Clinical characteristics of IgA nephropathy associated with low complement 4 levels

Figures & data

Figure 1. Flow chart of identification of IgAN patients.

Table 1. Characteristics of IgAN patients with low level of serum C4 compared with those without low level of serum C4.

	NlowC4 group (n = 413)	LowC4 group (n = 99)	p Value
Clinical characteristics
Age (years, mean ± SD)	33.01 ± 11.30	30.20 ± 10.30	0.02
Sex (male/female)	215/198	50/49	0.8
MAP (mmHg, mean ± SD)	92.05 ± 12.41	89.52 ± 13.08	0.07
eGFR (ml/min, mean ± SD)	125.28 ± 37.77	140.87 ± 37.48	<0.001
24h proteinuria (mg, median(interquartile range))^a	680 (360, 1670)	410 (250, 1030)	<0.001
URBC (/μl, median(interquartile range))^a	38 (15, 73)	22 (7, 69)	0.05
Urinary NAG (g/gcr, median(interquartile range))^a	10.44 (6.27, 17.13)	7.15 (3.79, 7.15)	<0.001
UOP (mosm, mean ± SD)	683.97 ± 188.60	744.43 ± 178.70	0.006
IgA (mg/dl, mean ± SD)	311.25 ± 107.75	294.86 ± 101.83	0.2
IgG (mg/dl, mean ± SD)	1062.69 ± 343.55	1073.96 ± 343.94	0.8
IgM (mg/dl, mean ± SD)	153.37 ± 80.90	166.40 ± 71.11	0.2
C3 (mg/dl, mean ± SD)	102.02 ± 24.06	80.39 ± 16.86	<0.001
C4 (mg/dl, mean ± SD)	23.17 ± 7.20	13.40 ± 1.33	<0.001
Histopathologic features
Oxford classification
Mesangial hypercellularity
M0	166 (40.19)	50 (50.51)	0.07
M1	247 (59.81)	49 (49.49)
Endocapillary hypercellularity
E0	374 (90.56)	92 (92.93)	0.50
E1	39 (9.44)	7 (7.07)
Segmental glomerulosclerosis
S0	223 (54.00)	69 (69.70)	0.005
S1	190 (46.00)	30 (30.30)
Tubular atrophy/interstitial fibrosis
T0	279 (67.55)	86 (86.87)	<0.001
T1	97 (23.49)	10 (10.10)
T2	37 (8.96)	3 (3.03)
Crescent
Present (%)	237 (57.38)	50 (50.51)	0.2
Absent (%)	176 (42.62)	49 (49.49)
Katafuchi score (mean ± SD)	9.72 ± 3.69	7.86 ± 2.80	<0.001
Andreoli score (median(interquartile range))
Active	2.50 (2.00, 3.50)	2.00 (1.50, 3.00)	<0.001
Chronic	3.00 (2.00, 4.00)	2.00 (1.00, 4.00)	<0.001
Lee’s classification (≥grade III, n(%))	326 (78.93)	64 (64.65)	0.003
Renal immunoglobin/complement deposition
IgA (≥++, n(%))	392 (94.92)	92 (92.93)	0.4
IgG (≥++, n(%))	20 (4.84)	6 (6.06)	0.62
IgM (≥+, n(%))	323 (78.21)	88 (88.99)	0.02
C3 (≥++, n(%))	313 (75.29)	80 (80.81)	0.3
C4 (≥+, n(%))	26 (6.53)	0 (0)	0.008

Notes: MAP, mean arterial pressure; NAG, N-acetyl-beta-d-glucosaminidase; UOP, urinary osmotic pressure; Urinary erythrocytes (URBC).

^a24h proteinuria, URBC and urinary NAG with abnormal distribution were analyzed using log transferred form.

Table 2. Subgroup analysis of the characteristics of IgAN patients.

	Group				p Value			p Value^b
	NC group (n = 356)	LC4 group (n = 43)	BL group (n = 56)	LC3 group (n = 57)	LC4 vs. NC	BL vs. NC	LC3 vs. NC	LC4 vs. NC	BL vs. NC	LC3 vs. NC
Clinical characteristics
Age (years, mean ± SD)	33.03 ± 11.50	28.37 ± 11.95	31.61 ± 8.67	32.85 ± 10.00	0.01	0.4	0.9	–	–	–
Sex (male/female)	186/170	23/20	27/29	29/28	0.9	0.6	0.8	–	–	–
MAP (mmHg, mean ± SD)	92.62 ± 12.25	91.60 ± 14.55	82.93 ± 11.71	88.47 ± 12.93	0.6	0.009	0.02	–	–	–
eGFR (ml/min, mean ± SD)	124.67 ± 37.58	146.70 ± 43.48	136.74 ± 32.37	129.11 ± 39.05	<0.001	0.03	0.4	0.003	0.1	0.6
24h proteinuria (mg, median (interquartile range))^a	700 (370, 1780)	430 (270, 1075)	370 (220, 1030)	640 (290, 1420)	0.03	0.002	0.2	0.02	0.006	0.3
URBC (/μl, median (interquartile range))^a	38 (10, 68)	15 (2, 23)	46 (15, 83)	39 (23, 73)	<0.001	0.2	0.07	<0.001	0.3	0.09
Urinary NAG (g/gcr, median (interquartile range))^a	10.85 (6.27, 17.38)	6.73 (3.15, 10.78)	7.15 (4.40, 10.93)	9.29 (6.15, 15.17)	<0.001	0.001	0.4	<0.001	0.002	0.6
UOP (mosm, mean ± SD)	691.99 ± 186.69	798.95 ± 189.44	705.34 ± 161.27	634.02 ± 194.51	<0.001	0.6	0.03	0.002	0.9	0.01
Histopathologic features
Oxford classification
Mesangial hypercellularity
M0	151 (42.42)	24 (55.81)	26 (46.43)	15 (26.32)	0.09	0.6	0.02	–	–	–
M1	205 (57.58)	19 (44.19)	30 (53.57)	42 (73.68)				–	–	–
Endocapillary hypercellularity
E0	322 (90.45)	40 (93.02)	52 (92.86)	52 (91.23)	0.6	0.6	0.9	–	–	–
E1	34 (9.55)	3 (6.98)	4 (7.14)	5 (8.77)				–	–	–
Segmental glomerulosclerosis
S0	196 (55.06)	29 (67.44)	40 (71.43)	27 (47.37)	0.1	0.02	0.3	–	–	–
S1	160 (44.94)	14 (32.56)	16 (28.57)	30 (52.63)				–	–	–
Tubular atrophy/interstitial fibrosis								–	–	–
T0	242 (67.98)	39 (90.70)	47 (83.93)	37 (64.91)	<0.001	0.05	0.3	–	–	–
T1	85 (23.88)	3 (6.98)	7 (12.50)	12 (21.05)				–	–	–
T2	29 (8.15)	1 (2.33)	2 (3.57)	8 (14.04)				–	–	–
Crescent
Present (%)	201 (56.46)	21 (48.84)	29 (51.79)	36 (63.16)	0.3	0.5	0.3
Absent (%)	155 (43.54)	22 (51.16)	27 (48.21)	21 (36.84)
Katafuchi score (mean ± SD)	9.60 ± 3.72	7.51 ± 2.66	8.13 ± 2.90	10.46 ± 3.43	<0.001	0.004	0.09	–	–	–
Andreoli score (median (interquartile range))
Active	2.50 (2.00, 3.50)	2.00 (1.50, 2.50)	2.50 (2.00, 3.00)	2.50 (2.00, 3.50)	<0.001	0.1	0.5	–	–	–
Chronic	3.00 (2.00, 4.00)	2.00 (1.00, 3.00)	2.00 (1.00, 4.00)	3.00 (2.00, 4.75)	0.007	0.03	0.03	–	–	–
Lee’s classification (≥grade III, n(%))	279 (78.37)	26 (60.47)	38 (67.86)	47 (82.46)	0.01	0.08	0.5	–	–	–
Renal immunoglobin/complement deposition
IgM (≥+, n(%))	280 (78.65)	38 (88.37)	50 (89.29)	43 (75.44)	0.1	0.06	0.6	–	–	–
C4 (≥+, n(%))	24 (6.98)	0 (0.00)	0 (0.00)	2 (3.7)	0.2	0.06	0.6	–	–	–

Notes: NAG, N-acetyl-beta-D-glucosaminidase; UOP, urinary osmotic pressure; Urinary erythrocytes (URBC).

^a24h proteinuria, URBC and urinary NAG with abnormal distribution were analyzed using log transferred form.

^bp Value adjusted by age, MAP using a generalized linear model.

Table 3. Clinical characteristics of the follow-up patients compared with the lost to follow-up patients.

	LowC4 group			NlowC4 group
Parameters	Follow up n = 46	Lost to follow-up n = 53	p Value^a	Follow up n = 194	Lost to follow-up n = 219	p Value^b	p Value^c	p Value^d
Clinical characteristics
Follow up period (months)	40.56 (34.03, 46.62)	–	–	38.23 (32.87, 44.76)	–	–	0.3	–
Age (years, mean ± SD)	30.96 ± 10.44	29.55 ± 10.23	0.5	34.87 ± 10.78	31.36 ± 11.51	0.001	0.03	–
Sex (male/female)	21/25	29/24	0.4	101/93	114/105	0.9	0.4	–
MAP (mmHg, mean ± SD)	89.28 ± 13.26	89.74 ± 13.04	0.9	92.83 ± 12.61	91.37 ± 12.22	0.2	0.09	0.2
eGFR (ml/min, mean ± SD)	138.20 ± 42.74	143.22 ± 32.43	0.5	125.10 ± 38.33	125.43 ± 37.35	0.9	0.05	0.2
24h proteinuria (mg, median (interquartile range))^e	370 (230, 630)	415 (260, 1070)	0.3	605 (330, 1250)	800 (410, 2520)	0.001	0.03	0.05
Histopathologic features
Oxford classification
Mesangial proliferation
M0	25 (54.35)	25 (47.17)	0.5	110 (56.70)	82 (37.44)	0.2	0.2
M1	21 (45.65)	28 (52.83)		84 (43.30)	137 (62.56)
Endocapillary proliferation
E0	41 (89.13)	51 (96.23)	0.2	173 (89.18)	201 (91.78)	0.4	0.9
E1	5 (10.87)	2 (3.77)		21 (10.82)	18 (8.22)
Segmental sclerosis								–
S0	33 (71.74)	36 (67.92)	0.7	110 (56.70)	113 (51.60)	0.3	0.06	–
S1	13 (28.26)	17 (32.08)		84 (43.30)	106 (48.40)			–
Tubular atrophy/interstitial fibrosis								–
T0	38 (82.61)	48 (90.57)	0.5	126 (65.92)	153 (68.80)	0.2	0.05	–
T1	6 (13.04)	4 (7.55)		53 (26.82)	44 (20.94)			–
T2	2 (4.35)	1 (1.89)		15 (7.26)	22 (10.26)			–
Crescent								–
Present (%)	25 (54.35)	25 (47.17)	0.5	107 (55.15)	130 (59.36)	0.4	0.9
Absent (%)	21 (45.65)	28 (52.83)		87 (44.85)	89 (40.64)
Katafuchi score (mean ± SD)	8.34 ± 3.00	7.45 ± 2.57	0.1	9.96 ± 3.51	9.51 ± 3.83	0.2	0.004	–
Andreoli score (median (interquartile range))
Active	2.00 (1.50, 3.00)	2.00 (1.50, 2.50)	0.7	2.50 (2.00, 3.50)	2.50 (2.00, 3.50)	0.4	0.05	–
Chronic	2.00 (1.50, 3.50)	2.00 (1.00, 4.00)	0.6	3.00 (2.00, 4.00)	3.00 (2.00, 4.00)	0.8	0.02	–
Lee’s classification (≥++, n(%))	32 (60.38)	32 (69.57)	0.3	158 (81.44)	168 (76.71)	0.2	0.07	–
Renal immunoglobin/complement deposition
IgM (≥+, n(%))	41 (89.13)	47 (88.68))	0.9	148 (76.29)	175 (79.91)	0.4	0.06	–
C4 (≥+, n(%))	0 (0.00)	0 (0.00)	–	8 (4.26)	18 (8.57)	0.08	0.4	–
Treatment
ACEI/ARB	20 (47.62)	–		109 (60.89)	–		0.1
Immunosuppressive therapy^f
Steroid only	6 (13.04)	–		12 (6.19)	–		0.1
Immunosuppressors only	3 (6.52)	–		5 (2.58)	–		0.2
Steroid+immunosuppressors	2 (4.35)	–		27 (13.92)	–		0.08

Notes: ^ap Value comparing the follow-up cases with the lost to follow-up subgroup in LowC4 group.

^bp Value comparing the follow-up subgroup with the lost to follow-up subgroup in NLowC4 group.

^cp Value comparing the follow-up subgroup in LowC4 group with the follow-up subgroup in NLowC4 group.

^dp Value comparing the follow-up subgroup in LowC4 group with the follow-up subgroup in NLowC4 group adjusted by age using a generalized linear model.

^e24h proteinuria with abnormal distribution was analyzed using log transferred form.

^fImmunosuppressors including cyclophosphamide, mofetil mycophenolate, leflunomide.

Figure 2. A Kaplan–Meier renal survival curve suggested the accumulative survival rate was lower in the LowC4 group than that in the NlowC4 group (p = 0.05).

Table 4. Univariate and multivariate analysis of independent prognosis factors for the primary outcome.

	Univariable analysis		Multivariable analysis
Factor	Hazard ratio (95% CI)	p Value	Hazard ratio (95% CI)	p Value
LowC4	3.61 (0.90–14.48)	0.07	9.69 (1.90–49.48)	0.03
eGFR	0.86 (0.72–1.03)	0.1	0.84 (0.70–0.99)	0.04
Segmental glomerulosclerosis	6.39 (1.28–31.95)	0.02	10.38 (1.79–60.30)	0.03

Notes: This Cox proportional hazard model was fitted to explore the independent prognostic value including age, MAP, eGFR, 24h proteinuria, serum C3 level(binary variable, low C3 or not), serum C4 level (binary variable, low C4 or not), treatment (ACEI/ARB, steroid and/or immunosupressor) and pathological parameters based on Oxford IgAN classification including endocapillary hypercellularity, mesangial hypercellularity, interstitial fibrosis/tubular atrophy, segmental glomerulosclerosis, crescents. The primary outcome was defined as the serum creatinine increased 1.5 times from baseline.