High-Efficiency and

High-Flux Hemodialysis
Sivasankaran Ambalavanan
Gary Rabetoy
Alfred K. Cheung

H
emodialysis remains the major modality of renal replacement
therapy in the United States. Since the 1970s the drive for
shorter dialysis time with high urea clearance rates has led to
the development of high-efficiency hemodialysis. In the 1990s, certain
biocompatible features and the desire to remove amyloidogenic 2-
microglobulin has led to the popularity of high-flux dialysis. During
the 1990s, the use of high-efficiency and high-flux membranes has
steadily increased and use of conventional membrane has declined [1].
In 1994, a survey by the Centers for Disease Control showed that
high-flux dialysis was used in 45% and high-efficiency dialysis in 51%
of dialysis centers (Fig. 3-1) [1].
Despite the increasing use of these new hemodialysis modalities the
clinical risks and benefits of high-performance therapies are not well-
defined. In the literature published over the past 10 years the definitions
of high-efficiency and high-flux dialysis have been confusing.
Currently, treatment quantity is not only defined by time but also by
dialyzer characteristics, ie, blood and dialysate flow rates. In the past,
when the efficiency of dialysis and blood flow rates tended to be low,
treatment quantity was satisfactorily defined by time. Today, however,
treatment time is not a useful expression of treatment quantity because
efficiency per unit time is highly variable.

CHAPTER

3
3.2 Dialysis as Treatment of End-Stage Renal Disease

Dialyzers
FIGURE 3-2
50
HIGH-PERFORMANCE EXTRA- The four high-
CORPOREAL THERAPIES FOR performance extra-
END-STAGE RENAL DISEASE corporeal therapies
40
for end-stage renal
disease are listed [2].
30 High-efficiency hemodialysis
Centers, %

High-flux hemodialysis
Hemofiltration, intermittent
20 Hemodiafiltration, intermittent

10

0
1986 1988 1990 1992 1994 1996
Year

FIGURE 3-1
Centers using high-flux dialyzers have increased threefold from
1986 to 1996 because of their ability to remove middle molecules.
(From Tokars and coworkers [1]; with permission.)

FIGURE 3-3
DEFINITIONS OF FLUX, PERMEABILITY, AND EFFICIENCY Definitions of flux, permeability, and efficiency. The urea value KoA,
as conventionally defined in hemodialysis, is an estimate of the clear-
ance of urea (a surrogate marker of low molecular weight uremic
Flux toxins) under conditions of infinite blood and dialysate flow rates.
Measure of ultrafiltration capacity The following equation is used to calculate this value:
Low and high flux are based on the ultrafiltration coefficient (Kuf)
QbQd 1-Kd/Qb
KoA= ln
Low flux: Kuf <10 mL/h/mm Hg
Qb-Qd 1-Kd/Qd
where Ko = mass transfer coefficient
High flux: Kuf >20 mL/h/mm Hg
A = surface area
Permeability
Qb = blood flow rate
Measure of the clearance of the middle molecular weight molecule (eg, 2-microglobulin)
Qd = dialysate flow rate
General correlation between flux and permeability
ln = natural log
Low permeability: 2-microglobulin clearance <10 mL/min
Kd = mean of blood and dialysate side urea clearance
High permeability: 2-microglobulin clearance >20 mL/min As conventionally defined in hemodialysis, flux is the rate of water
Efficiency transfer across the hemodialysis membrane. Dissolved solutes are
Measure of urea clearance removed by convection (solvent drag effect).
Low and high efficiency are based on the urea KoA value Permeability is a measure of the clearance rate of molecules of
Low efficiency: KoA <500 mL/min middle molecular weight, sometimes defined using 2-microglobulin
High efficiency: KoA >600 mL/min (molecular weight, 11,800 D) as the surrogate [3,4]. Dialyzers that
permit 2-microglobulin clearance of over 20 mL/min under usual
Ko—mass transfer coefficient; A—surface area. clinical flow and ultrafiltration conditions have been defined as high-
permeability membrane dialyzers. Because of the general correlation
between water flux and the clearance rate of molecules of middle
molecular weight, the term high-flux membrane has been used
commonly to denote high-permeability membrane.
 High-Efficiency and High-Flux Hemodialysis 3.3

FIGURE 3-4
1000
Theoretic KoA profile of high- and low-flux dialyzers and high-
High flux and low-efficiency dialyzers. Note that here the definition of KoA
100 applies to the product of the mass transfer coefficient and surface
area for solutes having a wide range of molecular weights, and is
not limited to urea. Note also the logarithmic scales on both axes
[3]. Ko—mass transfer coefficient; A—surface area. (From Cheung
10
KOA, mL/min

and Leypoldt [3]; with permission.)

Low flux

High efficiency
0.1 Low efficiency

0.01
10 100 1000 10,000 100,000

Solute molecular weight, D

FIGURE 3-5
CLASSIFICATION OF HIGH- Classification of high-performance dialysis. Some authors have defined high-efficiency
PERFORMANCE DIALYSIS hemodialysis as treatment in which the urea clearance rate exceeds 210 mL/min. High-flux
dialysis, arbitrarily defined as a 2-microglobulin clearance of over 20 mL/min, is achieved
using high-flux membranes [3,4].
High-efficiency low-flux hemodialysis
High-efficiency high-flux hemodialysis
Low-efficiency high-flux hemodialysis

400
CHARACTERISTICS OF HIGH-EFFICIENCY DIALYSIS
350 KOA=1000
Urea clearance rate, mL/min

300
Urea clearance rate is usually >210 mL/min
250
KOA=500 Urea KoA of the dialyzer is usually >600 mL/min
200 Ultrafiltration coefficient of the dialyzer (Kuf) may be high or low
Clearance of middle molecular weight molecules may be high or low
150
Dialysis can be performed using either cellulosic or synthetic membrane dialyzers
100

50 Ko—mass transfer coefficient; A—surface area.

0
0 50 150 250 350 450 500 FIGURE 3-7
Blood flow rate, mL/min Characteristics of high-efficiency dialysis. High-efficiency dialysis is
arbitrarily defined by a high clearance rate of urea (>210 mL/min).
High-efficiency membranes can be made from either cellulosic or
FIGURE 3-6 synthetic materials. Depending on the membrane material and surface
Comparison of urea clearance rates between low- and high-efficiency area, the removal of water (as measured by the ultrafiltration coeffi-
hemodialyzers (urea KoA = 500 and 1000 mL/min, respectively). cient or Kuf) and molecules of middle molecular weight (as measured
The urea clearance rate increases with the blood flow rate and by 2-microglobulin clearance) may be high or low [3,4,6,7].
gradually reaches a plateau for both types of dialyzers. The plateau
value of KoA is higher for the high-efficiency dialyzer. At low blood
flow rates (<200 mL/min), however, the capacity of the high-efficien-
cy dialyzer cannot be exploited and the clearance rate is similar to
that of the low-flux dialyzer [3,6]. Ko—mass transfer coefficient;
A—surface area. (From Collins [6]; with permission.)
3.4 Dialysis as Treatment of End-Stage Renal Disease

FIGURE 3-8
DIFFERENCES BETWEEN HIGH- AND Differences between high- and low-efficiency hemodialysis.
LOW-EFFICIENCY HEMODIALYSIS Conventional hemodialysis refers to low-efficiency low-flux
hemodialysis that was the popular modality before the 1980s [3,6].

High efficiency, mL/min Low efficiency, mL/min

Dialyzer KoA ≥600 <500
Blood flow ≥350 <350
Dialysate flow ≥500 <500
Bicarbonate dialysate Necessary Optimal

Ko—mass transfer coefficient; A—surface area.

TECHNICAL REQUIREMENTS CONCENTRATION OF DIALYSATE FACTORS INFLUENCING BLOOD

FOR HIGH-EFFICIENCY DIALYSIS IN HIGH-EFFICIENCY DIALYSIS FLOW IN HIGH-EFFICIENCY
HEMODIALYSIS

High-efficiency dialyzer Dialysate Concentration

Large surface area (A) Type of access
Sodium 139–145 mEq/L
High mass transfer coefficient (Ko) Native arteriovenous fistulae, polytetrafluoroethyl-
Potassium 0–4 mEq/L
Both (high KoA) ene grafts, twin catheter systems:
Acetate 2.5–4.5 mEq/L
High blood flow (≥350 mL/min) high blood flow rate, >350 mL/min
Bicarbonate 35–40 mEq/L
High dialysate flow (≥500 mL/min) Permanent catheters, temporary intravenous
Magnesium 1 mEq/L catheters: low blood flow rate, <350 mL/min
Bicarbonate dialysate
Calcium 2.5–3.5 mEq/L Needle design: size, thickness, and length
Glucose 0–200 mg/dL Blood tubing
Pump design
FIGURE 3-9
Technical requirements for high-efficiency FIGURE 3-10
dialysis. The KoA is the theoretic value of
Concentration of dialysate in high-efficiency FIGURE 3-11
the urea clearance rate under conditions of
dialysis. Although the concentration of Factors influencing blood flow in high-effi-
infinite blood and dialysate flow. High blood
other ions is variable, high bicarbonate ciency hemodialysis. Arteriovenous fistulae
and dialysate flow rates are necessary to
concentration, relative to that of acetate, often have blood flow rates of over 1000
achieve optimal performance of high-effi-
is essential for high-efficiency dialysis in mL/min, as measured by current noninvasive
ciency dialyzers. Bicarbonate-containing
order to minimize the transfer of acetate devices. Polytetrafluoroethylene grafts and
dialysate is necessary to prevent symptoms
into the patient. the newly introduced twin catheter systems
associated with acetate intolerance (ie, nausea,
vomiting, headache, and hypotension), also are capable of providing the blood
worsening of metabolic acidosis, and car- flow rates necessary for high-efficiency
diac arrhythmia [6,8,9]. Ko—mass transfer hemodialysis. In contrast, most other tem-
coefficient; A—surface area. porary or semipermanent catheters cannot
provide sufficient blood flow reliably
enough for adequate dialysis delivery in a
short time period. Needles, blood tubing
diameter, and blood pumps may also con-
tribute to this problem [8,9].
 High-Efficiency and High-Flux Hemodialysis 3.5

CAUSES OF HIGH-EFFICIENCY BENEFITS OF HIGH- LIMITATIONS OF HIGH-

DIALYSIS FAILURE EFFICIENCY DIALYSIS EFFICIENCY DIALYSIS

Access-related Higher clearance of small solutes, such as urea, Hemodynamic instability

Low blood flow rate compared with conventional dialysis without Low margin of safety if short treatment
High recirculation rate increase in treatment time time is prescribed
Time-related Better control of chemistry Potential vascular access damage
Patient not adherent to prescribed time Potentially reduced morbidity Dialysis disequilibrium syndrome
Staff not adherent to prescribed time Potentially higher patient survival rates
Failure to adjust time for conditions such as alarm,
dialysate bypass, and hypotension
FIGURE 3-14
FIGURE 3-13 Limitations of high-efficiency dialysis.
Benefits of high-efficiency dialysis. With Removal of a large volume of fluid over a
FIGURE 3-12 improved control of biochemical parameters short time period (2–2.5 h) increases the like-
Causes of high-efficiency dialysis failure. (such as potassium, hydrogen ions, phosphate, lihood of hypotension, especially in patients
The maintenance of a high blood flow rate urea, and other nitrogenous compounds) with poor cardiac function or autonomic
(>350 mL/min) is essential for high-efficiency the potential exists for reduced morbidity neuropathy. The loss of a fixed amount of
hemodialysis. Fistula recirculation, regardless and mortality without increasing dialysis treatment time has a proportionally greater
of the blood flow rate, compromises treatment time [5,7]. impact during a short treatment time than
achievement of the urea Kt/V goal. during a long treatment time. Thus, the
Interruptions during the prescribed short margin of safety is narrower if a short
treatment time further compromise the treatment time is used in conjunction with
overall delivery of the prescribed Kt/V [6,7]. high-efficiency dialysis compared with
K—urea clearance; t—time of therapy; conventional hemodialysis with a longer
V—volume of distribution. treatment time. Although unproved, high
blood flow rates may predispose patients to
vascular access damage. Rapid solute shifts
potentially precipitate the dialysis disequilib-
rium syndrome in those patients with a very
high blood urea nitrogen concentration,
especially during the first treatment [3,7,9].

FIGURE 3-15
CHARACTERISTICS OF HIGH-FLUX DIALYSIS Characteristics of high-flux dialysis. Because of the high ultrafiltra-
tion coefficients of high-flux membranes, high-flux dialysis requires
an automated ultrafiltration control system to avoid accidental
Dialyzer membranes are characterized by a high ultrafiltration coefficient profound intravascular volume depletion. Because high-flux mem-
(Kuf > 20 mL/h/mm Hg) branes tend to have larger pores, clearance of middle molecular
High clearance of middle molecular weight molecules occurs (eg, 2-microglobulin) weight molecules is usually high. Urea clearance rates for high-flux
Urea clearance can be high or low, depending on the urea KoA of the dialyzer dialyzers are still dependent on urea KoA values, which can be
Dialyzers are made of either synthetic or cellulosic membranes either high (ie, high-flux high-efficiency) or low (ie, high-flux low-
High-flux dialysis requires an automated ultrafiltration control system efficiency) [3,4,10]. Ko—mass transfer coefficient; A—surface area.
3.6 Dialysis as Treatment of End-Stage Renal Disease

TECHNICAL REQUIREMENTS POTENTIAL BENEFITS OF LIMITATIONS OF

FOR HIGH-FLUX DIALYSIS HIGH-FLUX DIALYSIS HIGH-FLUX DIALYSIS

High-flux dialyzer Delayed onset and risk of dialysis-related amyloidosis Enhanced drug clearance, requiring supplemental
Automated ultrafiltration control system because of enhanced 2-microglobulin clearance dose after dialysis
[11,12] High cost of dialyzers
Increased patient survival resulting from higher
clearance of middle molecular weight molecules
[12,13,15,16]
FIGURE 3-16
Reduced morbidity and hospital admissions [14,16]
Technical requirements for high-flux dialysis. FIGURE 3-18
Improved lipid profile [16,17]
Because of the potential for reverse filtration Limitations of high-flux dialysis. The
Higher clearance of aluminum [18]
(movement of fluid from dialysate to the enhanced clearance of drugs depends on
Improved nutritional status [19,20]
blood compartment) to occur, use of a the physicochemical characteristics of
Reduced risk of infection [16,21]
pyrogen-free dialysate is preferred but not the specific drug and dialysis membrane.
Preserved residual renal function [22] Because of their relative high costs, high-
mandatory. Bicarbonate concentrate used
to prepare dialysate is particularly prone to flux dialyzers are usually reused.
bacterial overgrowth when stored for more
than 2 days [5,8].
FIGURE 3-17
Potential benefits of high-flux dialysis.
Data are accumulating that support many
potential benefits of high-flux dialysis.
Large-scale randomized prospective trials,
however, are unavailable.

FIGURE 3-19
EXAMPLES OF COMMONLY USED DIALYZERS Examples of commonly used dialyzers.
“Efficiency” refers to the capacity to remove
urea; “flux” refers to the capacity to remove
Dialyzer type Material KoA (in vitro), mL/min water, and indirectly, the capacity to remove
Surface area, m2
molecules of middle molecular weight.
Low-flux low-efficiency Cellulosic membranes can be either low flux
CA90 Cellulose acetate 0.9 410 or high flux. Similarly, synthetic membranes
CF12 Cuprammonium 0.7 418 can be either low flux or high flux. High-
Low-flux high-efficiency efficiency membranes usually have large
CA150 Cellulose acetate 1.5 660 surface areas.
T150 Cuprammonium 1.5 730
High-flux low-efficiency
F50 Polysulfone 0.9 520
PAN 150P Polyacrylonitrile 1.0 420
High-flux high-efficiency
CT190 Cellulose triacetate 1.9 920
F80 Polysulfone 1.8 945

Ko—mass transfer coefficient; A—surface area.

Adapted from Leypoldt and coworkers [4] and Van Stone [22].
 High-Efficiency and High-Flux Hemodialysis 3.7

Solutes

Cb Cb Cb Postdilution

Ultrafiltrate
Solute flux

Fluid flux

Cd Solute flux
Predilution
Blood Membrane Ultrafiltrate Blood Membrane Ultrafiltrate
Blood

FIGURE 3-20 FIGURE 3-21 FIGURE 3-22

Solute transport in hemodialysis. The primary Solute clearance in hemofiltration. Fluid replacement in hemofiltration.
mechanism of solute transport in hemodialysis Hemofiltration achieves solute clearance Because hemofiltration achieves substan-
is diffusion, although convective transport by convection (or the solvent drag effect) tial solute clearance by removing large
is also contributory. Solutes small enough through the membrane. In contrast to volumes of plasma water (which contains
to pass through the dialysis membrane diffuse diffusive hemodialysis, fluid flux is a pre- the dissolved solutes), the removed fluid
down a concentration gradient from a higher requisite for the removal of solutes during must be replaced. The replacement fluid
plasma concentration (Cb) to a lower dialysate hemofiltration, whereas the concentration can be infused into the extracorporeal
concentration (Cd). The arrow represents gradient is not. For small solutes (eg, urea) circuit before the blood enters the filter
the direction of solute transport. that traverse the membrane unimpeded, (predilution, or replacement before expen-
concentrations in the blood compartment diture) or after the blood leaves the filter
(Cb) and ultrafiltrate compartment (Cuf) (postdilution). More replacement fluid is
are equivalent. For some molecules of mid- required when it is given before filtration
dle molecular weight whose movement rather than after to provide equivalent
across the membrane is partially restricted, solute clearance because the plasma in
Cuf is lower than is Cb (ie, the sieving coef- the filter (and therefore the ultrafiltrate)
ficient, defined as Cuf/Cb, is less than 1.0). is diluted in the predilution mode.

FIGURE 3-23
Addition of diffusive transport in hemodiafiltration. In hemodiafiltration, diffusive transport
Postdilution is added to hemofiltration to augment the clearance of solutes (usually small solutes such
as urea and potassium). Solute clearance is accomplished by circulating dialysate in the
dialysate-ultrafiltrate compartment. Hemodiafiltration is particularly useful in patients
Ultrafiltrate who have hypercatabolism with large urea generation.
Dialysate

Predilution

Blood
3.8 Dialysis as Treatment of End-Stage Renal Disease

Membranes
Bacteria FIGURE 3-24
Backfiltration, or reverse filtration, of endotoxins (ET) from dialysate to blood. Reverse
filtration of ET is particularly prone to occur when high-flux membranes are used and the
Macrophage dialysate is heavily contaminated with bacteria (>2000 CFU/mL) and may result in pyrogenic
ET
reactions. The dialysis membranes are impermeable to intact ET; however, their fragments
(some of which still are pyrogenic) may be small enough to traverse the membrane. Although
the membrane is impermeable to bacteria and blood cells, a mechanical break in the membrane
could result in bacteremia.

ET fragments

Dialysate Membrane Blood

FIGURE 3-25
H 2O
Dialysis membranes with small and large pores. Although a general correlation exists
H 2O
between the (water) flux and the (middle molecular weight molecule) permeability of dialysis
H 2O membranes, they are not synonymous. A, Membrane with numerous small pores that allow
H 2O high water flux but no 2-microglobulin transport. B, Membrane with a smaller surface
H 2O area and fewer pores, with the pore size sufficiently large to allow 2-microglobulin transport.
The ultrafiltration coefficient and hence the water flux of the two membranes are equivalent.

H 2O
H 2O
H 2O
H 2O

A
FIGURE 3-26
Scanning electron microscopy of a conventional low-flux-membrane
hollow fiber (panel A) and a synthetic high-flux-membrane hollow fiber
(panel B). The low-flux membrane consists of a single layer of relatively
homogenous material. The high-flux membrane has a three-layer struc-
ture, ie, finger, sponge, and skin. The skin is a thin semipermeable layer B
that functions as the selective barrier; it is mechanically supported by
the sponge and finger layers. (Magnification: finger,  14,000; sponge
 17,000; skin  85,000.) (Courtesy of Goehl H, Gambrogroup).
 High-Efficiency and High-Flux Hemodialysis 3.9

Dialysate flow rate

FIGURE 3-27
300
Effect of the dialysate flow rate (Qd) on the urea clearance rate by
280 a high-efficiency dialyzer with a urea KoA value of 800 mL/min.
260 At low blood flow rates (<200 mL/min), no difference exists in
Urea clearance rate, mL/min

urea clearance rates between the two different Qd conditions,

240
because equilibrium in urea concentrations between blood and
220 dialysate is readily achieved. When the blood flow rate is high
200 (>300 mL/min), the higher Qd maintains a higher concentration
gradient for diffusion of urea, and therefore, the urea clearance
180 rate is higher. Recent studies have shown that the KoA value of dia-
160 lyzers also increases with higher dialysate flow rates [4], presumably
because of more uniform distribution of dialysate flow. Therefore, the
140 Qd=800 actual urea clearance rate may increase further (red line). Ko—mass
120 Qd=500 transfer coefficient; A—surface area.
100
200 250 300 350 400 450 500
Blood flow rate, mL/min

Backfiltration
FIGURE 3-28
Pressure inside the blood compartment (dark colored arrow) and
Blood flow Dialysate flow the dialysate compartment (light colored arrow) with a fixed net
zero ultrafiltration rate. The pressure gradually decreases in the
Blood /Dialysate Blood /Dialysate blood compartment as blood travels from the inlet toward the outlet.
150 inlet outlet outlet inlet
Pbi Beyond a certain point along the dialyzer length (x, where the two
pressure lines intersect), the pressure in the dialysate compartment
140 exceeds that in the blood compartment, forcing fluid to move from
Pressure, mm Hg

Pdi
the dialysate to the blood compartment. This movement of fluid
in the direction opposite to that of the designed ultrafiltration is
130
Ultrafiltrate x called backfiltration. Backfiltration may carry with it contaminants
Back filtrate (eg, endotoxins) from the dialysate. Increasing the net ultrafiltra-
120 tion rate shifts the pressure intersection point to the right and
Pdo
diminishes backfiltration.
110

Pbo
100
3.10 Dialysis as Treatment of End-Stage Renal Disease

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