Introduction: The aim of this study was to evaluate the predictive value of the serum IgA/C3 ratio and glomerular C3 deposits in kidney biopsy in adult IgA nephropathy. Methods: The study included 718 adult IgAN patients diagnosed based on kidney biopsy. Patients without corticosteroids or immunosuppressive drugs >1 month were regularly followed up for at least 1 year or until the study endpoint. The optimum serum IgA/C3 ratio was calculated by the AUROC-based cutoff ratio. Proteinuria, creatinine, eGFR, serum IgA, and serum C3 were evaluated at baseline. Kidney biopsy was categorized using the Oxford classification, with a calculation of the MEST-C score. The degree of glomerular C3 staining was semiquantitatively determined (grade 0, no or trace; grade 1, mild; grade 2, moderate; grade 3, marked) by immunofluorescence microscopy. The patients were divided into four groups by the serum IgA/C3 ratio and glomerular C3 staining. Results: The baseline data suggested that when the serum IgA/C3 ratio was at the same level, patients with a high glomerular C3 staining score (≥2) always had mesangial proliferation, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis (group 1 vs. group 2; group 3 vs. group 4). When glomerular C3 staining was at the same level, proteinuria was significantly higher in patients with serum IgA/C3<2.806 (group 1 vs. group 3; group 2 vs. group 4), which was contrary to previous studies that have suggested that the serum level of IgA/C3 was associated with disease severity. Hence, this study set out to investigate the combined effects of the serum IgA/C3 ratio and glomerular C3 staining on the renal outcome in adult IgA nephropathy. Renal survival analysis indicated that serum IgA/C3 ≥2.806 and glomerular C3 staining ≥2 (group 1) may be correlated with a poorer prognosis, especially in different clinicopathological characteristics of IgAN patients based on the subgroup analysis. Multivariate Cox analysis demonstrated that hypertension, serum creatinine, CKD stage, T1/2 and C3 staining were independent predictive factors of renal survival. Conclusions: The combination of serum IgA/C3 and C3 staining may contribute to improved optimization of the prognostic model in IgAN patients, especially patients with different sexes and degrees of disease. However, further study is required for validation in the future.

Immunoglobulin A (IgA) nephropathy (IgAN) is one of the most common primary glomerulonephritis types worldwide and most frequently in Asia, with the highest prevalence of 30–60% of all kidney biopsy diagnoses in patients [1]. IgAN is associated with an increased risk of end-stage renal disease (ESRD) and mortality in patients with severe estimated glomerular filtration rate (eGFR) decline and renal pathological lesions in the first year after diagnosis [2, 3]. It is difficult to stratify and treat for the very broad clinical presentation. Currently, except for the blockade of the renin-angiotensin-aldosterone system, patients at high risk of disease progression, such as those with renal syndrome and urine protein levels greater than 1 g/d after optimally supported treatment for 3–6 months, or those with renal biopsy showing severe active lesions, should consider corticosteroids (CS) therapy. If ineffective, immunosuppressants like morphine may be added [4]. However, CS and immunosuppressive therapies remain controversial in the clinical setting for the treatment of IgAN [5]. With a better understanding of the pathogenic mechanisms of IgA nephropathy, a number of targeted therapeutic drugs for IgA nephropathy have entered clinical trials, including targeted mucous membrane immunologists, targeted B-cell regulators (e.g., BAFF/APRIL inhibitors), and targeted complement system regulators, such as the CFB factor inhibitor LNP023 [6]. Thus, there is a lack of personalized and specific therapeutic strategies. The diagnosis of IgAN is based on the presence of IgA immune complex deposits in the mesangium [7]. Previous studies have suggested that the pathogenesis of IgAN is related to abnormal synthesis of deglycosylated IgA1, in situ immune complex formation, and complement activation [8]. However, few laboratory markers have been used to predict the therapeutic response and prognosis of IgAN before diagnosis or treatment.

Prior studies have reported that serum IgA and deglycosylated IgA1 levels are significantly increased in adult IgAN patients [9], and the serum IgA/complement factor 3 (IgA/C3) ratio is higher than that in other glomerular diseases [10]. Komatsu et al. reported that glomerular C3 staining was related to the severity of renal pathology [11]. Patients with severe-stage IgAN had significantly higher serum IgA levels than non-IgAN patients, while serum C3 levels were decreased compared to non-IgAN patients [12]. Additionally, a recent study demonstrated that the serum IgA/C3 ratio and glomerular C3 staining can predict the progression of IgA nephropathy in children [13]. Given the pathogenesis relationship between adults and children, the serum IgA/C3 ratio and glomerular C3 staining may have a likely impact on adult IgAN patients, but no study has proven this. Thus, we speculated that this study could provide more exact evidence for the predictive outcomes of IgAN by using a combination of the serum IgA/C3 ratio and glomerular C3 staining.

This study was approved by the Ethics Committee of the West China Hospital of Sichuan University (ethical approval number 2019-33). Written informed consent was obtained from all participants prior to study and retrospectively registered in the Thai Clinical Trials Registry (TCTR20180313004, March 13, 2018). This study adhered to the Helsinki Declaration.

Patients

This study retrospectively involved 1,731 adult patients with newly diagnosed biopsy-proven IgAN at West China Hospital from December 2007 to February 2020. The inclusion criteria were as follows: follow-up period ≥12 months; predominance of IgA deposits in the glomerular mesangium by renal biopsy pathology; and complete serum IgA, serum C3, and pathological glomerular C3 staining data. The exclusion criteria were as follows: (i) secondary IgAN due to systemic diseases such as systemic lupus erythematosus, Henoch-Schönlein purpura, liver cirrhosis, diabetic nephropathy, and Reiter’s syndrome; (ii) patients with heart, brain, liver, lung, and other important organ failure or other systemic immune diseases, such as ankylosing spondylitis, psoriasis, tuberculosis, malignant tumor, etc.; (iii) chronic kidney disease (CKD) stage 5, acute kidney injury or kidney transplant patients; and (iv) previous treatment with CS or immunosuppressive drugs >1 month.

Clinical and Pathological Data

Clinical information at the time of biopsy and outpatient records, such as sex, age, systolic blood pressure, diastolic blood pressure, serum creatinine (Scr), eGFR, serum albumin (Alb), uric acid, 24-h proteinuria level, serum IgA, serum C3, the use of antihypertensive and immunosuppressive drugs, and kidney pathology data of all patients, were assessed. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Serum IgA and C3 were measured using the immunoturbidimetry method, and the reference ranges were 836–2,900 mg/L and 0.785–1.520 g/L, respectively. Hypertension was defined as blood pressure >140/90 mm Hg or the use of antihypertensive agents. Follow-up duration was defined as the interval between renal biopsy and the last outpatient visit, death, or ESRD. Renal biopsy specimens of all patients were reviewed by experienced pathologists and nephrologists who were blinded to each other’s evaluations as well as the patients’ clinical data. When there were inconsistencies or doubts among pathologists and nephrologists, these were submitted to a higher-level pathologist for review. Pathological lesions were graded according to the Oxford classification: mesangial proliferation (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), and fibrocellular/cellular crescents (C) [14]. The degree of glomerular C3 staining was semiquantitatively determined (grade 0, no or trace; grade 1, mild; grade 2, moderate; grade 3, marked) by immunofluorescence microscopy.

Treatment modalities were recorded, including the use of CS or other immunosuppressants and renin-angiotensin system inhibitors (RAS-I). Patients refusing to take steroids or immunosuppressants were given optimal supportive therapy. Treatment modalities were categorized into two groups: support treatment group: optimized dose of ACEI or ARB; immunosuppressants group: supportive care combined with CS (0.5–1 mg/kg prednisone daily, tapering down within 6–8 months; with or without cyclophosphamide 2 mg/kg daily for 3 months, MMF 1–2 g daily for 6–8 months, cyclosporine 3–5 mg/kg daily for 6–8 months, or tacrolimus 0.03–0.05 mg/kg daily for 6–8 months).

Grouping

All patients were divided into two groups according to the proteinuria range: proteinuria >3.5 g and proteinuria ≤3.5 g. Serum IgA and C3 were measured using the immunoturbidimetry method at baseline, and the serum IgA/C3 ratio was calculated to apply a receiver operating characteristic (ROC) curve-based cutoff ratio that had optimal sensitivity and specificity for two proteinuria groups, which was in accordance with the guidelines of the Clinical and Laboratory Standards Institute (CLSI/NCCLS) [15]. Finally, all patients were divided into group 1 (serum IgA/C3≥2.806 and C3 staining≥2), group 2 (serum IgA/C3≥2.806 and C3 staining<2), group 3 (serum IgA/C3<2.806 and C3 staining≥2), and group 4 (serum IgA/C3<2.806 and C3 staining<2) based on glomerular C3 staining grade and the optimal ROC-cutoff value of the serum IgA/C3 ratio.

Endpoint

The composite endpoint in this study was a renal function decline of >50% in eGFR, ESRD, and/or death. A renal function decline of >50% in eGFR was defined as a >50% decrease in eGFR relative to baseline from the time of biopsy. ESRD was defined as eGFR <15 mL/min/1.73 m2, chronic dialysis, or renal transplantation.

Statistical Analysis

Categorical variables are presented as frequencies and percentages and were compared using Fisher’s and χ2 tests. Continuous variables are expressed as the mean ± standard deviation or median with interquartile range and were analyzed by an unpaired t test or the Kruskal-Wallis H test or the nonparametric Mann-Whitney U test as appropriate for normally and nonnormally distributed variables (the Shapiro-Wilk test). ROC was used to calculate the serum IgA/C3 ratio with optimal sensitivity and specificity in two different proteinuria groups. Then, all patients were divided into group 1, group 2, group 3, and group 4 based on glomerular C3 staining grade and the optimal ROC-cutoff value of the serum IgA/C3 ratio. Kidney survival for each group was estimated using the Kaplan-Meier method with a log-rank test. Univariate analysis, followed by multivariate regression, was used to determine independent predictors or risk factors. The relationship between parameters and renal survival was assessed through Cox regression. Results were expressed as hazard ratios and 95% confidence intervals. IBM SPSS Statistics 22.0 was used for statistical analysis, and a p value <0.05 was considered significant.

According to the inclusion and exclusion criteria, 718 patients with IgAN (311 men and 407 women) were enrolled in our study (Fig. 1). The average age was 34.04 ± 11.09 years. Patients were followed for 42.7 ± 21.3 months. The proteinuria levels of patients in our cohort ranged from 0.3 to 34.6 g/day. Among the 718 patients, 489 participants (68.1%) had proteinuria ≥1 g/day, and 155 (21.6%) had proteinuria >3.5 g/day. Serum IgA ranged from 698 to 6,890 mg/L, while 322 (45.0%) patients had increased serum IgA levels (>2,900 mg/L). Serum C3 levels ranged from 0.098 to 1.83 g/L, 174 (24.2%) patients had decreased serum C3 levels (<0.785 g/L), and only 4 (0.6%) patients had slightly increased serum C3 levels (>1.52 g/L). CKD stages 1, 2, 3, and 4 were found in 364 patients (50.7%), 182 patients (25.4%), 144 patients (20.1%), and 28 patients (3.9%), respectively. A total of two hundred eight-three patients (39.4%) accepted support treatment, while four hundred thirty-five (60.6%) patients accepted immunosuppressants according to the therapeutic strategy.

Fig. 1.

Flow diagram. IgA, immunoglobulin A; C3, complement 3.

Fig. 1.

Flow diagram. IgA, immunoglobulin A; C3, complement 3.

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Selection and the Optimal Cutoff Value of the Serum IgA/C3 Ratio

Proteinuria is correlated with the progression of IgAN. Patients were divided into different groups according to proteinuria levels (3.5, 1, and 0.75 g/day) to compare the serum IgA/C3 ratio. According to Figure 2, the serum IgA/C3 ratio was significantly different between different proteinuria groups, especially in the proteinuria ≤3.5 g/kg/day group and the proteinuria >3.5 g/kg/day group. As reported in previous studies, our study used the ROC curve to determine the optimal cutoff value of the IgA/C3 ratio for the ≤3.5 g/kg/day proteinuria group and the >3.5 g/kg/day proteinuria group [13]. The optimal cutoff value of the serum IgA/C3 ratio calculated by the ROC curve was 2.806, with a sensitivity and specificity of 63.9% and 58.7%, respectively (Table 1). Next, all patients were divided into a serum IgA/C3<2.806 (294 patients) group and a serum IgA/C3≥2.806 (424 patients) group. The levels of 24-h urine protein, serum albumin, eGFR, serum creatinine, and histological variables in different groups were compared (Table 2). Patients in the serum IgA/C3<2.806 group presented with significantly higher 24-hour proteinuria and lower serum albumin than those in the serum IgA/C3≥2.806 group. However, there were no significant differences in clinical and histological variables in groups according to C3 staining. It was reported that the serum IgA/C3 ratio was higher compared with other glomerular diseases [10], and glomerular C3 staining was related to the severity of renal pathology [11]. In this study, Kaplan-Meier analysis was carried out to explore their potential impacts. The difference in prognosis between the serum IgA/C3≥2.806 group and the serum IgA/C3<2.806 group was not statistically significant (p = 0.656, online suppl. 1A; for all online suppl. material, see https://doi.org/10.1159/000536114). Similar results were also found between the C3 staining≥2 group and the C3 staining<2 group (p = 0.582, online suppl. 1B). These results suggest that the serum IgA/C3 ratio or C3 staining is not an independent protective factor for the prognosis of IgAN patients. Hence, in the next part of this study, we will explore the prognosis of IgAN by using a combination of the serum IgA/C3 ratio and glomerular C3 staining.

Fig. 2.

Comparison of serum IgA/C3 ratio according to 24 h-proteinuria. p < 0.001. UP, urine protein; IgA, immunoglobulin A; C3, complement 3.

Fig. 2.

Comparison of serum IgA/C3 ratio according to 24 h-proteinuria. p < 0.001. UP, urine protein; IgA, immunoglobulin A; C3, complement 3.

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Table 1.

Optimal cutoff value of serum IgA/C3 ratio in IgAN patients for proteinuria ≤3.5 g/day group and proteinuria >3.5 g/day group

CutoffSensitivitySpecificityAUC (95% CI)p value
Serum IgA/C3 2.806 0.639 0.587 0.620 (0.568–0.671) <0.001 
CutoffSensitivitySpecificityAUC (95% CI)p value
Serum IgA/C3 2.806 0.639 0.587 0.620 (0.568–0.671) <0.001 

AUC, areas under the ROC curves; IgA, immunoglobulin A; C3, complement 3.

Table 2.

Clinicopathological data of IgAN patients according to serum IgA/C3 ratio or glomerular C3 staining

ParametersGroupsp value
serum IgA/C3<2.806 (n = 294)serum IgA/C3≥2.806 (n = 424)
Urine protein, g/24 h 2.1 (1.0, 3.9) 1.3 (0.7, 2.5) <0.001 
Serum albumin, g/L 39.0 (33.0, 43.0) 40.0 (37.0, 43.0) 0.004 
eGFR, mL/min/1.73 m2 91.1 (61.7, 116.4) 89.4 (59.5, 113.0) 0.779 
Serum creatinine, μmol/L 86.0 (65.0, 119.0) 85.4 (66.0, 112.0) 0.730 
M1, n (%) 208 (70.7) 324 (76.4) 0.088 
E1, n (%) 16 (5.4) 23 (5.4) 0.992 
S1, n (%) 149 (50.7) 241 (56.8) 0.103 
T1/2, n (%) 60 (20.4) 95 (22.4) 0.522 
C1/2, n (%) 75 (25.5) 106 (25.0) 0.877 
ParametersGroupsp value
serum IgA/C3<2.806 (n = 294)serum IgA/C3≥2.806 (n = 424)
Urine protein, g/24 h 2.1 (1.0, 3.9) 1.3 (0.7, 2.5) <0.001 
Serum albumin, g/L 39.0 (33.0, 43.0) 40.0 (37.0, 43.0) 0.004 
eGFR, mL/min/1.73 m2 91.1 (61.7, 116.4) 89.4 (59.5, 113.0) 0.779 
Serum creatinine, μmol/L 86.0 (65.0, 119.0) 85.4 (66.0, 112.0) 0.730 
M1, n (%) 208 (70.7) 324 (76.4) 0.088 
E1, n (%) 16 (5.4) 23 (5.4) 0.992 
S1, n (%) 149 (50.7) 241 (56.8) 0.103 
T1/2, n (%) 60 (20.4) 95 (22.4) 0.522 
C1/2, n (%) 75 (25.5) 106 (25.0) 0.877 
C3 staining <2 (n = 130)C3 staining ≥2 (n = 588)
Urine protein, g/24 h 1.7 (0.9, 3.6) 1.6 (0.7, 3.0) 0.131 
Serum albumin, g/L 40 (31.8, 44.0) 40.0 (36.0, 43.0) 0.086 
eGFR, mL/min/1.73 m2 92.3 (68.8, 117.0) 89.1 (59.0, 114.5) 0.213 
Serum creatinine, μmol/L 80.0 (65.8, 107.3) 86.8 (66.0, 117.0) 0.053 
M1, n (%) 72 (55.45) 460 (78.2) <0.001 
E1, n (%) 5 (3.8) 34 (5.8) 0.378 
S1, n (%) 64 (49.2) 326 (55.4) 0.198 
T1/2, n (%) 17 (13.1) 138 (23.5) 0.009 
C1/2, n (%) 26 (20.0) 155 (26.4) 0.131 
C3 staining <2 (n = 130)C3 staining ≥2 (n = 588)
Urine protein, g/24 h 1.7 (0.9, 3.6) 1.6 (0.7, 3.0) 0.131 
Serum albumin, g/L 40 (31.8, 44.0) 40.0 (36.0, 43.0) 0.086 
eGFR, mL/min/1.73 m2 92.3 (68.8, 117.0) 89.1 (59.0, 114.5) 0.213 
Serum creatinine, μmol/L 80.0 (65.8, 107.3) 86.8 (66.0, 117.0) 0.053 
M1, n (%) 72 (55.45) 460 (78.2) <0.001 
E1, n (%) 5 (3.8) 34 (5.8) 0.378 
S1, n (%) 64 (49.2) 326 (55.4) 0.198 
T1/2, n (%) 17 (13.1) 138 (23.5) 0.009 
C1/2, n (%) 26 (20.0) 155 (26.4) 0.131 

IgA, immunoglobulin A; C3, complement 3; eGFR, estimated glomerular filtration rate.

Baseline Characteristics of Patients Categorized according to the Serum IgA/C3 Ratio and Glomerular C3 Staining

Various studies have assessed whether glomerular C3 staining may play a vital role in renal prognosis in IgAN patients [16‒18]. To further analyze the other risk factors, this serum IgA/C3 ratio was combined with glomerular C3 staining. All 718 patients were classified according to the serum IgA/C3 ratio and glomerular C3 staining into four groups to better understand the relationship between the risk factors C3 staining and serum IgA/C3 ratio: group 1 (serum IgA/C3≥2.806 and C3 staining≥2) (250 patients), group 2 (serum IgA/C3≥2.806 and C3 staining<2) (174 patients), group 3 (serum IgA/C3<2.806 and C3 staining≥2) (128 patients), and group 4 (serum IgA/C3<2.806 and C3 staining<2) (166 patients). The baseline data of the four groups are shown in Table 3. There were no baseline differences among the four groups in follow-up, age, sex, hypertension, systolic blood pressure, diastolic blood pressure, serum albumin, endocapillary proliferation, or crescents. When the serum IgA/C3 ratio was at the same level, patients with a high glomerular C3 staining score (≥2) always had mesangial proliferation, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis (group 1 vs. group 2; group 3 vs. group 4). When glomerular C3 staining was at the same level, proteinuria was significantly higher in patients with serum IgA/C3<2.806 (group 1 vs. group 3; group 2 vs. group 4). Interestingly, serum creatinine was significantly lower and eGFR was higher in group 4 (serum IgA/C3<2.806 and C3 staining<2) than in group 1 (serum IgA/C3≥2.806 and C3 staining≥2). These findings were not consistent with some previous studies. These discrepancies suggested that serum IgA/C3 or glomerular C3 staining alone may not be sufficient to predict prognosis. Therefore, it is necessary to investigate the combined effects of the serum IgA/C3 ratio and glomerular C3 staining on the renal outcome.

Table 3.

Baseline clinicopathological characteristics of IgAN patients in different groups

ParametersGroup 1 (n = 250)Group 2 (n = 174)Group 3 (n = 128)Group 4 (n = 166)
Clinical 
 Follow-up, months 35.4 (25.6, 54.7) 37.1 (28.8, 56.7) 38.9 (26.8, 61.3) 37.1 (28.8, 56.6) 
 Male, n (%) 110 (44.0) 71 (40.8) 50 (39.1) 80 (48.2) 
 Age, years 31 (25, 40) 35 (26, 42) 30 (25, 39) 35 (27, 42) 
 Hypertension, n (%) 82 (32.4) 60 (34.5) 51 (39.8) 67 (40.1) 
 SBP, mm Hg 125 (116, 141) 125 (113, 140) 130 (119, 150) 125 (113, 140) 
 DBP, mm Hg 81 (75, 94) 80 (74, 93) 85 (75, 96) 80 (74, 93) 
 Urine protein, g/24 ha,b,c 1.3 (0.7, 2.5) 1.5 (0.7, 2.6) 2.1 (0.8, 3.9) 1.5 (0.7, 2.6) 
 Serum albumin, g/L 40.00 (37.00, 43.00) 40.25 (35.38, 43.10) 39.00 (34.00, 43.00) 40.3 (35.4, 43.1) 
 Serum creatinine, μmol/Lb 87.0 (66.0, 117.0) 83.4 (66.0, 108.0) 93.0 (69.0, 132.0) 83.4 (66.0, 108.0) 
 eGFR, mL/min/1.73 m2b 89.1 (56.3, 113.0) >90.0 (65.5, 114.7) 79.0 (52.2, 104.9) >90.0 (65.5, 114.7) 
 CKD stage 1 123 (49.2) 90 (51.7) 52 (40.6) 99 (59.6) 
 CKD stage 2 58 (23.2) 47 (27.0) 43 (33.6) 34 (20.5) 
 CKD stage 3 60 (24.0) 30 (17.2) 26 (20.3) 28 (16.9) 
 CKD stage 4 9 (3.6) 7 (4.0) 7 (5.5) 5 (3.0) 
 M1d,b,e,f 207 (82.8) 117 (67.2) 103 (80.5) 105 (63.3) 
 E1 13 (5.2) 10 (5.7) 9 (7.0) 7 (4.2) 
 S1d,b 153 (61.2) 88 (50.6) 69 (53.9) 80 (48.2) 
 T1/2e,b,e,f 69 (27.6) 26 (14.9) 37 (28.9) 23 (13.9) 
 C1/2 62 (24.8) 44 (25.3) 40 (31.3) 35 (21.1) 
Treatment, n (%) 
 Support treatment 107 (42.4) 73 (42.0) 49 (38.3) 55 (33.1) 
 Immunosuppressants 144 (57.6) 101 (58.0) 79 (61.7) 111 (66.9) 
ParametersGroup 1 (n = 250)Group 2 (n = 174)Group 3 (n = 128)Group 4 (n = 166)
Clinical 
 Follow-up, months 35.4 (25.6, 54.7) 37.1 (28.8, 56.7) 38.9 (26.8, 61.3) 37.1 (28.8, 56.6) 
 Male, n (%) 110 (44.0) 71 (40.8) 50 (39.1) 80 (48.2) 
 Age, years 31 (25, 40) 35 (26, 42) 30 (25, 39) 35 (27, 42) 
 Hypertension, n (%) 82 (32.4) 60 (34.5) 51 (39.8) 67 (40.1) 
 SBP, mm Hg 125 (116, 141) 125 (113, 140) 130 (119, 150) 125 (113, 140) 
 DBP, mm Hg 81 (75, 94) 80 (74, 93) 85 (75, 96) 80 (74, 93) 
 Urine protein, g/24 ha,b,c 1.3 (0.7, 2.5) 1.5 (0.7, 2.6) 2.1 (0.8, 3.9) 1.5 (0.7, 2.6) 
 Serum albumin, g/L 40.00 (37.00, 43.00) 40.25 (35.38, 43.10) 39.00 (34.00, 43.00) 40.3 (35.4, 43.1) 
 Serum creatinine, μmol/Lb 87.0 (66.0, 117.0) 83.4 (66.0, 108.0) 93.0 (69.0, 132.0) 83.4 (66.0, 108.0) 
 eGFR, mL/min/1.73 m2b 89.1 (56.3, 113.0) >90.0 (65.5, 114.7) 79.0 (52.2, 104.9) >90.0 (65.5, 114.7) 
 CKD stage 1 123 (49.2) 90 (51.7) 52 (40.6) 99 (59.6) 
 CKD stage 2 58 (23.2) 47 (27.0) 43 (33.6) 34 (20.5) 
 CKD stage 3 60 (24.0) 30 (17.2) 26 (20.3) 28 (16.9) 
 CKD stage 4 9 (3.6) 7 (4.0) 7 (5.5) 5 (3.0) 
 M1d,b,e,f 207 (82.8) 117 (67.2) 103 (80.5) 105 (63.3) 
 E1 13 (5.2) 10 (5.7) 9 (7.0) 7 (4.2) 
 S1d,b 153 (61.2) 88 (50.6) 69 (53.9) 80 (48.2) 
 T1/2e,b,e,f 69 (27.6) 26 (14.9) 37 (28.9) 23 (13.9) 
 C1/2 62 (24.8) 44 (25.3) 40 (31.3) 35 (21.1) 
Treatment, n (%) 
 Support treatment 107 (42.4) 73 (42.0) 49 (38.3) 55 (33.1) 
 Immunosuppressants 144 (57.6) 101 (58.0) 79 (61.7) 111 (66.9) 

C, crescents; CKD, chronic kidney disease; DBP, diastolic blood pressure; E, endocapillary proliferation; eGFR, estimated glomerular filtration rate; G, glomerulosclerosis; M, mesangial proliferation; S, segmental sclerosis; SBP, systolic blood pressure; T, tubular atrophy/interstitial fibrosis.

aStands for p < 0.05 between groups 1 and 3.

bStands for p < 0.05 between groups 1 and 4.

cStands for p < 0.05 between groups 2 and 4.

dStands for p < 0.05 between groups 1 and 2.

eStands for p < 0.05 between groups 2 and 3.

fStands for p < 0.05 between groups 3 and 4.

Clinical Outcome and Renal Survival

At the end of follow-up, 1 patient (0.6%) in group 2 and 3 patients in group 4 (1.8%) died (Table 4). Patients in group 3 had a significantly higher rate of 50% decline in eGFR, ESRD, and combined endpoint than patients in group 2. Kaplan‒-Meier analysis demonstrated that the median survival time for group 1 was 87 months, and the survival rates at 87 months for groups 2, 3, and 4 were 0.806, 0.804, and 0.697, respectively (Fig. 3a). Combined with the Kaplan-Meier survival curve, these results suggested that patients with serum IgA/C3≥2.806 and C3 staining≥2 seemed to have a trend of worse outcome (group 1 vs. group 2, p = 0.083). Further analysis showed that renal survival rates were remarkably lower in group 1 than in group 4 in patients with 24-hour proteinuria ≥1 g (Fig. 3e). For male IgAN patients, the renal outcome was significantly good in group 2 with serum IgA/C3≥2.806 and C3 staining<2. For female IgAN patients, Kaplan-Meier analysis revealed that the group with serum IgA/C3≥2.806 had a significantly poor renal outcome (group 2 vs. group 4, p = 0.027) (Fig. 3c). In addition, the renal survival rate significantly differed between group 2 and group 3 in IgAN patients with CKD stage 1–2 and receiving support treatments (Fig. 3f, h). No significant differences were detected in other subgroup analyses with different clinical parameters (Fig. 3).

Table 4.

Clinical outcomes of IgAN patients at the end of study

OutcomesGroup 1 (n = 250), n (%)Group 2 (n = 174), n (%)Group 3 (n = 128), n (%)Group 4 (n = 166), n (%)p value
50% decline in eGFR* 28 (11.2) 12 (6.9) 20 (15.6) 14 (8.4) 0.083 
ESRD* 18 (7.2) 11 (6.3) 18 (14.1) 13 (7.8) 0.120 
Death 0 (0.0) 1 (0.6) 0 (0.0) 3 (1.8) 0.076 
Combined endpoint* 29 (11.6) 14 (8.0) 21 (16.4) 16 (9.6) 0.132 
OutcomesGroup 1 (n = 250), n (%)Group 2 (n = 174), n (%)Group 3 (n = 128), n (%)Group 4 (n = 166), n (%)p value
50% decline in eGFR* 28 (11.2) 12 (6.9) 20 (15.6) 14 (8.4) 0.083 
ESRD* 18 (7.2) 11 (6.3) 18 (14.1) 13 (7.8) 0.120 
Death 0 (0.0) 1 (0.6) 0 (0.0) 3 (1.8) 0.076 
Combined endpoint* 29 (11.6) 14 (8.0) 21 (16.4) 16 (9.6) 0.132 

The composite endpoint was death, 50% decline in eGFR and/or ESRD.

ESRD, end-stage renal disease; eGFR, estimated glomerular filtration rate.

* p < 0.05 between groups 2 and 3.

Fig. 3.

Kaplan-Meier analysis for the endpoint of four groups. The composite endpoint was death, 50% decline in eGFR and/or ESRD. a Kaplan-Meier analysis for all patients. b, c Kaplan-Meier analysis for patients with different gender. d, e Kaplan-Meier analysis for patients with different urine protein to the endpoint of ESRD. f, g Kaplan-Meier analysis for patients with different CKD stages. h, i Kaplan-Meier analysis for patients with different treatment.

Fig. 3.

Kaplan-Meier analysis for the endpoint of four groups. The composite endpoint was death, 50% decline in eGFR and/or ESRD. a Kaplan-Meier analysis for all patients. b, c Kaplan-Meier analysis for patients with different gender. d, e Kaplan-Meier analysis for patients with different urine protein to the endpoint of ESRD. f, g Kaplan-Meier analysis for patients with different CKD stages. h, i Kaplan-Meier analysis for patients with different treatment.

Close modal

Predictive Factors of Renal Outcome

Univariate analysis showed that age, sex, hypertension, proteinuria, serum creatinine, serum albumin, CKD stage at baseline, and the presence of mesangial proliferation (M1), segmental sclerosis (S1), and tubular atrophy/interstitial fibrosis (T1/2) were significantly associated with increased renal outcome risk in this study. However, the multivariable model included only hypertension, serum creatinine, CKD stage at baseline, T1/2 and C3 staining as independent predictive factors of renal survival (Table 5).

Table 5.

Univariate and multivariate Cox proportional hazard model for the renal outcome in 722 IgAN patients

ParametersVIFUnivariateMultivariate
HR95% CIp valueHR95% CIp value
Age 1.2 1.0 1.00–1.04 0.1 1.0 0.96–1.01 0.3 
Male 1.3 1.6 1.02–2.47 0.0 0.7 0.42–1.27 0.3 
Hypertension 1.2 4.1 2.56–6.44 <0.001 1.8 1.09–3.11 0.0 
Proteinuria>1 g/day 1.8 5.7 2.74–12.46 <0.001 2.1 0.88–4.81 0.1 
Serum creatinine 3.0 1.0 1.01–1.02 <0.001 1.0 1.01–1.01 <0.001 
Serum albumin 1.3 1.0 0.94–0.99 0.0 1.0 0.97–1.07 0.4 
Serum IgA 2.2 0.9 0.72–1.13 0.4 1.2 0.82–1.66 0.4 
Serum C3 1.5 0.3 0.10–1.03 0.1 0.3 0.08–1.47 0.1 
Serum IgA/C3≥2.806 2.5 0.9 0.58–1.41 0.7 0.9 0.41–1.81 0.7 
CKD 3-4 2.7 14.2 8.21–24.60 <0.001 2.9 1.41–6.06 0.0 
M1 1.2 3.4 1.49–7.89 0.0 1.5 0.61–3.50 0.4 
E1 1.1 1.8 0.76–4.05 0.2    
S1 1.2 2.5 1.56–4.11 <0.001 1.2 0.68–1.95 0.6 
T1/2 1.5 12.9 7.76–21.43 <0.001 3.5 1.89–6.62 <0.001 
C1/2 1.2 1.4 0.90–2.27 0.1    
C3 staining≥2 1.1 1.2 0.64–2.20 0.6 0.4 0.23–0.88 0.0 
IT treatments 1.6 0.8 0.52–1.27 0.4    
ParametersVIFUnivariateMultivariate
HR95% CIp valueHR95% CIp value
Age 1.2 1.0 1.00–1.04 0.1 1.0 0.96–1.01 0.3 
Male 1.3 1.6 1.02–2.47 0.0 0.7 0.42–1.27 0.3 
Hypertension 1.2 4.1 2.56–6.44 <0.001 1.8 1.09–3.11 0.0 
Proteinuria>1 g/day 1.8 5.7 2.74–12.46 <0.001 2.1 0.88–4.81 0.1 
Serum creatinine 3.0 1.0 1.01–1.02 <0.001 1.0 1.01–1.01 <0.001 
Serum albumin 1.3 1.0 0.94–0.99 0.0 1.0 0.97–1.07 0.4 
Serum IgA 2.2 0.9 0.72–1.13 0.4 1.2 0.82–1.66 0.4 
Serum C3 1.5 0.3 0.10–1.03 0.1 0.3 0.08–1.47 0.1 
Serum IgA/C3≥2.806 2.5 0.9 0.58–1.41 0.7 0.9 0.41–1.81 0.7 
CKD 3-4 2.7 14.2 8.21–24.60 <0.001 2.9 1.41–6.06 0.0 
M1 1.2 3.4 1.49–7.89 0.0 1.5 0.61–3.50 0.4 
E1 1.1 1.8 0.76–4.05 0.2    
S1 1.2 2.5 1.56–4.11 <0.001 1.2 0.68–1.95 0.6 
T1/2 1.5 12.9 7.76–21.43 <0.001 3.5 1.89–6.62 <0.001 
C1/2 1.2 1.4 0.90–2.27 0.1    
C3 staining≥2 1.1 1.2 0.64–2.20 0.6 0.4 0.23–0.88 0.0 
IT treatments 1.6 0.8 0.52–1.27 0.4    

C, crescents; C3, complement 3; CKD, chronic kidney disease; E, endocapillary proliferation; G, glomerulosclerosis; IT, immunosuppressants; IgA, immunoglobulin A; M, mesangial proliferation; S, segmental sclerosis; T, tubular atrophy/interstitial fibrosis; VIF, variance inflation factor.

IgAN is a common primary glomerulonephritis in adults, and its prevalence varies across geographic regions: 30–60% in Asians, 20–30% in Europeans, and less than 5% in Africans [1]. The Kidney Disease Improving Global Outcome (KIDGO) guidelines recommended CS for patients with eGFR >50 mL/min per 1.73 m2 and persistent proteinuria >1 g/day who have not responded to 3–6 months of optimized supportive care with renin-angiotensin system blockers [4]. Clinically, a wide spectrum of clinical and pathologic features have been reported. Meanwhile, treatment responses and renal prognosis remain discordant results [19]. Indeed, it is difficult to remain completely consistent with the guidelines in clinical practice. Hence, safe, reliable, personalized methods with high sensitivity and specificity and fewer complications will be needed. To date, the gold standard for the diagnosis of IgAN is renal puncture pathology biopsy, which is characterized by predominant IgA deposits in the glomerular mesangium; complement 3, IgG, and IgM deposition are also common [20]. Previous studies suggested that circulating levels of IgA1 with an abnormally O-glycosylated hinge region, termed galactose-deficient IgA1 (Gd-IgA1), are increased in up to 90% of patients with IgAN from different regional cohorts [21, 22]. However, increased serum levels of Gd-IgA1 were also reported in healthy subjects and unaffected relatives of IgAN patients, and white patients with IgAN exhibited significantly higher Gd-IgA1 levels than Chinese patients [23, 24]. These results suggested that the sensitivity and specificity of Gd-IgA1 were limited and that it was insufficient to replace renal biopsy as a diagnostic criterion. In addition, several reports have shown decreased serum C3 and increased glomerular C3 deposits in the mesangium, which are associated with the risk of progressive IgAN [25]. However, data about the effect and pathogenesis of C3 in IgAN are limited. As mentioned in the literature review, alternative and lectin pathways were involved in complement activation with C3 and mannose-binding lectin deposits in IgAN [26‒28], and a random forest model with 262 Chinese IgAN patients showed that C3 staining could increase the AUROC and F-measure for ESRD prediction [29]. Yang X’s retrospective analysis with 1:1 propensity score matching in 1,564 Chinese IgAN patients reported that decreased serum C3 levels were not a prognostic marker in renal progression [30]. Moreover, several studies found that either serum IgA/C3 [31] or serum IgA/C3 ratio and glomerular C3 staining [32] could predict outcome in IgA nephropathy children. These findings may be somewhat limited by the heterogeneity of the research design and ethnic population, and risk stratification remains a challenge in IgAN. In this retrospective study of 718 Chinese patients with IgAN, we aimed to establish the combined prognostic value of serum IgA/C3 and mesangial C3 deposition in predicting renal outcome. Our results evaluated the role of serum IgA/C3 and mesangial C3 deposition in renal prognosis in adult IgAN patients. In our study, the serum IgA/C3 ratio was significantly higher in the urine protein ≤3.5 g/day group, which is consistent with the results reported by Gong WY et al. [10]. ROC analysis of the serum IgA/C3 ratio revealed optimal selectivity for a cutoff ratio of 2.806. This ratio led to a sensitivity of 63.9% and a specificity of 58.7%. The group with serum IgA/C3≥2.806 tended to have worse histology than the group with serum IgA/C3 <2.806, but urinary protein was the opposite. Tomino et al. revealed that the serum IgA level was significantly higher, while the C3 level was lower in patients with severe IgAN than in those with non-IgAN [12]. A further study with more focus on the combined effects of the serum IgA/C3 ratio and glomerular C3 staining on the renal outcome in the different stages of IgAN is therefore suggested. On the other hand, C3 staining ≥2 was clearly worse histologically, while urinary protein was unchanged in both groups. For these contradictory results, the serum IgA/C3 ratio was combined with glomerular C3 staining to examine the prognosis in IgA nephropathy in this study. Notable is that, based on our findings, these two indicators may not be able to differentiate between the severity of these patients’ clinical manifestations at baseline. The values of clinical indicators such as hypertension, urine protein, and serum creatinine were not highest in group 1 (serum IgA/C3≥2.806 and C3 staining≥2), but patients tended to have a worse prognosis, with 11.6% of patients reaching the composite endpoints. Moreover, Kaplan-Meier analysis also proved a significant decrease in median survival time of 87 months for group 1, while the survival rates at 87 months for groups 2, 3, and 4 were 0.806, 0.804, and 0.697, respectively. It is worth noting that the survival curve of group 1 decreased rapidly after 80 months compared with group 3. These results indicate that the long-term prognosis needs more attention in IgAN patients with serum IgA/C3 ≥2.806 and C3 staining ≥2. There were significant variances in prognosis after follow-up visits in groups with milder or less significant disparities in clinical performance at the baseline, implying that the combination of the two markers could be more clinically suggestive. In addition, the higher urine protein and lower eGFR at renal biopsy could be attributed to poor renal outcome in the combined endpoints and renal survival rate for group 3. We could not perform propensity score matching analysis to eliminate the influence of differences at baseline on the renal outcome owing to the small sample size and complexity of grouping. Intervene experiments to avoid confounding may be needed to further verify the hypothesis.

In the present study, glomerular C3 staining was closely related to the prognosis of IgAN. In accordance with previous results [16, 32, 33], we confirmed the importance of C3 staining ≥2 as an adverse prognostic factor for renal survival in adult IgAN patients. The survival curves in the four categories indicated no statistical differences in the immunosuppressants group but significant statistical differences in the support group, as shown in Figure 3h, i). In the support group, group 2 had a substantially better prognosis than group 3, indicating that C3 staining ≥2 may indicate poor prognoses. And because serum C3, serum IgA, and repeated renal biopsy after immune suppressant use are not routinely performed in IgA nephropathy patients, we are temporarily unable to determine how immune inhibitors will affect these two predictive indicators.

At the end of follow-up, even over half of those received immunosuppressants, and the rate of ESRD in group 3 and renal survival in group 1 were lowest. Surprisingly, patients in group 4 presented with significantly more severe proteinuria but higher eGFR, and the use of immunosuppressants was maximum. However, their endpoints were not the best. Most studies in the field of IgAN have only focused on CS or other immunosuppressive agents [34]. To date, far too little attention has been given to complement [17, 35]. In patients with significant positive glomerular C3 staining, glucocorticoids and immunosuppressive agents may not be beneficial, while complement-targeting therapies have a potential benefit for IgAN [36‒38]. In IgAN, complement proteins activate. IgAN biopsy samples show C3, properdin, C4d, mannose-binding lectin, and C5b-9 deposits in mesangium and no C1q, confirming alternative and lectin pathway activity [39]. Higher C3 scores in groups 1 and 3 in this study were associated with a worse renal prognosis, which was consistent with previous studies; while C3 sediment was thought to be associated with supplemental activation, we hypothesized that the associated drug use would be better for patients with high C3 renal sediment scores. Recently, in phase 2/3 trials, treatment with a blocking antibody against mannose-binding protein-associated serine protease 2 (MASP-2, a crucial enzyme of the lectin pathway) (NCT03608033) and C3 (NCT03453619) was suggested to have a potential benefit for IgAN.

The results from Kaplan-Meier analysis showed that the renal survival of IgAN was not dependent on patients’ baseline eGFR levels and CKD stages. However, it was a significant independent predictor of poor renal outcome by Cox analysis, which was similar to previous reports [40]. In accordance with previous results [40‒42], it was also found that hypertension, serum creatinine, T1/2 and C3 staining were significant independent predictors of poor renal outcome in the multivariable model. Moreover, compared to a retrospective study that enrolled 1,012 IgAN patients at a single center in Japan [43], our study showed more severe histological characteristics (M1 532/718, 74.1%; E1 39/718, 5.4%). The reason for the differences in these observations may be attributable in part to different indications for renal biopsy among countries and different grades of renal injury among IgAN patients. These results suggest that more factors, such as serum IgA/C3 and C3 staining, should be included to obtain personalized treatment. It is clear that large-sample clinical trials and cohorts are needed before conclusions can be drawn.

There are several limitations in our study. First, individuals were recruited with a relatively small sample size from a single center, and most of them were Han Chinese. Hence, it might not be perfectly safe to apply our findings to other ethnic groups. Second, the potential confounders selected in this study were limited. Other unmeasured confounders, such as ethnicity, treatment regimens, diet composition, climate, and smoking status, could not be eliminated in the present study. Finally, this is a retrospective study with unmatched baseline characteristics of patients in different groups. A well-designed controlled study may provide more receivable information to further verify the hypothesis.

In conclusion, the combination of serum IgA/C3 and C3 staining may contribute to improved optimization of the prognostic model in IgAN patients, especially patients with different sexes and degrees of disease. However, further study is required for validation in the future.

This research was in compliance with the Declaration of Helsinki and approved by the Ethics Committee of West China Hospital of Sichuan University (ethical approval number 2019-33). Written informed consent was obtained from each patient.

The authors declare that they have no conflicts of interest.

There was no funding for this study.

W.Q. and Y.T. conceived and designed the study; D.Y. and G.P. wrote the main manuscript text; and S.W. and A.Q. prepared the figures. All authors reviewed the manuscript.

Due to privacy policy, the datasets analyzed in this study are not publicly available, but they are available from the corresponding author upon reasonable request.

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