Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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.0007 sodium, 135–145 mmol l

1

;

0008 potassium, 3.5–5.0 mmol l

1

;

0009 calcium, 8.5–10.2 mg dl

1

;

0010 magnesium, 1.8–2.4 mg dl

1

Analytical Methods

0011 Many methods exist for the assay of electrolytes.

These methods include flame emission spectropho-

tometry (FES), atomic absorption spectrophotometry

(AAS), electrochemical analysis with ion-selective

electrodes (ISE), redox titration, colorimetry, and

fluorescent probes. In the clinical laboratory, the ma-

jority of the analyses are performed by FES, ISE, and

colorimetry. (See Calcium: Properties and Determin-

ation; Sodium: Properties and Determination.)

Flame Emission Spectrophotometry

0012 Flame emission spectrophometry is most commonly

used for the analysis of Na

and K

. When metals

such as Na

and K

are sufficiently heated in a flame,

they emit light of wavelengths characteristic of the

metal. The metal ions absorb heat energy, which

causes electrons to be driven out of their normal

orbital position. These excited metal atoms are said

to be in high-energy states and are very unstable.

The extra energy is given off in the form of light.

When Na

and K

are excited, they emit spectra

with sharp, bright lines at 589 and 768 nm, respect-

ively. Within certain limits, the amount of light given

off by the excited atoms is proportional to the con-

centration of the metal ions in the solution. To pre-

pare a flame emission spectrophotometer for

detecting Na

and K

, standard solutions containing

known concentrations (two levels) of these electro-

lytes are aspirated into the instrument. The digital

readout is then set to the known concentrations of

the fluid being aspirated. When the flame photometer

has been so calibrated, the fluid containing the un-

known concentration is aspirated, and the result indi-

cating the concentration is read from the digital

display.

0013 Another FES-type system, inductively coupled

argon plasma (ICAP), utilizes the principle of atomic

emission spectrophotometry. It is similar to FES,

except that the plasma has a much higher excitation

temperature. This results in lower limits of detection,

a wide dynamic range, and virtual freedom from

chemical interference. It is possible to use ICAP for

the analysis of metals, such as sodium and potassium,

as well as many nonmetals, such as sulfur and boron;

however, Cl



cannot be assayed by using ICAP spec-

trophotometry. Although the principle of ICAP has

been used to develop automated instrumentation,

at present this system has not been used in clinical

laboratories.

Atomic Absorption Spectrophotometry

0014Atomic absorption spectrophotometry is not com-

monly employed in clinical laboratories. As AAS is

much more sensitive than FES, AAS is used as a

reference method for many analytical procedures.

The principle on which AAS is based is similar to

FES. In AAS, however, the flame serves to dissociate

the element from its chemical bonds and place it in a

ground state at which it is capable of absorbing light

of a wavelength specific for the element. The method

involves using hollow cathode lamps containing

the metal of interest. The metal in the lamp is sub-

jected to an electric current, causing it to emit light at

a characteristic wavelength specific to the element in

the lamp. This light passes over a burner to a special

detector that measures emitted intensity.

0015To prepare an AAS for analyzing electrolytes, a

standard solution containing a known concentration

of the metal of interest is aspirated into the burner;

the atoms in this field absorb the light proportional

to their concentration in the fluid. The resulting

decrease in intensity of the beam of light given off

from the hollow cathode lamp is then set on a digital

readout to reflect the known concentration. Once

the instrument has been so calibrated, the unknown

fluid is aspirated, and the electrolyte concentra-

tion can be obtained from the digital display. This

method can be used in the analysis of Na

2þ

, and Mg

2þ

Ion-selective Electrodes

0016Potentiometry with ISE is a comparatively recent

development in the electrolyte analytical field. It is

the measurement of the electrical potential difference

between two electrodes, which, in contact with one or

more electrolyte solutions, form an electrochemical

cell. A high-impedance voltmeter measures the elec-

trical potential difference between the two electrodes.

Ion-selective electrodes respond preferentially to a

particular ion species in solution. Some potentiomet-

ric analytical methods use an ion-selective indicator

electrode and a reference electrode. A method de-

veloped by Eastman Kodak and used on their Ekta-

chem analyzer uses two identical ISE mounted in a

single-use disposable slide. The reference fluid con-

taining ions at fixed concentration is applied to the

reference electrode. The sample fluid is simultan-

eously applied to the indicator electrode. The two

solutions are allowed to form a liquid junction in

the bridge portion of the slide. This arrangement

constitutes a concentration cell.

ELECTROLYTES/Analysis 2037

0017 The specific components of the cell vary according

to the ion being tested. Over the physiological range,

the relationship between the measured cell potential

and the logarithm of the molal concentration of the

ion being tested from the fluid is linear. The junction

potential is produced between the reference fluid and

the sample fluid in the bridge portion of the analysis

slide. The magnitude and sign of the junction poten-

tial depend on the total ionic concentration and com-

position of the fluid but are primarily determined by

the Cl



and Na

concentrations. The magnitude of

this term is minimized by using a reference fluid

having ionic concentrations near physiological aver-

ages. Applications of this have been developed for the

analysis of carbon dioxide (CO

), Cl



,Na

, and K

The results are normally reported in molar units.

0018 Other methods employing ISE technology use elec-

trodes of a nondisposable variety. Glass electrodes are

made from specially formulated glass with added

oxides of various metals. For example, the most prac-

tical sodium electrode is made of specialized glass,

selective for Na

. A solid-state electrode employing

a homogeneous membrane of silver chloride is used

for Cl



analysis of sweat by direct measurement from

the skin surface. A liquid ion-exchange electrode with

an ion-selective carrier embedded in a polyvinylchlor-

ide matrix is used for chloride analysis of body fluids.

A liquid ion-exchange membrane electrode, incorpor-

ating the antibiotic valinomycin as the K

binder, is

the most selective for potassium. A gas electrode is

available for total CO

(HCO



) analysis. This

involves a combination of a glass pH electrode and

a reference electrode in contact with a weakly buf-

fered electrolyte solution behind a membrane perme-

able to CO

gas. When the CO

gas is forcibly

released from the sample, it diffuses through the

membrane and reacts with water in a buffer solution,

resulting in a change in the hydrogen ion activity of

the buffer. The pH electrode senses the change in

hydrogen ion activity, which is an indication of the

concentration of the CO

present in the sample fluid.

Ion-selective electrodes have been incorporated into

many automated systems used in clinical laboratories

for assaying the ‘electrolyte profile.’

Redox Titration

0019 Redox titration is characterized by the transfer of

electrons from one substance to another with an end

point determined calorimetrically or potentiometri-

cally. This method is used for the determination of

2þ

. Calcium is precipitated as calcium oxalate,

which is treated with sulfuric acid. The oxalic acid

formed is redox-titrated with potassium permangan-

ate (oxidant). This method is time-consuming and is

not used in clinical laboratories.

Colorimetry

0020In clinical laboratories, colorimetry is commonly

employed for the analysis of Ca

2þ

and Mg

2þ

. The

analysis is based on reacting the metal with an indica-

tor dye to form a colored complex. The density of

the resulting complex is related to the concentration

of the metal and can be measured spectrophotome-

trically. A common dye used for assaying total

calcium inbodyfluid iso-cresolphthaleincomplexone.

This reagent contains other compounds (8-hydroxy-

quinoline, urea, and ethanol) which serve to mask

interferences and enhance the reaction. Magnesium

is commonly determined by complexing Mg

2þ

with

a Calmagite reagent, resulting in another chromo-

phore which can also be measured spectrophotome-

trically. (See Spectroscopy: Visible Spectroscopy and

Colorimetry.)

Fluorescent Probes

0021The assay of intracellular levels of Ca

2þ

can be con-

ducted in living cells by the use of fluorescent probes.

These dyes are introduced into the cell as an ester

derivative which is nonpolar and thus freely diffusible

across cell membranes. Once within the cell, the com-

pounds are hydrolyzed by nonspecific esterases pre-

sent in the cytosol. The resulting cation is trapped

within the cell owing to its inability to traverse the

plasma membrane. Thus, the cation gradually accu-

mulates intracellularly. When excited at a given wave-

length, its fluorescence reflects the concentration of

free cytosolic calcium.

See also: Calcium: Properties and Determination;

Physiology; Coenzymes; Magnesium; pH – Principles

and Measurement; Potassium: Physiology; Sodium:

Properties and Determination; Physiology;

Spectroscopy: Visible Spectroscopy and Colorimetry

Further Reading

Anon. (1986) Test methodologies. Potentiometric method-

ology, section 2. In: Ektachem Clinical Chemistry

Products Manual. Rochester, NY: Eastman Kodak.

Blick KE and Liles SM (1985) Principles of Clinical

Chemistry. New York: John Wiley.

Henry JB (1984) Clinical Diagnosis and Management by

Laboratory Methods, 17th edn. Philadelphia, PA: WB

Saunders.

Parker SP (ed.) (1989) McGraw Hill Dictionary of Scientific

and Technical Terms. New York: McGraw-Hill.

Tietz NW, Pruden EL and Sigaard-Anderson O (1987) Elec-

trolytes, blood gases and acid–base balance. In: Tietz

NW (ed.) Fundamentals of Clinical Chemistry, 3rd edn.

Philadelphia, PA: WB Saunders.

Tsien RY (1989) Fluorescent probes of cell signalling.

Annual Review of Neuroscience 12: 227–253.

2038 ELECTROLYTES/Analysis

Water–Electrolyte Balance

Y L Cheng and A W Yu, The Chinese University of

Hong Kong, Hong Kong, China

Background

0001 The water–electrolyte balance is regulated tightly in

the human body for the normal function of cells and

organs. The kidneys have a critical role in regulating

the composition of water and several important inor-

ganic ions (sodium, potassium, chloride, bicarbonate,

hydrogen ion, calcium, and phosphate) in the body

and thus homeostasis. This is maintained by an

appropriate balance between the excretion of these

electrolytes by the kidneys and the daily intake.

Hypernatremia and hyponatremia (excess and inad-

equate plasma sodium), hyperkalemia and hypokale-

mia (excess and inadequate plasma potassium) are

the most common electrolyte disorders and result

from an imbalance between intake and excretion of

water and these electrolytes. This article is a consider-

ation of the interactions of hormones and the auto-

nomic nervous system on renal tubules in maintaining

the water–electrolyte balance.

Water Balance

Water Content in the Body

0002 Water is the most abundant component in the human

body. Total body water is about 50% of body weight

for normal adult women and about 60% of body

weight for normal adult men. Fat has far less water

than other body tissues. Consequently, women, obese

people and the elderly contain less water in propor-

tion to their body weight because, generally, they

have proportionately more body fat.

0003 Body water is distributed in two major compart-

ments that are separated by cell membranes: the intra-

cellular fluid (ICF) and the extracellular fluid (ECF).

Approximately two-thirds of the total body water is

in the ICF and one-third in the ECF. The distribution

of total body water in each compartment is shown in

Figure 1.

0004 Water distribution in the ICF and ECF depends on

the number of particles (electrolytes and macromol-

ecules) confined in these compartments. The con-

centration of an individual substance in the two

compartments may not be equal because the cell

membrane has different permeabilities and channels

for different substances. The concentration of a

substance in a solution can be expressed as osmolality.

Some substances, such as urea and alcohol, freely

cross most cell membranes. ‘Effective osmolality,’ or

tonicity, refers to the osmolality that contributes

to non-freely permeable substances. Water will move

across the cell membrane along the osmotic

gradient, i.e., from a compartment with a low effective

osmolality to a compartment with a high effective

osmolality, until the tonicity is equal on both sides of

the membrane. The normal plasma osmolality is

about 285–295 mosmoles (mOsm) per kilogram of

water.

Water Intake and Water Output

0005In the steady state, water intake must be equal to

water output. For a normal adult, the usual water

intake is about 1.5–2.5 l per day (which includes

ingested water and water contained in foods), and

the endogenous water production by oxidative me-

tabolism is about 0.5 l per day. Water loss is through

urine (about 1–2 l per day), ‘insensible water loss’ by

evaporation of water through skin and lungs (about

1 l per day), and stool excretion (about 0.1–0.2 l per

day). Urine is the only route by which water excretion

Transcellular water

Bone matrix

Dense connective

tissue

Interstitium

Plasma

1.5%

4.5%

11.5%

3.0%

Extracellular

compartment

25%

Intracellular

compartment

36%

fig0001Figure 1 Distribution of body water in typical adult men,

expressed as a percentage of body weight.

ELECTROLYTES/Water–Electrolyte Balance 2039

can be closely regulated. Apart from water intake,

urine output also relates directly to the solute excre-

tion, and it cannot be reduced below a certain min-

imal value required to carry the solute load. This is

known as ‘obligatory kidney water loss.’ In order

to produce a maximally concentrated urine (urine

osmolality approximately 1200 mOsm kg

1

), for in-

stance, a daily solute load of 600 mOsm requires

a minimal obligatory urine output of 0.5 l per day

(600 mOsm divided by 1200 mOsm kg

1

) to excrete

the solute.

Regulation of Water Balance

0006 Water balance is the result of the interaction of thirst

and arginine vasopressin (AVP), which is also termed

antidiuretic hormone, to maintain a stable plasma

tonicity. The sensation of thirst promotes water

intake, and AVP regulates urinary water excretion.

AVP is a nine-amino acid polypeptide that is synthe-

sized in the hypothalamus and stored in the posterior

pituitary. Upon stimulation, AVP is released into the

blood circulation. It then binds to the receptor

(known as AVP receptor 2) on the basolateral mem-

brane, opens up the water channel (known as the

aquaporin-2 channel) in the apical membrane of the

principal cells of the collecting ducts in the kidneys,

and increases the water permeability. The medullary

interstitium surrounding the collecting ducts is hyper-

tonic with an osmolality up to 1200 mOsm kg

1

When the water channels are open, water is re-

absorbed along the osmotic gradient. In the absence

of AVP, the kidneys excrete a large amount of hypo-

osmotic fluid rapidly. Urine osmolality reflects the

kidneys’ ability to dilute (removal of water) or con-

centrate (conservation of water) the urine. In a

normal adult, the urine osmolality varies from 80 to

1200 mOsm kg

1

0007 Thirst is more important than the AVP mechanism.

In the absence of AVP secretion (e.g., patient with

cranial diabetes insipidus), urinary water loss will

increase. If the thirst mechanism is intact, water bal-

ance can still be maintained by an increase in water

intake. However, patients with a defective thirst

mechanism will be predisposed to dehydration, even

if the AVP mechanism is normal.

Control of Thirst and AVP Secretion

0008 Both osmotic and nonosmotic factors are involved in

the regulation of thirst and AVP release. Amongst

these, the osmotic factor (i.e., plasma tonicity) is

more important. The factors and their effects are

summarized in Tables 1 and 2.

0009 The osmolality sensor (osmoreceptor), the thirst

center, and the AVP secretory cells are located in the

hypothalamus. The sensor is a group of specialized

cells that is remarkably sensitive to the changes of

tonicity in the ECF. When there is a water deficit

(Figure 2), plasma tonicity will increase. The osmo-

receptors will send a signal to both the thirst center

and the AVP secretory cells. Intake of water will be

increased, and the kidneys will retain water via the

action of released AVP.

0010Conversely, when there is excessive water (Figure 2),

plasma tonicity will decrease. Both the thirst center

and secretion of AVP will be inhibited to promote net

urinary water loss. These responses act as a feedback

loop to keep the plasma tonicity and, hence, the body

water content within tight limits.

Kidneys and Water Balance

0011A nephron is the functional unit of the kidneys. Each

kidney contains approximately one million such units.

A nephron is composed of a glomerulus and a renal

tubule (Figure 3). The renal tubule is subdivided fur-

ther into the proximal convoluted tubule, the loop

tbl0001Table 1 Control of thirst

Factors Stimulation Inhibition

Osmotic " Tonicity # Tonicity

Nonosmotic # ECF volume " ECF volume

Congestive heart failure Dopamine antagonists

Hormones/drugs

Angiotensin II

Catecholamines

Parasympathomimetic

drugs

tbl0002Table 2 Control of arginine vasopressin release

Factors Stimulation Inhibition

Osmotic " Tonicity # Tonicity

Nonosmotic # ECF volume " ECF volume

# Blood pressure " Blood pressure

Nausea/pain/anxiety Hormones/drugs

Congestive heart

failure

Dopamine

antagonists

Liver disease Ethanol

Hypoglycemia Norepinephrine

Adrenal insufficiency

Hormones/drugs

Angiotensin II

General anesthetics

Barbiturates

Chlorpropamide

Clofibrate

Cyclophosphamide

Nicotine

Vincristine

2040 ELECTROLYTES/Water–Electrolyte Balance

of Henle, the distal convoluted tubule, and the col-

lecting duct.

0012 The glomeruli filter about 180 l of fluid (which

contains water, electrolytes, and glucose) each day.

Up to 90–99% of the filtered water is reabsorbed by

the renal tubules. It is reabsorbed passively in the

proximal convoluted tubules (60–70% of the filtered

water) and the descending limbs of the loops of Henle,

with down osmotic gradients created by the active

transport of sodium and chloride out of the lumina.

Water is not permeable in the ascending limb of the

loop of Henle and the distal convoluted tubule. The

final urine volume is determined by the action of AVP

on the collecting ducts.

Sodium Balance

Sodium Content in the Body

0013 For a normal adult, total body sodium content is

about 55–60 mmol per kilogram of body weight.

The distribution of sodium in different compartments

of the body is shown in Figure 4.

0014 Sodium is the major cation in the ECF. Its concen-

tration is about 135–145 mmol l

1

and 3 mmol l

1

the ECF and ICF, respectively. The high sodium con-

tent in the ECF is maintained by sodium–potassium–

adenosine triphosphatase (Na

–K

–ATPase) pumps.

The Na

–K

–ATPase pump is located in the cell

membrane, and it hydrolyzes a molecule of adeno-

sine triphosphate to release energy to pump three

sodium molecules out of the cells (from ICF to

ECF) and to transport two potassium molecules

into the cells (from ECF to ICF). In normal circum-

stances, sodium and its accompanying anions

(mainly chloride) contribute to more than 90% of

the effective osmolality in the ECF. As noted previ-

ously, effective osmolality determines the volume in

the corresponding compartment. Therefore, sodium

is the major determinant of the ECF volume. An

excess in total body sodium content leads to expan-

sion of the ECF volume, and a deficit in total body

sodium content is associated with contraction of the

ECF volume. A stable ECF volume is essential to

maintain tissue perfusion, because the plasma

volume (one of the compartments in ECF) is directly

proportional to the ECF volume.

Sodium Intake and Excretion

0015A typical Western diet contains approximately

150 mmol of sodium per day. However, social and

cultural differences in dietary habits can have a sig-

nificant effect on sodium intake. Amounts of sodium

can be up to 300 mmol per day in some areas in Japan

to less than 30 mmol per day in the New Guinea

Highlands. In normal health, the amount of sodium

Change of plasma tonicity

Osmoreceptors

Thirst

Plasma tonicity Plasma tonicity

Water intake

ThirstAVP AVP

Water retention

Normalization of plasma tonicity

Water loss

Water excretion Water intake Water excretion

Feedback loop Feedback loop

fig0002 Figure 2 Pathway of water conservation/excretion. AVP, arginine vasopressin.

ELECTROLYTES/Water–Electrolyte Balance 2041

excretion in the stool (about 5 mmol per day) and

sweat (about 10 mmol per day) is small and cannot

be regulated. Urine is the only route by which sodium

excretion can be precisely regulated to match the

sodium intake. Depending on the dietary intake and

the status of body sodium content, urinary sodium

loss can range from less than 1 mmol in a state of

sodium deficit, to more than 500 mmol per day in a

state of sodium excess. Thus, the kidneys have an

important role in maintaining sodium balance and

ensuring a stable ECF volume.

Kidneys and Sodium Balance

0016 In people with normal kidney function, the glomeruli

filter about 25 000 mmol sodium each day. This

amount is approximately six times the total body

sodium. Consequently, control of sodium reabsorp-

tion is important in maintaining sodium homeostasis.

As shown in Table 3, most of the filtered sodium

(60–70%) is reabsorbed at the proximal convoluted

tubules. Twenty to twenty-five per cent is reabsorbed

at the thick ascending limbs of the loops of Henle,

and another 10–15% is reabsorbed at the distal

nephrons (distal convoluted tubules and collecting

ducts).

0017Although the distal nephron is responsible for a

relatively small amount of sodium recovery, this seg-

ment of renal tubule is important for fine-tuning

sodium reabsorption.

0018There are two pathways by which sodium is re-

absorbed from the lumen to the renal tubular cells:

the paracellular pathway and the transporters at the

luminal membrane (Figure 5).

0019The paracellular pathway refers to channels be-

tween renal tubular cells. Sodium is freely permeable

in these channels in the proximal convoluted tubule

and the thick ascending limb of the loop of Henle, but

not in the distal nephron. The transporters at the

luminal membrane are different in various segments

of the renal tubule (Table 3). There are generally three

Bowmans capsule

Glomerulus

Afferent arteriole

Juxtaglomerular

apparatus

Macula densa

Thick ascending

limb of loop

of Henle

Distal

convoluted tubule

Collecting duct

Cortex of

kidney

Medulla of

kidney

Ascending limb of

loop of Henle

Descending limb of

loop of Henle

Proximal

convoluted tubule

fig0003 Figure 3 Nephron and juxtaglomerular apparatus.

2042 ELECTROLYTES/Water–Electrolyte Balance

classes of transporters, namely sodium exchanger,

sodium cotransporter, and specific sodium channel.

The sodium exchanger moves sodium into the cell in

exchange for another cation (for instance, potassium

and hydrogen ion) moving out of the cell. The sodium

cotransporter couples sodium entry with the entry of

other solutes, such as amino acids, glucose, phos-

phate, potassium, and chloride. The specific sodium

channel is present in the principal cells of the cortical

and medullary collecting duct (the intercalated cell is

the other cell type in the collecting duct that is in-

volved in acid or bicarbonate secretion and potassium

reabsorption). Under the effect of aldosterone, the

channel opens and allows passage of sodium ions

only.

0020 The pathways share the same mechanism for

sodium transport (Figure 5). There are Na

–K

–

ATPase pumps that operate across the base of renal

tubular cells and also across their lateral walls into

the intercellular spaces (also known as the basolateral

membrane). The pumps pump out sodium and keep

the intracellular sodium at a low level, which then

provides a steep electrochemical gradient favoring

reabsorption of sodium from the lumen, through the

various pathways (paracellular pathway and sodium

transporters), into the cells. Having entered the renal

tubular cell, the sodium then moves across the

basolateral membrane into the peritubular space

by the Na

–K

–ATPase pumps. The sodium then

enters the peritubular capillary and returns back to

the ECF.

Regulation of Urinary Sodium Excretion

0021Numerous mechanisms have been implicated in the

regulation of sodium balance and maintenance of a

stable ECF. It is unclear whether there are any other

mechanisms that have not been discovered yet. The

identified mechanisms are overlapped and extensively

interrelated. Failure of one of the mechanisms does

not result in significant long-term effects. This ar-

rangement is important to maintain stability of the

ECF volume. The more constant the ECF volume,

the more the body will be protected from changes

in the external environment.

0022The sensing mechanisms include: (1) mechano-

receptors in the walls of large blood vessels and

cardiac chambers (detecting changes in vascular dis-

tension); (2) chemoreceptors in the renal tubule

(macula densa, responding to an alternation in lu-

minal sodium and chloride ions concentration); (3)

volume receptors in the central nervous system (sen-

sitive to a change in sodium level in the cerebrospinal

fluid); and (4) peripheral tissue receptors (monitoring

the adequacy of tissue perfusion). The sensors feed

back signals to several mediating mechanisms, and

the kidneys are then ‘informed’ by renal nerves, hor-

mones, and physical factors to retain or excrete

sodium in the urine.

0023Factors that affect sodium reabsorption by the

renal tubule are listed in Table 3. The major mediat-

ing mechanisms are described below.

0024-Tubuloglomerular feedback The thick ascending

limb of the loop of Henle has a cortical segment that

closely relates to the afferent arteriole of the parent

glomerulus. The cells in this particular segment of the

renal tubule constitute the macula densa. The macula

densa, the corresponding afferent arteriole, and the

nearby extraglomerular mesangium are collectively

called the juxtaglomerular apparatus (Figure 3).

Changes in the delivery and composition of the fluid

flowing past the macula densa elicit changes in

glomerular filtration of the same nephron via the inter-

action of angiotensin II and nitric oxide. For instance,

an increase in the delivery of fluid to the macula densa

or a low sodium and chloride concentration in the

fluid will stimulate the juxtaglomerular apparatus.

The renin–angiotensin system is then activated to

reduce urinary sodium excretion.

2.6%

43.1%

11.7%

11.2%

29.0%

Extracellular

compartment

97.6 %

Intracellular

compartment

2.4 %

Transcellular

water

Bone matrix

Dense connective

tissue

Interstitium

Plasma

fig0004 Figure 4 Distribution of body sodium, expressed as a percent-

age of total body sodium content.

ELECTROLYTES/Water–Electrolyte Balance 2043

0025 -Renin–angiotensin system and aldosterone When

there is sodium depletion or a reduction in kidney

perfusion (for instance, secondary to a low ECF

volume), the juxtaglomerular apparatus releases an

enzyme, called renin, in the circulation. Renin then

acts on angiotensinogen to release angiotensin I. The

latter is converted to angiotensin II under the action

of the angiotensin-converting enzyme. Angiotensin II

stimulates the release of aldosterone, a hormone

produced by zona glomerulosa cells of the adrenal

cortex.

0026 Angiotensin II reduces urinary sodium excretion by

constricting the glomerular arterioles and decreasing

the volume of glomerular filtrate, by enhancing

sodium reabsorption at the proximal convoluted

tubule, and by increasing the responsiveness of tubu-

loglomerular feedback to a given concentration of

sodium and chloride ions at the macula densa. Aldos-

terone enhances sodium reabsorption by opening up

the specific sodium channels at the collecting ducts,

and by stimulating the action and synthesis of Na

–

–ATPase pumps at the basolateral membrane of

renal tubular cells.

0027-Sympathetic nervous system The kidneys receive a

rich supply of sympathetic nerves. There is evidence

that sodium and volume depletion activate renal

sympathetic nerves. The kidneys then conserve

sodium by constricting the glomerular arterioles, by

increasing sodium reabsorption at the proximal con-

voluted tubules, by increasing renin release from jux-

taglomerular apparatus, and by interacting with AVP

and atrial natriuretic peptide (ANP).

0028-Atrial natriuretic peptide Atrial natriuretic peptide

is a peptide hormone and is synthesized by atrial

myocytes in cardiac atria. When the ECF volume is

expanded, the atrial wall distends, and ANP is re-

leased. ANP enhances sodium excretion by inhibiting

sodium reabsorption at the collecting duct.

Response to Dietary Sodium Intake

0029Although the relative importance of the different

regulatory mechanisms is not well established, many

studies suggest that the renin–angiotensin system,

aldosterone, and the sympathetic nervous system

appear to be more important in conserving sodium

tbl0003 Table 3 Tubular sodium absorption

Sodiumreabsorption pathways

Renal tubule Amount of

reabsorbed

sodium (%)

Paracellular

pathways

Luminal transporters Factorsthat stimulateluminal

transporter to enhance sodium

reabsorption

Factors that inhibit luminal

transporter to decrease

sodium reabsorption

Proximal convoluted tubule 60–70% Presence Sodium–hydrogen

ion exchanger

a-Adrenergic agonist

Dopamine

Angiotensin II

Parathyroid hormone

Thyroid hormone

Sodium–amino

acids/glucose/

phosphate

cotransporter

Loop of Henle (thick

ascending limb)

20–25% Presence Sodium-2 chloride–

potassium ion

cotransporter

Arginine vasopressin Loop diuretics

Prostaglandin E

Cytochrome P450

metabolites of

arachidonic acid

Distal convoluted tubule 10% Absence Sodium–chloride

ion cotransporter

Aldosterone Thiazide diuretics

Angiotensin II

Sympathetic nerves

Collecting duct 5% Absence Sodium channel Aldosterone

Potassium-sparing

diuretics

Arginine vasopressin

Atrial natriuretic

peptide

Bradykinin

-Adrenergic

agonists

Atrial natriuretic

peptide

Prostaglandin E

Factors affecting the sodium–hydrogen ion exchanger.

Factors affecting the sodium channel at the cortical collecting duct.

Factors affecting the sodium channel at the medullary collecting duct.

2044 ELECTROLYTES/Water–Electrolyte Balance

for people with a low sodium intake, and the tubulo-

glomerular feedback seems to be more important in

excreting excessive sodium for people with a very

high sodium intake.

Potassium Balance

Potassium Content in the Body

0030 The total body potassium content is dependent on

sex, age, and, most importantly, muscle mass (which

contains 60–75% of total body potassium), and is

approximately 40–45, and 50–55 mmol per kilogram

of body weight for normal adult women and men,

respectively. These values decrease with age and are

20% less in the elderly because of a decrease in

muscle mass.

0031 About 90% of the body’s potassium is in the ICF.

Only 0.4% of the body’s potassium is distributed in

the vascular space of the ECF (Figure 6).

0032Potassium is the major cation in the ICF, and the

intracellular potassium concentration is approxi-

mately 150 mmol l

1

. In the ECF, however, the

plasma potassium level normally ranges from only

3.5 to 5.0 mmol l

1

. The intracellular-to-extracellular

potassium concentration ratio is the most important

determinant of the resting membrane potential of

neuromuscular tissue. Disturbances in this ratio will

predispose patients to several clinical disorders, such

as cardiac arrhythmia and neuromuscular problems.

Factors that Maintain the Potassium Distribution

Between ICF and ECF

0033Potassium leaks passively from the cell to the ECF

space through the ion-selective potassium channels

in the cell membrane. A high intracellular potassium

concentration is maintained by Na

–K

–ATPase

pumps that actively transport potassium molecules

back into the cells. Factors that alter the activity

of Na

–K

–ATPase pumps and ion-selective potas-

sium channels affect the transcellular potassium

Sodium

exchanger

Sodium

co-transporter

Specific sodium

channel

Paracellular

pathway

Lumen

or H

Other

solutes

Renal

tubular

cells

−K

−

ATPase

pump

−K

−

ATPase

pump

−K

−

ATPase

pump

Peritubular

capillary

Basolateral

membrane

3Na

fig0005 Figure 5 Renal transport of sodium. K

, potassium ion; H

, hydrogen ion; Na

, sodium ion; Na

–K

–ATPase pump, sodium–

potassium–adenosine triphosphatase pump. The sodium exchanger moves Na

into the cell in exchange for another cation (e.g., K

and H

), sodium cotransporter couples sodium entry with the entry of other solutes (e.g., amino acids, glucose, phosphate, K

and

chloride ion), and the Na

–K

–ATPase pump pumps out three Na

and transports in two K

ELECTROLYTES/Water–Electrolyte Balance 2045

distribution, resulting in hypo- or hyperkalemia with-

out any change in the total body potassium content.

These factors are listed in Table 4.

Potassium Intake and Excretion

0034 Potassium is present in all protein-containing foods,

particularly meats. Each gram of dietary protein con-

tains approximately 1 mmol of potassium. Hence,

potassium intake is directly related to protein intake.

The average Western diet provides 60–100 mmol

of potassium each day. In the steady state, about

80–95% of the daily potassium intake is excreted in

urine, 5–20% is excreted in the stools (mainly by the

colon), and less than 5% is eliminated in sweat.

However, in renal failure (with a glomerular filtration

rate of less than 20 ml min

1

) or diarrhea, potassium

loss from the gastrointestinal tract can be significant.

Moreover, potassium loss in sweat may be important

if perspiration is excessive.

Kidneys and Potassium Balance

0035About 720 mmol of potassium is filtered through the

glomeruli each day. Both potassium reabsorption

and secretion occurs in renal tubules. The majority

of the filtered potassium (66–75%) is reabsorbed

passively at the proximal convoluted tubules and

actively (via the sodium-2 chloride–potassium ion

cotransporter) in the ascending limbs of the loops

of Henle so that only 5–10% of the filtered potas-

sium remains in the early distal convoluted tubules.

Fine regulation of potassium excretion occurs at the

distal nephron. The collecting duct is the major site

of potassium secretion. Under the effect of Na

–K

–

ATPase pumps at the basolateral membrane of the

tubular cell (resulting in a high intracellular potas-

sium concentration) and the effect of sodium absorp-

tion via the sodium channels at the luminal

membrane (resulting in a negative electrical gradient

in the lumen), an electrochemical gradient is set up to

promote potassium secretion via the potassium se-

lective channels on the luminal surface of the princi-

pal cells of the collecting duct. Factors that modify

tbl0004 Table 4 Factors that regulate the transcellular potassium

distribution

Movement of potassium

Acid^base status

Acidosis by mineral acid (e.g.,

hydrochloric acid)

ICF !ECF

Acidosis by organic acid (e.g., lactic

acid, b-hydroxybutyric acid,

methylmalonic acid)

No effect

Alkalosis ECF !ICF

Insulin ECF !ICF

Glucagon ICF !ECF

-Adrenergic agonist ECF !ICF

a-Adrenergic agonist ICF !ECF

Aldosterone ? ECF !ICF

Hyperosmolality (e.g., mannitol,

hyperglycemia)

ICF !ECF

Exercise ICF !ECF

Transcellular water, 1%

Dense connective tissue, 0.4%

Interstitium, 1%

Plasma, 0.4%

Bone matrix, 7.6%

Extracellular

compartment

10.4%

Intracellular

compartment

89.6%

fig0006 Figure 6 Distribution of body potassium, expressed as a percentage of total body potassium content.

2046 ELECTROLYTES/Water–Electrolyte Balance