Uremic Toxicity

Kawanishi H, Takemoto Y (eds): Scientific Aspects of Dialysis Therapy: JSDT/ISBP Anniversary Edition.
Contrib Nephrol. Basel, Karger, 2017, vol 189, pp 189–196 (DOI: 10.1159/000450781)

Evidence for Targeting

Low-Molecular-Weight Proteins in
Hemodialysis and Hemodiafiltration
Kenji Tsuchida a · Kojiro Nagai b · Narushi Yokota c · Satoru Yamada c ·
Hiroyuki Michiwaki d · Jun Minakuchi c
a Department of Kidney Disease, Kawashima Dialysis Clinic, b Department of Nephrology, Tokushima University,
c Department of Kidney Disease, Kawashima Hospital, and d Department of Clinical Engineer, Kawashima Dialysis Clinic,
Tokushima, Japan

HDF therapy, which is associated with albumin loss, was

Abstract
Background: With the identification of β2-microglobulin
(β2MG) as an active participant in dialysis-related amyloid
fibril formation, low-molecular-weight proteins (LMWPs)
are now recognized as a distinct class of uremic toxins, and
numerous compounds in this category have been identi-
fied. The class of LMWPs, although not precisely defined,
has a molecular weight range of approximately 1,000–
50,000 Da. With this in mind, dialysis prescriptions have
been modified to increase the efficiency of uremic solute
removal. Many studies have characterized the dialytic re-
moval of β2MG and it is therefore regarded as a surrogate
for LMWPs. Summary: In Japan, dialysis membranes that
can efficiently remove β2MG are recommended. Recently,
researchers have reported that β2MG is not only a uremic
toxin that should be removed, but also a predictor of the
prognosis of dialysis patients. In Japan, hemodiafiltration
(HDF), especially on-line HDF, and protein-permeable he-
modialysis (HD) is being actively carried out, and it is often
reported that prognosis is improved by decreasing the
concentrations of substances larger than β2MG. It is im-
portant, then, that dialysis prescriptions achieve effective
clearance of such substances. Key Messages: Over 2,000
uremic substances have been identified that form or ac-
implemented targeting the LMWPs. Here, we report the
effects of albumin-losing blood purification (HD/HDF) for
the purpose of removing LMWPs.
© 2017 S. Karger AG, Basel
What Are Low-Molecular-Weight Proteins?
Uremic syndrome is characterized by retention
of various solutes that would normally be excret-
ed by the kidneys. The substances that interact
negatively with biologic functions are called ure-
mic toxins. In recent years, uremic toxicity has
been actively researched and dozens of retention
solutes, including several uremic toxins, have
been identified [1–3]. It is thought that the num-
ber of uremic toxins that accumulate in the body
of patients with kidney dysfunction amounts to
thousands when including the metabolic prod-
ucts from the internal organs.
The molecular weight of uremic toxins varies
132.239.1.231 - 12/14/2016 4:48:18 AM

cumulate because of renal failure and cause various symp- widely, from the low-to-moderate-molecular-
toms and complications. Focusing on these facts, HD or weight region of urea, creatinine, and uric acid, to
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low-molecular-weight proteins (LMWPs) repre-
sented by β2-microglobulin (β2MG) and to the
high-molecular-weight region for globulin and
lipids. According to the classification of uremic
toxins based on size and binding properties, we
have free water-soluble low-molecular-mass
compounds (<0.5 kDa), middle molecules (0.5–
60 kDa), and protein-bound solutes [4].
With the identification of β2MG as an active
participant in dialysis-related amyloid fibril for-
mation, LMWPs are now recognized as a distinct
class of uremic toxins, and numerous compounds
in this category have been identified. LMWPs as
a class, although not precisely defined, have a mo-
lecular weight range of approximately 1,000–
50,000 Da [5].
Among LMWPs, complement factor D, a
23.5-kDa upregulator of the alternative comple-
ment pathway, is prototypical and characteristic
of the metabolism in patients with normal renal
function and varying degrees of renal insufficien-
cy [6]. Leptin, a 16-kDa protein secreted by adi-
pocytes, regulates body composition by lowering
food intake and increasing the metabolic rate [7].
Cystatin C, adrenomedullin, and retinal binding
protein differ not only in molecular weight, but
also in their source of generation, molecular di-
mension, and degree of protein binding [8]. With
these facts in mind, dialysis prescriptions have
been modified to increase the efficiency of such
uremic solute removal.
β2-Microglobulin as a Surrogate Marker
β2MG is regarded as surrogate for LMWP since
its dialytic removal has been reported by many
studies. Dialysis membranes that can efficiently
remove β2MG are recommended in Japan [9].
Researchers recently reported that β2MG is not
only a uremic toxin whose level should be de-
creased, but also a factor related to the prognosis
of dialysis patients [10, 11]. Both the HEMO
study [10] and Okuno et al. [11] reported that
mortality decreased when the predialysis serum
β2MG level was 27.5–34 mg/l, indicating that di-
alysis therapy needs to actively decrease the level
190
Kawanishi H, Takemoto Y (eds): Scientific Aspects of Dialysis Therapy: JSDT/ISBP Anniversary Edition.
Contrib Nephrol. Basel, Karger, 2017, vol 189, pp 189–196 (DOI: 10.1159/000450781)
of uremic substances such as β2MG. In the clini-
cal guidelines for ‘Maintenance Hemodialysis:
Hemodialysis Prescriptions’ issued by the
Japanese Society for Dialysis Therapy (JSDT),
Chapter 2 explains the dialysis dose and effect for
β2MG [12]. It makes the following statements:
(1) The predialysis serum β2MG level at the max-
imum interval is a factor related to prognosis.
(2) It is recommended that dialysis conditions
achieve a maximum predialysis serum β2MG
concentration <30 mg/l.
(3) It is preferable that dialysis conditions achieve
a maximum predialysis serum β2MG concen-
tration of 25 mg/l.
(4) Decreasing the concentrations of substances
larger than β2MG can improve the prognosis.
Effect of Serum β2-Mcroglobulin on Mortality
in Hemodialysis Patients
A retrospective study was designed and imple-
mented by the Kawashima Hospital Group
(KHG), Tokushima, Japan [13]. Clinical records
were analyzed for 748 patients [475 men, 273
women; mean age: 62.7 ± 12.7 years; hemodialy-
sis (HD) vintage: 103.0 ± 88.5 months; 21.4%
with diabetes] who started HD in April 2006. The
patients were divided into 2 groups according to
their predialysis serum β2MG levels: <30-mg/l
group (n = 537; mean age: 62.0 ± 12.6 years; HD
vintage: 99.3 ± 90.7 months; predialysis serum
β2MG level: 24.6 ± 4.0 mg/l) and ≥30-mg/l group
(n = 211; mean age: 64.2 ± 12.7 years; HD vintage:
112.5 ± 82.0 months; predialysis serum β2MG
level, 35.1 ± 5.0 mg/l). Survival probability was
generated using the Kaplan-Meier analysis.
During a mean follow-up period of 61.9 ± 13.5
months, there were 174 deaths. Kaplan-Meier
analysis showed that mortality was significantly
lower in patients in the <30-mg/l group than in
patients in the ≥30-mg/l group (p < 0.0001; fig. 1).
A multivariate Cox proportional hazards model
showed that predialysis serum β2MG was a sig-
nificant predictor for mortality (hazard ratio =
132.239.1.231 - 12/14/2016 4:48:18 AM
1.036, 95% CI: 1.015–1.057; p < 0.0009) after ad-
justment for age, HD vintage, presence of diabe-
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Tsuchida · Nagai · Yokota · Yamada · Michiwaki · Minakuchi
 100
80
Patency rate (%)
60
40
20
Fig. 1. Mortality of predialysis serum 0
β2MG level <30 mg/l, and ≥30 mg/l
with p < 0.25 by logistic regression
analysis. Kaplan-Meier method, * p <
0.0001, by log-rank analysis.
tes, predialysis serum albumin, and blood urea
nitrogen (table 1).
The JSDT recommends that dialysis condi-
tions achieve a predialysis serum β2MG level at a
maximum interval <30 mg/l. Given that lower
mortality was seen in the <30-mg/l group inde-
pendent of age, HD vintage, presence of diabetes,
predialysis serum albumin, and blood urea nitro-
gen, it would appear that the guidelines are ap-
propriate. Accordingly, we should determine
which dialysis conditions can achieve effective
removal of β2MG.
Relationship between the Removal of Low-
Molecular-Weight Proteins and Albumin in
Hemodialysis/Hemodiafiltration Treatment
α1MG (molecular weight: 30,000 Da) is an
LMWP. It was reported that the associations ob-
served between albumin leakage and β2MG and
between albumin leakage and β2MG/α1MG in
HD and HDF using a polysulfone membrane that
causes protein leakage showed no correlation be-
tween albumin leakage and β2MG removal rate.
However, it did show a significant correlation
with α1MG removal rate [14]. These findings in-
dicate that the separation of albumin and sub-
stances in the α1MG region is limited and needs
to be improved. The development of high-flux
Evidence for Targeting LMWPs in HD and HDF
Kawanishi H, Takemoto Y (eds): Scientific Aspects of Dialysis Therapy: JSDT/ISBP Anniversary Edition.
Contrib Nephrol. Basel, Karger, 2017, vol 189, pp 189–196 (DOI: 10.1159/000450781)
*
(<30 mg/l)
(–30 mg/l)
0 10 20 30 40 50 60 70
Months
membranes with improved separation character-
istics is one idea, but it is difficult to achieve.
Large-volume predilution HDF using a large-size
membrane may allow for the separation of sub-
stances in the α1MG region and albumin, which
would achieve the original purpose of HDF to re-
move LMWPs. If HDF membrane development
can improve filtration performance, there will be
no limit to the volumes of substitution fluid and
ultrafiltration in predilution HDF, and we might
be able to achieve higher solute removal perfor-
mance. At the moment, however, if we remove
the LMWPs, albumin will be removed with them.
Low-Molecular-Weight Protein Removal
during Albumin-Permeable Hemodialysis [15,
16]
Over 2,000 uremic substances have been identi-
fied that form or accumulate because of renal fail-
ure and cause various clinical symptoms and
complications. Focusing on these facts, HD ther-
apy, which is associated with albumin loss, was
implemented targeting the substances in the re-
gions whose molecular weights are larger than
β2MG. We designed a retrospective study to ana-
lyze clinical recordings from all patients who
132.239.1.231 - 12/14/2016 4:48:18 AM
started HD between April 2005 and March 2013
in the dialysis center of KHG.
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191
Table 1. Multivariate Cox model analysis with actual measured values of variables

Univariate Multivariate (full model) Multivariate (final model)

HR 95% CI p value HR 95% CI p value HR 95% CI p value

Age (/1 year) 1.085 1.069–1.101 <0.0001 1.075 1.054–1.096 <0.0001 1.082 1.063–1.101 <0.0001
HD duration (/1 month) 0.999 0.998–1.001 0.4009 1.001 0.999–1.004 0.191 1.002 1.000–1.004 0.0449
Diabetes (vs. non-DM) 0.468 0.342–0.639 <0.0001 0.446 0.284–0.698 0.0004 0.544 0.385–0.768 0.0006
Serum β2MG (/1 mg/l) 1.059 1.037–1.081 <0.0001 1.037 1.012–1.062 0.0029 1.036 1.015–1.057 0.0009
Serum CL (/1 mEq/l) 0.926 0.883–0.971 0.0014 0.897 0.803–1.002 0.0538 0.906 0.863-0.952 <0.0001
Serum albumin (/1 g/dl) 0.137 0.098–0.191 <0.0001 0.322 0.148–0.696 0.0040 0.342 0.200–0.585 <0.0001
Blood urea
Pre- (/1 mg/dl) 0.971 0.949–0.994 0.0014 1.070 1.027–1.115 0.0013 1.076 1.034–1.119 0.0003
Post- (1 mg/dl) 0.964 0.954–0.974 <0.0001 0.963 0.944–0.962 0.0002 0.962 0.944–0.979 <0.0001

DM = Diabetes mellitus; HR = hazard ratio.

First, patients were classified into 3 groups ac-
cording to albumin loss during one HD session:
<1-gram dialysis membrane group, 1- to 3-gram
dialysis membrane group, and ≥3-gram dialysis
membrane group. There were no significant dif-
ferences in patient baseline characteristics (age,
sex, HD vintage, eKt/V, Hb, serum albumin level)
between the groups.
Second, patients were classified into 2 groups
according to pore type of the dialysis membrane
used: broad-pore-type dialysis membrane (albu-
min-sieving coefficient: ≥0.03) group and nar-
row-pore-type dialysis membrane (albumin-
sieving coefficient: <0.03) group. There were no
significant differences in patient baseline charac-
teristics (age, sex, HD duration, serum albumin,
creatinine, phosphorus level) between the 2
groups.
Survival probability was estimated using the
Kaplan-Meier method.
Data from 702 patients were included in the
analysis. For albumin loss, the <1-gram group (se-
rum albumin level 35.3 ± 3.1 g/l) consisted of 142
patients, the 1- to 3-gram group (serum albumin
level 35.5 ± 3.3 g/l) consisted of 455 patients, and
the ≥3-gram group (serum albumin level 36.6 ±
2.6 g/l) consisted of 105 patients. The survival
89, 81, and 70% in the 1- to 3-gram group; and 99,
98, 95, 92, and 88% in the ≥3-gram group. Among
the 3 groups, the survival rate was lowest, and sig-
nificantly so, in the ≥3-gram group (fig. 2).
The broad-pore group consisted of 117 pa-
tients (mean age: 61.1 years; 73 men, 44 women)
and the narrow-pore group consisted of 586 pa-
tients (mean age: 61.0 years; 378 men, 208 wom-
en). The 1-, 2-, 3-, 5-, and 7-year survival rates
were 98, 96, 93, 90, and 83% in the broad-pore
group and 98, 93, 89, 78, and 68% in the nar-
row-pore group. The survival rate was lowest,
and significantly so, in the broad-pore group 7
years from the initiation of dialysis therapy
(fig. 3).
To increase the clearance of LMWPs, synthet-
ic membranes with high water permeability
(high-flux membranes) were recently intro-
duced. There are numerous uremic toxins, espe-
cially protein-bound solutes with biological ac-
tivities, and it is difficult to remove these solutes
unless broad-pore dialysis membranes are used.
It thus appears to be safe to use the broad-type
membranes in the initial stage of dialysis treat-
ment within 7 years from initiation.
The results of this study suggest that HD
treatment using albumin loosing, broad-pore di-
132.239.1.231 - 12/14/2016 4:48:18 AM

rates at 1, 2, 3, 5, and 7 years were, respectively, 98, alysis membranes plays an important role in the
92, 86, 67, and 54% in the <1-gram group; 97, 94, outcome of chronic long-term HD patients.
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192 Tsuchida · Nagai · Yokota · Yamada · Michiwaki · Minakuchi

Kawanishi H, Takemoto Y (eds): Scientific Aspects of Dialysis Therapy: JSDT/ISBP Anniversary Edition.
Contrib Nephrol. Basel, Karger, 2017, vol 189, pp 189–196 (DOI: 10.1159/000450781)
 1.0 –JUDPJURXS

1 to 3-gram group
0.8
*

Patency rate
0.6
<1-gram group

0.4

0.2
Fig. 2. Effect of membrane type on
mortality in the <1-gram albumin
0
loss group, 1- to 3-gram albumin
0 10 20 30 40 50 60 70 80 90
loss group, and ≥3-gram albumin
Months
loss group. Kaplan-Meier method,
* p < 0.05, by log-rank analysis.

1.0

0.8
*
Patency rate

0.6

0.4

0.2
Narrow pore
Broad pore
0
0 10 20 30 40 50 60 70 80 90
Months

Fig. 3. Effect of membrane pore type (broad versus narrow) on mortality. Narrow pore: albumin
sieving coefficient <0.03; broad pore: ≥0.03. Kaplan-Meier method, * p < 0.05, by log-rank analysis.

Low-Molecular-Weight-Protein Removal [17]. However, 2 recent, prospective, randomized

during Albumin-Permeable Hemodiafiltration
On-line HDF usually has larger albumin leakage
than HD. Recently, the ESHOL Study Group re-
studies (CONTRAST and Turkish studies) failed
to demonstrate a survival advantage of on-line
HDF over HD [18, 19]. Discussion of these in-
consistent results clarified that a high convection
132.239.1.231 - 12/14/2016 4:48:18 AM

ported that high-efficiency postdilution on-line volume (e.g. 25 liters per session) is needed to re-
HDF reduces 3-year survival compared with HD duce all-cause mortality. In all 3 trials, the mean
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Evidence for Targeting LMWPs in HD and HDF 193

Kawanishi H, Takemoto Y (eds): Scientific Aspects of Dialysis Therapy: JSDT/ISBP Anniversary Edition.
Contrib Nephrol. Basel, Karger, 2017, vol 189, pp 189–196 (DOI: 10.1159/000450781)
Table 2. Our on-line HDF prescription: albumin leakage (g/session)

Predilution Postdilution
Convection volume, l/session 60 72 84 96 8 10 12 16 20

HDF filter Albumin leakage, g/session Albumin leakage, g/session

ABH-21F 0.8 1.8

ABH-21P (type 1) 1.9 2.3 3.5 4.4 2.1 2.5 3.4 4.1
ABH-21P (type 2) 3.3 4.7 7.8 8
MFX-25S eco 2.8 3.5 3
MFX-25U eco 4.6 4.4 5.6 6.4 5.5 6.6 8.6 11.9
MFX-30U eco 6.8 8.8 9.5 10.2 12.3 15
FIX-250S eco 4.1 3 3.7 5.6 6.4 6.6
FIX-250U eco 6 6.6 6.6 7.7 8.2 9.7
TDF-20H 2.1 3.2 2.2 5.5 8.5
GDF-21 10.3 11.1 13.8 8.1 13.6 21.1

QB = 280 ml/min, total QD = 500 ml/min, treatment time: 4 h. ABH: Asahi Kasei Medical, Co., Ltd., Tokyo, Japan; MFX, FIX:
Nipro, Osaka, Japan; TDF: Toray Medical Co., Ltd., Tokyo, Japan; GDF: Nikkiso Co., Ltd., Tokyo, Japan.

serum albumin level was lower in the on-line
HDF group than in the HD group, although the
difference was not significant in the ESHOL and
CONTRAST studies.
We do not know the admissible amount of al-
bumin leakage. We have already clarified that
HD with 8.1-gram albumin leakage per HD ses-
sion for 2 months can induce a significant de-
crease in serum albumin and increase in serum
total cholesterol, even though the level of the re-
duced form of albumin that is associated with
cardiovascular disease in dialysis patients re-
mained stable [20]. Our on-line HDF prescrip-
tion referring to the index of albumin leakage per
dialysis session is shown in table 2.
Conclusion
In Japan, HDF, especially on-line HDF, and pro-
tein-permeable HD have been actively carried
out, and it has frequently been reported that
prognosis is improved by decreasing the concen-
trations of substances greater than β2MG. It is
view of these results, clinically acceptable albu-
min leakage has beneficial effects on mortality in
maintenance HD/HDF patients.
The primary idea behind albumin leakage in
dialysis therapy is that a certain level of leakage
cannot be avoided if the volume of LMWP ac-
cumulated in blood for removal must be in-
creased. In normal renal function, approximate-
ly 10 g of albumin is filtered in the glomerulus
per day, decomposed in the renal tubule, reab-
sorbed as amino acid, and then resynthesized
into albumin in the liver. In dialysis patients,
however, albumin that is bound to biologically
active substances or the oxidized form of albu-
min that has lost its antioxidant effect cannot be
filtered from the kidneys and accumulates.
Therefore, the second idea behind albumin leak-
age is to remove biologically active substances
that bind to albumin and function as uremic tox-
ins, remove albumin without its antioxidant ef-
fect, and facilitate synthesis of new albumin with
an antioxidant effect [21]. Acceleration of albu-
min metabolism not only helps the removal of
uremic toxic substances, but also the mainte-
132.239.1.231 - 12/14/2016 4:48:18 AM

therefore important that dialysis prescription nance of albumin functions.

achieves effective clearance of such substances. In
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194 Tsuchida · Nagai · Yokota · Yamada · Michiwaki · Minakuchi

Kawanishi H, Takemoto Y (eds): Scientific Aspects of Dialysis Therapy: JSDT/ISBP Anniversary Edition.
Contrib Nephrol. Basel, Karger, 2017, vol 189, pp 189–196 (DOI: 10.1159/000450781)
Acknowledgements to the principles expressed in the Declaration of
Helsinki. This study was reviewed and approved by
The authors thank all the participants and our collab- the Institutional Review Board of Kawashima Hos-
orator, Daisuke Hirose, at Kawashima Naruto Clinic. pital (No. 0012).

Statement of Ethics
Disclosure Statement
The details of this study were explained to patients
in advance and their written consent was obtained. K.T., K.N., N.Y., S.Y., H.M., and J.M. have no finan-
All clinical investigations were conducted according cial relationships to disclose.

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Contrib Nephrol. Basel, Karger, 2017, vol 189, pp 189–196 (DOI: 10.1159/000450781)
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Kenji Tsuchida
Department of Kidney Disease, Kawashima Dialysis Clinic
6-1 Kitasakoichiban-cho
132.239.1.231 - 12/14/2016 4:48:18 AM

Tokushima-shi, Tokushima 770-0011 (Japan)

E-Mail ktsuchida@khg.or.jp
Univ. of California San Diego
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196 Tsuchida · Nagai · Yokota · Yamada · Michiwaki · Minakuchi

Kawanishi H, Takemoto Y (eds): Scientific Aspects of Dialysis Therapy: JSDT/ISBP Anniversary Edition.
Contrib Nephrol. Basel, Karger, 2017, vol 189, pp 189–196 (DOI: 10.1159/000450781)