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Summary Report:
Clinical Study Comparing the Basic Performance and Blood Compatibility

Characteristics of Nipro Sureflux-17G, Nipro Elisio-17M and Fresenius
F8HPS
Peter Ahrenholz
Roland E. Winkler
1
Nipro_Report_Comparison of Sureflux17G_Elisio17M and F8HPS.doc
1. Study Objective
The dialyzers Sureflux-17G and ELISIO-17M are new mid-flux dialyzers made from
Cellulose Triacetate and Polynephron fiber designed and manufactured by Nipro Japan.
The dialyzers have already been subjected to in-vitro testing, and all legally required
biological safety tests have been conducted and certified by an external institute. A
number of clinical studies have already been successfully completed for this membrane.
Both dialyzer types have the CE marking.
The aim of the study is to compare the performance characteristics and

hemocompatibility of the Nipro dialyzers Sureflux-17G, ELISIO-17M and Fresenius
F8HPS. This is a feasibility study not for publication and will be kept confidential. The
core parameters are basic characteristics for Nipro internal use.
2. Membranes and Dialyzers
UF Coeff. Surface
Dialyzer
Dialyzer Labelling Membrane Sterilization
Manufacturer
mL/h/mmHg m2
Cellulose-
Nipro Sureflux-17G Nipro, Japan 18.4 1.7 Gamma
Triacetate
Nipro ELISIO-17M Polynephron Nipro, Japan 22.0 1.7 Gamma
Polysulfone Fresenius,
Fresenius F8HPS 18.0 1.8 Heat
(Helixone) Germany
3. Study Design
3.1 Patients
Eight stable patients with end-stage renal disease on conventional in-center thrice
weekly hemodialysis were selected and included in the study. Each patient underwent
one study week of three consecutive hemodialysis treatments with each dialyzer type.
Blood samples were taken during the last treatments.
The patients were selected according to the inclusion/exclusion criteria (see enclosure
“Proposal”).
Because 1 patient dropped out during the study (hospitalization), a new patient was
enrolled after the Sureflux-17G measurements (pat. MW replaced by KM)
Altogether the following patients were enrolled:
2
Dry
Age
no. Initials Sex weight HD Since Original Disease
Years
kg
1 BH f 70 47,5 08/1994 glomerular nephropathy
2 DJ m 75 73,0 02/2010 diabetic nephropathy
3 KJ m 63 57,5 12/2001 vascular nephropathy
4 MI f 78 72,5 10/2008 diabetic nephropathy
5 FH f 82 70,0 10/2010 diabetic nephropathy
6 HF f 75 68,0 01/2003 interstitial nephropathy
7 MW f 75 47,0 03/2011 vascular nephropathy
8 RK m 86 98,0 10/2007 glomerular nephropathy
9 KM m 61 78,5 10/2009 diabetic nephropathy
The investigation had the character of a clinical study according to the German “Gesetz
über Medizinprodukte (Medizinproduktegesetz – MPG), § 23b” and with reference to the
European Standard ISO 14155 and the Declaration of Helsinki.
All patients were informed about the aim of the study, the risks, and rights and have
signed a consent form.
3.2 Procedures during the Study
Treatment parameters:
Treatment mode: Hemodialysis.

Blood flow Qb = 300 ml/min, dialysate flow Qd = 500 ml/min, the weight loss
ultrafiltration rate (Qf) was as prescribed by the physician. Qb and Qd remained
unchanged for the duration of the treatments.
All treatments were performed with Fresenius 5008 or 4008 machines.
Pre-rinsing of dialyzers and heparinization were performed per clinic’s routine procedure
(pre-rinsing with 1000 ml saline).
Blood Sampling:
Blood was collected at appropriate time intervals for the evaluation of performance and
hemocompatibility:
3
Performance 30 min 180 min
Clearance Urea a, v a, v
‘’ Phosphate a, v a, v
‘’ Creatinine a, v a, v
Performance pre 240 min
Removal Rate Urea a a

‘’ Phosphate a a
‘’ Creatinine a a
Hemocompatibility Pre 15 min 30 min 60 min 180 min 240 min
WBC a a a a a a
Platelet Count a a a a a a
Hb / Hct a a a a a a
C5a a v v v v v
TAT a - - v v v
Residual blood
*)
behaviour
a: arterial sample (= pre-dialyzer)
v: venous sample (= post-dialyzer)
*) visual evaluation after intensive rinsing and photo of the fiber bundle
Pre-dialysis blood samples were drawn from the arterial needle before starting the blood
pump and before heparinization. The samples taken during the treatment were collected
while the blood and dialysate flows were at the targeted rates and while the prescribed
ultrafiltration rates were applied. All samples apart from the blood count tubes were
centrifuged within 30 min and deep frozen until measurement.
After treatment and retransfusion the dialyzers were intensive rinsed by means of
reverse osmosis water from the dialysate to the blood side (pressure about 1...2 bar).
Thereafter the number of permanently clotted fibers were estimated and judged
according to the following grading:
Number of Clotted Fibers
0 – 10 11 – 20 21 – 50 51 – 100 >100
Mark 1 2 3 4 5
4
4. Location and Duration of the Study
The study was performed in the dialysis unit of Drs. Winkler/Michelsen/Sehland in

Rostock between October 28 and November 17, 2011. This unit is certified complying
with the standard ISO 9001:2000.
5. Laboratory Methods
Laboratory measurements were conducted by a laboratory certified according to DIN

IES 17025 (Gemeinschaftspraxis für Laboratoriumsmedizin, Rostock,
www.labormedicus.de).
The following methods were used:
Product
Parameter Method Manufacturer
Information
blood count automatic Sysmex SE-9000
urea Standard method Diasys Automat Hitachi 717
creatinine
phosphate
ß2-Microglobulin ELISA (MEIA) Abbott Axsym
C5a Enzyme DRG Instruments EIA-3327

Immunoassay GmbH, Germany
TAT Enzyme Siemens Enzygnost TAT
Immunoassay micro
6. Data Analysis/Calculations
Data analysis was done using Microsoft Excel software. All parameters were given as
mean and standard error of measurements (SEM).
Differences between the results were tested using the Student´s t-test. A p-value of
<0.05 was considered as statistically significant.
Because of changing hematocrit values during the treatments, plasma concentrations

were corrected using the formula (1):
ccorr = c* (Hct0/Hctn)*(1-Hctn)/(1-Hct0)
Hct0 = pre treatment hematocrit;

Hctn = hematocrit value at sampling time n
Whole blood measures (blood cell counts) were corrected using the formula
Ccorr = C*Hct0/Hctn
5
In any cases the whole blood clearance data were measured. Indeed not all test
substances (urea, creatinine, inorganic phosphate) are distributed uniformly between
blood cells and blood plasma. Therefore, sometimes the plasma clearance is used
instead of the whole blood clearance (2). For a comparison of the efficacy of dialyzers,
as intended in the case of this study, only differences between the dialyzer types are
important, so that the whole blood clearance can be used.
The whole blood clearance K [ml/min] was calculated using the formula:
K = Qbi(cbi-cbo)/cbi + Qfcbo/cbi
Qbi: blood flow at dialyzer inlet; cbi: blood concentration at dialyzer inlet; cbo: blood
concentration at dialyzer outlet; Qf: ultrafiltration rate.
The removal rates RR were calculated by:
RR [%] = (1 – cpost/cpre)*100
cpre: pre-treatment concentration cpost: post-treatment concentration
7. Results and Discussion
The detailed results are given in the enclosure 1: Excel-tables and figures.
7.1 Clearance Data
7.1.1 Time Dependence of Clearance
The clearance determinations were conducted at 30 min and 180 min. Significant
differences between 30 min and 180 min values were not found. Only in the case of the
dialyzer F8HPS there is a tendency to slightly smaller 180-min-values. This behavior is
compatible with the tendency of increased clotting of F8HPS (see TAT, platelet counts
and visual evaluation in Excel-Tables “Comparisons”).
7.1.2 Comparison of the Clearance Data
For the comparison of the whole blood clearance data of the different dialyzer types the
mean values of 30 min and 180 min were calculated. The comparison can be found in
the Excel Table “Comparisons”.
6
Comparison of UREA clearance values Comparison of CREATININE clearance values Comparison of PHOSPHATE clearance values
Qb = 300 ml/min Qb = 300 ml/min Qb = 300 ml/min
(means of 30 and 180 min values) (means of 30 and 180 min values) (means of 30 and 180 min values)
350,0
350,0 350,0
n.s.
n.s.
300,0
300,0 300,0
p=0.00001 p=0.007
238 240 251 248 246
250,0
231 250,0 250,0 237 231
215
200,0
200,0 200,0
ml/min
ml/min
ml/min
150,0 150,0
150,0
100,0 100,0
100,0
50,0 50,0 50,0
0,0 0,0 0,0

Sureflux17G ELISIO17M F8HPS Sureflux17G ELISIO17M F8HPS Sureflux17G ELISIO17M F8HPS
Fig. 1: Comparison of the clearance data (means of the 30 min and 180 min Values)
The following table summarizes the results:
Test substance
Sureflux 17G ELISIO 17 M F8 HPS
Clearance [ml/min]
urea 238.0 231.1 239.8
247.9
creatinine 251.1 245.7
214.9 p=0.007 vs.F8HPS
phosphate 236.8 p=0.00001 vs.ELISIO 231.3
The clearance data are means of the 30-min and 180-min-values (n = 16)
It can be stated that there are no statistically significant differences between the 3
dialyzer types concerning urea and creatinine, but the ELISIO 17M shows a tendency
towards somewhat smaller clearance values. Concerning the phosphate clearance the
ELISIO 17M has significant smaller clearance data.
7.2 Removal Rates (RR)
Whereas the clearance describes the instantaneous dialyzer performance, the removal
rate represents the overall efficiency of the treatment. The latter is dependent not only
on the dialyzer performance but also on individual characteristics of the patient such as
compartment volumes and transfer kinetics. Therefore the removal rates do not
necessarily reflect the differences of the dialyzer clearances in the same manner.
7
Com parison of UREA Rem oval Rates Com parison of CREATININE Rem oval Rates Com parison of PHOSPHATE Rem oval Rates
Qb = 300 m l/m in Qb = 300 m l/m in (rem oval of …% after 240 m in)
(rem oval of …% after 240 m in) (rem oval of …% after 240 m in)
100,0 100,0 100,0
90,0 90,0 90,0

n.s.
n.s. p=0.01
80,0 76 80,0 80,0
75 76
p=0.04
69 68 69 70,0 66
70,0 70,0
62 62
60,0 60,0
60,0
%
50,0
%
50,0
%
50,0
40,0 40,0
40,0
30,0 30,0
30,0
20,0 20,0
20,0
10,0 10,0
10,0
0,0 0,0
0,0
Sureflux17G ELISIO17M F8HPS Sureflux17G ELISIO17M F8HPS
Sureflux17G ELISIO17M F8HPS
Fig. 2: Comparison of the removal rates (RR)
The following table shows the results of the RR measurements:
Test substance
Sureflux 17G ELISIO 17 M F8 HPS
Removal Rate [%]
urea 76.3 74.6 75.6
creatinine 69.4 68.5 68.6
phosphate 66.0 p=0.01vs.F8HPS

61.8 62.5
p=0.04vs.ELISIO
There are no significant differences between the dialyzers concerning urea and
creatinine, but with regard to phosphate the dialyzer Sureflux 17G is superior to ELISIO
17M and F8HPS.
The blood samples for the determination of the removal rates were taken after a blood
pump speed reduction to 50 ml/min for 30 sec. Therefore the conditions for the
determination of the dialysis dose Kt/V are given (DOQI guidelines).
8
Com parison of Kt/V-values
(Daugirdas-Form ula and m achine display)
2,50
Sureflux17G
ELISIO17M
2,00 F8HPS
1,69 1,67
1,62
1,47 1,45
1,41 1,36
1,50
1,26 1,30
1,00
0,50
0,00
Kt/V
spKt/V eqKt/V machine
Fig.3: Comparison of the dialysis dose Kt/V calculated with the Daugirdas-Formula and
displayed by the dialysis machine (Fresenius 4008 or 5008)
The Kt/V-values (single pool and equilibrated Kt/V) confirm a slightly larger urea
elimination of the dialyzers Sureflux 17G and F8HPS versus ELISIO 17M. The machine
display of Kt/V is based on the on-line clearance measurement of the Fresenius
machine. Obviously the Fresenius machine comes to a better result for the Fresenius
dialyzer. Generally the on-line Kt/V leads to smaller values than the determination from
blood measurements. This is due to the use of a calculated urea distribution volume
which based on the Watson-formula and delivers overestimated volumes.
7.3 Hemocompatibility
The hemocompatibility was assessed by means of the counts of white blood cells
(WBC), platelets, the complement factor C5a, the Thrombin-Antithrombin-III-complex
(TAT) and a visual judging of clotted fibers.
7.3.1 White Blood Cells
Concerning the white blood cells a transient leukopenia is typical for dialysis
membranes (e.g. 3). This is more or less pronounced depending on the membrane
material (cellulose: strong leukopenia, synthetic membranes such as polyethersulfone
and polysulfone: mild).
The drop of white blood cells is mainly caused by monocytes and neutrophil
granulocytes. This behavior is due to the activation of monocytes and granulocytes by
contact with artificial surfaces such as dialyzer membranes (e.g. 4, 5). All compared
dialyzer types show a mild but significant white blood cell drop between 20% (F8 HPS)
and 24 % (Sureflux 17G) with a maximum at 15 min:
9
Comparison of the White Blood Cell Counts
10,00
9,00
8,00
7,00
6,00
Gpt/L
5,00
4,00
3,00
2,00
1,00
0,00
0 50 100 150 200
min
Fig. 4: Comparison of the time dependence of white blood cells
The differences between the 3 dialyzer types are statistically not significant (see Excel
Tables “Comparisons”)
7.3.2 Complement Activation
In any cases the leukocyte drop during dialysis is accompanied by an increase of

complement factors such as C3a and C5a at the same treatment time, followed by a
reduction towards the end of treatment. This can be observed in the cases of all three
dialyzer types:
Comparison of the Complement Activation Factor C5a

6,0
5,0
4,0
Sureflux17G
ng/ml
3,0 ELISIO17M
F8HPS
2,0
1,0
0,0
0 50 100 150 200 250
min
10
Fig. 5: Comparison of the activation of complement factor C5a
Obviously the dialyzer Sureflux 17G has the largest C5a increase (such as the WBC
decrease), but the differences between the three dialyzer types are statistically not
significant.
7.3.4 Hemodialyzer-induced thrombogenicity
The dialyzer thrombogenicity can be judged roughly by counting the platelets during the
treatment time and an estimation of the clotted fibers after treatment. The contact
system is generally believed to be the main trigger of the coagulation cascade during
the extracorporeal detoxification (6, 7). Therefore parameters such as thrombin-
antithrombin III complex (TAT), platelet factor 4 (PF-4) and beta-thromboglobulin (ß-TG)
can be used to characterize the thrombogenicity of dialyzer membranes.
7.3.5 Platelet Count
All compared dialyzer types show a similar time dependence of the platelet count (fig.
6). There is a small decrease after the treatment start (hct-corrected) of 5-7 % and a
recovery to about 98 % after 240 min. The platelet drop of the Sureflux 17G appears to
be somewhat larger, but the differences to the other dialyzer types are not statistically
significant (maybe because of large individual differences of the platelet count and the
small sample size).
Comparison of the Platelet Counts

250
200
Sureflux17G
150
ELISIO
Gpt/L
F8HPS
100
50
0
0 50 100 150 200 250
min
Fig. 6: Comparison of the platelet count during the treatment time
7.3.6 Thrombin-Antithrombin-III Complex (TAT)
11
Fig. 7 shows the time course of TAT for the 3 compared dialyzers.
Com parison of TAT

60,0
50,0
40,0
ng/ml
30,0 Sureflux17G
ELISIO17M
20,0 F8HPS
10,0
0,0
0 50 100 150 200 250
m in
Fig. 7: Time dependence of thrombin-antithrombin-III complex (TAT)
Generally an increase during the contact time with the dialyzer membranes can be
stated. For all dialyzers the TAT increase is significant, but because of the large scatter
statistical differences between the dialyzer types could not be detected. A tendency for
the smallest TAT increase of ELISIO 17M and the largest one of F8 HPS can be seen in
the figure 7.
7.3.7 Visual Estimation of Clotted Fibers
Once per week the clotted capillaries in the patients’ dialyzers were estimated after
application. For this purpose the residual blood after retransfusion was removed by
means of ultrafiltration with reverse osmosis water from dialysate compartment to blood
compartment (about 1 bar water pressure). The permanently clotted fibers on the
dialyzer surface were counted and judged by means of a grading:
Number of clotted fibers

0 – 10 11 – 20 21 – 50 51 – 100 >100
grade 1 2 3 4 5
Dialyzer: Sureflux 17G ELISIO 17M F8 HPS
mean grade:
2,0 3,5 4,6
(n = 8)
As a result the dialyzer Sureflux 17G showed the smallest number of permanently
clotted fibers, followed by ELISIO 17M. The dialyzer F8 HPS had by far the largest
12
number of clotted fibers. This is consistent with the larger TAT increase and platelet
decrease.
The dialyzer bundles and caps were photographed after rinsing (see attached file).
8. General Survey
During all dialysis treatments with Sureflux 17G, ELISIO 17 M and F8 HPS dialyzers
adverse reactions were not observed.
9. Conclusions
• There are only small differences between the 3 dialyzer types concerning the
clearance data. The Sureflux 17G shows somewhat better clearance date
compared with the ELISIO 17M. The phosphate clearance data of Sureflux 17G
and F8 HPS are significantly better than the phosphate clearance of ELISIO
17M.
• The removal rates confirm a slight superiority of the Sureflux 17G. The
phosphate elimination by the ELISIO 17M is significantly smaller than that of
both, Sureflux 17G and F8 HPS. The calculated dialysis dose Kt/V is similar for
Sureflux 17G and F8 HPS, but somewhat larger than that of ELISIO 17M.
• Concerning the hemocompatibility significant differences were not found between

the three dialyzers with respect to the white blood cell counts and the
complement factor C5a. But there is a tendency to a slightly larger WBC drop
and C5a increase for the dialyzer Sureflux 17G.
• The thrombogenicity judged by platelet count, TAT and residual blood estimation
is the smallest one for the Sureflux 17G and ELISIO 17M, whereas the F8 HPS
has a comparatively larger thrombogenicity.
Rostock, December 20, 2011
13
Dr. Peter Ahrenholz Dr. Roland E. Winkler
Principal Investigator Clinical Investigator
Enclosures:
o References
o Excel Tables and Diagrams
o Study Protocol
References
1. W. van Beaumont: Evaluation of hemoconcentration from hematocrit

measurements. Journal of Applied Physiology, Vol. 32, No. 5, May 1972, 712-
713
2. Krieter DH, Lemke H-D, Wanner C: A new synthetic dialyzer with advanced
permselectivity for enhanced low-molecular weight protein removal. Artif. Organs
32(7): 547-554
3. Craddock PR, Fehr J, Dalmasso AP, Brighan KL, Jacob HS: Hemodialysis
leukopenia. Pulmonary vascular leukostasis resulting from complement activation
by dialyzer cellophane membranes. J Clin Invest. 1977 May; 59(5): 879-88
4. von Appen K, Goolsby C, Mehl P, Goewert R, Ivanovich P: Leukocyte adhesion

molecules as biocompatibility markers for hemodialysis membranes.
ASAIO J 1994 Jul-Sep;40(3):M609-15
5. Combe C, Pourtain M, de Precigout V, Baquey A, Morel D, Potaux L,

Vincendeau P, Bezian JH, Aparicio M: Granulocyte activation and adhesion
molecole during hemodialysis with cuprophane and high-flux biocompatibile
membrane. Am J Kidney Dis 1994, Sep;24(3):437-42
6. Schultze G, Hollmann S, Sinah P: Formation of thrombin-antithrombin III complex

using polyamide and hemophan dialyzers. Int J Artif Organs 1992 Jun;15(6):
370-373
14
7. Frank RD, Weber J, Dresbach H, Thelen H, Weiss C, Floege J: Role
of contact system activation in hemodialyzer-induced thrombogenicity. Kidney Int
2001 Nov;60(5): 1972-81
15

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Nipro_Report_Comparison of Sureflux17G_Elisio17M and F8HPS.

Clinical Study Comparing the Basic Performance and Blood Compatibility

The aim of the study is to compare the performance characteristics and

2. Membranes and Dialyzers

Nipro ELISIO-17M Polynephron Nipro, Japan 22.0 1.7 Gamma

Altogether the following patients were enrolled:

2 DJ m 75 73,0 02/2010 diabetic nephropathy

3 KJ m 63 57,5 12/2001 vascular nephropathy

4 MI f 78 72,5 10/2008 diabetic nephropathy

5 FH f 82 70,0 10/2010 diabetic nephropathy

6 HF f 75 68,0 01/2003 interstitial nephropathy

7 MW f 75 47,0 03/2011 vascular nephropathy

8 RK m 86 98,0 10/2007 glomerular nephropathy

9 KM m 61 78,5 10/2009 diabetic nephropathy

3.2 Procedures during the Study

Treatment mode: Hemodialysis.

Performance 30 min 180 min

Performance pre 240 min

Removal Rate Urea a a

Hemocompatibility Pre 15 min 30 min 60 min 180 min 240 min

Number of Clotted Fibers

4. Location and Duration of the Study

The study was performed in the dialysis unit of Drs. Winkler/Michelsen/Sehland in

Laboratory measurements were conducted by a laboratory certified according to DIN

The following methods were used:

C5a Enzyme DRG Instruments EIA-3327

Because of changing hematocrit values during the treatments, plasma concentrations

Hct0 = pre treatment hematocrit;

The removal rates RR were calculated by:

cpre: pre-treatment concentration cpost: post-treatment concentration

7. Results and Discussion

7.1 Clearance Data

7.1.1 Time Dependence of Clearance

7.1.2 Comparison of the Clearance Data

50,0 50,0 50,0

0,0 0,0 0,0

The following table summarizes the results:

7.2 Removal Rates (RR)

100,0 100,0 100,0

90,0 90,0 90,0

Fig. 2: Comparison of the removal rates (RR)

The following table shows the results of the RR measurements:

phosphate 66.0 p=0.01vs.F8HPS

spKt/V eqKt/V machine

7.3.1 White Blood Cells

Fig. 4: Comparison of the time dependence of white blood cells

7.3.2 Complement Activation

In any cases the leukocyte drop during dialysis is accompanied by an increase of

Comparison of the Complement Activation Factor C5a

7.3.4 Hemodialyzer-induced thrombogenicity

7.3.5 Platelet Count

Comparison of the Platelet Counts

Fig. 6: Comparison of the platelet count during the treatment time

7.3.6 Thrombin-Antithrombin-III Complex (TAT)

Com parison of TAT

Fig. 7: Time dependence of thrombin-antithrombin-III complex (TAT)

7.3.7 Visual Estimation of Clotted Fibers

Number of clotted fibers

Dialyzer: Sureflux 17G ELISIO 17M F8 HPS

• Concerning the hemocompatibility significant differences were not found between

Rostock, December 20, 2011

1. W. van Beaumont: Evaluation of hemoconcentration from hematocrit

4. von Appen K, Goolsby C, Mehl P, Goewert R, Ivanovich P: Leukocyte adhesion

5. Combe C, Pourtain M, de Precigout V, Baquey A, Morel D, Potaux L,