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After its proposal as a marker of dialysis adequacy in the Kt/Vurea (clearance of urea multiplied by dialysis duration and
eighties of last century, Kt/Vurea helped to improve dialysis normalized for urea distribution volume) was first proposed as
efficiency and to standardize the procedure. However, the a parameter of dialysis adequacy in a period of worrisome
concept was developed when dialysis was almost uniformly mortality on dialysis in the USA. After the randomized
short and was applied thrice weekly with small pore cellulosic National Cooperative Dialysis Study had demonstrated that a
dialyzers. Since then dialysis evolved in the direction of many higher time averaged urea concentration was related to higher
strategic alternatives, such as extended or daily dialysis, large hospitalization,1 Kt/Vurea emanated from a post hoc mechan-
pore high-flux dialysis, and convective strategies. Although istic study on the same data.2 The threshold of this absolute
still a useful baseline marker, Kt/Vurea no longer properly value was originally set at 0.8 but soon was increased to 1.2 or
covers up for most of these modifications so that urea higher. With the introduction of Kt/Vurea, adequacy of dialysis
kinetics are hardly if at all representative for those of other was no longer assessed by a single static pre-dialysis value, of
solutes with a deleterious effect on morbidity and mortality which the low concentration could be due to negative
of uremic patients. This is corroborated in several clinical confounders such as low protein intake for urea or low muscle
studies showing a dissociation between removal of urea and mass for creatinine. Kt/Vurea instead is a dynamic parameter
that of other uremic toxins. In addition, randomized that assesses removal by dialysis as a whole (Kt), including not
controlled trials showed no benefit of increasing Kt/Vurea. only clearance but also dialysis length and above all a correction
Finally, this parameter also hardly is evocative for metabolic for body mass (V). For the first time not only the therapy but
or intestinal generation of toxins, for their removal by also the patient was taken into account by acknowledging that a
residual renal function and for the complex interaction of voluminous person needs more dialysis compared with a tiny
dialysis length with removal pattern and patient outcomes. one. This led to a more standardized dialysis approach and
We conclude that apart from being a baseline parameter of was translated into a better survival with higher Kt/Vurea in
dialysis adequacy, Kt/Vurea insufficiently represents all novel essentially observational studies.3,4
strategic changes of modern dialysis. Kt/Vurea is too simple a However, Kt/Vurea quite soon appeared to be far from the
concept for the complexities of uremia and of todays dialysis. only determinant of outcomes of dialysis. A study by Owen
Kidney International (2015) 88, 460465; doi:10.1038/ki.2015.155; et al.5 demonstrated a relation between urea reduction ratio
published online 10 June 2015 (as surrogate for Kt/Vurea) and outcomes, but a much stronger
KEYWORDS: hemodialysis; urea; uremia; uremic toxins 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.
even shorter (mostly 2.53 h) than what was standard Definition of the kinetic model mass balance per compartment
elsewhere (4 h). G2 E2 G1 E1
Since then the dialysis concept has changed markedly, with d(V1C1)
KR = G1 E1 (KR + KD + KER) C1
many alternatives to standard, by the introduction of large K21 dt
+ K21 (C2 C1)
pore high-flux dialyzers, convective strategies such as V2, C2 V1, C1 KD
The question arises whether Kt/Vurea is still representative for Figure 1 | Basic principles of kinetic modeling. Uremic solute is
the kinetics of solutes preferentially removed by these primarily removed from the plasmatic compartment by dialysis
causing a fast decrease in its concentration. Only once this plasmatic
alternative strategies, which usually have no added value for concentration starts to decrease sufficiently, concentration in the
the removal of urea in contrast to their impact on the extra-plasmatic compartment can also decrease, based on a diffusive
elimination of many other solutes. 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
THE EVIDENCE OF THE TOXICITY OF UREA IS LIMITED clearance; K21, inter-compartmental clearance; V, distribution volume;
To the best of our knowledge, only a few experimental studies V1, plasmatic volume; V2, extra-plasmatic volume.
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 following administration. In dialysis kinetics, the disappearance
resistance in vitro and in mice. In an in vitro study, Vaziri of solutes out of these remote compartments is studied during
et al.11 showed disruption of the intestinal epithelial barrier their removal by dialysis. Although a large number of different
function by derangement of tight junctions. Trcherel et al.12 compartments are possible, in theory two compartments are
explored regulatory proteins of apoptosis and showed an critical: (1) the plasma compartment, from which solute
upregulation of Bcl2-associated death promoter, a pro- removal by dialysis is relatively easy if dialyzer pores are large
apoptotic protein. enough, and (2) the (sum of) extra-plasmatic compartment(s)
The clinical equivalent to these experimental suggestions is, where solute concentration tends to lag behind on plasma
however, scanty. Adding urea to the dialysate up to concentra- concentration, as inter-compartmental shifts largely depend on
tions two to three times higher than usual in dialysis patients diffusion from high to low concentration, which is hindered by
induced no consistent changes in uremic symptoms.13 Increas- a variable resistance from the compartmental boundaries.
ing urea removal in controlled trials had no impact on hard The more important this resistance, the more dialysis adequacy
clinical outcomes.6,7 An observational study by Koeth et al.14 will be reduced. Also post-dialytic rebound, creating a
found an association with mortality of homocitrulline, a marker quick increase in uremic solute concentration immediately
of carbamylation to which also urea is supposed to contribute. after dialysis due to the backlog of extra-plasmatic concentra-
However, the concentration of urea was only modestly tion, is an epiphenomenon of this process (Figure 2).
correlated to that of homocitrulline, with an R2 of 0.14, Resistance to shifts between compartments is minimal for
suggesting that other factors than urea were more important for urea compared with other solutes,16 which, as a consequence,
homocitrulline generation and its association to death. In are more difficult to remove. Hence, the question should be
addition, urea by itself was not related to mortality.14 raised whether urea kinetics are representative for uremic
Thus, urea, in spite of its everyday application as marker of toxins at large.
dialysis adequacy, has rarely been assessed for its toxicity and In the next sections, we will describe discrepancies between
up till now has not been proven in clinical studies to affect solute kinetics of urea and that of other uremic toxins, based
outcomes. Its choice as a marker cannot really be supported on the classical subdivision of uremic toxins in small water
by robust biochemical or clinical arguments. However, even if soluble compounds, protein-bound solutes, and middle
urea would be a recognized toxin, there remain questions molecules.17
about the representativeness of Kt/Vurea for the removal of
other uremic retention solutes. Small water soluble compounds
The question has been raised whether urea as one of the small
THE KINETICS OF UREA ARE NOT REPRESENTATIVE FOR water soluble compounds would have similar kinetics as other
OTHER SOLUTES, OF WHICH TOXICITY IS BETTER solutes with the same characteristics, such as the guanidino
DOCUMENTED compounds, which have a well-documented biologic (toxic)
Basic principles of kinetic modeling impact.18 However, when their kinetics were compared,
(Figures 1 and 2) The concept of dialysis kinetic analysis lays at distribution volume was definitely different and mostly larger
the origin of urea kinetic modeling.15 The basic principle is the for the guanidino compounds as compared with urea, giving
mirror image of pharmacokinetics, where the distribution rise to less efficient removal.19 Those mathematical findings
pattern of a drug throughout the body to reach the most remote were corroborated by assessing in vivo concentrations of
compartments is studied after the plasma concentration rises guanidino compounds in erythrocytes, the most easily
Calibration of the kinetic model by fitting on in vivo data bound toxins. In a study comparing high-flux hemodialysis
with peritoneal dialysis, hemodialysis was more efficient for
Post dialysis the removal of both urea and p-cresol, a surrogate for the
C2
rebound sum of p-cresol conjugates.26 However, this better removal
Concentration
Table 1 | Negative aspects of Kt/Vurea as an index of dialysis showing an outcome disadvantage for these more efficient
adequacy and outcomes alternatives.
In clinical studies Kt/Vurea is not often the sole and the most consistent Does this mean that we have to discard the concept of
determinant of dialysis outcomes Kt/Vurea completely? It is useful to have a parameter of
Raising Kt/Vurea above standard in randomized trials does not improve
outcomes
minimum adequacy, especially in the start phase of dialysis or
Proof of the toxic effect of urea is scarce when parameters that are essential for clearance are disturbed
Clinical studies supporting the toxicity of urea are almost nonexistent longitudinallye.g., with vascular access problems. Hence,
Dialysis kinetics of urea are dissimilar to the kinetics of many other uremic Kt/Vurea can be kept as guard of minimal dialysis adequacy,
retention solutes
Concentration pattern during dialysis of many solutes can be dissociated
however, without forgetting that many other factors not
from that of urea by applying alternative strategies to standard dialysis explained by Kt/Vurea have a key role as well.
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 DISCLOSURE
extending dialysis All the authors declared no competing interests.
Urea kinetics do not account for intestinal or metabolic generation of
uremic toxins
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