Hemodialysis International 2016; 20:1521

Hemodialysis International 2015; :

Complications

Personal viewpoint: Limiting maximum

ultrafiltration rate as a potential new
measure of dialysis adequacy

John W M AGAR
Department of Renal Medicine Barwon Health, University Hospital, Geelong, Victoria, Australia

Abstract
While the solute clearance marker (Kt/Vurea) is widely used, no effective marker for volume man-
agement exists. Two principles apply to acute volume change in hemodialysis: (1) the plasma refill
rate, the maximum rate the extracellular fluid can replace a contracting intravascular volume
(5 mL/kg/hour) and (2) the rate of intravascular volume contraction where coronary hypoperfu-
sion, myocardial stun, and vascular risk escalates (observed at 10 mL/kg/hour). In extended hour
and higher frequency hemodialysis, intravascular contraction rates are usually equilibrated by the
plasma refill rate, but in conventional in-center hemodialysis, volume contraction rates commonly
exceed the capabilities of the plasma refill rate, resulting in inevitable hypovolemia. To minimize
cardiovascular risk, fluid removal rates should ideally be 10 mL/kg/hour, acknowledging that this
may be challenging in the in-center setting. Two options exist to limit volume removal to >10 mL/
kg/hour: restricting interdialytic weight gain (always conflict-fraught, often unachievable) or
extending sessional duration to allow additional removal time. Just as Kt/Vurea quantifies solute
removal, a simple-to-apply rate variable should also apply for volume removal. As predialysis and
target postdialysis weights are both known, a simple measurea maximum rate for ultrafiltration
(UFRmax)would advise the sessional duration (T) required to minimize organ stun by removing the
required fluid load (V) from any patient of predialysis weight (W). This would ensure a removal rate
no greater than 10 mL/kg/hourT (hours) = V (mL)/10 W (kg). Used together, Kt/Vurea and UFRmax
would form a solute and volume composite, each dialysis treatment continuing until both solute
and volume requirements are fulfilled.

Key words: Hemodialysis, key performance indicator (KPI), maximum ultrafiltration rate, treat-
ment duration, myocardial stun

INTRODUCTION tended consequence of this concentration on scientific

INTRODUCTION tended consequence
correctness of this
is that novel concentration
ideas, on scientific
innovative thought, and
Editors and journals are now expected to focus on peer- correctness
unproven but is interesting
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are denied and
a formal
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reviewed, journals are now medicine,
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method. While medicine,
understandable and one
and laudable, statistical
unin- forum forofpresentation and debate, outside the dubious
structure Internet blogging.
method. While understandable and laudable, one unin- structure of Internet blogging.
One mark of a living journal should be that it allows
Correspondence to: J. W. M. Agar, MBBS, FRACP, FRCP andOne mark of aaliving
encourages journal
designated should
forum be that
within it allows
its pages for
Correspondence to: J.ofW.
(Lond), Department M. Agar,
Renal MBBS,
Medicine FRACP,
Barwon FRCP
Health, and encourages aofdesignated
the publication forumbut
peer-approved, within its unproven
as yet pages for
(Lond), Department
University Hospital, of Renal Medicine
Geelong, Barwon
PO Box 281, Health,
Geelong, Vic. the publication
ideas. Few, if any,of peer-approved,
unproven conceptsbut asinyettheunproven
field of
University Hospital,
3220, Australia. Geelong,
E-mail: PO Box 281, Geelong, Vic.
johna@barwonhealth.org.au ideas. Few, if (HD)
hemodialysis any, unproven concepts
have appeared sincein Scribner
the fieldandof
3220, Australia. E-mail: johna@barwonhealth.org.au hemodialysis (HD) have appeared since Scribner and

C 2015 International Society for Hemodialysis

V
DOI:10.1111/hdi.12288
2015 International Society for Hemodialysis
DOI:10.1111/hdi.12288 15
1
Agar
Agar
Oreopoulos published their astute concept for a time and
frequency measure of good dialysis, the Hemodialysis
Product, over a decade ago.1 I believe the concept pro-
posed in this paper is at least worthy of critical
examinationto stimulate debate, ideas, and future trial
research to develop a daily bedside volume marker for
HD.
Hemodialysis has had a solute key performance indica-
tor (KPI)Kt/Vurea or, in some jurisdictions, the urea
reduction ratio (URR)for more than 3 decades,2 yet no
simple, easy-to-apply marker for volume status yet exists.
Proposing an ultrafiltration rate maximum (UFRmax), this
paper argues that a simple, practical measure to limit
the maximum rate of volume removal could become an
additional essential dialysis KPI to use to determine the
duration of each dialysis session in conjunction with
Kt/Vurea. Each dialysis would continue until both KPIs
were achieved.
Urea transport and diffusion kinetics bear little or no
relationship to the kinetics of most metabolic wastes.
While urea moves rapidly down a concentration gradient,
many of the more important uremic toxins (phosphate as
a prime example) move slowly down time-dependent gra-
dients, yet oddly, this knowledge has not yet displaced
urea from its favored position. For better or worse, Kt/Vurea
remains enshrined as the marker of dialysis adequacy,3,4
and has fostered the now ingrainedbut erroneous
belief that once adequate urea clearance has been
achieved, it is then OK to turn the machine off and
prepare for the next patient.
In the view of this author, that commonly held view is
wrong, and by administratively enshrining a belief that
Kt/Vurea is the best and only measure of dialysis adequacy,
treatment complacency has been encouraged and the
quest for continuing improvement in dialysis delivery
retarded. In fact, current dialysis systems and membranes
are now so efficient that adequate urea clearance is
almost a given. This is not so for volume management. Yet,
arguably, volume management may exert a more telling
influence over clinical dialysis morbidity and mortality
than does small solute clearance.
In a post hoc analysis of the Hemodialysis (HEMO)
Study, a trial designed to determine whether an increase in
dialysis dose or the use of high-flux membranes might
improve patient outcomes, Flythe et al. examined the UFR
data from the HEMO study,5 although unfortunately the
trial was not specifically designed to assess the UFR. This
weakened their analysis in several ways: trial randomiza-
tion impacted treatment length and treatment length
affects the UFR; no correction was possible for body size,
a clear UFR variable, and their data were adjusted for
16
2 Hemodialysis
interdialytic weight gain (IDWG)but IDWG is a deter-
minant of UFR. Despite these shortcomings, their analysis
found that the absolute risk to survival increased if the
UFR exceeded 13 mL/kg/hour in patients without pre-
existing congestive cardiac failure (CHF), and for those
with prior CHF, survival risk increased when the UFR
exceeded 10 mL/kg/hour. But, confounding their analysis,
they also found that in patients without CHF, survival in
the UFR range 1013 mL/kg/hour was better than that for
those with the lesser UFR of <10 mL/kg/hour, although it
is important to reiterate that the UFR was not a primary
design component for the HEMO study. Thus, while a
certain conclusion remains elusive, a UFR risk maximum
somewhere in the range of 1013 mL/kg/hour was likely.
In the context of this opinion piece, it is important to
note that my use of the term volume refers specifically to
the circulating blood volume and the effect a dialysis treat-
ment has upon it. In this context, volume does not mean
total body water, all-compartment volume, or dry weight.
The measurement of the volume impact of any single
dialysis treatment can often be confused with the mea-
surement of dry weight, with the assessment of the latter
including all manner of the bedside useful, and not-so
useful. To determine dry weight, there are supporters of
a variety of measurement techniques: bio-impedance
options, inferior vena cava (IVC) ultrasound, isotope dilu-
tion, and brain natriuretic peptide, among other
methods.6,7 However, none has yet provided an easy,
bedside risk assessment tool for the safe rate of volume
extraction for a single dialysis session. Nor do any cur-
rently show promise of providing an immediate, predialy-
sis, practical, and cost-neutral application for daily use in
every patient and in every dialysis unit.
Are dry weight assessment techniques important? Yes,
certainly. But, are current options likely to provide a useful
daily volume management guide? No, at least not for the
present, as current techniques to accurately and rapidly
determine dry weight remain flawed.
In this paper, I propose a simple KPI for the limitation
of UFRone that is all and only about determining a
maximum rate of safe volume removal from the intravascular
space. It does not reflect, except by implication, beyond
the circulating blood volume to the extracellular or intra-
cellular volumes, as these are equilibratory spaces that
only fully equalize after dialysis. A KPI that proscribes an
UFRmax, and demands that dialysis sessions be extended,
where necessary, to meet that KPI, may become a useful
risk-assessment tool for each dialysis treatment for each
individual patient.
Any useful volume KPI must be simple, easily
applied, applicable at the bedside predialysis, and have a
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clear and interpretable meaning for both staff and patient.
But, before developing a workable volume KPI, two
important concepts that impact the circulating blood
volume must be understood:
Plasma refill rate (PRR)
The PRR, a very inexact number as many factors impact its
calculation, estimates the rate at which the extravascular
space can restore a diminishing intravascular volume. The
few attempts to quantify a mean average PRR for a mean
average patient (if there is one) have all derived a mean
maximum PRR somewhere in the range 56 mL/kg/
hour.8,9 However, both significant patient-to-patient
variability and varying clinical circumstance as
one example, any variation in the serum albumin
concentrationhampers both the practical interpretation
and clinical application of the PRR to real-time dialysis
management.
To explain the PRR in my own simple terms: if the
removal rate of fluid from the plasma volume (e.g., during
dialysis) exceeds the capacity of the extracellular fluid
(ECF) to sustain an unaltered intravascular volume by
synchronous volume replenishment, then the intravascu-
lar volume must fall. The rate of plasma volume contrac-
tion can be estimated by the difference between the
removal rate (always known) and the refill rate (always
notional).
However, the capacity of the extravascular space to refill
the intravascular space is rate-limited. It has a finite
maximum. If too much fluid is removed too fast, the PRR
will be exceeded and plasma volume contraction is thus
inevitable. However, if the mean maximum PRR does lie
within the notional range of 56 mL/kg/hour for the non-
existent average person, then intravascular volume con-
traction must occur if the rate of volume removal during
dialysis exceeds 56 mL/kg/hour.
While it is clearly nave to use a single figure for the PRR
of all patients in all clinical circumstancesweight, size,
gender, capillary permeability, albumin level, inflamma-
tory status, cardiovascular competency, and nutritional
status (among other factors) will all have an impact upon
itit is important to note that these same factors also
similarly impact bio-impedance, isotope dilution, and the
other commonly considered, generally more complex,
and significantly more costly ways that are currently pro-
posed for assessing dry weight.
If a simple, practical, predialysis estimate of a safe rate
of intradialytic fluid removal could be agreed upon, this
UFR-limiting estimate would then allow dialysis treatment
time to become the second titration variable for an indi-
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Limiting
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ultrafiltration in hemodialysis
in hemodialysis
vidual dialysis session, used in conjunction with Kt/Vurea.
Until a better solute marker is found to replace Kt/Vurea,
each dialysis session would be required to continue until
both solute and volume standards have been achieved.
Some patients may reach their volume KPI quickly. In
this event, the dialysis would be Kt/Vurea-dependent.
Others may reach the required Kt/Vurea but require addi-
tional time to assure volume safety. Some dialysis sessions
would inevitably lengthen, but others may not. Some may
even contract on volume criteria alone. Some dialysis
clinicians have already used the threat and/or application
of extended dialysis sessional times as an effective deter-
rent against IDWG.10 They found that when they
introduced limited maximum UF rate policy, patients
preferredand madebehavioral changes to reduce
their IDWG rather than extend the duration of dialysis.
Notwithstanding that some patients may voluntarily
adhere more closely to fluid restrictions if threatened by
durational extension, the implementation of a variable
dialysis treatment time policy based on an UFRmax for
those who are not sufficiently encouraged, would clearly
prove a logistic hurdle for dialysis programs to overcome.
Future studies to examine practical ways to implement
flexible-length dialysis sessions based on a maximum safe
UFR are needed.
So, what might be a safe rate maximum for
ultrafiltration?
Organ stunning
McIntyre et al. recently described the concept of myocar-
dial stun during HD.1113 Their demonstration of the
effects of acute intradialytic volume contraction on myo-
cardial hypoperfusion and the resultant functional myo-
cardial stunning has provided us with evidence that there
appears to be a rate of intravascular volume depletion during
maintenance HD that risks tissue hypoperfusion and target
organ stun.
While first describing myocardial stunning as a result of
reduced coronary perfusion during dialysis, this group has
also reported similar data supporting cerebral stun
through reduced carotid and/or vertebral perfusion.14,15
Indeed, the potential list of at-risk tissues seems as long as
is organ number, including the potential for a negative
impact on residual renal function from recurrent mini-
episodes of acute kidney injury during dialysis as acute
intravascular volume contraction translates into reduced
residual renal tissue perfusion.
In further support of the concept, Jefferies et al. have
shown that extended duration and higher frequency dialy-
sis regimens abrogate dialysis-induced cardiac injury,16
3
Agar
Agar
although the incidence of diabetes and ischemic heart
disease in the in-center controls in this study was signifi-
cantly higher than in the two home-based comparator
groups, weakening the conclusions of the study.
Saran et al. have reported potential perfusion-related
injury if the UFR exceeds 10 mL/kg/hour,17 Movilli et al.
have shown subsequent data to suggest that exceeding a
UFR of 13 mL/kg/hour appears harmful18 and Flythe et al.
have shown that extending treatment time is an effective
way to reduce IDWG and lessen dialysis-related morbid-
ity.19 Finally, as Movilli et al. have provided data to show
that the failure to achieve target weight is directly associ-
ated with the risk of death, slowing the UFR to more
securely reach the target weight should directly and posi-
tively impact outcome.20
While the study of Jefferies et al. 16 into the effect of
UFR on myocardial perfusion assessed echocardiographic
regional myocardial wall motion as the surrogate perfu-
sion marker, the same end point has produced similar
outcomes in a study into the effects of lowering dialysis
fluid temperature to 0.5C less than the predialysis tym-
panic membrane temperature.21 Thus, although much of
the current literature surrounding myocardial perfusion
cites the UFR as the key determinant, there may clearly be
other irons in this fire.
Although other factors may clearly be implicated, the
linkage between high UFR and reduced organ perfusion
and tissue oxygenation leading to functional stunning
does appear to add weight to the volume story. If these
data can be confirmed by further prospective studies, it
seems likely that reduced organ perfusion may begin to
occur when fluid is removed from the intravascular
volume at a rate exceeding 10mL/kg/houra rate
roughly twice the estimated maximum plasma refill
capacitywhile perfusion injury and survival risk seem
almost certain to occur when volume removal rates exceed
13mL/kg/hour.
One unsolved conundrum is the relationship between
ultrafiltration and body size: is a UFR of 10 (or 13) mL/
kg/hour the same in all circumstancese.g., does a single,
fixed UFR have the same physiological effect in a 50, 100,
or 150 kg patient, or in a male vs. a female where total
body water is in different proportions? Clearly, this is
unlikely. Thus, to set a single UFRmax as a KPIas I am
suggestingmay simply compound a current error or
introduce new ones. At present, there are no right answers
to these questions but, by fixing the UFRmax at the seem-
ingly safer and lower limit of 10 mL/kg/hour, we may
buy time to provide these answers.
What seems certain is that while much emphasis has
been placed on adequate solute clearance (currently
18
4 Hemodialysis
Kt/Vurea) as the yardstick by which adequate dialysis is
judged, the survival impact of excessive UFRwhile less
emphasized in guideline literaturemay prove as or even
more important. More comparative studies between the
impact of solute and volume criteria are required to
resolve this issue as well.
Although more studies are required to solve these
uncertainties, three volume-related rules-of-thumb
appear to emerge:
1. Intravascular volume contraction will likely begin to
occur during maintenance HD if fluid is removed at a
rate >56 mL/kg/hour.
2. Reduced organ perfusion is risked if fluid is removed
during maintenance HD at a rate >10 mL/kg/hour.
3. Reduced organ perfusion will almost certainly result if
fluid is removed during maintenance HD at a rate
>13 mL/kg/hour.
When setting a UFR-limiting maximum, it could be
debated whether this should be a safety maximum or a
risk maximum. A safe maximum might be a UFR of
10 mL/kg/hour, while a risk maximum might better be
set at 13 mL/kg/hour.
Despite the fact that two complex and still debated
mechanismsthe PRR and organ perfusion stun
underpin these three simplified contraction statements, if
used together, they can inform a suggested maximal rate
for volume removal. In this paper, I have chosen safety
over risk and therefore preferred to nominate a UFRmax of
10 mL/kg/hour. It is recognized that others may prefer
the more conservative approach of 13 mL/kg/hour. It is
also recognized that the fixing of any value may be pre-
mature. However, as the point of this paper is to stimulate
discussion and further research into establishing an
accepted UFRmax, this is immaterial.
A safe UFRmax can be calculated by applying a simple
formula: T = V/(10 W), while an escalating risk
UFRmax can be calculated by: T = V/(13 W), where: T is
the sessional duration (hours), V is the ultrafiltration
volume (mL) required to return the patient to his/her
intended postdialysis weight, and W is the predialysis
body weight (kg).
Table 1 shows several simulated examples of the dialy-
sis duration required to meet the two UFRmax limits, one at
10 mL/kg/hour and the other one at 13 mL/kg/hour,
for patients of different predialysis body weight and
IDWG.
Mean UFR data from the Dialysis Outcomes and Prac-
tice Profiles Study (DOPPSII) show that the mean UFR in
the United States is 9.8 3.7 mL/kg/hour17a rate signi-
fying significantly faster fluid-removal rates in the United
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Table 1 Examples of the effect of varying interdialytic weight gain (W) and volume to remove (V) on dialysis duration (T)
where UFRmax is 10 or 13 mL/kg/hour
Predialysis Interdialytic (V)olume to Dialysis (T)ime UFRmax Dialysis (T)ime UFRmax
Number (W)eight (kg) weight gain (kg) remove (mL) 10mL/kg/h (required h) 13mL/kg/h (required h)
1 56.75 2.65 2650 4.7 3.6
2 39.7 2.75 2750 6.9 5.3
3 117 5.2 5200 4.4 3.4
4 54.25 3.3 3300 6.1 4.7
5 41.3 2.25 2250 5.5 4.2
6 154 7.5 7500 4.2 3.75
7a 68.5 0.8 800 1.2 0.9
8b 56.75 2.65 2650 + 250 (=2900) 5.1 3.9
In all circumstances, dialysis duration is determined by both Kt/Vurea and UFRmax, with dialysis continuing until both key performance indicator
(KPI) have been achieved.
UFRmax = maximum ultrafiltration rate.
a
Example 7: As the predicted dialysis duration by UFRmax is short, dialysis should continue until Kt/Vurea criteria are reached. Here, Kt/Vurea
becomes the duration defining KPI.
b
Example 8: If additional drying down is required, the additional volume to remove (mL) is simply added to the numeratorin this example,
an extra 250 mL.

States when compared with the mean UFR for Europe and
Japan. As this suggests that 50% of US patients must
already have a UFR in excess of 10 mL/kg/hour, the intro-
duction of a KPI that proscribes 10 as a maximum would
clearly place a significant logistic burden on providers.
Dialysis sessional times are fixedand shortfor almost
all patients and in almost all circumstances, regardless of
individual variations in gender, age, race, or body habitus.
While clearly an inappropriate practice, the logistic and
economic concerns of providers have prevented flexible
dialysis duration from being a natural feature of most
dialysis programs. Patients have been led to believe that
shorter treatment times are acceptable, fuelling an under-
standable reticence to increase the sessional duration.
Instead, confrontational situations are the usual landscape
in many dialysis services, the result of repetitive argu-
ments between staff and patients about interdialytic fluid
intake, salt intake, and weight gain.
Meanwhile, the most effective solution to volume man-
agement in maintenance HDthe use of flexible extension
of dialysis timehas been allocated to the too-hard
basket. Yet, a physiological solution, the extension (or
contraction) of individual dialysis sessional times based
on the paired use of solute clearance (Kt/Vurea) and a
calculated safe UFRmax, has been staring us in the face.
Although patients must clearly continue to be encour-
aged to contribute to volume control through sensible
limitations of fluid and salt intake, it is commonly
counterproductive to focus solely on the imposition of
unrealistic, and often unachievable, interdialytic fluid
restrictions. This practice commonly has the undesirable
effect of transforming the dialysis room into an uncom-
fortable battleground between staff and patients. The
normal paradigm of achieving ideal or approximated dry
weight by removing excessive amounts of fluid over a
short time period and harassing patients to reduce their
fluid intake has never worked. We need to rethink this
process.
Postdialysis thirst and the resultant excessive fluid gain
that inevitably occurs in the following interdialytic period
is also commonly the direct result of imposing an intra-
dialytic UFR that contracts the intravascular volume so
rapidly that thirst is irresistible.22 The subsequent and
excessive IDWG that then becomes unavoidable is not the
patients fault. Although we may find it difficult to admit,
it is we who are at fault for this. It is we who have
encouraged and prescribed unreasonably short treat-
ments, treatments that have sought the removal of too
much fluid, too fast. Unfortunately, this dynamic seems
poorly understood, with avoidable conflict being the
result. The patient is labeled noncompliant, a label that
often exacerbates the schism, when, in truth, the brutality
and speed of the treatment regimen has been the root
cause of the problem.
Dialysis services might begin to approach a more flex-
ible rostering system by first performing a prospective
assessment of the number of patients in their program
whose treatment timeon a volume basis alonemight
require longer treatments and how long those extensions
might be. It should be remembered that some patients,
on volume criteria alone, may be satisfactorily managed
with a shorter time, although in this circumstance, the

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secondary assessment of solute clearance criteria would between those with a UFR <10mL/kg/hour and those
need review before any unlikely shortening of dialysis with a UFR >10mL/kg/hour.
times were to be recommended. Using a combination of
These data would inform the potential staffing, rostering,
volume first, solute second review, it should be possible
and economic impacts of ensuring that 95% of collective
to match any patients requiring shorter treatments with
dialysis times complied with a UFRmax of <10mL/kg/hour
those needing longer sessions, rostering for both ends of
by the smart rostering of patients into longer and shorter
the duration spectrum within a multishift dialysis day.
sessional shifts. On volume criteria alone, some patients
While such changes would inevitably create at least short-
may qualify for shorter treatments, especially those
term administrative difficulty, the longer-term results
patients with a very high body mass index. In this event,
would likely benefit patient outcomes.
solute criteria (Kt/Vurea) would play the clear duration-
But, it seems clear that the necessary duration for
defining role. But, if both volume and solute criteria had
volume removal for any single dialysis treatment can be
to be met within the durational context of a dialysis
easily predicted, predialysis. The predialysis weight and
session then, unlike now, Kt/Vurea would no longer be
target postdialysis weight are both known, even if the
viewed as the sole determinant of dialysis adequacy. On
accurate true dry weight is not. Thus, by ensuring that the
occasions where the volume criterion is reached prior to
maximum intradialytic UFR is never greater than 10 mL/
reaching the required Kt/Vurea, UFR could be turned off
kg/hour, it is simple, from a purely volume perspective, to
but the treatment should continue until Kt/Vurea has also
calculate how long any one dialysis session will need to be
been achieved.
to achieve the target end-dialysis weight at a organ perfu-
While most data suggest that volume, not solute, most
sion safe rate.
commonly impacts dialysis survival, volume has histori-
Dialysis sessional duration would become the second
cally been neglected in the adequate vs. good dialysis
essential sessional KPI to Kt/Vurea. Sessional time would be
debate. But, by introducing a volume KPI, the duration
dictated by both solute clearance (Kt/Vurea) and sessional
inadequacy of most current dialysis programs will be
duration required to achieve the target postdialysis weight
better appreciated, excessive fluid-removal rates will be
within stun-safe limits. This would avert the majority of
avoided, and symptom relief and reduced perfusion-
patient-reported dialysis symptoms. Hypotensive episodes,
related morbidity and mortality would be the result.
nausea and vomiting from splanchnic hypoperfusion,
cramp, and dialysis fatigue would likely be mitigated.
Prolonged postdialysis recovery times (which are linked DISCLOSURE
with poorer survival)23 would shorten. Patients would The author has no conflicts of interest to declare.
rapidly learn and understand the value of time in their
dialysis program and would quickly learn that shorter
dialysis durations relate directly to excessive weight gain Manuscript received May 2014; revised January 2015.
from activated postdialysis thirst, a knowledge that would
help reinforce interdialytic volume management. Above
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