Efficacy and safety of Mahuang Fuzi and Shenzhuo Decoction for treatment of primary membranous nephropathy: a multicenter prospective trial

Figures & data

Figure 1. Study flowchart.

Table 1. Baseline clinical characteristics of participants.

	Total (n = 198)
Age (years)	49.0 (38.0, 60.0)
Male (%)	127 (64.1)
Nephrotic syndrome (%)a	119 (60.1)
Laboratory indicators
24hUP (g/d)	7.4 (4.4, 12.3)
ALB (g/L)	27.5 (21.3, 33.5)
SCr (μmol/L)	66.1 (54.3, 83.2)
eGFR (mL/min/1.73 m^2)	106.9 (86.9, 137.0)
TCHO (mmol/L)	6.5 (5.2, 8.4)
TG (mmol/L)	1.8 (1.3, 2.8)
LDL-C (mmol/L)	3.8 (3.0, 5.4)
aPLA2R
Positive patients (%)b	92 of 102 (90.2)
Titers (RU/mL)	106.0 (47.2, 219.2)
KDIGO risk evaluationc
Low risk (%)	31 (15.7)
Moderate risk (%)	56 (28.3)
High risk (%)	111 (56.1)
Medical history
HIST (%)	88 (44.4)
Diabetes (%)	29 (14.6)
Hypertension (%)	91 (46.0)

24hUP: 24 h urine protein; ALB: albumin; SCr: serum creatinine; eGFR: estimated glomerular filtration rate; TCHO: total cholesterol; TG: triglyceride; LDL-C: low-density lipoprotein cholesterol; aPLA2R: M-type phospholipase A2 receptor autoantibody; HIST: history of immunosuppressive therapy.

Data are presented as mean (SD) or median (IQR) for continuous measures, and n (%) for categorical measures.

^a The manifestations of nephrotic syndrome include: 24hUP ≥ 3.5g/d, serum albumin < 30g/L, edema, and/or hyperlipidemia.

^b Positive patients defined as a titer of PLA2R antibody is higher than 20 RU/mL.

^c KDIGO risk evaluation of membranous nephropathy is according to KDIGO 2021 clinical practice guideline for the management of glomerular diseases.

Table 2. Response rate of participants at 12, 24, and 36 months.

	Total (n = 198)	95% CI
0–12 months
PR + CR (%)	64/198 (32.3%)	25.8%, 38.9%
CR (%)	19/198 (9.6%)	5.5%, 13.7%
0–24 months
PR + CR (%)	116/198 (58.6%)	51.7%,65.5%
CR (%)	43/198 (21.7%)	15.9%, 27.5%
0–36 months	Total (n = 130)	95% CI
PR + CR (%)	91/130 (70.0%)	62.0%, 78.0%
CR (%)	44/130 (33.8%)	25.6%, 42.1%

CR: complete response after treatment; PR: partial response after treatment.

Table 3. Baseline clinical characteristics of participants (grouped according to HIST or age, respectively).

	With HIST (n = 88)	Without HIST (n = 110)	p Value	Youth (<60) (n = 146)	Elder (≥60) (n = 52)	p Value
Age	49.0 (38.0, 58.8)	49.5 (38.8, 61.0)	.635
Male (%)	58 (65.9)	69 (62.7)	.643	95 (65.1)	32 (61.5)	.649
Nephrotic syndrome (%)	52 (59.1)	67 (60.9)	.795	93 (63.7)	26 (50)	.083
Laboratory indicators
24hUP (g/d)	7.8 (4.8, 13.7)	7.0 (4.0, 11.0)	.089	8.0 (4.8, 13.6)	9.4 (6.6, 13.0)	.003
ALB (g/L)	27.5 (18.9, 34.2)	27.5 (22.3, 32.5)	.397	26.1 (20.5, 33.8)	24.9 (19.1, 30.8)	.043
SCr (μmol/L)	67.5 (56.4, 92.3)	65.1 (53.8, 81.4)	.091	66.0 (54.2, 83.1)	78.0 (60.5, 101.0)	.815
eGFR (mL/min/1.73 m^2)	102.2 (79.1, 128.1)	110.0 (90.0, 140.8)	.124	108.6 (89.7,140.8)	92.2 (62.9, 123.0)	.063
TCHO (mmol/L)	6.5 (5.2,8.6)	6.6 (5.2,8.3)	.712	6.5 (5.2, 8.7)	6.7 (5.7, 8.5)	.491
TG (mmol/L)	1.9 (1.3,2.7)	1.8 (1.4, 2.9)	.812	1.9 (1.3, 2.9)	1.9 (1.3,3.0)	.680
LDL-C (mmol/L)	3.9 (2.9,5.6)	3.8 (3.0,5.8)	.803	3.8 (3.1, 5.6)	4.0 (3.5, 5.6)	.285
aPLA2R
Positive patients (%)	38 of 40 (95)	54 of 62 (87.1)	.190	75 of 81 (92.6)	17 of 21 (81.0)	.110
Titers (RU/mL)	108.0 (50.5, 215.8)	100.0 (45.2, 283.0)	.936	101.1 (50.8, 216.6)	176.0 (53.0, 431.3)	.735
KDIGO risk evaluation
Low risk (%)	13 (14.8)	18 (16.4)	.760	21 (14.4)	10 (19.2)	.409
Moderate risk (%)	22 (25.0)	34 (30.9)	.359	36 (24.7)	20 (38.5)	.058
High risk (%)	53 (60.2)	58 (52.7)	.291	89 (61.0)	22 (42.3)	.020
Medical history
HIST (%)				67 (45.9)	21 (40.4)	.020
Diabetes (%)	16 (18.2)	13 (11.8)	.205	19 (13.0)	10 (19.2)	.276
Hypertension (%)	47 (53.4)	44 (40.0)	.057	62 (42.5)	29 (55.8)	.098

24hUP: 24 h urine protein; ALB: albumin; SCr: serum creatinine; eGFR: estimated glomerular filtration rate; TCHO: total cholesterol; TG: triglyceride; LDL-C: low-density lipoprotein cholesterol; aPLA2R: M-type phospholipase A2 receptor autoantibody; HIST: history of immunosuppressive therapy.

Figure 2. Survival analysis of remission rates. (A, B) The survival analysis of PR + CR or CR rate, grouped according to with or without HIST. The light blue line means with HIST, the dark blue line means without HIST, and the red line means total. (C, D) The survival analysis of PR + CR or CR rate, grouped according to whether the age is over 60 years old. The light blue line means elder, the dark blue line means youth, and the red line means total. Other abbreviations are the same as the previous tables.

Table 4. Response rate of participants at 12, 24, and 36 months (grouped according to HIST or age, respectively).

	With HIST (n = 88)	Without HIST (n = 110)	p Value	Youth (<60) (n = 146)	Elder (≥60) (n = 52)	p Value
0–12 months
PR + CR	25/88 (28.4%)	39/110 (35.5%)	.292	46/146 (31.5%)	18/52 (34.6%)	.681
CR	8/88 (9.1%)	11/110 (10.0%)	.829	13/146 (8.9%)	6/52 (11.5%)	.580
0–24 months
PR + CR	45/88 (51.1%)	71/110 (64.5%)	.057	80/146 (54.8%)	36/52 (69.2%)	.070
CR	14/88 (15.9%)	29/110 (26.4%)	.076	27/146 (18.5%)	16/52 (30.8%)	.065
0–36 months
PR + CR	36/59 (61.0%)	55/71 (77.5%)	.042	62/94 (66.0%)	29/36 (80.6%)	.104
CR	16/59 (27.1%)	28/71 (39.4%)	.139	28/94 (29.8%)	16/36 (44.4%)	.114

CR: complete response after treatment; PR: partial response after treatment; HIST: history of immunosuppressive therapy.

Figure 3. The change trend of primary indexes. (A) 24hUP trend for PR + CR patients, non-remission patients, and all patients. The dashed line below indicates that 24hUP is less than 3.5 g/d. (B) ALB trend for PR + CR patients, non-remission patients, and all patients. The dashed line above indicates that ALB is greater than 35 g/L. The dark blue square indicates no remission, the light blue triangle indicates PR + CR, and the red circle indicates all patients.

Figure 4. Forest plots of hazard ratios in baseline predictors for remission. The blue squares show no statistical differences and red triangle indicates statistical difference. The dashed line indicates that HR = 1.0. To the left of the dashed line indicates that this factor is a risk factor for remission, to the right of the dashed line indicates a beneficial factor, and crossing the dashed line indicates that this factor has no effect on MN remission.

Table 5. Correlation between baseline predictors and mitigation outcomes by multivariate COX regression analysis.

	Model A		Model B		Model C
	HR (95% CI)	p Value	HR (95% CI)	p Value	HR (95% CI)	p Value
Gender	0.93 (0.64, 1.34)	.688	0.91 (0.61, 1.35)	.627	0.92 (0.64, 1.34)	.664
Age	1.01 (0.99, 1.02)	.282	1.00 (0.99, 1.02)	.677	1.01 (0.99, 1.02)	.375
Nephrotic syndrome	0.59 (0.42, 0.85)	.004
24hUP			0.91 (0.86, 0.95)	<.001
ALB			1.01 (0.98, 1.04)	.535
eGFR	1.01 (1.00, 1.01)	.047	1.01 (1.00, 1.01)	.228	1.00 (1.00, 1.01)	.119
High risk (KDIGO)					0.62 (0.43, 0.88)	.007
With HIST	0.69 (0.48, 0.98)	.036	0.86 (0.49, 0.98)	.037	0.71 (0.50, 1.01)	.055

24hUP: 24 h urine protein; ALB: albumin; eGFR: estimated glomerular filtration rate; HIST: history of immunosuppressive therapy; HR: hazard ratio.

For model A, gender, age, nephrotic syndrome, eGFR, and with HIST were included in Cox regression analysis. For model B, nephrotic syndrome was replaced by 24hUP and ALB. For model C, nephrotic syndrome was replaced by high risk (KDIGO).

Data availability statement

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