· To define the
concepts: Dehydration, hyponatraemia, intracellular fluid volume (ICV),
extracellular fluid volume (ECV), interstitial fluid (ISF), overhydration, oxidation water, radioactivity, specific
activity, and total body water.
· To describe the
daily water balance, the K+- and Na+-balance, sweat
secretion, the ionic composition in blood plasma, the water content of fat-
and muscle- tissue and the daily water transfer across the gastro-intestinal
mucosa. To describe the osmotic pressure in the body fluids, the measurement
of fluid compartments by indicator dilution, the measurement of total body-K+ and -Na+ and
the related dynamic pools.
· To draw models of
the body fluid compartments.
· To explain the
influence of age, sex and weight on the size of the total body water and its
phases. To explain disorders with increased or reduced extracellular fluid
volume and shock.
· To apply and use the above concepts in problem solving and in case histories.
· The law of
conservation of matter states that mass or energy can neither be created nor
destroyed (the principle of mass balance). The principle is here used to
measure physiological fluid compartments and the body content of ions.
· Concentration: The concentration of a solute is the amount of solute in a given fluid volume.
· Dehydration is a clinical condition with an abnormal reduction of one or more of the major
fluid compartments (ie, total body water with shrinkage of blood volume or
· Dextrans are polysaccharides of high molecular weight.
· Intracellular fluid
volume (ICV) refers to the volume of fluid
inside all cells. This volume normally contains 26-28 litre (l) out of the
total 42 l of water in a 70-kg person. - One litre of water equals one kg of
· Extracellular fluid
volume (ECV) refers to the interstitial and the plasma volume. The ECV contains the
remaining water (14-16 kg) with most of the water in tissue fluid (ISF) and
about 3 kg of water in plasma. - Interstitial fluid (ISF) is the tissue fluid
between the cells in the extravascular space.
· Hyperkalaemia refers to a clinical condition with plasma-[K+] above 5 mM (mmol/l of plasma).
· Hypokalaemia refers to a clinical condition with plasma-[K+] below 3.5 mM.
· Hypernatraemia refers to a clinical condition with plasma-[Na+] above 145 mM.
· Hyponatraemia refers
to a clinical condition with plasma-[Na+] below 135 mM.
· Oedema refers to a clinical condition with an abnormal accumulation of tissue fluid
or interstitial fluid.
· Osmolality is a measure of the osmotic active particles in one kg of water.
Plasma-osmolality is given in Osmol per kg of water. Water occupies 93-94% of
plasma in healthy persons. Plasma osmolality is normally maintained constant
by the antidiuretic hormone feedback system.
· Overhydration refers to a clinical condition with an abnormal increase in total body water
resulting in an increased ECV and thus salt accumulation.
· Oxidation water or metabolic water (oxidative phosphorylation) refers to the daily water production by
combustion of food - normally 300-400 g of water daily in an adult.
· Radioactivity is
measured as the number of radioactive disintegrations per s (in Becquerel or Bq per l). One disintegration per s equals one Bq.
· Total body water is
destributed between two compartments separated by the cell membrane: The
intracellular and the extracellular fluid.
This paragraph deals with 1. The three major fluid compartments, 2. Water
balance, 3. Body potassium, 4. Body sodium, 5. The indicator dilution
principle, 6. The
renin-angiotensin-aldosterone cascade, 7. Output
contol, 8. Regulation of
renal water excretion, and 9. Regulation of renal sodium
first about the nephron (paragraph 1 of Chapter
1. The three major fluid compartments
The three major body fluid compartments are
the intracellular fluid volume (ICV), the interstitial fluid volume (ISV) and
the vascular space (Chapter 1, Fig.1-4). Water
permeable membranes separate the three compartments, so that they contain
almost the same number of osmotically active particles per kg. The three
compartments have the same concentration expressed as mOsmol per kg of water
or the same freeze-point depression. They are said to be isosmolal, because they have the same osmolality.
The so-called lean body mass, which means a body stripped of fat, contains 0.69
parts of water (69%) of the total body weight in all persons. - Such high
values are observed in the newborn and in extremely fit athletes with minimal
body fat. Babies have a tenfold higher water turnover per kg of body weight
than adults do.
As an average females have a low body water
percentage compared to males. Such differences show sex dependency, but the important factor is the relative content of body fat, since fat tissue contains significantly less water (only 10%)
than muscle and other tissues (70%). This is why the relative water content
depends upon the relative fat content.
The average for most healthy persons is 60%
of the body weight. Sedentary, overweight persons contain only 50-55 % water
dependent on the body fat content.
The relative content of body fat rises with increasing age and body weight, and the relative
mass of muscle tissue becomes less. Consequently, the body water fraction
falls with increasing body weight and age. Aging implies loss of cells, but
the ECV is remarkably constant through life and under disease conditions.
Each body (weight 70 kg) contains 4 mol of
both sodium and potassium (ie, the total ion pool). A minor fraction of the
potassium is radioactive. The calcium and magnesium content is 25 and 1 mol,
In the renal tubule cells the epithelium is
a single layer of cells, joined by junctional complexes near their luminal
border (Fig. 25-7). Solutes can traverse the epithelium through transcellular
or paracellular pathways. Virtually every cell membrane in the body contains
the Na+- K+-pump, which maintains the low intracellular Na+-concentration and develops the
negative, intracellular voltage. In the renal tubule cells the Na+-
K+-pump, is located in the basolateral membrane. Read more about
the nephron in Chapter 25 and about hormonal control later in paragraph 8 and 11 of this Chapter.
Unfortunately, the simple laws of dilute
solutions are unprecise at physiological concentrations. Rough estimates are
based on the assumptions that extracellular sodium is associated with
monovalent anions and that deviations in osmolality are twice the deviation in
plasma sodium concentration.
ICV: The dominating intracellular solute is potassium (K+), balanced by
phosphate and anionic protein, whilst the dominating extracellular solute is
NaCl. All compartments have almost the same osmolality 300 mOsmol* kg-1 of water. The thin cell membrane - or the endothelial barrier between ISF and
plasma in the vascular phase - cannot carry any important hydrostatic
gradient. Water passes freely between the extra- and intra-cellular
compartment, as osmotic forces govern its distribution and the membranes are
24-1: The daily water transfer across the gastrointestinal barrier in a
healthy standard person.
ICV comprises 26-28 kg out of the total 42-kg of water in a 70‑kg person
ECV: The ECV compartment comprises the remaining water (14-16 kg) with most of the
water in tissue fluid (interstitial
fluid or ISF) and 3 kg of water
in plasma (Chapter 1, Fig. 1-4). The size of the ECV compartment is
proportional to the total body Na+. Changes in plasma osmolality
indicate problems in water balance.
A [Na+] in ECV of 150 mmol per kg
of plasma water corresponds to a total osmolality of 300 mOsmol per kg.
Alterations in plasma-[Na+]
(osmolality) will be followed by similar changes of the ECV osmolality,
because the permeability of of the capillary barrier for Na+ and
water is almost equal.
The daily water transfer across the
gastrointestinal tract amounts to approximately 9 l in each direction (Fig.
2. Water balance
A healthy person on a mixed diet in a
temperate climate receives 1000 ml with the food and drinks 1200 ml daily.
Balance is maintained as long as the water loss is the same (Fig. 24-2).
24-2: The daily water balance in a 70-kg healthy person on a mixed diet. The
apparent imbalance between input (2200 ml) and output (2500 ml) is covered by
300 ml of metabolic water.
Water is lost in the urine (1500 ml), in the
stools (100 ml), in sweat and evaporation from the respiratory tract (900 ml)
as a typical example.
The total loss of water is 2500 ml, and this
corresponds perfectly to the intake plus a normal production of 300 ml of metabolic
water per 24 hours (Fig. 24-2).
3. Body potassium
daily dietary intake of potassium varies with the amount of fruit and
vegetables consumed (75-150 mmol K+daily).
More than 90% of the body potassium is
located intracellularly. Only a few percent of the K+ in the body
pool are found outside the cells and subject to control (Fig.
24-3). The main
renal K+-reabsorption is passive and paracellular through tight
junctions of the proximal tubules. Moreover K+-excretion can
vary over a wide range from almost complete reabsorption of filtered K+ to urinary excretion rates in excess of filtered load (ie, net secretion of K+).
in the cell membrane, maintains the high intracellular [K+] and the low intracellular [Na+].
The energy of the terminal phosphate bond of ATP is used to actively extrude
Na+ and pump K+ into the cell. The membrane also
contains many K+ - and Cl- -channels, through which the
two ions leak out of the cell. In
myocardial cells, as in skeletal muscle and nerve cells, K+ plays a major role in determining the resting membrane potential
(RMP), and K+ is important for optimal operation of enzymatic
normal conditions, the RMP of the myocardial cell is determined by the dynamic
balance between the membrane conductance to K+ and to Na+.
As [K+]out is reduced during hypokalaemia, the membrane depolarises causing
voltage-dependent inactivation of K+-channels and activation of Na+-channels,
allowing Na+ to make a proportionally larger contribution to the
24-3: The total body K+-pool in a healthy person comprises 4000
mmol with more than 90% intracellularly. The normal ECG and the ECG of a
patient with hyperkalaemia is shown to the right.
K+ -permeability is
around 50 times larger than the Na+ -permeability, so the RMP of
normal myocardial cells (typically: -90 mV) almost equals the equilibrium
potential for K+ (-94 mV).
excretion of K+ by overload is almost
entirely determined by the extent of
distal tubular secretion in the principal
cells. Any rise in serum [K+] immediately results in a marked
rise in K+-secretion. This transport mechanism is controlled by aldosterone and by K+. Aldosterone stimulates the secretion of K+ and H+ by the principal cells of the renal
distal tubules and collecting ducts (Fig.
25-11). This is why chronic acidosis
decreases and chronic alkalosis increases K+-secretion. –
Actually, acute acidosis may reduce K+-secretion.
Of the consumed K+, 75-150 mmol is daily absorbed in the intestine. Since 90% is excreted
renally in a healthy person, there must be a minimum in a typical volume of
1500 ml of daily urine with a concentration of (75/1.5) = 50 mM. Normal
urinary [K+] is at least 30 mM. A high urinary [K+] is indicative of a high total body K+ or a high intake of K+.
normal excretion fraction (Chapter
25) for K+ is 0.10 (10% or 90 mmol of the 900 mmol in the daily
filtrate) corresponding to the daily intake (Fig.
24-4). A K+ -poor
diet leads to hypokalaemia with less than 20 mmol K+ in the daily
urine. A K+ -rich diet triggers a large secretion and a high
excretion in the urine (Box 25-1). A low urinary [K+] is indicative of a low total body K+ or of extracellular acidosis with
transfer of K+ from the
cells in exchange of H+. A low [K+] in the distal tubule cells reduces the K+ -excretion.The normal plasma-[K+] level is dependent upon the
exchange with the cells, the renal excretion rate, and the extrarenal losses
through the gastrointestinal tract or through sweat.
of total and exchangeable body potassium
Our natural body potassium is 39K,
but we also contain traces of naturally occurring radioactivity (0.00012 or
0.012% is 40K with a half-life of 1.3×109 years). When using this natural tracer, injection of radioactive tracer is
The person to be examined is placed in a
sensitive whole body counter, and the total
activity of the tracer 40K in the body (S Bq) is measured.
activity (SA) is the concentration of
radioactive tracer in a fluid volume divided by the concentration of naturally occurring, non-radioactive mother-substance. The concentration of mother-substance is
traditionally measured in mmol per l (mM). SA is equal to radioactivity (A) per non-radioactive mass unit, m (ie, A/m in
Bq/mol). Following even distribution, the SA for a certain substance must be
the same all over the body. SA is preferably measured in plasma (with
scintillation counters or similar equipment).
activity (SA) is here the number of Bq 40K
per mol of mother substance (39K) in the whole body. We can
calculate all 39K or total
body potassium: S/SA mol per whole body - when SA is known to be 0.012% or
a fraction of 0.00012. The total body
potassium of a healthy person is 4000 mmol. The SA of 40K
implies a 40K/39K ratio of 0.48 mmol/4000 mmol
ion pool in our body is the dynamic part of the total specific ion
content. The remaining content is fixed as insoluble salts in the bones. The
dynamic character implies the use of a dilution principle to measure such a
In order to measure the exchangeable body
potassium pool, a radioactive tracer is injected, such as 42K with
a physical half-life of 12 hours (12.4 hours) and urine is collected. The
first urine sample is from the first 12 hours, and the second sample is
covering 12 - 24 hours. The total
tracer dose given must be adjusted for by the loss of tracer in the urine and
by the radioactive decay during the first 12 hours mixing period. The two
urine samples obtained are examined for tracer and for natural potassium. The
tracer is assumed to distribute just as natural potassium after 12 - 24 hours.
When the tracer is distributed evenly in the exchangeable body potassium, its
SA must be the same in urine, plasma or elsewhere in the body. The
exchangeable body potassium is calculated by Eq. 24-2 .
The specific activity for the tracer (SA Bq
per mol) is known from the plasma measurements. In this way we measure the
exchangeable body potassium. The normal values are 41 mmol 39K per kg body weight for females, and 46
mmol per kg for males.
4. Body sodium (23Na)
The exchangeable body sodium is easy to measure using the dilution principle and a minimum
Our natural non-radioactive body sodium is 23Na.
We administer the radioactive tracer, 24Na, with a physical
half-life of 15 hours. We have to use a total period of 30 hours to secure
even distribution in the ECV.
The total tracer dose given, must be
adjusted for by the loss of tracer in the urine, and the radioactive decay of 24Na
(see the decay law in Chapter 1). The exchangeable body sodium is calculated
by Eq. 24-2.
We know the specific activity for the tracer
(SA Bq/mol) from the plasma measurements; therefore calculation of the
exchangeable body 23Na is easy.
The normal value for exchangeable body
sodium is 40 mmol/kg of body weight. In a patient with a body weight of 75 kg
the exchangeable sodium is (75 × 40) = 3000 mmol. The
non-exchangeable sodium is fixed in the bones.
body sodium is measured following discrete radiation with a method called neutron
activation analysis. The whole body of the patient is exposed to radiation
with neutrons. A small fraction of the natural 23Na now becomes
radioactive sodium (24Na) by uptake of an extra neutron.
A sensitive whole body counter records the radiation from 24Na. Now
we can calculate the total body sodium.
Normally, the total body sodium is 1000 mmol
larger than the exchangeable sodium due to the fixed sodium content of the bones (1000 + 3000 mmol =
4000 mmol 23Na).
24-4: Body fluid electrolytes. Water permeable membranes separate the three
compartments, which contain almost the same number of osmotically active
particles per kg.
The sum columns of
electrolyte equivalents in muscle cells are essentially higher than the
extracellular sum columns of equivalents, because cells contain proteins, Ca2+,
Mg2+ and other molecules with several charges per particle (Fig.
The above columns show the ionic composition
per kg of water, so we have 150 mmol of Na per kg of plasma water. Normally,
one litre of plasma has a weight of 1.040 kg and contains 10% of dry material.
Consequently, one litre of plasma contains 0.940 l of water, and the rest
consists of plasma proteins and small ions. Thus the fraction of water in
plasma (Fwater) is typically 0.94.
5. The indicator dilution principle
conservation is always the underlying principle.
The amount of indicator n mol distributes in V litres of distribution
We measure the concentration Cp in mM, following even distribution, and calculate V:
V = n/Cp.
Errors: Uneven distribution
of indicator introduces a systematic error. - A non-representative
concentration of indicator in the plasma makes it insufficient to correct for
plasma proteins alone. - Loss of indicator to other compartments is
inevitable. - Elimination or synthesis of indicator in the body occurs as
frequent errors. - The indicator may be toxic or in other ways change the size of the compartment to be measured.
body water, ECV, plasma volume, and the elimination rate constant are measured
5 a. Total body water
Total water is measured by the help of the
dilution principle. Tritium marked water is a good tracer. The equilibrium period is 3-6 hours. n mol of indicator
divided by Cp mmol of indicator per l is equal to the distribution
volume (V) for the indicator.
adolescents and children have normal values around 60% of the body weight
assuming one l of water to be equal to one kg. Adult males and females with a
sedentary life style and larger fat fractions contain only 50% of water.
is measured by administration of a priming
dose of inulin intravenously. Then inulin is infused to maintain a steady
state with constancy of the plasma concentration of inulin (Cp).
The patient then urinates, and the infusion
is stopped with collection of a plasma sample. For the next 10 hours the
patient collects his urine, which makes it possible to measure all the body
inulin present at the end of the infusion (n mol) assuming all inulin
Dividing n with Cp gives the
volume of distribution (V) after correcting for the difference in protein
concentration between plasma and ISF (Eq. 24-1).
Chromium-ethylene-diamine-tetra-acetate (51Cr-EDTA) is a chelate with a
structure that cannot enter into cells. The chelate molecule contains
radioactive Cr, making it easy to measure. The 51Cr-EDTA
distributes and eliminates itself in the extracellular fluid volume (ECV) just
as inulin and is therefore used to measure ECV. – For clearance
measurements, we inject a single dose intravenously, and draw blood samples
every hour for 5 hours. The clearance of 51Cr-EDTA is independent
of Cp and a good estimate of GFR just like the inulin
clearance. Since the indicator is cleared from the ECV only, it is
possible to measure its size. Such methods - including renal lithium
reabsorption - are important during renal function studies. Normal values for
ECV are approximately 20% of the body weight or 14-17 kg.
ill patients with debilitating diseases often maintain their ECV remarkably
well in spite of marked reductions in the cell mass of their body.
5 c. The plasma volume
Also here, the dilution principle is used.
The indicator for plasma volume can be Evans Blue (T1824) that
binds to circulating plasma albumin. A small dose of albumin, marked with
radioactive iodine, is also a good indicator (iodine 131 has a
physical half-life of 8 days).
The indicator concentration in plasma (Cp)
is measured every 10-min for an hour after the administration, and the log of
Cp is plotted with time. Extrapolation to the time zero determines
the maximum concentration of indicator in plasma. This corrects for the
biological loss, while the indicator distributes itself in the plasma phase.
The tracer dose divided by Cp at time zero provides us with the intravascular plasma volume. Normal values for the plasma volume are
close to 5% of the body weight.
In diabetics and hypertensive patients the
tracer is lost more readily through their leaky capillaries to the
interstitial fluid than in healthy persons (increased transcapillary escape).
6. The renin-angiotensin-aldosterone cascade
densa is described in paragraph 9 of Chapter
most likely intrarenal trigger of the renin-angiotensin-aldosterone cascade is
the falling NaCl concentration of
the reduced fluid flow at the macula densa in the distal renal tubules (Fig.
The NaCl concentration at the macula densa
falls, when we lose extracellular fluid, move into the upright position and
when the blood pressure falls.
Renin is a proteinase that separates the
decapeptide, angiotensin I, from the liver globulin, angiotensinogen.
When angiotensin I passes the lungs or the
kidneys, a dipeptide is separated from the decapeptide by angiotensin
converting enzyme (ACE). This process produces the octapeptide, angiotensin
II has multiple actions that
minimize renal fluid and sodium losses and maintain arterial blood pressure.
1. Angiotensin II stimulates the aldosterone secretion by the
adrenal cortex, and through this hormone it stimulates Na+-reabsorption
and K+-(H+)-secretion in the distal tubules (Fig.
- Angiotensin II is in itself a potent stimulator of tubular Na+-reabsorption.
2. Angiotensin II inhibits further renin release by negative
3. Angiotensin II constricts arterioles all over the body
including a strong constriction of the efferent and to some extent also the afferent arteriole.
Hereby, the renal bloodflow (RBF) and to a lesser extent the glomerular
filtration rate (GFR) is reduced.
4. Angiotensin II inhibits the absolute proximal tubular
reabsorption – contributing to the reduction of GFR.
5. Angiotensin II enhances sympathetic nervous activity.
24-5: The renin-angiotensin-aldosterone cascade.
Sympathetic stimulation of the renal nerves
stimulates renin secretion directly via b-adrenergic
receptors on the JG cells just as falling blood pressure in the preglomerular
arterioles. - b-blocking
drugs and angiotensin II inhibit the renin secretion (Fig 24-5).
The combined effects from the whole renin
cascade is extracellular fluid homeostasis.
contrast, exposure to stress and painful stimuli triggers the combined
sympatho-adrenergic system with release of catecholamines, gluco- and
mineralo-corticoids, and ACTH from the hypophysis. ACTH stimulates further the
secretion of the glucocorticoid, cortisol, from the adrenal cortex.
The body uses output control, when it is overloaded with water or with sodium.The
most important osmotically active solute in ECV is NaCl, because it only
passes into cells in small amounts. Urea, glucose and other molecules with
modest concentration gradients are without importance, because they distribute
almost evenly in the fluid compartments. Healthy persons use two primary control
systems: 1) The osmolality (osmol per kg of water) or ion concentration controls our elimination of water. 2) The change of blood volume (ECV) or
pressure controls sodium excretion - not osmolality.Only when the arterial blood pressure falls drastically the body will drop its protection of normal concentration. In such a disease
state large amounts of ADH molecules are released in an attempt to improve the
volume and blood pressure.
8. Regulation of renal water excretion The primary control of the renal water
excretion is osmolality control (Fig.
24-6). Since 2/3 of the body water normally is located within the cells, this
is also an intracellular volume control.Following water deprivation even an increase
in plasma osmolality of only one per cent stimulates both the hypothalamic
osmoreceptors and similar (angiotensin-II-sensitive) thirst receptors. Thirst
may increase the water intake of the individual and thus increase the ECV,
with negative feedback to the thirst receptors. Activation
of the hypothalamic osmoreceptors and thirst receptors increases the
hypothalamic neurosecretion to the neurohypophysis and releases antidiuretic
hormone (ADH or vasopressin). Hyperosmolality elicits a linear increase in
plasma ADH, which causes water retention (Fig. 24-6) until isosmolality is
increases the reabsorption of water from the fluid in the renal cortical and
medullary collecting ducts. ADH binds to receptors on the basolateral surface of the tubule cells, where they liberate and
accumulate cAMP. This messenger passes through intermediary steps across the
cell to the luminal membrane, where the number of water channels (aquaporin 2)
are increased. The luminal cell membrane is thus rendered water-permeable,
which increases the renal water retention. The increased water reabsorption
leads to a small, concentrated urine volume (antidiuresis), and a net gain of
water that returns ECF osmolality towards normal. Initially, osmolality
control overrides blood volume control.
Fig. 24-6: Primary osmolality control of the renal
water excretion. ADH
and thirst systems maintain osmolality and ICV within narrow limits.
Water overload decreases ECF osmolality and has the reverse effect, because the hypothalamic
osmoreceptors suppress the ADH release, and the renal water excretion is
increased already after 30 min (Fig. 24-6). When a person rapidly drinks one
litre of water, the intestine absorbs water. Ions diffuse into the intestinal
lumen and the blood osmolality falls causing a block of the ADH secretion (Fig.
water is distributed evenly in all three body fluid compartments – just like
intravenous infusion of one litre of 5% glucose in water. Intake
of one l of isotonic saline implies ECV expansion, without dilution of body
fluids. This expansion will not increase the urine volume much, so the
increased ECV can be sustained for many hours. An intravenous infusion of one
l of large dextran molecules (macrodex) stays mainly in the vascular space.
9. Regulation of renal sodium excretion
healthy persons, changes of blood volume (or ECV) or blood pressure control sodium excretion (Fig.
24-7). The dominating cation of
the ECV is Na+ . The sodium intake is balanced by the sodium
excretion as long as the thirst and other homeostatic systems are functional. During
conditions where sodium intake exceeds renal sodium excretion, total body
sodium and ECV increase. Conversely, total body sodium and ECV decrease, when
sodium intake is lower than renal sodium excretion. This is because volume-pressor-receptors detect the size of the
circulating blood volume (ECV) or pressure, and effector mechanisms adjust the
renal sodium excretion accordingly.
volume-pressor-receptors are widely distributed. Low-pressure
receptors are found in the
pulmonary vessels and in the atria. An increased blood volume can also
increase the arterial blood pressure and stimulate the well-known high-pressure
baroreceptors in the carotid sinus and the aortic arch. Increased arterial
pressure reduces sympathetic tone – also in the kidneys, whereas decreasing
arterial pressure enhances sympathetic tone and renal salt retention. Arterial
pressure receptors are also located in the renal preglomerular arterioles. Both stimuli in Fig. 24-7 release renin
from macula densa, whereby angiotensin II and aldosterone is secreted (both
sodium retaining hormones).
decrease in circulating blood volume leads to a decrease in NaCl delivery to
the macula densa and release of the renin cascade. Conversely, an increase in
circulating blood volume with increased NaCl delivery to the macula densa
suppresses renin release and increases sodium excretion (Fig. 24-7).
Fig. 24-7: Primary blood volume-pressure control of
the renal Na+ -excretion. The effective circulating blood volume is
protected – also during shock (Na+ -retention) and during
Increased salt intake increases blood volume and leads to natriuresis, possibly augmented by release
of ANP (see below), nitric oxide and other factors. The excretion of Na+ depends
upon several effector mechanisms out of which three are classical: The first factor is the glomerular
filtration rate (GFR), which is responsible for the size of the filtered
flux of Na+ across the glomerular barrier in the kidneys. Renal
prostaglandins, generated in response to angiotensin II, are involved in
maintaining the filtered flux of Na+.
The second factor is the renin-angiotensin-aldosterone
cascade (Fig. 24-5).
The third factor consists of peptides with natriuretic
effects. The most well-known peptide is called atrial
natriuretic peptide (ANP) and originates from granules of the atrial
myocytes. A low circulating blood volume with low atrial pressure increases
renal sympathetic tone, reduces the stimulus of the low-pressure receptors in
the atrial wall and thus the ANP secretion. Hereby, the natriuresis is
reduced. - Renal natriuretic peptide or urodilatin from the distal tubule
cells is related to ANP. Urodilatin has been isolated from human urine and
contains four amino acids more than ANP. An
increase in effective circulating blood volume, increases atrial pressure,
reduces sympathetic tone and releases ANP and urodilatin leading to increased
main purpose of these mechanisms is to maintain
an effective circulating blood volume by an increase or a decrease of the
renal excretion of Na+. Initially, osmolality control is dominating. Finally, after a dangerous reduction in blood volume,
volume-pressure receptors override the hypothalamic osmoreceptors and
stimulate the ADH release and thirst. In the terminal phase, the body protects
effective circulating blood volume at the expense of ECF osmolality.
paragraph deals with 1. Dehydration, 2. Overhydration, 3.
Hyponatraemia, 4. Hypernatraemia, 5. Hypokalaemia, and 6.
Dehydration is an abnormal
reduction of the major fluid volumes (total body water with shrinkage of
ECV). When we lose more than 5% of the total body water it has clinical
consequences. The condition is life threatening if the patient loses 20 %.
and surgery with a period of water deprivation, imply a rise in ECF osmolality
and thus stimulation of both thirst and the hypothalamic osmoreceptors,
whereby ADH is released. - Symptoms and signs of
dehydration are thirst, dry mucous
membranes, and decreased skin elasticity or turgor due to loss of ISF.
of effective circulating blood volume implies a low blood pressure in both the
venous and the arterial system. Loss of more than one litre of ECV causes postural
hypotension with dizziness, confusion and cerebral failure. Empty veins
and cold skin characterise the peripheral venoconstriction. Finally, there is
extreme tachycardia, which turns into terminal bradycardia and an arterial
blood pressure that approach zero.
Loss of salt and water
frequently develops into hypo-osmolal
dehydration (Fig. 24-8). This is because the thirst forces the patient to
drink (salt free) water. Water dragged into the
cells further reduces the hyposmolal ECV (Fig. 24-8). The small ECV elicits a
hyperaldosteronism, which is called secondary,
because it is not initiated as primary hypercorticism in the adrenal cortex. A
precise compensation of the water loss results in pure
hyponatraemia, where water eventually is drawn from ECV into the cells.
The low [Na+] around the swelling cells reduces the potential gradient across the cell
membranes with increased neuromuscular irritability (muscular twitching) and
dehydration is a proportional loss of water and
solutes. There is no concentration gradient over the cell membranes, and the
loss is mainly from ECV (Fig. 24-8).
24-8: Dehydration (hyperosmolal, isosmolal and hyposmolal).
dehydration occurs in persons deprived of water.
The hyperosmolal ECV drags water from ICV and dehydrates the cells (Fig.
24-8). This is intracellular
The hyperosmolality liberates ADH to
restrict the water loss. The patient excretes a very small urine volume.
Persons deprived of water at sea may drink
seawater. Sea water is hypertonic saline and the victims die faster. When
hypertonic saline reaches the ECV it aggravates the intracellular dehydration
simultaneously with an extracellular overhydration. Intracellular dehydration
leads to respiratory arrest and death of thirst.
2. Overhydration Overhydration is an abnormal increase of total body
water - in particular ECV, and
thus salt accumulation. The increase in the interstitial fluid volume is
called oedema. Overhydration frequently occurs among patients in fluid therapy
(ie, overhydration of iatrogenous origin).
salt intake by mouth is compensated by increased salt excretion by normal
a large saline infusion (0.9% NaCl) will expand ECV and total body water
(isosmolal overhydration in Fig. 24-9). Inappropriately
large infusions of saline lead to iatrogenous hyperosmolal overhydration, if
they lose more water than salt (Fig. 24-9). Hyperosmolality drags water from the cells,
so that the patient develops intracellular
dehydration with hallucinations, loss of consciousness and eventually
respiratory arrest. The patient with hyposmolal overhydration is typically in fluid treatment and
develops muscle cramps and disorientation. The skin turgor is normal. A low
serum - [Na+] confirms the diagnosis. The water overload in ECV is
dragged into the cells in hyposmolal overhydration until osmolality balance
In the brain and the muscles this intracellular
overhydration causes headache, disorientation, increased spinal pressure,
coma and muscle cramps. Both hyposmolal and
hyperosmolal intracellular overhydration
conditions are characterised by cerebral symptoms and signs.
24-9: Overhydration (hyperosmolal, isosmolal, and hyposmolal).
renal failure with decreased GFR reduces the flux of filtered NaCl (first
factor) and thus the Na+ -excretion.
Oedema is a clinical condition where the
interstitial fluid volume (ISF) is abnormally large.
ISF is usually due to increased hydrostatic venous pressure (heart insufficiency), or a reduced colloid osmotic pressure (hypoproteinaemia) as predicted from Starlings
law for transcapillary transport.
protein synthesis (liver disease) and abnormal
protein loss with the urine (proteinuria) causes hypoproteinaemia. Thus
protein-losing kidneys are involved.
Capillary damage (allergy, burns,
inflammation etc) with increased capillary permeability causes local oedema.
– Obstruction to lymphatic drainage can also cause oedema (scarring after
radiation therapy, elephantiasis etc).
Cardiac insufficiency with increased venous pressure and oedema formation increases sympathetic tone
and thus releases the renin-angiotensin-aldosterone cascade (Fig. 24-5) causing Na+ -retention.
cirrhosis activates the cascade in a similar way
- possibly including the release of nitric oxide.
Hypoalbuminaemia reduces the colloid osmotic pressure of plasma, whereby water is distributed
from the vascular space to the ISF. The fall in effective circulatory volume
activates the renin cascade and leads to Na+ -retention.
NSAIDs can activate the renin-angiotensin-aldosterone cascade, and the increased aldosterone leads to Na+ -retention and overhydration.Angiotensin
antagonists and ACE-inhibitors are utilized clinically to block the effects of angiotensin II in
congestive heart failure, diabetes mellitus and hypertension.
Blockade of the
cascade reduces both preglomerular and postglomerular resistances.The supine position at bed rest
increases venous return. This implies an increased cardiac output (Starlings
law), a reduced ANF secretion from the atrial walls and a reduced
renin-angiotensin-aldosterone cascade. This is why bed rest is beneficial for
disorders with salt accumulation.
(ie, plasma-[Na+] below 135 mM) is associated with dehydration, overhydration or normohydration
(ie, a normal ECV and total body sodium content).
Hyponatraemia with reduced ECV (ie, salt-deficient hyponatraemia) is caused by a salt loss in excess
of the high water loss (ie, hyposmolal dehydration in Fig
24-10). This is seen
in any type of hypoadrenalism including the rare primary hypoadrenalism
Addison’s disease the entire adrenal cortex is destroyed by autoimmune
reactions (80%) or by malignancy or infection. All three types of hormones are insufficiently produced
(mineralocorticoids, glucocorticoids and sex hormones). The lack of
aldosterone leads to Na+ -excretion and K+-retention
with hyponatraemia combined with hyperkalaemia resulting in dehydration and
Hyponatraemia is developed in the following
way (Fig. 24-10):
1. The first step is the salt loss in excess of the water
2. Since the ECF-[Na+] is low, the ADH secretion is suppressed, and the water excretion is increased.
Hereby, both the ISF and the vascular spaces are reduced often by more than
3. This is an adequate stimulus for the volume-pressure
receptors, which override the osmoreceptors, whenever the effective
circulatory volume is threatened.
24-10: The three body fluid compartments in a patient with salt-deficient
The volume-pressure receptors stimulate both
thirst and the release of ADH. The effective circulating volume is protected
at the expense of osmolality! Still the blood pressure is falling, which
impairs cerebral perfusion, causing confusion, headache and coma.
The hyponatraemia implies a reduced resting
membrane potential and thus a low threshold for neuromuscular stimulation
resulting in muscle cramps.
The large renal loss is seen with osmotic diuresis (hyperglycaemia and uraemia), excessive use of
diuretics, renal tubular reabsorption defects, adreno-cortical insufficiency
as aldosterone-antagonist-intoxication or other types of hypoaldosteronism.
The extra-renal loss is often large from excessive sweating, diarrhoea, haemorrhage, vomiting, loss
with ascites or bronchial secretion, and transudation from cutaneous defects.
Normal kidneys normally compensate extra-renal loss. The urinary excretion of
salt and water falls in response to volume depletion, so the urine is
concentrated - but with less than 10 mM Na+.
sweat is a hypotonic solution,
because Na+ is reabsorbed in the duct system. The [Na+]
can increase up to 80 mM with increasing sweat flow - due to the limited time for the aldosterone-controlled Na+-reabsorption.
salt intake by mouth or intravenously is required as a supplement to the
treatment directed at the primary cause.
plasma- [Na+] in a chronically salt-deficient patient suggests a high aldosterone secretion
from the adrenal zona glomerulosa. Further administration of aldosterone
therefore may not have any effect.
Hyponatraemia with increased ECV (water-excess
hyponatraemia) is often caused by cardiac, hepatic, and renal insufficiency or
by hypoalbuminaemia - see hyposmolal overhydration (Fig.
Hyponatraemia with normal ECV is often caused by
stress (surgery, psychogenic polydipsia), abnormally high ADH release (in the
syndrome of inappropriate antidiuretic hormone secretion, and in vagal
neuropathy), increased sensitivity to ADH by drugs such as chlorpropamide and
tolbutamide, or by intake of ADH-like substances (oxytocin).
Pseudo-hyponatraemia is characterised by a
spuriously low plasma value measured conventionally in the total volume of
plasma, which includes an extra volume in cases with hyperlipidaemia or
hyperproteinaemia etc. Plasma osmolality or plasma-Na+ measured
with ion selective electrodes is the choise and the direct read value is
normal. This is because Na+ is confined to the aqueous phase.
of artefactual hyponatraemia (taking blood from an extremity into which
isotonic glucose is infused) is also unnecessary.
The normal plasma-[Na+] is 135-145 mM, and values above 170
mM are rare. Excessive infusion of saline (0.9% NaCl or 154 mM) can lead to
hypernatraemia. Such alarmingly high levels create an emergency situation,
where glucose infusion is indicated initially in order to reduce the high
level slowly. The increased plasma osmolality elicits a strong desire to
cause is sometimes water deficit due to pituitary diabetes insipidus, or to nephrogenic
diabetes insipidus, where ingestion of nephrotoxic drugs have made the renal
collecting ducts resistant to ADH. – Osmotic diuresis also causes water
deficit with hypernatraemia just as excessive loss of water through the skin
Primary hyperaldosteronism (Conns disease) and all types of secondary hyperaldosteronism also lead to
hypernatraemia combined with hypokalaemia and enlarged blood volume.
failure and convulsions are alarming signs, but there are no specific symptoms
and signs of hypernatraemia.
polydipsia and thirst suggest diabetes. Diabetes mellitus is easy to diagnose,
and diabetes insipidus shows a low urinary osmolality. Pituitary diabetes
insipidus is treated with an analogue of ADH (desmopressin, with a low
normal potassium ion concentration in blood plasma is 3.5-5 mM. Hypokalaemia
is caused by renal or extra-renal K+ -loss or by restricted intake.
Long standing use of diuretics without KCl compensation is a
frequent cause of hypokalaemia.
Hyperaldosteronism (increased aldosterone
secretion) is another cause.
Vomit fluid only contains 5-10 mM of K+. Still, prolonged vomiting develops into
hypokalaemia, because the Na+-loss stimulates the aldosterone
secretion, which increases K+-excretion
in the kidneys.
Profuse diarrhoea causes marked hypokalaemia,
also because the diarrhoea fluid contains up to 50 mM of K+.
Hypokalaemia is seen in cardiac patients receiving digoxin treatment. Digoxin toxicity is imminent, because digoxin
firmly binds to myocardial cells in hypokalaemia. Treatment must be directed
towards the underlying cause. Infusion of potassium -rich fluid is dangerous,
because of the marginal distance to hyperkalaemia.The reduced extracellular K+ hyperpolarises the cell membrane (increases the negativity of the
voltage across the membrane). This reduces the excitability of neurons and muscle cells. Thus, hypokalaemia can result in muscle weakness and
paresis. Hypokalaemia is associated with an increased frequency of cardiac
arrhythmias with atrial and ventricular ectopic beats in particular in
patients with cardiac disease . - Hypokalaemia inhibits release of adrenaline,
aldosterone and insulin.
Acute hyperkalaemia (ie, plasma-[K+] above 5 mM) is a normal condition following severe exercise, and normal
kidneys easily eliminate K+ .
disease states the causes are insufficient renal excretion or increased release
from damaged body cells as during long lasting hunger, exercise or in severe
burns. A plasma- [K+] above 7 mM is life
threatening due to asystolic cardiac arrest. Long term intake of b-blocking
drugs, which inhibit the Na+-K+-pump, leads to
hyperkalaemia that is accentuated by exercise.
reduces the size of the resting membrane potential (reduces the negativity of
the voltage), whereby the threshold for firing is approached in neurons and
striated muscle cells. The increased excitability in hyperkalaemia results in
muscle contractions, cramps followed by muscle weakness. Hyperkalaemia leads
to decreased cardiac excitability, hypotension, bradycardia and eventual
asystole. The ECG is characterised by increased duration of the QRS-complexes and tented T-waves due to
abrupt Ca2+-influx, contraction, and abrupt Ca2+ -binding (Fig. 24-3). Cardiac arrest occurs as ventricular fibrillation (the
heart can never produce smooth tetanus) or as asystole.
is used to drive K+ back into the cells - either by insulin infusion or by
glucose infusion in order to release more insulin from the pancreatic islets.
Usually, a combined glucose-insulin drop is applied.
hormones (adrenaline, aldosterone) also stimulate the Na+-K+-pump
and thereby increase cellular K+ -influx
· The indicator
dilution method: The indicator n mmol
distributes in V litres of distribution volume. We measure the concentration
Cp in mM, following even distribution, and calculate the volume, V:
24-1: V = n/Cp. (litre = mmol/(mmol/l)
· When the tracer is radioactive potassium and thus
distributed evenly in the exchangeable potassium pool, its specific Activity (SA) must be the
same in urine, plasma or elsewhere in the pool.
body potassium =
(Injected - eliminated)/SA. (Mol = Bq/(Bq per mol)
We know the specific activity for the tracer
(SA Bq per mol) from the plasma measurements. In this way we measure the
exchangeable body potassium. The normal values are 41 mmol 39K per kg body weight for females, and 46
mmol per kg for males.
· The following concentrations are found in normal plasma:
[Na+] 135-145, [K+]
3.5-5, [Cl-] 96-106, [bicarbonate] 24, and total-[Ca2+]
· The concentration of low molecular ions in the ultrafiltrate is affected by the Donnan effect (normally 5% for monovalent ions), and by
the fractional content of water in plasma (0.94 normally):
Eq. 24-3: [Low
molecular ions] = Plasma conc. * Donnan factor/ 0.94.
= 141× 0.95/0.94
= 143 mmol/l of ultrafiltrate. Based on the Donnan effect alone, this result
is less than 141. The Donnan effect on monovalent cations is simply more than
compensated by the protein volume effect or fractional content of water in
[Cl-] = 103×1.05/0.94
= 115 mmol/l of ultrafiltrate. Based on the Donnan effect this result should
be greater than 103 and the protein volume effect contribute further. Such an
ultrafiltrate is present in the kidneys and in ISF.
· The extracellular fluid volume (ECV) can be measured if all inulin
molecules are collected in the urine over 10-15 hours after the inulin
Eq. 24-4: ECV = Amount of inulin excreted/(Cp/0.94).
The inulin distribution volume is more or less identical to
· Concentration of molecules in the filtrate are calculated
24-5: Cfiltr =
per l of ultrafiltrate).
This value depends upon the fractional
content of water in plasma (Fwater = 0.94 l of water per l of
plasma) and of the fraction of free, unbound molecules (Ffree). For
uncharged, free molecules like inulin Ffree is 1, and for
protein-bound molecules Ffree is lower than 1
of the following statements has True/False options:
A. Hyponatraemia with normal ECV is often caused by stress, abnormally
high ADH release, increased sensitivity to ADH by drugs, or by intake of
B. The total water
content of a healthy person is 60%, and an extremely obese adult contains
relatively more water.
C. Hyponatraemia is
defined as a plasma-[Na+] below 145 mM.
D. A plasma- [K+] above 4.5 mM is life-threatening.
E. An infusion of one l of 5% glucose is distributed evenly
into all three compartments just as pure water. An infusion of one l of saline
remains mainly in the ECV, whereas an infusion of one l of macrodex stays
mainly in the vascular space.
Case History A
healthy male with a body weight of 70 kg has a normal extracellular osmolality
(300 mOsmol kg-1), and a normal ICV/ECV of 28/14 kg or l of water.
day he is the victim of severe burns and he suffers a water loss of 2.5 l of
water (the salt loss is covered).
1. Calculate the
new ECV osmolality following the water loss.
Does this hyperosmolality have consequences?
3. Following total restitution of the water compartments the patient
undergoes surgery with skin grafts. During the long procedure he receives
sufficient water by glucose infusion, but he looses 900 mOsmol NaCl. Calculate
the new osmolality.
Is it dangerous for a healthy individual to lose 6 kg of water without
Is it dangerous for a healthy individual to lose 6 kg of water as an isosmolal
fluid from the ECV?
Case History B
female patient (age 22 years; weight 71 kg) is in hospital suspect of
potassium imbalance. She has taken diuretics for 2 years. She is tired and
sleepy; her legs are paretic. The ECG shows prolongation of the Q-T interval,
depression of the S-T segments and flattening of the T-waves. Her blood pH is
7.57 and the serum K+ -concentration is 2.9 mM. One morning she
receives an intravenous injection of a solution containing the radioactive
isotope of potassium (555,000 Becquerel, Bq, of 42K+ with a physical half-life of 12 hours). Following the injection her urine is
collected in two periods (0-12 and 12 -24 hours). The first urine collection
contained 40 mmol K+ (39K+) and 4144 Bq 42K+.
The second urine specimen contained 40 mmol K+ and 2220 Bq 42K+.
Both urine specimens were analysed for radioactivity exactly 24 hours after the injection, where the specific activity of her plasma
was 55.5 Bq/mmol. The 42K+, retained after the first 12
hours, distribute in her body just like all other exchangeable K+.
The body contains traces (0.012% of the total) of naturally occurring
radioactivity (40K) with a half-life of 1.3 × 109 years.
the exchangeable K+ pool of her body after the 12‑hour
distribution period. - Is the result normal?
the elimination rate constant (k) for exchangeable K+ in her body,
and the biological half-life for this K+ in hours. Calculate the
ratio between the physical and the biological half-life of K+.
is the cause of her disease?
4. Describe the actions of diuretics.
5. Describe a method for measurement of her total body potassium.
Case History C
This case requires knowledge of the renal function (Chapter
groups of substances are evenly distributed in the ECV of a healthy
25-year-old man. His weight is 70 kg, and his extracellular volume (ECV) is 14
L. Both groups of substances disappear solely by excretion through the
kidneys. His GFR is 120 ml/min, and his renal plasma flow (RPF) is 700 ml/min.
is representative for one family of substances. Inulin is only ultrafiltered
in the kidneys. What fraction (k1) of the total amount of inulin in
the body is maximally excreted in the urine per min?
2. The other substances are not only ultrafiltered, but they are also
undergoing tubular secretion to such an extent that they totally disappear
from the blood during the first passage. What is the elimination rate constant
(k2) for these substances?
to solve the problems before looking up the answers.
· Water permeable
membranes separate the three body fluid compartments, so that they contain
almost the same number of osmotically active particles (expressed as mOsmol
per kg of water or the same freeze-point depression). The three compartments are the intracellular fluid volume (ICV), the
interstitial fluid volume (ISV) and the vascular space.
· The sum columns of
electrolyte equivalents in muscle
cells are essentially higher than the extracellular sum columns, because cells
contain proteins, Ca2+, Mg2+ and other molecules with
several charges per particle.
· Females contain less
water as an average compared to males. Such differences show sex dependency,
but the important factor is the fraction of body fat, since fat tissue
contains significantly less water than other tissues (only 10%). Sedentary,
overweight persons contain 50-55 % water dependent on the body fat content,
and regardless of sex.
hyperaldosteronism (Conns hypercorticism disease) and all types of secondary
hyperaldosteronism also lead to hypernatraemia combined with hypokalaemia and
enlarged blood volume. Cerebral failure and convulsions are alarming signs,
but there are no specific symptoms and signs of hypernatraemia.
· Polyuria, polydipsia
and thirst suggest diabetes insipidus and low urinary osmolality is a clear
indication. Pituitary diabetes insipidus is treated with an analogue of ADH
(desmopressin, with a low pressor-effect).
· Regulation of K+-balance:
The daily intake of K+ is matched by the renal K+-excretion
and our daily urine contains 2-5 g of K+.
· Acid-base balance.
The pH of the ICV and the ECV is maintained within narrow limits (many
metabolic processes are sensitive to pH). The acid-base balance is
accomplished by co-operative action of the kidneys and the lungs.
reduces the excitability of neurons, muscle cells and the myocardial
syncytium. Thus, hypokalaemia can result in muscle weakness, paresis, and
cardiac arrhythmias with ectopic beats and cardiac arrest in diastole.
increases the excitability of neurons, muscle cells and the myocardium.
· Acute hyperkalaemia
is a normal condition following severe exercise, and normal kidneys easily
eliminate this. In disease states the causes of hyperkalaemia are insufficient
renal excretion or increased release from the body cells as during long
· A plasma- [K+] above 7 mM is life threatening due to ventricular fibrillation or cardiac
arrest in systole. Tented T-waves and increased QRS-complexes characterise the
P, P. Bie, and H.C. Engell. ‘Salt and water in culture and medicine.’ Munksgaard, Copenhagen, 1993.
F. G. “Physiology of potassium balance.” Am.J. Physiol. 275 (Adv.
Physiol. Educ. 20): S142-S147, 1998.
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