Clinical evaluation of strengthening spleen and draining dampness in the treatment of idiopathic membranous nephropathy: a retrospective 10-year follow-up study

Abstract

OBJECTIVE:

To evaluate the 10-year therapeutic efficacy of Traditional Chinese Medicine (TCM) using the Strengthening Spleen and Draining Dampness therapy in the management of idiopathic membranous nephropathy (IMN).

METHODS:

A single-center, retrospective analysis was conducted on patients diagnosed with IMN who met predefined inclusion and exclusion criteria. Data were collected from the Department of Nephrology at Longhua Hospital, affiliated with Shanghai University of Traditional Chinese Medicine, between January 2007 and December 2011. Clinical parameters including 24-h urinary protein, serum albumin, serum creatinine, and estimated glomerular filtration rate (eGFR, EPI) were assessed at baseline and at 1, 3, 5, and 10 years of follow-up. The efficacy of the Strengthening Spleen and Draining Dampness therapy was analyzed using repeated measures analysis of variance (ANOVA). Kaplan-Meier survival curves and multivariate proportional hazards model (Cox regression models) were employed to identify factors associated with treatment outcomes.

RESULTS:

A total of 265 patients were included, with a median follow-up duration of 96 months (36, 122). TCM treatment significantly reduced 24-h urinary protein levels (P < 0.001), and increased serum albumin levels (P < 0.001), while serum creatinine remained stable (P = 0.187). Remission rates at 1, 3, 5, and 10 years were 52.81%, 69.71%, 68.39%, and 72.36%, respectively, and the rates of avoiding composite outcome events at the same intervals were 98.27%, 94.29%, 94.19%, and 93.50%. In the subgroup receiving TCM only, remission rates were 56.67%, 84.44%, 76.32%, and 82.86%. For patients treated initially with Western Medicine followed by TCM, the rates were 52.83%, 65.85%, 67.47% and 67.75%. In the cohort of patients who received TCM as their first-line therapy, remission rates were 49.23%, 62.50%, 61.76%, and 69.23%. Multivariate Cox regression analysis revealed that the duration of TCM treatment [hazard ratio (HR) = 0.826, 95% confidence interval (CI) (0.779, 0.876), P < 0.001], presence of hypertension [HR = 1.912, 95% CI (1.181, 3.094), P = 0.008], baseline serum albumin level [HR = 0.930, 95% CI (0.894, 0.969), P < 0.001], and the rate of serum albumin increase within the first year of treatment [HR = 0.930, 95% CI (0.909, 0.957), P < 0.001] were significantly associated with clinical outcomes.

CONCLUSION:

The Strengthening Spleen and Draining Dampness therapy demonstrated robust short- and long-term efficacy in treating IMN, with high rates of remission and renal survival over 10 years. Key factors influencing clinical remission included the duration of TCM treatment, baseline serum albumin levels, the presence of hypertension, and the rate of increase in serum albumin within the first year. These findings suggest that this TCM approach provides a viable long-term treatment option for IMN.

1. INTRODUCTION

Idiopathic membranous nephropathy (IMN), a leading cause of nephrotic syndrome in adults, is an organ-specific autoimmune disorder whose incidence has significantly increased in recent years.^1,2 In China, the rise in IMN-related morbidity has outpaced that of other primary glomerular diseases.^1,2 The management of IMN remains a substantial clinical challenge as a result of its refractory nature. While immunosuppressive therapies (ISTs) have demonstrated considerable success, approximately one-third of patients exhibit resistance, dependence, or intolerance to these treatments or their associated adverse effects.^3,4 In recent years, rituximab has emerged as the preferred first-line therapy in IMN;^5-8 however, its high cost imposes a significant financial burden on patients.⁹

In China, the integration of Traditional Chinese Medicine (TCM) into treatment regimens is widely accepted, particularly among patients who experience unsatisfactory outcomes or cannot tolerate the adverse effects of immunotherapy.^10-12 For over two decades, our team has utilized TCM in the diagnosis and management of IMN. A previous one-year randomized controlled multicenter trial demonstrated that our clinical experience-based TCM regimen for membranous nephropathy (MN) produced therapeutic efficacy comparable to that of cyclophosphamide, with a superior safety profile.¹⁰ Given the protracted course of MN, it is critical to conduct long-term follow-up studies to comprehensively evaluate the sustained effects and determinants of TCM treatment. Therefore, we conducted a retrospective single-center 10-year follow-up study to assess the long-term effectiveness of TCM in IMN patients and to identify factors that may influence treatment outcomes.

2. METHODS

2.1. Study participants

This study employed a single-center retrospective analysis. The study cohort comprised all patients aged 18 to 80 years who were diagnosed with IMN through a combination of renal biopsy and clinical examination and who first presented at the Nephrology Department of Longhua Hospital, affiliated with Shanghai University of Traditional Chinese Medicine, between January 2007 and December 2011. Inclusion criteria required that patients received TCM treatment for a duration exceeding 12 months. Patients diagnosed with IMN concomitant with other pathological types were excluded from the analysis.

The study was approved by the institutional ethics committee (approval number: 2018LCSY008) and conducted in accordance with international regulatory standards, including the Declaration of Helsinki. Written informed consent was obtained from all participants prior to data collection. Clinical and laboratory data were collected at each patient’s scheduled follow-up visits, beginning with the initiation of TCM therapy and continuing through the final follow-up. At each follow-up, standard laboratory assessments were performed, including measurements of serum creatinine (via enzymatic assay), serum albumin (bromocresol green method), total cholesterol (glucose oxidase-peroxidase method), and 24-h urinary protein excretion. The estimated glomerular filtration rate (eGFR, mL/min per 1.73 m²) for each patient was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.

2.2. Treatment protocols

Patients were classified into three primary treatment groups based on their utilization of therapeutic interventions during the follow-up period: (a) TCM only, (b) initial treatment with Western Medicine (WM) failure, then received TCM, (c) a combination of TCM and WM. The detailed treatment protocols are as follows: TCM1: patients in this group received TCM treatment focusing on spleen strengthening and dampness drainage without prior exposure to conventional WM. TCM2: this group included patients who had received WM treatment for over 6 months, experienced treatment failure (defined as a 24-h urinary protein excretion of ≥ 3.5 g), and discontinued WM therapy for at least 6 months. Alternatively, it included patients who experienced relapse but were unwilling or unable to resume conventional WM. These patients subsequently received TCM therapy focused on spleen strengthening and dampness drainage at our center. TCM & WM: patients in this group received both TCM treatment (targeting spleen strengthening and dampness drainage) and conventional WM as initial treatment at our center.

All patients were administered a TCM decoction twice daily. Those in the combined treatment group also received conventional WM therapies, including glucocorticoids, immunosuppressants, and/or rituximab. Supportive care, consisting of a low-salt, high-quality protein diet, was provided to all patients. Additional treatments, such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, statins, and diuretics/anticoagulants, were prescribed as necessary. The TCM formula was prepared and supplied by the TCM Pharmacy at Longhua Hospital, affiliated with the Shanghai University of Traditional Chinese Medicine, and adjustments were made based on patient symptoms. The TCM regimen, designed to strengthen the spleen and drain dampness, comprised 12 Chinese herbs. The specific ingredients and dosage of the prescription are as follows (specific medication will be adjusted appropriately according to the changes in the condition): Huangqi (Radix Astragali Mongolici) 30 g, Shanyao (Rhizoma Dioscoreae Oppositae) 15 g, Dangshen (Radix Codonopsis) 30 g, Cangzhu (Rhizoma Atractylodis Lanceae) 15 g, Baizhu (Rhizoma Atractylodis Macrocephalae) 15 g, Fuling (Poria) 12 g, Zhuling (Polyporus) 12 g, Danggui (Radix Angelicae Sinensis) 15 g, Banzhilian (Herba Scutellariae Barbatae) 30 g, Baihuasheshecao (Herba Hedyotdis) 30 g, Jiangcan (Bombyx Batryticatus) 15 g, Yiyiren (Semen Coicis) 30 g.

2.3. Outcome measures

The primary outcome measures of this study included 24-h urinary protein excretion, serum albumin levels, and serum creatinine concentrations, which were assessed at 1, 3, 5, and 10 years post-treatment. Complete remission (CR) was defined as the maintenance of stable renal function, characterized by a serum creatinine change of ≤ 15% from baseline, proteinuria < 0.3 g/24 h, and serum albumin ≥ 35 g/L. Partial remission (PR) was defined as a reduction in proteinuria of ≥ 50% from baseline, with proteinuria levels ranging from 0.3 to 3.5 g/24 h, and serum albumin levels ≥ 30 g/L. Non-response was defined as the failure to achieve either CR or PR. Relapse was characterized by a proteinuria level > 3.5 g/24 h following at least 4 weeks of sustained CR or PR, or an increase of > 50% from the lowest urinary protein value post-treatment with TCM.¹³ The remission rate (%) was calculated as follows: (CR + PR) / total cases × 100.

Composite outcomes included a doubling of serum creatinine from baseline, the initiation of renal replacement therapy, including peritoneal dialysis, hemodialysis, or renal transplantation, and all-cause mortality. Treatment dropout was defined as discontinuation of TCM after 1 year with no subsequent follow-up.

2.4. Statistical analysis

Data analysis was conducted using IBM SPSS Statistics software (version 26.0; IBM, Armonk, NY, USA). Categorical variables are expressed as frequencies and percentages, while continuous variables with a normal distribution are reported as means ± standard deviations. Non-normally distributed data are presented as medians with interquartile ranges (25th, 75th percentiles). Changes in outcome measures over time were analyzed using repeated measures analysis of variance (ANOVA). The assumption of sphericity was tested using Mauchly’s test, and in cases where the assumption was violated, the Greenhouse-Geisser correction was applied to adjust the degrees of freedom and P-values. Post-hoc comparisons were performed using Fisher’s least significant difference method. Kaplan-Meier survival analysis was employed to plot composite outcome events, and the rates of these events were compared between groups. Cox proportional hazards regression was used to identify factors associated with IMN remission during TCM treatment. Variables included in the multivariate Cox regression model were selected based on univariate analysis and clinical relevance. A P value of < 0.05 was considered statistically significant.

3. RESULTS

3.1. Study participants and baseline characteristics

Between January 2007 and December 2011, a total of 393 patients with an initial diagnosis of IMN were identified at our institution. Following exclusion criteria, 128 patients were removed from the cohort, including 12 with secondary MN, eight patients with age mismatches, 65 patients with less than 1 year of TCM treatment, and 43 patients with less than 1 year of follow-up. Consequently, 265 patients [166 men (62.64%) and 99 women (37.36%); male-to-female ratio of 1.68 : 1] were deemed eligible for analysis. These patients were divided into three treatment groups: 66 patients in the TCM1 group, 128 patients in the TCM2 group, and 71 patients in the TCM&WM group. Of the latter group, 40 patients were undergoing immunosuppressive drug withdrawal at the time of initiating TCM, while 31 patients received a combination of TCM and immunosuppressive drugs at the beginning of treatment (Figure 1). The median follow-up duration was 96 (36, 122) months. Notably, patients in the TCM1 and TCM2 groups demonstrated higher rates of 10-year follow-up completion and superior treatment compliance compared with the TCM & WM group. The average age of the cohort was (53 ± 14) years, with 67 patients (25.28%) aged 18-44 years, 90 patients (33.96%) aged 45-59 years, and 108 patients (40.76%) aged 60-80 years. The cohort presented with several comorbidities, including hypertension in 149 patients (56.23%), type 2 diabetes mellitus in 48 patients (18.11%), impaired glucose tolerance in one patient (0.38%), and coronary atherosclerosis in 19 patients (7.17%).

Figure 1. Follow-up flow chart.

TCM1: patients in this group received TCM treatment focusing on spleen strengthening and dampness drainage without prior exposure to conventional WM. TCM2: this group included patients who had received WM treatment, experienced treatment failure, and discontinued WM therapy for at least 6 months. Alternatively, it included patients who experienced relapse but were unwilling or unable to resume conventional WM. These patients subsequently received TCM therapy focused on spleen strengthening and dampness drainage at our center. TCM&WM: patients in this group received both TCM treatment and conventional WM as initial treatment at our center. TCM: Traditional Chinese Medicine; WM: Western Medicine; SMN: Secondary membranous nephropathy.

3.2. Laboratory indicators

In the overall cohort, a significant reduction in 24-h urinary protein levels was observed during the follow-up period when compared with baseline (F = 14.294, P < 0.001). Separate comparisons at each follow-up point (1, 3, 5, and 10 years) revealed consistent and significant reductions in 24-h urinary protein levels relative to baseline (all P < 0.001). Additionally, serum albumin levels increased significantly from baseline across the follow-up period (F = 11.999, P < 0.001), with sustained elevations at 1, 3, 5, and 10 years of follow-up (all P < 0.001). In contrast, serum creatinine levels remained stable over time (F = 1.771, P = 0.187), with no significant changes at 1, 3, 5, and 10 years when compared with baseline (P = 0.679, 0.351, 0.206, and 0.152, respectively). The eGFR exhibited a slight decline at 10 years of follow-up (F = 9.020, P < 0.001), although this decrease was clinically relevant in only 9.76% of patients, who experienced a reduction of > 40%. No significant differences in eGFR were observed at 1, 3, and 5 years compared with baseline (P = 0.973, 0.183, and 0.101, respectively). The proportions of patients with eGFR decreases of more than 10%, 20%, 30%, and 40% were 30.89%, 18.7%, 13.01%, and 9.76%, respectively (Table 1).

Table 1.

Changes in key clinical indicators before and after treatment ($\overline{x}\pm s$)

Item	Baseline	1 year (n = 231)	3 years (n = 175)	5 years (n = 155)	10 years (n = 123)
24-h urinary protein (g/d)	4.3±2.7	2.6±2.5a	1.8±2.1a	1.9±1.9a	1.7±2.7a
serum albumin (g/L)	25.6±6.8	30.3±9.8a	34.6±9.1a	35.4±8.4a	37.0±8.7a
Serum creatinine (μmol/L)	77.2±35.4	84.0±64.0	83.0±56.2	92.6±74.6	97.8±100.8
eGFR (EPI formula)	93.3±25.5	91.5±30.1	90.2±27.2	85.9±29.9	80.8±28.2a

Notes: eGFR (mL/min per 1.73 m²): estimated glomerular filtration rate; EPI: chronic kidney disease epidemiology collaboration formula. Categorical variables are expressed as frequencies and percentages, while continuous variables with a normal distribution are reported as means ± standard deviations. ^aP < 0.05, compared with baseline.

Subgroup analyses revealed a significant reduction in 24-h urinary protein levels in both the TCM1 and TCM2 treatment groups during the follow-up period compared to baseline (TCM1: F = 4.752, P = 0.002; TCM2: F = 9.978, P < 0.001). Correspondingly, serum albumin levels increased significantly in both subgroups (TCM1: F = 7.574, P < 0.001; TCM2: F = 9.123, P < 0.001). Serum creatinine levels remained stable in both treatment groups (TCM1: F = 2.151, P = 0.143; TCM2: F = 2.623, P = 0.115). However, eGFR was slightly reduced and significantly different from baseline in both groups (TCM1: F = 4.078, P = 0.045; TCM2: F = 5.344, P = 0.004; Table 2).

Table 2.

Changes in key clinical indicators before and after treatment ($\overline{x}\pm s$)

Group	Time	n	24-h urinary protein (g/d)	serum albumin (g/d)	Serum creatinine (μmol/L)	eGFR (EPI formula)
TCM1	0 year	66	4.3±2.2	26.3±6.5	67.3±19.2	100.1±18.4
	1 year	60	2.2±2.3	32.6±9.7	62.2±20.7	104.3±20.6
	3 years	45	1.2±1.9	38.7±7.8	66.9±26.4	99.3±18.8
	5 years	38	1.6±1.9	36.7±8.0	81.0±54.6	90.3±24.3
	10 years	35	1.1±2.2	39.4±6.2	73.4±27.7	83.8±17.5
TCM2	0 year	128	4.2±2.9	25.2±6.9	86.1±45.8	87.6±29.3
	1 year	106	2.8±2.0	29.4±9.3	97.6±86.1	85.9±33.1
	3 years	82	1.8±1.7	33.7±9.4	87.5±60.4	87.7±29.3
	5 years	83	1.9±2.0	35.1±8.4	90.3±63.6	86.0±29.6
	10 years	62	2.3±3.2	34.7±8.3	104.4±120.4	80.1±29.2
TCM & WM	0 year	71	4.5±2.5	25.7±6.8	70.2±16.9	97.2±21.7
	1 year	65	2.8±3.4	29.7±10.5	81.2±36.0	89.3±29.1
	3 years	48	2.1±2.6	32.5±8.9	90.5±66.7	85.8±28.9
	5 years	34	2.3±1.9	34.7±8.6	110.1±110.0	81.3±36.0
	10 years	26	1.0±1.5	39.8±10.7	105.9±96.7	79.6±34.7

Notes: TCM1: patients in this group received TCM treatment focusing on spleen strengthening and dampness drainage without prior exposure to conventional WM. TCM2: this group included patients who had received WM treatment, experienced treatment failure, and discontinued WM therapy for at least 6 months. Alternatively, it included patients who experienced relapse but were unwilling or unable to resume conventional WM. These patients subsequently received TCM therapy focused on spleen strengthening and dampness drainage at our center. TCM&WM: Patients in this group received both TCM treatment and conventional WM as initial treatment at our center. TCM: Traditional Chinese Medicine; WM: Western Medicine; eGFR (EPI) (mL/min per 1.73 m²): estimated glomerular filtration rate, calculated by chronic kidney disease epidemiology collaboration formula. Categorical variables are expressed as frequencies and percentages, while continuous variables with a normal distribution are reported as means ± standard deviations.

In the TCM & WM group, an increase in 24-h urinary protein levels was observed (F = 5.025, P = 0.039), while serum albumin levels exhibited an increase that was not statistically significant (F = 3.013, P = 0.099). Serum creatinine and eGFR remained relatively stable in this group (serum creatinine: F = 0.982, P = 0.4; eGFR—TCM & WM1: F = 1.410, P = 0.288; Table 2).

3.3. Response to treatment

The overall remission rates within the cohort were 52.81%, 69.71%, 68.39%, and 72.36% at 1, 3, 5, and 10 years of follow-up, respectively. Corresponding recurrence rates were 0%, 2.5%, 10.16%, and 18.52%, respectively. The primary contributing factors to recurrence were the rapid discontinuation of TCM and infections, with a minority of cases attributed to unknown causes. In the TCM1 group, remission rates at 1, 3, 5, and 10 years were 56.67%, 84.44%, 76.32%, and 82.86%, respectively. In the TCM2 group, remission rates were 52.83%, 65.85%, 67.47% and 67.75%, respectively. In the TCM & WM group, the remission rates at the corresponding follow-up intervals were 49.23%, 62.50%, 61.76%, and 69.23% (Tables 3 and 4).

Table 3.

Overall efficacy analysis [n (%)]

Item	1 year (n = 231)	3 years (n = 175)	5 years (n = 155)	10 years (n = 123)
CR	40 (17.32)	59 (33.71)	54 (33.55)	52 (42.28)
PR	82 (35.50)	63 (36.00)	52 (34.84)	37 (30.08)
Remission rate (%) (CR+PR)	122 (52.81)	122 (69.71)	106 (68.39)	89 (72.36)
RE	0 (0.00)	1 (2.50)	6 (10.16)	10 (18.52)

Notes: CR was defined as the maintenance of stable renal function, characterized by a serum creatinine change of ≤ 15% from baseline, proteinuria < 0.3 g/24 h, and serum albumin ≥ 35 g/L. PR was defined as a reduction in proteinuria of ≥ 50% from baseline, with proteinuria levels ranging from 0.3 to 3.5 g/24 h, and serum albumin levels ≥ 30 g/L. Relapse was characterized by a proteinuria level > 3.5 g/24 h following at least 4 weeks of sustained CR or PR, or an increase of > 50% from the lowest urinary protein value post-treatment with TCM. The remission rate (%) was calculated as follows: (CR + PR) / total cases × 100. TCM: Traditional Chinese Medicine; CR: complete remission; PR: partial remission; RE: relapse.

Table 4.

Efficacy analysis across different treatment groups [n (%)]

Group	Time	n	CR	PR	CR+PR	RE
TCM1	1 year	60	12 (20.0)	22 (36.7)	34 (56.7)	0 (0.0)
	3 years	45	23 (51.1)	15 (33.3)	38 (84.4)	0 (0.0)
	5 years	38	18 (47.4)	11 (29.0)	29 (76.3)	1 (4.4)
	10 years	35	20 (57.1)	9 (25.7)	29 (82.9)	1 (5.6)
TCM2	1 year	106	13 (12.3)	43 (40.6)	56 (52.8)	0 (0.0)
	3 years	82	21 ( (25.6)	33 (40.2)	54 (65.9)	1 (7.7)
	5 years	83	24 (28.9)	32 (38.6)	56 (67.5)	4 (19.1)
	10 years	62	19 (30.7)	23 (37.1)	42 (67.8)	8 (33.3)
TCM & WM	1 year	65	15 (23.1)	17 (26.2)	32 (49.2)	0 (0.0)
	3 years	48	15 (31.3)	15 (31.3)	30 (62.5)	0 (0.0)
	5 years	34	12 (35.3)	9 (26.5)	21 (61.8)	1 (6.7)
	10 years	26	13 (50.0)	5 (19.2)	18 (69.2)	1 (8.3)

Notes: TCM1: patients in this group received TCM treatment focusing on spleen strengthening and dampness drainage without prior exposure to conventional WM. TCM2: this group included patients who had received WM treatment, experienced treatment failure, and discontinued WM therapy for at least 6 months. Alternatively, it included patients who experienced relapse but were unwilling or unable to resume conventional WM. These patients subsequently received TCM therapy focused on spleen strengthening and dampness drainage at our center. TCM&WM: patients in this group received both TCM treatment and conventional WM as initial treatment at our center. CR was defined as the maintenance of stable renal function, characterized by a serum creatinine change of ≤ 15% from baseline, proteinuria < 0.3 g/24 h, and serum albumin ≥ 35 g/L. PR was defined as a reduction in proteinuria of ≥ 50% from baseline, with proteinuria levels ranging from 0.3 to 3.5 g/24 h, and serum albumin levels ≥ 30 g/L. Relapse was characterized by a proteinuria level >3.5 g/24 h following at least 4 weeks of sustained CR or PR, or an increase of > 50% from the lowest urinary protein value post-treatment with TCM. The remission rate (%) was calculated as follows: (CR + PR) / total cases × 100. TCM: Traditional Chinese Medicine; WM: Western Medicine; CR: complete remission; PR: partial remission; RE: relapse.

3.4. Survival analysis

Composite outcome events, observed in 31 patients, included nine deaths, 11 initiations of dialysis, and 11 cases of doubled serum creatinine levels. The incidence of composite events was 4.55% (3/66) in the TCM1 group, 13.28% (17/128) in the TCM2 group, and 15.49% (11/71) in the TCM & WM group. Kaplan-Meier survival analysis demonstrated event-free survival rates of 98.27%, 94.29%, 94.19%, and 93.50% at 1, 3, 5, and 10 years of follow-up, respectively (Figure 2). Throughout the follow-up period, no statistically significant differences in cumulative survival were observed among the groups (log-rank χ ² = 5.688, P = 0.128; Figure 3).

Figure 2. Kaplan-Meier survival analysis for patients who reached the composite outcomes events.

Figure 3. Kaplan-Meier survival analysis comparing patients in different groups who did not reach the composite outcomes events.

TCM1: patients in this group received TCM treatment focusing on spleen strengthening and dampness drainage without prior exposure to conventional WM. TCM2: this group included patients who had received WM treatment, experienced treatment failure, and discontinued WM therapy for at least 6 months. Alternatively, it included patients who experienced relapse but were unwilling or unable to resume conventional WM. These patients subsequently received TCM therapy focused on spleen strengthening and dampness drainage at our center. TCM&WM: Patients in this group received both TCM treatment and conventional WM as initial treatment at our center. TCM: Traditional Chinese Medicine; WM: Western Medicine.

3.5. Cox regression analysis

The clinical medication profiles of patients were assessed, with particular focus on the use of immunosuppressive agents, which included gluco-corticoids, cyclo-phosphamide (CTX), cyclosporine, tacrolimus (FK506), Leigongteng (Radix et Rhizoma Tripterygii), myco-phenolate mofetil (MMF), and leflunomide. The distribution of patients receiving these medications is presented in the previous section (2.2 Treatment protocols).

Univariate Cox regression analysis was conducted to explore factors associated with treatment outcomes. Regardless of whether the patient experienced their first onset, several variables were found to be significantly correlated with therapeutic efficacy. These variables included duration of TCM therapy, patient age, presence of comorbid hypertension, baseline serum albumin, baseline serum creatinine, baseline eGFR (EPI), the rate of urinary protein reduction during the first year of follow-up, and the rate of serum albumin increase during the same period. Multivariate Cox risk regression analysis was performed by incorporating variables that demonstrated statistical significance in the univariate analysis. The results identified that the duration of TCM treatment (HR = 0.826, 95% CI: 0.779-0.876, P < 0.001), presence of hypertension (HR = 1.912, 95% CI: 1.181-3.094, P = 0.008), baseline serum albumin (HR = 0.930, 95% CI: 0.894-0.969, P < 0.001), and the rate of serum albumin increase within the first year of follow-up (HR = 0.930, 95% CI: 0.909-0.957, P < 0.001) were independent predictors of therapeutic efficacy in patients with IMN (Table 5).

Table 5.

Factors influencing the efficacy of the TCM treatment plan (univariate and multivariate Cox regression analysis, n = 265)

Item	Univariate			Multivariate
	HR (95.0% CI)	P value		HR (95.0% CI)	P value
Incipient	0.596 (0.378, 0.938)	0.025		-	-
Use of immunosuppressants	1.268 (0.838, 1.919)	0.262		-	-
Use of ARB and / or ACEI drugs	1.027 (0.695, 1.516)	0.895		-	-
Treatment course of TCM	0.843 (0.803, 0.884)	0.000		0.826 (0.779, 0.876)	0.000
Sex	1.072 (0.721, 1.593)	0.731		-	-
Age	1.329 (1.035, 1.707)	0.026		-	-
Hypertension	1.565 (1.045, 2.344)	0.030		1.912 (1.181, 3.094)	0.008
Diabetes	0.742 (0.447, 1.233)	0.250		-	-
Proteinuria (g/d)	1.023 (0.961, 1.089)	0.474		-	-
Serum albumin(g/L)	0.943 (0.916, 0.972)	0.000		0.930 (0.894, 0.969)	0.000
Serum creatinine (μmol/L)	1.008 (1.004, 1.012)	0.000		-	-
eGFR (EPI)	0.988 (0.981, 0.995)	0.001		-	-
Urinary protein decline rate (1 year duration)	0.917 (0.854, 0.986)	0.018		-	-
Serum albumin rise rate (1 year duration)	0.954 (0.931, 0.977)	0.000		0.930 (0.909, 0.957)	0.000

Notes: ARB: angiotensin receptor blocker; ACEI: angiotensin converting enzyme inhibitors; TCM: Traditional Chinese Medicine; eGFR (EPI) (mL/min per 1.73 m²): estimated glomerular filtration rate, calculated by chronic kidney disease epidemiology collaboration formula; HR: hazard ratio; CI: confidence interval.

Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the predictive accuracy of these independent influencing factors for IMN remission. The AUC for TCM treatment duration, baseline serum albumin, and the rate of serum albumin increase within 1 year of follow-up were all above 0.5, indicating moderate predictive value. Specifically, the AUC for TCM treatment duration was 0.664 (95% CI: 0.587-0.741), for the rate of serum albumin increase within 1 year was 0.670 (95% CI: 0.594-0.745), and for baseline serum albumin was 0.643 (95% CI: 0.566-0.721). In contrast, the AUC for the presence of hypertension was 0.384 (95% CI: 0.307-0.462) (Figure 4).

Figure 4. ROC curve for influencing factors of treatment efficacy in 265 patients.

TCM: Traditional Chinese Medicine; ROC: receiver operating characteristic.

4. DISCUSSION

Globally, nephrologists are dedicating increasing attention to the study of MN given its rising annual morbidity rates.¹⁴ In response to the limitations of IST,¹⁵ ongoing research efforts aim to develop more advanced and effective treatment strategies. TCM, with its extensive history of use in China, has demonstrated favorable clinical outcomes, enhanced patient acceptability, and improved safety profiles in MN management.^16,17 Notably, TCM appears to complement existing medical interventions for this disease.

4.1. Analysis of clinical characteristics

A total of 265 Chinese patients were included in this study (male-to-female ratio = 1.68 : 1). The average age at disease onset was (53 ± 14) years, which is slightly older than the typical onset age observed in European populations (40-50 years), and the sex ratio was more balanced (male-to-female ratio, 2-3 : 1).^18-21 The majority of patients in the TCM group were classified as medium- or high-risk according to the 2021 Kidney Disease Improving Global Outcomes MN risk classification, necessitating more aggressive treatment. At baseline, the TCM2 group exhibited significantly higher serum creatinine levels and lower eGFR compared with the other groups, indicating more advanced renal function impairment. This may be attributed to the ineffectiveness of previous treatments prior to inclusion in this study.

4.2. Analysis of clinical efficacy

This study demonstrates that Strengthening Spleen and Draining Dampness therapy is associated with a significant reduction in urinary protein and an improvement in serum albumin levels. Moreover, the therapeutic efficacy of this TCM treatment appeared to increase with longer treatment durations, with the most pronounced improvements occurring within the first three years of follow-up. Therefore, the data support a recommendation that TCM treatment duration should not be shorter than three years.

In terms of recurrence, the highest rate observed in this study was 18.52%, which is notably lower than the rates reported in other studies, where 20%-30% of patients with MN experience relapse following conventional WM treatment.^22-24 In China, 42% of patients relapsed after receiving glucocorticoid therapy combined with cyclosporine during an average follow-up of 50 months.²⁵ These findings suggest that long-term TCM treatment, particularly the Strengthening Spleen and Draining Dampness approach, may be more effective in preventing MN recurrence, providing more sustained and stable outcomes compared to standard WM approaches. Serum creatinine levels remained relatively stable for most patients during the follow-up period, although the eGFR slightly decreased over the 10-year period. A reduction in eGFR of more than 40% was observed in 9.76% of patients at the 10-year mark. This decline is lower than that reported in a Japanese study on MN using hormone therapy, where eGFR decreased by 40% in 18% and 43% of patients at 5 and 10 years, respectively.²⁶ In terms of renal survival, U.S. data on 1,189 IMN patients showed survival rates of 86% at 5 years, 65% at 10 years, and 59% at 15 years, with 20%-40% progressing to end-stage renal disease within 10-15 years.²⁷ Additionally, a 2005 Meta-analysis of 18 randomized controlled trials by Italian researchers found that immunosuppressive therapy did not improve long-term renal survival in IMN patients with nephrotic syndrome.²⁸ By contrast, our findings suggest that TCM treatment may enhance long-term renal survival and provide protective benefits against progression to end-stage renal disease.

Subgroup analysis revealed that TCM, whether used alone or in combination with immunosuppressive therapy, yielded favorable outcomes across different IMN populations. Notably, the combination of TCM and WM did not appear to confer superior benefits compared with TCM monotherapy, indicating that TCM might mitigate the adverse effects associated with immunosuppressive drugs. However, further research is needed to determine whether TCM can fully replace immunosuppressive therapies in clinical practice. For patients with refractory MN who transitioned from ineffective immunosuppressive therapy to TCM, the highest effective rate of 67.75% was observed, with 30.65% of these patients achieving clinical remission. These findings suggest that Strengthening Spleen and Draining Dampness therapy may offer significant therapeutic benefits for patients with refractory MN, potentially providing broader clinical utility in MN management.

4.3. Analysis of Cox regression results

Multivariate Cox regression analysis revealed that neither age nor gender significantly influenced therapeutic outcomes. In contrast, long-term and consistent utilization of TCM was more strongly associated with improved treatment efficacy. Importantly, no severe adverse effects directly attributable to TCM were observed. These findings align with previous research, which reported that approximately 50% of patients presented with hypertension.²⁹ Our Cox regression analysis demonstrated that IMN patients with hypertension had a 1.912 times higher risk of therapeutic failure compared with non-hypertensive patients, underscoring the need for active management of even mild to moderate hypertension.³⁰ Serum albumin plays a crucial role in promoting the reabsorption of interstitial fluid by modulating colloid osmotic pressure, thereby increasing circulating blood volume, improving renal blood flow, and enhancing renal perfusion. Previous studies have shown that decreased serum albumin levels compromise the body’s ability to mitigate oxidative stress, which may exacerbate disease progression.³¹ Consistent with these findings, our results demonstrate that both the rate of serum albumin increase and its elevation within the first year of treatment are significant predictors of clinical efficacy in IMN. A rapid rise in serum albumin levels is associated with better clinical outcomes, and TCM therapy has been shown to offer considerable therapeutic benefits in this context.¹⁰ Notably, our study found no significant correlation between 24-h urinary protein quantification and either prognosis or therapeutic efficacy.

4.4. Component analysis of TCM treatment

The therapeutic strategy of Strengthening Spleen and Draining Dampness has been an established and widely utilized treatment modality for IMN within the Department of Nephrology at Longhua Hospital, affiliated with Shanghai University of Traditional Chinese Medicine. This approach has undergone nearly three decades of clinical refinement and optimization. The key component of this formula, Huangqi (Radix Astragali Mongolici), functions by tonifying Qi and Yang, promoting diuresis, and reducing edema. Other herbal constituents, such as Shanyao (Rhizoma Dioscoreae Oppositae) and Dangshen (Radix Codonopsis), nourish both Qi and Yin while supporting spleen function. Baizhu (Rhizoma Atractylodis Macrocephalae) further augments spleen Qi, and Fuling (Poria) along with Yiyiren (Semen Coicis) facilitate diuresis, aiding in the removal of dampness. Together, these herbs act synergistically, with Huangqi (Radix Astragali Mongolici) playing a central role in both nourishing Qi and draining dampness. Existing studies have shown that the therapeutic mechanisms of these herbs involve anti-inflammatory, antioxidant, anti-fibrotic, and immune-regulatory effects, in addition to modulating anticoagulation and metabolic processes.³² The formula itself comprises over ten different medicinal herbs, with Huangqi (Radix Astragali Mongolici) demonstrating particularly potent anti-inflammatory and antioxidant properties.^32-34 In several animal models of renal disease, Huangqi (Radix Astragali Mongolici) has been shown to reduce proteinuria and alleviate kidney damage.^35,36 Furthermore, clinical trials have confirmed that the administration of Huangqi (Radix Astragali Mongolici) extract via injection significantly reduces proteinuria and ameliorates lipid abnormalities in patients with chronic glomerulonephritis.^37-40

This study is subject to certain limitations. The study population was relatively small, and potential retrospective bias cannot be excluded given the extended follow-up period and incomplete follow-up data for certain patients. Additionally, the absence of a control group receiving standard Western medical treatment limits a comprehensive evaluation of the long-term efficacy of TCM in managing IMN. Despite these limitations, the findings of this study corroborate previous research conducted at our institution¹⁰ and provide further evidence supporting the widespread clinical application of the Strengthening Spleen and Draining Dampness therapy in the treatment of IMN.

5. ACKNOWLEDGMENTS

We thank Phoebe Chi, MD, from Liwen Bianji (Edanz) (www.liwenbianji.cn), for editing the English text of a draft of this manuscript.

Funding Statement

Supported by the National Key Research and Development Project, Clinical Study on the Treatment of Refractory Membranous Nephropathy with the Treatment of Strengthening Spleen and Draining Dampness in Method using Single Group Target Value Method (No. 2019YFC1709403); Systematic Study on the Diagnosis and Treatment Rules of Membranous Nephropathy in Traditional Chinese Medicine (No. 2023YFC35033501, No. 2023YFC35033503)