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Prospective analysis of the efficacy of beraprost sodium combined with alprostadil on diabetic nephropathy and influence on rennin-angiotensin system and TNF-α

  • Authors:
    • Xinwei Xu
    • Xiaojing Pan
    • Song Li
  • View Affiliations

  • Published online on: December 2, 2019     https://doi.org/10.3892/etm.2019.8265
  • Pages: 639-645
  • Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Efficacy of beraprost sodium (BPS) combined with alprostadil on diabetic nephropathy (DN) and its influence on renin angiotensin system (RAS) and TNF-α were investigated. One hundred and two patients with type 2 diabetic nephropathy admitted to Weifang People's Hospital from July 2017 to January 2019 were selected and divided into two groups according to the treatment plan. Fifty patients with alprostadil were the control group and 52 patients with alprostadil combined with BPS were the combined group. Related indexes of fasting blood glucose, hemorheology, coagulation function, renal function, urine routine, liver function, renin angiotensin system and changes of TNF-α (ELISA) were observed, and the occurrence of adverse reactions of patients were recorded. The fasting blood glucose of patients in the two groups after treatment was lower than that before treatment (P<0.05). After treatment, blood viscosity, plasma viscosity and erythrocyte deformation exponent of patients in the two groups decreased (P<0.05), and the combined group was lower than the control group (P<0.05). After treatment, the average volume of fibrinogen (FIB), D dimer and platelets of the patients in the two groups decreased (P<0.05), and the combined group was lower than the control group (P<0.05). After treatment, UACR, CysC, β2-MG and α1-MG of patients decreased in the two groups (P<0.05), and the combined group was lower than the control group (P<0.05). After treatment, renin and angiotensin Ⅱ of patients decreased in both groups (P<0.05). TNF-α of patients in both groups decreased after treatment (P<0.05), and the combined group was lower than the control group (P<0.05). In conclusion, compared with alprostadil, BPS combined with alprostadil can effectively improve hemodynamics, coagulation function and renal function of DN patients, and inhibit expression of RAS-related factors and TNF-α, which is a more effective method for DN treatment.

Introduction

With the rising incidence rate of diabetes, the risk of morbidity and the occurrence of diabetes complications increases dramatically (1). Diabetic nephropathy (DN) is one of the serious microvascular complications of diabetes, accounting for approximately 40% of end-stage renal disease, second only to tubal nephritis (2,3). At present, the commonly used treatment methods mainly include controlling blood sugar, maintaining blood pressure and inhibiting renin angiotensin system (RAS). Due to the complicated pathogenesis of DN, there is no clinical method to completely treat DN. Although the occurrence of DN can be delayed, its development still cannot be prevented or reversed (4). DN is an inflammatory disease, therefore anti-inflammation is one of the keys to control the disease. Inflammatory cytokines are closely related to the disease process of DN. Inhibition of TNF-α expressions has been proved to have protective effects on the kidneys (5,6). Finding more effective drugs or treatments is a top priority.

Beraprost sodium (BPS) is an oral prostacyclin derivative, which has good antiplatelet aggregation, vasodilation and antioxidant activities. It can inhibit the proliferation of vascular smooth muscle cells and the production of inflammatory cytokines, increase blood flow, effectively improve microcirculation and increase erythrocyte deformation (7,8). Some studies have shown that BPS can effectively repair renal microvasculature and reduce renal interstitial fibrosis, inhibit local RAS key factors, angiotensin II receptor 1, angiotensin converting enzyme, angiotensinogen, promote expression of angiotensin II receptor 2, and delay the development of chronic renal failure (9,10). Alprostadil can increase the intimal blood flow of body nerve cells, dilate blood vessels and reduce the resistance of peripheral blood vessels. Moreover, alprostadil can inhibit platelet aggregation, effectively improve renal blood flow and reduce proteinuria (11,12). BPS and alprostadil have both been reported to treat DN (13,14), but there are few related studies on the combination of BPS and alprostadil, and its efficacy still needs further verification.

Therefore, the aim of this study was to provide references for clinical treatment of DN by investigating the efficacy of BPS combined with alprostadil on DN and its influence on renin angiotensin system and TNF-α.

Patients and methods

Study subjects

A total of 102 patients with type 2 diabetic kidney disease who were admitted to Weifang People's Hospital (Weifang, China) from July 2017 to January 2019, aged 40–60 years were studied. Based on whether alprostadil combined with BPS was the drug treatment, patients were divided into two groups. A total of 50 patients with alprostadil treatment were the control group and 52 patients with alprostadil combined with BPS were the combined group. Inclusion criteria: All the patients met the WHO 1999 diagnostic criteria for type 2 diabetic nephropathy (15) and were diagnosed as DN patients for the first time. The patients' urinary albumin/creatinine was ≥30 mg/mmol or ≤300 mg/mmol, and the urea nitrogen and creatinine indicators were within the normal range. Relevant treatments were not performed before serum samples were obtained, and clinical data of patients were complete. Exclusion criteria: Patients with renal failure, kidney stones and a medical history of digestive system diseases in active phase, adrenocortical hyperfunction, abnormal liver and heart-lung functions; pregnant women or breast-feeding patients; patients with mental diseases or abnormal brain judgment.

This study was approved by the Medical Ethics Committee of Weifang People's Hospital. Patients who participated in this research had complete clinical data. The signed informed consents were obtained from the patients or the guardians.

Treatment methods

All patients had a low-salt and low-fat diet, and according to their own blood glucose levels and kidney damage, all patients were treated with conventional drugs: oral administration of gliguidone or subcutaneous injection of insulin; administration of 100 mg/day aspirin (H31021877, Shanghai Baolong Pharmaceutical Co., Ltd.), 20 mg/day simvastatin (H20030207, Jingxin Pharmaceutical Co., Ltd.). Patients in control group were treated with 10 µg alprostadil + 50 ml normal saline intravenous drip for the first 2 weeks, once a day, and the administration was stopped after 2 weeks. Only conventional treatments were performed for the second 2 weeks. Patients in combined group were treated with the same drugs as the control groups for two weeks, then the administration of alprostadil was stopped. Combined with the conventional treatment, BPS was administered orally, 40 µg/time, twice a day.

Observation indicators

Related indexes of fasting blood glucose (blood glucose detector, Jinan Hanfang Medical Devices Co., Ltd.), hemorheology (automatic blood hemorheology analyzer, Jinan Gelite Technology Co., Ltd.), coagulation function (full automatic hemagglutination analyzer, Sysmex), renal function and 24 h urinary protein (Upro) (full automatic biochemical analyzer, Beckman Olympus), renin angiotensin system (full automatic chemiluminescence instrument, Wuhan Mingde Biotechnology Co., Ltd.), and changes of TNF-α (ELISA) were observed before and after treatment, and the occurrence of adverse reactions of patients in the two groups were recorded. TNF-α and ELISA kit were purchased from Diken (Shanghai) Trading Co., Ltd., article number: BE45471.

Statistical analysis

SPSS 19.0 (SPSS, Inc.) was used. The measurement data were expressed by n(%), and the comparison of rates between the two groups was performed by χ2 test. Enumeration data were expressed by mean ± SD. Comparison between the two groups was conducted by independent-samples t-test, and the comparison before and after treatment was conducted by paired-samples t-test. P<0.05 was considered as statistically significant.

Results

General information

There were 50 patients in the control group, including 35 males (70.00%), 15 females (30%), aged 52.38±9.36 years, and 52 patients in combined group, including 34 males (65.38%), 18 females (34.62%), aged 53.15±10.14 years. There was no significant difference in sex ratio and age of patients between the two groups (P>0.05), and there was no significant difference in BMI and other data of patients between the two groups (P>0.05) (Table I).

Table I.

Comparison of clinical data of patients between the two groups [n (%)] (mean ± SD).

Table I.

Comparison of clinical data of patients between the two groups [n (%)] (mean ± SD).

FactorsControl group (n=50)Joint group (n=52)χ2/t valueP-value
Sex 0.2480.618
  Male35 (70.00)34 (65.38)
  Female15 (30.00)18 (34.62)
Age (years)52.38±9.3653.15±10.140.3980.914
BMI (kg/m2)23.82±3.4124.16±4.140.4520.652
Course of diabetes (years)10.45±5.6210.29±5.810.1410.888
Retinopathy 1.1780.758
  No30 (60.00)29 (55.77)
  Simple type17 (34.00)17 (32.69)
  Maculopathy1 (2.00)3 (5.77)
  Proliferation2 (4.0)3 (5.77)
History of cardiovascular disease 0.8370.975
  Myocardial infarction12 (24.00)15 (28.85)
  Coronary artery disease3 (6.00)2 (3.85)
  Peripheral arterial disease3 (6.00)3 (5.77)
  Venous insufficiency4 (8.00)3 (5.77)
  Stroke or transient ischemic stroke2 (4.00)3 (5.77)
  Unknown26 (52.00)26 (50.00)
Glycosylated hemoglobin (%)7.06±1.587.17±1.650.3440.732
Smoking 1.9120.167
  Yes22 (44.00)30 (57.69)
  No28 (56.00)22 (42.31)
Analysis of complications of patients after treatment in the two groups

There were no significant adverse reactions in the groups, but mild adverse reactions still occurred. In the control group, there were 2 cases of mild vascular pain, 3 cases of mild nausea, 4 cases of diarrhea, and 5 cases of mild headache. The total adverse rate was 28.00%. In the combined group, there were 1 case of mild vascular pain, 1 case of mild nausea, 2 cases of diarrhea, and 2 cases of mild headache. The total adverse rate was 11.54%. There was a significant difference in the total adverse rate between the two groups (P<0.05) (Table II).

Table II.

Complications of patients after treatment in the two groups.

Table II.

Complications of patients after treatment in the two groups.

ComplicationsControl group (n=50)Combined group (n=52)t valueP-value
Vascular pain
  Mild pain2 (4.00)1 (1.92)0.3640.618
  Severe pain00
Nausea
  Mild nausea3 (6.00)1 (1.92)1.1240.358
  Severe nausea00
Diarrhea
  Mild diarrhea4 (8.00)2 (3.85)0.7940.432
  Severe diarrhea00
Headache
  Mild headache5 (10.00)2 (3.85)1.5100.265
  Severe headache00
Total adverse rate14 (28.00)6 (11.54)4.3820.047
Changes of blood glucose after treatment of patients in the two groups

Blood glucose levels of patients in control group before and after treatment were 7.02±0.42 mmol/l and 6.03±1.22 mmol/l, respectively, while blood glucose levels of patients in combined group before and after treatment were 6.99±0.46 mmol/l and 6.09±1.13 mmol/l, respectively. There was no statistical difference in fasting blood glucose of patients between the two groups before and after treatment (P>0.05), but the fasting blood glucose of patients in the two groups after treatment was lower than that before treatment (P<0.05) (Fig. 1).

Hemorheological changes of patients in the two groups after treatment

Before treatment, there was no difference in blood viscosity, plasma viscosity and erythrocyte deformation exponent of patients between the two groups (P>0.05). After treatment, blood viscosity, plasma viscosity and erythrocyte deformation exponent of patients between the two groups decreased (P<0.05), and the combined group was lower than the control group (P<0.05) (Table III).

Table III.

Hemorheological changes of patients after treatment in the two groups.

Table III.

Hemorheological changes of patients after treatment in the two groups.

Hemorheological changesControl group (n=50)Joint group (n=52)t valueP-value
Blood viscosity (m/pas)
  Before treatment21.03±2.2120.96±2.180.6160.842
  After treatment 13.52±2.65a 11.67±2.53a3.6070.001
Plasma viscosity (m/pas)
  Before treatment3.75±0.523.71±0.540.3810.704
  After treatment 2.11±0.71a 1.82±0.47a2.4410.016
Erythrocyte deformation exponent
  Before treatment8.68±1.478.66±1.530.0670.947
  After treatment 6.08±2.12a 4.05±2.24a4.697<0.001

a P<0.05, compared with the same group before treatment.

Changes of coagulation function of patients after treatment in the two groups

There was no difference in the average volume of plasma fibrinogen (FIB), D dimer and platelet of patients between the two groups before treatment (P>0.05). After treatment, the average volume of FIB, D dimer and platelet of patients in the two groups decreased (P<0.05), and the combined group was lower than the control group (P<0.05) (Table IV).

Table IV.

Changes of coagulation function of patients after treatment in the two groups.

Table IV.

Changes of coagulation function of patients after treatment in the two groups.

Coagulation function changesControl group (n=50)Joint group (n=52)t valueP-value
FIB (g/l)
  Before treatment5.12±0.825.15±0.710.1980.844
  After treatment 4.88±0.61a 4.54±0.67a2.6770.009
D dimer (µg/l)
  Before treatment1.86±0.641.84±0.820.1370.891
  After treatment 1.91±0.64a 1.37±0.77a3.844<0.001
Average platelet volume (fl)
  Before treatment12.24±1.9512.25±1.880.0260.979
  After treatment 10.93±1.92a 9.72±1.12a3.906<0.001

a P<0.05, compared with the same group before treatment. FIB, fibrinogen.

Changes of renal function of patients after treatment in the two groups

There was no difference in UACR, CysC, β2-MG and α1-MG of patients between the two groups before treatment (P>0.05). After treatment, UACR, CysC, β2-MG and α1-MG of patients decreased in the two groups (P<0.05), and the combined group was lower than the control group (P<0.05) (Table V).

Table V.

Changes of renal function of patients after treatment in the two groups.

Table V.

Changes of renal function of patients after treatment in the two groups.

Renal function changesControl group (n=50)Joint group (n=52)t valueP-value
UACR (µmol/l)
  Before treatment31.11±4.1329.96±3.37   1.5440.126
  After treatment 19.73±2.42a 12.12±1.88a17.775<0.001
CysC (mg/l)
  Before treatment2.21±0.342.27±0.37   0.8520.396
  After treatment 1.53±0.21a 0.93±0.22a14.079<0.001
β2-MG (mg/l)
  Before treatment3.92±0.613.93±0.51   0.0900.929
  After treatment 2.84±0.47a 1.93±0.36a11.004<0.001
α1-MG (mg/l)
  Before treatment16.23±2.1416.37±2.27   0.3200.750
  After treatment 12.74±1.82a 8.43±1.18a14.246<0.001
Upro (mg/day)
  Before treatment132.52±8.97130.64±7.61   1.1430.256
  After treatment62.14±6.3958.68±5.91   2.8410.006

a P<0.05, compared with the same group before treatment. UACR, urine protein creatinine ratio; CysC, plasma cystatin C; β 2-MG, β 2 microglobulin; α1-MG, urine α1 microglobulin.

Changes of related indexes of renin angiotensin system of patients after treatment in the two groups

Before treatment, there was no difference in renin and angiotensin II of patients between the two groups (P>0.05). After treatment, renin and angiotensin II of patients decreased in both groups (P<0.05), and the combined group was lower than the control group (P<0.05) (Table VI).

Table VI.

Changes of related indexes of renin angiotensin system of patients after treatment in the two groups.

Table VI.

Changes of related indexes of renin angiotensin system of patients after treatment in the two groups.

Related index changesControl group (n=50)Joint group (n=52)t valueP-value
Renin (pg/ml)
  Before treatment21.15±4.2621.24±4.330.1060.916
  After treatment 17.26±5.13a 13.41±3.79a4.323<0.001
Angiotensin II (pg/ml)
  Before treatment261.42±53.88275.73±54.611.3320.186
  After treatment 217.79±58.68a 157.27±40.79a6.068<0.001
ACE (U/l)
  Before treatment62.25±6.7163.94±7.581.1910.237
  After treatment45.62±5.4142.87±4.732.7360.007

a P<0.05, compared with the same group before treatment. ACE, angiotensin converting enzyme.

Changes of TNF-α after treatment in the two groups. Levels of TNF-α before and after treatment of patients in control group were 26.63±4.73 ng/l and 17.74±3.35 ng/l, respectively, while levels of TNF-α before and after treatment of patients in combined group were 26.14±4.68 ng/l and 11.54±2.17 ng/l, respectively. There was no difference in TNF-α of patients between the two groups before treatment (P>0.05). Levels of TNF-α of patients in the two groups decreased after treatment (P<0.05), and levels in combined group were lower than those in control group (P<0.05) (Fig. 2).

Discussion

The morbidity of diabetes is expected to increase to 7.7% in the world by 2030 (16). About one third of diabetic patients will be affected by DN. DN has become the main cause of end-stage renal disease in developed countries, with extremely high morbidity and mortality among diabetic patients (17,18). At present, there is no cure for DN. It is necessary to find the best treatment scheme to delay the development of early DN. This study analyzed therapeutic effects of BPS combined with alprostadil in DN and its influences on renin angiotensin system and TNF-α, providing theoretical reference for clinical treatment.

BPS and alprostadil have both been reported for the treatment of DN. BPS is reported to be used in combination with RAS inhibitor to effectively prevent the progress of DN (19). Alprostadil can improve renal blood supply of DN patients, effectively delay the occurrence of fibrosis and protect renal function (20), but reports of combined application of the two in DN are few. Mathiesen et al (21) reported that BPS combined with alprostadil can protect renal function of DN patients, reduce proteinuria, improve glomerular filtration function and microcirculation disturbance, and inhibit platelet activation. BPS combined with alprostadil in the treatment of chronic renal failure has also been reported indicating that this treatment method can improve glomerular filtration rate, reduce urinary albumin excretion rate, slow down the increase of serum creatinine, reduce levels of FIB and D-dimer, thus delaying the progress of chronic renal failure caused by chronic glomerulonephritis, and with good safety (22). Results of the present study show that BPS combined with alprostadil can more effectively inhibit platelet and repair glomerular filtration, thereby improving hemodynamics, coagulation and renal function in patients with DN, which are similar to the previously reported results (21,22), and effects of combination and alprostadil alone on blood glucose are similar. At present, there is no study confirming that BPS or alprostadil can affect glucose metabolism in human body. Our study found no adverse reaction of patients in the two groups, which may be related to the duration of the treatment. Based on the above results, BPS combined with alprostadil has better efficacy on DN, and will not increase the occurrence of adverse reactions in the short-term.

RAS exists in the circulatory system and is a humoral regulation system composed of hormones and enzymes, mainly including renin and angiotensin. It is of great significance to maintain the balance of body blood pressure, water, electrolyte and the stability of internal environment (23,24). Our results show that BPS combined with alprostadil has another advantage in that it can effectively inhibit RAS, which is of great significance for maintaining the blood pressure of patients. In 1979, alprostadil was found to inhibit renin-angiotensin-aldosterone system (25). In subsequent studies, BPS derivative of alprostadil was also found to inhibit expression of RAS-related factors in mice, thus delaying the development of chronic renal failure (8), but influences of alprostadil on RAS are still uncertain.

Changes of TNF-α after treatment were analyzed. TNF-α changes glomerular hemodynamics and promotes the increase of vascular endothelial permeability. It can also promote infiltration of inflammatory cells, new formation of extracellular matrix, production of reactive oxygen species and blood flow disorders. Moreover, overexpression levels of TNF-α are closely related to the occurrence of proteinuria (26,27). Collectively, the evidence suggests that TNF-α plays an important role in the pathogenesis of DN. It is also suggested that improving TNF-α level is important for treating DN. Our results show that BPS combined with alprostadil can reduce TNF-α level in patients' peripheral blood more effectively. In other disease-related studies, alprostadil has been shown to reduce TNF-α level in patients' serum and urinary protein is also reduced. Previous studies (28,29) have shown that BPS and alprostadil can reduce the level of TNF-α and achieve protection for the human body. In blood glucose metabolism, insulin activates glucose transporter 4 (GLUT4) translocation to the cell membrane to reduce blood glucose levels (30), while AKT phosphorylation promotes the translocation of GLUT4 and down-regulates TNF-α (31). Prostaglandins promote AKT phosphorylation (32), while BPS promotes AKT expression (10). Therefore, BPS combined with proproterol in the treatment of renal injury can control blood glucose levels by activating AKT and inhibit TNF-α-induced apoptosis and autophagy.

However, because this study is a prospective analysis, there will inevitably be some selectivity bias and Hawthorne effect. Thus, further study is required. A multi-center clinical randomized controlled study will be conducted in the future. The analysis on safety still needs to be verified, but we will continue to track patients and record their future changes.

Compared with alprostadil therapy, BPS combined with alprostadil can more effectively improve hemodynamics, coagulation function and renal function of DN patients, and inhibit expression of RAS related factors and TNF-α, which is a more effective method to treat DN.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

Authors' contributions

XX wrote the manuscript, analyzed and interpreted the patient general data. XP performed chemiluminescence and ELISA. SL was responsible for the analysis of observation indicators. All the authors read and approved the final manuscript.

Ethics approval and consent to participate

This study was approved by the Medical Ethics Committee of Weifang People's Hospital (Weifang, China). Patients who participated in this research had complete clinical data. The signed informed consents were obtained from the patients or the guardians.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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January 2020
Volume 19 Issue 1

Print ISSN: 1792-0981
Online ISSN:1792-1015

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APA
Xu, X., Pan, X., & Li, S. (2020). Prospective analysis of the efficacy of beraprost sodium combined with alprostadil on diabetic nephropathy and influence on rennin-angiotensin system and TNF-α. Experimental and Therapeutic Medicine, 19, 639-645. https://doi.org/10.3892/etm.2019.8265
MLA
Xu, X., Pan, X., Li, S."Prospective analysis of the efficacy of beraprost sodium combined with alprostadil on diabetic nephropathy and influence on rennin-angiotensin system and TNF-α". Experimental and Therapeutic Medicine 19.1 (2020): 639-645.
Chicago
Xu, X., Pan, X., Li, S."Prospective analysis of the efficacy of beraprost sodium combined with alprostadil on diabetic nephropathy and influence on rennin-angiotensin system and TNF-α". Experimental and Therapeutic Medicine 19, no. 1 (2020): 639-645. https://doi.org/10.3892/etm.2019.8265