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CUN. CHEM. 4017, 1220-1227
(1994)
of the Clearance Concept to Hyponatremic and Hypernatremic Disorders:
Application
A Phenomenological Analysis
Abmed
Said Shoker
The kidney and its response to the antidiuretic hormone
(ADH) are the principal protective mechanisms necessary
to maintain a normal plasma tonicity (osmolality). Hence,
determination of the response of the ADH-renal axis to an
abnormal plasma tonicity is an important step to understanding water homeostasis. Determination of free water
clearance is the most direct clinical method to measure
the ability of the kidney to reabsorb or excrete water; itcan
be used as a sensitive method to study water metabolism,
describing the abnormal water homeostasis in simple
quantitative terms. A positive electrolyte-free water clearance denotes the excretion of excess free water. A negative electrolyte-free water clearance indicates reabsorption of excess free water. During hypertonicity, an
increased concentration of ADH enhances renal reabsorptionof free water. With diminished ADH secretion and
normal renal function, a substantial volume of free water
is cleared in response to hypotonicstimuli. A positivefree
water clearance >0.4 L/day in hypertonic conditions or a
negative free water clearance during hypotonicity confirms an abnormal ADH-renal axis response.
Indexing
renal function/free water clearance/plasma
hormone/electrolytes/osmolality
Terms:
Ily/antidiuretic
tonic-
GeneralPathophyslologyof PlasmaTonlcityDisorders
Because cell membranes
cannot sustain a large difference in osmotic pressure for any length of time, rapid
water movement
across body water compartments
is of
vital importance
to buffer the osmotic gradient
on cellular membranes
(1-4). Such buffering mitigates major
changes but does not normalize
the plasma osmolality
(tonicity).
The role played by water movement
in preventing major changes in plasma osmolality is similar
to that of weak acids and bases acting as buffers
in
preventing
major acid/base
imbalance.
Correction of
plasma tomcity
is the function
of the antidiuretic
hormone (vasopressin,
ADH) (5), thirst (6), and the kidney
(7, 8).’
Division of Nephrology, Department of Medicine, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan S7N OXO,Canada. Fax 306-966-8021.
‘Nonstandard abbreviations: ADH, antidiuretic hormone (vasopreasin); ECF, extracellular
fluid; ICF, intraceliular
fluid; C,
osmolal clearance; CeL, electrolyte (Na + K) clearance; C,,, free
water clearance;
EWC, electrolyte-free
water clearance; SIADH,
syndrome of inappropriate
antidiuretic
hormone; and TBS, total
body salt.
Received October 22, 1993; accepted April 11, 1994.
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CUN1CAL CHEMISTRY, Vol. 40, No.7, 1994
Because sodium is the main impermeable
cation in
the extracellular
fluid (ECF), the concentration
of serum sodium (and of its accompanying anion) is the main
determinant
of the effective plasma tomcity (9, 10). Except in conditions of increased blood glucose or the presence of exogenous impermeable
substances, hyponatremia and hypernatremia
are synonymous with hypo- and
hypertonicity,
respectively
(11). Plasma
tonicity
is
sensed by special osmoreceptors
in the anterior
hypothalamus
(5, 12, 13). The activation
set point varies
from person to person (14), but in normal adults ranges
between 275 and 290 mosmol/kg water. Pregnancy decreases the set point of osmoreceptor
activation.
Plasma
sodium concentration
is the physiological
stimulus of
the osmoreceptors.
Mannitol is also an efficient stimulus, and above-normal
blood glucose decreases
the sensitivity of the osmoreceptors
(15).
Stimulation
of the
osmoreceptors
induces secretion of ADH, which is produced by the hypothalamic
neurohypophysial
tract and
stored in the posterior lobe of the pituitary
gland. The
neurotransmitters
that mediate
this action are unknown. The second major response to changes in plasma
tonicity is the perception of thirst (16).
After gain or loss of water, the addition of sodium to
the ECF space or its removal will result in water moving in the direction that buffers the effect of osmotic
pressure changes on cell membranes. Water movement
keeps the osmotic pressure inside and outside the cell
equal (except for the Donann effect). Hence, the change
in osmotic pressure induced by gain or loss of water or
salt is shared by the intracellular
fluid (ICF) and the
ECF spaces. Hypotonicity
induces two main responses:
(a) a decrease
in thirst perception and (b) a diminished
secretion of ADH, so that the production of urine is in
dilute form until the water excess is excreted. Failure of
either mechanism
leads to hyponatremia.
Hypernatremia stimulates
thirst and enhances
conservation
of
free water through increased
ADH secretion. Hypertonicity is maintained
in the event of failure
of either
response. Therefore, hypo- and hypernatremia
are metabolic disorders of water, not of sodium.
Thirst and the renal ability to reabsorb or secrete
a
substantial amount of free water are the chief effector
responses necessary
to maintain
a stable plasma tonicity (7, 17). Measurement
of these effector responses
is
the next logical step in determining
the causes of abnormal plasma tonicity.
Significance of CalculatingUrinaryOsmolaland Free
Water Clearances
Definitions
Osmolality
(9, 10) refers to the thermodynamic
effect
of the total number of osmotically
active partides (in
millimoles)
dissolved in 1 kg of distilled water. It is this
property that is measured
by freezing point or vapor
pressure methods. Plasma osmolality
is determined
as
the total number of permeable
(e.g., urea) and impermeable (e.g., Na, glucose) osmoles.
Tonicity
(9, 10) describes the behavior of cells in a
solution. By definition,
an isotonic solution is one in
which the particular
cells maintain
a normal volume; a
hypertonic
solution is one in which the cells shrink to a
new volume; and a hypotonic solution is one in which
they swell to a new volume. Plasma tonicity (effective
osmolality)
is measured
as the total number of only the
impermeable
and osmotically
active solutes.
Renal clearance (18), C, is defined as the volume of
plasma required to supply the quantity of substance x in
a given time. A positive value means that substance x is
excreted
more than absorbed; a negative value denotes
that substance x is retained. In general, C, = (LT.
V)/P,
where U, is the urine concentration
of x, Vis the
urine flow rate, and P,, is the plasma concentration
of x.
Osmolal clearance (19-22), Cogm, is measured
as:
Coem
=
(1)
(Uo#{248}m11)/P
U,,, is the urinary osmolal concentration
is the plasma osmolal concentration.
Effective
osrnolal clearance
(electrolyte
clearance),
is measured as:
where
and
P
GeL =
(U2(Na
+ K)
V)/P2(Na
+ K)
CeL,
(2)
This equation defines the osmolal clearance
of only the
effective osmoles, Na, K, and their accompanying
anions.
Sodium clearance is calculated
as:
CNa
=
(U2Na
V)IP2N
This is the measure by which the renal ability to defend
the effective plasma volume is assessed.
Decreased
or
inefficient
blood volume is associated
with decreased
CNa. Unlike
the sodium concentration
in spot (untimed)
urine, the clearance of sodium is corrected for the urine
flow rate.
In conditions
of plasma hypertonicity,
the expected
normal
renal response is to reabsorb an excess of free
water. In hypotonic states, the excess free water is expected to be excreted. To directly determine whether the
kidney is reabsorbing
or excreting an excess volume of
free water, use of the clearance concept is helpful. This
approach is based on the premise that measuring
free
water clearance is the most direct method to determine
whether free water has been abstracted from, or added
to, the tubular fluid during urine concentration.
Such a
phenomenological
analysis (8,21) may improve the un-
derstanding
of water homeostasis
disorders.
A C
of 1
mllmin
(1.44 ldday) means that the osmoles excreted
per day occupy a theoretical plasma volume of 1.44 L. If
the urine volume is 1.44 Ldday, then the excreted osmoles occupy the same urine volume as in the plasma
and the urinary water concentration
is similar to that of
plasma water, i.e., no free water is added to or deleted
from the final urine. Hence, the free water clearance
(C,0),
can be calculated
as the difference between
urine flow rate and Cm:
CH20
=
V
-
Cosm
(4)
Unlike urine osmolality, the calculation of free water
clearance is corrected
by the urinary excretion of osmoles. When C,,m >V, more free water has been absorbed than secreted by the renal tubules-a
negative
clearance
of free water. A positive clearance
of free
water is predicted
when V >Cm,
i.e., there is a net
excretion of free water. From Eqs. 1 and 4, a relatively
increased urinary to plasma noneffective omolal concentration should increase
Cm and decrease C,0. Because plasma tonicity is determined only by the concentration of the effective osmoles (impermeable
osmoles,
e.g., plasma electrolytes),
a more accurate treatment of
the free water deficit or surplus should exdude the noneffective osmolal (permeable osmoles that do not alter
tonicity, e.g., urea and ainmonium
salts) clearance from
the above calculations.
Electrolyte-free
water clearance
(EWC) (23, 24) is defined as the volume of plasma required
to supply the
quantity of the free water present in a given time. EWC
can be measured
as the urine flow rate minus the effective osmolal (electrolyte) clearance (Cej), i.e., the clearance of Na and K and their accompanying
anions. Thus
EWC=V-
V
U2(Na
+ K)
(5)
P2(Na
+ K)
In the presence of effective osmoles in the urine other
than Na and K (e.g., glucose and mannitol), their clearances also should be incorporated in the equation:
EWC
=
-
V U[2(Na +
P[2(Na
K) + other effective osmoles]
+ K) + other effective oemolee}
(6)
Although
the relation between
and EWC has
not been rigorously tested, EWC is considered a more
accurate
method
to measure free water clearance.
Increased urinary urea, as in catabolic states, increases
Cosm. Hence at any given
urine flow rate, C,0 would
underestimate
free water clearance
compared with that
calculated
via EWC. Also, in sodium-retaining
states,
CH2O may underestimate
the actual free water clearance while overestimating
the free excreted water in the
syndrome
of inappropriate
ADH (SIADH) (22). Similarly,
during chronic metabolic acidosis, the urinary
concentration
of NH can exceed 150 mmol/L. The increased noneffective
osmolal
clearance
makes C,
CLINICAL CHEMISTRY, Vol. 40, No. 7, 1994
1221
difficult to interpret.
EWC excludes the
of the ineffective
osmoles
on the measurement of free water clearance.
A negative EWC indicates that during urine concentration more free water
has been abstracted
from the tubular
fluid than excreted. A positive value denotes a net removal of free
water from the plasma.
To maintain
a stable plasma osmolality,
the kidney
ordinarily
modifies the urine osmolal and water excretion to match the fluid gain.
measurement
spurious
effect
Reference intervals
During
a pretranspiantation
workup, 18 healthy
adults, potential kidney transplant
donors, were studied. All persons consented
to participate
in the study,
and the protocol followed the ethical standards
of this
institution.
The ages of the individuals
varied from 19 to
54 years (mean ± SD, 33 ± 10.56); 12 were men, and
none was taking
any medications.
All had normal renal
inquiry
showed that they were on an
North American
diet. Their 24-h urine proffle
ranges (and mean ± SD) were: volume, 0.86-2.65 L (1.5
± 0.55); sodium
excretion, 88-357 mmol (138.5 ±
function.
average
Dietary
52.99); potassium
excretion, 30-150 mmol (65.28 ±
22.07); urea excretion, 239-950 mmol (419 ± 169.98);
osmolality, 229-985.5
mosmol (609 ± 266); and creatinine, 10-24.6 mmol (14.62 ± 3.33). Table 1 illustrates
the calculated
water and osmolal clearances.
Similar
values are obtained from the literature (25-27).
These
values are obtained only during normal plasma tonicity
and volume.
Because
clinically
many
patients
with abnormal
plasma tonicity may also have volume depletion, it was
necessary
to measure the minimum free water clearance after short-term fasting. Ten healthy adults participated in this part of the study, all of whom gave
consent, which also followed the ethical standards
of
this institution.
Their ages varied from 19 to 42 years
(29 ± 11.2). All were nonsmokers
and not taking any
medications.
All had normal renal function. All had
been on an average North American
diet. They then
fasted for 16 h, during which time they ingested
no
fluids. They collected their urine during the last 2 h of
fasting, from which the
mean values (± SD) of the
urinary electrolytes
and osmolality
were extrapolated:
urine volume, 0.68 L (± 0.1); sodium, 68.2 mmol (± 6.7);
Table 1.
Urinary
clearancemeasurements(24 h) from
18 normal adults.
Clearance, Llday
saranas
Rang.
3
0.57
0.62
-7.08
-1.1
CNa
EWC#{176}
Calculated
b
to 8.74
to 2.9
to 2.24
to -1.6
to +0.86
from Eq. 4.
Calculated from Eq. 5.
1222
CUNICALCHEMISTRY,Vol.40, No. 7, 1994
Mean * SD
5.69 ± 1.48
1.51 ±0.50
1.12 ± 0.38
-4.25 ± 1.48
-0.02 ± 0.51
potassium,
55.9 mmol (± 9.3); and osmolality, 914.1
mosmolJkg water (± 89.3). At the same time, their serum sodium had risen from a prefasting baseline of 137
mmolJL (± 1.16) to 140.3 mmolIL (± 0.95) (P <0.05, by
Wilcoxon’s unranked
t-test). Serum potassium was 3.9
mmol/L (± 0.6) at baseline, 3.79 mmolIL (± 0.2) at the
end of fasting (not significantly
different). Serum osmolality increased from 285.4 (± 1.7) to 291 mosmol/kg
water (± 2.05) after fasting (P <0.05). Mean weight loss
was 1.4 kg (± 0.6). The calculated
C0 was -2.88 L/day
(± 4.61), EWC was 0.035 L/day (± 0.11), GeL was 0.58
L/day (± 0.08), and Cosm was 2.12 L/day (± 0.36). Both
the CH2O and EWC were not significantly
different from
clearances
measured
at ad libitum conditions of fluid
and food intake.
Although ADH secretion increased as expected from
the significant
change in plasma tomcity and sodium
concentration,
the free water clearances and water volume reabsorbed by the kidney were not much different
from measurements
under normal conditions. This finding could be explained by the relative increase in noneffective osmolal secretion (urea) under conditions
of
fluid deprivation.
A further extension of these observations
is patients
with substantial
volume depletion and intact renal concentrating ability. These patients produce significantly
concentrated
urine while conserving sodium to protect
blood volume. Under such conditions,
the calculated
EWC is slightly positive. To ifiustrate, let us consider a
patient with significant
hypovolemia
due to nonrenal
fluid loss. A classical urine profile may include sodium
20 mmol/L, potassium 70 mmolIL, urine osmolality
800
mosmol/L, and urine volume 0.4 L/day. Because the
urine electrolytes and volume are usually significantly
decreased,
the calculated
EWC is expected from Eqs. 2
and 5 to be <0.4 L/day. These observations
suggest that
short-term fasting and mild volume depletion per se do
not induce significant change in EWC, and that significant volume depletion is associated
with a slightly positive EWC in spite of increased ADH secretion.
The
renal response to the homeostasis
mechanisms
recruited
to protect blood volume and to remove the waste products through the kidney takes precedent over the renal
ability to reabsorb more free water as measured
by
EWC. There is an obligatory volume of free water that
must be secreted with the waste product, mainly urea.
Note that during hypotonicity,
the renal ability to
excrete free water increases significantly.
Because >20
L is delivered to the distal renal segment for further
dilution to 50 mosmol/kg water or for concentration
to
1200 mosmol/kg water (8, 28-30), the calculated
EWC
can vary significantly.
An increased
EWC (20 L/day)
attests to the renal ability to defend the body against
hypotonic disorders. During hypertonicity,
EWC is normally <0.4 llday. In conditions of hypovolemia
or ineffective blood volume, urine volume is usually decreased
to <1 L/day and Na concentration
to <10 mmol/L (31,
32). With plasma Na 100 mmol/L, applying Eq. 3
gives the expected CNa of 0.1 L/day.
Previous attempts to describe body water homeostasis
in quantitative
the clearance
reasons:
axis response, hyponatremia
is associated with EWC of
>10 L/day and a positive C0.
Under such conditions,
an EWC of <0.5 L/day signifies abnormal ADH secretion or responsiveness,
abnormal renal diluting mechanisms, or both. Further determination
of TBS as determined
by the sodium
clearance
can define
the
pathophysiological
abnormality.
During hypertonicity,
EWC is expected to be <0.4 L/day. Either EWC >0.4
L/day or a positive CH2O indicates an abnormal ADHrenal axis response. Determination of the sodium clearance can help categorize the blood volume state, which
can directly determine
the appropriateness
of the ADHkidney response to plasma tonicity disorders.
In particular, CNa is the variable by which the renal response to
blood volume changes is measured; unlike spot urine Na
concentration,
CNa calculation eliminates urine volume
as a variable. In the presence of decreased TBS content,
as determined by the bedside clinical examination
of the
intravascular
volume, or diminished effective blood volume, an increased CNa (>0.2 L/day) confirms a renal
source of sodium wasting. Note, however, that irrespective of plasma tonicity values, hypovolemic
conditions
are associated
with a concentrated
small volume of
urine. The renal capacity to respond to ADH is restricted because of the decreased delivery of fluid to the
distal tubules and the requirement
to remove the noneffective osmoles. Thus, as illustrated
in the above example, hypovolemic
patients with hype- or hypernatremia will have a slightly positive EWC (<0.4 L/day).
A slightly positive EWC is the result of the integrated
renal response to changes in blood volume and tonicity
and the requirement
to remove waste products. Urine
osmolality is ordinarily expected to be more than twice
that of plasma in hypovolemic
conditions. From Eqs. 1
terms have been few. As discussed here,
concept can be useful for the following
1) It determines
the net balance of all effector elements that affect water homeostasis.
2) It can quickly and accurately
determine
the ADHrenal axis response to an abnormal plasma tonicity: A
positive EWC reflects a net water excretion; a negative
EWC indicates a net free water gain by the kidney.
3) During plasma hypotonicity
the expected normal
increase
in the EWC can reach +20 L/day, whereas
during hypertonicity
EWC is normally <0.4 L/day. The
measurement
of free water clearance,
therefore,
gains
more discriminatory
ability to determine the ADH-renal axis response in conditions of abnormal plasma tonicity than under normal plasma tonicity.
4) Describing
the body water quantitatively
promotes better understanding
of the mechanisms
involved.
5) In some difficult cases, where multiple effector elements are in play, phenomenological
description of the
existing water balance can have diagnostic value (see
cases 4 and 5 below).
6) The clearance
concept can help explicate the principles involved in correcting plasma tonicity disorders.
Suggested Phenomenological Approach to Diagnosing
Disorders of Plasma Tonicity
Tables 2 and 3 ifiustrate
a phenomenological
approach to water homeostasis
disorders. After determining the ADH-renal
axis response, the clinical assessment of total body salt (TBS) and the calculation of CNa
or spot urinary
sodium, as the currently used method,
would help categorize
the etiology
of an abnormal
plasma tonicity. In the presence of intact ADH-renal
Table 2. Phenomenoiogical approach to hypotonicity: check EWC; then assess TBS and measure CN$(L/day)EWC, L/day> 10 L/day = normal ADH-renal axis response
I I free water intake, e.g., psychogenic
polydipsia; <10->0.5 = Impaired ADH-renal axis response; <0.5 = abnormal ADH-renal axis response.
-
TBS
TBS normal,
normal
Inappropriate t ADH
hypothyroidism, e.g.,
drugs, hypoadrenalism
f C,, (O.2)
Hypovolemia due to
renal salt losses
ADH
tTBS
C,(<O.1)
Hypovolemia due to
extrarenal salt
losses -. I ADH
t C,(>O.2)
Retention of H20 > Na,
e.g., renal disease
(<O.1)
Ineffective plasma volume
I ADH, liver disease,
CHF, nephrotic syndrome
CHF, chronicheartfailure.
Table 3. Phenomenoiogical approach to hypertonicity:
check EWC; then check TBS and measure C,,1,,(L/day).
TBS
TBA normal,
C,,, normal
C
(O.1)
EWC <0.4 1./day = normal ADH-renal axis response
Nonrenal fluid losses partially
(Hypovolemia - I ADH)
corrected with salt, e.g., I
I Extrarenal hypotonic
insensible losses
fluid losses
Essential hypematremia
EWC >0.4 1./day = abnormal ADH-renal axis response
Diabetes insipidus (pure water
diuresis)
t C,.(>O.2)
C TBS,
(O.2)
Osmotic diuresis (pure solute
diuresis)
Renal losses of H20 > Na
(mixed water and solute
diuresis), e.g., renal diseases
(Hypervolemia -e
ADH)
e.g., hyperaldosteronism:
Cushing syndrome, bicarbonate
and hypertonic salt infusion
CLINICAL CHEMISTRY, Vol. 40, No. 7, 1994
1223
and
4, the absolute value of C0
that of the urine
conditions.
volume
ordinarily
exceeds
in hypovolemic
and is negative
Examples
To clarify the usefulness
of the clearance concept, I
present a few ifiustrative
examples. For simplicity, all
measurements
are taken per 24 h; they can, of course, be
calculated
per minute.
Case 1. Patients with polyuria secondary to chronic
interstitial
nephritis cannot dilute or concentrate their
urine efficiently. A man with this disease who had pneumonia and was unable to drink >1 L daily developed
volume
depletion.
His serum osmolality
was 320
mosmol/kg water, his serum sodium was 155 mmol/L,
potassium
3.5 mmol/L, and urea 24 mmolJL. At the
same time, he maintained
a urine volume of 3 L/day,
urine osmolality 300 mosmollkg water, urine sodium 45
mmol/L, potassium 25 mmol/L, and urea 140 mmol/L.
Why did he develop hypernatremia?
Calculating his C
(Eq. 1) gave 2.81 L/day; his C0
(Eq. 4) was +0.19 L/day; and, from Eq. 5, his EWC was
3
[3(45 + 25)/(155 + 3.5)] = +1.68 Li/day.
Hypovolemia
and hypertonicity
are potent stimuli for
ADH secretion.
Consequently,
a normal
renal response
would have been associated with a negative free water
clearance.
Because
of the renal disease,
however, he
could not conserve free water in the presence of hypertonicity.
He also lost a larger amount of hypotonic fluid
-
than under normal conditions (the obligatory losses) due
to the fever. This explains why he developed hypernaBecause of the hypovolemia,
the expected CNa
should have been 0.1 L/day. The relatively increased
CNa (from Eq. 3), 0.87 L/day, identifles
a renal saltlosing state. This condition could have been avoided if a
similar amount of free water and salt, equal to that lost
by the kidney and the obligatory
losses, was given. Notice that his net free water secretion is underestimated
if the urea clearance is not deleted from calculating
the
tremia.
effective
osmolal
clearance.
Case 2. Recently,
a patient
with a known lung cancer
presented
to the emergency room feeling unwell. Clinically, he was euvolemic.
A repeated blood testing
showed sodium at 113 mmol/L, potassium
4 mmol/L,
osmolality 235 mosmol/kg water, and creatinine
70
mo1/L. The urine indices were sodium 85 mmol/L, potassium
80 mmol/L, osmolality
750 mosmol/kg water,
and volume 1.2 llday. His thyroid and adrenal functions
have been normal. What was the cause of his hypona-
tremia?
If the renal response to hyponatremia
was intact, he
should have had a markedly positive free water clearance because of the significantly
inhibited
ADH secretion induced by the hypotomcity.
The C0
was -2.63
I.Iday (Eq. 4). The calculated
EWC was -0.49 Ilday (Eq.
5). This means that the kidney retained
excess
free
water,
which eventually
led to the hyponatremia.
Instead of secreting
the excess water, as a normal response
to hyponatremia,
a net free water was reabsorbed
by the
kidney. The Cc,sm of 3.83 L/day and CNa of 0.9 L/day were
1224
CLINICAL CHEMISTRY, Vol. 40, No. 7, 1994
normal ranges. They reflect a normal
within
tent and the renal
response
TBS convolume. In this
to dilute the urine
to plasma
hyponatremic
case, the inability
(EWC is negative), in the presence of euvolemia and
normal
renal,
adrenal,
and thyroid functions,
is diagnostic of inappropriately high concentrations of ADH
(SIADH,
due to the carcinoma
in this case). Under the
ADH, water has been reabsorbed
efficiently by the distal tubules, leading
to a concentrated urine. Notice that, in this example,
the free water
clearance
as estimated
by CH2O overestimated
the free
water absorption,
because
urea was eliminated
from the
EWC but not from the C0 calculation.
Case 3. An opposite example is a patient with partial
diabetes insipidus, who ordinarily
had a serum sodium
effect
of increased
of 135 mmol/L, potassium 4 mmol/L, and osmolality 285
mosmol/kg water. His usual urine profile showed sodium 40 mmo]/L, potassium
20 mmol/L, osmolality
100
water, and urine 7 L/day. Because of a recent
he had been unable to drink enough. In the
emergency room he was euvolemic. Laboratory
results
showed the following
serum proffle: sodium 155 mmol/L,
potassium
3 mmol/L, and osmolality 325 mosmol/kg
water; urine values were: sodium 40 mmol/L, potassium
20
mmol/L, volume 5 L/day, and osmolality
200 mosmollkg
water. Why did he develop hypernatremia?
The calculated C
of 3.07 Ilday and CN of 1.3 ldday
were within normal limits. it is obvious that the normovolemic hypernatremia
was due to the loss of free water.
His baseline CH2O was 4.54 and the EWC was 4 L/day.
During his sickness, the EWC was 3.1 Llday. Because of
the relative lack of ADH, this person has been clearing
excess free water that is present in 3.1 L of plasma daily.
The free water intake was not enough to compensate for
his excessive free water losses during his sickness. In a
euvolemic
hypernatremic
patient, a positive EWC is
diagnostic
of diabetes insipidus. Under these circumstances, he should have been given a simil’ir amount
of
free water to prevent the development
of hypertonicity
and hypernatremia.
While he was sick, the C0 (+ 1.93
ldday) underestimated
the free water losses by 1.1
I.Iday.
The next three examples illustrate
that measurement
of EWC is a more accurate method than CH2O to determine the renal ability to excrete or conserve water because EWC excludes the spurious effect of the noneffective osmolal clearance from the equations.
Case 4. A middle-aged
man with recently diagnosed
lymphoma was started on chemotherapy,
including cymosmol/kg
influenza,
clophosphamide.
A few days later, he developed
pneumonia
and felt unwell, with intermittent
nausea.
He
was treated with isotonic saline, 100 mLlh, for 3 days.
His serum
creatinine
had been normal. Because of a
recent increase
in urine output,
his intravenous
infusion was increased
to 250 niL/h, and a nephrological
assessment was requested. On examination
he was euvolemic, and his oral intake was adequate. His serum
profile then showed: sodium 131 mmol/L, potassium
4
mmol/L, urea 4 mmol/L, creatinine
70 molJL,
and osmolality
270 mosmol/kg water. His urine
profile
showed: sodium 150 mmolfL, potassium
30 mmol/L, osmolality
370 mosmol/kg water, and volume 6 L/day.
What causes polyuria and hyponatremia?
Urine
volume consists of two components:
free and
isosmotic water. An increase in either component can
cause polyuria,
i.e., water and (or) solute diuresis. The
current approach to polyuria is illustrated
elsewhere
(19,26,33,34).
If one applies the clearance concept from
reference values mentioned
in Table 1, an increased
EWC above 1 L/day suggests pure water diuresis. Polyuria due to sodium-diuresis
is associated with CNa> 2.5
L/day.
In case 4, the polyuria was caused by the increased
sodium clearance as measured by the increased daily
sodium excretion (900 mmol) and CNa of 6.87 L/day. He
did not have diabetic insipidus because his EWC was 2
L/day. The negative free water clearance indicates that
more free water was reabsorbed than excreted. This
explains the hyponatremia,
which was due to an underlying high concentration
of A1)H caused by stress (35),
nausea (36), and cyclophosphaniide
(37). Severe hyponatremia did not occur because the free water absorbed
by the kidney was not much larger than the nonrenal
obligatory losses. This was a case of mixed solute diuresis and an inappropriate
high concentration
of ADH.
Only calculating
the water and solute clearances could
easily and precisely
describe the hyponatremia
and
polyuria in this case.
Case 5. A 40-year-old
man with known chronic alcoho! liver disease was admitted to the intensive care unit
because of intracerebral
bleeding. His course was complicated with upper gastrointestinal
bleeding and further acute deterioration
in his liver functions. A SwanGanz catheter was inserted to manage his fluid therapy.
He had been on half-isotonic saline (NaC1 4.25 g/L) at 50
mLfh. His electrolytes
had been normal with a serum
creatinine of 100 imoWL. His urine output was stable at
0.5-0.8 L/day. Over the last 2 days his urine output
increased to 2-3 L a day, and his serum sodium increased to 155 mmol/day. The nephrology service was
asked to assess the cause of hypernatremia
and polyuria. On examination,
he was hemodynamically
stable
with a blood pressure of 100/50 mmHg. He had +4 lower
limb edema and ascites. His right atrial pressure was 10
mmHg, and his wedge pressure was 13 mmHg. His most
recent blood tests showed a serum sodium of 155 mmol/L,
potassium
4 mmol/L, bicarbonate
26 mmol/L, chloride
116 mmol/L, glucose 8 mmoJ/L, urea nitrogen 40 mmol/L,
creatinine
110 janol/L, and osmolality
360 mosmol/kg
water. His concurrent urine profile showed sodium 5
mmol/L and potassium
35 mmoIjL, and it was negative
for sugars or ketones; urea was 500 mmol/L, osmolality
600 mosmol/L, and 24-h urine volume was 3 L.
Hypertonicity
stimulates
the secretion of ADH. Consequently, if the ADH-renal
axis response is intact, the
EWC is expected to be less than 0.4 L/day. If so, hypernatremia in that condition could be secondary to the
nonrenal hypotonic fluid losses. This patient, however,
had an EWC of + 2.25 L/day, which confirms an inappropriate renal free water loss. His sodium clearance
was 0.096 Ldday, which signifies an enhanced
sodiumconserving
state, most likely due to the ineffective blood
volume (17, 38). Most of the urine osmoles were due to
the nonelectrolyte
urea component
(1500 mmollday).
This case constituted
an instance
of water-osmotic
di-
uresis associated
with an increased
sodium conserving
state. The water-solute
diuresis explains the relatively
increased
urine volume. The increased
noneffective osmolal clearance masked the diabetes insipidus. If he did
not have a significantly decreased effective blood volume, his urine volume would have been larger and less
concentrated.
Clearly, applying the clearance concept,
the presence of diabetes insipidus can be easily determined in the presence of relatively hypertonic urine.
Case 6. A 35-year-old
woman was admitted
to the
hospital because of diabetes ketoacidosis.
She had a
25-year history of juvenile-onset
diabetes mellitus for
which she was taking insulin. During the 2 weeks prior
to admission, she had a flu-like syndrome and was unable to eat her meals; for 3 days she developed nausea
and vomiting. In the 2 days before admission, she had
progressive
weakness
and felt extremely
unwell, and
stopped taking insulin for 24 h. On admission she was
found volume-depleted.
Her respiratory
rate was 20/
mm, pulse rate 110/mm, and blood pressure
100/50
mmllg. The remainder of the clinical examination
was
otherwise unremarkable.
Her serum profile showed sodium of 120 mmoJIL, potassium
3 mmol/L, chloride 80
mmol/L,
bicarbonate
12 mmol/L,
blood sugar
40
mmol/L, creatinine
130 mol/L,
and urea nitrogen 17
mmolJL. Arterial blood pH was 7.2 and plasma osmolality, 315 mosmollkg body water. Her first 24-h urine
proffle showed a volume of 2 L, osmolality
600 mosmollkg water, sodium 70 mmol/L, potassium 30 mmoL’L,
urea nitrogen 300 mmol/L, and sugar 15 mmolIL. Why
did she develop hyponatremia?
Glucose requires insulin to cross most cellular membranes. In conditions of lack of insulin, the increased
blood sugar concentration
exerts an osmotic effect,
causing a shift of water from the intracellular
compartment to the extracellular
fluid space (9). The shifted
water dilutes the solutes present in the extracellular
space, including sodium. For each 1 mmol increase in
blood glucose above the normal concentration,
serum
sodium decreases by 0.3 mmolJL (20). In this case, the
markedly
increased
blood sugar above the normal
range (about 35 mmol) is expected
to dilute serum
sodium by 0.3 x 35 = 10.5 mmol. Strictly speaking,
correction of hyperglycemia
in this case would be expected to increase
the serum sodium concentration
from 120 to 130.5 mmol/L.
The calculated
C0
was -1.81 L/day, which represents the clearances
of all effective (Na, K, and their
associated
anions; Cl and ketone bodies; and glucose)
and noneffective
osmoles. Because plasma glucose exerts an osmotic pressure on cellular membrane, in conditions of hyperglycemia
the renal clearance
of glucose
(C)
must be added to the electrolyte
clearance
in
order to measure
the “effective” osmolal clearance.
Urine ketone anions are present as salts of sodium.
CLINICAL CHEMISTRY, Vol. 40, No. 7, 1994
1225
Therefore, their effective osmolal clearance is incorporated in the electrolyte clearance. From Eq. 6, the free
water clearance can be rewritten as EWC = V
(C0L +
In this case, the renal glucose clearance was (15
x 2)/40 = 0.75 14/day. CeL was 1.63. The net renal clearance of osmoles that can affect plasma tonicity in this
case was CaL + Cgiucoe = 1.63 + 0.75 = 2.38 Lfday.
Hence, EWC = 2
2.38/day = -0.38 L/day. The negative free water clearance explained the hyponatremia.
It
was induced by the increased
ADH secretion by volume
depletion, nausea,
and vomiting.
This case illustrates
the importance of adding the renal clearances of other
effective osmoles to that of sodium and potassium when
one is measuring the free water clearance.
Osmolites such as methanol or ethanol permeate cellular membranes
easily. They do not change plasma
tonicity, which is affected only by the impermeable
osmoles (9). Therefore, unlike glucose, they do not directly
induce changes in plasma sodium concentration.
Because plasma osmolality is measured
by the number of
the total osmoles present, these alcohols of low molecular weight can substantially
increase plasma osmolality
as measured
in the laboratory. Hence, the osmolal gap,
as measured
from the equation: osmolal gap
measured plasma osmolality
calculated plasma osmolality [2 x serum sodium concentration
+ glucose
(in
mmol/L) + urea (in mmol/L)], is increased.
When one
measures
the free water clearance, the renal clearances
of these alcohols and their metabolites should be treated
as noneffective
osmoles such as urea.
Measurements
of the osmolal and free water clearances are of particular
importance
in understanding
management
of hyponatremia
and hypernatremic
disorders. As illustrated
in Table 4, volume-depleted
patients develop significantly
diminished
effective (Na)
osmolal clearance. Hence, they will be able to retain the
solutes (e.g., NaC1) administered.
Correction of plasma
tonicity in these cases is much easier than in patients
with SIADH or diabetes insipidus. In hyponatremic
conditions due to SIADH, the urinary effective osmolal
clearance is normal, i.e., relatively higher compared to
-
-
-
Table 4. ClassIcal urine profile In prerenal azotemla
due to nonrenal fluid losses, SIADH, dIabetes
Inelpidus, and sodIum-Induced dluresis (e.g.,
salt-losIng nephropathy).
Urine
msasuremnt
Volume
Urine sodiumb
Urine
osmolalit?
Prerenal
azotsmla
SIADH
‘I,
ft
tc
fd
f fd
J, Je
N
C.L
EWC
a
Diabetes
inelpidus
N
ft
Salt
diureals
ft
ft
ft
t
N
With hypo-, normo-or hypematremia.
“Spot” (untimed) urinespecimens.
C Na concentration
vanes becauseof differenturinevolumes;however, total
Na secretionis similar to that ingested as long as the patientis euvolemic.
d f osmolality from
In urine volume.
osmolalityfrom I In urine volume.
N, normal.
1228
CLINICAL CHEMISTRY, Vol. 40, No. 7, 1994
patients.
Free water clearance
in hyponatremic
patients is inappropriately
negative.
Correction of plasma tonicity by the infusion of isotonic
saline is mitigated
by the relatively increased salt clearance and negative free water clearance. This explains
why, in these cases, it is important to administer solutions with higher osmolality than the urine. Administration of furosemide may be necessary
to enhance free
water and decrease
salt clearances
(8). Patients with
diabetes insipidus have a significantly
positive free water clearance. To maintain
normal plasma tonicity, they
are required to drink a similar volume of free water to
match their free water losses. An important
point to
observe, as ifiustrated
in cases 2 and 3, is that the
osmolal and sodium clearances
are indicators
of the
effective blood volume and not plasma tonicity. Assuming a normal renal response, as long as the effective
blood volume is normal, urine sodium reflects the oral
intake (31, 32). In a hypo- or hypernatremic
patient,
with a normal effective blood volume, the volume excreted is similar to the volume ingested. Protection of
blood volume overrides plasma tonicity control. In patients with volume depletion or diminished
effective
blood volume, the kidney is expected to concentrate the
urine because of an increased ADH concentration
(38)
and to conserve
sodium (<10 mmol/L) because of increased aldosterone
secretion and recruitment
of the
other renal sodium-conserving
mechanisms
(39-41).
CNa is significantly
decreased, and EWC is expected to
be less than 0.4 L/day. These patients conserve both
sodium (to protect their intravascular
volume) and water and excrete the other waste solutes in a smaller
urine volume. That is why, in conditions associated with
ineffective blood volume, such as congestive
heart failure, sodium retention results in edema. It is the retained excess water more than sodium that leads to
hyponatremia.
volume-depleted
Conclusion
I have tried to ifiustrate the usefulness
of calculating
the free water and osmolal clearances in the analysis of
hype- and hypernatremic
disorders. If one considers the
multiplicity
of regulatory mechanisms
that control water homeostasis,
an initial description
of the final net
effector response in quantitative
terms would help to
understand the mechanisms
involved. Because free water clearance is the most direct clinical method to determine the renal ability to conserve or excrete free
water, the ADH-renal
axis response
to abnormal
plasma tonicity can be easily determined
by using the
clearance concept. During hypertonicity,
an increased
ADH concentration
would enhance the renal free water
reabsorption.
A net free water gain results in normalization of the plasma hypertonicity.
In the presence of
a diminished
ADH secretion and normal renal function, the body is able to clear a significant
volume of
free water in response to hypotonic stimuli. A positive
free water clearance
above 0.4 L/day in hypertonic
conditions
or a negative
free water clearance
during
hypotonicity
indicates
abnormal ADH-renal
axis re-
sponses.
To determine
the etiology, one must assess
total body salt and urinary
sodium. Such phenomenological analysis
can complement
the current
clinical
approaches.
I thank Bev Shober and Pat Neigel for their assistance.
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