Art & science life sciences 1942 march 19 vol 28 no 29.docx

Art & science life sciences: 19
42 march 19 :: vol 28 no 29 :: 2014 © NURSING STANDARD /
RCN PUBLISHING
Abstract
Assessment and careful maintenance of fluid and electrolyte
balance
in patients is an essential part of the nurse’s role. This article
explores
fluid and electrolyte balance with reference to the normal
physiology
of body fluids and regulation of fluids and electrolytes. It also
considers some common conditions associated with fluid
imbalance.
Authors
Ella McLafferty Retired, was senior lecturer, School of Nursing
and
Midwifery, University of Dundee.
Carolyn Johnstone Lecturer in nursing, School of Nursing and
Charles Hendry Retired, was senior lecturer, School of Nursing
and
Alistair Farley Retired, was lecturer in nursing, School of
Nursing and
Correspondence to: [email protected]
Keywords
Body fluids, diffusion, electrolytes, filtration, fluid balance,
hormonal

control, ion pump, oedema, osmosis
Review
All articles are subject to external double-blind peer review and
checked for plagiarism using automated software.
Online
Guidelines on writing for publication are available at
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Fluid and electrolyte balance
McLafferty E et al (2014) Fluid and electrolyte balance.
Nursing Standard. 28, 29, 42-49. Date of submission: July 26
2011; date of acceptance: December 14 2011.
in body fat in females that accounts for the lower
water content (Thibodeau and Patton 2012). The
amount of fat in the body has an influence on the
proportion of water – the more fat in the body, the
lower the percentage of water.
Age also influences the amount of body fluids.
Newborn infants’ total body mass can be up to
can be up to 80% water and this can be higher
in premature infants (Thibodeau and Patton
2012). Chow and Douglas (2008) stated that the
percentage of water in the body gradually reduces
with gestational age from around 86% at 26 weeks
to 80% at 32 weeks and to about 78% at full term.
This occurs as a result of the accumulation of body
fat during development. In the newborn infant,
body weight can be a good indicator of fluid loss
and balance (Chow and Douglas 2008). As people
age, there is a gradual decrease in the percentage of

body water. This is a result of a gradual reduction
in muscle mass and a gradual increase in body
fat (Thibodeau and Patton 2012) . It is important
that nurses are aware of these changes because
differences in body water percentage can affect the
concentration of water soluble drugs in the body
(Thibodeau and Patton 2012).
Fluid compartments
Body fluids exist in two main compartments:
intracellular and extracellular compartments
(Brooker and Nicol 2011). Fluid within the
body’s cells is known as cytosol and accounts for
about two thirds of all body fluids; it is separated
from extracellular fluids by the cell membrane.
Extracellular fluid accounts for about one third of
body fluids (Tortora and Derrickson 2009a) and
is further separated into two compartments, the
interstitial fluid and plasma contained within the
blood vessels. The cells are surrounded by interstitial
fluid, which accounts for 80% of extracellular
fluid. However, interstitial fluid also includes
lymph, cerebrospinal fluid, synovial fluid, aqueous
humor and vitreous body, and pleural, pericardial
and peritoneal fluids (Tortora and Derrickson
2009b). Plasma or intravascular fluid makes up the
remaining 20% of extracellular fluid; this is the fluid
component of the blood and is separated from the
interstitial fluid by the capillary membrane.
There is constant movement of fluids between
compartments. Fluids can cross the cell membrane
FLUID AND ELECTROLYTE balance is crucial
in maintaining homeostasis within the body. Nurses
may play a role in regulating body fluids to ensure

patient health and prevent conditions that may result
from fluid and electrolyte imbalances.
Body uids
Water is the most abundant compound in the body,
accounting for around 55% of total body weight in
a non-obese adult. Gender is associated with slight
variations with water accounting for 60% of total
body weight in the average male and 50% of total
body weight in the female. It is the slight increase
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Channel protein
Glycolipid:
carbohydrate
Lipids
Peripheral protein

Extracellular fl uid
Pore
Phospholipid
bilayer
Cytosol
Integral proteins
Peripheral protein
Cholesterol
© NURSING STANDARD / RCN PUBLISHING march 19 :: vol
28 no 29 :: 2014 43
that separates intracellular fl uids from the
interstitial fl uids and can readily move through the
cell wall boundary between the interstitial fl uid
and plasma (Brooker and Nicol 2011).
Cell membrane
The cell membrane has a vital role in the
maintenance of fl uid and electrolyte balance and
is one of the most important components of the
cell (Porth 2011). The cell membrane controls
the movement of fl uids between the intracellular
and extracellular compartments (Porth 2011).
Structurally, the cell membrane consists mainly of
lipids and proteins and is known as a phospholipid
bilayer (Tortora and Derrickson 2009a) (Figure 1).
The main structure is created by the back-to-back
arrangement of phospholipids, which is stabilised by
cholesterol and glycolipids (Thibodeau and Patton

2012). Membrane proteins – integral proteins that
extend through the membrane and peripheral
proteins that are attached to the outside or inside of
the cell membrane – are scattered throughout this
layer (Tortora and Derrickson 2009a).
The cell membrane is selectively permeable,
allowing some substances to move in and out of
the cell, while restricting the movement of others
(Tortora and Derrickson 2009a). The structure
of the cell membrane accounts for some of the
selectivity; the phosphate heads face outward, while
the lipid tails face each other on the inside of the
membrane. This infl uences how cell membranes
work because the phosphate heads can mix with
water and the lipid tails cannot. Therefore, the
lipid-based membrane prevents water-soluble
substances from fl owing freely between intracellular
and extracellular fl uids. The phospholipid bilayer
forms a protective barrier around the cell and is
impermeable to all but lipid-soluble substances such
as fatty acids, fat-soluble vitamins, steroids, oxygen
and carbon dioxide (Tortora and Derrickson
2009a, Porth 2011). Free movement through the
cell membrane is also infl uenced by particle size, for
example large molecules such as glucose and amino
acids do not readily cross the cell membrane. Ions
such as potassium and sodium cannot freely move
through the cell membrane and rely on membrane
proteins to assist movement.
Membrane proteins have several roles. They act
as ion channels; some membrane proteins have a
hole through the middle forming a channel or pore
allowing certain substances such as potassium to

pass through (Tortora and Derrickson 2009a).
Some membrane proteins act as carriers to transport
or move substances across the cell membrane.
Substances are selectively regulated to be transported
in and out of the cell. For example, glucose attaches
to a glucose transporter protein on the outside
surface of the cell membrane, the protein changes
shape and the glucose passes through the membrane
and is released into the cell (Tortora and Derrickson
2009a). Some membrane proteins are involved
in catalysing specifi c chemical reactions inside or
outside the cell. In addition, membrane proteins
FIGURE 1
Cell membrane
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can act as receptors. These proteins are involved
in recognising and binding to substances such as
hormones (Tortora and Derrickson 2009a). For
example, if the insulin receptor did not recognise
and bind to insulin, glucose would not be able to
enter the cell. Some membrane proteins allow cell
recognition. During tissue formation, cells with the
same protein markers will recognise each other.
These proteins are important in immunity and
are vital to the body’s ability to recognise cells that
are foreign and potentially harmful (Tortora and

Derrickson 2009a).
Movement of uids and electrolytes
According to Tortora and Derrickson (2009a),
movement of substances across the cell membrane
is essential to cell functioning. It is vital that
glucose and oxygen are able to enter the cell to
allow metabolism to occur, while carbon dioxide
and substances produced by the cell must be
removed. In the human body, the solvent is water
and there are a variety of potential solutes such
as oxygen, nutrients or ions. An important factor
in the movement of solutes is the concentration
gradient. The concentration gradient refers to the
difference in concentration between two areas
or substances, for example the intracellular and
interstitial fluids. The movement from a high to
low concentration is referred to as movement
with or down the concentration gradient,
while movement from an area of low to high
concentration is referred to as movement against
or up the concentration gradient (Tortora and
Derrickson 2009a). There are two general types of
movement: passive transport and active transport
(Thibodeau and Patton 2012).
Passive transport
The passive movement of solutes is via diffusion
and of solvent (water) is via osmosis. Filtration is
the movement of both solvent and solute under
pressure (Thibodeau and Patton 2012). There are
several types of diffusion: simple, facilitated and
diffusion through ion channels.
Simple di�sion Lipid-soluble substances can
move freely across the cell membrane down the

concentration gradient, and this is an important
method of movement for oxygen and carbon
dioxide. Other substances such as fatty acids,
steroids, and fat-soluble vitamins A, D, E and K
also diffuse through the cell membrane in this way
(Tortora and Derrickson 2009a).
Facilitated di�sion Some substances need assistance
to diffuse across the cell membrane. Facilitated
diffusion involves membrane proteins without the
need for energy. An example of a substance that
moves by facilitated diffusion is glucose, which is too
large to cross the cell membrane by simple diffusion
and which requires transporter proteins that change
shape to allow glucose to diffuse through the cell
membrane down the concentration gradient.
Di�sion through ion channels Ion channels in
membrane proteins allow the movement of specific
electrolytes through the cell membrane. Some
channels are open and allow specific electrolytes
to leak across the cell membrane down the
concentration gradient (Porth 2011). Other channels
are gated, only opening when stimulated to do so,
and these channels have an important role in the
electrical activity of several body cell types (Tortora
and Derrickson 2009a). For example, the movement
of impulses along the axon of a nerve is a result of
the movement of electrically charged ions across
nerve cell membranes. Local anaesthetic works by
blocking gated sodium channels, thereby blocking
the nerve impulse (Tortora and Derrickson 2009b).
Osmosis Osmosis is the diffusion of water across a
selectively permeable membrane, and this occurs

between compartments and cells to maintain
water balance (Thibodeau and Patton 2012).
Water passes through membranes by moving
between neighbouring phospholipid molecules via
simple diffusion or through integral membrane
proteins that function as water channels. Fluids
in the body contain substances that cannot move
across membranes, and this creates pressure
on that membrane called the osmotic pressure.
Osmotic pressure depends on the amount of solute
in the solution, with more concentrated solutions
having a higher osmotic pressure (Tortora and
Derrickson 2009a).
Osmotic pressure between the cell and the
interstitial fluid is balanced and constant, therefore
cells do not usually swell or shrink because of water
movement. Fluid in the body is said to be isotonic
if it has the same electrolyte concentration as body
cells, and cells bathed in it do not swell or shrink.
This principle is used to determine fluid replacement
therapy, for example 0.9% sodium chloride is
isotonic for red blood cells so can be used as simple
fluid replacement. Fluids with a lower concentration
of solutes are hypotonic, while those with a higher
concentration are hypertonic.
In clinical practice, these solutions are used to
treat specific conditions. Hypotonic solutions are
used to treat dehydration because they encourage
the movement of fluid from the blood to the cells;
hypotonic fluids also form the basis of sports
rehydration. The administration of hypertonic fluids

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increases circulating blood volume by encouraging
the movement of fluid from the interstitial space to
the blood. Hypertonic fluids can be useful in cases
of head injury because administration will reduce
cerebral swelling by encouraging the movement of
fluid from the interstitial space in the brain to the
blood (Tortora and Derrickson 2009a).
Active transport
Active transport is required when a substance
has to be transported against the concentration
gradient. There are several types of active transport
mechanisms, and they mainly transport ions and
are known as ion pumps (Tortora and Derrickson
2009a). One example of this type of transport
is the movement of sodium out of the cell and
movement of potassium into the cell. Movement
of this nature requires energy in the form of
adenosine triphosphate (ATP), the cell energy
produced as a result of cell metabolism.
The concentration of sodium is around 14
times greater outside the cell than it is inside the
cell (Porth 2011), therefore sodium can naturally
leak into the cell through ion channels. Since it
is osmotically active, increasing levels of sodium
would encourage the inflow of water and cause
the cell to swell with potential to rupture. The
concentration of potassium inside the cell is around

35 times greater than that outside the cell, and
potassium also leaks out through ion channels.
If allowed to leak out without being returned to
the cell, increasing levels of interstitial and plasma
potassium could have catastrophic consequences
for nerve and muscle function (Porth 2011).
The sodium-potassium pump (Figure 2) consists
of an integral membrane protein that is activated by
the attachment of three sodium ions in the cytosol.
Following this attachment, ATP is hydrolysed
forming adenosine diphosphate (ADP), attaching a
phosphate group to the pump protein, and releasing
energy from the phosphate bond that drives the
change in shape of the pump protein. When the
pump protein has changed shape, the three sodium
ions are expelled from the cell. Externally, two
potassium ions attach to the pump protein, causing
the phosphate to be released from the protein, the
protein to be returned to its original shape and the
potassium ions to be released into the cell (Tortora
and Derrickson 2009a). Movement against the
concentration gradient is vital in maintaining
sodium, potassium and water balance in the body.
This is clinically significant when physiological
shock occurs because there is a deficit of energy
available to drive this reaction. This failure
ultimately leads to failure of the sodium-potassium
pump, an increase in sodium levels inside the cell
and subsequent swelling of the cell. In addition,
there is an increase in potassium outside the cell,
affecting nerve and muscle activity.
Movement between plasma and the

interstitial space
Movement of fluid, electrolytes and other dissolved
solutes is relatively free between plasma and
the interstitial fluid as a result of filtration and
reabsorption (Tortora and Derrickson 2009a). At
the arterial end, blood hydrostatic pressure inside the
capillary is higher than interstitial fluid hydrostatic
pressure in the interstitial fluid surrounding it,
filtering fluid out of the capillary. Larger molecules
such as plasma proteins and red blood cells do not
normally cross the capillary membrane because of
their size (Scales and Pilsworth 2008).
FIGURE 2
Sodium-potassium pump
Extracellular fluid
Cytosol
Na+
gradient
Na+/K+
ATPase
3 Na+
3 Na+
expelled
ADPK+
gradient
2 K+

2 K+
imported
ADP = adenosine diphosphate; ATP = adenosine triphosphate; P
= phosphate; K = potassium; Na = sodium
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Plasma proteins play a vital role in the
maintenance of fluid balance because they create
an osmotic pressure inside the capillaries, often
referred to as colloid osmotic pressure (Brooker
and Nicol 2011), drawing fluid into the capillaries.
As blood flows towards the venous end of the
capillary, the blood hydrostatic pressure combined
with the blood colloid osmotic pressure results in
a net inwards pressure, thus the majority of fluid

and electrolytes are reabsorbed into the capillary
(Tortora and Derrickson 2009a). This process is
vital in maintaining compartment fluid balance and
preventing tissue swelling. There is a small deficit
of fluid return to the capillaries, but this fluid does
not accumulate in the interstitial space because it is
returned to the circulation via the lymphatic system,
ensuring fluid balance is maintained.
Fluid regulation
Fluid balance in the body remains relatively stable,
and is maintained mainly by the action of the
kidneys. An average of 1,600mL of fluid is gained
through drinking and a further 700mL is gained
as part of food, with water being absorbed by
the gastrointestinal (GI) tract. Around 200mL
of water is produced each day as a by-product of
cell metabolism (Tortora and Derrickson 2009b).
About 100mL of fluid is lost via the GI tract as part
of faeces, 600mL of fluid evaporates from the skin,
300mL of fluid is lost through respiration and the
kidneys account for the remaining 1,500mL of
fluid loss (Tortora and Derrickson 2009b). Thus,
there is an average water balance of 2,500mL in
and 2,500mL out daily.
It is important to remember that these levels
can vary considerably, for example diarrhoea
would significantly increase GI fluid loss. When
fluid loss alters via other body systems changes,
the action of the kidneys alters accordingly as does
urine production.
Fluid gain
Fluid loss and gain are carefully regulated
processes. When fluid is lost from the body in

increasing amounts, the simplest way to increase
fluid levels is through liquid intake. Dehydration
refers to total loss of body fluid associated with
a decrease in circulating fluid volume and an
increase in osmolarity (Welch 2010), and triggers
the thirst mechanism. Fluid gain in the body is
essentially a homeostatic mechanism triggered by
dehydration. Signs of dehydration include weight
loss, headache, rapid but shallow breathing,
rapid weak thready pulse, reduced urine output,
constipation, dry mouth with thicker saliva, dry
skin and sunken eyes (Welch 2010).
Thirst is an important clinical sign that can be
absent in older people (Welch 2010). When fluid
levels fall, blood pressure falls triggering the release
of renin from the kidneys and this promotes the
formation of angiotensin II, which stimulates the
thirst centre in the hypothalamus. The thirst centre
is also stimulated by a dry mouth, an increase
in blood osmolarity and lowered blood pressure
(Tortora and Derrickson 2009b). When the thirst
mechanism is triggered, the usual response is to
drink fluids to restore fluid balance. Nurses should
remember that some individuals such as young
children and older adults will be unable to respond
to this trigger and to drink, therefore nurses should
offer these individuals fluids and assist them to
drink as part of nursing care (Speakman and Weldy
2002). Without appropriate assistance, young
children, older adults and those with learning
difficulties are at increased risk of dehydration
(Speakman and Weldy 2002, Welch 2010).
Fluid loss
The regulation of fluid loss from the body occurs

in the kidneys, with the volume of body fluid
determined by the loss of sodium chloride in urine
(Tortora and Derrickson 2009b). Daily intake of
sodium chloride can vary significantly, and the
kidneys alter levels of sodium chloride excreted
in urine through hormonal control. The three
main hormones that alter the reabsorption rates
of sodium and chloride are antidiuretic hormone
(ADH) angiotensin II, aldosterone and atrial
natriuretic peptide (ANP) (Tortora and Derrickson
2009b). A negative feedback mechanism involving
secretion of ADH maintains the blood osmotic
pressure, and sodium and water concentrations,
within normal limits.
Changes in sodium levels in plasma will alter
blood volume, for example a significant increase in
sodium will lead to an increase in circulating blood
volume and therefore blood pressure, causing the
blood vessel walls to stretch. This increased stretch
is detected by baroreceptors in the carotid bodies,
arch of the aorta and walls of the atria (Porth
2011). Once stimulated by the increase in blood
volume, these receptors initiate the sympathetic
nervous system response and lead to a reduction in
the release of ADH from the pituitary gland. The
sympathetic nervous system response increases the
glomerular filtration rate along with a decrease in
renin production, and less reabsorption of sodium
and water. Sensors in the kidney are also stimulated
by an increase in renal perfusion, which decreases
the secretion of renin (Speakman and Weldy 2002).
Renin usually activates the
renin-angiotensin-aldosterone system, which
results in conversion of angiotensin I to angiotensin

28 no 29 :: 2014 47
II, increasing sodium reabsorption in the renal
tubules. Angiotensin II also regulates the secretion
of aldosterone from the adrenal cortex, which
increases sodium reabsorption while increasing the
secretion of potassium (Porth 2011). The osmotic
pull of sodium encourages the reabsorption of
water into the capillaries, thus increasing blood
volume. Therefore, a reduction in renin will
decrease the reabsorption of sodium and water,
ultimately lowering blood sodium levels. Intake
of water in response to the thirst mechanism
decreases the osmolarity of blood and interstitial
fluid, and ADH secretion ceases. ANP is released
from specialised cells in the atria in response to
stretch caused by over filling, increasing sodium
excretion in the renal tubules and reducing
circulating blood volume (Porth 2011).
Electrolytes
There are several electrolytes in the human body
and each performs a vital role. It is beyond the
scope of this article to discuss all of these, therefore
the focus is on the role of sodium and potassium.
Sodium
Sodium has a vital role in the maintenance of fluid
balance and is responsible for plasma osmolarity.
It is the most abundant extracellular cation
(Hogan et al 2007). Normal plasma sodium levels
are 133-148mmol/L(Blann 2006). Sodium also

plays a role in nerve and muscle cell electrical
activity that drive action potentials (impulses)
through the neurones or muscle fibres (Tortora
and Derrickson 2009b). Chloride ions are closely
related to sodium and potassium, with movement
of chloride through the cell membrane occurring
via a shared transport protein.
Hyponatraemia can occur as a result of impaired
renal function, fluid loss related to burns, impaired
ADH secretion, sodium loss associated with
some diuretics and hyperglycaemia in patients
with diabetes (Porth 2011, Thibodeau and Patton
2012). Individuals with hyponatraemia present
with muscle weakness, dizziness, headache,
hypotension and tachycardia, leading potentially to
coma (Tortora and Derrickson 2009b). Treatment
depends on the underlying cause of and aims to
maintain fluid balance between compartments.
A hypertonic saline solution can be administered
possibly with a loop diuretic, which will increase the
serum level of sodium while encouraging the loss of
excess fluid (Porth 2011). When renal impairment
is diagnosed, carefully planned renal management
may be required, which will include fluid and
specific electrolyte restrictions.
Hypernatraemia is relatively rare, but can occur
because of excessive consumption of salt, prolonged
diarrhoea or dehydration (Thibodeau and Patton
2012). Symptoms include an intense thirst,
hypertension, oedema, agitation and convulsions
(Tortora and Derrickson 2009b). Hypernatraemia,
when associated with dehydration, is managed
with oral or intravenous fluid replacement. Care

must be taken if administering hypotonic fluids
intravenously because there is a risk of making
the blood relatively hypotonic, causing cerebral
oedema (Porth 2011).
Potassium
Potassium is the most abundant intracellular
cation, with an intracellular concentration of
140-150mmol/L and with a normal blood plasma
concentration of 3.3-5.6mmol/L (Blann 2006).
Potassium has a role in maintaining normal action
potentials in muscles and nerve cells, as well as
assisting in cardiac muscle cell activity. Potassium
also has an important role in maintaining
acid-base balance, with the pH of intracellular
and extracellular fluids being maintained by the
movement of potassium and hydrogen between
compartments (Hogan et al 2007). For example,
when metabolic acidosis occurs, hydrogen moves
into the cell in exchange for potassium (Porth
2011), reducing the hydrogen levels and, therefore,
the acidity of the blood. Although insulin is
associated with maintaining blood glucose levels, it
also increases the activity of the sodium-potassium
pump, thereby increasing the movement of
potassium into the cell (Porth 2011).
Hypokalaemia can be caused by excess fluid
loss, decreased levels of potassium intake, renal
impairment, overuse of laxatives, GI losses and
some diuretics (Tortora and Derrickson 2009b,
Thibodeau and Patton 2012). Presenting features
include thirst, muscle fatigue and cramps,
increased urine output and confusion (Tortora and
Derrickson 2009b, Porth 2011). Because of the role
of potassium in maintaining normal cardiac cell

activity, the most serious effects of hypokalaemia
are electrocardiogram (ECG) changes that can
lead to ventricular arrhythmias in severe cases.
Management can be as simple as increasing in the
dietary intake of potassium through foods such as
bananas or spinach, although supplements are also
available (Porth 2011). Intravenous replacement
therapy must be managed with care because of the
risk of hyperkalaemia.
Hyperkalaemia is related to high potassium
intake levels, tissue trauma caused by burns or crush
injuries, or renal failure where the kidneys cannot
excrete potassium (Tortora and Derrickson 2009b,
Thibodeau and Patton 2012). Presenting features
include skeletal muscle weakness, possibly leading to
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paralysis, irritability, nausea and vomiting (Tortora
and Derrickson 2009b, Thibodeau and Patton
2012). The most serious effects of hyperkalaemia
relate to cardiac muscle function bringing about
significant changes to normal cardiac muscle
electrical activity and ECG changes. These changes
can be so severe that ventricular fibrillation and
cardiac arrest can occur (Porth 2011).
Managing hyperkalaemia is crucial, but the speed
of the increase in the serum level of potassium will
be linked to the cause, which will dictate treatment.

Dietary intake of potassium can be reduced and is
an essential part of therapy when renal failure is the
underlying cause of chronic hyperkalaemia. Many
salt substitutes are rich in potassium and care must
be taken when using these (Hogan et al 2007). As
renal failure progresses, renal replacement therapy
(renal dialysis) may be needed. The administration
of calcium counteracts the effects of potassium
on the myocardium by exchanging calcium for
potassium ions, although this effect is short lived
and must be supported by other therapies such as
administration of glucose and insulin (Porth 2011).
Conditions associated with uid imbalance
Imbalances in fluid volume are more likely to occur
in infants, young children and older people. Kidney
function is not yet mature in the young, while
kidney function and the sensation of thirst decreases
in older people (Speakman and Weldy 2002).
Fluid de‡cit
Dehydration refers to an insufficiency in body
water as a result of excessive fluid loss or
inadequate fluid gain (Gould 2006). Porth (2011)
referred to an isotonic deficit as being a fluid
deficit where there is a proportional loss of fluid
and sodium, leading to a decrease in extracellular
fluid. When there is a reduction in the circulating
blood volume, the balance of electrolytes remains
relatively unchanged (hypovolaemia). Fluid can be
lost from the body in several ways, including GI
losses related to vomiting and diarrhoea, excessive
sweating related to strenuous exercise and diuresis
associated with diabetic ketoacidosis, for example
(Porth 2011). Conditions such as peritonitis can
lead to a shift of fluid from the circulation to the

interstitial spaces, creating a relative hypovolaemia
(Gould 2006).
The signs and symptoms of fluid deficit include
thirst; reduced urine output and increasing
concentration of the urine as the body attempts
to conserve water; drier mucous membranes,
particularly visible in the mouth where the saliva
will be more viscous; and sunken eyes. Other less
visible signs include headache and confusion,
a weak thready pulse as well as increased capillary
refill time, reduced blood pressure and rapid
shallow breathing (Gould 2006, Porth 2011). Blood
test results will indicate an increase in red blood
cell and urea concentrations. Porth (2011) classified
fluid deficit in terms of severity, with a mild deficit
relating to a 2% loss of body weight, a moderate
deficit relating to a 5% loss and a severe deficit
relating to more than 8% loss of body weight.
Managing hypovolaemia is relatively simple
and involves appropriate fluid replacement along
with managing the underlying condition. Fluid
replacement can be oral if tolerated or intravenous if
required. An accurate record of fluid balance must be
maintained to ensure prevention of fluid overload.
Fluid excess
Isotonic fluid excess refers to an increase in overall
sodium levels and the related retention of water. It
is possible for this to occur as a result of an increase
in sodium intake, but it is more likely to be related
to a reduction in sodium elimination because of
an underlying condition (Porth 2011). Several
conditions such as renal failure, heart failure and

liver failure can lead to decreased levels of sodium
elimination (Porth 2011). Cardiac failure occurs
when the heart’s pumping ability is impaired, leading
to activation of the renin-angiotensin-aldosterone
system and ultimately to retention of sodium and
water (Nicholas 2004). Renal failure leads to a
reduced ability to filter the blood because of a
reduced glomerular filtration rate and reduced ability
to reabsorb electrolytes leading to increasing levels of
sodium in the blood. Aldosterone is metabolised by
the liver and in liver failure this is impaired, resulting
in an increase in sodium and water retention (Porth
2011). Increasing levels of sodium and water lead to
an increase in extracellular fluids.
Fluid excess presents as oedema and associated
weight gain. Increased fluid volume in the vascular
compartment can lead to a bounding pulse and
venous distension. As the condition worsens,
pulmonary oedema can occur leading to symptoms
of breathlessness (Porth 2011). Treatment will
often centre on managing the underlying condition
although sodium and fluid restriction can generally
reduce the blood volume. Diuretics are useful to
encourage sodium loss (Porth 2011).
Oedema
Oedema is swelling caused by an increase in the
interstitial fluid volume (Porth 2011). There are
several possible causes such as an increase in
capillary filtration pressure, a decrease in colloid
osmotic pressure, increase in capillary membrane
permeability and obstruction to lymph flow
(Porth 2011).

28 no 29 :: 2014 49
Capillary filtration pressure (pressure inside
the capillary that forces the movement of fluid
across the capillary membrane to the interstitial
space) can be increased as a result of an increase
in blood (hydrostatic) pressure (Casey 2004). This
increase in pressure can be caused by an increase
in circulating blood volume. Colloid osmotic
pressure is created by proteins in the blood that
exert an osmotic pull, drawing fluids back into the
capillaries; this pressure will be reduced if blood
levels of protein fall. Because the liver manufactures
plasma proteins, the level of plasma proteins
will fall in liver failure. Starvation can reduce the
manufacture of plasma protein as a result of the
reduced intake of amino acids, while renal failure
leads to loss of plasma proteins in the urine.
Localised oedema is often a result of damage
to capillary membranes because of burns,
inflammation or the immune response, and this
increases membrane permeability, allowing
proteins to move across cells taking fluid with
them. The amount of fluid reabsorbed following
filtration through the capillary wall is not equal
and there is a net deficit of fluid return. This
excess fluid in the interstitial space is reabsorbed
by the lymphatic capillaries and returned to the
circulation. If lymphatic vessels become blocked
or damaged, this return of fluid can be impaired,
leading to oedema (Porth 2011). Obstruction
to lymphatic flow often occurs following
mastectomy and the removal of axillary lymph

glands, leading to localised lymphoedema in the
affected arm (Porth 2011).
Conclusion
Alterations in fluid and electrolyte balance can
have serious consequences. Fluid and electrolyte
balance is vital to life and it is clear that many
conditions can affect this balance. Maintaining
and monitoring fluid balance is usually the
responsibility of the nurse, therefore it is essential
that nurses understand the importance of this
when providing patient care NS
References
Blann A (2006) Routine Blood
Results Explained. M&K Publishing,
Keswick, Cumbria
Brooker C, Nicol M (2011)
Alexander’s Nursing Practice.
Fourth edition. Churchill
Livingstone Elsevier, Edinburgh.
Casey G (2004) Oedema:
causes, physiology and nursing
management. Nursing Standard.
18, 51, 45-51.
Chow JM, Douglas D (2008) Fluid
and electrolyte management in
the premature infant. Neonatal
Network. 27, 6, 379-386.
Gould B (2006) Pathophysiology
for the Health Professions.

Third edition. Saunders Elsevier,
Philadelphia PA.
Hogan MA, Gingrich MM, Overby
P, Ricci MJ (2007) Fluids,
Electrolytes, & Acid-Base Balance.
Second edition. Pearson Prentice
Hall, Upper Saddle River NJ.
Nicholas M (2004) Heart failure:
pathophysiology, treatment and
nursing care. Nursing Standard.
19, 11, 46-51.
Porth CM (2011) Essentials of
Pathophysiology. Third edition.
Wolter Kluwer Health/Lippincott
Williams & Wilkins, Philadelphia
PA.
Scales K, Pilsworth J (2008) The
importance of fluid balance in
clinical practice. Nursing Standard.
22, 47, 50-57.
Speakman E, Weldy NJ (2002)
Body Fluids & Electrolytes. A
Programmed Presentation.
Eighth edition. Mosby,
St. Louis MO.
Thibodeau GA, Patton KT (2012)
Structure & Function of the Body.
14th edition. Mosby, St. Louis MO.

Tortora GJ, Derrickson BH
(2009a) Essentials of Anatomy
and Physiology. Eighth edition
International Student Version.
John Wiley and Sons,
Hoboken NJ.
Tortora GJ, Derrickson BH
(2009b) Principles of Anatomy
and Physiology. Volume 2 –
Maintenance and Continuity
of the Human Body. 12th edition.
John Wiley and Sons,
Hoboken NJ.
Welch K (2010) Fluid balance.
Learning Disability Practice.
13, 6, 33-38.
POINTS FOR PRACTICE
Nurses can be encouraged to develop strategies to ensure that
fluid
management is a priority if the following questions are asked
regularly:
imbalance?
rements considered as part of regular
nursing
care?
nursing care
in your clinical area?
re-established in your clinical area?

GLOSSARY
Diffusion
Passive movement of molecules from an area of higher
concentration to
an area of lower concentration until equilibrium is reached.
Filtration
The movement of a liquid and some substances dissolved in it
through a
barrier. The barrier prevents some larger molecules from
passing through.
Hypertonic
A hypertonic solution will have a high concentration of
electrolytes
(a higher osmotic pressure) compared with body cells and can
cause
cells to shrink as a result of osmosis.
Hypotonic
A hypotonic solution will have a low concentration of
electrolytes
(a lower osmotic pressure) compared with body cells and can
cause
cells to swell as a result of osmosis.
Isotonic
An isotonic solution has the same electrolyte concentration
(same
osmotic pressure) as body cells.
Osmosis
Movement of water through a semi-permeable membrane.
Movement of
the water occurs because of a difference in concentration on
each side
of the membrane and continues until equilibrium is reached. The
water
moves because the molecules dissolved in the fluid are too large
to cross
the membrane.

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Electrolyte Disorders Associated With Cancer
Mitchell H. Rosner and Alan C. Dalkin
Patients with malignancies commonly experience abnormalities
in serum electrolytes, including hyponatremia, hypokalemia,
hyperkalemia, hypophosphatemia, and hypercalcemia. In many
cases, the causes of these electolyte disturbances are due to
common etiologies not unique to the underlying cancer.
However, at other times, these electrolyte disorders signal the
pres-
ence of paraneoplastic processes and portend a poor prognosis.
Furthermore, the development of these electrolyte abnormal-
ities may be associated with symptoms that can negatively
affect quality of life and may prevent certain chemotherapeutic
regimens. Thus, prompt recognition of these disorders and
corrective therapy is critical in the care of the patient with
cancer.

Q 2014 by the National Kidney Foundation, Inc. All rights
reserved.
Key Words: Cancer, Hyponatremia, Hypokalemia,
Hypercalcemia, Hypophosphatemia
Introduction
Electrolyte disorders are commonly encountered in the
patient with cancer. In most cases, these disorders are as-
sociated with etiologies seen in all types of patients and
are not specifically linked to the malignancy or its ther-
apy (for example, diuretic-induced hyponatremia or hy-
pokalemia). In other cases, electrolyte disorders are due
to paraneoplastic syndromes or are specifically associ-
ated with chemotherapeutic regimens. When these
malignancy-specific electrolyte disorders are manifest,
they can lead to life-threatening complications that re-
quire emergent therapy. Thus, proper recognition and
treatment of these disorders is important in the overall
care of the patient with cancer. This review will discuss
selected malignancy-associated electrolyte disorders.
From Division of Nephrology, University of Virginia Health
System, Char-
lottesville, VA; and Division of Endocrinology and Metabolism,
University of
Virginia Health System, Charlottesville, VA.
Conflict of interest: M.H.R has served as a consultant to Otsuka
and
Novartis; A.D. declares no relevant financial interests.
Address correspondence to Mitchell H. Rosner, MD, Division of
Nephrol-
ogy, Box 800133 HSC, University of Virginia Health System,

Charlottesville,
VA 22908. E-mail: [email protected]
� 2014 by the National Kidney Foundation, Inc. All rights
reserved.
1548-5595/$36.00
http://dx.doi.org/10.1053/j.ackd.2013.05.005
Hyponatremia Associated With Cancer
Hyponatremia is the most common electrolyte disorder
encountered in patients with malignancies. Studies
have reported a prevalence that ranges from approxi-
mately 4% to as high as 47%.1,2 Approximately 14% of
hyponatremia encountered in medical inpatients is due
to an underlying malignancy-related condition.3 It is im-
portant to note that nearly half of these cases represented
hospital-acquired hyponatremia, suggesting that man-
agement of these patients (most likely with intravenous
fluids) significantly contributes to the development of hy-
ponatremia.
Hyponatremia is clearly associated with significant
morbidity and mortality when it occurs in the patient
with cancer. For instance, hospital length of stay is nearly
doubled in patients with moderate to severe hyponatre-
mia.1 The hazard ratio for death within 90 days after
the diagnosis of hyponatremia was 4.74 in those patients
with moderate hyponatremia and 3.46 in patients with
more severe hyponatremia.1 Other studies have also
demonstrated a marked association with hyponatremia
and mortality in patients with non-Hodgkin’s lym-
phoma, renal cell carcinoma, gastric cancer, and small-
cell lung cancer.4-6 Hyponatremia may affect patient
response to therapy, as shown in non-Hodgkin’s
Advances in Chronic Kidney Disease, Vo
lymphoma, in which patients with serum sodium less
than 137 mEq/L had a lower rate and shorter duration

of remission after chemotherapy as compared with
patients with higher sodium levels.4 Likewise, hypona-
tremia may limit the use of chemotherapeutic options
that require extensive hydration. Symptoms attributable
to hyponatremia, such as confusion, lethargy, and head-
ache, may also further compromise quality of life in this
population. It is debatable whether hyponatremia inde-
pendently contributes to these poor outcomes or is sim-
ply a marker of disease severity, progression, and
overall debility. A recent study would argue that the lat-
ter is the case, although correction of hyponatremia be-
fore hospital discharge does seem to improve outcomes
whereas persistent hyponatremia was associated with
worse outcomes.7-10
The differential diagnosis of hyponatremia in patients
with cancer is extensive (Table 1) and requires a careful
history, physical examination, and laboratory evaluation
to elucidate the etiology. It should be emphasized that the
symptoms related to hyponatremia may be nonspecific
and attributable to the underlying disease and its ther-
apy. Thus, clinicians should measure serum sodium
values in patients with symptoms compatible with hypo-
natremia rather than assume that the etiology is due to
the underlying disease. Understanding the etiology of
hyponatremia is critical in allowing proper management.
For example, intravenous 0.9% saline would be the ap-
propriate therapy in a patient with hypovolemic hypona-
tremia due to vomiting but not for a patient with the
syndrome of inappropriate ADH secretion (SIADH). In
some cases of drug-associated hyponatremia, simply
l 21, No 1 (January), 2014: pp 7-17 7
Delta:1_given name
Delta:1_surname
mailto:[email protected]

http://dx.doi.org/10.1053/j.ackd.2013.05.005
Rosner and Dalkin8
stopping the offending medication along with transient
free water restriction will lead to correction of the hypo-
natremia.
The most common etiology of hyponatremia that is di-
rectly related to malignancy is SIADH. The diagnostic cri-
teria for SIADH are listed in Table 2.11 This syndrome can
be associated with many different types of malignancy
and antineoplastic therapies (Table 3), but it is most
commonly seen with small-cell lung cancer, in which as
many as 10% to 15% of patients are hyponatremic at
presentation and as many as 70% of patients have
significant elevations of plasma arginine vasopressin
(AVP).12-16 Although hyponatremia may be quite severe
at presentation with small-cell lung cancer, only 25%
have symptoms that can be attributable to hyponatremia,
suggesting that in most instances hyponatremia develops
slowly and insidiously.15 It is controversial whether the
development and severity of hyponatremia correlates
with tumor burden and the extent of metastatic dis-
ease.12-16 In 1 study, the presence of SIADH did not affect
response to chemotherapy or overall survival.15 However,
other studies showed a higher mortality rate in those
CLINICAL SUMMARY
� Electrolyte disorders in patients with cancer are common
and can be secondary to either the cancer or its therapy.
� The most common electrolyte disorder seen in cancer
patients is hyponatremia; this is most commonly due to
the syndrome of inappropriate ADH secretion.

� Electrolyte disorders in cancer patients are associated with
a poor prognosis; appropriate treatment may improve
short term outcomes and quality of life.
patients with small-cell lung
cancer and a serum sodium
less than 130 mEq/L, and
hyponatremia in small-cell
lung cancer patients is
generally a poor prognostic
feature.6,17–19 An intriguing
possibility regarding the
association of SIADH with
poor outcomes in patients
with small-cell lung cancer
isthatAVPitself may directly
stimulate tumor growth.20
The next most common malignancy types associated
with SIADH are head and neck tumors (occurring in
3% of these patients).21 Outside of small-cell lung cancer
and head and neck cancers, most data linking SIADH
with tumor subtypes come from isolated case reports
that may be confounded by abnormal kidney or adrenal
function or the use of medications associated with
SIADH. In fact, only small-cell lung cancer cell lines
have been demonstrated to produce AVP.6 Furthermore,
serial measurements of AVP reflect the state of small-
cell lung cancer, with levels falling during remission
and increasing with recurrence.13,15 It should be noted
that measurement of plasma vasopressin is difficult
and requires proper handling and prompt processing,
and conditions such as thrombocytosis can hinder
quantification.
Antineoplastic drugs are also well known to cause hy-

ponatremia, and the mechanism of action for many of
these agents may involve SIADH (Table 3). The drugs
most conclusively associated with SIADH are cyclophos-
phamide, vinblastine, and vincristine.22 An important
contributor to the development of severe hyponatremia
associated with cyclophosphamide is that aggressive hy-
dration protocols are used to prevent hemorrhagic cysti-
tis. Cisplatin has been demonstrated to cause SIADH and
to lead to a salt-losing nephropathy that can exacerbate
the development of hyponatremia.23
In some cases SIADH may be subclinical with patients
demonstrating only mild degrees of asymptomatic hypo-
natremia (serum sodium values 130-135 mEq/L). How-
ever, when patients are challenged with a water load or
hypotonic fluids, severe hyponatremia may result.24
This has been specifically demonstrated with small-cell
lung cancer, in which 65% of patients had abnormalities
in water handling when administered a water load.12
This is also consistent with the finding that a large per-
centage of hyponatremia cases encountered in patients
with cancer develop in the hospital setting.1
In patients with SIADH, it is common to see secondary
elevations of atrial natriuretic peptide (ANP).25,26 The
elevations in ANP are due to a combination of increased
atrial stretch secondary to the mild volume expansion
that occurs with AVP-induced water retention and the
direct effect of AVP to
increase ANP secretion.27
Nonphysiological release of
ANP by small-cell lung
cancers has also been dem-

onstrated, and this ANP-
driven kidney sodium loss
may also contribute to the
development and worsen-
ing of hyponatremia in these
patients.6,28,29 Thus, the
development of hypon-
atremia in patients with
small-cell lung cancer may be multifactorial.
Therapeutic options for the treatment of hyponatre-
mia in the patient with cancer are the same as for other
causes of hyponatremia and rely on the presence of
related symptoms, the duration of hyponatremia, and
the volume status of the patient. If possible, correction
of the underlying cause is the optimal therapy. How-
ever, for many patients with malignancy-related
SIADH, the hyponatremia may be more refractory to
therapy; the underlying cancer cannot be cured, or the
causative medications cannot be easily stopped. In these
cases, other therapeutic options must be explored. In the
case of severe (serum sodium , 110 mEq/L) or symp-
tomatic acute-onset (,48 hours from onset) hyponatre-
mia, the use of 3% hypertonic saline (with or without
a loop diuretic to prevent volume overload), which
leads to a rapid increase in the serum sodium and im-
provement in neurological symptoms, should be consid-
ered. It is important to note that in these circumstances,
the neurological symptoms typically improve with
small (4-5%) increases in the serum sodium, and more
Table 1. Etiologies of Hyponatremia in Patients With Cancer
a. Syndrome of inappropriate antidiuretic hormone secretion

b. Gastrointestinal fluid losses due to vomiting, diarrhea,
enteric fistulas, and nasogastric suctioning
c. Third-spacing (sequestration of fluid from the intravascular
space) such as from ascites or anasarca
d. Kidney failure
e. Drugs: diuretics, cisplatin, carboplatin, selective serotonin
reuptake inhibitors, nonsteroidal anti-inflammatory
agents, steroid withdrawal, cyclophosphamide, vinca
alkaloids, narcotics, haloperidol, carbamazepine
f. Adrenal insufficiency
g. Liver failure
h. Heart failure (such as malignant pericardial disease)
i. Central nervous system disorders (primary or metastatic
disease)
j. Hypothyroidism
k. Primary polydipsia
l. Cerebral salt-wasting
m. Natriuretic-peptide-induced kidney salt-wasting

n. Pain and emotional stress
o. Nausea, vomiting
p. Inappropriate intravenous fluids
Electrolytes and Cancer 9
rapid correction beyond this is seldom warranted.30 In
all cases in which 3% saline is used, frequent monitoring
of the serum sodium is required and a correction rate
greater than 10 mEq/L over the first 24 hours of therapy
should be avoided.
Fluid restriction (generally to 500 mL less than the
daily urine output) is an option for mild hyponatremia
that may be transient in nature. However, fluid restriction
may be particularly difficult in the patient with cancer in
which chemotherapy regimens require hydration proto-
cols and the restriction of fluids may compromise nutri-
tion and quality of life. Thus, the efficacy of fluid
restriction should be carefully assessed and other thera-
pies should be used when the burden of this maneuver
outweighs its benefits. A newer, physiologically based
Table 2. Diagnostic Criteria for Syndrome of Inappropriate
Antidiuretic Hormone Secretion
12,13
Essential criteria
� Decreased serum osmolality (,275 mOsm/kg)
� Urine osmolality . 100 mOsm/kg
� Clinically euvolemic
� Urine sodium . 30 mEq/L on a normal daily sodium intake
� Normal thyroid and adrenal function

� No recent use of diuretics
Supplemental criteria
� Plasma uric acid , 4 mg/dL
� Blood urea nitrogen , 10 mg/dL
� Failure to correct hyponatremia (or worsening
hyponatremia) after 1-2 L of 0.9% saline
� Correction of hyponatremia with fluid restriction
� Abnormal result on test of water load (,80% excretion of
20 mL water/kg body weight over a period of 4 h) or
inadequate urinary dilution (,100 mOsm/kg H2O)
� Plasma arginine vasopressin level elevated relative to
plasma osmolality
therapy for hyponatremia is to antagonize the vasopres-
sin type-2 receptor, the site of action for vasopressin in
the distal tubule that leads to water retention. In the
United States, 2 vasopressin-receptor antagonists are
approved by the U.S. Food and Drug Administration (con-
ivaptan and tolvaptan). Conivaptan is an intravenous-
only preparation that can only be used up to 4 days;
thus, it is not appropriate long term for patients with
malignancy-associated SIADH. Tolvaptan is an oral agent
that is approved foreuvolemic and hypervolemichypona-
tremia. Tolvaptan was studied in the pivotal Study of As-
cending Levels of Tolvaptan in Hyponatremia-1 (SALT-1)
and SALT-2 trials,31 although neither trial specifically ad-
dressed hyponatremia in patients with underlying malig-
nancy. Of note, some patients will still require some
degree of fluid restriction to normalize serum sodium
levels, especially in those patients with urine osmolalities
greater than 600 mOsm/kg.32 Tolvaptan is contraindi-

cated in patients with hypovolemic hyponatremia, vol-
ume depletion, and anuria as well as in those who
cannot perceive or respond appropriately to thirst, and it
should not be used in patients whose serum sodium levels
need to be urgently raised. Moreover, acute hepatotoxicity
has been reported with tolvapatan; hence, the U.S. Food
and Drug Administration has limited its use to 1 month
or less.
Hyperkalemia Associated With Cancer
Hyperkalemia in the patient with cancer is often attribut-
able to acute kidney injury, rhabdomyolysis, or tumor lysis
syndrome (which are discussed in other articles in this
journal).Lesscommoncausesincludeadrenalinsufficiency
associated with metastatic disease or drugs such as ketoco-
nazole, metapyrone, calcineurin inhibitors (stem cell trans-
plant patients), nonsteroidal anti-inflammatory agents,
trimethoprim, and heparin.
Of particular importance in this patient population is
pseudohyperkalemia.33 The presence of pseudohyperka-
lemia should be considered in any patient with marked
leukocytosis or thrombocytosis (for example, patients
with chronic lymphocytic leukemia acute myeloctic
leukemia or essential thrombocytosis), in which elevated
potassium values are obtained in the absence of corre-
sponding clinical symptoms or changes on the electrocar-
diogram. It is caused by a shift of potassium out of
platelets or leukocytes after a blood draw and when
a blood clot has formed. If the initial sample was serum,
repeat measurement using simultaneously drawn
plasma and serum specimens should be performed to ob-
serve for disparate results. A serum-to-plasma potassium
gradient greater than 0.4 mEq/L is diagnostic of pseudo-
hyperkalemia.33 Because of this issue, it is recommended
that plasma samples be used in those patients with ex-

treme leukocytosis or thrombocytosis. However, another
phenomenon that can be seen in plasma samples is
Table 3. Malignancies and Therapies Associated With the
Syndrome of Inappropriate Antidiuretic Hormone Secretion
Cancers Therapies
Small-cell lung cancer Cyclophosphamide
Head and neck Hematopoietic stem cell transplantation*
Brain (primary and metastatic) Bortezomib*
Hematological (lymphoma, leukemia, multiple myeloma)
Vincristine, vinblastine
Skin (melanoma) Ifosfamide
Gastrointestinal (esophageal, gastric, pancreatic, colon)
Cisplatin, carboplatin
Gynecological Melphalan*
Breast Methotrexate*
Prostate Interferon-a and g*
Bladder Levamisole*
Sarcomas Pentostatin*
Thymoma Monoclonal antibodies (alemtuzumab, bevacizumab)*

Adrenal Interleukin-2*
Busulfan*
Chlorambucil*
Cytarabine, fludarabine*
Hydroxyurea*
Imatinib*
*Mechanism of action is not definitive, but it may involve
syndrome of inappropriate antidiuretic hormone secretion.
Rosner and Dalkin10
reverse pseudohyperkalemia.34 Here, a falsely high po-
tassium level is found in plasma samples (defined as a se-
rum-to-plasma potassium gradient ,0.4 mEq/L). The
true mechanism of reverse pseudohyperkalemia has not
yet been established, but it is likely due to minor leakage
of intracellular potassium from leukemic cells due to me-
chanical stressors (pneumatic tube transport and speci-
men sampling into vacuum tubes) or heparin-induced
lysis of leukocytes during laboratory processing.
Therapy of hyperkalemia in this patient population is
the same as for other patient groups.
Table 4. Etiologies of Hypokalemia in the Patient With Cancer
Inadequate potassium intake
- Poor nutrition, anorexia
Excessive gastrointestinal losses

- Vomiting (chemotherapy-induced)
- Diarrhea (chemotherapy-induced, tumor-associated,
postsurgical resection)
- Posturetosigmoid diversion
Kidney losses- Diuretics
- Hypercalcemia
- Hypomagnesemia
- Postobstructive diuresis
- Drugs
- Amphotericin B
- Aminoglycosides
- Cisplatin
- Ifosfamide
- Glucocorticoids
- Lysozymuria with acute leukemia
- Mineralocorticoid excess
- Primary hyperaldosteronism (adrenal adenoma or
carcinoma)

- Renin-producing tumors
- Ectopic adenocorticotropin syndrome
Intracellular shifts
- Pseudohypokalemia
- Use of growth factors and vitamin B12 therapy
Hypokalemia Associated With Cancer
Hypokalemia is the second most common electrolyte dis-
order encountered in the patient with cancer.35 In most
cases, the etiology of hypokalemia is multifactorial and
includes medications that can cause tubular damage
(such as cisplatin, ifosfamide, amphotericin B, and ami-
noglycoside antibiotics) as well as gastrointestinal and
kidney losses of potassium. Hypokalemia is also com-
monly seen in conjunction with other electrolyte disor-
ders such as hyponatremia and hypomagnesemia and
reflects the underlying etiologies such as diuretic use. Pa-
tients with hypercalcemia may also develop hypokale-
mia due to the kaliuretic effect of the elevated calcium
level as well as due to the injudicious use of diuretics in
this population.36 Transcellular shifts can also occur post-
phlebotomy, leading to spurious hypokalemia.37 This
phenomenon is usually encountered in patients with
marked leukocytosis (.100,000/mL) and with blood
that is kept at room temperature for prolonged periods
of time. Rapid separation of the plasma and storage at
4�C limits this issue.
Specific etiologies of hypokalemia encountered in the
patient with cancer are depicted in Table 4. Ectopic adre-
nocorticotropin hormone (ACTH) syndrome is an un-
common cause of severe hypokalemia and typically

presents with severe hypercortisolemia, increased skin
pigmentation, diabetes, bone loss, hyperlipidemia, gener-
alized infections (especially fungal), hypertension, men-
tal status changes, and Cushingoid habitus.38 Excess
cortisol overloads cellular mechanisms to limit mineralo-
corticoid receptor access to glucocorticoids, thereby en-
hancing kidney potassium excretion. Numerous tumors
can produce ectopic ACTH, with the most common etiol-
ogies including bronchial carcinoid tumors, small-cell
lung cancer, lung adenocarcinomas, thymic tumors, pan-
creatic tumors, and medullary thyroid cancer.38 Of note,
more than 50% of these tumors are found in the lung or
thymus, although in 10% to 15% of cases of ectopic
ACTH syndrome, the source remains unknown.39 Diag-
nosis rests on biochemical/endocrine testing to docu-
ment elevated ACTH levels in the presence of
hypercortisolism followed by radiographic localization.38
The optimal management of this syndrome is surgical ex-
cision, but this can only be achieved with curative intent
in up to 40% of cases; thus, drugs that antagonize the syn-
thesis of glucocorticoids such as metapyrone and ketoco-
nazole may also be needed.38 Patients with occult ectopic
ACTH syndrome will likely need adrenalectomy to
achieve a biochemical cure.38 Prognosis in this syndrome
is dependent on the etiology, and patients with small-cell
lung cancer have the worst prognosis with survival gen-
erally less than 12 months after diagnosis.38
A prominent association between hypokalemia and
acute myelogenous leukemia (specifically subtypes M4
and M5) has been noted, with 40% to 60% of these pa-

tients developing significant hypokalemia at some point
in their disease course.35,40 Of importance is that
hypokalemia in these patients is usually associated with
other electrolyte and acid-base disorders (hyponatremia,
hypocalcemia, hypophosphatemia, hypomagnesemia
and non-anion gap metabolic acidosis), suggesting
a more global tubular defect in these patients.40 The
Figure 1. Regulation of phosphaturia. Kidney phosphate excre
(FGF-23) and parathyroid hormone (PTH) along with an as-y
Dihydroxy vitamin D stimulates phosphate absorption, which in
Feedback inhibition results from FGF-23 and phosphate inhibiti
reduce PTH secretion.
mechanism of hypokalemia is due to inappropriate
kaliuresis and has been postulated to be secondary to in-
creased serum lysozyme levels and lysozymuria-induced
tubular damage.41 The frequency of hypokalemia is so
high that patients with acute myelogenous leukemia
should have frequent laboratory monitoring and electro-
lyte supplementation as needed.
The treatment for hypokalemia in patients with malig-
nancy is similar to that used in patients without an un-
derlying malignancy. A thorough review is beyond the
scope of this manuscript. For a more in-depth discussion,
the reader is directed to an excellent review by Unwin
and colleagues.42
Hypophosphatemia Associated With Cancer
The regulation of phosphate balance reflects the actions
of an array of factors altering phosphate absorption and
excretion as well as changes related to the intimate con-
nection between phosphate and calcium levels.43 In pa-
tients with malignancy, pathologic derangement at any
of several regulatory steps can result in hyper- or hypo-
phosphatemia. Hence, it is important for the clinician to
have an understanding of phosphate homeostasis (Fig

1) as a backdrop upon which to evaluate altered phos-
phate levels in patients with cancer (Fig 2).
Dietary intake of phosphate usually exceeds the
recommended daily allowance of 700 mg for adults,
tion is driven by bone-derived fibroblast growth factor-23
et unidentified factor from the gastrointestinal tract. 1,25-
turn drives phosphaturia and parathyroid hormone release.
on of 1-a-hydroxylase as well as the actions of vitamin D to
Figure 2. The role of fibroblast growth factor-23 (FGF-23) in
tumor-induced osteomalacia (TIO). Production of FGF-23 from
the
osteoblast and osteocyte is inhibited by dentin matrix protein-1
(DMP-1) and phosphate-regulating gene with homologies to
endopeptidases on the X chromosome (PHEX) by as-yet unclear
mechanisms. 1,25-Dihydroxy vitamin D (1,25(OH)2D) stim-
ulates FGF-23, which in turn favors phosphaturia. Changes in
phosphate level feedback at the osteoblast/osteocyte (hyper-
phosphatemia stimulates FGF-23 synthesis and secretion
whereas hypophosphatemia inhibits FGF-23). FGF-23 also
inhibits parathyroid hormone (PTH), which in turn lowers
1,25(OH)2D. In patients with TIO, tumor production of FGF-23
is un-
restrained and the normal feedback inhibition to the parathyroid
gland and the osteoblast/osteocyte is ineffective at lowering
FGF-23.
Rosner and Dalkin12
and much of it is not absorbed. Changes in dietary
phosphate intake alter the expression of the sodium-
phosphate cotransporter IIB (such that a reduction in
dietary intake of phosphate enhances absorption
whereas excess dietary intake results in reduced intesti-

nal absorption) by an as yet unknown mechanism(s).44
Moreover, an undefined communication between the
gastrointestinal tract and the kidney appears to exist be-
cause there is rapid appearance of phosphaturia after
phosphate absorption.45
In contrast, 30% of gastrointestinal phosphate trans-
port is dependent on the actions of active vitamin D—
1,25-dihydroxy vitamin D (1,25(OH)2D).
46 Other factors,
including phosphate, calcium, insulin-like growth
factor-1 and the ‘‘phosphatonins’’ (such as fibroblast
growth factor-23 [FGF-23] and secreted frizzled-related
peptide), can modify that effect.47 The actions of vitamin
D on intestinal cellular function are complex and enhance
expression of the sodium-phosphate cotransporter IIB.48
Parathyroid hormone (PTH) is an essential hormonal
regulator of kidney phosphate handling. PTH (and
PTH-related peptide [PTHrP]) acts via a G-protein-
coupled cell surface receptor, PTH receptor-1.49 In terms
of kidney phosphate balance, PTH acts on the proximal
tubule cells to drive internalization of the sodium-
phosphate cotransporters NaPi-IIa and IIc, preventing re-
absorption of phosphate and enhancing phosphaturia.50
PTH secretion is regulated by calcium (via the calcium-
sensing receptor), phosphate (via an unknown mecha-
nism), and vitamin D (via a direct action on PTH release
as well as via the effects of hypercalcemia).
The final regulatory component in maintaining phos-
phate balance includes a group of factors referred to as
phosphatonins, which directly regulate phosphate concen-
tration.47 The most important member of this family is

FGF-23, produced primarily by osteoblasts and osteocytes,
which is important in the healthy individual and several
disease states.51 FGF-23 acts via fibroblast growth factor
receptor-1 and the co-receptor a Klotho to inhibit kidney
expression of the sodium-phosphate transporter 2a and
2c, thereby promoting phosphaturia and hypophosphate-
mia.52,53 Phosphate and 1,25(OH)2D are the major stimuli
for FGF-23.54,55 Indeed, there may exist a feedback
regulatory loop because FGF-23 inhibits the formation of
1,25(OH)2D, an action which then, in turn, would limit fur-
ther production of FGF-23.56 The relationship between
FGF-23 and PTH is complex. As noted, FGF-23 inhibits
the activation of vitamin D, thereby indirectly increasing
PTH. On the other hand, FGF-23 can directly inhibit
PTH secretion. Thus, FGF-23, like PTH and vitamin D, is
involved in a complex regulatory cascade for phosphate.
Additional factors also bear upon phosphate meta-
bolism, although their role in physiology and the
mechanism(s) by which they act are unclear.57 The
phosphate-regulating gene with homologies to endo-
peptidases on the X chromosome (PHEX), which cleaves
matrix extracellular phosphoglycoprotein (MEPE), an-
other potential regulator of phosphate, can inhibit
FGF-23. Dentin matrix protein plays a similar role in
the inhibition of FGF-23. Excess MEPE has been associ-
ated with hypophosphatemia (see below) because of ac-
tions at the intestinal tract and the kidney.
Disordered regulation of phosphate, as a consequence
of neoplasia, is relatively common. Cachexia and malnu-
trition, including calcium and vitamin D deficiency, can
directly result from malignancy or as the result of cancer

treatment. These patients present with low normal serum
calcium levels, or frank hypocalcemia, hypophosphate-
mia, low vitamin D, and elevated PTH levels. Chemo-
therapy, including cisplatin, can damage renal tubules
and result in phosphate wasting. In addition, multiple
myeloma can directly alter kidney phosphate reabsorp-
tion and result in phosphaturia and hypophosphatemia.
Certain malignancies, such as lymphoma, may contain
the enzyme 1-a hydroxylase and lead to increased levels
of active vitamin D metabolites and cause hypercalcemia
and, to a lesser degree, hyperphosphatemia.
More complex, and more rare and indolent, is the syn-
drome of tumor-induced osteomalacia (TIO), also known
as oncogenic osteomalacia, in which tumor production of
phosphaturic factors such as FGF-23 results in phosphate
wasting, hypophosphatemia, and osteomalacia.58 A wide
array of neoplasms has been described, including malig-
nancies such as chondrosarcoma and osteoblastoma,
although the most common neoplasm is a hemangioperi-
cytoma. Ossifying fibromas, giant-cell tumors, and gran-
ulomas causing TIO have also been described. These
neoplasms are generally mesenchymal in origin (phos-
phaturic mesenchymal tumor, mixed connective tissue
variant), with a high degree of vascularity but absent or
low levels of mitotic activity.58
The initial steps in the evaluation of a patient with ac-
quired hypophosphatemia include a thorough evaluation
of medications, nutritional status, and medical history. In
the presence of hypercalcemia, causes of hyperparathy-
roidism should be pursued (chemistry panel including
calcium, albumin, kidney function, PTH, and PTHrP). If
there is coexistent hypocalcemia, vitamin D status must
be ascertained. In patients with a normal calcium level
and hypophosphatemia, the presence of kidney phos-

phate wasting should be pursued. Assessment of either
the percentage tubular reabsorption of phosphate or the
tubular maximum for phosphate corrected for the glo-
merular filtration rate can be used.58 If phosphate wast-
ing is confirmed, measurement of FGF-23 levels can be
performed. As noted, there are multiple potential causa-
tive factors; therefore, a ‘‘normal’’ FGF-23 level does not
eliminate the diagnosis of TIO.
Most neoplasms associated with TIO are found in the
limbs or sinuses. Because of their small size and slow
growth rate, it is not uncommon for the tumor to remain
occult, thereby warranting more extensive imaging stud-
ies.58,59 F-18-Fluorodeoxyglucose positron emission to-
mography, with computed tomography (FDG-PET/CT)
is favored at our institution, but 111Indium octreotide
scintigraphy has also been useful. Because of the lack of
specificity in these scans, especially FDG-PET/CT, fol-
low-up imaging with standard computed tomography
or magnetic resonance imaging is essential. If the neo-
plasm remains elusive, venous sampling for FGF-23 has
been attempted with some success.60
The mainstay of therapy is surgical resection because
removal is usually curative. Phosphate levels rapidly in-
crease because the half-life of FGF-23 is relatively short.61
Symptoms of hypophosphatemia may also improve
quickly, although the time needed to heal from osteoma-
lacia is longer and more variable. Metastatic disease
(often in the lung), or late recurrence, has been reported
in a few individuals.62,63 For individuals in whom
the tumor cannot be found, or if metastatic disease
prevents surgical cure, medical therapy with vitamin D
and phosphate is essential. As noted, these patients are
often deficient in 1,25(OH)2D because of the inhibition

of the 1-a hydroxylase step by FGF-23. In that light, calci-
triol is the preferred form of vitamin D used in these in-
dividuals, at doses between 1 and 3 mg/day, but it is
often limited by the development of hypercalcemia.
Phosphate supplements, usually 1 to 3 g/day in divided
dosing, are given using any of several available sodium
phosphate or potassium phosphate preparations. Dosing
of phosphate is generally limited by the development of
loose stools. In our practice, it has been difficult to
achieve a normal phosphate level in these patients.
Reaching a phosphate level between 2 and 2.5 mg/dL
is usually adequate to greatly reduce symptoms and pro-
mote, to some degree, healing of osteomalacia.
For those individuals in which one is unable to iden-
tify the site of the neoplasm, regular follow-up is essen-
tial. Careful examination of the extremities as well as
the head and neck are areas of focus. Sequential measure-
ment of phosphate is helpful, especially to gauge whether
replacement is adequate. In addition, we have had most
patients complete a 24-hour urine for calcium, phospho-
rous, and creatinine once they are stable. Because oral
supplementation with phosphate and vitamin D can ex-
acerbate hyperphosphaturia, there is a substantial risk
of developing calcium phosphate kidney stones; hence,
thiazide diuretics may be needed to help reduce urine
calcium excretion.
Hypercalcemia and Cancer
In patients with an underlying malignancy, most in-
stances of disordered regulation of calcium generally
involve the development of hypercalcemia.64 In the eval-
uation of disordered calcium, one must keep in mind that
circulating calcium is in part bound to albumin such that
the measured calcium level must be corrected for the al-
bumin.65 The severity of hypercalcemia in patients with

cancer will vary greatly and is dependent on the mecha-
nistic basis for the hypercalcemia as well as the patient’s
overall health status and hydration. In the presence of
mild hypercalcemia (10.5-11.5 mg/dL), patients may be
asymptomatic or have fatigue, malaise, constipation, or
Rosner and Dalkin14
anorexia. As the degree of hypercalcemia worsens, bone
pain (either related directly to the presence of malignancy
or secondary to increased bone remodeling), abdominal
pain (peptic ulcer disease), polyuria (nephrogenic diabe-
tes insipidus), and weakness are common. In severe hy-
percalcemia with levels above 14 mg/dL, neurologic
changes including altered mental status, confusion, and
coma may be present, warranting immediate interven-
tion and hospitalization.
The regulation of calcium concentrations is primarily
via the actions of PTH and vitamin D. As with phosphate,
PTH activates bone turnover and thereby favors the re-
lease of bone calcium stores, along with phosphate, into
the circulation. Again, PTH initiates this action via the
PTHR1 on the osteoblast, which in turn signals the oste-
oclast via the RANK/RANKL pathway.49,50 At the
collecting system, PTH drives calcium reabsorption and
phosphate excretion as well as activation of vitamin D,
which favors the absorption of calcium and phosphate
from the gastrointestinal tract. Calcium concentration in
the circulation dictates signaling via the calcium-
sensing receptor to provide feedback inhibition.
Perturbations at each of these steps in the homeostasis
of calcium can be detected as a potential cause of disor-
dered calcium regulation in patients with malignancy.

In general, there are 3 broad categories of hypercalcemia.
Most commonly, tumors can synthesize and secrete PTH-
like substances, specifically PTHrP, which increases bone
turnover and the release of calcium stores. Squamous-cell
carcinomas of the lung, cervix, and esophagus as well as
certain lymphomas, kidney cell carcinoma, and adeno-
carcinoma of the breast, prostate, and ovary have been re-
ported to cause hypercalcemia via PTHrP release.66-68
Likewise, although considerably less common, tumors
can make PTH themselves, including neoplasms of
pulmonary, ovarian, thyroid, and pancreatic origin.
A second, less common mechanism for the develop-
ment of hypercalcemia in patients with malignancy in-
volves the direct actions of metastatic tumor cells to
cause local osteolysis. The degree to which bone metasta-
ses cause hypercalcemia correlates directly with the bone
tumor burden. Each metastasis likely releases factors
such as prostaglandins or PTHrP that stimulate local os-
teoclast activity and the release of calcium into the circu-
lation. This scenario is most commonly noted in patients
with metastatic breast and lung cancers as well as in pa-
tients with extensive multiple myeloma.69-71
The third general mechanism in which patients with
cancer experience hypercalcemia includes the activa-
tion of vitamin D by the tumor itself, most commonly
seen in Hodgkin lymphoma and non-Hodgkin lym-
phoma, as well as multiple myeloma.72 In patients
with tumors directly activating vitamin D, hypercalce-
mia with hypoparathyroidism is generally observed
due to feedback inhibition of calcium on the normal
parathyroid glands.
Therefore, the evaluation of the cancer patient with hy-
percalcemia includes an investigation toward these po-

tential causes. After confirmation of true hypercalemia,
measurement of circulating PTH levels is the first most
important step. If the PTH levels are inappropriately nor-
mal, or elevated, evaluation for a coexistent parathyroid
adenoma should be sought because tumor-related pro-
duction of PTH itself is rare. More likely, PTH levels
will be suppressed, and other etiologies need to be
sought. Generally, other laboratory results may provide
a clue to aid in the investigation. A low phosphorus level,
perhaps coupled with an elevated marker of bone turn-
over such as alkaline phosphatase, can indicate PTHrP-
mediated disease. Of note, alkaline phosphatase is
derived from numerous sources, including liver and
bone, and hence is relatively nonspecific. Hyperphospha-
temia in the presence of hypercalcemia, especially in the
absence of coexisting kidney insufficiency, often indicates
a vitamin D-mediated etiology. Thus, additional testing
generally should include measurement of phosphorus,
1,25(OH)2D, PTHrP, and alkaline phosphatase along
with a serum and urine protein electrophoresis looking
for light-chain disease.
The therapy for hypercalcemia can be complex, in-
volves short- and long-term interventions, and is highly
dependent on the mechanism by which hypercalcemia
develops.73 The initial step, regardless of the cause, is
the emergent reduction in circulating calcium concentra-
tion. The mainstay of therapy is intravenous hydration
with a goal of increasing kidney clearance of calcium.
Most patients with significant hypercalcemia are volume
depleted at presentation, and a reduced glomerular filtra-
tion rate can exacerbate the hypercalcemia with ongoing
mobilization from bone. Aggressive intravenous hydra-
tion with 0.9% saline, usually at 200 to 500 mL/hour, is
the initial regimen suggested to establish a kidney urine
output of more than 75 mL/hour. If hydration results in

excessive fluid retention and potentially cardiac compro-
mise, usually congestive failure, the addition of a loop di-
uretic is suggested. Furosemide at increasing doses can
be used to facilitate the forced saline diuresis, but only af-
ter vigorous hydration has been achieved.74
To block mobilization of calcium from bone, antire-
sorptive therapy is generally mandatory. The primary
class of medications with which one can accomplish
this is via use of the bisphosphonates. The high-potency
bisphosphonates, available for intravenous dosing, in-
clude pamidronate, zolendronic acid, and ibandronate.
Pamidronate and zolendronic acid are approved by the
U.S. Food and Drug Administration for the treatment of
hypercalcemia. Ibandronate has been shown to have effi-
cacy in this setting, but hypercalcemia is not an approved
indication. Each of these agents targets the osteoclast to
reduce resorption.75 Tubular injury and glomerular dam-
age have been reported. Therefore, each agent should be
dose-adjusted when used in patients with kidney
insufficiency. Alternative antiresorptive agents include
denosumab, a monoclonal antibody directed against
RANKL. Denosumab is not cleared by the kidney; hence,
kidney insufficiency does not alter dosing or efficacy.
Denosumab has documented benefit in metastatic
cancers and can reduce skeletal-related events.76,77 In
addition, denosumab (along with the intravenous
bisphosphonates) has antiresorptive actions that can
extend for weeks to months, providing a longer term
effect.
For patients with tumor-induced hypercalcemia re-

sulting from excess 1-a hydroxylase, corticosteroid ther-
apy may be beneficial. Intravenous hydrocortisone, at
doses of 200 to 300 mg/day, can inhibit the 1-a hydroxy-
lase and reduce 1,25(OH)2D levels.
78 Although the re-
sponse is not rapid, limitation of dietary calcium may
be helpful in expediting the effect. High doses of cortico-
steroids can have a direct action on the underlying malig-
nancy (for example, certain lymphomas). After a period
of 3 to 5 days of intravenous steroid administration, it
is standard practice to transition the patients to oral dos-
ing, usually prednisone at 10 to 30 mg/day.
Hypocalcemia, Hypomagnesemia, and Cancer
Although rare, and described primarily in case reports,79,80
some malignancies are associated with hypocalcemia. The
tumors are usually metastatic to bone and have osteoblastic
activity. Hypomagnesemia can be associated in patients
with cancer, although this disturbance is generally the
result of therapy rather than being due to the underlying
disease state.
Summary
Proper management of the patient with cancer is com-
plex, and their medical treatment often includes efforts
to restore electrolyte levels to or toward normal. Disor-
dered regulation of sodium, potassium, phosphate, and
calcium composes a substantial proportion of these ab-
normalities and are relatively commonplace in this pa-
tient population. In many instances, until they are
corrected, electrolyte disturbances can affect health and
may limit treatment of the underlying neoplasia. An un-
derstanding of the pathologic basis for the specific chem-
ical imbalance is essential for the clinician to institute

a proper and effective corrective measure.
References
1. Doshi SM, Shah P, Lei X, Lahoti A, Salahudeen AK.
Hyponatremia
is hospitalized cancer patients and its impact on clinical
outcomes.
Am J Kidney Dis. 2012;59(2):222-228.
2. Berghmans T, Paesmans M, Body JJ. A prospective study on
hypo-
natremia in medical cancer patients: epidemiology, etiology and
differential diagnosis. Support Care Cancer. 2000;8(3):192-197.
3. Gill G, Huda B, Boyd A, et al. Characteristics and mortality
of severe
hyponatremia-a hospital-based study. Clin Endocrinol.
2006;65(2):
246-249.
4. Dhaliwal HS, Rohatiner AZS, Gregory W, et al. Combination
che-
motherapy for intermediate and high-grade non-Hodgkin’s lym-
phoma. Br J Cancer. 1993;68(4):767-774.
5. Osterlund K. Factors confounding evaluation and treatment
effect
in lung cancer. Lung Cancer. 1994;10(suppl 1):S97-S103.
6. Gross AJ, Steiberg SM, Reilly JG, et al. Atrial natriuretic
factor and
arginine vasopressin production in tumor cell lines from
patients
with lung cancer and their relationship to serum sodium. Cancer
Res. 1993;53(1):67-74.
7. Waikar SS, Mount DB, Curhan GC. Mortality after

hospitalization
with mild, moderate and severe hyponatremia. Am J Med.
2009;122(9):857-865.
8. Wald R, Jaber BL, Price LL, Upadhyay A, Madias NE.
Impact of
hospital-associated hyponatremia on selected outcomes. Arch
Intern
Med. 2010;170(3):294-302.
9. Chawla A, Sterns RH, Nigwekar SU, Cappuccio JD. Mortality
and
serum sodium: do patients die from or with hyponatremia. Clin
J
Am Soc Nephrol. 2011;6(5):960-965.
10. Hansen O, Sorensen P, Hansen KH. The occurrence of
hyponatre-
mia in SCLC and the influence on prognosis: a retrospective
study
of 453 patients treated in a single institution in a 10-year
period.
Lung Cancer. 2010;68(1):111-114.
11. Schwartz WB, Bennett W, Curelop S, Bartter FC. A
syndrome of re-
nal sodium loss and hyponatremia probably resulting from inap-
propriate secretion of antidiuretic hormone. Am J Med. 1957;
23(12):529-542.
12. Comis R, Miller M, Ginsberg S. Abnormalities in water
homeosta-
sis in small cell anaplastic lung cancer. Cancer. 1980;45(9):
2414-2421.
13. Padfield P, Morton J, Brown J, et al. Plasma arginine

vasopressin in
the syndrome of antidiuretic hormone excess associated with
bron-
chogenic carcinoma. Am J Med. 1976;61(6):825-831.
14. Biran H, Feld R, Sagman U, et al. Carcinoembryonic
antigen, argi-
nine vasopressin and calcitonin as markers of early small cell
lung
cancer relapse. Tumour Biol. 1989;10(5):258-267.
15. List AF, Hainsworth JD, Davis BW, Hande KR, Greco FA,
Johnson DH. The syndrome of inappropriate secretion of
antidiu-
retic hormone (SIADH) in small-cell lung cancer. J Clin Oncol.
1986;4(8):1191-1198.
16. Pettengill O, Faulkner C, Wurster-Hill D, et al. Isolation
and char-
acterization of a hormone-producing cell line from human small
cell anaplastic carcinoma of the lung. J Natl Cancer Inst.
1977;58(3):511-516.
17. Osterlind K, Andersen P. Prognostic factors in small cell
lung can-
cer: multivariate model based on 778 patients treated with
chemo-
therapy with or without irradiation. Cancer Res. 1986;46(8):
4189-4194.
18. Osterlind K, Hansen HH, Dombernowsky P. Determinants of
com-
plete remission induction and maintenance in chemotherapy
with
or without radiation of small cell lung cancer. Cancer Res.
1987;47(10):2733-2736.

19. Souhami RI, Bradbury I, Geddes DM, et al. Prognostic
significance
of laboratory parameters measured at diagnosis in small cell
carci-
noma of the lung. Cancer Res. 1985;45(6):2878-2882.
20. Sethi T, Rozengurt E. Multiple neuropeptides stimulate
clonal
growth of small cell lung cancer: effects of bradykinin,
vasopressin,
cholecystokinin, galanin and neurotensin. Cancer Res.
1991;51(13):
3621-3623.
21. Ferlito A, Rinaldo A, Devaney KO. Syndrome of
inappropriate anti-
diuretic hormone secretion associated with head and neck
cancers:
review of the literature. Ann Otol Rhinol Laryngol. 1997;106(10
Pt 1):
878-883.
22. Berghmans T. Hyponatremia related to medical anticancer
treat-
ment. Support Care Cancer. 1996;4(5):341-350.
http://refhub.elsevier.com/S1548-5595(13)00077-3/sref1

Rosner and Dalkin16
23. Hamdi T, Latta S, Jallad B, et al. Cisplatin-induced renal
salt wast-
ing syndrome. South Med J. 2010;103(8):793-799.
24. Bissram M, Scott FD, Rosner MH. Risk factors for

symptomatic hy-
ponatremia: the role of pre-existing asymptomatic
hyponatremia.
Intern Med J. 2007;37(3):149-155.
25. Kimura T, Abe K, Ota K, et al. Effects of acute water load,
hyper-
tonic saline infusion and furosemide administration on atrial
natri-
uretic peptide and vasopressin release in humans. J Clin
Endocrinol
Metab. 1986;62(5):1003-1010.
26. Weinand ME, O’Boynick PL, Goetz KL. A study of serum
antidiu-
retic hormone and atrial natriuretic peptide levels in a series of
pa-
tients with intracranial disease and hyponatremia.
Neurosurgery.
1989;25(5):781-785.
27. Manning P. Vasopressin-stimulated releases of atriopeptin:
endo-
crine antagonists in fluid homeostasis. Science.
1985;229(4711):
395-397.
28. Kamoi K, Ebe T, Hasegawa A, et al. Hyponatremia in small
cell
lung cancer. Mechanism not involving inappropriate AVP secre-
tion. Cancer. 1987;60(5):1089-1093.
29. Bliss DAJ, Battey JF, Linnoila RJ, et al. Expression of the
atrial natri-
uretic factor gene in small cell lung cancer tumors and tumor
cell

lines. J Natl Cancer Inst. 1990;82(4):305-310.
30. Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW,
Sterns RH.
Hyponatremia treatment guidelines 2007. Expert panel
recommen-
dations. Am J Med. 2007;120(11 suppl 1):S1-S21.
31. Schrier RW, Gross P, Gheorghiade M, et al, SALT
Investigators. Tol-
vaptan, a selective oral vasopressin V2-receptor antagonist, for
hy-
ponatremia. N Engl J Med. 2006;355(20):2099-2112.
32. Verbalis JG, Adler S, Schrier RW, et al. Efficacy and safety
of oral
tolvaptan therapy in patients with the syndrome of inappropriate
antidiuretic hormone secretion. Eur J Endocrinol. 2011;164(5):
725-732.
33. Sevastos N, Theodossiades G, Archimandritis AJ.
Pseudohyperka-
lemia in serum: a new insight into an old phenomenon. Clin
Med
Res. 2008;6(1):30-32.
34. Abraham B, Fakhar I, Tikaria A, et al. Reverse
pseudohyperkalemia
in a leukemic patient. Clin Chem. 2008;54(2):449-551.
35. O’Regan S, Carson S, Chesney RW, Drummond KN.
Electrolyte and
acid-base disturbance in the management of leukemia. Blood.
1977;49(3):345-353.
36. Aldinger S, Samaan NA. Hypokalemia with hypercalcemia.

Preva-
lence and significance in treatment. Ann Intern Med.
1977;87(5):
571-573.
37. Naparstek Y, Gutman A. Case report: spurious hypokalemia
in my-
eloproliferative disorders. Am J Med Sci. 1984;288(4):175-177.
38. Isidori AM, Kaltsas GA, Grossman AB. Ectopic ACTH
syndrome.
Front Horm Res. 2006;35:143-156.
39. Hernandez I, Espinosa-de-los-Monteros AL, Mendoza V, et
al. Ec-
topic ACTH-secreting syndrome: a single center experience
report
with a high prevalence of occult tumor. Arch Med Res.
2006;37(8):
976-980.
40. Milionis HJ, Bourantas CL, Siamopoulos KC, Elisaf MS.
Acid-base
and electrolyte abnormalities in patients with acute leukemia.
Am J
Hematol. 1999;62(4):201-207.
41. Mason DY, Howes DT, Taylor CR, Ross BD. Effect of
human lyso-
zyme (muramidase) on potassium handling by the perfused rat
kidney. A mechanism for renal damage in human monocytic leu-
kaemia. J Clin Pathol. 1975;28(9):722-727.
42. Unwin RJ, Luft FC, Shirley DG. Pathophysiology and
management
of hypokalemia: a clinical perspective. Nat Rev Nephrol.

2011;7(2):
75-84.
43. Bergwitz C, Juppner H. Regulation of phosphate
homeostasis by
PTH, vitamin D and FGF23. Annu Rev Med. 2010;61:91-104.
44. Marks J, Debnam ES, Unwin RJ. Phosphate homeostasis and
the
renal-gastrointestinal axis. Am J Physiol Ren Physiol.
2010;299(2):
F285-F296.
45. Berndt T, Thomas LF, Craig TA, et al. Evidence for a
signaling axis
by which intestinal phosphate rapidly modulates renal
phosphate
reabsorption. Proc Natl Acad Sci U S A. 2007;104(26):11085-
11090.
46. Wilz DR, Gray RW, Dominguez JH, Lemann J Jr. Plasma
1,25-(OH)
2-vitamin D concentrations and net intestinal calcium,
phosphate,
and magnesium absorption in humans. Am J Clin Nutr. 1979;
32(10):2052-2060.
47. Sommer S, Berndt T, Craig T, Kumar R. The phosphatonins
and the
regulation of phosphate transport and vitamin D metabolism. J
Ste-
roid Biochem Mol Biol. 2007;103(3-5):497-503.
48. Katai K, Miyamoto K, Kishida S, et al. Regulation of
intestinal Na1-
dependent phosphate co-transporters by a low-phosphate diet
and

1,25-dihydroxyvitamin D3. Biochem J. 1999;343(Pt 3):705-712.
49. Juppner H, Gardella TJ, Brown EM, et al. Parathyroid
hormone and
parathyroid hormone-related peptide in the regulation of
calcium
homeostasis and bone development. In: DeGroot LJ, Jameson
JL,
eds. Endocrinology. Philadelphia, PA: Elsevier Saunders; 2006:
1377-1417.
50. Foster IC, Hernando N, Biber J, Murer H. Proximal tubular
han-
dling of phosphate: a molecular perspective. Kidney Int. 2006;
70(9):1548-1559.
51. Juppner H, Wolf M, Salusky IB. FGF-23: more than a
regulator of
renal phosphate handling? J Bone Miner Res. 2010;25(10):2091-
2097.
52. Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of
fibroblast
growth factor-23 signaling by klotho. J Biol Chem.
2006;281(10):
6120-6123.
53. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts
canonical
FGF receptor into a specific receptor for FGF23. Nature. 2006;
444(7120):770-774.
54. Nishi H, Nii-Kono T, Nakanishi S, et al. Intravenous
calcitriol ther-
apy increases serum concentrations of fibroblast growth factor-
23 in

dialysis patients with secondary hyperparathyroidism. Nephron
Clin Pract. 2005;101(2):c94-c99.
55. Burnett SM, Gunawardene SC, Bringhurst FR, et al.
Regulation of
C-terminal and intact FGF-23 by dietary phosphate in men and
women. J Bone Miner Res. 2006;21(8):1187-1196.
56. Inoue Y, Segawa H, Kaneko I, et al. Role of the vitamin D
receptor
in FGF23 action on phosphate metabolism. Biochem J.
2005;390(Pt
1):325-331.
57. Quarles LD. Endocrine functions of bone in mineral
metabolism
regulation. J Clin Invest. 2008;118(12):3820-3828.
58. Chong WH, Molinolo AA, Chen CC, Collins MT. Tumor-
induced
osteomalacia. Endocr Relat Cancer. 2011;18(3):R53-R77.
59. Andreopoulou P, Millo C, Reynolds J, et al. Multimodality
diagno-
sis and treatment of tumor induced osteomalacia. Endocr Rev.
2010;31(suppl 1):OR08-6S49.
60. Andreopoulou P, Dumitrescu CE, Kelly MH, et al. Selective
venous
catheterization for the localization of phosphaturic
mesenchymal
tumors. J Bone Miner Res. 2011;26(6):1295-1302.
61. Khosravi A, Cutler CM, Kelly MH, et al. Determination of
the elim-
ination half-life of fibroblast growth factor-23. J Clin

Endocrinol
Metab. 2007;92(6):2374-2377.
62. Clunie GP, Fox PE, Stamp TC. Four cases of acquired
hypophospha-
taemic (‘oncogenic’) osteomalacia. Problems of diagnosis,
treatment
and long-term management. Rheumatology. 2000;39(12):1415-
1421.
63. Ogose A, Hotta T, Emura I, et al. Recurrent malignant
variant of
phosphaturic mesenchymal tumor with oncogenic osteomalacia.
Skeletal Radiol. 2001;30(2):99-103.
64. Stewart AF. Clinical practice. Hypercalcemia associated
with can-
cer. N Engl J Med. 2005;352(4):373-379.
65. Labriola L, Wallemacq P, Gulbis B, Jadoul M. The impact
of the as-
say for measuring albumin on corrected (’adjusted’) calcium
con-
centrations. Nephrol Dial Transplant. 2009;24(6):1834-1838.
66. Saburo S, Yano S. Molecular pathogenesis and its
therapeutic mo-
dalities of lung cancer metastasis to bone. Cancer Metastasis
Rev.
2007;26(3-4):685-689.

Art & science life sciences 1942 march 19 vol 28 no 29.docx

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