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Artículo de Actualización
The Role of Daily Dialysis in the Control
of Hyperphosphatemia
Steven G. Achinger, Juan Carlos Ayus*
*Division of Nephrology, University of Texas Health Science Center San Antonio, San Antonio, Texas.
Correspondencia: Juan Carlos Ayus, MD, FACP, FASN. Professor of Medicine, Director of Dialysis Services, Texas Diabetes Institute, University of Texas
Health Science Center San Antonio, San Antonio, Texas. Mail Code 7882. 7703 Floyd Curl Drive, San Antonio, Texas 78229-3900. E-mail: [email protected]
Abstract
In patients with end-stage renal disease (ESRD), hyperphosphatemia occurs in the vast majority of patients. The numerous
clinical sequelae of hyperphosphatemia include secondary hyperparathyroidism and increased risk of cardiovascular death.
Chronic hemodialysis as it is currently practiced in the United
States does not remove sufficient phosphate to control serum
levels within accepted guidelines. The inadequacy of conventional hemodialysis in removing phosphate mandates the use of
phosphate binders in virtually all hemodialysis patients. Despite
their proven efficacy, these medications fail to control phosphorous in seventy percent of hemodialysis patients. Additionally,
these medications may have untoward side effects that must be
considered since they are typically intended for lifetime use.
Quotidian hemodialysis has in previous uncontrolled studies
shown promise in reducing serum phosphorus while at the same
time reducing or eliminating the need for phosphate binders.
Recent results from our group demonstrate for the first time in a
controlled fashion the efficacy of short daily dialysis in controlling serum phosphorus.
Key Words: Phosphorus, phosphorus control, daily hemodialysis,
short daily hemodialysis, quotidian hemodialysis, secondary
hyperparathyroidism
Cardiovascular disease is present in ESRD patients at rates 10-20
times higher than in the general population and accounts for
50% of deaths among ESRD patients.1,2 Hyperphosphatemia is an
emerging risk factor for cardiovascular mortality in the ESRD
population.2 The pathogenesis of cardiac disease in the ESRD
population is complex but involves the interplay of traditional
risk factors along with risk factors that are specific to the dialysis
population. The novel risk factors among dialysis patients include
hyperphosphatemia, elevated calcium x phosphorus (Ca x P)
product, lipoprotein (a), hyperhomocysteinemia, chronic inflammation and left ventricular hypertrophy.2-9 Recently, in a rodent
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model, hyperphosphatemia has been shown to induce myocardial
hypertrophy, independent of effects on hyperparathyroidism or
cardiovascular calcification.10 Thus hyperphosphatemia must be
viewed in the broad context of a cardiovascular risk factor in
addition to its role in initiating secondary hyperparathyroidism.
Conventional hemodialysis does not remove sufficient phosphate
to maintain phosphorus balance in the vast majority of
hemodialysis patients.2,11 A four hour hemodialysis session will
clear 34 mmol of phosphate (1054 mg of phosphorus),12,13 which
is not sufficient to keep up with the typical phosphorus intake of
800-2000 mg per day (equivalent to 25.8-64.5 mmol of phosphate) in the Western diet. Attempts to enhance phosphate
removal through alterations in dialysate composition and dialysis
membranes have been largely unsuccessful.14,15
The inability of hemodialysis to adequately remove phosphorus is
mainly due to the inaccessibility of phosphate during the treatment. Phosphate exists mainly in the intracellular compartment.
During a hemodialysis session with either a high flux or low flux
dialyzer, serum phosphorus decreases rapidly, reaching a
hypophosphatemic nadir at about 120 minutes.13,16 There is an
immediate post-dialysis rebound in which the serum phosphorus
level can even exceed the pre-dialysis value.13,14,16,17 Phosphate
efflux into the dialysate is greatest during the first hour of the
treatment, corresponding to the time during which serum phosphorus levels are highest.13 Phosphate efflux then falls off, but
remains at roughly half the initial value at the end of the treatment despite a stable serum phosphorus levels (Figure 1a). As
noted by previous investigators,13,16,18-20 these kinetics suggest a
two-phase model of phosphorus removal, the first entailing
removal of phosphate from the extracellular fluid compartment,
followed by continued dialysis clearance of phosphorus as phosphate is mobilized from a second (intracellular) pool which maintains serum phosphorus levels (Figure 1b).
Thus, the limiting factor in phosphate removal is not the phosphate flux across the dialyzer,15,16 but two other main factors. The
first is the rapidity of phosphate removal during the first phase,
The Role of Daily Dialysis in the Control of Hyperphosphatemia
or early part of the hemodialysis treatment and the second is the
rapidity of intracellular phosphate mobilization during the second phase. The determinant of phosphate removal during this
first phase is the serum phosphorus level; this is in fact the most
important clinical factor affecting phosphate removal during
hemodialysis.14 Higher serum phosphorus levels allow great phosphate removal during each treatment. Surface area of the dialyzer is also important with larger surface areas removing more, but
the flux of the dialyzer is not important.15,16 The determinant of
phosphate removal during the second phase of hemodialysis is
the rapidity of phosphate mobilization from body pools (Figure
1a). It has been shown that hemodiafiltration can increase phosphate mobilization from the tissues by increasing the post-dialytic phosphate rebound.17 Thus hemodiafiltration acutely
increases pre-dialytic phosphorus levels, but over three months
decreases serum phosphorus.17 The proposed mechanism for the
increased phosphate removal is the convective removal of this
solute during hemodiafiltration.17-20 Unfortunately, hemodiafiltration is a modality not readily available to ESRD patients in the
United States.
Since conventional 3 times per week hemodialysis is inadequate
to maintain phosphate balance at acceptable serum levels of
phosphorus, the use of phosphate binders is mandatory to minimize phosphorus absorption from the diet. Currently two options
exist in the United States to bind intestinal phosphate on a
chronic, long term basis: calcium-based binders and sevelamer.
Calcium acetate and calcium carbonate are effective in reducing
serum phosphorus levels in hemodialysis patients and in reducing
secondary hyperparathyroidism.21 However, concerns have been
raised about the safety of the long term use of calcium based
binders because of the potential for the chronic calcium load to
induce cardiovascular calcification, especially in the context of
the use of vitamin D analogues.22,23 Sevelamer hydrochloride, a
Table 1. Summary of Daily Dialysis Studies
Author (Ref)
No. of
subjects
Dialysis Modality
Prescription /
(Duration)
Phosphorus Control
Other Factors
Kooistra [18]
13
Daily home hemodialysis
6 times weekly (6
months)
Decrease dose of P binders
Decreased blood pressure
in hypertensive patients
Uldall [17]
5
Nocturnal hemodialysis
5-7 nights/wk, 8
hrs/night, (6-16
months)
Discontinue P binder use
Increased dietary protein intake
Mucsi [20]
7
Nocturnal hemodialysis
6 nights/wk,
8 hrs/night,
(5 months)
Discontinue P binder use
Increased dietary protein intake
Lindsay [21]
12
Nocturnal hemodialysis
5-6 nights/wk,
6-8 hrs/night,
(5 36 months)
Decreased use of P binder , Decreased Ca x P product
Improved blood pressure
control, Improved QOL
11
Short daily hemodialysis
5-6 days/wk,
1.5-2.5 hrs/day,
(5 36 months)
Decreased Ca x P product
Improved blood pressure
control, Improved QOL
51
Conventional hemodialysis
3 days/wk
4 hrs/day
(One year)
No change in phosphorus, continued use of phosphate binders
Decreased iPTH
26
Short daily hemodialysis
6 days/wk
3 hrs/day
(One year)
Decreased serum phosphorus,
73% patients discontinue the use
of phosphate binders at 12 months
Decreased iPTH
Mizani [23]
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quaternary amine anion exchange resin that binds phosphate
ions and releases hydrochloric acid is an alternative phosphate
binder that is neither aluminum nor calcium based.24 This agent is
also effective in reducing phosphorus and reducing hyperparathyroidism and does not expose the patient to a calcium
load. Because of its mechanism of action, sevelamer can lead to
an acid load and in animal studies has been associated with acidosis.25 Nonetheless, despite use of these phosphate binders,
dietary phosphorus restriction, and conventional hemodialysis,
seventy percent of patients on hemodialysis fail to achieve goals
for serum phosphorus and Ca x P product recommended in the
K/DOQI guidelines.2,11
In order to control serum phosphorus more effectively in our
ESRD population as a whole, dialytic removal of phosphorus
must be improved. Given the kinetics of phosphate removal during dialysis, it is clear that the time of dialysis must be increased
in order to achieve better phosphate removal with hemodialysis.
The HEMO study demonstrated that increased dose of dialysis,
without much increase in time of dialysis did not favorably
affect mortality.26 Despite these findings, several groups have
found beneficial effects on cardiovascular risk factors: blood
pressure control, improved anemia by reducing erythropoietin
requirements, and regression of left ventricular hypertrophy27-31
with the use of quotidian dialysis. Additionally, control of serum
phosphorus is reportedly improved with the use of either daily or
nocturnal dialysis.31-35 In our study, instead of dividing the twelve
hour weekly time over six two-hour sessions, we increased both
the total time and the frequency of hemodialysis (six times per
week for three hours) in order to maximize phosphate removal.36
Assuming a low phosphorus intake of 900 mg per day of phosphorus (equivalent to 29 mmol of phosphate), and phosphorus
kinetics shown in figure 1a, conventional hemodialysis is woefully inadequate at achieving phosphorus balance, while short daily
hemodialysis comes much closer to this goal without the use of
phosphate binders (Figures 2a and 2b).
There are only four studies of quotidian dialysis that address the
issue of phosphorus control.32-35 The summary of our review of
the literature is presented (Table 1). A universal finding in these
studies is either a decrease in requirement for phosphate binders
or complete cessation of these agents.32-35 Additionally, concurrent increases in protein intake have been reported in two of
these studies.32,34 Lindsay and colleagues reported a significant
decrease in Ca x P product using a short daily hemodialysis regimen (1.5 - 2.5 hours a day, six days a week), and using nocturnal
hemodialysis.35 In the nocturnal hemodialysis group this was
achieved with a reduction in the use of phosphate binders.35
Our study is the first to assess, in a large group of patients, the
efficacy of short daily hemodialysis in reducing serum phosphorus in a controlled manner.36 Our study employed a protocol
Table 2. The San Antonio Prospective Study on Daily Dialysis
Baseline
6 months
12 months
Conventional Hemodialysis, CHD (N=51)
Ca (mg/dL)
9.0 ± 0.70
8.8 ± 0.55
8.9 ± 0.65
P (mg/dL)
5.0 ± 1.49
4.9 ± 1.12
5.1 ± 1.14
iPTH (pg/mL)
717 ± 361
255 ± 182 *
428 ± 312 *
27 mmol
34 mmol
Short Daily Hemodialysis, SDHD (N=26)
Ca (mg/dL)
8.4 ± 1.26
9.0 ± 0.66 *
8.9 ± 0.74 *
P (mg/dL)
6.3 ± 2.57
4.6 ± 1.06 *
4.0 ± 1.19 *
iPTH (pg/mL)
690 ± 596
337 ± 255 *
312 ± 193 *
Adapted from Mizani and Ayus (ref 36)
73% of SDHD patients discontinued phosphate binders at 12 months.
* P < 0.05 vs. baseline (intra-group comparison)
†P < 0.05 SDHD vs. CHD (inter-group comparison)
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Figure 1a. Phosphate removal during hemodialysis is greatest in the first
hours of the treatment. Data are taken from Hou et al (ref 13). The
hourly
The Role of Daily Dialysis in the Control of Hyperphosphatemia
Figure 1b. Phosphate removal during hemodialysis involves two phases. The figure depicts two phases of phosphate removal. At the start of the treatment, the rate limiting step is the rapidity of phosphate removal from the extracellular fluid as depicted by the large arrow. The second phase occurs
when the serum phosphorus level has reached a nadir and the removal is limited by phosphate mobilization from the tissues.
Figure 2a. Conventional hemodialysis alone leads to significantly positive phosphorus balance. Using the phosphate removal from a four hour
hemodialysis treatment shown in figure 1a, and assuming a phosphorus
intake of 900 mg (equivalent to 29 mmol of phosphate), the predicted
phosphate balance using conventional hemodialysis over the week is
shown.
Figure 2b. Short daily hemodialysis alone is close to achieving phosphate balance. Using the phosphate removal from a three hour
hemodialysis treatment shown in figure 1a, and assuming a phosphorus
intake of 900 mg (equivalent to 29 mmol of phosphate), the predicted
phosphate balance using short daily hemodialysis over the week is
shown.
that called for three hours of hemodialysis six times per week.
The conventional hemodialysis group was treated for four hours
three times per week. In addition to delivering a 60% greater
weekly Kt/V, this short daily hemodialysis (SDHD) regimen maximizes phosphate removal, by increasing the total dialysis time. In
our study, 77 hemodialysis patients matched for age, sex and
comorbidities were treated with either conventional thriceweekly dialysis (n = 51) or were treated with short daily
hemodialysis (n = 26). Table 2 summarizes the observations from
this study. A significant reduction in PTH levels of 55% and 40%
was seen in the SDHD and conventional dialysis groups, respectively. A significant decrease in serum phosphorus levels was seen
in the patient group treated with SDHD (6.3 + 2.57 mg/dL at
baseline, 4.61 + 0.6 mg/dL at 6 months of treatment, and 4.0 +
1.19 mg/dL at 12 months of dialysis treatment, p<0.004) that
was not seen in the patients on conventional hemodialysis. This
statistically significant reduction in serum phosphorus occurred
despite the withdrawal of phosphate binders in 73% of the
SDHD group while the phosphate binder requirements were
unchanged in the control group. To our knowledge, this is the
first controlled study to demonstrate effective control of serum
phosphorus level using short daily hemodialysis in a large group
of patients with ESRD.
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In conclusion, uncontrolled hyperphosphatemia is a serious
shortcoming in the delivery of hemodialysis in the United States.
In addition to exposing patients to the morbidity of secondary
hyperparathyroidism, it is increasingly clear that hyperphosphatemia is a serious cardiac risk factor.2 Conventional hemodialysis does not remove adequate phosphorus to maintain phosphorus balance without the use phosphate binders. Even the addition of these medications is not sufficient to attain KDOQI
guidelines for control of phosphorus and Ca x P product in the
majority of patients and all phosphate binders have potential
side effects which must be considered. Previous investigators
have shown that daily hemodialysis is efficacious in controlling
serum phosphorus.32-35 Our group has shown for the first time in a
large group of patients, in a controlled manner, that short daily
hemodialysis can control hyperphosphatemia while nearly eliminating the need for phosphate binders.36 In our opinion, daily
hemodialysis is the best treatment to control hyperphosphatemia
and ameliorate both the metabolic and cardiovascular complications of this disorder.
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