. . . . . . . . . . . . . . . 81

Chapter 5
Case 5-1

Ketoacidosis
This Man Is Anxious to Know Why He Has
Ketoacidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Hyperglycemia and Acidemia. . . . . . . . . . . . . . . . . . . . . . 112
Sam Had a Drinking Binge Yesterday. . . . . . . . . . . . . . . . 127




Case 5-2
Case 5-3

Chapter 6
Case 6-1
Case 6-2
Case 6-3

 etabolic Acidosis: Acid Gain Types
M
Patrick Is in for a Shock. . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Metabolic Acidosis Associated With Diarrhea. . . . . . . . . 143
Severe Acidemia in a Patient With Chronic
Alcoholism���������������������������������������������������������������������143

Chapter 7
Case 7-1
Case 7-2
Case 7-3

 etabolic Alkalosis
M
This Man Should Not Have Metabolic Alkalosis. . . . . . . 172
Why Did This Patient Develop Metabolic Alkalosis
so Quickly? ������������������������������������������������������������������� 173
Milk-Alkali Syndrome, but Without Milk . . . . . . . . . . . . . . 173

Chapter 9
Case 9-1

 odium and Water Physiology
S

A Rise in the PNa After a Seizure. . . . . . . . . . . . . . . . . . . . 216

Chapter 10
Case 10-1
Case 10-2
Case 10-3
Case 10-4

 yponatremia
H
This Catastrophe Should Not Have Occurred! . . . . . . . . .
This Is Far From Ecstasy!. . . . . . . . . . . . . . . . . . . . . . . . . .
Hyponatremia With Brown Spots. . . . . . . . . . . . . . . . . . .
Hyponatremia in a Patient on a Thiazide Diuretic . . . . . .

Chapter 11
Case 11-1
Case 11-2
Case 11-3

Hypernatremia
Concentrate on the Danger. . . . . . . . . . . . . . . . . . . . . . . . 311
What Is “Partial” About Partial Central Diabetes
Insipidus? ��������������������������������������������������������������������� 311
Where Did the Water Go? . . . . . . . . . . . . . . . . . . . . . . . . . 311

Chapter 12
Case 12-1
Case 12-2

Polyuria
Oliguria With a Urine Volume of 4 L per Day. . . . . . . . . . 340
More Than Just Salt and Water Loss. . . . . . . . . . . . . . . . . 340



267
267
268
268

xi


xii

List of Cases

Chapter 13
Case 13-1

 otassium Physiology
P
Why Did I Become so Weak?. . . . . . . . . . . . . . . . . . . . . . . 361

Chapter 14
Case 14-1
Case 14-2
Case 14-3

 ypokalemia
H
Hypokalemia With Paralysis. . . . . . . . . . . . . . . . . . . . . . . 394
Hypokalemia With a Sweet Touch. . . . . . . . . . . . . . . . . . . 395
Hypokalemia in a Newborn. . . . . . . . . . . . . . . . . . . . . . . . 395

Chapter 15
Case 15-1
Case 15-2
Case 15-3

Hyperkalemia
Might This Patient Have Pseudohyperkalemia?. . . . . . . . 435
Hyperkalemia in a Patient Treated With Trimethoprim. . 435
Chronic Hyperkalemia in a Patient with Type 2
Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436

Chapter 16
Case 16-1

Hyperglycemia
And I Thought Water Was Good for Me! . . . . . . . . . . . . . 470


List of Flow Charts

Chapter 2
Flow Chart 2-1
Flow Chart 2-2

 ools to Use to Diagnose Acid–Base D
T
­ isorders
Initial Diagnosis of Acid–Base Disorders . . . . . . . . . 37
Steps in the Clinical Approach to Patients
with Hyperchloremic Metabolic Acidosis
Based on Evaluating the Rate of Excretion
of NH4+ Ions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45


Chapter 3
Flow Chart 3-1

 etabolic Acidosis: Clinical Approach
M
Initial Steps in the Evaluation of the Patient
with Metabolic Acidosis . . . . . . . . . . . . . . . . . . . . 55
Determine the Basis of Metabolic Acidosis. . . . . . . . 62

Flow Chart 3-2

Chapter 4
Flow Chart 4-1
Flow Chart 4-2
Flow Chart 4-3

Chapter 7
Flow Chart 7-1
Flow Chart 7-2

Chapter 10
Flow Chart 10-1
Flow Chart 10-2

 etabolic Acidosis Caused by a Deficit of NaHCO3
M
Approach to the Patient with Metabolic
Acidosis and a Normal PAnion gap. . . . . . . . . . . . . . 71
Approach to the Patient with Hyperchloremic
Metabolic Acidosis (HCMA) and a Low Rate
of Excretion of NH4+ Ions. . . . . . . . . . . . . . . . . . . 82
Approach to the Patient with Distal Renal Tubular
Acidosis (RTA) and a Urine pH Close to 7. . . . . . 85
Metabolic Alkalosis
Pathophysiology of Metabolic Alkalosis
due to a Deficit of Cl– Salts. . . . . . . . . . . . . . . . . 177
Clinical Approach to the Patient With ­Metabolic
Alkalosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Hyponatremia
Initial Steps in the Clinical Approach to the
Patient With Hyponatremia. . . . . . . . . . . . . . . . . 276
Diagnostic Approach to the Patient With
Chronic Hyponatremia . . . . . . . . . . . . . . . . . . . . 286


Chapter 11
Flow Chart 11-1
Flow Chart 11-2
Flow Chart 11-3

Hypernatremia
Emergencies Associated With ­Hypernatremia . . . . 322
Hypernatremia: Assessing the Renal ­Response . . . 324
Hypernatremia With a High Urine Flow Rate. . . . . 325


Chapter 12
Flow Chart 12-1
Flow Chart 12-2
Flow Chart 12-3

Polyuria
Approach to the Patient With Polyuria. . . . . . . . . . . 344
Approach to the Patient With Water ­Diuresis. . . . . 346
Approach to the Patient with Osmotic Diuresis. . . 350


Chapter 14
Flow Chart 14-1

Hypokalemia
Initial Steps in the Management of a ­Patient
With Hypokalemia. . . . . . . . . . . . . . . . . . . . . . . . 401
Determine Whether the Major Basis of
Hypokalemia Is an Acute Shift of K+ into Cells. . . 402

Flow Chart 14-2

xiii

xiv

List of Flow Charts

Flow Chart 14-3
Flow Chart 14-4

 hronic Hypokalemia and Metabolic ­Acidosis. . . . 404
C
Chronic Hypokalemia With Metabolic ­Alkalosis
and a High UK/UCreatinine . . . . . . . . . . . . . . . . . . . 405


Chapter 15
Flow Chart 15-1

Hyperkalemia
Initial Treatment of the Patient With ­
Hyperkalemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
Determine if the Cause of Hyperkalemia
Is a Shift of K+ Ions Out of Cells. . . . . . . . . . . . . 445
Steps in the Clinical Diagnosis of the Cause
of Chronic Hyperkalemia. . . . . . . . . . . . . . . . . . . 446

Flow Chart 15-2
Flow Chart 15-3

Chapter 16
Flow Chart 16-1

Hyperglycemia
Diagnostic Approach to the Patient With
a Severe Degree of Hyperglycemia. . . . . . . . . . . 482


c h a p t e r

1

Principles of Acid–Base
Physiology
Introduction...................................................................................................... 4
Objectives........................................................................................................... 4
P A R T A CHEMISTRY OF H+ IONS....................................................................... 5
H+ ions and the regeneration of ATP..................................................... 5
Concentration of H+ ions............................................................................. 6
P A R T B DAILY BALANCE OF H+ IONS............................................................. 7
Production and removal of H+ ions........................................................ 7
Buffering of H+ ions....................................................................................11
Role of the kidney in acid–base balance..............................................15
Urine pH and kidney stone formation................................................25
P A R T C INTEGRATIVE PHYSIOLOGY.............................................................27
Why is the normal blood pH 7.40?.......................................................27
Metabolic buffering of H+ ions during a sprint...............................28
Discussion of questions.............................................................................29

3

4

acid–base

Introduction

ABBREVIATION
BBS, bicarbonate buffer system
DEFINITIONS
•Acids are compounds that are
capable of donating H+ ions;
when an acid (HA) dissociates, it
yields an H+ ion and its conjugate
base or anion (A−).
•Bases are compounds that are
capable of accepting H+ ions.
•Valence is the net electrical charge
on a compound or an element.
HA ⇌ H + + A −

ACIDEMIA VERSUS ACIDOSIS
•Acidemia describes an increased
concentration of H+ ions in plasma.
•Acidosis is a process in which
there is an addition of H+ ions
to the body; this may or may not
cause acidemia.
ACID–BASE TERMS
•Concentration of H+ ions: The
normal value in plasma is 40 ± 2

nmol/L, which is 0.000040
mmol/L.
•pH is the negative logarithm of
the [H+] in mol/L, its normal value
in plasma is 7.40 ± 0.02.
−
•HCO3 ions: the conjugate base
of carbonic acid is the “H+ ion
remover” of the BBS; its concentration in plasma is close to
25 mmol/L, but there are large
fluctuations throughout the day
(22 to 31 mmol/L).
•PCO2: The major carbon waste
product of fuel oxidation is carbon
dioxide. Its concentration is
reflected by its partial pressure
(PCO2). The normal arterial PCO2
is 40 ± 2 mm Hg. The PCO2 in
blood-draining skeletal muscles is
∼6 mm Hg greater than the arterial PCO2 at rest.

Our goal in this chapter is to describe the physiology of hydrogen ions (H+)
and how acid–base balance is achieved. From a chemical perspective, H+
is the smallest ion (atomic weight 1) and its concentration in body fluids
is tiny (a million-fold lower than that of its major partner, HCO3−). Never­
theless, H+ ions are extremely powerful because they are intimately involved
in the capture of energy from oxidation of fuels by driving regeneration
of adenosine triphosphate (ATP4−). In this context, the electrical charge on
the protons is far more important than their chemical concentration.
The concentration of H+ ions in body fluids must be maintained in a

very narrow range. If their concentration rises, H+ ions will bind to intracellular proteins, and this changes their charge, shape, and possibly their functions, with possible dire consequences. Hence, a system is needed to remove
H+ ions, even if their concentration is not appreciably elevated. This function is achieved by the bicarbonate buffer system (BBS). The special feature
that allows the BBS to function as an effective buffer is that a low PCO2
drives the reaction of H+ ions with HCO3− anions (see Eqn 1). Because a
small increase in H+ ion concentration in plasma stimulates the respiratory
center and causes hyperventilation, the concentration of CO2 in each liter
of alveolar air and hence in the arterial blood will be lower. Nevertheless,
as we stress throughout this chapter, because the bulk of the BBS is in the
intracellular fluid and the interstitial space of skeletal muscles, a low PCO2
in their capillary blood is required to ensure the safe removal of H+ ions.
Removal of H+ ions by the BBS leads to a deficit of HCO3− ions. Accordingly, one must have another system that adds new HCO3− ions to the
body as long as acidemia persists. This task is achieved by the kidneys, in
the metabolic process of excretion of ammonium ions (NH4+ ) in the urine.
A high rate of excretion of NH4+ ions must be achieved while maintaining a urine pH that is close to 6.0 to avoid precipitation of uric acid. Base
balance is maintained by excreting an alkali load in the urine as a family
of organic anions rather than HCO3− ions. This avoids having a high urine
pH and the risk of precipitation of calcium phosphate in the luminal fluid.


H + + HCO3−

CO2 + H2 O

(1)

OBJECTIVES
  

nTo describe the major processes that lead to acid and base balance.

Acid Balance
1.Production of acids: H+ ions are produced in a metabolic process
when all of their products have a greater anionic charge than all
of their substrates.
2.Buffering of H+ ions: This should minimize H+ ion binding to
proteins in vital organs (i.e., the brain and the heart). To do so,
−
H+ ions must react with HCO3− ions. The vast majority of HCO3
ions in the body is in the interstitial and intracellular compartments of skeletal muscle. The key to achieving this function is to
have a low PCO2 in the capillaries of skeletal muscle.
3.Kidneys add new HCO 3− ions to the body: This occurs primarily when NH4+ ions are excreted in the urine.

Base Balance
1.Input of alkali: This occurs primarily when fruit and vegetables
are ingested because they contain the K+ salts of organic acids
that are metabolized to yield HCO3− anions.
2.Elimination of alkali: This is achieved in a two-step process: (1)
the alkali load stimulates the production of endogenous organic


1  :  principles of acid–base physiology
−
acids (e.g., citric acid), the H+ ions of which eliminate HCO3
anions, and (2) the kidneys excrete organic anions (e.g., citrate
anions) with K+ ions in the urine.
nTo emphasize that acid–base balance is achieved while
maintaining the urine pH close to 6.0. This minimizes the
risk of forming uric acid precipitate if the urine pH were
acidic (pK = 5.3), or calcium phosphate precipitate if the
urine pH were alkaline (pK = 6.8). In addition, eliminating

alkali via the excretion of organic anions (e.g., citrate anions)
lowers the concentration of ionized calcium in the urine.
  

PART A

CHEMISTRY OF H+ IONS

H+ IONS AND THE REGENERATION OF ATP
Three important steps constitute the metabolic process for the regeneration of ATP (called coupled oxidative phosphorylation); this involves
H+ ions in a major way. First, the energy needed to perform biological work in the cytosol of cells (e,g., ion pumping by Na-K-ATPase) is
provided when the terminal high-energy phosphate bond in ATP4- is
hydrolyzed. This converts ATP4- to adenosine diphosphate (ADP3−),
divalent inorganic phosphate ( HPO4 2 − ) ions, and H+ ion. Second,
ADP enters the mitochondria on the adenine nucleotide translocator,
while ATP exits. HPO4 2 − ions and H+ ions enter mitochondria by a
symporter. Third, oxidation of the reduced form nicotinamide adenine
dinucleotide (NADH, H+) produces nicotinamide adenine dinucleotide (NAD+) and two electrons. This represents the first step in the
electron transport chain. Flow of these electrons through coenzyme Q
and ultimately cytochrome C releases the energy that is used to pump
H+ ions from the mitochondrial matrix through the inner mitochondrial membrane. This creates a very large electrical driving force (∼150
mV) and a smaller chemical driving force for H+ ion re-entry. This

Hϩ

Hϩ

NADH ϩ Hϩ
NADϩ
Matrix

ADP + Pi

ATP

Figure 1-1  H+ Ions and the Regeneration of ATP. The horizontal structure represents the inner mitochondrial membrane with its inner and outer bilayers.
The dashed line at the top represents the outer mitochondrial membrane. Oxidation of the reduced form of nicotinamide adenine dinucleotide (NADH, H+)
produces NAD+ and two electrons. Flow of these electrons through the electron
transport chain releases the energy that is used to pump H+ ions from the
mitochondrial matrix through the inner mitochondrial membrane. This creates
a very large electricochemical driving force for H+ ion re-entry. This energy is
recaptured as H+ ions flow through the H+ ion channel portion of the H+adenosine triphosphate (ATP) synthase in the inner mitochondrial membrane,
which is coupled to ATP regeneration from ADP and inorganic phosphate (Pi).
ADP, Adenosine diphosphate.

5


6

acid–base

energy is recaptured as H+ ions flow through the H+ ion channel portion of the H+-ATP synthase in the inner mitochondrial membrane,
which is coupled (linked) to ATP4- regeneration provided that ADP3and HPO4 2 − are available inside these mitochondria (Figure 1-1).
Hence, availability of ADP in the mitochondria sets an upper limit on
the rate of coupled oxidative phosphorylation (see margin note).

Uncoupling of Oxidative Phosphorylation

ATP/ADP TURNOVER
•It is important to appreciate that

the actual concentration of ATP
in cells is small (∼5 mmol/L)
and that of ADP is extremely tiny
(∼0.02 mmol/L), but their rate of
turnover is enormous.
•The weight of ATP in the brain is
just a few grams (concentration
of ATP 0.005 mol/L, molecular
weight ∼700 g/mol, brain weight
in adult of about 1.5 kg— 80% of
which is intracellular fluid [ICF]).
•The brain consumes close to
3 mmol of O2 per minute or
4.5 mol of O2 per day. Because
~6 mol of ATP are formed per
mole of O2 consumed, the brain
regenerates 27 mol of ATP per day
(4.5 mol of O2 × 6 ATP/O2). Hence,
the daily turnover of ATP in the
brain is almost 20 kg (27 mol × mol
wt ∼700 g/1000 = 18.9 kg).
BENEFIT OF H+ ION BINDING
TO HEMOGLOBIN
•When H+ ions bind to hemoglobin
in systemic capillaries, hemoglobin can off load oxygen (O2) at a
higher PO2, which improves the
diffusion of O2 into cells.
•In contrast, when H+ ions dissociate from hemoglobin in the
capillaries in the lungs (driven
by a higher PO2), this leads to a

greater uptake of O2 from alveolar
air for a given alveolar PO2.
AMOUNT OF H+ IONS IN THE
BODY
•ECF: 15 L × 40 nmol/L = 600 nmol
•ICF: 30 L × 80 nmol/L = 2400 nmol

This limitation by availability of ADP3- (rate of biological work) on the
rate of fuel oxidation can be bypassed if oxidation of more fuel than
what is needed to regenerate ATP4- is advantageous. This is achieved
by uncoupling of oxidative phosphorylation. In this process, H+ ions
re-enter the mitochondrial matrix by a different H+ ion channel, one
that is not linked to the conversion of ADP3- to ATP4-.

CONCENTRATION OF H+ IONS
The concentration of H+ ions in all body compartments must be maintained at a very low level. This is because H+ ions bind very avidly to
histidine residues in proteins. Binding of H+ ions to proteins changes
their charge to a more positive valence, which might alter their shape,
and possibly their functions. Because most proteins are enzymes,
transporters, contractile elements, and structural compounds, a change
in their functions could pose a major threat to survival. Nevertheless, there are examples when this binding of H+ ions to proteins has
important biologic functions (see margin note).
The concentration of H+ ions in body fluids is exceedingly tiny (in
the nmol/L range) and, moreover, is maintained within a very narrow
range. In the extracellular fluid (ECF) compartment, the concentration of H+ ions is 40 ± 2 nmol/L, while in the ICF compartment, the
concentration of H+ ions is ∼80 nmol/L. In fact, the concentration of
their partner, HCO3− ions, in the ECF compartment (∼25 mmol/L), is
almost one million-fold higher than that of H+ ions.
This is impressive because an enormous quantity of H+ ions is produced and removed by metabolism each day relative to the amount of
H+ ions in the body (see margin note). In more detail, acids are obligatory intermediates of carbohydrate, fat, and protein metabolism. For

example, because adults typically consume and oxidize about 270 g
(1500 mmol) of glucose per day, at least 3000 mmol (3,000,000,000
nmol) of H+ ions are produced as pyruvic and/or L-lactic acids in glycolysis when work is performed and ATP4− is converted to ADP3−.
The complete oxidation of pyruvate/L-lactate anions to CO2 and H2O
removes the H+ ions almost as quickly as they are formed. In an adult
eating a typical Western diet, a net of ~70 mmol (70,000,000 nmol)
of H+ ions are added daily to the body. Hence, small discrepancies
between the rates of formation versus removal of H+ ions, if sustained,
can result in major changes in concentration of H+ ions. This implies
that there are very effective control mechanisms that minimize fluctuations in concentration of H+ ions in body fluids.
QUESTIONS
(See Part C for discussion of questions)
1-1 In certain locations in the body, H+ ions remain free and are not bound.
What is the advantage in having such a high concentration of H+ ions?
1-2 What is the rationale for the statement, “In biology only weak acids kill”?


1  :  principles of acid–base physiology

PART B

DAILY BALANCE OF H + IONS

PRODUCTION AND REMOVAL OF H+ IONS
  

•H+ ion production: H+ ions are produced when neutral compounds are converted to anions.
•H+ ion removal: H+ ions are removed when anions are converted to neutral products.
  
+

To determine whether H ions are produced or removed during
metabolism, we use a “metabolic process” analysis. A metabolic
process is made up of a series of metabolic pathways that carry out
a specific function; these pathways may be located in more than
one organ. To establish the balance for H+ ions in a metabolic process, one needs only examine the valences of all of its substrates
and products, while ignoring all intermediates (see Chapter 5 for
more details). If the sum of all of these valences is equal, there is no
net production or removal of H+ ions. When the products of a metabolic process have a greater anionic charge than its substrates, H+
ions are produced (e.g., incomplete oxidation of the major energy
fuels, carbohydrates, and fats). Conversely, when the products of a
metabolic process have a lesser anionic charge than its substrates,
H+ ions are removed.
About 85% of kilocalories consumed, in a typical Western diet, are
in the form of carbohydrates and fat. There is no net production of
H+ ions when glucose and triglycerides are completely oxidized to
CO2 + H2O because the substrates and the end products of these
metabolic processes are neutral compounds. There is a net H+ ion
load, however, when complete oxidation of these fuels does not occur.
L-Lactic acid accumulates during hypoxia, because its rate of production from glycolysis far exceeds its rate of removal via oxidation and/
or gluconeogenesis. Ketoacids are produced during states of a net lack
of insulin if their rate of production from metabolism of free fatty
acids (triglycerides) in the liver exceeds their rate of removal by the
brain and the kidneys.
The metabolism of certain dietary constituents leads to the
addition of H+ ions (e.g., proteins) or HCO3− ions (e.g., fruit and
vegetables) to the body. A general overview of the components of
the daily turnover of H+ ions is illustrated in Figure 1-2. Overall,
one must examine balances for both acids and bases to have a true
assessment of H+ ion balance.

Acid Balance
Oxidation of two classes of amino acids (cationic amino acids [e.g.,
lysine, arginine] and sulfur-containing amino acids [e.g., cysteine,
methionine]) yields an H+ ion load (Table 1-1). In contrast, H+ ions
are removed during the oxidation of anionic amino acids (e.g., glutamate, aspartate), because all the products of their oxidation are neutral compounds (urea, glucose, or CO2 + H2O). Because the number
of cationic and anionic amino acids is nearly equal in the amino acid
mixture in beefsteak, the H+ ion load that causes a deficit of HCO3−
ions is mainly from the metabolism of sulfur-containing amino acids
that yield sulfuric acid (H2SO4).

7


8

acid–base

Acid-Base Balance

Acid balance
Production of H

Base balance

+

Production of HCO3Ϫ
+

2 H + SO42Ϫ

Diet

+

2 K + 2 HCO3Ϫ

Diet

+

Removal of H
2 H+ + 2 HCO3Ϫ

Removal of HCO3Ϫ
2 CO2 + 2 H2O

+

Glucose

2 H + Citrate

2Ϫ

Excrete organic anions

Add “new” HCO3Ϫ

2 NH4+ + SO42Ϫ

Urine

Urine

+

2 K + Citrate 2Ϫ

Figure 1-2  Overview of the Daily Turnover of H+ Ions. Acid balance is shown on the left, and base
balance is shown on the right. There are three components to acid balance: (1) production of H+
ions, (2) HCO3− ions remove this H+ ion load, and (3) the kidneys add new HCO3− ions to the
body when NH4+ ions are excreted in the urine. There are also three components to base balance:
(1) the alkali load of the diet is converted to HCO3− ions in the liver, (2) organic acids are formed
in the liver and their H+ ions remove HCO3− ions, and (3) excretion of these new organic anions
along with the potassium (K+) ions from the diet in the urine.
TABLE 1-1 H+ ION FORMATION OR REMOVAL IN METABOLIC

REACTIONS

Reactions that yield H+ ions (more net negative charge in products than in substrates)
Glucose → L-lactate– + H+ (new L-lactate anions)
C16 fatty acid → 4 ketoacid anions− + 4H+ (new ketoacid anions)
Cysteine → urea + CO2 + H2O + 2 H+ + SO4 2 − (new SO4 2 − anions)
Lysine+ → urea + CO2 + H2O + H+ (loss of cationic charge in lysine)
Reactions that remove H+ ions (more net positive charge in products than in substrates)
L-Lactate– + H+ → glucose (L-lactate anion removed)
Glutamate– → urea + CO2 + H2O
Citrate3− + 3 H+ → CO2 + H2O (citrate anion removed)
H+ are neither produced nor removed in the following reactions

Glucose → glycogen or CO2 + H2O (neutrals to neutrals)
Triglyceride → CO2 + H2O (neutrals to neutrals)
Alanine → urea + glucose or CO2 + H2O (neutrals to neutrals)

H2SO4
H+ ions cannot be eliminated by metabolism of SO4 2 − anions to neutral end products (because no such pathway exists) or by being excreted
bound to SO4 2 − anions in the urine (because of the low affinity of
SO4 2 − anions for H+ ions). Hence, these H+ ions must be titrated initially with HCO3− ions and, as a result, CO2 is formed. Acid balance is
restored when these SO4 2 − anions are excreted in the urine with an
equivalent amount of NH4+ ions because new HCO3− ions are generated
in this process (Figure 1-3).


1  :  principles of acid–base physiology
Diet

1

ECF

2

2 HCO3Ϫ

2 Hϩ

2 CO2 + 2 H2O

Sulfur-AA
2 HCO3Ϫ

SO42Ϫ
Urine

Glutamine

3

SO42Ϫ

2 NH4ϩ

2 NH4ϩ

Figure 1-3  H+ Ion Balance during the Metabolism of Sulfur-Containing Amino Acids. Renal events are represented in the large shaded area. When sulfurcontaining amino acids are converted to SO4 2 − anions, H+ ions are produced (site 1). H+ ions react with HCO3− ions, and this produces a deficit of
HCO3− ions in the body (site 2). To achieve H+ ion balance, new HCO3− ions
must be regenerated. Metabolism of the amino acid glutamine in cells of
proximal tubules produces NH4+ ions and dicarboxylate anions. HCO3− ions
are added to the body when these anions are metabolized to a neutral end
product and NH4+ ions are excreted in the urine with SO4 2 − anions (site 3).
ECF, Extracellular fluid.
CO2 + H2O
K+

+
RNA-P−

K+ +

H2 PO4−

H+

HCO3−

2 K+
+
P-Cr2−

2 K+ + H PO42−
HCO3−

2 K+ + H PO42−
HCO3−

K+
H+
K+ + H2 PO4−

HCO3−

CO2 + H2O

H+
K+ + H2 PO4−

CO2 + H2O
K+ + OA−

Figure 1-4  H+ Ion Balance during the Metabolism of Organic Phosphates. The upper rectangle
represents the body, the lower, large shaded rectangle represents events in the kidney, the small

shaded rectangle represents excretion in the urine. The acid–base impact of the metabolic process
involving phosphate depends on whether their metabolism resulted in the addition of the monovalent inorganic phosphate (H2 PO4−) or the divalent inorganic phosphate (HPO4 2 −  ) to the body.
As shown in the left panel of the figure, if H2 PO4− were added to the body and then excreted in the
urine as H2 PO4−, there is no net loss or gain of HCO3− ions in this process. On the other hand, if
HPO4 2 − were added to the body, at a urine pH of ∼6 it will be excreted as H2 PO4−. Hence, a new
HCO3− ion is generated in this process (right panel of the figure). To maintain acid–base balance in
response to this alkali load, there is increased production of endogenous organic acids. Their H+
ions remove these HCO3− ions, while their conjugate bases (organic anions [OA−]) are excreted in
the urine as K+ salts. P-Cr  2−, Phosphocreatine 2−; RNA-P, ribonucliec acid.

Dietary phosphate
The source of phosphate in the diet consists primarily of intracellular
organic phosphates (including energy storage compounds e.g., ATP4−
and phosphocreatine2− in beefsteak, and nucleic acids [RNA, DNA])
and phospholipids, which are primarily in organ meat (e.g., liver). The
accompanying cation for both forms of intracellular organic phosphates
is primarily potassium (K+) ions. The acid–base impact of the metabolic
process involving phosphate depends on whether their metabolism
resulted in the addition of the monovalent
inorganic
phosphate (H2 PO4− )
(
)
2−
or the divalent inorganic phosphate HPO4 to the body. In more detail,
if H2 PO4− were added, because it has a pK of 6.8, close to one bound H+
ion per H2 PO4− is released in the body at normal blood pH values (7.40)

9

10

acid–base

ABBREVIATIONS
OA–, organic anions
PCT, proximal convoluted tubule
RENAL HANDLING OF ORGANIC
ANIONS
•Approximately 360 mEq of
organic anions are filtered daily
(glomerular filtration rate [GFR] of
180 L/day, concentration of OA−
in plasma ∼2 mEq/L). Of these
anions, 90% are reabsorbed and
only ∼10% are excreted.
•An alkali load diminishes the
reabsorption of organic anions
such as citrate in the PCT, and
hence increases their excretion in
the urine to achieve base balance.

URINE CITRATE AS A WINDOW
ON pH OF THE PROXIMAL
TUBULE CELL
•A low pH in PCT cells increases
the reabsorption of citrate; the
urine becomes virtually citrate
free.

•A higher pH in PCT cells diminishes the reabsorption of citrate
and thereby increases its excretion
rate.

(Figure 1-4). These H+ ions react with HCO3− ions, creating a deficit of
HCO3− ions in the body. To achieve H+ ion balance, new HCO3− ions
must be regenerated. This occurs in two steps: (1) the kidney converts
CO2 + H2O to H+ ions + HCO3− ions and (2) these H+ are secreted and
−
bind to filtered HPO4 2 − anions. Thus, H2 PO4 is excreted when the urine
pH is in the usual range (i.e., ∼6), while HCO3− ions are added to the
body. Hence, elimination of H+ ions produced during the metabolism of
organic phosphates to H2 PO4− does not require the excretion of NH4+
ions. There is no net loss or gain of HCO3− ions in this process.
On the other hand, if HPO4 2 − were added to the body, at a urine pH
of ∼6, it will be excreted as H2 PO4−. Hence, new HCO3− ions are generated in this process. To maintain acid–base balance, one possible mechanism is increased production of endogenous organic acids in response to
this alkali load. Their H+ ions remove this HCO3− ion load, while their
conjugate bases are excreted in the urine as K+ salts (see Figure 1-4).

Base Balance
All the emphasis so far has been on the production and removal of H+
ions. The diet, however, also provides an alkali load that is produced during the metabolism of a variety of organic anions in fruit and vegetables
(Figure 1-5). Although it would have been nice from a bookkeeping
point of view to have these HCO3− ions titrate some of the H+ ion load
from H2SO4 produced from metabolism of sulfur-containing amino
acids, this occurs only to a minor extent. The advantage of not having the
dietary alkali load titrate dietary acid load becomes evident when considered in the context of minimizing the risk of kidney stone formation.
Dietary organic anions are first converted to HCO3− ions in the liver.
This avoids having a potentially toxic anion enter the systemic circulation (e.g., citrate anions, which chelate ionized calcium in plasma). In
response to the alkali load, a variety of organic acids (e.g., citric acid) are

produced in the liver. The fate of their H+ ions is similar: the removal
by HCO3− ions. To prevent the synthesis of HCO3− ions at a later time,
the conjugate bases of these organic acids are made into end products
of metabolism by being excreted with K+ ions in the urine (see margin
note), and hence base balance is achieved. As discussed later, the pH of
cells of the proximal convoluted tubule (PCT) plays an important role in
determining the rate of excretion of citrate and other organic anions in
the urine. In fact, the rate of excretion of citrate in the urine is thought to
provide a window on pH in the cells of PCT (see margin note).
Diet

ECF

1
Kϩϩ

HCO3Ϫ

CO2

Hϩ

OAϪ

2
Glucose

OAϪ
Kϩ
OAϪ

Urine

3
OAϪ

PHCO3 =
less renal OAϪ
reabsorption

Figure 1-5  Overview of Base Balance. Base balance is achieved in three
steps. The first is the production of HCO3− ions from dietary K+ salts of
organic anions in the liver (site 1). This is followed by the production of
organic acids in the liver; their H+ ions titrate these HCO3− ions (site 2). The
renal component of the process is shown in the large shaded area (site 3).
The organic anions are filtered and only partially reabsorbed by the kidney;
hence, they are made into end products of metabolism by being excreted
in the urine. ECF, Extracellular fluid.


1  :  principles of acid–base physiology

From an integrative physiology point of view, the elimination of
dietary alkali in the form of organic anions has a number of advantages
in terms of minimizing the risk of kidney stone formation. In more
detail, it avoids the excretion of HCO3− ions, and hence the likelihood of
kidney stones that form when the urine pH is too high (e.g., CaHPO4).
In addition, the elimination of this dietary alkali in the form of citrate
anions lessens the likelihood of forming calcium-­containing kidney
stones because citrate anions chelate ionized ­calcium in the urine.
QUESTION

(See Part C for discussion of questions)
1-3 Does consumption of citrus fruit, which contains a large quantity of
citric acid and its K+ salt, cause a net acid or a net alkali load?

BUFFERING OF H+ IONS
  

•The most important goal of buffering is to minimize the binding of H+ ions to intracellular proteins in vital organs (e.g., the
brain and the heart)
  
The traditional view of the buffering of H+ ions during metabolic acidosis is “proton-centered” (i.e., it focuses solely on diminishing the
concentration of H+ ions). It is based on the premise that H+ ions are
very dangerous; therefore, anything that minimizes a rise in their concentration is beneficial. An argument to support this view is that a
high concentration of H+ ions may depress myocardial contractility.
The evidence for this effect, however, is from experimental studies in
animals or isolated perfused hearts preparations. Furthermore, it is
not consistent with the very high cardiac output observed during a
sprint when the blood pH may be below 7.0. In addition, this view of
buffering of H+ ions does not take into consideration the price to pay
to achieve this goal. In more detail, binding of H+ ions to proteins will
change their “ideal or native” valence (protein0) to become more cationic or less anionic (protein+) (see Eqn 2). This may alter their shape
and possibly their functions (as enzymes, transporters, contractile elements, or structural compounds), which may have deleterious effects.
H+ + Protein0 → H·Protein+(2)
We emphasize a different way to analyze buffering of an H+ ion load
and suggest that a “brain protein-centered” view of buffering of H+ ions
in the patient with metabolic acidosis may offer a better way to understand the pathophysiology, which has important implications for therapy. The major tenet of this view is that the role of buffering is not simply
to lower the concentration of H+ ions but to minimize the binding of
H+ ions to proteins in cells of vital organs (e.g., the brain and the heart).

Bicarbonate Buffer System

  

•H+ ions must by removed by the BBS to avoid their binding to
intracellular proteins.
•A low PCO2 is a prerequisite for optimal function of the BBS.
  
Even though at plasma pH of 7.4, the BBS is very far displaced
from its pK (pH ∼6.1) and hence is not an ideal chemical buffer,

11


12

acid–base
(Tiny)
ϩ

(Huge)

H + HCO3Ϫ

H2CO3

H2O + CO2

PTN0
H•PTN ϩ

Figure 1-6  Buffer Systems. Proteins in cells have an “ideal charge” (depicted as PTN0). Binding of H+ ions to these proteins increases their net

positive charge (H·PTN+) and may compromise their functions. Hence, the
key principle is that new H+ ions must be removed by binding to HCO3−
ions so that very few H+ ions can bind to proteins (PTN0) in cells. To force
H+ ions to bind to HCO3− ions, the PCO2 must fall in cells despite the fact
that cells produce an enormous quantity of CO2.

QUANTITY OF BICARBONATE
IONS IN THE BODY
ECF compartment:
25 mmol/L × 15 L = 375 mmol
ICF compartment:
12.5 mmol/L × 30 L = 375 mmol

nevertheless it is the most important physiologic buffer. This is
caused by the fact that it can remove H+ ions without requiring a
high H+ ion concentration. As shown in Eqn 1, a low PCO2 “pulls”
the BBS reaction to the right. As a result, the concentration of
H+ ions falls, which decreases the binding of H+ ions to proteins
(­Figure 1-6). In addition, the BBS is capable of removing a large
quantity of H+ ions because there is a large amount of HCO3− ions
in the body, ≈750 mmol in a 70 kg adult (see margin note).
Which PCO2 is important for the bicarbonate buffer system
to function optimally?
  

ABBREVIATIONS
EABV, effective arterial blood
volume

•The arterial PCO2 reflects, but is not equal to, the PCO2 in

brain cells; it sets a minimum value for the PCO2 in capillaries
of all other organs in the body.
•The bulk of the BBS is in the interstitial space and in cells of
skeletal muscle, hence PCO2 in muscle capillary blood reflects
the effectiveness of the BBS in removing an H+ ion load.
  
The process to lower the PCO2 begins with stimulation of the respiratory center in the brain. This is a most appropriate response because
it ensures that the brain will always have an “ideal” PCO2 in its ECF
and ICF compartments. In more detail, hyperventilation results in
a lower arterial PCO2. Because the rate of production of CO2 in the
brain is relatively constant (i.e., its oxygen consumption does not
vary appreciably and its blood flow is autoregulated), a lower arterial PCO2 will predictably result in a lower PCO2 in the ECF and ICF
compartments of the brain. Therefore, there is only a minimal binding
of H+ ions to intracellular proteins in the brain during metabolic acidosis, which decreases the possible detrimental effects on neuronal
function. Accordingly, the arterial PCO2 reflects the PCO2 in brain
cells in the absence of a marked degree of contraction of the effective
arterial blood volume (EABV) during which the brain fails to autoregulate its rate of blood flow.
The question, however, is whether a low arterial PCO2 is sufficient
to ensure optimal function of the BBS in other organs. Because CO2
diffuses rapidly, distances are short, and time is not a limiting factor, the PCO2 in capillaries is virtually identical to the PCO2 in cells
and in the interstitial compartment of the ECF in a given region.
Therefore, it is the capillary PCO2 (rather than the arterial PCO2)
that reveals whether the BBS has operated efficiently in removing a
load of H+ ions (Table 1-2). Notwithstanding, the arterial PCO2 sets
the lower limit for the PCO2 in capillaries.


1  :  principles of acid–base physiology
TABLE 1-2 THE BLOOD PCO2 AND ITS IMPLICATIONS FOR BRAIN

PROTEIN-CENTERED BUFFERING OF H+

SITE OF SAMPLING

BBS BUFFERING

FUNCTIONAL IMPLICATIONS

•Arterial PCO2

•Reflects the PCO2
in brain if the
blood flow rate is
­autoregulated
•Not really able to
define site of H+ ion
buffering
•Reflects the PCO2 in
skeletal muscle cells
and their interstitial
compartment

•Assesses alveolar
­ventilation
•Sets the lower limit for the
capillary PCO2
•Cannot tell if H+ ions are
bound to brain proteins

•Mixed venous PCO2

•Brachial vein PCO2

•A low venous PCO2 is
needed to force H+ ions to
be buffered by HCO3− ions
in muscle cells
•A high PCO2 suggests that
the BBS in muscle is not
functioning optimally; as a
result, H+ ions may bind to
brain proteins.

BBS, Bicarbonate buffer system.

The capillary PCO2 is higher than the arterial PCO2 because
cells consume O2 and add CO2 to their capillary blood. The capillary PCO2 is influenced by the value of the arterial PCO2 and the
rate of addition of CO2 to capillary blood in individual organs. For
instance, if most of the oxygen in each liter of blood delivered to
a certain area is consumed, the PCO2 in its capillary blood will
rise appreciably. There are two conditions in which most of the
O2 delivered in a liter of blood is consumed: (1) a rise in the rate
of metabolism without a change in the rate of blood flow, or (2) a
decrease in the rate of blood flow with no change in the rate of O2
consumption.
Although the capillary PCO2 reveals whether the BBS has operated
efficiently, one cannot measure it directly. The venous PCO2, however,
closely reflects the capillary PCO2 in its drainage bed. There is one
caveat—if an appreciable quantity of blood shunts from the arterial
to the venous circulation and bypasses cells, this venous PCO2 does
not reflect the PCO2 in the interstitial space and in cells in its drainage bed.

The question now is which venous PCO2 should be measured to
assess the effectiveness of the BBS. Because of its size, skeletal muscle
has the largest content of HCO3− ions in the body in its cells and interstitial space. Therefore, in patients with metabolic acidosis, the PCO2
should be measured in free-flowing brachial venous blood to assess
the effectiveness of the BBS.
Failure of the bicarbonate buffer system
The main cause of failure of the BBS in skeletal muscle is a very
marked decline in its blood supply—this is the case when metabolic acidosis is accompanied by a contracted EABV. Hence, while
the arterial PCO2 may be low due to stimulation of the respiratory
center by acidemia, the PCO2 in intracellular fluid and interstitial
space in muscle may not be low enough for effective buffering of
H+ ions by the BBS (Figure 1-7). As a result, the degree of acidemia may become more pronounced and more H+ ions may bind to
proteins in the extracellular and intracellular fluids in other organs,
including the brain. Notwithstanding, because of autoregulation of
cerebral blood flow, it is likely that the PCO2 in brain capillary blood

13


14

acid–base
Normal EABV

[H+]

CO2

H+ + HCO3−

HCO3− + H+

CO2
PTN•H+

CO2

PTN0

PTN0

Muscle

CO2

Brain
Low EABV

[H+]
HCO3− + H+

CO2

↑CO2

PTN•H+

PTN0

Muscle

H+ + HCO3−
PTN0

CO2

PTN•H+

CO2

Brain

Figure 1-7  Buffering of H+ Ions in the Brain in a Patient with a Contracted Effective Arterial
Blood Volume (EABV). Buffering of H+ ions in a patient with a normal effective arterial blood
volume and thereby a low venous PCO2 is depicted in the top portion of the figure. The vast
majority of H+ ion removal occurs by bicarbonate buffer system (BBS) in the interstitial space
and in cells of skeletal muscles. Buffering of an H+ ion load in a patient with a contracted
EABV and thereby a high venous PCO2 is depicted in the bottom portion of the figure. A high
PCO2 prevents H+ ion removal by the BBS in muscles. As a result, the circulating H+ ion concentration rises, which increases the H+ ion burden for brain cells. Unless there is a severe degree
of contraction of the EABV and failure of auto-regulation of cerebral blood flow, the BBS in the
brain will continue to titrate much of this large H+ ion load. Because of the limited content of
HCO3− ions in the brain and because the brain receives a relatively larger proportion of blood
flow, there is a risk that more H+ ions will bind to proteins in the brain cells.

will change minimally unless there is a severe degree of contraction of
the EABV and failure of autoregulation of cerebral blood flow. Hence,
the BBS in the brain will continue to titrate much of this large H+ ion
load. Considering, however, the limited content of HCO3− ions in the
brain, and that the brain receives a relatively larger proportion of the
cardiac output, there is a risk that more H+ ions will bind to proteins

in the brain cells, further compromising their functions.
In summary, patients with metabolic acidosis and a contracted
EABV have a high PCO2 in venous blood draining skeletal muscle,
and therefore they fail to titrate an H+ load with their BBS in skeletal
muscle. Hence, there is a much higher H+ ion burden in their brain
cells, with possible detrimental effects. At usual rates of blood flow
and metabolic work at rest, brachial venous PCO2 is about 46 mm
Hg, which is ∼6 mm Hg greater than the arterial PCO2. If the blood
flow rate to the skeletal muscles declines because of a low EABV, the
brachial venous PCO2 will be increased to greater than 6 mm Hg
higher than the arterial PCO2. Based on this analysis, it follows that
in patients with metabolic acidosis, the clinician should administer
enough saline to increase the blood flow rate to muscle to restore
the usual brachial venous minus arterial PCO2 difference, i.e., back
to ∼6 mm Hg.


1  :  principles of acid–base physiology

15

QUESTIONS
(See Part C for discussion of questions)
1-4 Why is the L-lactic acidosis that occurs during cardiogenic shock so
much more devastating than the L-lactic acidosis that occurs during a sprint if the Pl-lactate, arterial pH, and PHCO3 are identical?
1-5 Th
 e heart extracts close to 70% of the oxygen from each liter of coronary artery blood. What conclusions can you draw about buffering
of H+ ions in the heart? Might there be advantages because of this
high extraction of O2 per liter of blood flow?

ROLE OF THE KIDNEY IN ACID–BASE BALANCE
The kidneys must perform two tasks to maintain acid balance. First,
the kidney must reabsorb virtually 100% of the filtered HCO3− ions;
this is achieved primarily by H+ ion secretion in the PCT. Second, the
kidneys must add new HCO3− ions to the body to replace what is lost
in buffering of an added acid load; this is achieved principally in the
metabolic process that ends by excreting NH4+ ions in the urine.

Reabsorption of Filtered HCO3– Ions
  

•The kidneys must prevent the excretion of the very large quantity of filtered HCO3− ions. In this process there is no addition
of new HCO3− ions to the body.
  
It is important to recognize that a huge amount of HCO3− is
filtered and reabsorbed each day (GFR of 180 L/day 
× 
PHCO3
25 mmol/L = 4500 mmol). The bulk of filtered HCO3− ions (approximately
80% [∼3600 mmol/day] [see margin note]) is reabsorbed by the PCT.

ABBREVIATIONS
NBCe1, electrogenic Na-bicarbonate
cotransporter 1
mTAL, medullary thick ascending
limb
MCD, medullary collecting duct

PERCENT OF FILTERED HCO3−
REABSORBED IN PCT

•This is a minimum estimate of
the percent of the filtered HCO3−
ions that is reabsorbed in PCT.
This is because it is based on
data from micropuncture studies
in rats. The site of micropuncture, the last accessible part of
the PCT on the surface pf the
cortex, is, however, not the end of
the PCT.

Reabsorption of NaHCO3 in the proximal convoluted tubule
Reabsorption of HCO3− ions in PCT occurs in an indirect fashion via
H+ ion secretion. In this process, the PCT reclaims the vast majority
of filtered HCO3− ions, but there is no generation of new HCO3− ions.
Nevertheless, if this process were to fail, there will be a loss of NaHCO3
in the urine and the development of metabolic acidosis (this disorder
is called proximal renal tubular acidosis; it is discussed in Chapter 4).
The process of HCO3− ion reabsorption in PCT has four interconnected steps (Figure 1-8):
1. H+ ion secretion into the luminal fluid.
  This is largely mediated by the Na+/H+ exchanger-3 (NHE-3) in the
apical membrane of PCT cells. This is an electroneutral exchanger
because for every Na+ ion reabsorbed, one H+ ion is secreted into
its lumen. The driving force to reabsorb Na+ ions by NHE-3 is provided by the very low concentration of Na+ ions inside PCT cells,
because of the active transport of Na+ ions out of cells by Na-KATPase in their basolateral membrane.
2. Secreted H+ ions combine with HCO3− ions in the lumen to form H2CO3.
  H2CO3 dissociates into CO2 and H2O. This dissociation reaction
occurs virtually as soon as H2CO3 is formed because it is catalyzed
by the enzyme carbonic anhydrase IV (CAIV), an isoform of carbonic anhydrase that is bound to the brush boarder of PCT cells.
CO2 that is formed in the lumen crosses the apical membrane and
enters the PCT cells (see margin note).

ENTRY OF CO2 INTO PCT CELLS
•This was thought to occur by
diffusion of CO2 through the lipid
bilayer of the apical membrane of
PCT cells.
•There are data to suggest that
entry of CO2 is via the luminal
water channel, AQP1, which can
also behave as a gas channel.


16

acid–base

Naϩ

Naϩ

NHE-3

HCO3Ϫ

NBCe1
Hϩ

Hϩ

(HCO3Ϫ)3

H2CO3

H2CO3

CAIV
CAII

CO2ϩH2O
H2O

CO2

AQP1

Figure 1-8  Reabsorption of NaHCO3 in the Proximal Convoluted Tubule.
The components of the process of indirect reabsorption of NaHCO3 are
shown in the figure. H+ ion secretion is largely via Na+/H+ exchanger
3 (NHE-3). HCO3− ions exit the cell via an electrogenic Na-bicarbonate
cotransporter (NBCe1). This process requires a luminal carbonic anhydrase (CA)IV and intracellular CAII. CO2 that is formed in the lumen enters
the cell likely via a luminal aquaporin 1 water channel (AQP1).

3. I nside the cell, CO2 and H2O recombine to form H2CO3.
  Another isoform of carbonic anhydrase, carbonic anhydrase
II (CAII) is present inside cells; it accelerates the dissociation of
H2CO3 into H+ ions and HCO3− ions. While H+ ions are secreted
into the luminal fluid, HCO3− ions exit the cell across the basolateral membrane, completing the process of indirect reabsorption of
HCO3− ions.
4. HCO3− ions exit from PCT cells.
  HCO3− ions are transported out of PCT cells at the basolateral membrane via a sodium coupled, electrogenic bicarbonate cotransporter, NBCe1. This transporter permits an ion complex of one  Na+

ion and the equivalent of three HCO3− ions to exit as a divalent
2−
anion, Na(HCO3− )3 .
Regulation of proximal tubular reabsorption of bicarbonate ions
Luminal HCO3− ion concentration
HCO3− reabsorption is increased as luminal HCO3− ion concentration
rises because there are more H+ ion acceptors in the luminal fluid. The
opposite is also true: HCO3− ion reabsorption is decreased with a fall
in luminal HCO3− ion concentration.

Luminal H+ ion concentration
A higher concentration of H+ ions in the lumen of the PCT inhibits
H+ ion secretion. This scenario occurs, for example, when a patient
is given acetazolamide, a drug that inhibits luminal carbonic anhydrase. In this setting, H+ ion secretion is diminished because of the
rise in the concentration of carbonic acid (H2CO3) and thereby of
H+ ions in the lumen; hence, a smaller amount of filtered HCO3−
ions is reclaimed.


1  :  principles of acid–base physiology

17

Concentration of H+ ions in PCT cells
A rise in the concentration of H+ ions in PCT cells stimulates the
secretion of H+ ions because of the binding of H+ ions to a modifier
site on NHE-3, which activates this cation exchanger. Intracellular
acidosis also increases NBCe1 activity. These effects, however, are
not very important during metabolic acidosis because of the smaller
filtered load of HCO3− ions.

Changes in intracellular H+ ion concentration may explain the
effect of K+ ions to modulate the reabsorption of HCO3− ions in
the PCT. Hypokalemia is associated with intracellular acidosis,
enhanced reabsorption of HCO3− ions (together with stimulation
of ammoniagenesis), and the development of metabolic alkalosis.
In contrast, hyperkalemia is associated with a fall in H+ ion concentration in PCT cells, diminished reabsorption of HCO3− ions
(together with decreased ammoniagenesis), and the development
of hyperchloremic metabolic acidosis.
Peritubular HCO3− ion concentration
An increase in the peritubular concentration HCO3− ions decreases
HCO3− ion reabsorption in the PCT.
Peritubular PCO2
A high peritubular PCO2 stimulates the reabsorption of NaHCO3
by the PCT (see margin note). The PHCO3 is elevated in patients with
chronic respiratory acidosis.
Angiotensin II
Angiotensin II, which is released in response to a decreased EABV,
is the most important regulator of reabsorption of NaHCO3 in the
PCT. Angiotensin II stimulates NaHCO3 reabsorption by activating
protein kinase C, which in turn phosphorylates and activates NHE-3.
As discussed in Chapter 10, activating NHE-3 and the reabsorption
of NaHCO3 in the PCT leads to an increased reabsorption of NaCl
in this nephron segment.
Parathyroid hormone
Acting through adenylyl cyclase and production of cyclic adenosine
monophosphate (cAMP), parathyroid hormone has a small effect to
inhibit the reabsorption of HCO3− ions in the PCT.
To illustrate the interplay of the different factors that affect reabsorption of HCO3− ions in PCT, consider this example of a patient
who was given a diuretic and developed hypokalemia. PHCO3 will
rise initially because of a decreased ECF volume (contraction alkalosis). In addition, hypokalemia is associated with intracellular acidosis, which stimulates ammoniagenesis and hence the addition

of new HCO3− ions to the ECF compartment. Factors that stimulate the reabsorption of HCO3− ions in the PCT include a higher
luminal concentration of HCO3− ions, the effect of angiotensin II
(released in response to a lower EABV) to activate NHE-3, the effect
of intracellular acidosis (associated with hypokalemia) to activate
NHE-3 and NBCe1, and the higher peritubular PCO2 (metabolic
alkalemia suppresses ventilation, leading to a compensatory rise in
the arterial PCO2). On the other hand, the rise in the peritubular

EFFECT OF PERITUBULAR
HCO3− ION CONCENTRATION,
PERITUBULAR PCO2
•To separate the effects of peritubular HCO3− ion concentration
versus peritubular PCO2 and/
or peritubular pH on HCO3− ion
reabsorption in PCT, a technique
to generate “out of equilibrium”
HCO3− ion solution was developed.
Its premise is that the reaction of
CO2 and H2O to generate H2CO3
occurs relatively slowly, whereas
the reaction of dissociation of
H2CO3 to H+ ions and HCO3− ions
occurs rapidly. Hence, methods
were developed to rapidly mix two
solutions with different compositions and use the resulting solution
before it comes to equilibrium.
•Studies using this technique
showed that altering the peritubular pH at fixed HCO3− and PCO2
did not change the reabsorption
of HCO3− ions by the PCT. It was

then suggested that the basolateral membrane contains proteins
that function as HCO3− ion and/
or CO2 sensors to mediate the
effects of peritubular HCO3− and
peritubular PCO2 on HCO3− ion
reabsorption in the PCT.