Hemodialysis Adequacy: A Review
Ankit N. Mehta, MD; Andrew Z. Fenves, MD
The authors are with the Department of Internal Medicine, Division of Nephrology, Baylor University Medical Center, Dallas,
Texas. Dr. Fenves is co-Editor in Chief of D&T.
ABSTRACT: “Adequate dialysis” is interpreted as the amount of dialysis required to keep a patient alive and
relatively asymptomatic. Since the inception of hemodialysis, there have been numerous approaches to quantify
the delivered dialysis dose in a reproducible manner, and to link the dialysis dose with clinical outcomes.
H
emodialysis has been performed
in some form for more than half a
century. A description of Willem
Kolff’s dialyzer and of the first
clinical dialysis was published back in
1944.1 Murray and collegues performed
the first human hemodialysis in North
America.2 At its inception, the dialysis
prescription was empirically determined,
and “adequate dialysis” was interpreted
as the amount of dialysis required to keep
the patient alive and relatively asymptom-
atic. Subsequently, there have been numer-
ous approaches to quantify the delivered
dialysis dose in a reproducible manner,
and to link the dialysis dose with clinical
outcomes.
Urea Kinetic Modeling, Kt/V,
and URR
Measurement of the dialysis dose has, for
the most part, relied on estimation of clear-
ance of the small, water-soluble, nitrog-
enous waste product urea, and hence the
mathematical model is referred to as urea
kinetic modeling (UKM). It assumes that
urea is distributed in a single, well-mixed
pool. (Two-pool models exist but are gen-
erally considered not any more accurate to
justify their complexity in daily use.) UKM
also assumes that urea is generated at a
constant rate by protein metabolism and
is removed at a constant rate by residual
renal function, and intermittently by dialy-
sis. Hence, in a person with negligible
renal function, the extent of urea removal
provides a measure of dialysis adequacy,
and the rate of production correlates with
dietary protein intake.
Kt/V is a dimensionless ratio repre-
senting fractional urea clearance, where K
is the dialyzer urea clearance (expressed
in liters per hour), t is time on dialysis
(expressed in hours), and V is the volume
of distribution of urea (expressed in liters).
It is computed using UKM. Kt/V derived
DOI: 10.1002/dat.20392
from single-pool urea kinetics and is
referred to as spKt/V. A value of spKt/V
of 1 would imply that the total volume of
blood completely cleared of urea during
a dialysis session would be equal to the
volume of distribution of urea.
When dialysis flow rate and blood flow
rate are increased, and the time on dialysis
is shortened, the treatment is not as efficient
because solute disequilibrium is enhanced
and there is more time for solute to accumu-
late between dialysis sessions. Correction
for the solute disequilibrium can be made
by adjusting the Kt/V for the rebound in
urea, which happens mainly in the 30–60
minutes immediately post dialysis. The
resultant Kt/V is termed equilibrated Kt/V
or eKt/V. Numerous equations have been
developed by Daugirdas and others to help
derive the eKt/V from spKt/V.3-5 eKt/V is
usually about 0.2 units lower than spKt/V,
but this depends on dialysis efficiency.
Another measure of delivered dialysis
dose is the urea reduction ratio (URR).
Because the relative decrease in urea con-
centration during dialysis is the most sig-
nificant determinant of Kt/V, direct mea-
surement of URR has been proposed as
a simpler substitute for more complex
equations or for formal urea modeling to
calculate dialysis dose, as follows:
URR = (BUNpre ⫺ BUNpost)/BUNpre
where BUNpre is pre-dialysis urea concen-
tration and BUNpost is post-dialysis urea
concentration. By convention, the value
is multiplied by 100 and expressed as a
percentage. It is also termed percentage
reduction in urea (PRU).
Online clearance is the term used when
the dialysis dose is calculated by measuring
conductivity or ionic clearance across the
dialysis membrane. Multiple ions can be
tracked at the same time to minimize error,
and the delivered Kt/V can be predicted
in real time before the treatment is over.
Although sound in theory, the practical
application is limited.
UKM is also used to calculate the pro-
tein catabolic rate (PCR) and the protein
catabolic rate normalized to body weight
(nPCR), both of which are useful measures
of nutrition.
Limitations of UKM
One of the drawbacks of UKM is the
choice of urea as the ideal marker for
measurement. Urea has a molecular weight
of 60 daltons and is considered a small
electro-neutral solute. It is clear that rate of
removal of a solute depends, among other
factors, on its molecular weight, charge,
volume of distribution, and protein bind-
ing. Hence, clearance of substances with
much larger molecular weights, like vita-
min B12, would be different from that of
urea. Similarly, phosphate, which is bound
to albumin and has a large intracellular
presence, will have a different clearance
from urea. Thus, clearance of urea cannot
be extrapolated to other substances as each
“uremic toxin” behaves differently.
UKM does not take into account resid-
ual renal function, which has a significant
impact on patient outcome.6 Even though
urea clearance by the kidneys (Kru) can be
calculated, it is clear that Kru and Kt from
Kt/V are not additive. Also, it has been
shown that V calculated by anthropometric
formulas systematically overestimates vol-
ume by about 15%.7
Another limitation is that as the fre-
quency and duration of dialysis increases,
the measurement of Kt/V becomes less
precise. This is because the difference
between the pre-dialysis and post-dialysis
urea concentration becomes less and less
as the time on dialysis increases. Hence, the
application of Kt/V as a measure of dialysis
adequacy for patients on more frequent
dialysis regiments, such as daily nocturnal
dialysis, may not be as precise.
Also, an increasing Kt/V in a patient
due to a falling V is not necessarily a sign
of improving dialysis. A falling V may be
January 2010 Dialysis & Transplantation 1
 reflecting a loss of lean body mass and
hence be a poor nutritional prognostic sign.
Similarly, a weight gain in a malnourished
patient leading to a rising V may be incor-
rectly interpreted as inadequate dialysis,
since Kt/V will be lower. Because modeled
V is by itself a predictor of mortality, use of
dialysis dose factored by V may confound
dialysis dose-versus-mortality relationships
in complex ways.
There is also a tendency to overesti-
mate the time on dialysis. Interruptions
for saline administration, dialysis machine
alarms, dialyzer clotting, and so on all tend
to be included as “time on dialysis.”
The measurement of K ⫺ dialyzer urea
clearance is difficult. The value provided
by manufacturers is frequently calculated
by in vitro measurements using aqueous
solutions of urea and often overestimates
in vivo clearance.
Also, the accuracy of the Kt/V calcula-
tions depends on timing/method of blood
draws, before and after dialysis, which are
a potential source of error. The National
Kidney Foundation’s kidney diseases out-
come quality initiative (KDOQI) guide-
lines have addressed this issue and have
recommendations for pre-dialysis and post-
dialysis blood draw techniques.8
National Cooperative Dialysis
Study (NCDS)
The NCDS was the first multicenter, ran-
domized controlled trial of hemodialysis
adequacy in which UKM was used to adjust
the dialysis parameters in order to achieve
the pre-determined target urea levels for the
various study groups.9 Using a two-by-two
factorial design, 160 patients were random-
ized to two different urea time-averaged
concentrations (TAC; 100 vs. 50 mg/dL) and
to two different treatment times (2.5–3.5 vs.
4.5–5.5 hours) and followed up for 6 months.
Outcome was either success or failure, with
failure being defined as death, hospitaliza-
tion, or withdrawal from the study for medi-
cal reasons. The high urea/short time group
had the most morbidity and that arm of the
study was prematurely discontinued; similar
but slightly lower morbidity was noted in the
high urea/long time group. The relationship
between high urea and treatment failure was
clear. The statistical relationship between
treatment time and patient outcome in this
2 Dialysis & Transplantation January 2010
study was considered not to be significant
because of a p value of 0.056
In 1985 Gotch and Sargent re-examined
and re-interpreted the NCDS data.10 They
mechanistically analyzed the data looking
for a relationship between Kt/V and prob-
ability of failure, producing quite different
results. When outcomes were analyzed as a
function of Kt/V, a discontinuous function
was said to result, such that probability
of failure was high at Kt/V less than 0.8,
then sharply decreased at 0.9, and did
not decrease further as Kt/V rose. These
authors concluded that Kt/V was the best
indicator of dialysis adequacy.
Hemodialysis (HEMO) Study
The HEMO study was a randomized clini-
cal trial with a two-by-two factorial design
in which 1,846 patients undergoing thrice-
weekly dialysis were assigned randomly
to a standard or high dose of dialysis and
to a low-flux or high-flux dialyzer. In
the standard-dose group, the mean (⫾SD)
urea-reduction ratio was 66.3 ⫾ 2.5%, the
single-pool Kt/V was 1.32 ⫾ 0.09% and the
equilibrated Kt/V was 1.16 ⫾ 0.08% in the
high-dose group, the values were 75.2 ⫾
2.5%, 1.71 ⫾ 0.11% and 1.53 ⫾ 0.09%
respectively. Flux, estimated on the basis
of ␤2-microglobulin clearance, was 3 ⫾
7 mL/min in the low-flux group and 34 ⫾
11 mL/min in the high-flux group.
The primary outcome, death from any
cause, was not significantly influenced by
the dose or flux assignment: the relative
risk of death in the high-dose group as
compared with the standard-dose group
was 0.96 (95% confidence interval, 0.84–
1.10; p = 0.53), and the relative risk of
death in the high-flux group as compared
with the low-flux group was 0.92 (95%
confidence interval, 0.81–1.05; p = 0.23).
In conclusion, patients undergoing hemo-
dialysis thrice weekly appear to have no
major benefit from a higher dialysis dose
than that recommended by current U.S.
guidelines or from the use of a high-flux
membrane.11
Observational Data and DOPPS
There have been reports in the literature
suggesting that longer dialysis results in
better patient outcomes. A study by Held
and colleagues investigated the relation-
ship of 3-year mortality to duration of
dialysis in a 1984–1985 national random
sample of 600 hemodialysis patients from
36 dialysis units.12 Mortality was nega-
tively associated with duration of dial-
ysis treatments, as shown by the Cox
model, adjusted for other patient and
dialysis unit covariates. With adjustment
for other covariates, patients receiving
an average dialysis treatment duration of
less than 3.5 hours had relative mortality
risks of 1.17–2.18 compared with those
who had treatments longer than 3.5 hours
(mortality risk of 1.0). The authors con-
cluded that duration of the dialysis proce-
dure is an important element in determining
patient mortality as one of the factors deter-
mining the adequacy of dialysis.
In a study by Port and colleagues, data
from billing records of over 45,000 dialy-
sis patients during months 10–15 of end-
stage renal disease were used to classify
each patient into one of five categories of
hemodialysis dose by urea reduction ratio
(URR) ranging from <60% to >75%.13 Cox
regression models were used to calculate
relative risk (RR) of mortality after adjust-
ment for demographics, body mass index
(BMI), and 18 comorbid conditions. In
each of three body-size groups by BMI, the
RR was 17%, 17%, and 19% lower per 5%
higher URR category among groups with
small, medium, and large BMI, respective-
ly (p < .0001 for each group). The authors
concluded that a higher dialysis dose, sub-
stantially above the KDOQI guidelines
(URR > 65%), is a strong predictor of
lower patient mortality for patients in all
body-size groups.
More data on the results of longer treat-
ment times come from the Dialysis Outcomes
and Practice Patterns Study (DOPPS), which
included 22,000 hemodialysis patients from
seven countries.14 Logistic regression was
used to study predictors of treatment times
(TT) > 240 minutes. Cox regression was
used for survival analyses. Statistical adjust-
ments were made for patient demographics,
comorbidities, dose of dialysis (Kt/V), and
body size. Europe and Japan had significant-
ly longer (p < 0.0001) average TT than the
United States (232 and 244 minutes vs. 211
in DOPPS I; 235 and 240 minutes vs. 221 in
DOPPS II). Kt/V increased concomitantly
with TT in all three regions, with the largest
œ
absolute difference observed in Japan.
Hemodialysis Adequacy
TT > 240 minutes was independently associ-
ated with significantly lower RR of mortal-
ity (RR = 0.81; p = .0005). Every 30 minutes
of additional hemodialysis was associated
with a 7% lower RR of mortality (RR = 0.93;
p < 0.0001). The RR reduction with longer
TT was greatest in Japan. A synergistic
interaction occurred between Kt/V and TT
(p = 0.007) toward mortality reduction.
Longer TT and higher Kt/V were indepen-
dently as well as synergistically associated
with lower mortality.
Practice Guidelines
The National Kidney Foundation’s KDOQI
provides a list of “preferred measures of
the delivered dialysis dose’’8 It lists spKt/V
determined by UKM as the most preferred
adequacy measure, followed by eKt/V, dia-
lyzer clearance using ionic conductance,
and URR, in that order.
The KDOQI work group, after review-
ing all the evidence, suggested that the
minimally adequate dose of hemodialysis
given 3 times per week to patients with
residual renal function of less than 2 mL/
min/1.73m2 should be an spKt/V (exclud-
ing residual kidney function [RKF]) of
1.2 per dialysis: and for treatment times
less than 5 hours, an alternative minimum
dose is a URR of 65%.8 The target dose
for hemodialysis given 3 times per week
with residual renal function of less than
2 mL/min/1.73m2 should be an spKt/V of
1.4 per dialysis not including RKF, or URR
of 70%.
The European best practice guidelines
recommend that the minimum prescribed
hemodialysis dose per session for a thrice-
weekly schedule should be eKt/V ⱖ 1.2 or
spKt/V ⱖ 1.4.15
Conclusions
The optimal time and dose for hemodi-
alysis remain controversial. There is ample
evidence that longer treatment time and
higher dose may be beneficial. For exam-
ple, both nocturnal and short daily hemo-
dialysis, two modalities that have signifi-
cantly higher treatment time, have shown
a survival advantage.16,17 It is difficult to
explain why a higher dose of standard in-
center thrice-weekly dialysis has not been
shown to be beneficial. One explanation
may be that the inherent high morbidity
and mortality in this population masks a
potential benefit of improved clearance. In
the end, formulas only serve as a guide, and
nephrologists need to use these and other
clinical factors to ultimately decide on the
dose of dialysis. D&T
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January 2010 Dialysis & Transplantation 3