SPECIAL ARTICLE

Blood Pressure Control in Dialysis Patients:

Importance of the Lag Phenomenon
Bernard Charra, MD, Jonas Bergstrom, MD, and Belding H. Scribner, MD
Failure by the world dialysis community to understand and use the dry-weight method of blood pressure (BP)
control has resulted in an increasing incidence of treatment-resistant hypertension, which remains the principal
cause of cardiovascular morbidity and mortality. This failure may in part be because the relationship between the
extracellular volume (ECV) and BP is not simple and linear, but complex, because of a lag of several weeks between
the normalization of the time-averaged ECV and the decrease in BP. Another cause for this failure may be the
unwillingness to taper and stop all antihypertensive medications during the transition from hypertension to
normotension. In this report, we describe in detail the lag phenomenon, document its presence during treatment in
other populations, and describe how this knowledge is used in the application of the dry-weight method of drug-free
BP control in the dialysis population.
r 1998 by the National Kidney Foundation, Inc.
INDEX WORDS: Hemodialysis; hypertension; dry weight; lag time; extracellular volume.

NUMBER OF RECENT publications show

that the procedure for controlling blood
pressure (BP) using the dry-weight method1 is
not well understood. The purpose of this report is
to show that with the dry-weight method of BP
control, the relationship between BP and extracellular volume (ECV) is not linear, but complex,
because of what we term the lag phenomenon.
BRIEF HISTORY

In 1960, one of the authors (B.H.S.) and his

colleagues saved the life of the first chronic
dialysis patient by curing his malignant hypertension using aggressive ultrafiltration.2
In the 1970s, long dialysis sessions combined
with a low-salt diet allowed the control of hypertension without antihypertensive medication in
90% of the patients.3-5 In recent years, shortening
of dialysis time has led to a resurgence of hypertension.6,7 Today, hypertension has become a

From the Centre de rein artificiel, Tassin, France; Department of Clinical Sciences, Division of Baxter Novum, Karolinska Institutet, Huddinge, Sweden; and the University of
Washington School of Medicine, Seattle, WA.
Received December 18, 1997; accepted in revised form
April 24, 1998.
Presented in part at the American Society of Nephrology
30th Annual Meeting, San Antonio, TX, November 2-5,
1997.
Address reprint requests to Bernard Charra, MD, Centre
de rein artificiel, 42 Avenue du 8-Mai-1945, 69160 Tassin,
France. E-mail: bcharra@aol.com

r 1998 by the National Kidney Foundation, Inc.

0272-6386/98/3205-0003$3.00/0
720

leading cause of morbidity and mortality in the

dialysis population.8,9
The entire Tassin experience with BP control,
which began more than 30 years ago, is shown in
Fig 1. It involves 712 patients. A detailed description of these patients has been published elsewhere.10 Each patients record showed this lag
phenomenon during what we term the probe for
dry weight. However, until now, we and other
investigators who have encountered this lag phenomenon11,12 have failed to delineate it or recognize its importance in understanding and implementing the dry-weight method of BP control,
especially in the dialysis population.
DESCRIPTION OF THE LAG PHENOMENON

Figure 1 shows the overall experience in Tassin with drug-free BP control using the dryweight method in 712 patients.10 Note that the
mean loss of predialysis weight from 64.3 kg
(95% confidence interval [CI], 63.7 to 64.8 kg)
to 62 kg (95% CI, 61.4 to 62.6 kg) is already
complete by the end of the first month (P
0.005), indicating, we believe, a decrease of
about 2 L in the predialysis ECV. A recent study
has confirmed, by direct measurement of the
ECV, an approximately 2- to 3-L difference between hypertensive and normotensive dialysis
patients.13
During this same month, the mean arterial
pressure (MAP) only decreased from 121 mm
Hg (95% CI, 119.0 to 122.6 mm Hg) to 108 mm
Hg (95% CI, 106.6 to 109.3 mm Hg). At this

American Journal of Kidney Diseases, Vol 32, No 5 (November), 1998: pp 720-724

LAG PHENOMENON

Fig 1. Postdialysis average weight (kilograms) and

predialysis average MAP (millimeters of mercury) in
712 Tassin patients in the 12 first dialysis months. The
line represents predialysis MAP 1 standard error of
the mean (SEM); the bars represent the mean postdialysis weight 1 SEM; (O), postdialysis weight; (),
predialysis MAP. Abbreviation: AntiHT, antihypertensive.

point, antihypertensive medications were still being withdrawn.

The MAP continued to decrease for another 8
months despite the withdrawal of antihypertensive medication in more than 90% of the 712
patients. It was this delay between the abrupt
normalization of ECV and the much more gradual
decrease in the predialysis MAP that we have
termed the lag phenomenon.
After the first month, serial changes in postdialysis weight no longer reflect the changes in
ECV because the patient becomes anabolic and
gains dry weight. This increase in dry weight is
consistent with a gradual increase in predialysis
serum creatinine level from 830 to 930 mol/L
over the next 12 months (P 0.001), despite a
constant dose of dialysis,10 which maintains the
urea Kt/V at greater than 1.6.
Figure 2 shows in more detail what happened
to ECV as reflected in body weight and MAP
during the first month in 96 patients started on
dialysis in Tassin since 1992. In this figure, we
used predialysis weight to reflect the size of the
ECV before treatment began. Figure 2 shows the
weight/ECV decreasing by approximately 2 L
early in the first month. Meanwhile, MAP decreased gradually over the same period, during
which time antihypertensive medications were
tapered.
Figure 3 shows a free graph of this lag phenomenon as we envision it. The predialysis ECV
decreased promptly, reaching a low within the

721

Fig 2. Predialysis average weight (kilograms) and

predialysis average MAP (millimeters of mercury) in 96
Tassin patients in the first hemodialysis month. The
line represents predialysis MAP 1 SEM; the bars
represent the mean postdialysis weight 1 SEM; (O),
predialysis weight; the bars represent predialysis MAP.

first month, after which it remained stable. The

predialysis MAP took months to finally stabilize,
long after antihypertensive medications had been
withdrawn.
OTHER EXAMPLES OF THE LAG
PHENOMENON

It is relevant that in the 1940s, Kempner11 was

able to treat essential hypertension successfully
by dietary sodium restriction alone using his
rice-fruit diet, which was virtually sodium free.
His success rate exceeded 50%, despite the almost impossible rigors of this difficult diet. The
lag between the institution of this diet and the
decrease in BP was at least 1 month. Direct
measurement by Murphy14 of the ECV before
and after the institution of the rice-fruit diet in 17
patients showed a very similar decrease to what
we have seen of approximately 2 L.
Another example of this lag phenomenon occurs when diuretics alone are used to treat hypertension. Responders have an initial ECV decrease of 1.5 to 2 L. The BP begins to decrease

Fig 3. Theoretical graph of predialysis ECV and

predialysis MAP during the first 12 months of hemodialysis. The grey line represents predialysis ECV; the
black line, the predialysis MAP.

 M, AND SCRIBNER
CHARRA, BERGSTRO

722

within the first week and continues to decrease

over 2 to 3 months.12
THE ECV AT DRY WEIGHT

At dry weight, the ECV as measured by standard isotopic methods is in the normal range.15
However, we believe that patients at dry weight
have an ECV that is at the low end of the normal
range. In this respect, dialysis patients may be
similar to such populations as the Yanomamo
Indians, who ingest an almost sodium-free diet
and have no hypertension.16 At dry weight, a
patient is completely intolerant to antihypertensive medications.
Serial measurements of the ECV during the
lag period using newer methodology, such as
bioimpedance,17 may help clarify this dynamic
relationship between ECV and BP. The clinical
availability of such measurements may make it
easier to achieve dry weight during the probe.
PROBING FOR DRY WEIGHT

From the practical standpoint, instituting the

dry-weight method of drug-free BP control in a
dialysis patient is not easy, especially during the
phase of normalizing BP while withdrawing BP
medications. We call this phase probing for dry
weight.1
What typically happens during the first month
is shown in Fig 2. Before the start of dialysis
treatment, 90% of our patients are hypertensive,
despite receiving antihypertensive medication.
Their ECV is expanded, even though most have
no edema.
At 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-sodium
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 strictly by trial and
error, governed by the patients tolerance, to
reduce to a minimum episodes of muscle cramps
and hypotension.
During this initial period, antihypertensive
medications are gradually withdrawn. Failure to
do so makes it impossible to achieve and maintain dry weight.
During this first month, the patients appetite
gradually improves. They become anabolic and

begin to put on real body weight. This change

soon begins to complicate the problem of determining postdialysis weight, which calls for careful medical judgment and supervision.
Obviously, the probe for dry weight represents
a difficult transition for the patients. This transition must be carefully explained to them and
ongoing support from physicians and staff are
absolutely essential. At the same time, the patients must be made to understand that once this
transition is over, they will feel much better. The
highly restrictive low-sodium diet can be liberalized somewhat.
It is important to explain to the patient that if
the initial rigidly restricted low-sodium diet is
followed, the blandness of food will disappear
within some weeks. The pleasant taste of unsalted food will be rediscovered and patients
often complain about the burning sensation when
normally salted food is ingested. We believe this
resetting of the taste for salt explains the very
rare complaint of thirst by our patients, as well as
the mean observed interdialytic weight gain of
only 1.6 kg.
The patient also must understand that, after
reaching dry weight, he no longer will have to
take antihypertensive medications, which, in the
dialysis patient, are poorly effective and, in the
dosages used, often have debilitating side effects.
Most important, it must be explained that by
curing the hypertension, the danger of having a
heart attack or a stroke is greatly reduced.
PATHOPHYSIOLOGY OF HYPERTENSION
IN THE DIALYSIS PATIENT

We postulate that during the probe for dry

weight, the reverse sequence of hemodynamic
modifications after a saline load in patients with
end-stage renal failure is experienced, as described by Guyton.18 This investigator has shown
that a sodium load results in a sequence that
includes ECV overload, transient increased cardiac output, and increased total peripheral resistance resulting in increased BP. Hypertension, in
turn, increases the natriuresis that returns the
ECV to an almost normal level. The difference in
ECV between normotension and hypertension
does not exceed 2% of body weight.18

LAG PHENOMENON

DISCUSSION

Failure to understand that relatively small

changes in time-averaged ECV, if sustained, can
have profound effects on BP because of gradual
changes in peripheral resistance has led to questions about the validity of the dry-weight method.19 However, this conclusion was mainly based
on acute studies that showed poor correlation
between increase in BP and weight gain during
one interdialytic period.20,21 Hence, these studies
did not consider the lag phenomenon. Indeed,
other studies22 using noninvasive technologies of
volume assessment concluded that ECV overload has an essential role in dialysis hypertension.
Even more to the point, we believe that a
recently completed report on BP control in the
dialysis patient by a prestigious committee23
should have acknowledged the scientific validity
of the dry-weight method of BP control as practiced in Tassin. One does not need a double-blind
study to prove that the dry-weight method is
scientifically valid any more than Kempner11
needed a double-blind study to prove that the
rice-fruit diet could cure essential hypertension,
because in those days, there was no other cure for
hypertension.
The same dilemma must be faced by the task
force of the National Kidney Foundation, which
currently is finalizing a report on how to stem the
epidemic of cardiovascular complications in the
end-stage renal disease population. At the basic
level, the answer is quite simple. Control of BP
using the dry-weight method will markedly reduce the incidence of cardiovascular complications, as the Tassin experience clearly shows.10
As we see it, the problem is how to adapt
drug-free, dry-weight control of BP to todays
incenter dialysis practice. Recent publications24-26
have shown that skillful manipulation of dialysate sodium concentration improves BP control
in patients undergoing short incenter dialysis.
More attention to lowering dietary sodium intake
also improves BP control.26
The recent use of long, very slow home dialysis sessions by Pierratos et al27 represents another solution to this problem. More extensive
use of chronic ambulatory peritoneal dialysis in
the early stages of end-stage renal disease dialytic therapy should provide an excellent way to
implement the dry-weight method of drug-free

723

BP control.28 Other solutions may be found once

there is again proper funding for clinical investigation in this area.2
In the meantime, a good beginning might be to
study and refine old and new dietary methods for
reducing the sodium intake of the US dialysis
population. For every gram that a patients sodium intake is reduced between each dialysis, the
need to remove ECV by ultrafiltration also is
reduced by approximately 300 mL. Also, the
reduction in cramps and hypotension during short
dialysis26 would serve as an incentive to patients
to comply with more sodium restriction in the
diet.
REFERENCES
1. Charra B, Chazot C, Laurent G, Calemard E, Terrat JC,
Vanel T, Jean G, Ruffet M: Clinical assessment of dry
weight. Nephrol Dial Transplant 11:16-19, 1996 (suppl 2)
2. Scribner BH: Milestones in nephrology: The treatment
of chronic uremia by means of intermittent hemodialysis. A
preliminary report. Trans Am Soc Artif Intern Organs 6:114122, 1960
3. Hegstrom RM, Murray JS, Pendras JP, Burnell JM,
Scribner BH: Hemodialysis in the treatment of chronic
uremia. Trans Am Soc Artif Int Organs 7:136-149, 1961
4. Comty C, Rottka H, Shaldon S: Blood pressure control
in patients with end-stage renal failure treated by intermittent dialysis. Proc Eur Dial Transplant Assoc 1:209-210,
1964
5. Vertes V, Cangiano JL, Berman LB, Gould A: Hypertension in end-stage renal disease. N Engl J Med 280:978981, 1969
6. Wizemann V, Kramer W: Short-term dialysis, longterm complications. Blood Purif 5:193-201, 1987
7. Cheigh JS, Milite C, Sullivan JF, Rubin AL, Stenzel
KH: Hypertension is not adequately controlled in hemodialysis patients. Am J Kidney Dis 19:453-459, 1992
8. Salem MM, Bower JD: Hypertension in the hemodialysis population. Am J Kidney Dis 29:811-812, 1997
9. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray
DC, Barre PE: Impact of hypertension on cardiomyopathy,
morbidity and mortality in end-stage renal disease. Kidney
Int 49:1379-1385, 1996
10. Charra B, Calemard E, Laurent G: Importance of
treatment time and blood pressure control in achieving
long-term survival on dialysis. Am J Nephrol 16:35-44,
1996
11. Kempner W: Treatment of hypertensive vascular disease with rice diet. Am J Med 8:545-577, 1945
12. Freis ED, Reda DJ, Materson BJ: Volume (weight
loss) and blood pressure response following thiazide diuretics. Hypertension 12:244-250, 1988
13. Katzarski KS, Charra B, Luik A, Habets J, Nisell J,
Filho JD, Leypoldt JK, Leunissen KML, Laurent G, Bergstrom J: Fluid state, blood volume and blood pressure
control in patients treated with long hemodialysis procedure.

724

A comparison with conventional hemodialysis treatment.

Nephrol Dial Transplant (in press)
14. Murphy RJF: The effect of rice diet on plasma
volume and extracellular fluid space in hypertensive subjects. J Clin Invest 29:912-917, 1950
15. Blumberg A, Nelp WD, Hegstrom RM, Scribner BH:
Extracellular volume in patients with chronic renal disease
treated for hypertension by sodium restriction. Lancet 2:6973, 1967
16. Freis ED: Salt, volume and the prevention of hypertension. Circulation 53:589-595, 1976
17. de Vries PMJM: Plasma volume changes during hemodialysis. Semin Dial 5:42-47, 1992
18. Guyton AC: Renal functional curve: A key to understanding the pathogenesis of hypertension? Hypertension
10:1-6, 1987
19. Kirchner KA: Hypertension in hemodialysis patients:
More questions than answers. Am J Kidney Dis 30:577-578,
1997
20. Luik AJ, van Kujik WHM, Spek J, de Heer F, van
Bortel LMA, Schiffers PMH, van Hoof JP, Leunissen KML:
Effects of hypervolemia on interdialytic hemodynamics and
blood pressure control in hemodialysis patients. Am J Kidney Dis 30:466-474, 1997
21. Savage T, Fabbian F, Giles M, Tomson CRV, Raine
AEG: Interdialytic weight gain and 48-hour blood pressure
in haemodialysis patients. Nephrol Dial Transplant 12:23082311, 1997

M, AND SCRIBNER
CHARRA, BERGSTRO

22. Katzarski KS, Nisell J, Randmaa I, Danielsson A,

Freyschuss U, Bergstrom J: A critical evaluation of ultrasound measurement of inferior vena cava diameter in assessing dry weight in normotensive and hypertensive hemodialysis patients. Am J Kidney Dis 30:459-465, 1997
23. Mailloux LU, Haley W: Hypertension in the ESRD
patient: Pathophysiology, therapy, outcomes, and future directions. Am J Kidney Dis 32:705-719, 1998
24. Flanigan MJ, Khairullah QT, Lim VS: Dialysate
sodium delivery can alter chronic blood pressure management. Am J Kidney Dis 29:383-391, 1997
25. Donohoe P, Farmer C, Dallyn P, Kingswood JC,
Goldsmith DJA, Sharpstone P: Low-sodium hemodialysis
without fluid removal improves blood pressure control in
chronic dialysis patients. Kidney Int 52:1119, 1997 (abstr)
26. Krautzig S, Janssen U, Koch KM, Granoleras C,
Shaldon S: Dietary salt restriction and reduction of dialysate
sodium to control hypertension in maintenance haemodialysis patients. Nephrol Dial Transplant 13:552-553, 1998
27. Pierratos A, Ouwendyk M, Francoeur R, Vas S, Raj
D, Ecclestone AM, Langos V, Uldall R: Nocturnal hemodialysis: Three-year experience. J Am Soc Nephrol 9:859-868,
1998
28. Young MA, Nolph KD, Dutton S, Prowant BF: Antihypertensive drug requirements in CAPD. Perit Dial Bull
4:85-88, 1984