Yunpiqiangshen gel (运脾强肾浸膏) improves quality of life in dialysis patients

Abstract

OBJECTIVE:

To evaluate the efficacy and safety of Yunpiqiangshen gel (运脾强肾浸膏) which composed of eleven herbs on quality of life (QOL) improvement.

METHODS:

We enrolled 180 patients lasted from January 2020 to December 2021. Seventy-eight patients received standards of care (control group) and 76 patients received Yunpiqiangshen gel [Traditional Chinese Medicine, (TCM) group] for 6 months in statistical analysis. The primary outcome assessed using Kidney Disease Quality of Life Short Form Questionnaire version 1.3 (KDQOL-SF^TM 1.3), including Short Form Health Survey (SF-36) and Kidney Disease Targeted Areas (KDTA) scores. The second outcomes included the TCM syndrome score, Fatigue Assessment Instrument (FAI) score, Modified Quantitative Subjective Global Assessment (MQSGA) score, anthropometric indicators, and blood chemical testing. Adverse events, including decompensated gastrointestinal symptoms, were evaluated.

RESULTS:

The results showed that the mean change of SF-36 (75 ± 13 vs 64 ± 16, F = 6.070, P = 0.015) and KDTA (76 ± 7 vs 70 ± 9, F = 4.118, P = 0.044) scores in the TCM group had an improvement (increase) from baseline, as compared with the control group. Yunpiqiangshen gel also resulted in a significant improvement in almost dimensions of QOL. At the end of follow-up, the imputed percentage of patients in the response rate of TCM syndrome was greater in the TCM group than in the control group (76.32% vs 20.51%, χ ² = 48.02, P = 0.000). The fatigue, soreness of waist, anorexia, abdominal distension, loose stool, and constipation were alleviated after Yunpiqiangshen gel therapy. The FAI (98.58 ± 25.08 vs 131.21 ± 31.85, F = 8.745, P = 0.004) and MQSGA (10.13 ± 2.84 vs 12.83 ± 3.85, F = 11.396, P = 0.001) scores in the TCM group had an improvement (reduce) from baseline compared with the control group. A higher level of albumin of patients in the TCM group compared with the control group. Diarrhea, vomit, and loose stool were more common in the TCM group, but generally mild in severity.

CONCLUSION:

Compared with the standards of care, added Yunpiqiangshen gel was a safe and effective therapy for improving QOL in dialysis patients.

1. INTRODUCTION

Long-term complications of end stage renal disease (ESRD)-associated dialysis account for most illness, deaths and quality of life (QOL). QOL is important to patients receiving dialysis and for their care families. The core consequences of dialysis patients are maintenance of life participation activities and psychological state. For the moment, QOL associated with dialysis mainly include fatigue, malnutrition, insomnia, pruritus, microinflammatory and gastrointestinal discomfort symptoms. Clinical studies have shown that some Chinese medicine have beneficial effects with respect to chronic renal disease (CKD), largely in participants with gastrointestinal discomfort, whereas other medications have shown to have neutral effects.¹

Yunpiqiangshen gel (运脾强肾浸膏) is an oral traditional Chinese prescription suitable for dialysis patients due to their limit of liquid intake. It is composed of eleven Chinese herbs including Huangqi (Radix Astragali Mongolici), Dangshen (Radix Codonopsis), Baizhu (Rhizoma Atractylodis Macrocephalae), Fuling (Poria), Maiya (Fructus Hordei Germinatus), Jineijin (Endothelium Coreneum Gigeriae Galli), Duzhong (Cortex Eucommiae), Tusizi (Semen Cuscutae), Jixuecao (Herba Centellae Asiaticae), Qiannianjian (Rhizoma Homalomenae), and Luxiancao (Herba Pyrolae Callianthae). Our previous studies showed that Yunpiqiangshen formula improved the QOL-associated laboratory tests, appetite, and residual renal function in peritoneal dialysis patients.² Modern clinical studies also confirmed the importance of QOL on dialysis patients and potentials for prognosis in the ESRD.³ The present study aimed to evaluate the efficacy and safety of Yunpiqiangshen gel on ESRD manifestations and QOL improvement, using a multicenter and prospective design.

2. MATERIALS AND METHODS

2.1. Patients

This is a multicenter and prospective study, which conducted by Affiliated Hospital of Nanjing University of Chinese Medicine, Zhangjiagang Hospital of Chinese Medicine, and Jiangsu Province Hospital of Integration of Chinese and Western Medicine from January 2020 to December 2021. One hundred and eighty participants were assessed according to the sample size estimation formula on CKD. All of them were received maintenance hemodialysis (HD) or peritoneal dialysis (PD) treatment.

2.2. Traditional Chinese Medicine Yunpiqiangshen gel

The prescription of Yunpiqiangshen is composed of eleven Chinese herbs including Huangqi (Radix Astragali Mongolici), Dangshen (Radix Codonopsis), Baizhu (Rhizoma Atractylodis Macrocephalae), Fuling (Poria), Maiya (Fructus Hordei Germinatus), Jineijin (Endothelium Coreneum Gigeriae Galli), Duzhong (Cortex Eucommiae), Tusizi (Semen Cuscutae), Jixuecao (Herba Centellae Asiaticae), Qiannianjian (Rhizoma Homalomenae), and Luxiancao (Herba Pyrolae Callianthae). These herbs were mixed with dextrin (gel) that after boiled, filtrated, concentrated, sterilized, and finally became the Yunpiqiangshen gel. The weight of each package of Yunpiqiangshen gel is 25 g which containing 81 g Chinese herbs.

2.3. Ethical permission

The study was approved by Ethics Committee of Nanjing University of Chinese Medicine, the registration number is 2019NL-173-02.

2.4. Diagnostic criteria

Inclusion criteria were: (a) patients aged ≥ 18 years; (b) satisfied the diagnostic criteria for CKD5 and received dialysis more than 3 months; (c) satisfied the TCM syndromes for spleen and kidney Qi deficiency, and wet muddy.

Exclusion criteria were: (a) serious primary heart, liver, lung, or other malignant diseases that would affect their survival and QOL; (b) serious infection; (c) mentally disabled; (d) known allergies to the ingredients of Yunpiqiangshen gel.

2.5. Sample size estimation

The sample-size calculation in this study was based on 1:1 comparison principle. According to the prevalence and treatment target rates, the formula: n = (Uα + Uβ)²2P(1-P)/(P1-P0)² was used. In this study, the expulsion rate was designed to be 20%, the sample content required for each group was 90, and a total of 180 samples were required.

2.6. Study design and assessments

Eligible patients were assigned to receive standards of care, or Yunpiqiangshen gel based on standards of care for 6 months. Ninety participants in the control group were given standards of care, like hypertension, anemia, hyperuricemia, hyperlipidemia, calcium and phosphorus metabolism disorder therapy. Ninety participants in the TCM group were given herbal Yunpiqiangshen gel (25 g per packet, 2 packets per day) orally before or after meals twice a day. The Yunpiqiangshen gel prescriptions were composed of Huangqi (Radix Astragali Mongolici) 20 g, Dangshen (Radix Codonopsis) 12 g, Baizhu (Rhizoma Atractylodis Macrocephalae) 10 g, Fuling (Poria) 10 g, Maiya (Fructus Hordei Germinatus) 30 g, Jineijin (Endothelium Coreneum Gigeriae Galli) 10 g, Duzhong (Cortex Eucommiae) 10 g, Tusizi (Semen Cuscutae) 10 g, Jixuecao (Herba Centellae Asiaticae) 15 g, Qiannianjian (Rhizoma Homalomenae) 10 g, and Luxiancao (Herba Pyrolae Callianthae) 15 g. All medications in both groups were administered for 6 months.

During the 6 months, patients reported their status of QOL every 2 months using Kidney Disease Quality of Life Short Form Questionnaire version 1.3 (KDQOL-SF^TM 1.3), Fatigue Assessment Instrument (FAI), and Modified Quantitative Subjective Global Assessment (MQSGA). Anthropometric indicators including triceps skin fold (TSF), arm circumference (MAC), mid arm muscle circumference (MAMC), and grip were measured. TCM syndrome score and blood chemical testing were observed before and after treatment.

2.7. Efficacy outcomes

Primary outcome: the primary outcome of this study was the QOL of patients who had an improvement of 3 points from baseline at 6 months in the mean score on the KDQOL-SF^TM 1.3. This questionnaire incorporates 36 questions from the Short Form Health Survey (SF-36) and 12 items relating to Kidney Disease Targeted Areas (KDTA). The answers of patients to all items were calculated, producing the total score of the KDQOL-SF^TM 1.3 ranging from 0-100 with higher score indicating better QOL.

Secondary outcome: the secondary outcomes were the TCM syndrome score, FAI score, MQSGA score, anthropometric indicators, and blood chemical testing. FAI represents the fatigue of the patients, included changes of fatigue degree, environment, mentality and sleep. All of the items were calculated and higher score indicating severe fatigue. MQSGA represents the nutrition of the patients with higher score indicating worse nutrition. TSF, MAC, MAMC and grip were measured by thickness measurement with mean of three times. MAMC formula was calculated by MAC-3.14 × TSF. Blood chemical testing concludes hemoglobin, prealbumin, albumin, triglyceride, cholesterol, low-density lipoprotein cholesterol (LDL-C), transferrin, urea, creatinine, CO₂ combining power (CO₂CP), calcium, phosphate and parathyroid hormone (iPTH), using serum from patients.

2.8. Statistical analysis

Frequency and percentage were used to describe the uncontinuous variables. For comparisons between groups, categorical variables were analyzed using the χ² test. Quartitles and mean rank were used to describe the continuous variables. Categorical variables were analyzed using the Mann-Whitney U test for comparisons between groups, and Wilcoxon signed rank test for comparisons within groups. When measurement data follows normal distribution, the mean ± standard deviation ($\overline{x}\pm s$) was used to describe, categorical variables were analyzed using the t test. When measurement data does not follow normal distribution, M (P25, P75) was used to describe, categorical variables were analyzed using the non-parametric rank test. P value < 0.05 was considered statistically significant.

3. RESULT

3.1. Patient characteristics and baseline

A total of 180 patients were assessed in the present study between January 2020 and December 2021. All of patients were divided into control group and TCM group, with 90 cases (60 HD patients and 30 PD patients) in each group. Finally, 78 cases in control group and 76 cases in TCM group completed the study. Figure 1 showed the overview of the study. In control group, 1 case dropped due to transfer to HD and 11 cases dropped due to personal reasons. In TCM group, 9 cases dropped due to adverse event, 1 case dropped due to renal transplant, 1 case dropped due to accident, and 3 cases dropped due to personal reasons.

Figure 1. Overview of the trial.

PD: peritoneal dialysis; HD: hemodialysis; TCM: Traditional Chinese Medicine.

The demographic and baseline clinical characteristics of the patients are summarized in Table 1. At baseline, 57.7% of the patients were man. The prevalence of diabetes, coronary heart disease, cerebral infarction, anemia, hyperparathyroidism in control and TCM groups (23.08% and 19.74%, 8.97% and 6.58%, 12.82% and 14.47%, 35.90% and 42.11%, 20.51% and 15.79%, respectively) were lower than hypertension (89.74% and 93.42%). The blood chemical testing related to nutrition and renal function were presented as well. Besides urea, there were no statistically significant differences between two groups of patients in terms of age, gender, duration of dialysis, comorbidities, and other blood chemical testing.

Table 1.

Baseline demographics ($\overline{x}\pm s$)

Baseline demographics		Control (n = 78)	TCM (n = 76)
Age (years)		54.18±12.55	56.38±13.55
Male [n (%)]		45 (57.7)	48 (63.2)
Duration of dialysis (months)		53.88±50.00	47.54±52.20
Comorbidities [n (%)]	Hypertension	70 (89.74)	71 (93.42)
	Diabetes	18 (23.08)	15 (19.74)
	Coronary heart disease	7 (8.97)	5 (6.58)
	Cerebral infarction	10 (12.82)	11 (14.47)
	Anemia	28 (35.90)	32 (42.11)
	Hyperparathyroidism	16 (20.51)	12 (15.79)
Blood chemical testing	Hemoglobin (g/dL)	107.35±16.29	104.76±17.51
	Prealbumin (g/L)	237.70±105.20	247.31±103.24
	Albumin (g/L)	40.60±4.85	39.31±5.66
	Triglyceride (mmol/L)	2.05±1.36	1.75±1.04
	Cholesterol (mmol/L)	4.33±1.07	4.26±1.03
	LDL-C (mmol/L)	2.55±0.81	2.42±0.91
	Transferrin (ng/mL)	169.53±154.51	197.7±276.54
	Urea (mmol/L)	23.38±6.95	21.27±4.89
	Creatinine (μmol/L)	928.9±278.07	843.85±255.16
	CO2CP (mmol/L)	23.05±4.48	23.02±4.12
	Calcium (mmol/L)	2.48±0.29	2.43±0.27
	Phosphate (mmol/L)	1.71±0.52	1.65±0.44
	iPTH (pg/mL)	412.25±357.79	350.07±289.75
KDQOL-SF™ 1.3	SF-36	70.86±14.29	69.17±15.04
	Physical function	81.15±13.46	81.32±12.92
	Social function	70.67±19.52	67.93±22.10
	KDTA	71.75±9.73	70.61±9.40
	Symptom problem list	87.14±9.36	84.40±11.13
	Effects of kidney disease	71.59±15.37	71.83±16.34
	Burden of kidney disease	43.59±21.49	46.55±20.95
	Quality of social interaction	82.99±14.27	83.11±12.49
	Sleep	67.63±19.08	64.31±19.42
FAI		115.42±32.95	122.87±30.62
MQSGA		11.37±3.31	11.67±3.44
Anthropometry	TSF	12.54±2.95	11.76±2.79
	MAC	26.36±3.45	25.21±3.19
	MAMC	22.42±3.18	21.50±2.79
	Grip	26.03±8.43	26.49±8.95

Notes: control group: standards of care for 6 months; TCM group: Yunpiqiangshen gel treatment twice a day for 6 months. TCM: Traditional Chinese Medicine; LDL-C: low density lipoprotein; CO₂CP: CO₂ combining power; iPTH: parathyroid hormone; KDQOL-SF™ 1.3: kidney disease quality of life short form questionnaire version 1.3; SF-36: short form health survey; KDTA: kidney disease targeted areas; FAI: fatigue assessment instrument; MQSGA: modified quantitative subjective global assessment; TSF: triceps skin fold; MAC: arm circumference; MAMC: mid arm muscle circumference. Described as frequency and percentage, analyzed by χ ² test (male and comorbidities); described as mean ± standard deviation, analyzed by t test (other items).

The mean baseline SF-36 score was 70.86 ± 14.29 in control group and 69.17 ± 15.04 in TCM group, used to reflect general QOL. The KDTA score was assessed QOL associated with kidney disease, the mean of it was 71.75 ± 9.73 in control group and 70.61 ± 9.40 in TCM group. The mean baseline FAI score was 115.42 ± 32.95 (control group) and 122.87 ± 30.62 (TCM group). The mean base-line MQSGA score was 11.37 ± 3.31 (control group) and 11.67 ± 3.44 (TCM group). The mean baseline anthropometry including TSF, MAC, MAMC and grip were shown in the end of Table 1. There were no statistically significant differences between two groups of patients in terms of KDQOL-SF™ 1.3, FAI, MQSGA and anthropometry.

3.2. Primary outcome: Quality of life: KDQOL-SF^TM 1.3 scoring

Yunpiqiangshen gel resulted in significant improvements as compared with control group in the primary outcome. As shown in Table 2, at month 6, the QOL instrument who had an improvement (increase) of 2 points (months 2 and 6) from baseline on the SF-36 and KDTA scores were significantly greater in TCM group (P < 0.05). The TCM treatment effect was evident at month 2. In control group, the SF-36 and KDTA scores were reduced compared with that at baseline, and there was a significant difference (SF-36, P < 0.05) and no significant difference (KDTA, P > 0.05) before and after treatment. There was a significant difference between the two groups after treatment (P < 0.05).

Table 2.

Changes in patients with total SF-36 and KDTA score ($\overline{x}\pm s$)

Item	Group	Baseline	Month 2	Month 4	Month 6
SF-36	Control (n = 78)	71±14	70±15	67±14a	64±16a
	TCM (n = 76)	69±15	70±13a	73±11	75±13ab
KDTA	Control (n = 78)	72±10	71±9	71±9	70±9
	TCM (n = 76)	71±9	72±8a	73±7a	76±7ab

Notes: control group: standards of care for 6 months; TCM group: Yunpiqiangshen gel treatment twice a day for 6 months. TCM: Traditional Chinese Medicine; SF-36: short form health survey; KDTA: kidney disease targeted areas. Described as mean ± standard deviation, analyzed by t test. ^aP < 0.05, compared with baseline. ^bP < 0.05, compared with control group at month 6. SF-36 score, F = 6.070, P = 0.015; KDTA score, F = 4.118, P = 0.044.

As shown in Table 3, almost dimensions of QOL instrument showed significant improvement (increase) after Yunpiqiangshen gel therapy (P < 0.05). Between-group differences in favor of Yunpiqianghen gel, we observed for seven dimensions of QOL, including physical functioning, social function, symptom problem list, burden of kidney disease, effects of kidney disease, quality of social interaction, and sleep. The dimensions of QOL instrument in control group were reduced compared with that before treatment. There was a significant difference between the two groups before and after treatment, including “social function”, “symptom problem list”, “sleep” (P < 0.05).

Table 3.

Changes in patients with dimensions of QOL ($\overline{x}\pm s$)

Item	Group	Baseline	Month 2	Month 4	Month 6
Physical function	Control (n = 78)	81±13	80±15	81±15	80±15
	TCM (n = 76)	81±13	82±12	83±13a	84±15
Social function	Control (n = 78)	71±20	72±19	68±19	67±21
	TCM (n = 76)	68±22	70±18	69±18	73±16ab
Symptom problem list	Control (n = 78)	87±9	86±9	87±9	83±11a
	TCM (n = 76)	84±11	87±11a	89±9a	90±8ab
Burden of kidney disease	Control (n = 78)	44±21	45±23	43±21	42±20
	TCM (n = 76)	47±21	47±18	48±18	53±16a
Effects of kidney disease	Control (n = 78)	72±15	70±15	70±14	69±13
	TCM (n = 76)	72±16	73±13	75±13a	77±12a
Quality of social interaction	Control (n = 78)	83±14	82±15	81±13	80±11a
	TCM (n = 76)	83±12	84±11	83±13	84±13a
Sleep	Control (n = 78)	68±19	66±19	64±18a	63±19a
	TCM (n = 76)	64±19	66±16	71±14a	76±13ab

Notes: control group: standards of care for 6 months; TCM group: Yunpiqiangshen gel treatment twice a day for 6 months. TCM: Traditional Chinese Medicine. Described as mean ± standard deviation, analyzed by t test. ^aP < 0.05, compared with baseline. ^bP < 0.05, compared with control group at month 6. Physical function, F = 0.425, P = 0.515; social function, F = 5.032, P = 0.026; symptom problem list, F = 7.162, P = 0.008; burden of kidney disease, F = 3.685, P = 0.057; effects of kidney disease, F = 1.502, P = 0.222; quality of social interaction, F = 0.002, P = 0.967; sleep, F = 20.754, P = 0.000.

3.3. Secondary outcomes

3.3.1. TCM syndrome scoring

Yunpiqiangshen gel resulted in significant improvements as compares with control, in the TCM syndrome scores (Table 4). At month 6, the overall response rate of the TCM syndrome from baseline was greater in TCM group than in control group (76.32% vs 20.51%, P < 0.01). After Yunpiqiangshen gel treatment, the percentage of significant effect, valid, invalid were 28.95%, 47.37%, 23.68%, which had an effectivity on the TCM syndrome was better than control (P < 0.01). The mean change of total TCM syndrome score (4 ± 4 vs 8 ± 5, P < 0.01) in TCM group had an improvement from baseline, as compared with control group (8 ± 6 vs 6 ± 4, P > 0.05).

Table 4.

Response rate of the TCM syndrome [n (%)]

Item	Control (n = 78)	TCM (n = 76)	P value
Significant effect	4 (5.13)	22 (28.95)	< 0.01
Valid	12 (15.38)	36 (47.37)	< 0.01
Invalid	62 (79.49)	18 (23.68)	< 0.01
Overall response rate	16 (20.51)	58 (76.32)	< 0.01

Notes: control group: standards of care for 6 months; TCM group: Yunpiqiangshen gel treatment twice a day for 6 months. TCM: Traditional Chinese Medicine. Described as frequency and percentage, analyzed by χ ² test. Overall response rate: χ ² = 48.02, P = 0.000.

Several TCM syndromes including fatigue, soreness of waist, anorexia, abdominal distension, loose stool, and constipation were alleviated after Yunpiqiangshen gel treatment. At month 6, the percentage of patients who had symptoms in the TCM group were fewer. The change of TCM syndrome was greater in TCM group than in control group (P < 0.05) (Tables 5, 6).

Table 5.

Changes in TCM syndrome at 6 months compared with baseline

Syndrome	Group	Point	Rank mean	Statistic	P value
Fatigue	Control (n = 78)	Mon 6	15.00 (－)	－3.174	0.002
		Baseline	19.04 (+)
	TCM (n = 76)	Mon 6	18.48 (－)	－3.467	0.001
		Baseline	18.57 (+)
Soreness of waist	Control (n = 78)	Mon 6	12.45 (－)	－2.114	0.035
		Baseline	16.34 (+)
	TCM (n = 76)	Mon 6	15.30 (－)	－3.460	0.001
		Baseline	20.75 (+)
Anorexia	Control (n = 78)	Mon 6	16.33 (－)	－2.651	0.008
		Baseline	17.92 (+)
	TCM (n = 76)	Mon 6	11.74 (－)	－2.490	0.013
		Baseline	10.70 (+)
Abdominal distension	Control (n = 78)	Mon 6	10.21 (－)	－2.336	0.020
		Baseline	13.44 (+)
	TCM (n = 76)	Mon 6	8.80 (－)	－2.124	0.034
		Baseline	13.00 (+)
Loose stool	Control (n = 78)	Mon 6	8.50 (－)	－0.408	0.683
		Baseline	10.50 (+)
	TCM (n = 76)	Mon 6	8.79 (－)	－2.996	0.003
		Baseline	6.50 (+)
Constipation	Control (n = 78)	Mon 6	16.14 (－)	－2.604	0.009
		Baseline	15.30 (+)
	TCM (n = 76)	Mon 6	15.66 (－)	－4.759	0.000
		Baseline	11.00 (+)

Notes: control group: standards of care for 6 months; TCM group: Yunpiqiangshen gel treatment twice a day for 6 months. TCM: Traditional Chinese Medicine. Described as quartitles and mean rank, analyzed by Wilcoxon signed rank test. P < 0.05 means statistically significant.

Table 6.

Changes in TCM syndrome within two groups at month 6 [n (%)]

Syndrome		Control (n = 78)	TCM (n = 76)		Statistic	P value
Fatigue	Quartile	1 (75)	1 (25)	1 (50)	－4.113	0.000
	Rank mean	90.70	63.95
Soreness of waist	Quartile	1 (75)	0 (25)	1 (50)	－2.440	0.015
	Rank mean	85.45	69.34
Anorexia	Quartile	1 (75)	0 (25)	0 (50)	－4.671	0.000
	Rank mean	90.55	64.11
Abdominal distension	Quartile	1 (75)	0 (25)	0 (50)	－3.130	0.002
	Rank mean	85.95	68.83
Loose stool	Quartile	0 (75)	0 (25)	0 (50)	－2.824	0.005
	Rank mean	83.35	71.5
Constipation	Quartile	0.25 (75)	0 (25)	0 (50)	－4.867	0.000
	Rank mean	90.53	64.13

Notes: control group: standards of care for 6 months; TCM group: Yunpiqiangshen gel treatment twice a day for 6 months. TCM: Traditional Chinese Medicine. Described as quartiles and mean rank, analyzed by Mann-Whitney U test. P < 0.05 means statistically significant.

3.3.2. FAI scoring

At baseline, the mean of FAI score was 122.87 ± 30.62 (TCM group) and 115.42 ± 32.95 (control group). Yunpiqiangshen gel significantly improved (reduce) fatigue as compared with the control group as reported by the score on the FAI instrument, and there was a significant difference between TCM and control groups after treatment at month 6 (98.58 ± 25.08 vs 131.21 ± 31.85, F = 8.745, P = 0.004). The TCM treatment effect was evident at month 2 (113.86 ± 24.82) and month 4 (104.95 ± 23.81) within a significant difference (P < 0.05). In control group, the FAI score had an increase during treatment and there was a significant difference before and after treatment (P < 0.05).

3.3.3. MQSGA scoring

At baseline, the mean of MQSGA score was 11.67 ± 3.44 (TCM group) and 11.37 ± 3.31 (control group). MQSGA instrument showed the Yunpiqiangshen gel significantly improved (reduce) nutrition as compared with the control group before and after treatment at month 6 (10.13 ± 2.84 vs 12.83 ± 3.85, F = 11.396, P = 0.001). There was a significant difference in the TCM group between month 4 (10.72 ± 2.91) and baseline (P < 0.05). In control group, the MQSGA score had an increase during treatment and there was a significant difference before and after treatment (P < 0.05).

3.3.4. Indicators of anthropometry

After Yunpiqiangshen gel treatment, the anthropometry from baseline at month 6 in the TSF, MAC, MAMC and grip were more enhanced, and the differences were statistically significant (P < 0.05). We found these indicators were reduced or fewer change in control group after treatment, but still a significant difference in MAC and MAMC (P < 0.05). There was no significant difference between two groups before and after treatment (P > 0.05) (Table 7).

Table 7.

Changes in patients with indicators of anthropometry (cm, $\overline{x}\pm s$)

Item	Group	Baseline	Month 2	Month 4	Month 6
TSF	Control (n = 78)	12.5±3.0	12.5±2.8	12.3±2.7a	12.5±4.5
	TCM (n = 76)	11.8±2.8	12.1±3.1a	12.0±3.0a	12.1±2.6a
MAC	Control (n = 78)	26.3±3.5	26.2±3.3a	26.0±3.2a	25.8±3.2a
	TCM (n = 76)	25.2±3.2	25.4±2.8	25.5±3.1	25.8±2.7a
MAMC	Control (n = 78)	22.4±3.2	22.2±3.1a	22.1±3.0a	21.9±3.2a
	TCM (n = 76)	21.5±2.8	21.6±2.5	21.7±2.8	22.0±2.4a
Grip	Control (n = 78)	26.0±8.4	26.0±8.4	26.0±8.1	25.6±8.2
	TCM (n = 76)	26.5±9.0	27.0±8.8	27.4±8.8a	27.9±8.7a

Notes: control group: standards of care; TCM group: Yunpiqiangshen gel treatment twice a day. TCM: Traditional Chinese Medicine; TSF: triceps skin fold; MAC: arm circumference; MAMC: mid arm muscle circumference. Described as mean ± standard deviation, analyzed by t test. ^aP < 0.05, compared with baseline.

3.3.5. Indicators of blood chemical testing

Nutrition related laboratory tests, including hemoglobin, prealbumin, albumin, serum lipid, and renal function, were observed. A higher level of albumin of patients in TCM group had an increase after treatment at month 6 (P < 0.05). There were no substantial differences within other indicators between two groups (P > 0.05) (Table 8).

Table 8.

Changes in patients with indicators of blood chemical testing ($\overline{x}\pm s$)

Item	Group	Baseline	Month 6
Hemoglobin (g/dL)	Control (n = 78)	107.35±16.29	105.04±16.74
	TCM (n = 76)	104.76±17.51	105.57±16.46
Prealbumin (g/L)	Control (n = 78)	237.70±105.20	229.89±111.38
	TCM (n = 76)	247.31±103.24	241.95±101.76
Albumin (g/L)	Control (n = 78)	40.60±4.85	39.74±4.94
	TCM (n = 76)	39.31±5.66	40.98±4.80a
Triglyceride (mmol/L)	Control (n = 78)	2.05±1.36	2.15±1.67
	TCM (n = 76)	1.75±1.04	1.70±0.96
Cholesterol (mmol/L)	Control (n = 78)	4.33±1.07	4.38±1.21
	TCM (n = 76)	4.26±1.03	4.26±1.08
LDL-C (mmol/L)	Control (n = 78)	2.55±0.81	2.48±0.79
	TCM (n = 76)	2.42±0.91	2.40±0.82
Transferrin (ng/mL)	Control (n = 78)	169.53±154.51	167.87±167.16
	TCM (n = 76)	197.70±276.54	201.58±339.67
Urea (mmol/L)	Control (n = 78)	23.38±6.95	22.18±6.38
	TCM (n = 76)	21.27±4.89	27.14±5.11
Creatinine (μmol/L)	Control (n = 78)	928.9±278.07	941.45±285.5
	TCM (n = 76)	843.85±255.16	886.79±226.38
CO2CP (mmol/L)	Control (n = 78)	23.05±4.48	22.02±4.18
	TCM (n = 76)	23.02±4.12	21.97±3.72
Calcium (mmol/L)	Control (n = 78)	2.48±0.29	2.46±0.26
	TCM (n = 76)	2.43±0.27	2.40±0.28
Phosphate (mmol/L)	Control (n = 78)	1.71±0.52	1.78±0.57
	TCM (n = 76)	1.65±0.44	1.79±0.41
iPTH (pg/mL)	Control (n = 78)	412.25±357.79	382.08±404.65
	TCM (n = 76)	350.07±289.75	429.60±340.96

Notes: control group: standards of care for 6 months; TCM group: Yunpiqiangshen gel treatment twice a day for 6 months. TCM: Traditional Chinese Medicine; LDL-C: low density lipoprotein; CO₂CP: CO₂ combining power; iPTH: parathyroid hormone. Described as mean ± standard deviation, analyzed by t test. ^aP < 0.05, compared with baseline.

3.4. Adverse events

The overall incidence of adverse event was 13.3% in control group and 15.6% in TCM group. The most common adverse events in patients receiving Yunpiqiangshen gel were diarrhea, vomit, and loose stool; these events were generally mild in severity and resolved without clinical consequence. No serious adverse events occurred in this study. There were no substantial differences between the two groups (P > 0.05).

4. DISCUSSION

In the present study, Yunpiqiangshen gel led to significant improvement, as compared with standards of care, in QOL as assessed for the primary outcome. As well, secondary outcomes that included TCM syndrome score, FAI score, MQSGA score, anthropometric indicators, and blood chemical testing assessments favored Yunpiqiangshen over standards of care. No abnormal indicators of blood testing and fewer severe symptoms were found after Yunpiqiangshen gel intervention, demonstrating it has no obvious toxic side effects.

In the long-term dialysis treatment, dialysis adequacy, microinflammation, nutrition and mentality affect QOL of patients.^4,⇓-6 Poor QOL is characterized by some clinical manifestation, like fatigue, loss of appetite, insomnia, anemia, anxiety and irritability. For dialysis patients, improving their QOL is beneficial for maintaining a normal employment and lifestyle. Currently, the questionnaire is a commonly used disease perception scale to evaluate the variety of QOL as assessed for the primary outcome. The KDQOL-SF^TM 1.3 is a self-report measure developed for patients with renal disease or dialysis, including items that provide a measure of physical and mental health and renal disease-targeted items. Scores on the KDQOL-SF^TM 1.3 ranging from 0 to 100, with higher score indicating better dialysis-related QOL.⁷ In this study, we found that KDQOL-SF^TM 1.3 scores increased after 2 months therapy with Yunpiqiangshen gel compared to control.

In addition to KDQOL-SF^TM 1.3, FAI and MQSGA instruments are often beneficial to evaluate the QOL on dialysis patients. FAI instrument is evaluated to level of fatigue concluded physical fatigue and mental fatigue, with higher scores indicating more fatigue. MQSGA instrument is a used clinical method to evaluate the situation of nutrition through fat and muscle store, with lower scores indicating better nutrition. We found that FAI and MQSGA scores markedly decreased after Yunpiqiangshen gel therapy compared to standards of care. Patients in TCM group showed much more improvements on fatigue and nutrition at the end of treatment. In this study, we observed some TCM syndromes, especially those associated with gastro-intestinal reaction. After 6 months, the change of total TCM syndromes, as well as appetite and defecation, were greater in TCM group. Indicators of anthropometry were evaluated muscle mass and strength which due to protein synthesis and consumption. Clinical data has shown that TSF, MAC, MAMC and grip were more enhanced in TCM group, indicating that Yunpiqiangshen gel may contribute to protein synthesis and thus improve muscle function of arms. Moreover, serum biochemical indicators were detected to evaluate the therapeutic effect on nutrition and renal function. However, there were no significant differences before and after therapy within two groups, except albumin. In fact, albumin is reported more relevant to nutrition and protein synthesis.⁸ Therefore, our results indicated that Yunpiqiangshen gel might have an impact on the gastrointestinal recurrence and nutrition of dialysis patients.

The kidney being congenital origin, and the spleen being acquired foundation. The kidney Qi depends on cereal essence transformed by the spleen, meanwhile nutrition of water and food need kidney Yang. In dialysis patients, deficiency of spleen-Yang and kidney-Yang, and accumulated uremic toxins led them loss of appetite, nausea, vomit, constipation, even malnutrition.^9,10 Currently, invigorating kidney Yang, tonifying kidney Qi, and strengthening spleen Qi are important to improve QOL on dialysis patients. With the academic guidance of the Menghe Medical Sect, we use a gently and tonic therapy on spleen and kidney. The flavor of our prescription is mild, mainly uses Qi-invigorating and digestive drugs, to tonify kidney and bone. We made Yunpiqiangshen gel as a concentrated Chinese herbs decoction, with a bag of 25 g per package, because of water restriction in dialysis patients. Our previous observation showed Yunpiqiangshen decoction could relieve digestive and absorptive function, thus improve nutrition and QOL in peritoneal dialysis patients. As well, we found acupoint application within Yunpiqiangshen plaster was beneficial to relieve fatigue. As we known, tonifying kidney and activating blood circulation play a significant role in ESRD, deficiency of kidney Qi-Yin even kidney Yin-Yang could result in dialysis failure or death in theory of TCM. Here, we paid attentions to spleen and stomach, abnormal dysfunction of those transportation is mainly reflected in the appetite and nutrition. Enhanced spleen Qi has been approved to improve daily diet and essential nutrition. When spleen and stomach function improved, the dialysis patients are more easily increase protein intake and muscle mass, thus keeping normal physiological function and better QOL. Patients undergoing PD and HD are in two different states, and there are significant differences in TCM syndrome types. In this study, we enrolled dialysis patients within TCM syndrome type of spleen and kidney Qi deficiency, and wet muddy.

Dialysis treatment is one the most effective way to remove uremic toxin.¹¹ However, glucose, plasma electrolytes, protein and more benefit substances have been dialysed.¹² In terms of TCM, vital energy and nutrition essence were lost in process of dialysis. Deficiency of Qi and blood in most HD patients, which result in dysfunction of spleen and kidney. As well, during PD treatment, long-term retention of hyperglycemic peritoneal dialysis fluid in abdominal cavity make the spleen and stomach being stranded by dampness. Therefore, we proposed that enhancing the function of spleen, stomach and kidney is important to improve the QOL of dialysis patients. In accordance with TCM theory on treatment in ESRD, we mainly used Huangqi (Radix Astragali Mongolici), Dangshen (Radix Codonopsis), Baizhu (Rhizoma Atractylodis Macrocephalae), and Fuling (Poria) to tonify kidney-Qi, spleen-Qi and percolate dampness. Maiya (Fructus Hordei Germinatus) and Jineijin (Endothelium Coreneum Gigeriae Galli) were helpful to digest. Duzhong (Cortex Eucommiae) and Tusizi (Semen Cuscutae) effected on tonifying kidney kindly. Jixuecao (Herba Centellae Asiaticae) was used to activating blood circulation and detoxifying uremic toxins. Qiannianjian (Rhizoma Homalomenae) and Luxiancao (Herba Pyrolae Callianthae) worked on maintaining strong bones and collaterals. In this study, the appetite and muscle function were enhanced more by Yunpiqiangshen gel therapy, indicated that Chinese herbs have advantages in improving QOL. We found that this prescription is beneficial for TCM syndrome of spleen and kidney Qi deficiency, and wet muddy.

It is generally accepted that the pathophysiology of Yunpiqiangshen gel mainly involves microinflammation and nutrition response. Modern pharmacological studies have shown that the active Chinese herb ingredients have anti-inflammatory, immunomodulatory, bowel benefits, and bone mineral metabolism. The active components of Huangqi (Radix Astragali Mongolici), Astragalus polysaccharide or Astragaloside can inhibit the expression of inflammatory cytokine, NF-κB channel, production of nitric oxide, and regulate immune cells, thus contributing to its anti-inflammatory and immunomodulatory effects.¹³ Dangshen (Radix Codonopsis) and Baizhu (Rhizoma Atractylodis Macrocephalae) are beneficial for repair gastric mucosa and anti-ulcer.¹⁴ Studies have shown Fuling (Poria) effects on immunomodulatory activity through TLR4/TRAF6/NF-κB signaling both in vitro and in vivo.¹⁵ Maiya (Fructus Hordei Germinatus) and Jineijin (Endothelium Coreneum Gigeriae Galli) are mainly used for digestion and pain relief. These herbs could synergistically recover gastrointestinal disturbance in ESRD patients. Moreover, Duzhong (Cortex Eucommiae) and Qiannianjian (Rhizoma Homalomenae) have been found that promote the proliferation of bone marrow cells and differentiation into osteoblasts, thus preventing loss of bone during dialysis.^16,17 Studies indicated that Tusizi (Semen Cuscutae) is good at treat chronic nephritis and soreness in loin.¹⁸ Our previously study showed that Jixuecao (Herba Centellae Asiaticae) has anti-inflammation and antioxidant effects in high glucose induced peritoneal mesothelial cells.¹⁹ At present, we used Jixuecao (Herba Centellae Asiaticae) to relieve microinflammation in ESRD, expecting that extend the life of dialysis. As well, Luxiancao (Herba Pyrolae Callianthae) worked similar to Jixuecao (Herba Centellae Asiaticae), mainly contributing to anti-inflammation and protect the heart.²⁰

Our study first showed that TCM therapy improved QOL of dialysis patients which was characterized by increased total KDQOL-SF^TM 1.3 scores. Next, the scores of FAI and MQSGA were lower than baseline indicated that TCM therapy could improve dialysis related fatigue and malnutrition. Moreover, TCM therapy relieved several uncomfortable TCM syndromes due to regulating the functions of spleen and kidney. The improved indicators of anthropometry and albumin might be associated to better protein metabolism and muscle function. Finally, no abnormalities in blood chemical testing and serious adverse events were observed.

In conclusion，on the basis of standards of care, added Yunpiqiangshen gel for 6 months has good efficacy and safety for improving QOL of dialysis patients, within less adverse reactions. We identified the Yunpiqiangshen gel therapy is beneficial for improving dialysis related fatigue and malnutrition. As well, anthropometry and serum albumin were enhanced after Yunpiqiangshen gel treatment, compared with standards of care. However, the results need to be verified in large sample, longer follow-up time and randomized controlled clinical study. Our study may provide helpful TCM therapy for dialysis patients and potential methods for their renal rehabilitation.

Funding Statement

Supported by Jiangsu Science and Technology Development Project of Chinese Medicine: Yunpiqiangshen Improves Quality of Life in Dialysis Patients in Basis of Zou’s Theory of Kidney Disease (ZD201904), Jiangsu Province Hospital of Chinese Medicine Peak Talent Program: Study on Promotion of Rehabilitation of Dialysis Patients by Traditional Chinese Medicine (Y2021RC10), National Natural Science Foundation of China: Study of Astragalus on Peritoneum Function by Myostatin-mediated Protein Turnover of Skeletal Muscle Cells (82004295), Science and Technology Planning Project of Jiangsu Province: Mechanism Study of Astragalus on Peritoneal Fibrosis by Pyroptosis of Peritoneal Mesothelial Cell via Peritoneal Mesothelial Cell (BK20211393), Outstanding Young Doctor's Fund of Jiangsu Province Hospital of Chinese Medicine: Traditional Chinese Medicine Improves Quality of Life in Chronic Renal Disease (2023QB0133)