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mini review
Once upon a time in dialysis: the last days of Kt/V?
Raymond Vanholder1, Griet Glorieux1 and Sunny Eloot1
1
Nephrology Section, Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium
After its proposal as a marker of dialysis adequacy in the
eighties of last century, Kt/Vurea helped to improve dialysis
efficiency and to standardize the procedure. However, the
concept was developed when dialysis was almost uniformly
short and was applied thrice weekly with small pore cellulosic
dialyzers. Since then dialysis evolved in the direction of many
strategic alternatives, such as extended or daily dialysis, large
pore high-flux dialysis, and convective strategies. Although
still a useful baseline marker, Kt/Vurea no longer properly
covers up for most of these modifications so that urea
kinetics are hardly if at all representative for those of other
solutes with a deleterious effect on morbidity and mortality
of uremic patients. This is corroborated in several clinical
studies showing a dissociation between removal of urea and
that of other uremic toxins. In addition, randomized
controlled trials showed no benefit of increasing Kt/Vurea.
Finally, this parameter also hardly is evocative for metabolic
or intestinal generation of toxins, for their removal by
residual renal function and for the complex interaction of
dialysis length with removal pattern and patient outcomes.
We conclude that apart from being a baseline parameter of
dialysis adequacy, Kt/Vurea insufficiently represents all novel
strategic changes of modern dialysis. Kt/Vurea is too simple a
concept for the complexities of uremia and of todays dialysis.
Kidney International (2015) 88, 460465; doi:10.1038/ki.2015.155;
published online 10 June 2015
KEYWORDS: hemodialysis; urea; uremia; uremic toxins
Correspondence: Raymond Vanholder, Nephrology Section, Department of
Internal Medicine, 0K12, University Hospital Ghent, De Pintelaan 185, Gent
B9000, Belgium. E-mail: Raymond.vanholder@ugent.be
Received 29 August 2014; accepted 4 September 2014; published
online 10 June 2015
460
http://www.kidney-international.org
2015 International Society of Nephrology
Kt/Vurea (clearance of urea multiplied by dialysis duration and
normalized for urea distribution volume) was first proposed as
a parameter of dialysis adequacy in a period of worrisome
mortality on dialysis in the USA. After the randomized
National Cooperative Dialysis Study had demonstrated that a
higher time averaged urea concentration was related to higher
hospitalization,1 Kt/Vurea emanated from a post hoc mechan-
istic study on the same data.2 The threshold of this absolute
value was originally set at 0.8 but soon was increased to 1.2 or
higher. With the introduction of Kt/Vurea, adequacy of dialysis
was no longer assessed by a single static pre-dialysis value, of
which the low concentration could be due to negative
confounders such as low protein intake for urea or low muscle
mass for creatinine. Kt/Vurea instead is a dynamic parameter
that assesses removal by dialysis as a whole (Kt), including not
only clearance but also dialysis length and above all a correction
for body mass (V). For the first time not only the therapy but
also the patient was taken into account by acknowledging that a
voluminous person needs more dialysis compared with a tiny
one. This led to a more standardized dialysis approach and
was translated into a better survival with higher Kt/Vurea in
essentially observational studies.3,4
However, Kt/Vurea quite soon appeared to be far from the
only determinant of outcomes of dialysis. A study by Owen
et al.5 demonstrated a relation between urea reduction ratio
(as surrogate for Kt/Vurea) and outcomes, but a much stronger
consistent relationship was found for hypoalbuminemia, as an
index of malnutrition and fluid overload. In an analysis of the
Dialysis Outcomes Practice Pattern Study, dialysis length
appeared an important determinant of survival, even in
patients stratified for Kt /Vurea.4
When different thresholds of Kt/Vurea were compared in
controlled trials, increasing its value above standard did not
impact survival,6,7 suggesting that the upper limit of improving
outcomes based on this parameter had been reached. This
raised the question whether Kt/Vurea can grasp all effects of
modern dialysis in all its variants and also which potential
pitfalls skew its interpretation.
THE CONCEPT OF KT/VUREA IS BASED ON A TYPE OF DIALYSIS
THAT IS OFTEN NO LONGER APPLIED
Urea kinetic modeling was developed when hemodialysis was
applied almost systematically three times weekly with small
pore cellulosic dialyzers causing substantial inflammatory
reaction. Moreover, the session length of this dialysis
was usually short, and as Kt/Vurea was conceived in the US
Kidney International (2015) 88, 460465
R Vanholder et al.: The last days of Kt/V?
even shorter (mostly 2.53 h) than what was standard
elsewhere (4 h).
Since then the dialysis concept has changed markedly, with
many alternatives to standard, by the introduction of large
pore high-flux dialyzers, convective strategies such as
hemodiafiltration, extended dialysis, and frequent dialysis,8
which all have been shown to better remove molecules with
proven biological impact and/or result in better outcomes.9
The question arises whether Kt/Vurea is still representative for
the kinetics of solutes preferentially removed by these
alternative strategies, which usually have no added value for
the removal of urea in contrast to their impact on the
elimination of many other solutes.
THE EVIDENCE OF THE TOXICITY OF UREA IS LIMITED
To the best of our knowledge, only a few experimental studies
point to a toxic effect of urea at concentrations currently
observed in uremia. DApolito et al.10 found that urea induced
the generation of Radical Oxygen Species (ROS) and insulin
resistance in vitro and in mice. In an in vitro study, Vaziri
et al.11 showed disruption of the intestinal epithelial barrier
function by derangement of tight junctions. Trcherel et al.12
explored regulatory proteins of apoptosis and showed an
upregulation of Bcl2-associated death promoter, a pro-
apoptotic protein.
The clinical equivalent to these experimental suggestions is,
however, scanty. Adding urea to the dialysate up to concentra-
tions two to three times higher than usual in dialysis patients
induced no consistent changes in uremic symptoms.13 Increas-
ing urea removal in controlled trials had no impact on hard
clinical outcomes.6,7 An observational study by Koeth et al.14
found an association with mortality of homocitrulline, a marker
of carbamylation to which also urea is supposed to contribute.
However, the concentration of urea was only modestly
correlated to that of homocitrulline, with an R2 of 0.14,
suggesting that other factors than urea were more important for
homocitrulline generation and its association to death. In
addition, urea by itself was not related to mortality.14
Thus, urea, in spite of its everyday application as marker of
dialysis adequacy, has rarely been assessed for its toxicity and
up till now has not been proven in clinical studies to affect
outcomes. Its choice as a marker cannot really be supported
by robust biochemical or clinical arguments. However, even if
urea would be a recognized toxin, there remain questions
about the representativeness of Kt/Vurea for the removal of
other uremic retention solutes.
THE KINETICS OF UREA ARE NOT REPRESENTATIVE FOR
OTHER SOLUTES, OF WHICH TOXICITY IS BETTER
DOCUMENTED
Basic principles of kinetic modeling
(Figures 1 and 2) The concept of dialysis kinetic analysis lays at
the origin of urea kinetic modeling.15 The basic principle is the
mirror image of pharmacokinetics, where the distribution
pattern of a drug throughout the body to reach the most remote
compartments is studied after the plasma concentration rises
Kidney International (2015) 88, 460465
mini review
Definition of the kinetic model mass balance per compartment
G2 E2 G1 E1
d(V1C1)
KR = G1 E1 (KR + KD + KER) C1
K21 dt
+ K21 (C2 C1)
V2, C2 V1, C1 KD
KER
d(V2C2)
= G2 E2 K21 (C2 C1)
dt
V
Figure 1 | Basic principles of kinetic modeling. Uremic solute is
primarily removed from the plasmatic compartment by dialysis
causing a fast decrease in its concentration. Only once this plasmatic
concentration starts to decrease sufficiently, concentration in the
extra-plasmatic compartment can also decrease, based on a diffusive
concentration gradient. C1 and C2, solute concentration in V1 and V2;
E1 and E2, elimination rate in V1 and V2; G1 and G2, generation rate in
V1 and V2; KD, dialyzer clearance; KER, extra-renal clearance; KR, renal
clearance; K21, inter-compartmental clearance; V, distribution volume;
V1, plasmatic volume; V2, extra-plasmatic volume.
following administration. In dialysis kinetics, the disappearance
of solutes out of these remote compartments is studied during
their removal by dialysis. Although a large number of different
compartments are possible, in theory two compartments are
critical: (1) the plasma compartment, from which solute
removal by dialysis is relatively easy if dialyzer pores are large
enough, and (2) the (sum of) extra-plasmatic compartment(s)
where solute concentration tends to lag behind on plasma
concentration, as inter-compartmental shifts largely depend on
diffusion from high to low concentration, which is hindered by
a variable resistance from the compartmental boundaries.
The more important this resistance, the more dialysis adequacy
will be reduced. Also post-dialytic rebound, creating a
quick increase in uremic solute concentration immediately
after dialysis due to the backlog of extra-plasmatic concentra-
tion, is an epiphenomenon of this process (Figure 2).
Resistance to shifts between compartments is minimal for
urea compared with other solutes,16 which, as a consequence,
are more difficult to remove. Hence, the question should be
raised whether urea kinetics are representative for uremic
toxins at large.
In the next sections, we will describe discrepancies between
solute kinetics of urea and that of other uremic toxins, based
on the classical subdivision of uremic toxins in small water
soluble compounds, protein-bound solutes, and middle
molecules.17
Small water soluble compounds
The question has been raised whether urea as one of the small
water soluble compounds would have similar kinetics as other
solutes with the same characteristics, such as the guanidino
compounds, which have a well-documented biologic (toxic)
impact.18 However, when their kinetics were compared,
distribution volume was definitely different and mostly larger
for the guanidino compounds as compared with urea, giving
rise to less efficient removal.19 Those mathematical findings
were corroborated by assessing in vivo concentrations of
guanidino compounds in erythrocytes, the most easily
461
mini review
Calibration of the kinetic model by fitting on in vivo data
Post dialysis
C2
rebound
Concentration
C1
0 60 120 180 240 300
Time (min)
Figure 2 | Graphic illustration of the changes in solute
concentration during dialysis that are reflected by kinetic studies.
The diamonds illustrate real-life in vivo measurements of solute
plasma concentration. The black line illustrates the calculated decay
curve fitting the kinetic data to the measured concentrations. The
steeper decline at start is due to efficacious removal by dialysis, which
is not matched by the decay in the extra-plasmatic compartment
(gray line), because this depends on the building up of a sufficient
inter-compartmental concentration gradient. After some time, both
curves remain parallel to each other. The distance between both
curves depends on the ease (or difficulty) with which one solute
moves from one compartment to another: the less resistance, the
smaller the difference. The figure also illustrates the rebound
phenomenon at the end of dialysis: removal by dialysis ends but the
shift among compartments continues, causing a rise in concentration
(mirroring the decline at the beginning of dialysis). After some time
(depending on inter-compartmental resistance and gradient) both
curves tend to match. C1 and C2, solute concentration in V1 and V2.
reached extra-plasmatic compartment for concentration
assessment.20 These data show that urea kinetics are not
representative for all small water soluble compounds.
It was also possible to calculate which dialysis approach
would allow to remove guanidino compounds more effi-
ciently: for those with a larger distribution volume this was by
extending dialysis time, and for guanidino succinic acid with a
smaller distribution volume compared with urea this was by
increasing frequency.21
Protein bound molecules
A host of biological effects have been attributed to the large
family of the protein-bound solutes.18,22 Their kinetic pattern
is markedly different from that of urea.23 Protein binding
itself seems to have a key role, as dialysis removal and also the
shift from extra-plasmatic to plasmatic are to a large extent
hindered in proportion to the degree of protein binding.
This dissociation with urea kinetics is corroborated by
several clinical findings. Extended hemodialysis with a large
dialyzer membrane area and a high dialysate flow resulted in
an almost double indoxyl sulfate and p-cresyl sulfate clearance
compared with when a small dialyzer membrane area and
standard dialysate flows were combined with a slight increase
in blood flow. This finding sharply contrasted with the
identical urea clearances.24 Basile et al.,25 applying extended
dialysis while keeping total quantity of dialysate and blood
crossing the filter per session the same as with standard
dialysis, improved urea removal but not that of protein-
462
R Vanholder et al.: The last days of Kt/V?
bound toxins. In a study comparing high-flux hemodialysis
with peritoneal dialysis, hemodialysis was more efficient for
the removal of both urea and p-cresol, a surrogate for the
sum of p-cresol conjugates.26 However, this better removal
by hemodialysis was translated only in lower circulating
concentrations for urea. For p-cresol, in contrast, the
concentration was lower with peritoneal dialysis, exactly
opposite to what could be expected from the clearance
values.26 This discrepancy was confirmed in at least one other
study27 and suggests that, apart from removal adequacy,
solute concentration in dialysis patients may be the
consequence of other, non-dialysis phenomena;28 those are
unlikely to be grasped entirely by Kt/Vurea, a simple formula
assessing the kinetic pattern of one single molecule.
Middle molecules
Among the middle molecules (mostly peptides of more than
500 Da removed mainly by large pore (high-flux) dialyzers),
2-microglobulin kinetics have been studied most extensively,
although toxic characteristics and association with hard
outcomes have been described for many other middle
molecules as well.9 Kinetic data reveal that, as compared
with urea, the shift of 2-microglobulin from extra-plasmatic
to plasmatic volume is hampered substantially during high-
flux hemodialysis,29,30 which is translated into a considerable
rebound after dialysis.31
The clinical equivalent of these divergent kinetics can be
found in a study by Eloot et al.:32 when in the same patients
dialysis time was extended from 4 to 8 h while maintaining
dialyzer membrane area and total blood and dialysate flow
through the dialyzer per session the same, removal of
phosphate and 2-microglobulin were increased by, respec-
tively, 48.9% and 81.2% during the 8 h sessions, in spite of
unmodified Kt/Vurea.32 These findings suggest that Kt/Vurea
does not reflect the impact of time on the inter-
compartmental shifts and on dialysis removal of compounds
with more complex kinetics than urea, which receive more
time to shift out of the extra-plasmatic compartment if
dialysis is prolonged.
A dissociation between urea removal and that of middle
molecules was further corroborated in at least two controlled
hard outcome studies. In a comparison between low-flux
hemodialysis and hemofiltration, there was a borderline
significant survival advantage for hemofiltration.33 However,
at least as striking was the fact that with hemofiltration after
36 months of follow-up, in spite of a decreased Kt/Vurea,
predialysis 2-microglobulin had decreased, whereas it had
increased with an unmodified Kt/Vurea in case of low-flux
dialysis.33 Likewise, in the Membrane Permeability Outcomes
study comparing low-flux with high-flux hemodialysis and
showing a survival advantage for hypoalbuminemic patients
on high-flux membranes, 2-microglobulin concentration
was markedly lower during the entire study during high-flux
dialysis, although both groups were strictly held at the same
target Kt/Vurea.34
Kidney International (2015) 88, 460465
R Vanholder et al.: The last days of Kt/V?
Summary
The kinetic pattern of urea is not representative for that of
most other uremic solutes, many of which have been associated
with negative hard outcomes of kidney disease. In at least seven
clinical studies modifying elements that contribute to dialysis
adequacy, it was possible to dissociate urea removal or
concentration from that of other uremic toxins.2427,3234 It
would go too far to claim that there were no such discrepancies
at the time when Kt/Vurea was conceived, but the advent of
novel alternatives modifying the classical concept of dialysis
strengthened the evidence that Kt/Vurea fails to discern a
number of important factors affecting uremic toxin concentra-
tion and their impact on outcomes.
SEVERAL OTHER ELEMENTS IMPACTING SOLUTE
CONCENTRATION OR DIALYSIS OUTCOMES ARE NOT
COVERED BY KT/VUREA
The role of the intestine
In large cohorts of hemodialysis patients, the ratio between
the highest and lowest concentrations for several uremic
toxins exceeds 90%, which cannot be explained by differences
in dialysis adequacy alone.35,36 One up till now largely
neglected alternative factor is the generation of uremic toxins
by the intestinal microbiota.37 The concentration of several
compounds, among which indoxyl sulfate and p-cresyl
sulfate, was 50- to 100-fold lower in hemodialysis patients
without colon than in patients with a colon38 in spite of
similar Kt/Vurea. Subjects with normal kidney function
consuming a vegetarian diet produce less of these molecules
than subjects on a regular diet.39 In a multivariate model
adjusted for factors potentially determining concentration of
uremic toxins, not Kt/Vurea but residual renal function and
dietary protein intake as a surrogate for intestinal generation
were the only factors associated with their plasma levels.36
Assuming uremic toxin concentration as a key factor to
govern their biological effects, these data suggest that
intestinal generation as one of the main determinants of this
concentration is not taken into account by calculated Kt/Vurea.
It may be argued that protein nitrogen appearance as a
surrogate of protein intake is next to Kt/Vurea, another factor
that can be estimated by urea concentration patterns of
dialysis patients, and may substitute for this lack of
information delivered by Kt/Vurea alone. However, protein
nitrogen appearance is not as easily or frequently assessed as
Kt/Vurea. In addition, its relationship with uremic solute
generation is likely skewed by shifts in intestinal microbiotic
composition and modifications of intestinal assimilation and
fermentation due to uremia, which are not covered by simply
studying protein breakdown.37 In the study by Eloot et al.32
mentioned above, the low correlation factors between uremic
toxin concentration and protein nitrogen appearance,
although significant, also raise the suspicion that other factors
are even more important determinants.
If in future medical interventions to decrease intestinal
generation and absorption of uremic solutes such as the
administration of sorbents, prebiotics, or probiotics37 would
Kidney International (2015) 88, 460465
mini review
become a current practice, this would dissociate Kt/Vurea even
further from uremic toxin concentration.
The role of residual renal function
A second non-dialysis factor with a major impact on solute
concentration is residual renal function.40 In multivariate
analysis, residual renal function and not Kt/Vurea was next to
protein intake the main determinant of toxin concentration.36
It may be argued that this bias may be overcome by
including urinary urea removal in Kt/Vurea. However, if urinary
urea excretion is determined at all, this is not necessarily a
predictor of urinary removal pattern of other uremic solutes.
Indeed, urinary urea removal is likely to overlook the complex
relation between glomerular filtration and tubular secretion/
reabsorption in the urinary excretion of other components,
which is hardly predictable because of differences among
solutes,35,40,41 among patients, and probably also as renal
failure progresses. Therefore, serious doubts can be casted on
whether including urinary urea excretion into Kt/Vurea would
enable to figure out the complex but essential interaction
between kidney function and individual toxins.
Outcome-determining dialysis factors not directly linked to
dialysis adequacy
Finally, a number of confounders related to dialysis and
associated with outcomes are missed by Kt/Vurea. Especially,
dialysis length is a factor associated with mortality4 that
modifies Kt/Vurea counterintuitively. The shorter the dialysis,
the steeper the urea decay curve and, and especially if single
pool kinetics are applied, Kt/Vurea will be overestimated
because of a deflated post-dialysis urea value. Two pool urea
kinetics may compensate for this flaw. However, as shorter
dialysis is in addition linked to higher ultrafiltration rates per
unit of time, another factor associated with mortality,42 even
the correction by two pool kinetics will be incomplete, as
dialysis is not only about small solute removal but also about
electrolyte balance and maintenance of volume status. More-
over, the misbalance between compartments becomes more
prominent as dialysis procedures become more intensive (e.g.,
hemodiafiltration) or shorter, causing a more explicit distor-
tion between kinetics of urea and that of other molecules,
further jeopardizing the representativeness of Kt/Vurea.
Estimations of Vurea may be incorrect in subjects with
diverging body composition
Spalding et al.43 demonstrated an inconsistent relationship
between Vurea and the body surface area, resulting in a too low
dialysis dose than the one targeted in women and small men.
Likewise, also differences in body water may skew the
accuracy of Kt/Vurea.44
IS THERE A WAY OUT? KINETICS OF ANOTHER MOLECULE
THAN UREA? OR OPTIMIZED DIALYSIS WITHOUT FOCUSING
TOO MUCH ON KT/VUREA?
There is nothing wrong per se with an index of dialysis
adequacy that is based on a molecule that by itself has no
463
mini review
Table 1 | Negative aspects of Kt/Vurea as an index of dialysis
adequacy and outcomes
In clinical studies Kt/Vurea is not often the sole and the most consistent
determinant of dialysis outcomes
Raising Kt/Vurea above standard in randomized trials does not improve
outcomes
Proof of the toxic effect of urea is scarce
Clinical studies supporting the toxicity of urea are almost nonexistent
Dialysis kinetics of urea are dissimilar to the kinetics of many other uremic
retention solutes
Concentration pattern during dialysis of many solutes can be dissociated
from that of urea by applying alternative strategies to standard dialysis
Urea kinetics overlook partially or entirely the effect on removal of applying
large pore dialyzers or convection
Urea kinetics overlook partially or entirely the effect on removal of
extending dialysis
Urea kinetics do not account for intestinal or metabolic generation of
uremic toxins
Kt/Vurea insufficiently takes into account the effect of residual renal function
on solute removal
Kt/Vurea incompletely takes into account the effect of dialysis length on
solute removal
Kt/Vurea does not reflect technical aspects of dialysis with potential impact
on outcomese.g., ultrafiltration rates
Kt/Vurea does not reflect the impact of dialysis on electrolyte balance and
volume status
Vurea as an index of body water may be inaccurate in people with divergent
body composition
Abbreviation: Kt/Vurea, clearance of urea multiplied by dialysis duration and
normalized for urea distribution volume.
really convincing toxic impact. However, as Kt/Vurea is unable
to reflect the removal pattern of other key molecules involved
in uremic toxicity, this becomes a serious handicap that is
extra emphasized by the dissociation in concentration and
removal of urea versus other toxins with many of the newer
more efficient dialysis strategies.2427,3234 All negative argu-
ments about Kt/Vurea are summarized in Table 1.
Even more worrisome is that treating physicians and even
regulators might be satisfied if Kt/Vurea reaches a threshold,
without considering that dialysis adequacy is not a question of
dialysis of small water soluble solutes alone but that it
concerns many factors. Physicians or hospital directions
might be tempted to reduce dialysis time once Kt/Vurea
exceeds a threshold, which may create risks rather than solve
problems.
Do we then need a kinetic or a removal parameter based on
one or several other uremic toxin(s)? This might lure us into
the same trap as with Kt/Vurea. Uremic toxicity should be seen
as a complex multifactorial problem, and it will probably never
be possible to find one single solute that is representative for all
elements at play. It is merely impossible to synthesize the
complexity of solute removal during dialysis in one single
simple formula.
We are convinced that it is more useful to pursue by all
means optimal removal by increasing length and/or frequency
of dialysis, using large pore membranes, and eventually
convection, based on the currently available evidence reviewed
in.18 All in all, several controlled studies pointed to better
outcomes with such strategies, and there actually is no study
464
R Vanholder et al.: The last days of Kt/V?
showing an outcome disadvantage for these more efficient
alternatives.
Does this mean that we have to discard the concept of
Kt/Vurea completely? It is useful to have a parameter of
minimum adequacy, especially in the start phase of dialysis or
when parameters that are essential for clearance are disturbed
longitudinallye.g., with vascular access problems. Hence,
Kt/Vurea can be kept as guard of minimal dialysis adequacy,
however, without forgetting that many other factors not
explained by Kt/Vurea have a key role as well.
DISCLOSURE
All the authors declared no competing interests.
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