Fibrinogen-albumin ratio predicts treatment response in phospholipase A2 receptor-associated membranous nephropathy with nephrotic syndrome

Figures & data

Table 1. Characteristics of patients with different outcomes.

	CR + PR	NR	p-value
Parameter	n = 78	n = 32
Demographic characteristics Male sex, no (%)	52 (66.7%)	26 (81.3%)	0.126
Age, y	53.00 (39.75, 60.25)	53.00 (48.00, 61.00)	0.429
Clinical characteristics BMI, kg/m^2	25.72 (23.48, 27.70)	25.66 (22.69, 28.24)	0.976
SBP, mmHg	136.00 (125.75, 146.25)	137.50 (130.00, 155.75)	0.209
DBP, mmHg	87.26 ± 13.09	89.09 ± 10.91	0.485
Laboratory characteristics Serum anti-PLA2R Ab, RU/mL	96.96 (48.03, 223.56)	147.11 (89.38, 383.79)	0.019
Urinary protein, g/d	7.51 (5.19, 9.53)	7.83 (5.61, 12.32)	0.340
Prothrombin time, s	11.10 (10.78, 11.60)	10.95 (10.50, 11.48)	0.260
International normalized ratio	0.96 (0.94, 1.01)	0.96 (0.91, 1.00)	0.247
Activated partial thromboplastin time, s	26.60 (25.28, 28.85)	26.65 (25.80, 29.03)	0.605
Serum fibrinogen, g/L	4.45 ± 1.16	5.05 ± 1.23	0.016
Thrombin time, s	18.06 ± 1.07	17.73 ± 1.12	0.150
D - dimer, mg/L	0.83 (0.47, 1.62)	1.32 (0.80, 3.46)	0.014
TC, mmol/L	7.92 (6.26, 9.27)	7.78 (6.43, 10.11)	0.622
TG, mmol/L	2.28 (1.66, 3.21)	2.05 (1.51, 2.69)	0.338
HDL-C, mmol/L	1.41 (1.14, 1.57)	1.36 (1.20, 1.69)	0.662
LDL-C, mmol/L	5.06 (3.92, 5.99)	4.53 (4.06, 6.09)	0.859
Serum albumin, g/L	20.10 (17.48, 24.18)	18.30 (15.75, 21.58)	0.046
Serum creatinine, μmol/L	73.60 (59.60, 87.43)	75.10 (59.30, 95.60)	0.571
eGFR, ml/min/1.73m^2	97.12 (84.18, 108.90)	99.21 (75.30, 109.33)	0.854
Serum uric acid, μmol/L	382.69 ± 102.78	343.07 ± 119.39	0.083
FAR	0.21 (0.17, 0.27)	0.26 (0.21, 0.34)	0.006
Retinol binding protein, mg/L	49.44 ± 13.23	43.26 ± 11.92	0.024
CRP, mg/L	1.57 (1.38, 2.40)	2.40 (1.53, 5.02)	0.009
NLR	2.08 (1.55, 2.69)	2.26 (1.71, 3.54)	0.118
PAR	11.82 (8.73, 14.04)	12.18 (9.66, 15.62)	0.270
Hemoglobin, g/L	130.17 ± 18.83	129.09 ± 22.98	0.800
Serum IgG, g/L	5.15 (3.87, 6.61)	4.47 (3.02, 6.55)	0.113
Serum IgA, g/L	1.95 (1.52, 2.70)	2.02 (1.36, 2.58)	0.800
Serum IgM, g/L	0.96 (0.66, 1.39)	0.98 (0.75, 1.21)	0.767
Serum C3, g/L	1.03 ± 0.24	0.99 ± 0.23	0.415
Serum C4, g/L	0.28 ± 0.07	0.28 ± 0.09	0.864
Comorbid disease Hypertension, n (%)	37 (47.4%)	21 (65.6%)	0.083
Diabetes mellitus, n (%)	9 (11.5%)	4 (12.5%)	0.887
Infection, n (%)	3 (3.8%)	5 (15.6%)	0.031
Therapy Glucocorticoids no (%)	76 (97.4%)	29 (90.6%)	0.119
Immunosuppressive therapy, n (%)	75 (96.2%)	30 (93.8%)	0.052
CNIs	68 (87.2%)	26 (81.3%)
rituximab	3 (3.8%)	4 (12.5%)
cyclophosphamide	4 (5.1%)	0 (0%)
RAAS inhibitors	63 (80.8%)	28 (87.5%)	0.396

CR, complete remission; PR, partial remission; NR, non-remission/response; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; anti-PLA2R Ab, anti-phospholipase A2 receptor antibody; FAR, serum fibrinogen-albumin ratio; TC, total cholesterol; TG, triglycerides; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein; NLR, neutrophil-lymphocyte ratio; PAR, platelet-albumin ratio; IgG, immunoglobulin G; IgA, immunoglobulin A; IgM, immunoglobulin M; C3, complement 3; C4, complement 4; RAAS, renin-angiotensin-aldosterone system.

Data were presented as the mean ± standard, the median with interquartile range or counts and percentages. A two-tailed p < 0.05 in bold was considered statistically significant.

Figure 1. Flowchart of study participants. PMN, Primary membranous nephropathy; sMN, secondary membranous nephropathy; anti-PLA2R Ab, anti-phospholipase A2 receptor antibody; CR, complete remission; PR, partial remission; NR, non-remission.

Figure 2. Association of FAR and treatment response in all enrolled patients. A. Predictive performances of FAR for remission outcomes (CR or PR) evaluated by ROC curves. B. Incidence of CR and PR between groups stratified for FAR levels by Kaplan-Meier survival curve. Anti-PLA2R Ab positive PMN patients with FAR ≤ the cutoff value at the time of renal biopsy had significantly higher probability to achieve CR or PR compared with the patients with FAR above the cutoff (Log Rank test, p = 0.021). AUC, the area under the ROC curve; ROC, receiver operating characteristic.

Table 2. Clinical and pathological features of patients with PMN according to different levels of FAR.

Parameter	All	FAR		p-value
	n = 110	≤0.233 (n = 56)	>0.233 (n = 54)
Demographic characteristics
Male sex, n (%)	78 (70.9%)	37 (66.1%)	41 (75.9%)	0.255
Age, y	53.00 (42.75, 60.25)	53.50 (39.25, 57.75)	53.00 (44.00, 63.25)	0.501
Clinical characteristics
BMI, kg/m^2	25.72 (23.37, 27.77)	25.04 (23.20, 27.46)	26.05 (24.17, 28.88)	0.097
SBP, mmHg	136.00 (127.00, 148.00)	133.50 (124.00, 143.25)	139.50 (130.75, 156.50)	0.001
DBP, mmHg	87.79 ± 12.47	85.95 ± 10.49	89.70 ± 14.08	0.115
Laboratory characteristics
Serum anti-PLA2R Ab, RU/mL	108.91 (55.00, 242.30)	91.33 (50.70, 219.79)	134.11 (59.04, 349.44)	0.121
Urinary protein, g/d	7.62 (5.57, 10.68)	6.51 (5.16, 9.05)	8.91 (6.08, 12.14)	0.004
Prothrombin time, s	11.05 (10.70, 11.53)	11.00 (10.70, 11.55)	11.10 (10.70, 11.53)	0.649
International normalized ratio	0.96 (0.93, 1.00)	0.96 (0.93, 1.01)	0.96 (0.93, 1.00)	0.608
Activated partial thromboplastin time, s	26.60 (25.58, 28.85)	26.50 (25.13, 27.63)	27.00 (25.80, 29.65)	0.032
Serum fibrinogen, g/L	4.62 ± 1.20	3.77 ± 0.66	5.51 ± 0.98	<0.001
Thrombin time, s	17.97 ± 1.09	17.97 ± 1.08	17.96 ± 1.11	0.940
D - dimer, mg/L	0.97 (0.50, 1.81)	0.80 (0.46, 1.60)	1.07 (0.57, 1.93)	0.064
TC, mmol/L	7.88 (6.37, 9.35)	7.62 (5.78, 8.76)	8.36 (7.04, 10.09)	0.012
TG, mmol/L	2.13 (1.59, 2.98)	2.08 (1.37, 2.86)	2.35 (1.67, 3.10)	0.168
HDL-C, mmol/L	1.39 (1.14, 1.61)	1.41 (1.11, 1.63)	1.39 (1.17, 1.57)	0.816
LDL-C, mmol/L	4.99 (4.02, 5.99)	4.70 (3.31, 5.66)	5.40 (4.24, 6.23)	0.024
Serum albumin, g/L	19.50 (17.28, 23.63)	22.85 (18.63, 26.40)	18.10 (15.98, 19.93)	<0.001
Serum creatinine, μmol/L	73.6 (59.68, 89.80)	68.95 (56.60, 87.15)	77.40 (62.68, 93.65)	0.127
eGFR, ml/min/1.73m^2	98.36 (79.58, 108.90)	99.81 (85.42, 112.79)	95.84 (76.72, 107.17)	0.171
Serum uric acid, μmol/L	371.17 ± 108.82	393.43 ± 106.03	348.08 ± 107.80	0.028
Retinol binding protein, mg/L	47.64 ± 13.12	49.61 ± 13.28	45.60 ± 12.74	0.109
CRP, mg/L	1.57 (1.44, 3.17)	1.52 (1.15, 2.10)	2.18 (1.51, 3.82)	0.002
NLR	2.18 (1.59, 2.96)	2.14 (1.52, 2.94)	2.18 (1.77, 2.96)	0.499
PAR	11.97 (9.23, 14.43)	9.62 (8.04, 13.60)	12.93 (11.41, 15.92)	<0.001
Hemoglobin, g/L	129.85 ± 20.03	130.55 ± 19.98	129.13 ± 20.23	0.711
Serum IgG, g/L	4.78 (3.52, 6.57)	5.42 (3.98, 6.70)	4.47 (3.05, 6.28)	0.033
Serum IgA, g/L	1.96 (1.50, 2.63)	2.07 (1.68, 2.71)	1.80 (1.43, 2.48)	0.220
Serum IgM, g/L	0.97 (0.70, 1.34)	0.97 (0.71, 1.39)	0.96 (0.65, 1.31)	0.388
Serum C3, g/L	1.02 ± 0.24	0.96 ± 0.23	1.08 ± 0.23	0.005
Serum C4, g/L	0.28 ± 0.07	0.26 ± 0.07	0.30 ± 0.07	0.007
Comorbid disease
Hypertension, n (%)	58 (52.7%)	24 (42.9%)	34 (63.0%)	0.035
Diabetes mellitus, n (%)	13 (11.8%)	5 (8.9%)	8 (14.8%)	0.339
Infection, n (%)	8 (7.3%)	2 (3.6%)	6 (11.1%)	0.128
Therapy
Glucocorticoids, n (%)	105 (95.5%)	52 (92.9%)	53 (98.1%)	0.183
Immunosuppressive therapy, n (%)	105 (95.5%)	54 (96.4%)	51 (94.4%)	0.617
CNIs	94 (85.5%)	48 (85.7%)	46 (85.2%)
rituximab	7 (6.4%)	5 (8.9%)	2 (3.7%)
cyclophosphamide	4 (3.6%)	1 (1.8%)	3 (5.6%)
RAAS inhibitors	91 (82.7%)	42 (75.0%)	49 (90.7%)	0.029
Outcomes
CR	12 (10.9%)	9 (16.1%)	3 (5.6%)	0.077
PR	66 (60.0%)	37 (66.1%)	29 (53.7%)	0.186
NR	32 (29.1%)	10 (17.9%)	22 (40.7%)	0.008
Latest follow-up
follow-up period, m	36.8 (27.1,48.3)	37.7 (29.0,48.3)	36.7 (24.3,48.8)	0.662
30% eGFR decline or ESKD	26 (23.6%)	15 (26.8%)	11 (20.4%)	0.429
Pathological characteristics
Churg’s stages (I/II/III/IV)	12/74/23/1	5/38/12/1	7/36/11/0	0.707
Grade of IgG deposition (0/1/2/3)	1/2/20/87	0/1/12/43	1/1/8/44	0.620
Grade of C3 deposition (0/1/2/3)	10/60/23/17	3/33/13/7	7/27/10/10	0.379
Grade of PLA2R antigen deposition (0/1/2/3)	12/49/32/17	7/24/19/6	5/25/13/11	0.405
Grade of fibrinogen deposition (0/1/2/3)	41/40/24/5	22/22/11/1	19/18/13/4	0.466
Global sclerosis (%)	2.94 (0.00, 10.17)	2.79 (0.00, 10.83)	3.48 (0.00, 12.50)	0.413
Crescent, n. (%)	23 (20.9%)	8 (14.3%)	15 (27.8%)	0.082
Chronic tubulointerstitial injury (0/1/2/3)	55/44/8/3	29/20/6/1	26/24/2/2	0.419
Acute tubulointerstitial injury, n. (%)	75 (68.2%)	38 (67.9%)	37 (68.5%)	0.941

PMN, primary membranous nephropathy; FAR, serum fibrinogen-albumin ratio; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; anti-PLA2R Ab, anti-phospholipase A2 receptor antibody; TC, total cholesterol; TG, triglycerides; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein; NLR, neutrophil-lymphocyte ratio; PAR, platelet-albumin ratio; IgG, immunoglobulin G; IgA, immunoglobulin A; IgM, immunoglobulin M; C3, complement 3; C4, complement 4; RAAS, renin-angiotensin-aldosterone system; CNIs, calmodulin inhibitor; CR, complete remission; PR, partial remission; NR, non-remission/response; ESKD, end stage kidney disease.

Data were presented as the mean ± standard, the median with interquartile range or counts and percentages. A two-tailed p < 0.05 in bold was considered statistically significant.

Table 3. Correlations between FAR and clinical and pathologic parameters.

Parameter	FAR
	r	P
Male sex, no. (%)	−0.093	0.332
Age, y	0.037	0.704
BMI, kg/m^2	0.076	0.429
SBP, mmHg	0.263	0.006
DBP, mmHg	0.153	0.110
Serum anti-PLA2R Ab, RU/mL	0.238	0.012
Urinary protein, g/d	0.363	<0.001
TC, mmol/L	0.363	<0.001
TG, mmol/L	0.016	0.870
HDL-C, mmol/L	0.073	0.446
LDL-C, mmol/L	0.334	<0.001
eGFR, ml/min/1.73 m^2	−0.081	0.401
Serum IgG, g/L	−0.314	0.001
Serum IgA, g/L	−0.132	0.168
Serum IgM, g/L	−0.057	0.553
Serum C3, g/L	0.130	0.160
Serum C4, g/L	0.237	0.013
Churg’s stages (I/II/III/IV)	−0.032	0.652
Grade of IgG deposition (0/1/2/3)	0.149	0.036
Grade of C3 deposition (0/1/2/3)	0.012	0.866
Grade of PLA2R antigen deposition (0/1/2/3)	0.058	0.420
Grade of fibrinogen deposition (0/1/2/3)	0.086	0.231
Global sclerosis (%)	0.017	0.811
Crescent, n. (%)	−0.094	0.190

FAR, serum fibrinogen-albumin ratio; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; anti-PLA2R Ab, anti-phospholipase A2 receptor antibody; TC, total cholesterol; TG, triglycerides; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; IgG, immunoglobulin G; IgA, immunoglobulin A; IgM, immunoglobulin M; C3, complement 3; C4, complement 4.

A two-tailed p < 0.05 in bold was considered statistically significant.

Table 4. Risk factors of non-remission in PMN determined by univariate and multivariate cox regression.

Variable	FAR
	≤ 0.233 (n = 56)	>0.233 (n = 54)
Number of events, %	10 (17.9)	22 (40.7)
Model 1 HR(95%CI)	Reference	2.35 (1.11, 4.96)
P value	1	0.026
Model 2 HR(95%CI)	Reference	2.24 (1.05, 4.77)
P value	1	0.037
Model 3 HR(95%CI)	Reference	2.27 (1.01, 5.13)
P value	1	0.048

Hazard ratios (HR) and 95% confidence intervals (CI) were derived from Cox proportional hazards regression models. A two-tailed p < 0.05 in bold was considered statistically significant.

Model 1: unadjusted.

Model 2: adjusted for serum anti-PLA2R antibody.

Model 3: Model 2 plus age, gender, blood pressure and 24h urinary protein.

Figure 3. Association of FAR and treatment response in CNIs-receivers (A) Incidence of CR and PR between groups stratified for FAR levels by Kaplan-Meier survival curve in CNIs-receivers. (B) Predictive performances of variables for remission evaluated by ROC curves. ROC curve of FAR, anti-PLA2R Ab, and combination of FAR and anti-PLA2R Ab for remission outcomes. The AUC and the cutoff value of variables were presented in a separate table under the figure. *: Pairwise comparison; ^aFAR vs FAR + anti-PLA2R Ab; ^banti-PLA2R Ab vs FAR + anti-PLA2R Ab; ^cFAR vs anti-PLA2R Ab. FAR, fibrinogen-albumin ratio; CNIs, calcineurin Inhibitors; CR, complete remission; PR, partial remission; ROC, receiver operating characteristic. AUC, the area under the ROC curve.

Table 5. Risk factors of non-remission in CNIs-receivers determined by univariate and multivariate cox regression.

Variable	FAR
	≤ 0.233 (n = 47)	>0.233 (n = 47)
Number of events, %	5 (10.6%)	19 (40.4%)
Model 1 HR(95%CI)	Reference	3.83 (1.43, 10.29)
P value	1	0.008
Model 2 HR(95%CI)	Reference	3.63 (1.34, 9.82)
P value	1	0.011
Model 3 HR(95%CI)	Reference	4.00 (1.41, 11.31)
P value	1	0.009

Hazard ratios (HR) and 95% confidence intervals (CI) were derived from Cox proportional hazards regression models. A two-tailed p < 0.05 in bold was considered statistically significant.

Model 1: unadjusted.

Model 2: adjusted for serum anti-PLA2R antibody.

Model 3: Model 2 plus age, gender, blood pressure and 24h urinary protein.

CNIs, calcineurin inhibitors.