Hemodialysis International 2008; 12:412425

Special Article

Sodium, hypertension, and an explanation of

the lag phenomenon in hemodialysis
patients

Zbylut J. TWARDOWSKI
Department of Medicine, Division of Nephrology, University of Missouri, Columbia, Missouri, USA

Abstract
Sodium balance is precisely regulated by intake and output. The kidneys are responsible for adjusting
sodium excretion to maintain balance at varying intakes. Our distant ancestors were herbivores. Their
diet contained little sodium, so they developed powerful mechanisms for conserving sodium and
achieving low urinary excretion. About 10,000 years ago, early humans became villagers and discov-
ered that food could be preserved in brine. This led to increased consumption of salt. High salt intake
increases extracellular volume (ECV), blood volume, and cardiac output resulting in elevation of blood
pressure. High ECV induces release of a digitalis-like immunoreactive substance and other inhibitors of
Na1-K1-ATPase. As a consequence, intracellular sodium and calcium concentrations increase in vas-
cular smooth muscles predisposing them to contraction. Moreover, high ECV increases synthesis and
decreases clearance of asymmetrical dimethyl-L-arginine leading to inhibition of nitric oxide (NO)
synthase. High concentration of sodium and calcium in vascular smooth muscles, and decreased
synthesis of NO lead to an increase in total peripheral resistance. Restoration of normal ECV and blood
pressure are attained by increased glomerular filtration and decreased sodium reabsorption. In some
individuals, the kidneys have difficulty in excreting sodium, so the equilibrium is achieved at the ex-
pense of elevated blood pressure. There is some lag time between reduction of ECV and normalization
of blood pressure because the normal levels of Na1-K1-ATPase inhibitors and asymmetrical dimethyl-L-
arginine are restored slowly. In dialysis patients, all mechanisms intended to increase renal sodium
removal are futile but they still operate and elevate blood pressure. The sodium balance must be
achieved via dialysis and ultrafiltration. Blood pressure is normalized a few weeks after ECV is returned
to normal, i.e., when the patient reaches dry body weight. This is called the lag phenomenon.

Key words: Sodium homeostasis, blood pressure, peripheral resistance, intracellular sodium, nitric
oxide, lag phenomenon

Alle Ding sind Gift und nichts ohn Gift; allein die Dosis macht, das ein Ding
kein Gift ist
[All things are poison and nothing (is) without poison; only the dose makes
that a thing is no poison](ParacelsusTheophrastus Philippus
Aureolus Bombastus von Hohenheim).
Correspondence to: Z. J. Twardowski, MD, Dialysis Clinic
Inc., 3300 LeMone Industrial Boulevard, Columbia, MO
65201, USA.
E-mail: Twardowskiz@health.missouri.edu
A BRIEF HISTORY OF DIETARY SALT
For millions of years, our ancestors ate a vegetarian diet to
which no salt was added, so they developed powerful
mechanisms for conserving salt.1 Later, when human and
ape lines diverged, our ancestors began to eat moderate
amounts of meat. Gradually the amount of meat in
the diet increased until the diet of hunter-gatherers con-
tained 50% plants and 50% meat. The next step in dietary
evolution occurred about 10,000 years ago when people

412 r 2008 The Authors. Journal compilation r 2008 International Society for Hemodialysis

became villagers and developed farming and husbandry.
Initially the consumption of salt declined as the propor-
tion of meat in the diet declined; however, the consump-
tion of salt began to rise when it was discovered that meat
and other foods could be preserved by placing them into
brine. Salted food suppresses the salt taste buds in the
mouth so that natural foods become insipid. Gradually,
humans became addicted to salt2 and increased salt
consumption throughout millennia until the nineteenth
century. The somewhat reduced consumption of salt in
the twentieth century is probably related to introduction
of refrigeration for food preservation.1
SALT AND BLOOD PRESSURE IN
HUMANS
The earliest comment relating dietary salt to blood pres-
sure was by the Chinese emperor-philosopher Huang Ti
(The Yellow Emperor) in 1700 BC, who noted that . . . if
too much salt is used in food, the pulse hardens . . .3 In
the early twentieth century, several authors noted the re-
lation between blood pressure and salt intake.411 Ini-
tially, it was not clear whether it was sodium or chloride
responsible for elevation of blood pressure. Moreover, the
correlation was not generally accepted, and protein excess
was also considered as the cause of hypertension. The
value of a low-protein, low-salt diet for treatment of se-
vere hypertension was established by Walter Kempner in
the middle of twentieth century. In the preliminary paper
in 1944, Kempner reported in detail the results in 2 pa-
tients treated with a rice-fruit diet containing 2000 calo-
ries, 15 to 25 g protein, 4 to 6 g fat, 460 to 470 g
carbohydrates, 0.25 to 0.4 g sodium, and 0.1 to 0.15 g
chloride. The amount of fruit juice was usually 700 to
1000 mL/d. One patient, a 25-year-old male, had
chronic nephritis following acute glomerulonephritis had the highest levels of plasma renin activity and the
and the other, a 36-year-old male, had hypertensive car-
diovascular disease [and] vascular retinopathy.12 A sig-
nificant improvement was noted in both patients.
Kempner initially did not attribute the beneficial effect
of his diet to low salt intake, but rather to a combination
of all constituents of the rice diet; only later, on the ev-
idence from animal13 and human studies14 did he admit
that the very low sodium content might be responsible for
lowering blood pressure.15 An initial rapid decrease in
body weight due to reduction in body fluids stabilized
within a few weeks, but blood pressure continued to de-
crease.15 Grollman and his colleagues indicated that it is
sodium, not chloride, which is responsible for changes in
blood pressure. Several groups followed Kempners lead
and studied the problem in detail. In careful studies from
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Sodium is a uremic toxin
the Rockefeller Institute for Medical Research in New
York, NY, USA, it was found that the beneficial effect of a
rice-fruit diet on hypertension was not related to low
protein, low chloride, or loss of body mass, but to low
sodium.1618 After starting the rice diet, edema disap-
peared quickly, body weight and blood pressure fell, but
blood pressure and heart size continued to decrease after
body weight stabilized or increased in spite of the loss of
edema.19 Direct measurement of the interstitial fluid (total
extracellular fluid minus plasma volume) before and after
the institution of the rice-fruit diet in 17 patients showed a
decrease of approximately 1.7 L.20 [A]fter a period of about
3 weeks, some form of sodium equilibrium is reached be-
cause the volumes become and remain relatively con-
stant.20 Yet, blood pressure continued to decrease for
several weeks with continuation of the rice diet.19
In the late 1950s, blood pressures and salt intake,
based on 24-hour urine excretion, were determined in
several populations.2124 Those with low salt intakes,
such as the Alaskan Eskimo and Marshall Islanders, had
no hypertension. This is in agreement with other obser-
vations on populations ingesting extremely low-sodium
diets. One of the first observations, which started in the
1950s, was on Yanomamo Indians living in an area of
100,000 square miles in northern Brazil and southern
Venezuela, who do not use salt in their diets. In 24-hour
urine collections in adult males, sodium content was
1  1.5 mEq (SD); serum renin and aldosterone levels
were markedly elevated. Blood pressures in young males
and females are below 100 systolic and below 65 diastolic
and do not increase with age.25 Pregnant and lactating
females and their infants appear healthy on this low-salt
diet. The excretion of sodium in urine continues to be
extremely low (about 1 mEq/d) and sodium concentra-
tion in milk ranges from 5 to 9 mEq/L. Pregnant women
highest urinary excretion of aldosterone.26
On the contrary, populations with high salt intakes
such as inhabitants of Northern Japan, had a high per-
centage of hypertension. Studies in Japan in the early
1960s27 showed that in rural areas in Northern Honshu,
39% of the population over the age of 40 had hyperten-
sion and their salt intake averaged 26 g/d (450 mEq/d).
In large populations, significant correlations have been
found between the amount of salt in the diet and fre-
quency of hypertension. The Intersalt Cooperative Re-
search Group correlated 24-hour urine electrolytes and
blood pressure in over 10,079 men and women aged 20
to 59 in 52 populations from 32 countries around the
world.28 For all 52 centers, there was a positive correla-
tion between sodium excretion and systolic and diastolic
413
Twardowski
blood pressures. But even more significant was correla-
tion between age and blood pressure.2931
The relationship between salt intake and percentage of
hypertension in populations is not linear. In populations
where sodium intake is below 50 mmol/d, there is no
hypertension and no progressive rise in blood pressure
with age. In a few populations where sodium intake is 50
to 100 mmol/d, there is a steep rise in the percentage of
hypertensive individuals reaching about 25%. The per-
centage of hypertensives in populations with dietary so-
dium intake over 150 mmol/d levels off at about 30%
(Figure 1).32 Some individuals can handle salt much bet-
ter than others. Those who do not have increases in blood
pressure after increased sodium intake are termed salt re-
sistant, whereas those in whom substantial increases oc-
cur are termed salt sensitive. Those who are salt resistant
can remove high salt loads through decreased sodium
reabsorption in renal tubules.
The prevalence of high blood pressure in African
Americans is higher than in Caucasian Americans (38%
vs. 28%). The blood pressure of African Americans is
more sensitive to increases in salt intake. They also retain
an intravenous load of salt far longer than whites.33 It was
also found that the average pressure is higher in the black
population in the Western Hemisphere than in Africa. To
explain this discrepancy, a hypothesis was put forward
that the slave trade created conditions for a rapid natural
selection on an unprecedented scale.33 A hypothesis to
explain this phenomenon proposes that the process of
enslavement decimated those who were least able to con-
40 NaCl g 5.85 11.7 17.6
Prevalence of hypertension %
Sodium
30 threshold
20
10
Na g 2.3 4.6 6.9
0 determined in rats. In breeding experiments 2 strains de-
0 100 200 300
Sodium intake
mEq/day
Figure 1 Probable association between dietary sodium in-
take and the prevalence of hypertension in large popula-
tions. At sodium intake between 50 and 150 mEq/d, the
prevalence of hypertension in populations increases rapidly,
but at higher sodium intakes it levels off. Modified from
reference.32
414
serve salt and the survivors were those who had the high-
est ability to avidly reabsorb sodium in renal tubules.
Those able to conserve sodium were able to survive very
harsh conditions during transport from Africa to the
Western Hemisphere. Slave traders were cognizant of this
phenomenon as illustrated in the copper engraving of
1764 showing a slave trader licking a slaves face to de-
termine his suitability for the voyage across the Atlantic.1
This hypothesis has vigorous critics objecting to the no-
tion that hypertension in African Americans is related to a
genetic defect in the ability to excrete a high sodium in-
take.34 It may be argued that the ability to retain salt is not
a defect, but a favorable trait in a situation with limited
availability of salt. It seems easier to refrain from salt
where there is salt abundance than to find salt in areas
where it is scarce.
SALT AND BLOOD PRESSURE IN
ANIMALS
In normal animals, including dogs, rabbits, rats, baboons,
and chimpanzees, high dietary salt intake is associated
with hypertension.1 The work on rats and chimpanzees is
well documented and most relevant to the study on hy-
pertension.
Rats
In the late 1950s, Ball and Meneely fed 5 groups of rats
for 9 months with various amounts of dietary salt, rang-
ing from 2.8% to 9.8%. At the end of the experiment,
they compared the blood pressure in these 5 groups with
23.4 a control group with no added salt in the diet. They found
that a rise in blood pressure in the rats was proportional
to the content of salt in the diet.35 The blood pressure in
the groups showed a considerable scatter. This diversity
in susceptibility to the influence of dietary salt on blood
pressure was startlingly similar to humans. Lewis K. Dahl
studied the effect of salt intake in young rats and found
that when high salt intake was delayed the hypertension
was less pronounced. Dahl was also the first to show that
9.2 the hypertensive response to salt intake was genetically
400
veloped: Dahl salt-resistant and salt-sensitive rats.36
Chimpanzees
Routine data from the Southwest Foundation for Biomed-
ical Research in San Antonio, TX, USA, revealed that
chimpanzees had an age-related rise of blood pressure,
similar to the human population.37 These chimpanzees
Hemodialysis International 2008; 12:412425

were fed with biscuits (Purina Monkey Chow) containing
100 to 200 mmol of sodium per day, because it was as-
sumed that their salt intake should be similar to that of
humans. Eichberg, Denton, and Weisinger tried to lower
blood pressure by feeding biscuits containing low salt but
otherwise identical to high salt biscuits. The chimpanzees
refused to accept them, as they became addicted to salt,
began losing weight and were restored to the original
diet.38 However, this observation led to another study in a
colony of chimpanzees at the Centre International de Re-
cherche Medicale, in Franceville, Gabon.38 The chimpan-
zees in the colony were on a normal diet consisting of
vegetables and fruits containing o0.5 g of salt per day.
The colony was divided into 2 groups, each consisting of
13 animals matched for sex and age. The diet was iden-
tical in the 2 groups with the exception that the exper-
imental group received salt in increasing amounts up to
15 g/d for 20 months. Whereas in the control group,
blood pressure remained unchanged, blood pressure
increased significantly in the experimental group. The
increase of blood pressure varied greatly among individ-
uals, 5 animals in the experimental group had small or no
change in blood pressure; 8 animals had a large rise in
blood pressure, which reversed when salt addition was
discontinued.
EFFECT OF DIETARY SALT
RESTRICTION IN LARGE POPULATION
ON BLOOD PRESSURE AND
LONGEVITY
Hypertension is the leading cause of mortality in devel-
oped countries. Reduction in salt intake has been recom-
mended as an important approach to lowering blood
pressure in the United States and worldwide since
1972. Until the mid-1980s, salt intake in the United
States was decreasing; however, the use of salt recently
increased. Finland is one of the countries where dietary
salt reduction has been successful not only through the
official dietary and medical salt recommendations and
salt-labeling legislation but by population-wide education
in newspapers, television, and radio.39 From 1972 to
2002, the average salt intake in Finland dropped from 14
to 9 g/d, average blood pressure dropped by 10 mmHg,
stroke and coronary heart disease mortality fell by 75% to
80%. In the same period, the life expectancy increased
by several years in both sexes. There were other mea-
sures, which could contribute to these results (increased
dietary potassium, calcium, and magnesium, smoking
Hemodialysis International 2008; 12:412425
Sodium is a uremic toxin
cessation), but salt intake reduction was probably the
most important.
MECHANISM OF HYPERTENSION IN
RELATION TO VOLUME CHANGES
Small volume increases induce large
pressure increases
Blood pressure is determined by the interaction of cardiac
output and total peripheral resistance. One reason
changes in fluid volume have not been considered by
many hypertension researchers to be a major factor in
pressure control is that the measured extracellular blood
volumes in patients with essential hypertension (who
represent perhaps 95% or more of all hypertensive pa-
tients) are rarely significantly greater than normal.40
Guyton gives 2 examples how, in the long run, small vol-
ume increases are associated with high blood pressure
increases. The first relates to changes in fluid volume and
blood pressure caused by hyperaldosteronism in humans.
In one study, after hypertension was completely con-
trolled by spironolactone, the drug was withheld for sev-
eral weeks. During next 2 weeks, extracellular fluid
volume and blood pressure increased by 20% to 40%.
During the following 2 weeks, the extracellular volume
decreased toward normal, but blood pressure remained
elevated. Yet no other cause for the elevated blood pres-
sure was found in these patients, except for the small in-
crease in fluid volume. Another example was a study on
circulatory system variables, after acute volume loading in
dogs with reduced kidney mass to 30%. The study
showed, within 2 days, an increased extracellular fluid
and blood volume, increased cardiac output, slight de-
crease in total peripheral resistance, and a rise in blood
pressure. Within the following few days, extracellular and
blood volumes and cardiac output decreased; however,
total peripheral resistance increased and blood pressure
remained elevated (Figure 2).40 So, volume was restored
almost to normal but at the expense of elevated blood
pressure. Guyton postulated that the blood pressure re-
mained elevated by increased total peripheral resistance
due to autoregulation of blood flow at the tissue level.
Many experiments have shown that the excess blood flow
through any tissue causes a progressive increase in vas-
cular resistance.
Thus, in any situation where kidneys have difficulty
excreting salt, a sequence of mechanisms is triggered that
causes the blood pressure to rise. If kidneys have any
ability to increase salt and water removal, sodium balance
is restored at the expense of elevated blood pressure.
415
Twardowski

33% Blood
20 pressure
Extracellular fluid

Blood
volume (liters)

19 Fluid pressure
18 volume Fluid
volume
17
4%
16 Perpheral
resistance Perpheral
15 resistance
Blood volume

6.0
(Liters)

20% 5%
5.5 Institution Initial Months
of diuretic few weeks and beyond
5.0 therapy

Figure 3 Hemodynamic changes responsible for the antihy-

40% pertensive effects of diuretic therapy. Note that after an initial
7.0
Cardiac output

drop, blood pressure remained decreased even though fluid

(Liters/min)

6.5
volume returned partially toward normal. After prolonged
6.0
5% use of diuretics, lower blood pressure is related mostly to
5.5
decreased peripheral resistance. Modified from reference.42
5.0
Total peripheral

28
(mmHg/L/min)

treatment, the extracellular volume, plasma volume, and

resistance

26 33%
24 cardiac output returned toward pretreatment levels, while
22
the fall in blood pressure persisted as total peripheral re-
20
18
13% sistance decreased.41 In chronic use of thiazide diuretics,
blood pressure is normalized because of low peripheral
150
40% vascular resistance even though plasma and extracellular
Arterial pressure

140 30%
fluid volume returns partially toward normal (Figure 3).42
(mmHg)

130
120
110
100
0 2 4 6 8 10
Days
Figure 2 Changes in circulatory variables after volume load-
ing in dogs with reduced kidney mass to 30%. Beginning at
day 0, isotonic saline was infused for 2 weeks at about 6
times normal sodium intake. Note that at the fourteenth day
extracellular fluid volume increased only 4% compared to
day 0, but blood pressure increased 40%, mostly due to in-
creased total peripheral resistance. Modified from refer-
ence.40
Small volume reductions induce large
pressure decreases
After introduction of thiazide diuretics for treatment of
hypertension, blood pressure fall was noted in about two-
thirds of patients.41 The responders were apparently
cases of volume-dependent hypertension. During the ini-
tial few weeks, the extracellular fluid volume and plasma
volume fell. As a result, cardiac output and blood pres-
sure fell in spite of a rise of peripheral vascular resistance.
This initial fall in blood pressure was due to volume
changes, as restoration of volume immediately normal-
ized blood pressure. After 1 month or more of continued
REGULATORY MECHANISMS FOR
EXTRACELLULAR VOLUME
12 14
REDUCTION
The pressor effect of hypervolemia does not result from
an immediate direct effect of slight volume expansion,
because intravenous infusion of an amount of saline
equivalent to that retained does not raise blood pressure.
However, slight volume expansion indeed raises blood
pressure over time, suggesting some slowly acting indi-
rect mechanisms.43
Low potassium and natriuretic
hormones
Reduced potassium concentration in the inflowing blood
in tissues of animals produces vasoconstriction.44 In the
mid-1970s, the hypothesis was put forward that some
circulating factor or factors were responsible for augmen-
tation of vascular tone, increased total peripheral resis-
tance, and hypertension. Haddy and Overbeck45 and
Blaustein46 postulated that a circulating agent, perhaps
the natriuretic hormone, increases intracellular sodium
and calcium in vascular smooth muscles and, therefore,
vascular tension. In the mid-1990s, 2 review papers
summarized studies on the nature of the natriuretic

416 Hemodialysis International 2008; 12:412425

 Sodium is a uremic toxin

hormone and its function. Blaustein47 reported on dis-

Vmax normal
covery of endogenous ouabain (EO), inhibiting sodium
Active
pump leading to increased cytosolic sodium and calcium pump
resulting in increased vasoconstriction. The action of Ouabain sensitive Na K pump flux
(out)
ouabain was unaffected by a-adrenergic blockade. Haddy Vmax decreased
and Pamnani48 reviewed studies leading to the discovery b

Nai flux
of digitalis-like immunoreactive substance (DLIS).
a d
Two recently published papers49,50 review in depth the
c P increased
mechanisms leading to vasoconstriction in salt-depen- Passive
dent hypertension. The plasma of some patients with low
renin hypertension had Na1-K1-ATPase inhibiting activ- leak
ities. The source of DLIS and EO is thought to be the P normal flux
hypothalamus and/or adrenal gland, and the mechanism (in)

of release is suggested to be pulmonary distension. In- KD C2 C3

creased dietary salt increases the renal excretion of po-
tassium resulting in a small fall in plasma potassium level.
The pro-hypertensive actions of low potassium and in-
creased DLIS result from Na1-K1-ATPase inhibition in
vascular smooth muscle, heart muscle, and adrenergic
cells. This inhibition produces electrogenic depolariza-
tion of vascular smooth muscle cells (VSMCs) thereby
increasing Ca21 influx, decreasing Na1-Ca21 exchange,
thereby decreasing Ca21 efflux.50 It also increases intra-
cellular sodium concentration by decreasing sodium ef-
flux (Figure 4).49 Moreover, it decreases norepinephrine
reuptake and increases norepinephrine release by ad-
renergic nerve endings in blood vessels. All these mech-
anisms increase contractility of arteriole smooth muscle
cells leading to increased peripheral resistance and high
blood pressure.49,50
Other Na1-K1-ATPase inhibitors
In addition to DLIS and EO or oubain-like compound
(OLC), several other Na1-K1-ATPase inhibitors have
been found in plasma of chronically volume expanded,
low renin hypertensive patients: digoxin, marino-
bufagenin, proscillaridin, bufalin, and other digitalis-like
steroids.49,50 In general, these substances block potas-
sium vasodilatation, potentiate norepinephrine vasocon-
striction, increase vascular resistance, raise arterial
pressure, and produce natriuresis with Na1-K1-ATPase
[Nai]
Figure 4 The hypothetical effects of increased passive flux
and decreased sodium pump activity on intracellular sodium
concentration [Nai] in vascular smooth muscle. Pump flux
(active sodium efflux) is ouabain-sensitive, passive flux is
ouabain-insensitive sodium flux depending on the gradient.
The normal steady state (point a) occurs when pump efflux
equals passive influx, and intracellular sodium concentration
is normal (KD). A new steady state would be reached at a
higher [Nai] (C2) either due to increased influx with normal
efflux (b) or decreased efflux with normal influx (c). In
chronic volume expansion intracellular sodium is the highest
(C3) due to increased influx and decreased efflux, secondary
to inhibition ouabain-sensitive Na1-K1 pump (d). Modified
from reference.49
with left ventricular hypertrophy.52 Both ANP and BNP
increase natriuresis and diuresis. Whereas ANP acts pref-
erentially on the arterial system to reduce afterload, BNP
acts preferentially on the venous system reducing pre-
Chronic
DLIS
volume Vascular
expansion OLC Na , K -ATPase
inhibition
Blood pressure INa
ICa

inhibition, sodium accumulates in the cells, including

Vasoconstriction
VSMCs, rendering them prone to constriction (Figure 5). myocyte proliferation
Natriuresis

Cardiac natriuretic peptides Figure 5 Mechanism of blood pressure increase after

Atrial natriuretic peptide (ANP) and brain or B-type nat-
riuretic peptide or brain natriuretic peptide (BNP) are re-
leased from the heart in proportion to the degree of
stretch of the cardiac chambers in rats51 and in patients
chronic volume expansion due to inhibition of Na1-K1-AT-
Pase. OLC- ouabainlike compound; DLIS- digoxinlike
immunoreactive substance; INa1- intracellular sodium;
ICa21- intracellular calcium. Based on information from
references.49,50

Hemodialysis International 2008; 12:412425 417

Twardowski
load.53 Plasma BNP is markedly elevated in the majority
of patients on hemodialysis.54 Intensive dialysis lowers
the level of BNP.55 Both ANP and BNP inhibit release of
renin and aldosterone, antagonize the vasoconstrictive
actions of angiotensin and sympathetic stimulation. How-
ever, these actions are insufficient to prevent blood pres-
sure elevation in renoprival states.
Nitric oxide
Nitric oxide (NO), a neurotransmitter and potent vaso-
dilator molecule, is produced by endothelial cell nitric
oxide synthase (eNOS) from L-arginine via a 5-electron
redox reaction. NO also inhibits VSMC proliferation and
migration. High salt intake inhibits nitric oxide synthase
expression in the brain, resulting in activation of the
sympathetic nervous system and higher blood pressure.56
Inhibition of NO synthesis or inactivation by O2 creates
NO deficiency and results in unopposed vasoconstric-
tion, smooth muscle cell proliferation and hypertrophy.
Oxidative stress can promote the production of vasocon-
strictor molecules and primary salt retention by the
kidney. Ultimately, it leads to accelerated progression of
renal failure.57
Hyperosmolar states are associated with activation of
the inflammatory cascade, beginning with the high os-
molarity glycerol (HOG) mitogen-activated protein kinase
(MAPK) pathway and result in a rise in cellular glycerol
concentration to adapt the intracellular osmotic pressure
to the extracellular osmolarity.58,59 This sequence leads to
an increase in asymmetric dimethyl-L-arginine (ADMA)
leading to an inhibition of nitric oxide synthase and at the
same time stimulation of the formation of interleukin-8
(IL-8), transforming growth factor-b (TGF-b) and the in-
flammatory cascade.60 Asymmetrical dimethyl-L-arginine is
metabolized by dimethyl arginine dimethylaminohydrolase
(DDAH) to citrulline and dimethylamine.61 The activity of
this enzyme is diminished in conditions of oxidative stress,
hyperosmotic stress, and inflammation.58,62 High salt in-
take in hypertensive rats was also shown to diminish the
activity of DDAH.63 Figure 6 depicts the mechanism of
blood pressure increase in volume expansion and hyperos-
molar states due to inhibition of nitric oxide synthesis.
Osmotically inactive sodium
Some osmotically inactive sodium in the crystalline phase
of bone was postulated in the 1960s.64 Under conditions
of total starvation, this osmotically inactive sodium can be
mobilized and made available for exchange.65 Recently,
osmotically inactive sodium storage has been docu-
418
High Nitric
osmolarity ADMA oxide synthase
HOG - MAPK
pathway
DDAH Nitric
oxide
IL 8
TGF-
Blood pressure
Natriuresis Vasoconstriction
Figure 6 Mechanism of blood pressure increase after chronic
volume expansion due to inhibition of nitric oxide synthesis.
HOG= high osmolarity glycerol; MAKP=mitogen-activated
protein kinase; IL-8= interleukin-8; TGF-b=transforming
growth factor-beta; ADMA=asymmetric dimethyl-L-arginine;
DDAH= dimethyl arginine dimethylaminohydrolase; solid
arrow=activation; dashed arrow= inhibition. Based on data
from references.5863
mented in humans66 and rats consuming a high-salt
diet.67 Observations of astronauts in weightlessness
revealed a low-affinity, high-capacity, osmotically inactive
sodium reservoir.68 This reservoir may be located in
bone or might act through sodium/hydrogen exchange
on glycosoaminoglycans in dense connective tissue or
cartilage.
SALT IN CHRONIC KIDNEY DISEASE
There is a gamut of capabilities for sodium removal in
chronic kidney diseases (CKD) depending on the stage
and the primary cause of renal damage. Patients with
Bartter or Gitelman syndromes, chronic interstitial ne-
phritis, or other salt-losing nephropathies have dispro-
portionately high sodium losses in relation to glomerular
filtration.6971 Sodium removal may be well preserved
even in CKD stage 5 in such patients.
On the contrary, salt removal may be severely restricted
in glomerulonephritis, vascular,72 or diabetic nephropa-
thy.73,74 Koomans et al.75 studied blood pressure and
body fluid volume changes related to salt intake and ex-
cretion in patients with glomerulonephritis, polycystic
kidney disease, pyelonephritis, nephrosclerosis, analgesic
nephropathy, and congenital kidney hypoplasia in various
degrees of kidney insufficiency. In these patients, the in-
crease in blood pressure, when related to urinary sodium
excretion, rose exponentially with the decrease of creati-
nine clearance. Intravascular volume to extracellular
volume ratio increased more in patients with advanced
renal insufficiency and blood pressure increased more in
Hemodialysis International 2008; 12:412425

relation to the increase of extracellular volume in these
patients.
SALT IN HEMODIALYSIS PATIENTS
In terminal kidney failure, all mechanisms intended to
increase renal sodium removal are inefficient or futile. In
complete anuria, the sodium balance must be achieved
via dialysis and ultrafiltration. Thomas Addis, one of the
pioneers in studies of water and electrolyte disturbances,
was a mentor of Belding H. Scribner when he was a med-
ical student at Stanford University in San Francisco.
Scribner became very interested in this field and one of
his first publications was related to fluid and electrolyte
problems.76 It is not surprising that Scribners attention in
initial chronic dialysis patients was directed toward fluid
and electrolyte disturbances during dialysis treatment. He
saved the life of Clyde Shields, the first chronic hemo-
dialysis patient, from malignant hypertension by ultrafil-
tration over 76 hours. In the discussion of the preliminary
report on intermittent hemodialysis, Scribner et al.77 in-
dicated that As in the nephrectomized dogs, hyperten-
sion appears to be influenced by the size of the
extravascular space. The combination of dietary sodium
restriction and ultrafiltration during dialysis permits reg-
ulation of extracellular volume. In time, it may be possi-
ble to clarify the importance of the size of the extracellular
space in the etiology of hypertension and the effect its size
may have on modifying the response to antihypertensive
therapy. Many years later, Scribner in his memoir on the
beginning of intermittent dialysis, adverted to the treat-
ment of malignant hypertension in his first patient by ul-
trafiltration as . . . soon he became normotensive and
remained so to the rest of his life. This experience con-
vinced us that the key to treatment of hypertension in
dialysis patients was adequate control of the extracellular
volume, a principle that proved to be of immense impor-
tance from that point on.78 With some residual renal
function, a small amount of sodium is still removed and
helps maintain sodium balance. In many patients, urinary
sodium removal falls rapidly after starting dialysis. Clyde
Shields had urinary sodium of 100 mEq/24 h before start-
ing dialysis, and the urinary sodium dropped to 23 mEq/
24 h within a few weeks.77
In the late 1960s, the term dry body weight was in-
troduced. It was presumed that the reduction of blood
pressure to hypotensive levels by ultrafiltration and un-
associated with other obvious causes, represented the
achievement of a dry weight status.79 Others defined Only a few groups report excellent blood pressure control
dry weight as no clinical evidence of edema and optimal
body sodium content and volume of water.80
Hemodialysis International 2008; 12:412425
Sodium is a uremic toxin
In the 1960s and early 1970s, centers using long di-
alysis sessions combined with low-salt diets achieved
control of hypertension without antihypertensive medi-
cations in over 90% of dialysis patients.8183 Those cen-
ters where shorter or less frequent (twice weekly)
hemodialysis treatments were used reported higher inci-
dence of hypertension.80,84
Since the late 1970s, shortening of dialysis time has led
to a resurgence of hypertension and increased mortal-
ity.8587 With short dialysis, blood pressure could not be
controlled by control of extracellular volume and the
definition of dry body weight was gradually redefined
as the lowest weight a patient can tolerate before expe-
riencing hypotension or symptoms.88,89 However, with
rapid ultrafiltration, hypotension is dependent mostly on
low blood volume, which occurs long before the dry
body weight is achieved, because the refilling rate from
the extracellular space to the intravascular space is slower
than the ultrafiltration through the dialyzer.89,90 It is ex-
tremely difficult to estimate true dry body weight with
short dialysis. This is one of the reasons that the term dry
body weight, used in the 1960s, has been replaced with
the term target weight. This term means that this is the
weight the patient should have after dialysis, regardless
whether it is the true dry body weight or not. Taking
into account that over 75% of hemodialysis patients in
the United States require antihypertensive medications,91
while over 90% of patients treated with long dialysis as-
sociated with gentle ultrafiltration have normal blood
pressure without blood pressure drugs,92 we may safely
assume that most of the patients on short dialysis have
expanded extracellular space and do not achieve a true
dry body weight at the end of the hemodialysis session.
Similar to observations of Guyton in individuals with es-
sential hypertension (vide supra), the elevation of extra-
cellular volume in hypertensive hemodialysis patients is
very small.93 Again, as in patients with volume-
dependent hypertension, this small difference in volume
leads to defensive mechanisms geared toward increase in
renal salt excretion to lower extracellular volume. With-
out kidney function these efforts are futile; instead, they
result in vasoconstriction, elevation of blood pressure,
and all the consequences thereof.
BLOOD PRESSURE CONTROL
WITHOUT ANTIHYPERTENSIVE DRUGS
in over 90% of patients without blood pressure drugs, but
by strict volume control employing a low-sodium diet
419
Twardowski
and long dialysis duration9395 or very low-sodium diet
with thrice weekly 4-hour dialysis sessions.96,97
In the late 1960s, the dialysis unit at the Royal Free
Hospital in London, England, applied a special method to
control blood pressure without antihypertensive medica-
tions. Upon entering the hemodialysis programme all
antihypertensive drugs are withdrawn. Daily dialysis of
short duration (4 to 6 hours) is started using 1-m2 Kiil
dialyzer with cuprophane membranes. The removal of
excess sodium and water in hypertensive patients is ac-
complished by ultrafiltration during dialysis and restric-
tion of dietary sodium and water between dialyses.
Having completed the initial training and control period
in hospital, the patient starts overnight home hemodial-
ysis for 3 10-hour periods each week, using dialysis
fluid with a sodium concentration of 135 mmol/L. This
method allowed control of blood pressure in most
patients without recourse to bilateral nephrectomy or
hypotensive drugs.82
DRY BODY WEIGHT IN
HEMODIALYSIS PATIENTS
Assessment of dry body weight
In the era of short dialysis, the estimation of dry body
weight became very difficult, so multiple, so-called
objective methods have been proposed to aid with this
assessment, including cardiothoracic ratio on X-ray, elec-
tron beam CT scan of lung density, vena cava diameter
and collapsibility, monofrequency bioimpedance analysis
and multifrequency bioimpedance spectroscopy, blood
volume monitoring, and serum levels of natriuretic pep-
tides, and cyclic guanidine monophosphate.89 However,
none of them can replace clinical judgment.93,98 The
simple reason is that small increases in extracellular fluid
volume induce mechanisms to increase total peripheral
resistance and increase blood pressure. Such small
changes are not easily determined with so-called objec-
tive methods. Combining these methods increases com-
plexity, time, and cost. For practical purposes, an absolute
measurement of extracellular volume is not considered
necessary, as the normalization of blood pressure and ab-
sence of symptoms and signs of fluid overload or dehy-
dration is clinically sufficient. According to the Centre de
rein artificial in Tassin, France, where excellent blood
pressure control without blood pressure medications is
achieved in over 90% of patients, dry weight is defined as
the body weight achieved at the end of dialysis at which
the patient remains constantly normotensive until the
next dialysis without antihypertensive medications.93
420
Only in the small proportion of patients, whose blood
pressure cannot be normalized without antihypertensive
drugs in spite of sufficient dialysis duration and/or fre-
quency, and with conflicting clinical symptoms of body
water condition, noninvasive devices such as total body
impedance and/or vena cava inferior diameter may be
helpful in assessing volume state.99 However, it is worth
realizing that normal volume values may depend on the
frequency and duration of hemodialysis sessions.
Clinical assessment of dry weight
The clinical assessment of dry weight does not require
extra time and/or money. It is precise, but requires astute
clinical assessment, especially during initiation of chronic
dialysis, when the patient is still on blood pressure med-
ications. The Tassin group calls this initial phase of treat-
ment probing for dry weight. After the start of the
probe for dry weight, dialysis sessions are increased from
3 to 8 hours in length in 1-hour increments. Intense,
carefully monitored ultrafiltration plus a strict low-so-
dium diet permit a gradual reduction in the predialysis
weight of approximately 2 kg and postdialysis weight of
3 kg over the first 2 to 4 weeks. The actual rate of decrease
is by trial and error, governed by the patient tolerance, to
reduce to minimum episodes of muscle cramps and hy-
potension . . . antihypertensive medications are gradually
withdrawn.92 It is also important to be aware of the ex-
istence of the lag phenomenon (vide infra). Dry body
weight changes depend on the food intake and metabo-
lism, so the clinical circumstances must be monitored in a
systematic manner.93
DESCRIPTION OF THE LAG
PHENOMENON
The lag phenomenon, i.e., the delay of blood pressure
decrease after normalization of extracellular fluid volume,
was observed in the middle of the twentieth century after
introduction of the rice diet19,20 and during treatment
with thiazide diuretics41,42 (vide supra). In 1962, Scribner
commented that it is the average level of sodium in the
body over a long period of time that correlates with blood
pressure rather than the acute variation of volume.100 In
1967, it was noted that . . . in many patients a time lag
exists between reduction of E.C.V. and adequate control
of blood-pressure. Several days or weeks may be required
for adequate control even though striking weight loss
and, presumably, reduction of E.C.V. occurred immedi-
ately.101 The long-term relationship between body
weight and blood pressure is well illustrated in Figure 7
Hemodialysis International 2008; 12:412425
 Sodium is a uremic toxin

Weight Gradual ECV assessment

(Kg) withdrawal of NaCl restriction
AntiHT medications MAP mmHg
antihypertensive
89% < 5% Post HD weight medication(s)
67 125 Dialysate Na 138 140
pts
PreHD MAP 120 UF 0.10.15/mL/min/kg 0.30.6 L/h
66 Hemodialysis duration 15 24 h/week
115 Post HD wt 0.5 1.0 kg/week
65
110 Lag phase up to one month
64 Dry weight achieved
105 or
UF as needed wt
63
100
62 95
61 90 Normotension 90%95% Volume independent hypertension 5%10%
0 1 2 3 6 9 12 of antihypertensives Specific antihypertensive drugs
Dialysis time (months)
Figure 8 Diagram of blood pressure treatment at the start of
Figure 7 Evolution of postdialysis weight ( SEM) and pre- hemodialysis based on recommendations from refer-
dialysis mean arterial pressure (MAP) ( SEM) in first hemo- ences.82,93
dialysis (HD) year. Whereas almost 90% of patients were on
antihypertensive (AntiHT) medications at the start of dialy-
sis, o5% remained on antihypertensive drugs by the second pound acts by competing with NGNIGdimethyl-L-arginine
month of dialysis when a true dry body weight was achieved. (symmetric dimethyl-L-arginine; SDMA).102 Asymmetri-
Modified from reference.93 AntiHT =antihypertensive. cal dimethyl-L-arginine was found to be higher in patients
with atheriosclerotic disease and more in hemodialysis
than in peritoneal dialysis patients.103 The same is true in
the opposite direction when salt and volume are de-
from the experience in Tassin.93 The body weight post- creased.
dialysis, representing dry body weight drops to the The possible mechanism of the lag phenomenon is
lowest level 1 month after the initiation of dialysis. By presented in Figure 9. Normalization of blood pressure
that time, antihypertensive drugs are stopped in over 95% may depend on gradual decrease of intracellular sodium.
of patients. Dry body weight starts to increase because of With the inhibition of Na1-K1-ATPase, this process may
improvement in appetite, but blood pressure continues to
decrease.93 This delay in normalization of blood pressure Vasoconstriction
Chronic volume
after normalization of extracellular fluid volume repre- expansion myocyte proliferation
high blood pressure
sents the lag phenomenon. The diagram in Figure 8
illustrates blood pressure treatment at the start of hemo- Extracellular
Gentle UF during long
HD sessions. Low-salt diet
dialysis based on experiences from centers where blood volume normalized
pressure control without blood pressure medications
could be achieved in 90% to 95% of patients.82,93
Lag Phase

POSSIBLE MECHANISM OF THE LAG OLC

DDAH
SDMA
Osmotically inactive
Na moves slowly to
DLIS
PHENOMENON ADMA extravascular space
prolonging lag phase
As explained above, the pressor effect of hypervolemia INa Nitric
does not result from an immediate direct effect of slight ICa oxide Blood
volume expansion but from some slowly acting indirect pressure
Vasodilatation
mechanism. Humoral factors responsible for increased
peripheral vascular resistance accumulate gradually after
Figure 9 The mechanism of delayed blood pressure de-
chronic salt and volume expansion: digitalis-like sub- crease (lag phenomenon) after extracellular volume is slowly
stances, and other inhibitors of Na1-K1-ATPase, and in- normalized. OLC= ouabainlike compound; DLIS= digoxin-
hibition of NO synthesis. A potent inhibitor of NO like immunoreactive substance; INa1 =intracellular sodium;
synthesis, NGNGdimethyl-L-arginine (asymmetric dimeth- ICa21 = intracellular calcium; DDAH =dimethyl arginine
yl-L-arginine; ADMA) has been found to accumulate in dimethylaminohydrolase; SDMA= symmetric dimethyl-L-
plasma of patients with chronic renal failure. This com- arginine; ADMA =asymmetric dimethyl-L-arginine.

Hemodialysis International 2008; 12:412425 421

Twardowski
take several weeks. Increased synthesis of nitric oxide
may be delayed due to gradual increase in DDAH, SDMA,
and decrease in ADMA. The delay in blood pressure nor-
malization may also be associated with a slow release of
osmotically inactive sodium from bones, cartilage, dense
connective tissue, and the interstitial matrix lining the
intimal surfaces of blood vessels containing proteoglycans
and glycosaminoglycans.104
ACKNOWLEDGMENTS
Presented in part at the Annual Dialysis Conference in
Denver, CO, USA, February 19, 2007. I thank Joanna
Nowosielska for translations from French and Justyna
Mitka for translations from German.
Manuscript received October 2007; revised March 2008.
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