Perit Dial Int
29(2):
178-181
2009
© 2009 International Society for Peritoneal Dialysis
EFFECTS OF BERAPROST SODIUM, AN ORAL PROSTAGLANDIN I2 ANALOG, ON HEMOSTATIC FACTORS AND INFLAMMATION IN CHRONIC PERITONEAL DIALYSIS PATIENTS
Kyung Min Kim,
Hyun Woo Kim,
Jang Han Lee,
Jai Won Chang,
Jung Sik Park and
Soon Bae Kim
Division of Nephrology, Department of Internal Medicine, Asan Medical
Center, University of Ulsan College of Medicine, Seoul, Korea
Correspondence to: S.B. Kim, Department of Internal Medicine, Asan Medical
Center, 388-1 Poongnap-dong, Songpa-gu, Seoul, 138-736, Korea.
sbkim{at}amc.seoul.kr
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ABSTRACT
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Beraprost sodium, an orally active prostaglandin I2 analog with
vasodilatory, cytoprotective, antiplatelet, antithrombotic, and
anti-inflammatory effects, 120 µg daily for 8 weeks, decreased plasma
D-dimer, a marker of intravascular coagulation, and von Willebrand factor, a
marker for endothelial injury, in 100 chronic peritoneal dialysis patients.
Total cholesterol, triglycerides, high-density lipoprotein, apolipoprotein A1,
apolipoprotein B, albumin, prealbumin, fibrinogen, troponin-T, and
high-sensitivity C-reactive protein levels were not changed. Three patients
complained of headache and 1 patient experienced facial flushing; however, no
serious adverse effects were observed. These results suggest that beraprost
sodium is effective in partially reversing the thrombogenic coagulation
profile and endothelial injury in chronic peritoneal dialysis
patients.
KEY WORDS: Beraprost; inflammation; hemostatic factors.
Disturbances in hemostasis and increased inflammatory activity could be
partially responsible for the frequent cardiovascular disease observed in
dialysis patients. Prostaglandin I2 (PGI2; prostacyclin), an eicosanoid of the
cyclooxygenase pathway, causes relaxation of vascular smooth muscle in most
blood vessels and inhibits platelet aggregation. Beraprost sodium is a stable,
orally active PGI2 analog with vasodilatory, cytoprotective, antiplatelet,
antithrombotic, and anti-inflammatory effects
(1). It is now being used in
the treatment and prevention of cardiovascular diseases and pulmonary
hypertension, and in the prevention of thrombosis
(1).
The objective of this study was to evaluate the effects of beraprost sodium
on hemostatic factors and inflammation in patients receiving chronic
peritoneal dialysis (CPD).
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PATIENTS AND METHODS
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Between January 2007 and June 2007, a total of 100 end-stage renal disease
patients on CPD at Asan Medical Center Dialysis Clinic, Seoul, were included
in this prospective study. Informed consent was obtained from all subjects.
Patients with acute inflammation, infection, or other acute intercurrent
illness, and those administered medication known to affect cholesterol levels
or oxidation were excluded from the study. There were 49 men and 51 women;
mean age was 54 years. Median duration of CPD was 27 months (range 3 –
144 months). Underlying causes of renal disease included diabetic nephropathy
(n = 37), glomerulonephropathy (n = 7), hypertension
(n = 33), lupus nephritis (n = 1), and unknown cause
(n = 22).
The 100 patients were randomized to receive either 20 µg beraprost
sodium (Green Cross, Yong-In, Korea), 2 tablets 3 times per day for 8 weeks
(treatment group), or none (control group).
Clinical characteristics of the treatment and control groups after
randomization are listed in Table
1. There were no differences in age, sex, duration of CPD,
presence of diabetes as cause of end-stage renal disease, blood urea nitrogen,
serum creatinine, Kt/V, normalized protein catabolic rate (nPCR), or residual
renal function between the two groups.
Blood samples were taken from each patient before starting medication and
after 8 weeks. Total cholesterol, triglycerides, and high-density lipoprotein
cholesterol (HDL-C) were measured by enzymatic methods using a Hitachi 736-40
automatic analyzer (Hitachi, Tokyo, Japan). Apolipoprotein (Apo) A1 and ApoB
were measured by immunonephelometry using a Beckman Array 360 analyzer
(Beckman Instruments, Fullerton, CA, USA). Serum albumin was measured by a
bromcresol green method using a Hitachi 736-40 automatic analyzer. Serum
prealbumin was measured by nephelometry. Plasma fibrinogen concentration was
determined by the clotting method using the STA Fibrinogen kit (Diagnostica
Stago, Asnieres-sur-Seine, France). Concentrations of plasma D-dimer, a marker
of intravascular coagulation, and von Willebrand factor (vWF), a marker of
endothelial injury, were determined by the enzyme-linked immunosorbent assay
(ELISA) method using Asserachrom D-Di and Asserachrom vWF (Diagnostica Stago)
respectively. Serum troponin-T was measured by an electrochemiluminescence
immunoassay (ECLIA) method, using Troponin T STAT (Roche Diagnostic Systems,
Basel, Switzerland). High-sensitivity C-reactive protein (hs-CRP) was measured
by a particle-enhanced immunoturbidimetric method using a Cobas Integra 700
analyzer (Roche Diagnostic Systems). Kt/V urea and nPCR were calculated from
measurements of blood urea nitrogen using formal urea kinetic modeling
employing a single-pool variable-volume model.
All data are expressed as mean ± SD or median and range.
Between-group differences were compared by Student's t-test,
Mann–Whitney U test, or Fisher's exact test. Data obtained at baseline
and at 8 weeks were compared using a paired t-test or Wilcoxon signed-rank
test. Differences were considered statistically significant at p <
0.05.
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RESULTS AND DISCUSSION
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Of the 100 patients, 94 completed this study. Five patients in the
treatment group that did not take the prescribed dosage of beraprost sodium
were excluded from the analysis. Three patients developed headache, 1 patient
developed facial flushing, and 1 patient was hospitalized because of
peritonitis. One patient in the control group was hospitalized because of
hypoglycemia. Medication compliance in the treatment group, estimated by
counting returned tablets, was 95% throughout the study.
Changes in lipid profile, serum albumin, prealbumin, fibrinogen, D-dimer,
vWF, troponin-T, and hs-CRP levels from baseline to 8 weeks of beraprost
sodium therapy are listed in Table
2. Baseline values for all parameters were similar between the two
groups. In the control group, total cholesterol, triglycerides, HDL-C, ApoA1,
ApoB, albumin, prealbumin, fibrinogen, D-dimer, vWF, troponin-T, and hs-CRP
levels did not change over the 8-week study. In the treatment group, beraprost
sodium administration for 8 weeks was associated with significant reductions
in D-dimer levels, from 0.87 ± 1.12 to 0.62 ± 0.53 mg/L
(p < 0.05), and in vWF levels, from 135% ± 39% to 120%
± 31% (p < 0.05). In contrast, 8 weeks of beraprost sodium
administration did not affect total cholesterol, triglycerides, HDL-C, ApoA1,
ApoB, albumin, prealbumin, fibrinogen, troponin-T, or hs-CRP levels.
To the best of our knowledge, this is the first study to evaluate the
effects of PGI2 on hemostatic factors and inflammation in dialysis patients.
Beraprost sodium, at a fixed daily dose of 120 µg, was found to lower
plasma D-dimer and vWF levels.
There are several reports that PGI2 affects coagulation. Hatane et
al. (2) reported that PGI2
enhanced the expression of urokinase-type plasminogen activator. Tsutsui
et al. (3) reported
successful treatment of livedo vasculitis, a thrombogenic disorder, with PGI2.
Treatment with PGI2 to prevent clotting of the extracorporeal circuits has
also been performed in hemofiltration patients
(4). However, we were unable
find any report about the direct effects of PGI2 on plasma D-dimer or fibrin
degradation products.
We further showed in this study that PGI2 decreased plasma vWF levels in
CPD patients. Several experimental studies have shown protective effects of
PGI2 on endothelial cells. Ohata et al.
(5) reported that PGI2
administered in the forearms of patients with coronary artery disease was
associated with improvement of endothelium-dependent vasodilatation and a
decrement of vascular events. Another study showed that PGI2 reduced the
concentration of vascular cell adhesion molecule-1, a molecule expressed in
vascular endothelium, and prevented the progression of carotid artery
atherosclerosis in type 2 diabetic patients
(6). Prostaglandin I2 was also
tested in 27 type 2 diabetic patients with early-stage diabetic nephropathy
who showed signs of micro-albuminuria, which is associated with endothelial
dysfunction (7). It was
observed that urinary albumin excretion was significantly decreased after 18
and 24 months of PGI2 treatment. We were able to find only one study showing
that PGI2 decreased plasma vWF levels, and that was shown in patients with
severe pulmonary arterial hypertension
(8).
Prostaglandin I2 has been reported to have anti-inflammatory properties.
Prostaglandin I2 reduces the level of cytokines and growth factors, decreases
chemotaxis, diminishes or modulates the expression of adhesion molecules on
endothelial cells, neutrophils, and monocytes by a cAMP-dependent mechanism,
and down-regulates lymphocyte adhesion of endothelial cells
(9,10).
In addition, PGI2 regulates the synthesis of tumor necrosis factor-alpha in
leukocytes and macrophages and decreases its expression in monocytes and
endothelial cells (9). One
study showed that a stable prostacyclin analog reduced excessive tumor
necrosis factor-alpha levels in diabetic patients
(11). However, beraprost
sodium did not change hs-CRP levels in CPD patients in our study.
In the treatment group, 3 patients complained of headache and 1 patient
experienced facial flushing but no severe adverse effects were observed. In
most studies, beraprost is a generally well-tolerated agent and no serious
adverse effects related to the drug have been reported
(12,13).
In conclusion, we have shown here that beraprost sodium is effective in
partially reversing the thrombogenic coagulation profile and endothelial
injury in CPD patients.
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DISCLOSURE
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The author has no financial conflict.
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ACKNOWLEDGMENTS
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This study was supported by Baxter Korea.
Received 31 January 2008;
accepted 26 June 2008.
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ABSTRACT
PATIENTS AND METHODS
