Nephrology & Therapeutics

Maeda et al., J Nephrol Ther 2014, 5:1
http://dx.doi.org/10.4172/2161-0959.1000189

Research Article

Open AccessLong Dialysis Time is the More Important Factor of Erythropoietin
Response in Hemodialysis Patients with Diabetes than Kt/V
Atsuhiro Maeda1*, Kazuhito Takeda2, Kazuhiko Tsuruya1, Takanari Kitazono1, Hideyuki Mukai2, Shuuhei Miura2, Jiro Toyonaga2, Satsuki
Nakashita2, Tomo Komaki2, Keita Takae2, Kazuo Sakamoto2, Maki Maeda3, Nana Oyama3 and Toshiro Maeda3
12
3

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan
Department of Nephrology and Kidney Center, Aso-Iizuka Hospital, 3-83 Yoshio-machi, Iizuka 820-8505, Japan
Department of Kidney Center, Kouzenkai-Maeda Hospital, 2742-1 Tachibana-cho, Imari 848-0027, Japan

Abstract
Background: Though inadequate dialysis is a known risk factor for resistance to erythropoietin (EPO) therapy,
there is no consensus about the relationship between hemodialysis (HD) time and EPO requirement. Our study sought
to explore the relationship between EPO dosage and dialysis time in HD patients with diabetes.
Methods: We report a cross-sectional analysis of the relationship between EPO dosage and dialysis time in HD
patients with diabetes. A total of 77 patients with diabetes receiving maintenance HD at three outpatient HD facilities
in Japan were included. At one such facility, HD time was 6 hours (n=37), and at the other facilities, HD time was 4hours (n=40). In 6-hour HD patients and 4-hour HD patients, we studied parameters of weekly EPO requirement, Kt/V,
hemoglobin, ferritin, albumin, C-reactive protein and intact parathyroid hormone. These parameters were analyzed with
JMP9TM statistical software (SAS Institute).
Results: Means for hemoglobin, ferritin, albumin, C-reactive protein and intact parathyroid hormone were notsignificantly different between the 6-hour and 4-hour HD patient groups. The EPO requirement was significantly lower
among 6-hour HD patients (3111.8 ± 2360.8 versus 5682.9 ± 3863.3 U/week. P=0.0007). Kt/V was not significantly
different between the two groups.
Multiple regression analysis with EPO requirement as the dependent variable showed that dialysis time was the only
significant independent variable (P=0.0001).
Conclusions: Six-hour HD without a significant increase in dialysis dose, as judged by Kt/V, can reduce the doseof EPO in HD patients with diabetes.

Keywords: Erythropoietin requirement; Hemodialysis time; Kt/V;
Inadequate dialysis; Long hemodialysis; Membrane surface area; 6hour-hemodialysis

Introduction
Renal anemia is a very frequent problem that affects hemodialysis(HD) patients. The main pathogenic factor is a reduction inerythropoiesis caused by reduced renal production of erythropoietin(EPO) and by resistance of bone marrow cells to this hormone.
Before the 1990s, anemic HD patients were submitted to inefficient
treatment by blood transfusions and administration of androgenicanabolic steroids. The introduction of recombinant human EPO
therapy has improved quality of life for HD patients with severe anemia
and made it possible to control anemia in attempts to achieve normal
hemoglobin (Hb) target.
Randomized trials have shown increased mortality [1] or nobeneficial clinical effects [2] among those assigned to normal Hb targets.
High doses of EPO increase the risk of death and cardiovascular eventsin HD patients [3-5]. Given these findings, it is important to explore
the factors of Hb response to EPO.
Although some studies have proved that iron deficiency [610], inflammatory disorders [11,12], hyperparathyroidism [13,14],
malnutrition [15-17] and a low standardized HD dose of urea [18-22]
increase the EPO requirement, little actual study has been done to
explore the relationship between dialysis time and EPO requirement.
Our study was undertaken to test the a hypothesis that longer HD time
can reduce the EPO requirement in HD patients.

Methods
We conducted a cross-sectional study on a total of 77 diabetes
J Nephrol Ther
ISSN: 2161-0959 JNT, an open access journalpatients receiving maintenance HD for 7-240 months (median 62.4
months). Subjects were recruited from three outpatient HD facilities inJapan. At one facility, dialysis time was 6 hours (n=37), and at the othertwo facilities, dialysis time was 4 hours (n=40).
Included patients were age 20 years or older and had undergone
maintenance HD three times a week for at least six months as treatment
for end-stage renal disease due to type 2 diabetes mellitus. Patientswith any blood loss, blood transfusions, hospitalizations, or infections
occurring within six months preceding the study were excluded.
Conventional dialysis was performed with the use of high-flux
dialysis membranes and bicarbonate-based dialysate. All patients
received EPO and an iron preparation intravenously.
In 6-hour and 4-hour HD patients, we studied parameters of weekly
EPO requirement, Kt/V, membrane surface area, quantity of bloodflow (QB), quantity of dialysate flow (QD), age, length of treatment,*Corresponding author: Atsuhiro Maeda, Department of Medicine and Clinical
Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi,
Fukuoka 812-8582, Japan, Tel: +81-90-2399-7705; Fax: +81-92-642-5271; E-mail:trymaru0803@yahoo.co.jp
Received September 02, 2014; Accepted November 30, 2014; Published
December 07, 2014
Citation: Maeda A, Takeda K, Tsuruya K, Kitazono T, Mukai H, et al. (2014)
Long Dialysis Time is the More Important Factor of Erythropoietin Response
in Hemodialysis Patients with Diabetes than Kt/V. J Nephrol Ther 4: 189.
doi:10.4172/2161-0959.1000189
Copyright: © 2014 Maeda A, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author andsource are credited.

Volume 5 • Issue 1 • 1000189

Citation: Maeda A, Takeda K, Tsuruya K, Kitazono T, Mukai H, et al. (2014) Long Dialysis Time is the More Important Factor of Erythropoietin
Response in Hemodialysis Patients with Diabetes than Kt/V. J Nephrol Ther 4: 189. doi:10.4172/2161-0959.1000189

Page 2 of 3sex, body mass index (BMI), height, dry weight (DW), Hb, ferritin,albumin (Alb), C-reactive protein (CRP) and intact parathyroid
hormone (i-PTH). All data are expressed as mean ± SD. Statistics were
evaluated by regression analysis, Student’s t-test for unpaired data,
and multiple regression analysis. Significant differences were definedas p<0.05. Parameters were analyzed with JMP9TM statistical software(SAS Institute).

Results
Table 1 shows a comparison in 4-hour HD patients and 6-hour
HD patients between weekly EPO requirement and Kt/V, membranesurface area, QB, QD, age, length of treatment, sex, BMI, height, DW,
Hb, ferritin, Alb, CRP and i-PTH.
The EPO requirement was significantly lower in 6-hour HD
patients (3111.8 ± 2360.8 versus 5682.9 ± 3863.3 U/week. P=0.0007).
Membrane surface area was significantly smaller in 6-hour HD patients(1.1 ± 0.2 versus 1.6 ± 0.4 m2, P<0.0001), and Kt/V was not significantly
different between the two groups. Kt/V, QB, QD, age, length oftreatment, sex, BMI, height, DW, Hb, ferritin, Alb, CRP, and i-PTH
did not differ between the two groups.
Table 2 shows multiple regression analysis results for all patients,
with EPO dosage as a dependent variable. Dialysis time was the only
significant factor (r2=0.25. P=0.0001). Age, Kt/V, CRP, and ferritin
were not significant factors.

Discussion
The major new finding of the present study is that long HD without
4-hour HD, n = 40

6-hour HD, n = 37

p value

5682.9 ± 3863.3

3111.8 ± 2360.8<0.0007

Kt/V

1.4 ± 0.2

1.4 ± 0.2

NS

Membrane surface area(m2)

1.6 ± 0.4

1.1 ± 0.2

<0.0001

Quantity of blood flow (mL/minute)199.1 ± 23.3

188.4 ± 20.6

NS

Quantity of dialysate flow
(mL/minute)

485.6 ± 13.5

500.0 ± 0.0

NSAge (years)

65.4 ± 11.7

67.2 ± 9.2

NSLength of treatment (years)

5.3 ± 4.2

5.0 ± 4.2

NS

62.5

64.9

NS

Body mass index

21.4 ± 3.7

21.5 ± 3.1

NSHeight (cm)158.6 ± 8.5

161.1 ± 10.2

NS

Dry weight (kg)54.0 ± 10.8

55.8 ± 10.2

NS

Hemoglobin (g/dL)

11.1 ± 1.1

11.0 ± 0.9

NSFerritin (ng/mL)

175.9 ± 118.7

172.0 ± 88.6

NSAlbumin (g/dL)

3.7 ± 0.4

3.8 ± 0.4

NSC-reactive protein (mg/dL)

0.5 ± 0.7

0.4 ± 0.5

NS

Intact parathyroid hormone(ng/mL)137.1 ± 108.8

114.3 ± 122.3

NS

Epoetin dose (U/week)

Male (%)

Table 1: Comparison between epoetin dose, Kt/V, membrane surface area andother parameters in 4-hour HD and 6-hour HD.
CoefficientStandard errort statistic

Age

13.78

31.02

0.44

p value
0.66

Dialysis time

-1248.63

310.15-4.03

0.0001

Kt/V

1298.04

1573.96

0.82

0.41

C-reactive protein

428.90522.170.82

0.41

Ferritin

3.44

1.92

1.79

0.08

Table 2: Multiple regression analysis with weekly epoetin dose as dependent
variable.

J Nephrol Ther
ISSN: 2161-0959 JNT, an open access journala significant increase in dialysis dosage, as judged by Kt/V, may reduce
EPO dosage in HD patients.
Movilli et al. reported a negative relationship between EPO doseand Kt/V [15,16].
Gawada et al. also reported that EPO response was high at Kt/Vof 1.4 or higher [17]. However, these studies did not investigate theassociation between dialysis time and EPO requirement.
At the dialysis center in Tassin, France, 59 patients with 8-hour
HD were compared with 53 patients with 3- to 5-hour HD and EPO
requirement was lower in 8-hour HD patients than those in 3- to
5-hour HD patients [18]. However, Kt/V was also higher in the 8-hour
HD patients than 3- to 5-hour HD patients (1.93 and 1.55-1.58,
respectively).
In the present study, we found the lower EPO requirement among
6-hour HD patients despite a lack of difference in KtV, and the fact that
dialysis time was the only significant factor even in multiple regression
analysis. Thus dialysis time itself may be a crucial factor improving
response to EPO.
In turn, we attribute the lack of difference in Kt/V between 6-hourand 4-hour HD patients to a significantly smaller membrane surface
area in 6-hour HD patients. Since the opening of the 6-hour HD facility
in 1989, all HD patients there have undergone 6-hour HD using a
dialyzer with a small membrane surface area (1.1 ± 0.2), and Kt/V isalso by no means high (1.6 ± 0.4). Notwithstanding, results have been
extremely good, with 5-year survival for HD patients at 81.9%, 10-year
survival at 55.3%, and 15-year survival at 42.5%. Similar, good results
have also been obtained among HD patients with diabetes, with 5-year
survival at 79.7%, 10-year survival at 47.9%, and 15-year survival at
21.0% [19].
Although some studies have proved that the iron deficiency [57], inflammatory disorders [8,9], hyperparathyroidism [10,11], andmalnutrition [12,13] increase the EPO requirement, our study foundno significant differences among subject groups in ferritin, CRP,
i-PTH, and Alb.
High doses of EPO increase the risk of death and cardiovascular
events in HD patients [3,4]. Even though we cannot conclude that themortality risk is due to EPO toxicity, HD patients using high dosages of
EPO must be seen as high-risk cases. Long HD is known to have a good
survival prognosis [19-23], one factor of which may be the low EPO
requirement. EPO is also an extremely high-cost drug, and the reduced
EPO requirement in long HD also has an economic benefit.
Values of Kt/V do not reflect medium-large molecular weightsubstances and other aspects of dialysis dosage and can also provide agood result if V is low due to malnutrition; consequently, care is needed
when using this index as a dialysis dosage parameter [24,25].
Our study is a cross-sectional analysis among subjects of HD
patients with diabetes, which must be followed by a prospective
randomized analysis among subjects comprising all HD patients. The
detailed pathophysiology whereby long HD reduces EPO requirement
is also unclear and further basic research is needed.
In conclusion, our study shows that dialysis time rather than Kt/V
is the most important factor of EPO response in HD patients withdiabetes.
Acknowledgements
Support: None, Financial disclosures: None.

Volume 5 • Issue 1 • 1000189

Citation: Maeda A, Takeda K, Tsuruya K, Kitazono T, Mukai H, et al. (2014) Long Dialysis Time is the More Important Factor of Erythropoietin
Response in Hemodialysis Patients with Diabetes than Kt/V. J Nephrol Ther 4: 189. doi:10.4172/2161-0959.1000189

Page 3 of 3
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Citation: Maeda A, Takeda K, Tsuruya K, Kitazono T, Mukai H, et al. (2014)
Long Dialysis Time is the More Important Factor of Erythropoietin Response
in Hemodialysis Patients with Diabetes than Kt/V. J Nephrol Ther 4: 189.
doi:10.4172/2161-0959.1000189

J Nephrol Ther
ISSN: 2161-0959 JNT, an open access journal

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Volume 5 • Issue 1 • 1000189