Table Of ContentLook for these other volumes in the Mosby Physiology Series:
Blaustein, Kao, & Matteson: CELLULAR PHYSIOLOGY AND NEUROPHYSIOLOGY
Johnson: GASTROINTESTINAL PHYSIOLOGY
Pappano and Wier: CARDIOVASCULAR PHYSIOLOGY
White, Harrison, & Mehlmann: ENDOCRINE AND REPRODUCTIVE PHYSIOLOGY
Cloutier: RESPIRATORY PHYSIOLOGY
Hudnall: HEMATOLOGY: A PATHOPHYSIOLOGIC APPROACH
RENAL
PHYSIOLOGY
6TH EDITION
Bruce M. Koeppen, MD, PhD
Dean, Frank H. Netter MD School of Medicine
Quinnipiac University
Hamden, Connecticut
Bruce A. Stanton, PhD
Professor of Microbiology and Immunology
Andrew C. Vail Memorial Professor
The Geisel School of Medicine at Dartmouth
Hanover, New Hampshire
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
RENAL PHYSIOLOGY, SIXTH EDITION ISBN: 978-0-323-59568-1
Copyright © 2019 Elsevier Inc. All Rights Reserved.
Previous editions copyrighted 2013, 2007, 2001, 1997, 1992.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechan-
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This book and the individual contributions contained in it are protected under copyright by the Publisher (other
than as may be noted herein).
Notices
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds or experiments described herein. Because of rapid advances in
the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.
To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for
any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise,
or from any use or operation of any methods, products, instructions, or ideas contained in the material
herein.
Content Strategist: Marybeth Thiel
Content Development Specialist: Marybeth Thiel
Publishing Services Manager: Shereen Jameel
Senior Project Manager: Kamatchi Madhavan
Design Direction: Ryan Cook
Printed in the United States of America
Last digit is the print number: 9 8 7 6 5 4 3 2 1
This book is dedicated to our family, friends, colleagues,
and, most especially, our students.
P R E FAC E
When we wrote the first edition of Renal Physiology in 1992, teach the important aspects and fundamental concepts of
our goal was to provide a clear and concise overview of the normal renal function. We have emphasized clarity and
function of the kidneys for health professions students who conciseness in presenting the material. To accomplish this
were studying the topic for the first time. The feedback we goal, we have been selective in the material included. The
have received over the years has affirmed that we met our broader field of nephrology, with its current and future
goal, and that achievement has been a key element to the frontiers, is better learned later and only after the “big pic-
book’s success. Thus, in this sixth edition we have adhered ture” has been well established. For clarity and simplicity,
to our original goal, maintaining all the proven elements of we have made statements as assertions of fact even though
the last five editions. we recognize that not all aspects of a particular problem
Since 1992, much has been learned about kidney func- have been resolved.
tion at the cellular, molecular, and clinical levels. Although To the student: As an aid to learning this material, each
this new information is exciting and provides new and chapter includes a list of objectives that reflect the funda-
greater insights into the function of the kidneys in health mental concepts to be mastered. At the end of each chap-
and disease, it can prove daunting to first-time students ter, we have provided a summary and a list of key words
and in some cases may cause them to lose the forest for the and concepts that should serve as a checklist while work-
trees. To balance the needs of the first-time student with ing through the chapter. We have also provided a series of
our desire to present some of the latest advances in the field self-study problems that review the central principles of
of renal physiology, we have updated the highlighted text each chapter. Because these questions are learning tools,
boxes, titled “At the Cellular Level” and “In the Clinic,” to answers and explanations are provided in Appendix D.
supplement the main text for students who wish additional Multiple-choice questions and comprehensive clinical
detail. The other features of the book, which include clin- cases are included in other appendixes. We recommend
ical material that illustrates important physiologic princi- working through the clinical cases in Appendix A only after
ples, multiple-choice questions, self-study problems, and completing the book. In this way they can indicate where
integrated case studies, have been retained and updated. additional work or review is required.
To achieve our goal of keeping the book concise, we have We have provided a highly selective bibliography that is
removed some old material as new material was added. We intended to provide the next step in the study of the kid-
hope that all who use this book find that the changes have ney; it is a place to begin to add details to the subjects pre-
made it an improved learning tool and a valuable source of sented here and a resource for exploring other aspects of
information. the kidney not treated in this book.
To the instructor: This book is intended to provide stu- We encourage all who use this book to send us your
dents in the biomedical and health sciences with a basic comments and suggestions. Please let us know what we
understanding of the workings of the kidneys. We believe have done right as well as what needs improvement.
that it is better for the student at this stage to master a
few central concepts and ideas rather than to assimilate a Bruce M. Koeppen
large array of facts. Consequently, this book is designed to Bruce A. Stanton
vi
AC K N OW L E D G M E N T S
We thank our students at the Frank H. Netter MD School for this as well as for previous editions. Special thanks goes
of Medicine at Quinnipiac University and at the Geisel to Gerhard Giebisch, who has been a mentor and inspira-
School of Medicine at Dartmouth, who continually pro- tion for us.
vide feedback on how to improve this book. We also thank Finally, we thank Marybeth Thiel, Elyse O’Grady, and
our colleagues and the many individuals from around the the staff at Elsevier for their support and commitment to
world who have contacted us with thoughtful suggestions quality.
vii
PhysioofBl oodgFyyl uids
OBJECTIVES
Upocno mploetfth iciohsna ptthseetr u,ds ehnobtuea l bdl e Ina dditthiseot nu,ds ehnobtuea l bdtl doee fianneud n der
taon stwhefero llqouweisntgi ons: statnhfdeo llporwoipneogprf h tyiseiso ilmopgoirctaalnlty
• Howd ob odflyu icdo mpartdmieffwneitrtrs he specsto luatnifldou nisd s:
tot heviorl uamnetdsh eiiornc iocm positions•? M olaarniedtq yu ivalence
• Whaatrt ehd er ivfoirncrgee ss pofonrsm iobvleem en•t O smoptriecs sure
ofw ataecrr coesmlsel m braanntdeh sce a piwlallalr?y• Osmolaanrodis tmyo lality
• Howd ot hveo luomfte hsie n tracaeneldxl turlaar• Oncorteiscs ur'
cellfluulicador m partcmheannutgnsedv earr ious TonicitY._v>
pathophycsoinodliotgiiocn s?
KEVT ERMS
Steadyb-asltaantcee Toni(ciistoyth n,oontoincia,cn ,d Totbaoldw ya ter
Posibtailvaen ce hyp ertonic) Intracfleuli(ldIu ClFa)r
Negabtailvaen ce Isosmotic Extracfleuli(ldEu ClFa)r
Molarity Permeable Interflsutiidt ial
Equivalence Impermeable Plasma
Osmosis Effecotsimvoel e Thisrpda ce
Osmoptriecs sure Inffeectoisvmeo le Ascites
vanH'otff' lsa w Reflecctoieoffinc ient Capilwlaalrly
Osmolarity Osmoctoiecffi cient Starfolricnegs
Osmolality Oncoptriecs sure Capilfillatrrcyao teiffiocn(i Kern)t
Specgirfiacv ity Aquap(oArQiPn)
Onoef t hmea jfourn ctoifto hkneis d nietsyom s a intain
CONCEOPFST T EADY-BSATATLEA NCE
thveo luamnecd o mposoiftt hibeoo nd yfl'usic dosn
stadnets pwiitdveea riaintt ihdoean i ilnyt oafkw ea terT hheu mabno diyas n " opseyns tmeema,n"ti hnsagut b
ansdo luItnte hsci.hs a ptthecero ,n coefsp tte ady-ssttaantacreeae sd dteodt hbeo deya cdha ya,n sdi milarly
balainsic net rodAulcsteohd,ve. o luamnecd o mpossiubstaarnleco fresostm t hbeo deya cdha Tyh.ae m ounts
tioofnt hbeo dflyu'isad rsde i scutsops reodva ib daec kaddteood rl ofrsotmt hbeo dcyav na wriyd deelpye nding
groufonrtd h set uodfty h kei dnaesry esg uloartgoarnyos n.t heen viroancmcetenofost os,da nwda tdeirs,ep arsoe
Somoeft hbea spirci nctieprlmeisn,ao nlcdoo gnyc,e pctess asneedsv ,ec nu ltnuorramIlsns . u cahno pesny stem,
relattote hpder opeorfst oileuistn se osl uatliasorone thveo luamnecd o mposoiftt hibeoo ndfl yu iidmssa in
reviewed. taitnherdo tuhpgerh o coefss tse adyb-aslta.an tcee
1
2 CHAPTER 1 Physiology of Body Fluids
The concept of steady-state balance can be illustrated equivalence. Molarity is the amount of a substance rel-
by considering a river on which a dam is built to create a ative to its molecular weight. For example, glucose has a
manmade lake. Each day, water enters the lake from the molecular weight of 180 g/mol. If 1 L of water contains 1 g
various streams and rivers that feed it. In addition, water of glucose, the molarity of this glucose solution would be
is added by underground springs, rain, and snow. At the determined as:
same time water is lost through the spillways of the dam
1g/L
and by the process of evaporation. For the level of the lake =0.0056mol/Lor5.6mmol/L (1.1)
180g/mol
to remain constant (i.e., steady-state balance), the rate at
which water is added, regardless of source, must be exactly For uncharged molecules, such as glucose and urea,
matched by the amount of water lost, again by whichever concentrations in the body fluids are usually expressed in
route. Because the addition of water is not easily controlled, terms of molarity.a Because many of the substances of bio-
nor can the loss by evaporation be controlled, the only way logic interest are present at very low concentrations, units
to maintain the level of the lake constant is to regulate the are more commonly expressed in the millimolar range
amount that is lost through the spillways. (mmol/L).
To understand steady-state balance as it applies to the The concentration of solutes, which normally dis-
human body, the following key concepts are important. sociate into more than one particle when dissolved
1. T here must be a set-point from which deviations can in solution (e.g., sodium chloride [NaCl]), is usually
be monitored (e.g., the level of the lake in the previous expressed in terms of equivalence. Equivalence refers to
example or setting the temperature in a room by adjust- the stoichiometry of the interaction between cation and
ing the thermostat). anion and is determined by the valence of these ions.
2. T he sensors that monitor deviations from the set-point For example, consider a 1 L solution containing 9 g of
must generate effector signals that can lead to changes in NaCl (molecular weight = 58.4 g/mol). The molarity of
either input or output, or both, to maintain the desired this solution is 154 mmol/L. Because NaCl dissociates
set-point (e.g., electrical signals to adjust the spillway in into Na+ and Cl− ions, and assuming complete disso-
the dam analogy or electrical signals sent to either the ciation, this solution contains 154 mmol/L of Na+ and
furnace or air conditioner to maintain the proper room 154 mmol/L of Cl−. Because the valence of these ions is 1,
temperature). these concentrations also can be expressed as milliequiva-
3. E ffector organs must respond in an appropriate way to lents of the ion per liter (i.e., 154 mEq/L for Na+ and Cl−,
the effector signals generated by the set-point monitor respectively).
(e.g., the spillway gates must operate and the furnace or For univalent ions such as Na+ and Cl−, concentra-
air conditioner must turn on and off as appropriate). tions expressed in terms of molarity and equivalence
4. T he sensitivity of the system (i.e., how much of a devi- are identical. However, this is not true for ions having
ation away from the set-point is tolerated) depends on valences greater than 1. Accordingly, the concentration
several factors, including the nature of the sensor (i.e., of Ca++ (molecular weight = 40.1 g/mol and valence = 2)
how much of a deviation from the set-point is needed in a 1 L solution containing 0.1 g of this ion could be
for the sensor to detect the deviation), the time necessary expressed as:
for generation of the effector signals, and how rapidly the 01g/L
effector mechanisms respond to the effector signals. 401g/mol=25mmol/L
(1.2)
It is important to recognize that deviations from steady-
25mmol/L×2Eq/mol=5 mEq/L
state balance do occur. When input is greater than output,
a state of positive balance exists. When input is less than Although some exceptions exist, it is customary to
output, a state of negative balance exists. Although tran- express concentrations of ions in milliequivalents per liter.
sient periods of imbalance can be tolerated, prolonged
states of extreme positive or negative balance are generally
incompatible with life. a The units used to express the concentrations of substances in var-
ious body fluids differ among laboratories. The system of interna-
tional units (SI) is used in most countries and in most scientific
PHYSICOCHEMICAL PROPERTIES OF and medical journals in the United States. Despite this conven-
tion, traditional units are still widely used. For urea and glucose,
ELECTROLYTE SOLUTIONS
the traditional units of concentration are milligrams per deciliter
Molarity and Equivalence (mg/dL, or 100 mL), whereas the SI units are millimole per liter
(mmol/L). Similarly, electrolyte concentrations are traditionally
The amount of a substance dissolved in a solution (i.e., its expressed as milliequivalent per liter (mEq/L), whereas the SI units
concentration) is expressed in terms of either molarity or are mmol/L (see Appendix B).
CHAPTER 1 Physiology of Body Fluids 3
Initial condition Equilibrium condition
h
A B A B
Semipermeable membrane
Fig. 1.1 Schematic representation of osmotic water movement and the generation of an osmotic pressure.
Compartment A and compartment B are separated by a semipermeable membrane (i.e., the membrane is
highly permeable to water but impermeable to solute). Compartment A contains a solute, whereas com-
partment B contains only distilled water. Over time, water moves by osmosis from compartment B to com-
partment A. (Note: This water movement is driven by the concentration gradient for water. Because of the
presence of solute particles in compartment A, the concentration of water in compartment A is less than that
in compartment B. Consequently, water moves across the semipermeable membrane from compartment B
to compartment A down its gradient). This causes the level of fluid in compartment A to rise and the level in
compartment B to fall. At equilibrium, the hydrostatic pressure exerted by the column of water (h) stops the
movement of water from compartment B to A. Thus, at equilibrium, the hydrostatic pressure generated by
the height (h) of the column of water in compartment A is equal and opposite to the osmotic pressure gener-
ated by the solute particles in compartment A.
Osmosis and Osmotic Pressure
osmolarity (see the following discussion). Thus a solution
The movement of water across cell membranes occurs containing 1 mmol/L of solute particles exerts an osmotic
by the process of osmosis. The driving force for this pressure of 1 milliosmole per liter (1 mOsm/L).
movement is the osmotic pressure difference across the For substances that dissociate in a solution, n of Eq.
cell membrane. Fig. 1.1 illustrates the concept of osmo- (1.3) has a value other than 1. For example, a 150 mmol/L
sis and the measurement of the osmotic pressure of a solution of NaCl has an osmolarity of 300 mOsm/L because
solution. each molecule of NaCl dissociates into a Na+ and a Cl− ion
Osmotic pressure is determined solely by the number (i.e., n = 2). If dissociation of a substance into its compo-
of solute particles in the solution. It is not dependent on nent ions is not complete, n is not an integer. Accordingly,
factors such as the size of the solute particles, their mass, osmolarity for any solution can be calculated as:
or their chemical nature (e.g., valence). Osmotic pressure
(π), measured in atmospheres (atm), is calculated by van’t Osmolarity=Concentration×Numberofdissociable
particles
Hoff’s law as:
mOsm/L=mmol/L×numberofparticles/mol
π=nCRT (1.3) (1.4)
where n is the number of dissociable particles per mole-
Osmolarity and Osmolality
cule, C is total solute concentration, R is gas constant, and
T is temperature in degrees Kelvin (°K). Osmolarity and osmolality are often confused and incor-
For a molecule that does not dissociate in water, rectly interchanged. Osmolarity refers to the number of
such as glucose or urea, a solution containing 1 mmol/L solute particles per 1 L of solvent, whereas osmolality is
of these solutes at 37°C can exert an osmotic pressure the number of solute particles in 1 kg of solvent. For dilute
of 2.54 × 10−2 atm as calculated by Eq. (1.3) using the solutions, the difference between osmolarity and osmolal-
f ollowing values: n is 1, C is 0.001 mol/L, R is 0.082 atm ity is insignificant. Measurements of osmolarity are tem-
L/mol, and T is 310°K. perature dependent, because the volume of solvent varies
Because 1 atm equals 760 mm Hg at sea level, π for with temperature (i.e., the volume is larger at higher tem-
this solution also can be expressed as 19.3 mm Hg. peratures). In contrast, osmolality, which is based on the
Alternatively, osmotic pressure is expressed in terms of mass of the solvent, is temperature independent. For this
