Nephrol Dial Transplant (2000) 15 [Suppl 2]: 45–48
Nephrology
Dialysis
Transplantation
Acid–base correction and convective dialysis therapies
Ingrid Ledebo
Gambro Research, Lund, Sweden
Abstract Whichever dialysis therapy is used, there is a
similar need for correcting the acid–base balance. The
most important tool for this is the buffer in the dialysis
fluid and, when using convective therapies, also in the
substitution solution. The buffer source in all modern
versions of these therapies should be bicarbonate. The
more efficient the dialysis treatment in terms of small
solute transport, the more rapid the uptake of buffer.
Thus, optimally applied haemodiafiltration has the
potential for the largest buffer gain. The target for
acid–base correction in dialysis is to maintain patients
within or as close to the physiological plasma bicarbonate range as possible. However, cross-sectional studies
of acid–base status among patients treated with contemporary forms of dialysis often show moderate acidosis. As metabolic acidosis has been found to be an
important stimulus for protein catabolism in experimental studies, an association with nutritional problems has been sought in dialysis patients. This has
revealed a negative correlation between plasma bicarbonate and nutritional parameters. Acidotic patients
were found to have better nutritional status than
patients with normalized acid–base balance. However,
caution should be exercised when interpreting plasma
bicarbonate levels, since acidosis may be a cause as
well as an effect of excessive protein catabolism.
Although available clinical data suggest that the catabolic effect of mild acidosis can be compensated by
adequate nutrition and adequate dialysis, it should be
desirable to aim for a normalized acid–base balance in
combination with adequate nutritional intake and
delivery of dialysis.
Key words: acidosis; bicarbonate; convection; haemodiafiltration; haemofiltration
Introduction
Maintaining the acid–base balance in the body is one
of the major functions of the kidney and as such
Correspondence and offprint requests to: Ingrid Ledebo, PhD,
Gambro Research, Box 10101, S 220 10 Lund, Sweden.
should be replaced by dialysis in end-stage renal disease
patients. This is achieved by including a buffer in the
dialysis fluid, but the choice of buffer source and mode
of dialysis are important determinants for the acid–
base correction. As acidosis has been shown to affect
several metabolic processes in the body, there is general
agreement that it should be avoided, but the target for
correction is still subject to discussion.
Components of acid–base correction in dialysis
The buffer gain during a dialysis treatment should be
sufficient to compensate for the generation of acid
during the interdialytic period and also for any loss of
buffer that takes place during dialysis. The uptake of
buffer during dialysis serves not only to increase
the plasma bicarbonate level, but also to restore the
buffering capacity of other body buffer systems. If
the patient has been in positive hydrogen balance, his
non-bicarbonate buffer stores may have contributed
buffer equivalents and need to be regenerated [1]. This
can be seen as an extended bicarbonate distribution
space [2].
When bicarbonate is used as buffer in the dialysis
fluid, the uptake is determined by the mass transfer
rate across the membrane. Increasing the efficiency of
dialysis, in terms of small solute clearance, leads to
increased rates of transfer of bicarbonate into the
blood. However, it is the difference in concentration
between blood and dialysis fluid that makes up the
driving force for the transport and, when the gradient
is reduced gradually by rising blood bicarbonate levels,
the system approaches a steady state. The titration of
non-bicarbonate buffer stores still proceeds and therefore the treatment time is of importance for the total
uptake of buffer. When the buffer source is acetate or
lactate, which need to be metabolized before being
effective as buffers, the rate of metabolism may be the
limiting step and large amounts of bicarbonate may
be lost from the blood before steady-state conditions
are reached and there is a net gain of buffer [3].
In the various extracorporeal dialysis therapies,
buffer is administered by different routes. In haemodialysis (HD), the buffer in the dialysis fluid diffuses
across the membrane along a concentration gradient.
46
In haemodiafiltration (HDF ), there is buffer in the
dialysis fluid and additionally in the substitution solution, which is introduced directly into the blood. In
haemofiltration (HF ), buffer is provided only via the
substitution solution. Looking specifically at the convective therapies, HDF and HF, there are again differences affecting the buffer administration (Figure 1). In
classical HDF, which is HDF with substitution solution provided from bags with sterile fluid, the buffer
in the dialysis fluid is bicarbonate, while in the substitution solution it is most commonly lactate. In the
modern form of HDF which incorporates on-line
preparation of the substitution solution, bicarbonate
is the buffer in both fluids. Classical HF can be defined
as post-dilution with externally provided fluid in bags
and it is performed mainly with lactate as buffer source.
In modern HF, the substitution solution is prepared
on-line, it contains bicarbonate and is usually administered in pre-dilution mode.
When assessing the effect of these dialysis therapies
on the acid–base correction, the major factors that
contribute to a difference in buffer balance are thus
the treatment efficiency in terms of small solute clearance, the choice of buffer source and the actual buffer
concentration in the fluids. When performed under
optimal conditions at the same blood flow rate, HDF
provides the highest and HF the lowest small solute
clearance ( Figure 2). The order is the same for the
buffers, although the direction of transport is reversed,
but the buffer source determines whether the effect is
positive or negative on the buffer balance. For bicarbonate, it is positive; the higher the clearance the larger
the buffer gain. For acetate and lactate, it is negative;
the higher the efficiency the more buffer is lost initially
from blood.
Acid–base correction in HDF—clinical result
With the large number of variable treatment parameters in HDF, it is difficult to compare results and
draw conclusions from clinical studies. The group in
Fig. 1. Mode of administration and type of buffer used in dialysis
fluid and substitution solution in different forms of convective
therapies. HDF=haemodiafiltration; HF=haemofiltration; Bc=
bicarbonate; Lc=lactate.
I. Ledebo
Fig. 2. Relative small solute clearance for the extracorporeal dialysis
therapies when performed under optimal conditions at the same
blood flow rate. The impact of the choice of buffer on the net buffer
balance is shown by the arrows. HF=haemofiltration; HD=haemodialysis; HDF=haemodiafiltration; Ac=acetate; Lc=lactate; Bc=
bicarbonate.
Vicenza addressed the choice of buffer in a wellstructured study and compared classical HDF using
four different buffer combinations with HD using
bicarbonate [4]. For the correction of the acid–base
balance as well as for the reduction of intradialytic
symptoms, it was found to be more important to have
bicarbonate in the dialysis fluid than in the substitution
solution, but the best result was obtained when bicarbonate was used in both fluids. Optimal correction of
the acid–base balance was not achieved with any mode,
and the authors concluded that this would have
required higher bicarbonate concentration in the fluids.
In this study, the amount of convective transport was
modest and this may explain why the diffusive bicarbonate transport from the dialysis fluid was more
important than the convective transport from the
substitution solution.
With modern HDF, the contribution of diffusion
and convection, respectively, can be optimized and the
bicarbonate concentration in the fluid can be individualized to achieve the desired correction of the acid–base
balance. Canaud summarized his long experience of
on-line HDF by reporting 12 months data for a group
of 56 patients [5]. The double-pool urea Kt/V was
1.55, the normalized protein catabolic rate (nPCR)
was 1.12 g/kg/day and the plasma bicarbonate levels
were 22.8 mmol/l pre-dialysis and 29.9 mmol/l postdialysis. To avoid post-dialysis alkalosis, the bicarbonate concentration in the fluid had to be reduced from
39 to 35 mmol/l after an initial period of 6–9 months.
As no other change is reported, the reduced buffer
need indicates generally reduced acid production,
which could be a consequence of the normalized acid–
base status, or that previously depleted body buffer
stores are now refilled.
Acid–base correction in HF—clinical result
During the 1980s and early 1990s, lactate was generally
used as buffer source in HF treatments. Two early
reports of post-dilution HF with bicarbonate compared
the acid–base balance in patients treated first with
lactate and then with bicarbonate in the substitution
solution [6,7]. In both studies, higher plasma bicarbonate values could be demonstrated with bicarbonate,
but only when the bicarbonate concentration in the
fluid exceeded the lactate concentration with which it
was compared. These studies illustrate that in classical
HF the small solute clearance is so low that the
transport of lactate becomes the rate-limiting step
rather than the metabolism, and therefore the impact
of the choice of buffer is less.
The importance of the buffer concentration on the
net buffer balance was illustrated in a study from
Bologna, where the concentration of bicarbonate in
the substitution solution was increased in steps from
30 to 40 mmol/l [8]. The net gain of buffer was related
directly to the bicarbonate concentration.
In modern HF, the efficiency of small solute removal
is increased by pre-dilution, and with the use of bicarbonate in the fluid this has a positive effect on the
buffer uptake. The substitution solution can be individualized to the patient’s need, regarding composition
as well as volumes used.
Effects of metabolic acidosis in dialysis patients
Metabolic acidosis has been studied extensively in
experimental animals and in humans and found to be
an important stimulus for protein catabolism. In the
acidotic state, branched-chain amino acids and muscle
protein are degraded in a process where glucocorticoids
play an important role [9]. In renal failure patients,
the chronic exposure to acidosis could thus have serious
metabolic consequences and contribute to malnutrition
[10]. The widespread adoption of bicarbonate as buffer
in dialysis was brought about by demands for increased
dialysis efficiency, but also made it possible to increase
the plasma bicarbonate levels by providing more buffer
during dialysis [1]. During the 1990s, normalization of
the acid–base balance became an additional goal for
adequate dialysis. Prospective studies have now shown
that normalizing the acid–base balance leads to metabolic changes that reverse the deleterious effects of the
previous acidosis. Protein degradation decreased in
patients on HD as well as on continuous ambulatory
peritoneal dialysis (CAPD) when the metabolic acidosis
was corrected [11,12]. Long-term studies resulted in
significantly improved nutritional parameters such as
increased triceps thickness, midarm muscle circumference and body weight [13,14]. There was also improvement in morbidity, with fewer days spent in hospital
among patients with normalized acid–base balance
[14].
To determine the clinical importance of metabolic
acidosis in the dialysis population, the degree of acidosis has been correlated with signs of malnutrition.
Looking at the baseline status of the first 1000 patients
entering the HEMO study, the total carbon dioxide
(CO ) was found to be negatively correlated to the
2
nPCR [15]. If PCR is interpreted traditionally as a
surrogate for protein intake, this would indicate that
a normalized acid–base balance is connected with
reduced protein intake. A similar relationship between
plasma bicarbonate and PCR was reported previously
from other cross-sectional analyses of HD patients
[16,17]. However, one of these studies showed a positive correlation between plasma bicarbonate and the
albumin level [17]. This result stimulated a subsequent
cross-over study where patients were changed from a
slightly acidotic state to a normalized acid–base balance by oral administration of buffer [18]. The change
in acid–base status resulted in significantly reduced
PCR and increased albumin levels. The new acronym
for PCR, PNA which stands for protein equivalent of
nitrogen appearance, shows more correctly that it
indicates the amount and not the process by which
urea nitrogen is produced. In an acidotic patient, there
is likely to be degradation of internal as well as external
protein sources, and both are included in the PCR
term. When the acidosis is corrected, the endogenous
breakdown should disappear, which improves the
nutritional status and reduces the PCR. We could
therefore say that the PCR value connected with a
normalized acid–base status is the ‘normal’ PCR.
It is clear that acidosis contributes to increased PCR,
but we need also to consider the reverse; that a large
protein intake gives a high PCR and contributes to
acidosis. When we look at the plasma bicarbonate
level in the body, we should apply a model similar to
that which we apply to urea kinetics (Figure 3). The
urea level in the body is affected both by generation
from protein breakdown and by removal by dialysis,
assuming no kidney function. Therefore, a low BUN
indicates either low generation due to low protein
intake or large removal by dialysis. Looking only at
the BUN value does not tell us which, as we know
from urea kinetic modelling. In a similar way, the
bicarbonate in the body is determined by uptake during
dialysis and by regeneration of body buffers (Figure 3).
A low plasma bicarbonate can thus result from either
low uptake during dialysis or large regeneration of
Fig. 3. Single-pool models for urea and bicarbonate in the body,
assuming no kidney function.
48
body buffers, a consequence of a large production of
acid from a large intake of protein. For dialysis
patients, it is as important to determine whether their
acidosis results from poor buffer uptake or large protein intake, as it is to know whether their low BUN is
due to good dialysis or poor dietary intake.
A survey of laboratory data from 12 000 dialysis
patients showed that the risk of death profile at different serum CO levels was J-shaped. Increasing mortal2
ity was seen in acidotic states with CO <17.5 mmol/l,
2
but also when the CO level was >22.5 mmol/l [19].
2
This was a disturbing fact at the time, but our present
understanding of the relationship between PCR and
plasma bicarbonate offers a plausible explanation. As
the patient data originate from 1988 when acetate was
still widely used, a near-normal plasma bicarbonate
level was probably connected with a low protein intake
and these patients may therefore have been at risk
because of malnutrition. Patients with CO values in
2
the range of 17.5–20, although acidotic, were not
exposed, to an increased risk of death. It is possible
that the acidosis in many of these patients was caused
by excessive protein intake which protected them from
the catabolic effects.
The effect of acidosis on bone resorption has been
demonstrated in cell cultures and experimental animals,
but only a few studies have extended the observations
to large groups of dialysis patients [20]. A French
study from the early 1990s [21] showed that the
progression of hyperparathyroid bone disease was significantly delayed when the acid–base balance was
normalized. One reason for the weak evidence for a
beneficial effect of normalized acid–base balance on
bone disease in chronic renal failure patients could be
the complexity of the disease in these patients,
where disturbances in the calcium–phosphate–
vitamin D–parathyroid hormone balance are likely
to obscure the impact of most other factors.
General recommendations for acid–base correction
The target for acid–base correction is to maintain
patients within or as close to the physiological plasma
bicarbonate range as possible. The buffer uptake
during dialysis can be modified by changes in buffer
concentration, treatment efficiency and time, all of
which can be achieved easily in modern forms of
dialysis. Pre-dialysis acidosis is a sign of insufficient
availability of buffer during the interdialytic period.
Correcting this by increasing the buffer uptake during
dialysis might lead to post-dialysis alkalosis, which
should be avoided as alkalosis may be as detrimental
as acidosis. To achieve a more even acid–base status,
oral base supplement could be used during the interdialytic period.
The ambiguity of plasma bicarbonate levels and
PCR values and their impact on nutrition have raised
questions about the value of acid–base correction [22].
Although there is general agreement that severe metabolic acidosis should be corrected, it is also felt by
I. Ledebo
some nephrologists that adequate protein intake and
adequate dialysis could compensate for a certain degree
of acidosis. Still, aiming for a normalization of the
acid–base balance by using all the tools available to
us today should be the preferred approach, rather than
accepting a certain catabolism whose effect on various
body systems presently is unknown.
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