Ebook Core concepts in the disorders of fluid, electrolytes and acid base balance: Part 1

Core Concepts in the Disorders
of Fluid, Electrolytes
and Acid-Base Balance



David B. Mount • Mohamed H. Sayegh
Ajay K. Singh
Editors

Core Concepts
in the Disorders
of Fluid, Electrolytes
and Acid-Base Balance


Editors
David B. Mount, MD
Renal Division
VA Boston Healthcare System
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA, USA

Mohamed H. Sayegh, MD
Renal Division
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA, USA

Ajay K. Singh, MB, FRCP (UK)
Renal Division
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA, USA

ISBN 978-1-4614-3769-7
ISBN 978-1-4614-3770-3 (eBook)
DOI 10.1007/978-1-4614-3770-3
Springer New York Heidelberg Dordrecht London
Library of Congress Control Number: 2012941302
© Springer Science+Business Media New York 2013
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To my wife and children; Erika, Julia, and Nicholas
–DBM



Preface

Fluid, electrolyte, and acid–base disorders are central to the day-to-day practice of almost all areas of patient-centered medicine, both medical and surgical. Despite the steep learning curve for trainees, the underlying
pathophysiology and/or management is often viewed as “settled,” with the
perception that there is little in this field that is new. However, there have
been significant recent developments in all aspects of these important disorders. This book encompasses these new findings in comprehensive reviews
of both pathophysiology and clinical management, meant for both the nephrologist and the nonspecialist physician or medical trainee.
Virtually every subject in this textbook has witnessed major developments
in the last decade. New pathophysiology includes the molecular identification
of “pendrin” (SLC26A4) as the apical Cl−/HCO3− exchanger in b[beta]-intercalated cells [1, 2]; this transporter functions in distal chloride and bicarbonate transport, with evolving roles in the pathophysiology of hypertension and
metabolic alkalosis. A host of previously uncharacterized genetic tubular disorders have recently yielded to molecular genetics, with major impact of this
gene identification on the understanding of renal physiology and pathophysiology. In particular, the identification in 2001 [3] of causative mutations in
the WNK1 (With No K/Lysine) and WNK4 kinases in familial hypertension
with hyperkalemia (Gordon’s syndrome) led to a still-evolving cascade of
insight into the role of these and associated signaling proteins in the coordination of aldosterone-dependent and aldosterone-independent regulation of
distal potassium, sodium, and chloride transport [4]. Characterization of multiple genes for familial hypomagnesemia led to the identification of novel
magnesium transport pathways [5] and to the identification of cell-associated
epidermal growth factor as a major paracrine regulator of distal tubular magnesium transport [6]. Finally, characterization of FGF23 (fibroblast growth
factor-23) as the disease gene for autosomal dominant hypophosphatemic
rickets [7] uncovered a major new regulatory hormone in calcium and phosphate balance [8, 9].

At the clinical level, the spectrum of the acquired causes of electrolyte
disorders continues to expand. Examples include hypokalemia due to the activation of colonic potassium secretion in Ogilvie’s syndrome [10], and hypomagnesemia, with or without associated hypokalemia, after treatment with the
EGF antagonist cetuximab [6, 11, 12]. The management of electrolyte disorders has also evolved considerably in the last decade. Nowhere is this more

vii


Preface

viii

evident than in hyponatremia, with the recent availability of vasopressin
antagonists [13, 14] and the increasing familiarity with relowering of serum
sodium concentration in patients who have corrected too quickly [15].
The integrated analysis and management of fluid, electrolyte, and acid–
base disorders can be a daunting challenge, especially for trainees. With this
in mind, the last chapter includes ten real-life clinical vignettes that provide a
step-by-step analysis of the pathophysiology, differential diagnosis, and management of selected clinical problems.
Boston, MA, USA

David B. Mount
Mohamed H. Sayegh
Ajay K. Singh

References
1. Royaux IE, Wall SM, Karniski LP, et al. Pendrin, encoded by the Pendred syndrome
gene, resides in the apical region of renal intercalated cells and mediates bicarbonate
secretion. Proc Natl Acad Sci U S A. 2001;98:4221–6.
2. Verlander JW, Hassell KA, Royaux IE, et al. Deoxycorticosterone upregulates PDS
(Slc26a4) in mouse kidney: role of pendrin in mineralocorticoid-induced hypertension.

Hypertension 2003;42:356–62.
3. Wilson FH, Disse-Nicodeme S, Choate KA, et al. Human hypertension caused by
mutations in WNK kinases. Science 2001;293:1107–12.
4. Welling PA, Chang YP, Delpire E, Wade JB. Multigene kinase network, kidney transport, and salt in essential hypertension. Kidney Int. 2010;77:1063–9.
5. Schlingmann KP, Weber S, Peters M, et al. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat
Genet. 2002;31:166–70.
6. Groenestege WM, Thebault S, van der Wijst J, et al. Impaired basolateral sorting of
pro-EGF causes isolated recessive renal hypomagnesemia. J Clin Invest. 2007;
117:2260–7.
7. Consortium A. Autosomal dominant hypophosphataemic rickets is associated with
mutations in FGF23. The ADHR Consortium. Nat Genet. 2000;26:345–8.
8. Wolf M. Forging forward with 10 burning questions on FGF23 in kidney disease. J Am
Soc Nephrol. 2010;21:1427–35.
9. Alon US. Clinical practice. Fibroblast growth factor (FGF)23: a new hormone. Eur J
Pediatr. 2011;170:545–54.
10. Blondon H, Bechade D, Desrame J, Algayres JP. Secretory diarrhoea with high faecal
potassium concentrations: a new mechanism of diarrhoea associated with colonic
pseudo-obstruction? Report of five patients. Gastroenterol Clin Biol. 2008;32:401–4.
11. Cao Y, Liao C, Tan A, Liu L, Gao F. Meta-analysis of incidence and risk of hypomagnesemia with cetuximab for advanced cancer. Chemotherapy 2010;56:459–65.
12. Cao Y, Liu L, Liao C, Tan A, Gao F. Meta-analysis of incidence and risk of hypokalemia
with cetuximab-based therapy for advanced cancer. Cancer Chemother Pharmacol.
2010;66:37–42.
13. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin
V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355:2099–112.
14. Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Smith N. Assessment of the
efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol. 2007;27:447–57.
15. Perianayagam A, Sterns RH, Silver SM, et al. DDAVP is effective in preventing and
reversing inadvertent overcorrection of hyponatremia. Clin J Am Soc Nephrol. 2008;
3:331–6.

Contents

1 The Physiology of Water Homeostasis .......................................
Jeff M. Sands, David B. Mount, and Harold E. Layton

1

2

Disorders of Water Metabolism ..................................................
Joshua M. Thurman and Tomas Berl

29

3

Potassium and the Dyskalemias..................................................
Alan Segal

49

4

Disorders of Calcium, Phosphate, and Magnesium
Metabolism ...................................................................................
Ali Hariri, David B. Mount, and Ashghar Rastegar

103

Management of Fluid and Electrolyte Abnormalities
in Children ....................................................................................
John T. Herrin

147

5

6

Diuretic Therapy ..........................................................................
Arohan R. Subramanya and David H. Ellison

171

7

Renal Acidification Mechanisms.................................................
I. David Weiner, Jill W. Verlander, and Charles S. Wingo

203

8

Core Concepts and Treatment of Metabolic Acidosis ...............
Michael R. Wiederkehr and Orson W. Moe

235

9

Metabolic Alkalosis ......................................................................
F. John Gennari

275

10

Respiratory Acid–Base Disorders...............................................
Biff F. Palmer

297

11

Mixed Acid–Base Disorders ........................................................
Jeffrey A. Kraut and Ira Kurtz

307

12

Case Studies in Electrolyte and Acid–Base Disorders ..............
David B. Mount

327

Index ......................................................................................................

363

ix



Contributors

Tomas Berl, MD Department of Medicine, University of Colorado, Aurora,
CO, USA
David H. Ellison, MD Division of Nephrology and Hypertension,
Department of Medicine, Oregon Health and Science University, Portland,
OR, USA
F. John Gennari, MD Department of Medicine, University of Vermont,
Burlington, VT, USA
Ali Hariri, MD Section of Nephrology, Department of Medicine, Yale
School of Medicine, New Haven, CT, USA
John T. Herrin, MBBS, FRACP Attending Nephrology, Division of
Nephrology, Department of Medicine, Children’s Hospital, Boston, MA, USA
Jeffrey A. Kraut, MD Dialysis Unit and Department of Nephrology,
VHAGLA Healthcare System, David Geffen School of Medicine at UCLA,
Los Angeles, CA, USA
Ira Kurtz, MD, FRCP(C) Department of Medicine, Division of Nephrology,
University of California at Los Angeles, Los Angeles, CA, USA
Harold E. Layton, PhD Department of Mathematics, Duke University,
Durham, NC, USA
Orson W. Moe, MD Internal Medicine/Nephrology and Charles and Jane
Pak Center for Mineral Metabolism and Clinical Research, UT Southwestern
Medical Center, Dallas, TX, USA
David B. Mount, MD Renal Division, VA Boston Healthcare System,
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA,

USA
Biff F. Palmer, MD Internal Medicine, UT Southwestern Medical Center,
Dallas, TX, USA
Asghar Rastegar, MD Department of Internal Medicine, Yale School of
Medicine, New Haven, CT, USA
Jeff M. Sands, MD Department of Medicine, Renal Division, Emory
University, Atlanta, GA, USA

xi


xii

Mohamed H. Sayegh, MD Renal Division, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, USA
Alan Segal, MD Division of Nephrology, Department of Medicine, University
of Vermont, Burlington, VT, USA
Ajay K. Singh, MB, FRCP (UK) Renal Division, Brigham and Women’s
Hospital, Harvard Medical School, Boston, MA, USA
Arohan R. Subramanya, MD Department of Medicine, Renal-Electrolyte
Division, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Joshua M. Thurman, MD Department of Internal Medicine, University of
Denver School of Medicine, Aurora, CO, USA
Jill W. Verlander, DVM College of Medicine Core Electron Microscopy
Lab, Division of Nephrology, Hypertension and Transplantation, Department
of Medicine, University of Florida College of Medicine, Gainesville, FL,
USA
I. David Weiner, MD Department of Medicine, University of Florida
College of Medicine and North Florida/South Georgia Veterans Health System,
Gainesville, FL, USA

Michael R. Wiederkehr, MD Department of Nephrology, Baylor University
Medical Center, Dallas, TX, USA
Charles S. Wingo, MD Division of Nephrology, Department of Medicine,
University of Florida, Gainesville, FL, USA
North Florida/South Georgia Vetrans Health System, Gainesville, FL, USA

Contributors


1

The Physiology of Water
Homeostasis
Jeff M. Sands, David B. Mount,
and Harold E. Layton

Introduction
Water is the most abundant constituent in the body,
comprising approximately 50 % of body weight in
women and 60 % in men. Total body water is distributed in two major compartments: 55–75 % is
intracellular (intracellular fluid, ICF), and 25–45 %
is extracellular (extracellular fluid, ECF). The ECF
is further subdivided into intravascular (plasma
water) and extravascular (interstitial) spaces, in a
ratio of 1:3. Fluid movement between the intravascular and interstitial spaces occurs across the capillary wall and is determined by Starling forces.
The solute or particle concentration of a fluid is
known as its osmolality, expressed as milliosmoles
per kilogram (mOsm/kg) of water. Water easily
diffuses across most cell membranes to achieve
osmotic equilibrium (ECF osmolality = ICF osmolality). Water homeostasis is therefore critical to

J.M. Sands, M.D. ( )
Department of Medicine, Renal Division,
Emory University, 1639 Pierce Drive,
NE, WMB Room 338, Atlanta, GA 30322, USA
e-mail:
D.B. Mount, M.D.
Renal Division, VA Boston Healthcare System,
Brigham and Women’s Hospital, Harvard Medical
School, Boston, MA, USA
e-mail: ;

H.E. Layton, Ph.D.
Department of Mathematics, Duke University,
Box 90230, Durham, NC 27708-0320, USA

the maintenance of both circulatory integrity and
the normal osmolality of body fluids.
Vasopressin secretion, water ingestion, and
the renal concentrating mechanism collaborate to
maintain human body fluid osmolality between
280 and 295 mOsm/kg. The primary hormonal
control of renal water excretion is by arginine
vasopressin (AVP; also named antidiuretic hormone, ADH). Under normal circumstances, vasopressin’s circulating level is determined by
osmoreceptors in the hypothalamus, which trigger increases in vasopressin secretion (by the
posterior pituitary gland) when the osmolality of
the blood rises above a threshold value, about
292 mOsm/kg H2O; thirst and thus water intake
also increase above this threshold. The kidney
responds to changes in vasopressin levels by

varying urine flow (i.e., water excretion).
The mammalian kidney maintains blood
plasma osmolality and sodium concentration
nearly constant by means of mechanisms that
independently regulate water and sodium excretion. Since many mammals do not have continuous access to water, the ability to vary water
excretion can be essential for survival. Sodium
and its anions are the principal osmotic constituents of blood plasma, and since stable electrolyte
concentrations are also essential, water excretion
must be regulated by mechanisms that decouple
it from sodium excretion. The urine concentrating mechanism plays a fundamental role in regulating water and sodium excretion. When water
intake is large enough to dilute blood plasma,
a urine that is more dilute than blood plasma is

D.B. Mount et al. (eds.), Core Concepts in the Disorders of Fluid, Electrolytes and Acid-Base Balance,
DOI 10.1007/978-1-4614-3770-3_1, © Springer Science+Business Media New York 2013

1


2

produced. When water intake is so small that
blood plasma is concentrated, a urine that is more
concentrated than blood plasma is produced. In
both cases, the total urinary solute excretion rate
and the urinary sodium excretion rates are small
and normally vary within narrow bounds.
In contrast to solute excretion, urine osmolality varies widely in response to changes in water
intake. Following several hours without water
intake, such as occurs overnight during sleep,

human urine osmolality may rise to ~1,200 mOsm/
kg H2O, about four times plasma osmolality
(~290 mOsm/kg H2O). Conversely, urine osmolality may decrease rapidly following the ingestion of large quantities of water, such as commonly
occurs at breakfast; human (and other mammals)
urine osmolality may decrease to ~50 mOsm/
kgH2O. Most physiologic studies relevant to the
urine concentrating mechanism have been conducted in species (rodents, rabbits) that can
achieve higher maximum urine osmolalities than
humans. For example, rabbits can concentrate to
~1,400 mOsm/kg H2O, rats to ~3,000 mOsm/kg
H2O, mice and hamsters to ~4,000 mOsm/kg
H2O, and chinchillas to ~7,600 mOsm/kg H2O
(reviewed in [1, 2]).

Osmoreception
Regulation of Vasopressin Release
Vasopressin is synthesized in magnocellular neurons within the hypothalamus; the distal axons of
these neurons project to the posterior pituitary or
neurohypophysis, from which vasopressin is
released into the circulation (see Fig. 1.1).
Vasopressin secretion is stimulated as osmolality
increases above a threshold level, beyond which
there is a linear relationship between circulating
osmolality and vasopressin (Fig. 1.2). The X
intercept of this relationship in healthy humans is
~285 mOsm/kg H2O; vasopressin levels are
essentially undetectable below this threshold.
Changes in blood volume and blood pressure
are also potent stimuli for vasopressin release,

J.M. Sands et al.

albeit with a more exponential response profile.
Of perhaps greater relevance to the pathophysiology of hyponatremia, ECF volume strongly
modulates the relationship between circulating
osmolality and vasopressin release, such that
hypovolemia reduces the osmotic threshold and
increases the slope of the response curve to osmolality; hypervolemia has an opposite effect, increasing the osmotic threshold and reducing the slope of
the response curve (Fig. 1.2) [3]. Similar modulation of the osmotic response occurs in heart failure,
with both higher baseline vasopressin levels and
an exaggerated response to hypertonic IV contrast
[4]. A number of other stimuli have potent positive
effects on vasopressin release, including nausea,
angiotensin II, acetylcholine, relaxin, serotonin,
cholecystokinin, and a variety of drugs [5] (see
also Regulation of osmoreceptor function).
There are considerable male–female differences in the sensitivity of vasopressin release to
osmolality, with a greater male sensitivity compared with women in both the follicular and luteal
phase of the menstrual cycle [6]. Pregnancy is
also associated with a 6 mOsm/kg H2O drop in
the osmotic threshold for vasopressin release, in
addition to an 11 mOsm/kg H2O drop in the
osmotic threshold for thirst [7]. The physiology
of these relationships is very complex and often
contradictory due to a variety of genomic and
non-genomic effects of gonadal steroids [8]. In
males, testosterone appears to increase synthesis
and osmotic release of vasopressin [9]. Human
magnocellular neurons express both estrogen
receptor-b (ER-b) and estrogen receptor-a (ERa) [8]; activation of these homologous receptors

can have opposing effects on gene expression,
consistent perhaps with the complex and sometimes contradictory effects of estrogen. Several
lines of evidence suggest that activation of ER-a
increases vasopressin expression and release,
whereas ER-b attenuates vasopressin expression
and release [8]. In particular, ER-b is drastically
reduced in vasopressin-positive neurons by both
hypertonicity and hypovolemia [10], suggesting
inhibitory effects of ER-b on vasopressin expression and release.


1 The Physiology of Water Homeostasis

3

Fig. 1.1 Osmoregulatory circuits in the mammalian nervous system. Sagittal illustration of the rat brain, in which
the relative positions of relevant structures and nuclei have
been compressed into a single plane. Neurons and pathways are color coded to distinguish osmosensory, integrative, and effector areas. Vasopressin (AVP) is synthesized
in magnocellular neurons within the supraoptic (SON)
and paraventricular (PVN) nuclei of the hypothalamus;
the distal axons of these neurons project to the posterior
pituitary (PP) from which vasopressin is released into the

circulation. ACC anterior cingulate cortex, AP area postrema, DRG dorsal root ganglion, IML intermediolateral
nucleus, INS insula, MnPO median preoptic nucleus, NTS
nucleus tractus solitarius, OVLT organum vasculosum
laminae terminalis, PAG periaqueductal grey, PBN
parabrachial nucleus, PP posterior pituitary, PVN paraventricular nucleus, SFO subfornical organ, SN sympathetic nerve, SON supraoptic nucleus, SpN splanchnic
nerve, THAL thalamus, VLM ventrolateral medulla.
Adapted from Bourque [12] with permission

Regulation of Thirst

“off” response to drinking, with a rapid drop that
precedes any change in circulating osmolality
(see Fig. 1.3). Teleologically, this reflex response
serves to prevent over-hydration [11]. Although
the mechanisms involved are still somewhat
obscure, peripheral osmoreceptors in the oropharynx, upper gastrointestinal (GI) tract, and/or portal vein are postulated to sense the rapid change
in local osmolality and relay the information
back through the vagus nerve and splanchnic
nerves [12].
As with vasopressin release, thirst is stimulated by hypovolemia, although this requires a

Classically, the onset of thirst, defined as the
conscious need for water, was considered to have
a threshold of ~295 mOsm/kg H2O, i.e.,
~10 mOsm/kg H2O above that for vasopressin
release [6]. However, more recent studies using
semiquantitative visual analog scales to assess
thirst suggest that the osmotic threshold is very
close to that of vasopressin release, with a steady
increase in the intensity of thirst as osmolality
increases above this threshold [11] (see Fig. 1.3).
Thirst and vasopressin release share a potent


4

J.M. Sands et al.

Fig. 1.2 The influence of volume status on osmotic stimulation of vasopressin release in healthy adults. The heavy
oblique line in the center depicts the relationship of plasma
vasopressin to osmolality in normovolemic, normotensive
subjects. Labeled lines to the left or right depict the relationship when blood volume and/or pressure are acutely
decreased or increased, in hypovolemia or hypervolemia,
respectively

deficit of 8–10 % in plasma volume, versus the
1–2 % increase in tonicity that is sufficient to
stimulate osmotic thirst [13]. Angiotensin II is a
particularly potent dipsogenic agent, especially
when infused directly into the brain or, more
recently, overproduced in the subfornical organ
(SFO) in transgenic mice [14]. Double-transgenic
mice that express human renin from a neuronal
promoter and human angiotensinogen from its
own promoter were thus found to exhibit marked
increases in water and salt intake. This phenotype
is evidently caused by a marked increase in angiotensin II generation in neurons within the SFO
due to the neuronal overexpression of human
renin. Intracerebroventricular delivery of losartan
blocked this polydipsic phenotype, as did inactivation of a “floxed” allele of angiotensinogen
within the SFO, using adenoviral delivery of Cre
recombinase [14]. Transgenic mice that overexpress brain angiotensin II type Ia (AT1a) receptors from a neuronal promoter also demonstrate
increased intake of water and salt [15]. Finally,
mice lacking angiotensin II due to targeted deletion of the murine angiotensinogen gene do not
show impaired osmotic stimulation of thirst, but
do have impaired thirst response to various hypovolemic stressors [16]. Therefore, the neuronal

Fig. 1.3 The response of (a) plasma osmolality, (b) circulating vasopressin, and (c) thirst to hypertonic saline
followed by drinking (open diamonds) or water deprivation (filled diamonds). Thirst and vasopressin steadily
increase in response to increased osmolality, with a rapid
drop in both parameters after drinking (b and c) despite
the lack of acute change in osmolality (a). From McKenna
et al. [11], with permission


1 The Physiology of Water Homeostasis

effects of angiotensin II are evidently required for
hypovolemic thirst, but not osmotic thirst [16].
Angiotensin II-dependent thirst has been demonstrated in a number of mammalian and nonmammalian species [13], but seems to be
somewhat less potent in humans [17]. Although
the experimental physiology is suggestive of a
role for angiotensin II in thirst associated with
heart failure and other disorders, much of the evidence is understandably indirect [13]. Perhaps
the most compelling clinical evidence is the profound polydipsia that can accompany high-renin
states such as renal artery stenosis or reninsecreting tumors [13]. In addition, a number of
studies have implicated increased levels of angiotensin II in dialysis-associated thirst, with reduced
thirst after angiotensin converting enzyme (ACE)
inhibition [6].
Several ACE inhibitors (lisinopril, enalapril,
cilazapril, benazepril, and captopril) have been
associated with the development of the Syndrome
of Inappropriate Anti-Diuresis (SIAD, formerly
named Syndrome of Inappropriate Anti-Diuretic
Hormone Secretion, SIADH) and/or hyponatremia [6], which is superficially paradoxical
given the potent effect of angiotensin II on both
vasopressin secretion and thirst. The pathogenesis of hyponatremia in these patients is not

entirely clear. However, ACE inhibition in these
patients may have had much less effect on the
generation of angiotensin II within the central
nervous system (CNS), compared to systemic
angiotensin II, with central stimulation of both
vasopressin and thirst. Notably, ACE inhibitors
can be strongly polydipsic in both animals and
patients [6]. This polydipsia appears to be dependent on bradykinin generation by ACE inhibition,
with blockade of the effect by the bradykinin
antagonist B-9430 [18].
Finally, in SIAD, one could postulate that
thirst is also subject to abnormal regulation, with
a decreased threshold and/or altered relationship
to osmolality; indeed, the simple persistence of
water intake in SIAD, at osmolalities lower than
the typical threshold for thirst, is demonstrative
of such an abnormality. In a landmark study,
Smith et al. recently demonstrated that the osmotic
threshold for thirst is in fact reduced in patients

5

with SIAD, with thresholds that were almost
identical to the corresponding osmotic thresholds
for vasopressin release [19]. This suggests a
shared pathophysiology for the abnormal vasopressin release and thirst in SIAD, perhaps due to
alteration in osmoreceptor function (see below).
Of interest, the act of drinking reduced thirst in
the patients with SIAD, but did not attenuate
vasopressin levels [19], versus the normal response

of vasopressin to drinking (see Fig. 1.3).

Osmoreceptive Neural Networks
Seminal canine experiments some 60 years ago,
correlating the effect of carotid infusion of various osmolytes on urine output, led to the prescient postulation of a central “osmoreceptor”
[20]. The primary, dominant “osmostat” is
encompassed within the organum vasculosum of
the lamina terminalis (OVLT); this small periventricular region lacks a blood–brain barrier, affording direct sensing of the osmolality of circulating
blood. However, osmoreceptive neurons are
widely distributed within the CNS, such that
vasopressin release and thirst are controlled by
overlapping osmosensitive neural networks [12,
21–23] (see Fig. 1.1). Osmosensitive neurons are
thus found in the SFO and the nucleus tractus
solitarii, centers which help integrate regulation
of circulating osmolality with that of related phenomena, such as ECF volume [12, 21, 22]. As
discussed above, angiotensin II generation in the
SFO has a very potent dipsogenic effect [6].
Finally, the “magnocellular” neurons of the
hypothalamus, which synthesize and secrete
vasopressin, are located in the supraoptic and
paraventricular nuclei (Fig. 1.1) and are also
directly sensitive to changes in osmolality [24].
Experimental ablation of the OVLT and adjacent circumventricular regions leads to variable
defects in water intake and vasopressin release, in
a number of different species [25, 26]. In sheep,
ablation of the OVLT or SFO alone does not
affect osmotic-induced drinking; combined ablation of both regions is more effective, but with
some residual response. Complete abolition of
thirst is however seen after combined ablation of

6

the OVLT, the adjacent median preoptic nucleus
(MnPO), and much of the SFO (see Fig. 1.1)
[27]. Similar observations can be made in respect
to vasopressin release, in that combined ablation
of the OVLT, SFO, and MnPO is required to fully
abolish osmotic-induced release of vasopressin;
notably, “non-osmotic” stimuli such as hemorrhage and fever are still effective in inducing
vasopressin release in these animals [26].
In humans, functional magnetic resonance
imaging (fMRI) studies have revealed thirstassociated activation of the anterior wall of the
third ventricle, encompassing the OVLT, in two
out of four subjects treated with a rapid infusion
of hypertonic saline [28]. Clinically, a variety of
infiltrative, neoplastic, vascular, congenital, and
traumatic processes in this circumventricular
region can be associated with abnormalities in
thirst and vasopressin release. Patients with this
“adipsic” or “essential” hypernatremia generally
exhibit combined defects in both vasopressin
release and thirst [29]. In some cases, however,
thirst is impaired but not vasopressin release [29],
underscoring the functional redundancy and/or
plasticity of the osmosensitive neuronal network;
alternatively, the intrinsic osmosensitivity of the
magnocellular neurons that synthesize and secrete
vasopressin may preserve a residual osmoticinduced vasopressin release [26].

Increases in systemic tonicity cause electrophysiological activation of a subset of neurons
within the OVLT, MnPO, and SFO [12, 26]. This
is accompanied by increased expression of the
immediate-early transcription factor c-fos, a
marker of calcium-dependent neuronal activation
[12, 26]. Distinct subsets of neurons in the OVLT
and SFO project to magnocellular neurons within
the supraoptic and paraventricular nuclei (SON
and PVN); the pattern of c-fos induction corresponds to the known distribution of these same
neurons, indicating that the OVLT/SFO osmosensitive neurons are upstream activators of the magnocellular neurons that release vasopressin [26,
30]. Direct identification of bona fide osmoreceptive neurons, i.e., neurons that translate changes
in tonicity into alterations in action-potential discharge [12, 22], has been achieved using isolated
neurons or explants from the OVLT, the SFO, the
PVN, and the SON [6]. These neurons are

J.M. Sands et al.

generally activated by hypertonic conditions, i.e.,
exhibiting an increased action-potential discharge, and inhibited by hypotonic conditions
[12, 22].

Molecular Physiology of Osmosensitive
Neurons
Osmosensitive neurons from the SON differ dramatically from hippocampal neurons in that they
demonstrate exaggerated changes in cell volume
during cell shrinkage (hypertonic media) or cell
swelling (hypotonic media) [31]. In hippocampal
neurons, cell swelling evokes a rapid regulatory
volume decrease (RVD) response, whereas cell
shrinkage evokes a regulatory volume increase

(RVI) response. In consequence, if external tonicity is slowly increased or decreased these RVD
and RVI mechanisms are sufficient to prevent
any change in the cell volume of hippocampal
neurons; in contrast, osmosensitive neurons
exhibit considerable changes in cell volume during such osmotic ramps [31]. This relative lack of
volume regulatory mechanisms maximizes the
mechanical effect of extracellular tonicity and
generates an ideal osmotic sensor.
Osmosensitive neurons also depolarize after
cell shrinkage induced by exposure to hypertonic
stimuli, with a marked increase in neuronal spike
discharges; the associated current is unaffected
by anion substitution but is affected by substituting Na+ with K+, suggesting involvement of a
nonselective cation channel [24]; more recent
studies indicate a fivefold higher permeability for
Ca2+ over Na+ [32]. Hypotonic stimuli in turn
hyperpolarize the cells and essentially abolish
spike discharges [24]. Depolarization and spike
discharges, in the absence of hypertonicity, can
also be evoked by suction-induced changes in
cell volume during whole-cell voltage recording,
suggesting involvement of a stretch-inactivated
cation channel [24]. Furthermore, the external
blockade of stretch-sensitive cation channels with
gadolinium inhibits depolarization and spike discharges induced by hypertonic stimuli, without
affecting cell shrinkage [6]. Mechanosensitive,
stretch-inactivated cation channels are evidently
a key component of the osmoreceptor complex.

1 The Physiology of Water Homeostasis

Members of the transient receptor potential
(TRP) gene family of cation channels have
recently been implicated in neuronal osmosensing. A Caenorhabditis elegans (worm) TRP channel was initially identified as OMS-9, a gene
involved in osmotic-avoidance responses, with
expression in osmoreceptor neurons [33]. Liedtke
et al. demonstrated expression of the homologous
mammalian TRPV4 transcript in osmoreceptor
neurons in the OVLT and MnPO [34]; subsequent
immunohistochemistry revealed expression of
the TRPV4 protein in circumventricular neurons
[35]. The nonselective TRPV4 cation channel is
osmotically sensitive when expressed in mammalian cells [34, 36]. However, it functions as a
swelling-activated channel, inhibited by cell
shrinkage, the opposite behavior expected of the
shrinkage-activated and stretch-inactivated channel implicated in neuronal osmoreceptor function
[24, 37, 38]. Notably, however, mammalian
TRPV4 is capable of rescuing the avoidance
response to hypertonicity in C. elegans OSM-9
mutant worms, suggesting a critical in vivo role
in the osmotic response to hypertonicity [39].
The physiological characterization of TRPV4
knockout mice has yielded somewhat contradictory findings [35, 39], which nonetheless indicate
a role in central osmosensing. Liedtke et al. demonstrated reduced drinking in single-caged
TRPV4−/− mice, with an associated mild increase
in serum osmolality [39]. The mice also had an
exaggerated increase in serum osmolality after
water deprivation or intraperitoneal hypertonic
saline, with a blunted increase in vasopressin

[39]. The induction of c-fos after intraperitoneal
hypertonic saline was also attenuated in OVLT
neurons of these TRPV4−/− mice [39]. Finally,
TRPV4 knockout mice became hyponatremic
during treatment with the V2 agonist dDAVP
(Desmopressin), with a relative failure to reduce
drinking after the development of systemic hypotonicity. Consistent with an anti-dipsogenic effect
of TRPV4, the intracerebroventricular infusion
of a TRPV4 agonist reduces spontaneous drinking and drinking induced by angiotensin II; however, drinking induced by water deprivation or
hypertonic infusion was unaffected [40].
Using a separate TRPV4 knockout strain to
that of Liedtke et al., Mizuno et al. did not detect

7

abnormalities in baseline water intake or serum
osmolality [35], perhaps since this seems to
require housing in single cages to reduce group
behavioral influences [39]. With respect to vasopressin release, Mizuno detected an exaggerated
response to hypertonic stress in TRPV4 knockout
mice, compared to wild-type mice [35]; notably,
however, they only measured this response in one
mouse from each genotype [35], versus fourteen
mice per genotype in Liedtke et al. [39]. However,
using brain slices from five mice in each genotype, Mizuno et al. also demonstrated an exaggerated secretion of vasopressin in TRPV4
knockout mice sections, during graded increases
in tonicity [35].
More recently, Bourque et al. have implicated
TRPV1, a related member of the TRP channel
gene family, in the activation of osmoreceptor

neurons by hypertonic stimuli [41, 42]. These
authors detected the expression of TRPV1
C-terminal exons by RT-PCR in neurons from the
SON, without detectable expression of N-terminal
exons; vasopressin-positive neurons also stained
positive with a C-terminal TRPV1 antibody.
Given prior data on a mechanosensitive, shrinkage-activated TRPV1-TRPV4 cDNA [43], generated by fusion of N-terminal truncated TRPV1
sequence to the TRPV4 C-terminus [42], the
authors went on to characterize TRPV1 knockout
mice; the hypothesis was that an N-terminal truncated isoform of TRPV1 was the osmoreceptor
channel. Isolated magnocellular and OVLT neurons from these mice lack the usual depolarization and spike discharges induced by hypertonic
stress, indicating a critical role for TRPV1 [41,
42]. TRPV1 knockout mice also show a marked
decrease in the slope of the curve that relates systemic osmolality to circulating vasopressin, suggesting impairment but not abolition of
osmotic-induced vasopressin release [42]. In
addition, TRPV1−/− mice challenged with intraperitoneal hypertonic saline showed a 20 %
reduction in drinking compared to wild-type control mice [41], indicating impairment but not
abolition of osmotic-induced thirst. Again, however, as in the case of TRPV4 knockout mice [35,
39], there is a substantial discrepancy in the
reported phenotypes of TRPV1 knockout mice
[41, 42, 44]. In a more extensive study, Taylor


8

et al. have reported that TRPV1−/− mice have no
abnormality in water intake induced by hypovolemic or osmotic stimuli, with no detectable difference in the c-fos induction by hypertonicity
within OVLT neurons [44].
To summarize, shrinkage-activated, mechanosensitive cation channels [37, 38] appear to depolarize osmoreceptor neurons under hypertonic
conditions, leading to increased spike discharges

and downstream activation of thirst and vasopressin release. A relative lack of volume regulatory
mechanisms in osmoreceptor neurons also maximizes the cellular and mechanical effect of extracellular tonicity [31]. The swelling-activated
TRPV4 channel is expressed in osmoreceptor
neurons, where it may play an inhibitory role,
limiting the thirst response in hypotonicity and
perhaps downregulating osmotic-induced vasopressin release; however, there are substantial
differences in the reported phenotypes of TRPV4
knockout mice [35, 39], such that the exact role
of this channel is still unclear. TRPV1 appears to
be a critical component of the mechanosensitive
osmoreceptor, with loss of osmoreceptive neuronal depolarization and neuronal activation after
hypertonic stimuli in TRPV1−/− mice [41, 42].
However, the primary structure of the putative
N-terminal splice form of TRPV1 that mediates
this activity is not yet known; the reported
TRPV1–TRPV4 chimeric transcript that generates the only known shrinkage-activated, stretchinhibited TRP channel activity [43] is evidently a
cDNA cloning artifact [42]. Finally, the reported
phenotypes of TRPV1 knockout mice differ considerably [41, 42, 44].
A major unresolved issue is why the loss of
TRPV1 expression completely abrogates osmoreceptive neuronal activation [41, 42], yet has only
modest effects on thirst and vasopressin release
[41, 42, 44]. It is conceivable that other channel
subunits are capable of substituting for TRPV1 or
modulating the endogenous mechanosensitive
channels, perhaps in neuronal subtypes that are
distinct from those that have been tested thus far. It
is notable in this regard that TRPV2, a swellingactivated TRP channel, is also expressed in osmoreceptor neurons [45], along with TRPV1 and
TRPV4. A related issue is whether osmoreceptive

J.M. Sands et al.

neuronal activation is directly affected by loss of
TRPV4 function, given the lack of equivalent electrophysiology to that of TRPV1 mice [41, 42] in
TRPV4 knockout mice; conceivably these mice
have a gain in osmoreceptor sensitivity, should
TRPV4 function as a tonic or swelling-activated
inhibitor of osmosensitive neuronal activity.
Regardless, despite the many remaining questions
and controversies, the identification of TRPV1 and
TRPV4 as components of the osmoreceptor
mechanism(s) is a major advance.

Regulation of Osmoreceptor Sensitivity
Vasopressin release and thirst are regulated by a
number of hormones and neurotransmitters, via
effects on the inhibitory and excitatory interactions between osmoreceptor neurons in the OVLT
and downstream magnocellular neurons within
the PVN/SON, modulatory effects on glial–
neuronal interactions, and direct effects on
osmoreceptor gain in the various osmosensitive
neuronal subtypes [12, 26, 46]. Hypotonic inhibition of magnocellular neurons is thus due to a
combination of a decrease in synaptic excitation
by glutamatergic inputs from the OVLT, glycine
receptor activation and neuronal hyperpolarization in response to taurine release from surrounding astrocytes, and hyperpolarizing effect of
swelling-induced inhibition of the stretchinhibited osmoreceptor channel [46]. Hypertonic
activation of magnocellular neurons is in turn the
net effect of an increase in glutamatergic excitation by OVLT neurons, a reduction in the hyperpolarizing effect of glycinergic receptors due to
decreased taurine release from astrocytes, and
direct neuronal depolarization due to shrinkage
activation of the stretch-inhibited osmoreceptor

channel [46].
Several factors directly influence the sensitivity
of the stretch-inhibited osmoreceptor channel in
magnocellular neurons and presumably other osmosensitive neurons in the OVLT and SFO [6]. In particular, extracellular Na+ potentiates the response of
magnocellular neurons to hypertonic stimuli, such
that the number of spike discharges evoked by a
30 mOsm/kg H2O pulse of NaCl is ~600 % higher


1 The Physiology of Water Homeostasis

9

Fig. 1.4 Modulation of intrinsic osmosensitivity in magnocellular neurons. Changes in osmolality cause changes
in cell volume that alter the probability of opening of
stretch-inhibited (SIC) channels. In turn, changes in SIC
channel activity alter the membrane potential and firing
rate of magnocellular neurons and other osmoreceptor
neurons, leading to vasopressin secretion and thirst (see
text for details). Changes in [Na+]o modulate osmoreceptor currents by affecting the driving force through the

channel and by altering the relative permeability to Na+
ions. Osmotic stimuli are normally associated with
proportional changes in cerebrospinal [Na+] (dashed line).
Numerous excitatory peptides, particularly those mediating their actions through Gq/lh appear to enhance
osmosensory gain. This effect might be mediated by peptide-evoked changes in cell volume, cytoskeleton properties, and/or SIC channel gating. From Bourque et al. [46]
with permission

than that induced by a 30 mOsm/kg H2O pulse of
mannitol [47]. Increases in extracellular Na+ concentration appear to enhance the relative Na+ permeability of the stretch-inhibited osmoreceptor

channel, thus amplifying the electrophysiological
response to hypertonicity [47]. This phenomenon
provides an attractive explanation for the longstanding observation that vasopressin release can be
modulated by changes in the osmolality and/or Na+
concentration of cerebral spinal fluid (CSF); for
example, intraventricular infusion of hypertonic
sucrose has no evident effect on vasopressin release
in the absence of concomitant Na+, whereas parallel
changes in Na+ concentration and osmolality have a
synergistic effect [48]. Rather than separate central
Na+ and osmoreceptors, as previously hypothesized [48], the response of the stretch-inhibited

osmoreceptor channel is modulated by changes in
extracellular [Na+] (see also Fig. 1.4).
A host of peptide and non-peptide hormones
directly modulate the response of osmoreceptor
neurons to hypertonicity. Treatment of magnocellular neurons with angiotensin II, cholecystokinin, and other excitatory peptides causes
depolarization and an increase in excitatory discharges due to activation of a stretch-inactivated
cation channel that is inhibited by gadolinium,
i.e., the stretch-inhibited osmoreceptor channel
[49]. In addition, these peptides potentiate the
excitatory effect of hypertonicity, such that their
stimulatory effect on vasopressin release is due,
at least in part, to an increase in the “gain” of the
osmoreceptor mechanism [46, 49]. Many of the
receptors for these peptides signal through the


10

Gq/11 G protein, suggesting a shared signaling
pathway [46, 49] (see also Fig. 1.4). Angiotensin
II does not affect the volume responses of magnocellular neurons, i.e., the quantitative change in
cell volume induced by hypotonic or hypertonic
stimuli [50]. Rather, angiotensin II potentiates the
cellular mechanosensitivity of these neurons,
increasing the change in membrane conductance
in response to mechanical or osmotic shrinkage
[50]. This is associated with an increase in cortical
F-actin density, perhaps due to Gq/11-dependent
activation of the RhoA GTP-ase protein [50].
Regardless of the mechanism involved, the potentiation of osmoreceptor sensitivity by this and
other hormones likely underlies the modulation of
vasopressin release by ECF volume (see Fig. 1.2).
Finally, serotonin (5-HT, 5-hydroxytryptamine) plays an important role in regulating magnocellular neurons, such that serotonin itself,
serotoninergic precursors, serotoninergic releasers, selective serotonin reuptake inhibitors
(SSRIs), and serotonin agonists induce vasopressin release [6]. Vasopressin release induced by
serotonin appears to be mediated by 5-HT2C,
5-HT4, and 5-HT7 receptors [6], and is associated with c-fos induction in magnocellular neurons [51]. Although the effect of serotonin on
the stretch-inhibited osmoreceptor channel has
not been reported, it directly depolarizes and
excites magnocellular neurons [52]. This direct
excitatory effect of serotonin on magnocellular
neurons provides a mechanistic explanation for
the common association between SSRIs and SIAD
[6]. In addition, the recreational drug ecstasy
(MDMA, 3.4-methylenedioxymethamphetamine)
has potent serotoninergic effects, leading to induction of c-fos in magnocellular neurons [53], vasopressin release [54], and perhaps thirst [6]; these
effects explain the association between ecstasy
use and acute hyponatremia [55].

General Features of the Concentrating
Mechanism
All mammalian kidneys maintain an osmotic gradient that increases from the cortico-medullary
boundary to the tip of the medulla (papillary tip).

J.M. Sands et al.

This osmotic gradient is sustained even in
diuresis, although its magnitude is diminished
relative to antidiuresis [56, 57]. NaCl is the major
constituent of the osmotic gradient in the outer
medulla, while NaCl and urea are the major constituents in the inner medulla [56, 57]. The cortex
is nearly isotonic to plasma, while the inner medullary (papillary) tip is hypertonic to plasma, and
has osmolality similar to urine during antidiuresis [58]. Sodium and potassium, accompanied by
univalent anions and urea are the major urinary
solutes; urea is normally the predominant urinary
solute during a strong antidiuresis [56, 57].
The mechanisms for the independent control of
water and sodium excretion are mostly contained
within the renal medulla. The medullary nephron
segments and vasa recta are arranged in complex
but specific anatomic relationships, both in terms
of three-dimensional configuration and in terms of
which segments connect to which segments. The
production of concentrated urine involves complex interactions among the medullary nephron
segments and vasculature [59, 60]. In the outer
medulla, the thick ascending limbs of the loops of
Henle actively reabsorb NaCl. This serves two
vital functions: it dilutes the luminal fluid and it

provides NaCl to increase the osmolality of the
medullary interstitium, pars recta, descending
limbs, vasculature, and collecting ducts. Both the
nephron segments and vessels are arranged in a
countercurrent configuration, thereby facilitating
the generation of a medullary osmolality gradient
along the cortico-medullary axis. In inner medulla,
osmolality continues to increase, although the
source of the concentrating effect remains controversial. The most widely accepted mechanism
remains the passive reabsorption of NaCl, in excess
of solute secretion, from the thin ascending limbs
of the loops of Henle [61, 62].
Perfused tubule studies provided the basis for
many of the theories of how concentrated urine is
produced (reviewed in [2]). The cloning of many
of the proteins that mediate urea, sodium, and
water transport in nephron segments that are
important for urinary concentration and dilution
has provided additional insights into the urine
concentrating mechanism (Fig. 1.5). In general,
the urea, sodium, and water transport proteins are


1 The Physiology of Water Homeostasis

11

Fig. 1.5 Molecular identities and locations of the sodium,
urea, and water transport proteins involved in the passive
mechanism hypothesis for urine concentration in the inner

medulla [61, 62]. The major kidney regions are indicated
on the left. NaCl is actively reabsorbed across the thick
ascending limb by the apical plasma membrane Na-K-2Cl
cotransporter (NKCC2/BSC1), and the basolateral membrane Na/K-ATPase (not shown). Potassium is recycled
through an apical plasma membrane channel, ROMK.
Water is reabsorbed across the descending limb segments
by AQP1 water channels in both apical and basolateral
plasma membranes. Water is reabsorbed across the apical
plasma membrane of the collecting duct by AQP2 water
channels in the presence of vasopressin. Water is reab-

sorbed across the basolateral plasma membrane by AQP3
water channels in the cortical and outer medullary collecting ducts and by both AQP3 and AQP4 water channels in
the inner medullary collecting duct (IMCD). Urea is concentrated within the collecting duct lumen (by water reabsorption) until it reaches the terminal IMCD where it is
reabsorbed by the urea transporters UT-A1 and UT-A3.
According to the passive mechanism hypothesis (see
text), the fluid that enters the thin ascending limb from the
contiguous thin descending limb has a higher NaCl and a
lower urea concentration than the inner medullary interstitium, resulting in passive NaCl reabsorption and dilution
of the fluid within the thin ascending limb. AQP aquaporin, UT urea transporter

highly specific and appear to eliminate a molecular basis for solvent drag; this specifically suggests that the reflection coefficients should be 1.
For a detailed review of the transport properties,
the reader is referred to [2].

frequently referred to as the cortico-medullary
osmolality gradient, as it is distributed along the
cortico-medullary axis. Figure 1.7 illustrates the
principle of countercurrent multiplication. The
figure panels show a schematic of a short loop of

Henle; the left channel represents the descending
limb while the right channel represents the thick
ascending limb. A water-impermeable barrier
separates the two channels. Vertical arrows indicate flow down the left channel and up the right
channel. Horizontal arrows (left-directed) indicate active transport of solute from the right
channel to the left channel. Local fluid osmolality
is indicated by the numbers within the channels.
Successive panels represent the time course of
the multiplication process.

Countercurrent Multiplication
Countercurrent multiplication refers to the process by which a small osmolality difference, at
each level of the outer medulla, between fluid
flows in ascending and descending limbs of the
loops of Henle, is multiplied by the countercurrent flow configuration to establish a large axial
osmolality difference. This axial difference is


12

J.M. Sands et al.

Fig. 1.6 Countercurrent multiplication of a single effect
in a diagram of the loop of Henle in the outer medulla. (a)
Process begins with isosmolar fluid throughout both
limbs. (b) Active solute transport establishes a 20 mOsm/
kg H2O transverse gradient (single effect) across the
boundary separating the limbs. (c) Fluid flows halfway
down the descending limb and up the ascending limb. (d)

Active transport reestablishes a 20 mOsm/kg H2O transverse gradient. Note that the luminal fluid near the bend of
the loop achieves a higher osmolality than loop-bend fluid
in (b). (e) As the processes in (c, d) are repeated, the bend
of the loop achieves a progressively higher osmolality so
that the final axial osmotic gradient far exceeds the transverse 20 mOsm/kg H2O gradient generated at any level

The schematic loop starts with isosmolar
fluid throughout (Fig. 1.6a). In panel Fig. 1.6b,
enough solute has been pumped by an active
transport mechanism to establish a 20 mOsm/kg
H2O osmolality difference between the ascending and descending flows at each level. This
small osmolality difference, transverse to the
flow, is called the “single effect.” Osmolality
values after the fluid has convected the solute
halfway down the left channel and halfway up
the right channel are illustrated in Fig. 1.6c. In
Fig. 1.6d, a 20 mOsm/kg H2O osmolality difference has been reestablished by the active transport mechanism, and the luminal fluid near the
bend of the loop has attained a higher osmolality
than in Fig. 1.6a. A progressively higher osmolality is attained at the loop bend by successive

iterations of this process. A large osmolality
difference is generated along the flow direction,
as illustrated in Fig. 1.6e, where the osmolality
at the loop bend is nearly 300 mOsm/kg H2O
above the osmolality of the fluid entering the
loop. Thus, a 20 mOsm/kg H2O difference, the
“single effect,” has been multiplied axially down
the length of the loop by the process of countercurrent multiplication.
In short loops of Henle, the process of countercurrent multiplication is similar to the process
shown in Fig. 1.6. The tubular fluid emerging

from the end of the proximal tubule and entering
the outer medulla is isotonic to plasma (about
290 mOsm/kg H2O). That tubular fluid is concentrated as it passes through the proximal straight
tubule (pars recta) and on into the thin descending