Baseline Characteristics of the Participants
A total of 1976 patients were included according to the inclusion and exclusion criteria. The median age was 34.84±10.75 years, and 902 (45.65%) were male. The median serum creatinine and 24 hours urine protein were 92 (68- 132) umol/L and 1.03 (0.49-2.12) g/24h. The mean serum IgG level was 10.82 ± 3.23g/L. The demographic and clinical characteristics that were stratified into tertiles of the baseline SIg levels are shown in Table 1. Statistically significant differences in many epidemiologic and clinical features were observed in the three groups, except in serum C3, serum C4 and usage of RAAS inhibitors. Patients in the highest tertile of sIgG were more likely to have higher eGFR and lower 24h proteinuria, with less percentage of patients with usage of corticosteroid and immunosuppressant. The pathological characteristics of participants are shown in Table2. There were 237 cases (11.99%) with glomerular IgG deposition, 992 cases (50.20%) with glomerular IgM deposition, and 1593 (80.62%) with glomerular C3 deposition. We observed lower rates of endocapillary hypercellularity (E1), tubular atrophy or interstitial fibrosis (T1 or T2), cellular or fibrocellular crescents (C1 or C2) in G3 group than the other two groups. Taken together, the baseline analyses indicated that IgAN patients in the highest tertile of sIgG presented with significantly less severe clinical and pathological manifestations.
Table 1 Baseline Clinical Data of 1976 IgAN Patients
|
|
Serum IgG(g/L)
|
|
Variable
|
All (n=1976)
|
G1
≤9.50 (n=631)
|
G2
9.51-11.99 (n=664)
|
G3
≥12.00 (n=681)
|
P
|
Male[n(%)]
|
902 (45.65%)
|
330 (52.30%)
|
319 (48.04%)
|
253 (37.15%)
|
<0.001
|
Age (year)
|
34.84 ± 10.75
|
32.75 ± 10.35
|
35.22 ± 11.04
|
36.42 ± 10.52
|
<0.001
|
SBP(mmHg)
|
127.77 ± 19.88
|
129.13 ± 20.47
|
127.91 ± 20.36
|
126.36 ± 18.76
|
0.041
|
DBP (mmHg)
|
81.88 ± 13.73
|
83.22 ± 14.53
|
81.93 ± 13.66
|
80.59 ± 12.91
|
0.002
|
Hemoglobin (g/L)
|
128.74 ± 20.26
|
129.33 ± 20.74
|
129.89 ± 20.07
|
127.07 ± 19.93
|
0.027
|
Serum Creatinine(umol/L)
|
92.00 (68.00-132.00)
|
96.00 (72.00-142.50)
|
93.00 (70.00-131.00)
|
87.00 (64.00-123.00)
|
<0.001
|
eGFR[ml·min-1·(1.73m2)]
|
80.38 ± 33.09
|
77.80 ± 35.18
|
80.29 ± 31.96
|
82.86 ± 32.02
|
0.022
|
24h proteinuria(g/24h)
|
1.03 (0.48-2.11)
|
1.93 (0.96-3.54)
|
0.98 (0.46-1.90)
|
0.65 (0.34-1.17)
|
<0.001
|
Uric Acid (umol/L)
|
384.22 ± 138.59
|
401.57 ± 171.81
|
384.55 ± 117.88
|
367.52 ± 118.98
|
<0.001
|
Albumin(g/L)
|
38.23 ± 13.29
|
33.96 ± 8.14
|
39.45 ± 15.56
|
41.00 ± 13.77
|
<0.001
|
Serum IgA (g/L)
|
3.10 ± 1.08
|
2.80 ± 1.10
|
3.06 ± 0.95
|
3.42 ± 1.10
|
<0.001
|
Serum IgM (g/L)
|
1.14 (0.83-1.53)
|
1.07 (0.79-1.44)
|
1.12 (0.81-1.52)
|
1.22 (0.89-1.64)
|
<0.001
|
C3 (g/L)
|
1.02 ± 0.34
|
1.03 ± 0.39
|
1.00 ± 0.31
|
1.03 ± 0.32
|
0.142
|
C4 (g/L)
|
0.24 (0.19-0.28)
|
0.24 (0.19-0.29)
|
0.23 (0.19-0.28)
|
0.24 (0.19-0.29)
|
0.636
|
Treatment(%)
|
|
|
|
|
|
Immunosuppressant
|
|
|
|
|
<0.001
|
no
|
1057 (53.49%)
|
333 (52.77%)
|
351 (52.86%)
|
373 (54.77%)
|
|
yes
|
178 (9.01%)
|
83 (13.15%)
|
63 (9.49%)
|
32 (4.70%)
|
|
missing
|
741 (37.50%)
|
215 (34.07%)
|
250 (37.65%)
|
276 (40.53%)
|
|
Glucocorticoid
|
|
|
|
|
<0.001
|
no
|
757 (38.31%)
|
181 (28.68%)
|
265 (39.91%)
|
311 (45.67%)
|
|
yes
|
611 (30.92%)
|
296 (46.91%)
|
194 (29.22%)
|
121 (17.77%)
|
|
missing
|
608 (30.77%)
|
154 (24.41%)
|
205 (30.87%)
|
249 (36.56%)
|
|
RASi
|
|
|
|
|
0.080
|
no
|
822 (41.60%)
|
275 (43.58%)
|
253 (38.10%)
|
294 (43.17%)
|
|
yes
|
1154 (58.40%)
|
356 (56.42%)
|
411 (61.90%)
|
387 (56.83%)
|
|
Abbreviations: SBP, systolic blood pressure;DBP,diastolic blood pressure;eGFR, estimated glomerular filtration rate; RASi, renin-angiotensin system inhibitors.
Calculation of estimated glomerular filtration rate was detailed in the text.
Table 2 Baseline pathological Data of 1976 IgAN Patients
|
|
Serum IgG(g/L)
|
|
Pathological Variable(%)
|
All(n=1976)
|
G1
≤9.50 (n=631)
|
G2
9.51-11.99 (n=664)
|
G3
≥12.00 (n=681)
|
P
|
Lee’s Grade
|
|
|
|
|
<0.001
|
1
|
17 (0.86%)
|
9 (1.43%)
|
4 (0.60%)
|
4 (0.59%)
|
|
2
|
164 (8.30%)
|
45 (7.13%)
|
50 (7.53%)
|
69 (10.13%)
|
|
3
|
439 (22.22%)
|
139 (22.03%)
|
160 (24.10%)
|
140 (20.56%)
|
|
4
|
241 (12.20%)
|
95 (15.06%)
|
75 (11.30%)
|
71 (10.43%)
|
|
5
|
90 (4.55%)
|
43 (6.81%)
|
27 (4.07%)
|
20 (2.94%)
|
|
mesangial hyper cellularity
|
|
|
|
|
0.002
|
M0
|
782 (39.57%)
|
225 (35.66%)
|
266 (40.06%)
|
291 (42.73%)
|
|
M1
|
1116 (56.48%)
|
386 (61.17%)
|
378 (56.93%)
|
352 (51.69%)
|
|
missing
|
78 (3.95%)
|
20 (3.17%)
|
20 (3.01%)
|
38 (5.58%)
|
|
endocapillary hypercellularity
|
|
|
|
|
<0.001
|
E0
|
1521 (76.97%)
|
466 (73.85%)
|
523 (78.77%)
|
532 (78.12%)
|
|
E1
|
274 (13.87%)
|
110 (17.43%)
|
94 (14.16%)
|
70 (10.28%)
|
|
missing
|
181 (9.16%)
|
55 (8.72%)
|
47 (7.08%)
|
79 (11.60%)
|
|
segmental sclerosis
|
|
|
|
|
<0.001
|
S0
|
1152 (58.30%)
|
361 (57.21%)
|
359 (54.07%)
|
432 (63.44%)
|
|
S1
|
739 (37.40%)
|
244 (38.67%)
|
282 (42.47%)
|
213 (31.28%)
|
|
missing
|
85 (4.30%)
|
26 (4.12%)
|
23 (3.46%)
|
36 (5.29%)
|
|
tubular atrophy / interstitial fibrosis
|
|
|
|
|
0.002
|
T0
|
1169 (59.16%)
|
342 (54.20%)
|
415 (62.50%)
|
412 (60.50%)
|
|
T1
|
606 (30.67%)
|
214 (33.91%)
|
198 (29.82%)
|
194 (28.49%)
|
|
T2
|
107 (5.41%)
|
47 (7.45%)
|
28 (4.22%)
|
32 (4.70%)
|
|
missing
|
94 (4.76%)
|
28 (4.44%)
|
23 (3.46%)
|
43 (6.31%)
|
|
Spherical Sclerosis Ratio
|
11.11 (0.00-30.77)
|
12.50 (0.00-35.71)
|
12.50 (0.00-28.57)
|
9.52 (0.00-28.00)
|
0.010
|
Crescent
|
|
|
|
|
<0.001
|
C0
|
1010 (53.84%)
|
258 (43.14%)
|
345 (54.33%)
|
407 (63.30%)
|
|
C1
|
710 (37.85%)
|
254 (42.47%)
|
246 (38.74%)
|
210 (32.66%)
|
|
C2
|
156 (8.32%)
|
86 (14.38%)
|
44 (6.93%)
|
26 (4.04%)
|
|
missing
|
100 (5.06%)
|
|
|
|
|
Renal IgG Deposition
|
|
|
|
|
0.200
|
no
|
1605 (81.22%)
|
513 (81.30%)
|
543 (81.78%)
|
549 (80.62%)
|
|
yes
|
237 (11.99%)
|
82 (13.00%)
|
81 (12.20%)
|
74 (10.87%)
|
|
missing
|
134 (6.78%)
|
36 (5.71%)
|
40 (6.02%)
|
58 (8.52%)
|
|
Renal IgM Deposition
|
|
|
|
|
<0.001
|
no
|
891 (45.09%)
|
242 (38.35%)
|
318 (47.89%)
|
331 (48.60%)
|
|
yes
|
992 (50.20%)
|
365 (57.84%)
|
318 (47.89%)
|
309 (45.37%)
|
|
missing
|
93 (4.71%)
|
24 (3.80%)
|
28 (4.22%)
|
41 (6.02%)
|
|
Renal C3 Deposition
|
|
|
|
|
0.379
|
no
|
311 (15.74%)
|
95 (15.06%)
|
103 (15.51%)
|
113 (16.59%)
|
|
yes
|
1593 (80.62%)
|
517 (81.93%)
|
540 (81.33%)
|
536 (78.71%)
|
|
missing
|
72 (3.64%)
|
19 (3.01%)
|
21 (3.16%)
|
32 (4.70%)
|
|
Abbreviations:
M1, mesangial hypercellularity>0.5;
E1, presence of endocapillary hypercellularity;
S1, presence of segmental glomerulosclerosis;
T1, tubular atrophy/interstitial fibrosis 26–50% of cortical area;
T2, tubular atrophy/interstitial fibrosis >50% of cortical area.
C1, presence of crescents ≥1 glomerulus;
C2, presence of crescents > 25% of glomeruli;
Note: Values are expressed as median (interquartile range) or number (percentage).
Prognostic Value of sIgG for renal outcome
The median follow-up time was 33.00 (21 to 53) months. 232 patients developed endpoints: 106 cases in G1group (doubled serum creatinine: 53 cases, ESRD: 53 cases); 72 cases in G2 group (doubled serum creatinine:42 cases, ESRD: 30 cases); 34 cases in G3 group (doubled serum creatinine:26 cases, ESRD: 28 cases). The Kaplan-Meier survival analysis showed that the 3-year,5-year and 9-year renal survival rates of all participants were 95.62%, 89.95% and 76.81% respectively. As shown in Figure 3, Kaplan-Meier analysis showed that the cumulative renal survival rates were significantly higher in patients with elevated sIgG level than the patients with lower sIgG level. The correlations between clinicopathological parameters and renal end point were analyzed using a Cox regression model. In a univariate analysis(Table 3), blood pressure, 24h urine proteinuria, albumin, serum creatinine, sIgG, glomerular sclerosis ratio ,tubular atrophy/interstitial fibrosis, and IgM deposition were significantly associated with renal survival. A multivariate Cox regression analysis further showed that sIgG remained as an independent predictor of renal survival with the full model adjusted for confounding factors (age, sex, blood pressure, BMI etc). When sIgG was assessed as tertiles, a significantly lower risk of the end point(OR: 0.90, 95% CI: 0.84–0.95) was observed.In addition,there was a significant inverse association between sIgG concentrations and the risk of poor outcome in the IgAN participants (Figure 2). Stratified analyses were performed to further assess the association between sIgG and the renal outcome in the subgroups. None of the variables, including age (<35 vs ≥35 years; P for interaction=0.8037), sex (P for interac- tion=0.5571), eGFR levels (<60 vs ≥60 mL/ min/1.73 m2; P for interaction=0.4171), proteinuria (<3.5 vs ≥3.5g/24h; P for interaction=0.2470) or hypertension (yes vs no; P for interaction=0.8923), significantly modified the association between sIgG and the endpoint (Table 5).
Table 3 Univariate analysis of clinicopathologic parameters with renal progression in IgAN patients.
Variable
|
HR(95%CI)
|
P
|
SBP(mmHg)
|
1.03 (1.02, 1.03)
|
<0.0001
|
DBP (mmHg)
|
1.04 (1.03, 1.05)
|
<0.0001
|
Hemoglobin (g/L)
|
0.98 (0.97, 0.98)
|
<0.0001
|
Serum Creatinine(umol/L)
|
1.02 (1.01, 1.02)
|
<0.0001
|
24h proteinuria(g/24h)
|
1.31 (1.22, 1.40)
|
<0.0001
|
Albumin(g/L)
|
0.96 (0.93, 0.99)
|
0.0024
|
Serum IgG (g/L)
|
0.89 (0.86, 0.93)
|
<0.0001
|
Serum IgA (g/L)
|
0.92 (0.80, 1.05)
|
0.2121
|
Serum IgM (g/L)
|
0.90 (0.73, 1.12)
|
0.3498
|
C3 (g/L)
|
0.67 (0.37, 1.22)
|
0.1924
|
C4 (g/L)
|
1.48 (0.69, 3.19)
|
0.3160
|
mesangial hyper cellularity
|
|
|
M0
|
1.0
|
|
M1
|
1.55 (1.16, 2.09)
|
0.0035
|
missing
|
1.13 (0.52, 2.44)
|
0.7611
|
endocapillary hyper cellularity
|
|
|
E0
|
1.0
|
|
E1
|
1.02 (0.67, 1.55)
|
0.9221
|
missing
|
2.85 (1.96, 4.15)
|
<0.0001
|
segmental sclerosis
|
|
|
S0
|
1.0
|
|
S1
|
2.19 (1.65, 2.90)
|
<0.0001
|
missing
|
0.95 (0.43, 2.13)
|
0.9093
|
tubular atrophy / interstitial fibrosis
|
|
|
T0
|
1.0
|
|
T1
|
5.22 (3.76, 7.27)
|
<0.0001
|
T2
|
11.19 (6.96, 18.00)
|
<0.0001
|
Missing
|
1.81 (0.84, 3.93)
|
0.1302
|
Crescent
|
|
|
C0
|
1.0
|
|
C1
|
1.34 (1.00, 1.81)
|
0.0515
|
C2
|
2.15 (1.34, 3.45)
|
0.0016
|
missing
|
1.00 (0.50, 1.98)
|
1.0000
|
Renal IgG Deposition
|
|
|
no
|
1.0
|
|
yes
|
0.90 (0.57, 1.41)
|
0.6379
|
missing
|
2.20 (1.42, 3.41)
|
0.0004
|
Renal IgM Deposition
|
|
|
no
|
1.0
|
|
yes
|
1.46 (1.09, 1.95)
|
0.0104
|
missing
|
2.15 (1.21, 3.81)
|
0.0087
|
Renal C3 Deposition
|
|
|
no
|
1.0
|
|
yes
|
1.15 (0.78, 1.70)
|
0.4902
|
missing
|
1.05 (0.46, 2.39)
|
0.9016
|
Table 4 Multivariable COX regression analysis of serum IgG level with renal progression in IgAN patients.
Variable
|
Non-adjusted
|
Model 1
|
Model 2
|
Mode1 3
|
Model 4
|
Serum IgG, g/L
|
|
|
|
|
|
Serum IgG, increased per 1g/L
|
0.91
(0.86, 0.96) 0.0011
|
0.87
(0.84, 0.91) <0.0001
|
0.93
(0.89, 0.97) 0.0004
|
0.92
(0.88, 0.96) 0.0004
|
0.90
(0.84, 0.95) 0.0004
|
G1
(≤9.50)
|
1.0
|
1.0
|
1.0
|
1.0
|
1.0
|
G2
9.51-11.99
|
0.63
(0.42, 0.96) 0.0301
|
0.49
(0.36, 0.65) <0.0001
|
0.66
(0.48, 0.89) 0.0061
|
0.68
(0.49, 0.93) 0.0154
|
0.69
(0.47, 1.00) 0.0507
|
G3
(≥12.00)
|
0.49
(0.30, 0.80) 0.0045
|
0.35
(0.26, 0.48) <0.0001
|
0.57
(0.40, 0.80) 0.0010
|
0.56
(0.39, 0.80) 0.0016
|
0.50
(0.32, 0.77) 0.0019
|
P for trend
|
<0.0001
|
Data expression: HR (95% CI)
Model 1 was adjusted for: age, gender;
Model 2 was adjusted for : model1+ SBP, DBP, eGFR, 24h urine protein;
Model 3 was adjusted for : model2+M,E,S,T,C;
Model 4 was adjusted for: model 3+mediations (renin-angiotensin system inhibitors, glucocorticoid, immunosuppressant).
Table 5 Stratified analyses by possible modifications for the association between sIgG concentrations and the progression of IgAN
Source
|
(G1-G2)
<11.99g/L Events/(%)
|
G3≥12.00g/L
Events/(%)
|
HR(95%CI)
|
P for interaction
|
Age,years
|
|
|
|
0.8037
|
<35
|
103/730(14.11)
|
25/330(7.58)
|
0.64 (0.40,1.03)
|
|
≥35
|
75/564(13.30)
|
29/352(8.24)
|
0.67 (0.42,1.06)
|
|
Sex
|
|
|
|
0.5571
|
Male
|
95/649(14.64)
|
28/253 (11.07)
|
0.67 (0.41,1.11)
|
|
Female
|
83/645(12.87)
|
26/429(6.06)
|
0.70 (0.42,1.15)
|
|
eGFR, mL/min/1.73 m2
|
|
|
|
0.4171
|
<60
|
137/434(31.57)
|
42/199(21.11)
|
0.54 (0.37, 0.80)
|
|
≥60
|
41/862(4.77)
|
12/483(2.48)
|
0.67 (0.33,1.35)
|
|
Proteinuria,g/24h
|
|
|
|
0.2470
|
<3.5
|
123/1037(11.86)
|
49/623(7.87)
|
0.60(0.42,0.86)
|
|
≥3.5
|
52/205(25.37)
|
3/15(20.00)
|
0.89(0.19,4.10)
|
|
Hypertension
|
|
|
|
0.8923
|
yes
|
157/1161(13.52)
|
49/614(7.98)
|
0.62 (0.43,0.87)
|
|
No
|
21/133 (15.79)
|
5/68(7.35)
|
0.54 (0.17, 1.73)
|
|
Notes: adjusted for age, sex,, systolic blood pressure, eGFR, proteinuria, Mmesangial score, segmental glomerulosclerosis score, endocapillary hypercellularity score, tubular atrophy/interstitial fibrosis score and crescents score if not stratified.
Abbreviations: eGFR, estimated glomerular filtration rate; OR, odds ratio; CI, confidence interval.