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Clinical Significance of Combined IgM and C3 Staining in Primary IgA Nephropathy
Corresponding author: Xuexia Li, Department of Nephrology, Zhuhai Hospital of Intergrated Chinese and Western Medicine, Gongbei, Xiangzhou, Zhuhai, Guangdong, China. E-mail: sitalisa@163.com
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Received: ,
Accepted: ,
How to cite this article: Li X, Yuan X, Zhang X. Clinical Significance of Combined IgM and C3 Staining in Primary IgA Nephropathy. Indian J Nephrol. doi: 10.25259/IJN_711_2024
Abstract
Background
We aimed to investigate the clinical significance of combined glomerular IgM and C3 staining and renal outcome in adult IgA nephropathy (IgAN).
Materials and Methods
This retrospective study encompassed 69 adult patients with IgAN. The demographic and clinical data, including sex, age, diastolic blood pressure (DBP), systolic blood pressure (SBP), 24-hour urinary total protein (24hUP), WBCs, serum hemoglobin (Hb), serum platelets (PLT), serum creatinine (Scr), blood uric nitrogen (BUN), estimated glomerular filtration rate (eGFR), serum albumin (ALB), uric acid (UA), total cholesterol (CHO), triglyceride (TG), IgA, IgG, IgM, and complement 3 and 4 (C3 and C4) were evaluated at baseline. Kidney biopsy was categorized using the Oxford classification, along with the Mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, glomerular crescent, (MEST-C) score. The patients were divided into IgM-positive (IgM+) and-negative (IgM-) groups for analysis. Further, they were divided into four groups by glomerular IgM and C3 staining: IgM-positive C3-positive (IgM+ C3+) staining group, IgM-positive C3-negative (IgM+ C3-) staining group, IgM-negative C3-positive (IgM- C3+) staining group, and IgM-negative C3-negative (IgM- C3-) staining group. The hard renal endpoint was the onset of end-stage kidney disease (ESKD) within the follow-up period.
Results
The IgM+ group (n=47, 68%) had significantly higher levels of SBP, Scr, BUN, IgM, TG, 24hUP, tubular atrophy, and vessel hyaline change. Further analysis indicated that 43 (62.3%) patients had combined mesangial IgM and C3 deposition (IgM+ C3+ staining group). Compared with the other three groups, patients with combined IgM and C3 deposition had higher levels of DBP, SBP, Scr, BUN, IgM, TG, and 24-hour urine protein (24hUP), as well as tubular atrophy. We observed that the IgM+C3+ group had a higher prevalence of renal dysfunction compared to the other groups.
Conclusion
IgM positivity in patients with IgA showed a worse renal outcome. IgM+C3+ staining in patients with IgAN experienced a higher renal dysfunction prevalence.
Keywords
Complement 3
Immunoglobulin A nephropathy
Immunoglobulin A
Renal progression
Introduction
IgA nephropathy (IgAN), also known as Berger’s disease, is characterized by the predominant deposition of IgA in a granular fashion within the mesangial zones of glomeruli.1 IgAN is the most common glomerulonephritis in the world,2 with diverse clinical manifestations. Patients could be asymptomatic or have rapid, progressive kidney malfunction.
Diffuse mesangial IgA deposition is the defining hallmark of IgAN. Complement 3 (C3) is co-deposited with IgA in up to 90%, IgG in 40%, and IgM in 40% of cases.3 They may present in the same distribution.4 Glomerular C3 deposits affect the clinical pathologic features and emerged as independent predictors and risk factors for renal outcomes.5 Studies have shown that high intensity of glomerular C3 deposition is associated with the severity of renal lesions and predicts long-term poor renal survival in this disease.6 Mesangial IgM deposition was considered a potential risk factor for end-stage kidney disease (ESKD) in patients with advanced IgAN.7
Mesangial IgM and C3 deposition are commonly observed in patients with primary IgAN. Growing evidence suggests that IgM and C3 deposition play an essential role in IgAN. However, the co-deposition and its characteristics and prognosis have rarely been reported. In this way, we intend to clarify the clinical significance of combined glomerular IgM and C3 deposition in IgAN and their contribution to disease progression.
Materials and Methods
This was a retrospective cohort study of patients with IgAN in Zhuhai Hospital of Integrative Chinese and Western Medicine from 2020 to 2023. All participants provided written informed consent. The study was approved by the Zhuhai Hospital of Intergrated Chinese and Western Medicine. The demographic and clinical data, including sex, age, diastolic blood pressure (DSP), systolic blood pressure (SBP), 24-hour urine total protein (24hUP), WBC, serum hemoglobin (Hb), serum platelet (PLT), serum creatinine (Scr), blood uric nitrogen (BUN), estimated glomerular filtration rate (eGFR), serum albumin (ALB), uric acid (UA), THO, triglyceride (TG), IgA, IgG, IgM, C3, and C4 was recorded at baseline. The eGFR was calculated by the Modification of Diet in Renal Disease (MDRD) formulas.8
All kidney biopsy specimens were evaluated as per the Oxford classification (including crescent scores).9 Pathologic lesions were examined by light microscopy (LM), electron microscopy (EM), and immunofluorescence (IF). The MEST-C score was performed according to the Oxford standard, as shown in Table 1.10-12
| MEST-C classes | Criteria |
|---|---|
| Mesangial cell proliferation | |
| M0 | <50% |
| M1 | >50% |
| Capillary endothelial cell proliferation | |
| E0 | Absent |
| E1 | Present |
| Segmental glomerulosclerosis or adhesion | |
| S0 | Absent |
| S1 | Present |
| Tubular atrophy and interstitial fibrosis | |
| T0 | ≤25% |
| T1 | 26-50% |
| T2 | >50% |
| Crescent body (Cellular or fibrotic crescents) | |
| C0 | Absent |
| C1 | <25% |
| C2 | ≥25% |
M: Mesengial hypercellularity, E: Endocapillary hypercellularity, S: Segmental glomerulosclerosis, T: Tubular atrophy/interstitial fibrosis, C: Glomerular crescent
IgM and C3 deposits in the mesangium were determined using a direct IF assay on frozen sections. “IgM+ or C3+” refers to the presence of IgM and C3 antibodies within the mesangial region. Conversely, “IgM- or C3-” refers to no deposits in the mesangium.
All patients received optimized supported care with renin-angiotensin inhibition and lifestyle modifications according to KIDGO guidelines.
Statistical analysis
Data are expressed as mean±standard deviation (SD) or numbers and percentages. The t-test was used to compare the variables for parameters with a normal distribution. The Chi-square test was employed for comparisons between categorical variables. A p-value<0.05 was considered statistically significant for all analyses conducted in this study. The analysis was performed using GraphPad Prism 8.0 software.
Outcomes: the hard kidney endpoint event was ESKD (eGFR<15 mL/min/1.73m2).
Results
The study included 69 patients with primary IgAN, including the IgM+ group (n = 47, 68.12%) and the IgM- group (n = 22, 31.88%). All patients had IgA deposition. No patient had IgG or C1q deposition.
Baseline characteristics of the two groups have been summarized in Table 2. In terms of clinical information, the IgM+ group had significantly higher levels of SBP (p=0.015), BUN (p<0.0001), Scr (p<0.0001), serum IgM (p=0.0165), and 24hUP (p=0.0415). The IgM+ group had lower TG (p=0.0050). In terms of pathology, the IgM+ group had a significantly higher percentage of tubular atrophy (p=0.0223) and more vessel hyaline changes (p<0.0001). The two groups had no significant differences in other clinical characteristics or pathological parameters. Further, we explored the association between IgM deposition and kidney progression in patients with IgAN with follow-up. Six patients (12.76%) in the IgM+ group reached ESKD in 32 ± 25.44 months. One patient (4.54%) in the IgM- group reached ESKD in 60 months. The IgM+ group had a higher incidence of renal dysfunction (p=0.0252). The detailed information has been shown in Table 2. Significant differences in the index between the IgM+ and IgM- groups have been shown in Figure 1.
| Characters | Mean ± SD or n (%) | ||
|---|---|---|---|
| IgM+ (n = 47) | IgM- (n = 22) | p-value | |
| M/F | 25/22 | 14/8 | 0.935 |
| Age (years) | 37.5 ± 11.4 | 36.5 ± 10.3 | 0.627 |
| SBP (mmHg) | 137.5 ± 23.5 | 125.7 ± 14.2 | 0.015* |
| DBP (mmHg) | 92.3 ± 15.5 | 82.1 ± 10.6 | 0.059 |
| HGB (g/dL) | 13.5 ± 2.0 | 12.9 ± 2.0 | 0.948 |
| WBC (×103/uL) | 6.6 ± 1.7 | 6.4 ± 2.4 | 0.072 |
| PLT (×103/uL) | 247.9 ± 62.5 | 247.0 ± 72.9 | 0.377 |
| ALB (g/dL) | 4.3 ± 0.7 | 4.2 ± 0.8 | 0.407 |
| UA (mg/dL) | 7.0 ± 2.1 | 7.0 ± 2.3 | 0.598 |
| BUN (mg/dL) | 19.0 ± 9.8 | 15.4 ± 3.6 | <0.0001*** |
| Scr (mg/dL) | 1.5 ± 1.5 | 1.07 ± 0.4 | <0.0001*** |
| eGFR (mL/min/1.73 m2) | 77.1 ± 35.9 | 84.8 ± 25.9 | 0.108 |
| IgA (mg/dL) | 3.0 ± 1.1 | 3.2 ± 1.1 | 0.967 |
| IgG (mg/dL) | 12.3 ± 3.5 | 11.1 ± 2.7 | 0.232 |
| IgM (mg/dL) | 1.4 ± 0.7 | 1.2 ± 0.4 | 0.017* |
| C3 (mg/dL) | 1.1 ± 0.2 | 1.1 ± 0.2 | 0.333 |
| C4 (mg/dL) | 0.3 ± 0.1 | 0.3 ± 0.1 | 0.538 |
| CHO (mg/dL) | 205.1 ± 42.6 | 209.0 ± 50.3 | 0.269 |
| TG (mg/dL) | 150.5 ± 88.5 | 150.5 ± 141.6 | 0.005** |
| 24hUP (mg/24h) | 1577 ± 1690 | 1059 ± 1115 | 0.042* |
| Oxford classification | |||
| M (M0/M1) | 0/47 | 0/22 | 0.098 |
| E (E0/E1) | 44/3 | 21/1 | 0.469 |
| S (S0/S1) | 23/24 | 16/6 | 0.150 |
| T (T0/T1/T2) | 36/5/6 | 17/5/0 | 0.016* |
| C (C0/C1/C2) | 29/16/2 | 15/7/0 | 0.331 |
| Tubular atrophy (%) | 20.6 ± 21.4 | 12.9 ± 13.4 | 0.023* |
| Hayline change (Y/N) | 6/41 | 0/22 | <0.0001*** |
| ESRD (Y/N) | 6/41 | 1/21 | 0.025* |
*p < 0.05, **p < 0.01,***p < 0.001. DBP: Diastolic blood pressure, SBP: Systolic blood pressure, HGB: Serum hemoglobin, WBC: White blood cells, PLT: Serum platelets, ALB: Serum albumin, UA: Uric acid, BUN: Blood uric nitrogen, eGFR: estimated glomerular filtration rate, IgA: Immunoglubulin A, IgG: Immunoglobulin G, IgM: Immunoglobulin M, C3: Complement 3, C4: Complement 4, CHO: Total cholesterol, TG: Triglyceride, 24hUP: 24-Hour urinary total protein, M: Mesengial hypercellularity, E: Endocapillary hypercellularity, S: Segmental glomerulosclerosis, T: Tubular atrophy/interstitial fibrosis, C: Glomerular crescent, ESKD: End stage kidney disease
- Significant differences between IgM positive and IgM hostile groups between SBP, 24hUP, Scr, BUN, IgM, TG, Tubular Atrophy, and Vessel Hyaline.
Baseline demographic, clinical and pathological information among IgM+C3+, IgM+C3-, IgM-C3+, and IgM-C3- groups
Then the patients were further divided into four groups according to IgM and C3 deposition: IgM+C3+ staining group, IgM+C3- staining group, IgM-C3+ staining group, and IgM-C3- staining group. Of all, 43 patients (62.32%) were IgM+C3+ staining, four patients (5.80%) were IgM+C3- staining, 16 (23.19%) patients were IgM-C3+ staining, and six (8.69%) patients were IgM-C3- staining. The results indicated that the IgM+C3+ staining group had significantly higher levels of SBP p=0.013), DSP (p=0.0.018), WBC (p=0.043), BUN (p=0.000), Scr (p<0.0001), 24hUP (p =0.002), and significantly lower TG (p<0.0001). Regarding pathology, the IgM+C3+ staining group had a significantly higher percentage of tubular atrophy (p = 0.015) There are no significant differences in other criteria among the four groups.
Six patients (13.95%) in the IgM+C3+ staining group reached ESKD in 32 ± 25.44 months. One patient (16.67%) in the IgM-C3--staining group reached ESKD in 60 months. The detailed information has been shown in Table 3. Significant differences in the index among the four groups have been shown in Figure 2.
| Characters | Mean ± SD or n (%) | ||||
|---|---|---|---|---|---|
| IgM+ (N=47) | IgM- (N=22) | p-value | |||
| C3+ (n = 43) | C3- (n = 4) | C3+ (n = 16) | C3- (n = 6) | ||
| M/F | 23/20 | 2/2 | 10/6 | 4/2 | 0.878 |
| Age (years) | 36.8 ± 11.1 | 45.0 ± 13.5 | 37.8 ± 10.8 | 32.8 ± 8.7 | 0.864 |
| SBP (mmHg) | 137.5 ± 24.6 | 137.3 ± 6.2 | 125.3 ± 15.3 | 127.0 ± 12.2 | 0.013* |
| DBP (mmHg) | 93.1 ± 15.9 | 84.3 ± 7.5 | 84.7 ± 11.0 | 75.2 ± 4.8 | 0.018* |
| HGB (g/dL) | 13.2 ± 1.9 | 13.7 ± 3.3 | 13.2 ± 2.0 | 12.0 ± 1.7 | 0.499 |
| WBC (×103/uL) | 6.6 ± 1.7 | 6.5 ± 0.8 | 5.7 ± 1.4 | 8.3 ± 3.2 | 0.043* |
| PLT (×103/uL) | 249.5 ± 62.4 | 230.0 ± 70.6 | 248.4 ± 58.1 | 243.3 ± 110.5 | 0.231 |
| ALB (g/dL) | 4.2 ± 0.7 | 4.6 ± 0.6 | 4.4 ± 0.7 | 3.7 ± 0.7 | 0.792 |
| UA (mg/dL) | 7.0 ± 2.2 | 7.0 ± 0.7 | 6.7 ± 2.0 | 8.0 ± 2.9 | 0.173 |
| BUN (mg/dL) | 16.8 ± 10.1 | 14.8 ± 6.2 | 15.1 ± 4.2 | 15.4 ± 3.1 | 0.0004*** |
| Scr (mg/dL) | 1.6 ± 1.5 | 0.8 ± 0.3 | 1.1 ± 0.5 | 1.0 ± 0.3 | <0.0001*** |
| eGFR (mL/min/1.73 m2) | 74.2 ± 35.7 | 108.3 ± 22.1 | 84.4 ± 27.9 | 85.8 ± 22.1 | 0.382 |
| IgA (mg/dL) | 3.0 ± 1.1 | 2.8 ± 0.8 | 3.6 ± 0.7 | 2.1 ± 1.0 | 0.830 |
| IgG (mg/dL) | 12.3 ± 3.6 | 12.0 ± 2.7 | 11.7 ± 2.7 | 9.1 ± 1.9 | 0.319 |
| IgM (mg/dL) | 1.2 ± 0.7 | 2.0 ± 0.7 | 1.1 ± 0.4 | 1.4 ± 0.4 | 0.340 |
| C3 (mg/dL) | 1.1 ± 0.2 | 1.1 ± 0.3 | 1.0 ± 0.2 | 1.2 ± 0.2 | 0.144 |
| C4 (mg/dL) | 0.3 ± 0.1 | 0.3 ± 0.1 | 0.3 ± 0.1 | 0.30 ± 0.8 | 0.878 |
| CHO (mg/dL) | 205.1 ± 42.3 | 185.8 ± 38.7 | 205.1 ± 54.2 | 216.7 ± 46.2 | 0.877 |
| TG (mg/dL) | 141.6 ± 88.5 | 177.0 ± 70.8 | 132.8 ± 44.3 | 221.3 ± 265.5 | <0.0001*** |
| 24 hUP (mg/24h) | 1658 ± 1737 | 708.0 ± 641.3 | 726.1 ± 681.4 | 1948 ± 1588 | 0.002** |
| Oxford classification | |||||
| M (M0/M1) | 0/43 | 0/4 | 0/16 | 0/6 | 0.523 |
| E (E0/E1) | 40/3 | 4/0 | 16/0 | 5/1 | 0.466 |
| S (S0/S1) | 21/22 | 2/2 | 12/4 | 4/2 | 0.154 |
| T (T0/T1/T2) | 32/5/6 | 4/0/0 | 12/4/0 | 5/1/0 | 0.541 |
| C (C0/C1/C2) | 27/14/2 | 2/2/0 | 11/5/0 | 4/2/0 | 0.887 |
| Tubular atrophy (%) | 21.9 ± 21.9 | 7.5 ± 5.0 | 14.4 ± 12.8 | 9.2 ± 15.6 | 0.015* |
| Hyaline (Y/N) | 6/37 | 0/4 | 0/16 | 0/6 | 0.201 |
| ESRD (Y/N) | 6/37 | 0/4 | 0/16 | 1/5 | 0.371 |
DBP:Diastolic blood pressure, SBP: Systolic blood pressure, HGB: Serum hemoglobin, WBC: White blood cells, PLT: Serum platelets, ALB: Serum albumin, UA: Uuric acid, BUN: Blood uric nitrogen, eGFR: estimated glomerular filtration rate, IgA: Immunoglubulin A, IgG: Immunoglobulin G, IgM: Immunoglobulin M, C3: Complement 3, C4: Complement 4, CHO: Total cholesterol, TG: Triglyceride, 24hUP: 24-Hour urinary total protein, M: Mesengial hypercellularity, E: Endocapillary hypercellularity, S:Segmental glomerulosclerosis, T: Tubular atrophy/interstitial fibrosis, C: Glomerular crescent, ESKD: End stage kidney disease. *p < 0.05, **p < 0.01,***p < 0.001
- Significant differences in DSP, SBP, WBC, BUN, Scr, TG, 24hUP, and tubular atrophy among IgM+C3+, IgM+C3-, IgM-C3+, and IgM-C3- groups.
Figure 3 shows renal survival rates among the four groups given the same standard treatments according to the KIDGO guideline.
- Renal Survival Rate among IgM+C3+, IgM+C3-, IgM-C3+, and IgM-C3- groups.
Risk factors for kidney disease progression in patients with IgAN
We further analyzed differences between patients who reached the kidney hard endpoint (ESKD group) and those with stable kidney function (non-ESKD group). Patients in the ESKD group suffered from higher SBP (p<0.0001), DSP (p=0.001), 24h UP (p<0.0001), UA (p<0.0001), Scr (p<0.0001), and BUN (p<0.0001) at the time of renal puncture. Patients in the ESKD group had significantly lower HGB (p= 0.008), eGFR (p< 0.0001), TP (p=0.033), and IgG (p=0.033) at the time of renal biopsy. In terms of pathology, tubular atrophy (p<0.0001) was more significant in the ESKD group. A detailed description has been attached in Table 4. Figure 4 shows the differences between the ESKD and the non-ESKD groups.
| Characters | Mean ± SD or n (%) | ||
|---|---|---|---|
| Non-ESKD (n = 62) | ESKD (n = 7) | p-value | |
| Male/Female | 6/1 | 33/29 | 0.103 |
| Age (years) | 37.3 ± 11.2 | 36.1 ± 9.4 | 0.796 |
| SBP (mmHg) | 129.9 ± 17.80 | 167.7 ± 24.0 | <0.0001*** |
| DBP (mmHg) | 87.2 ± 13.5 | 105.6 ± 16.6 | 0.001** |
| HGB (g/dL) | 13.4 ± 2.0 | 11.3 ± 1.4 | 0.008** |
| WBC (×103/uL) | 6.5 ± 1.9 | 7.0 ± 1.3 | 0.515 |
| PLT (×103/uL) | 250.3 ± 66.4 | 223.9 ± 54.4 | 0.315 |
| ALB (g/dL) | 4.3 ± 0.7 | 3.8 ± 0.6 | 0.057 |
| UA (mg/dL) | 6.8 ± 2.0 | 9.4 ± 1.8 | 0.002** |
| BUN (mg/dL) | 15.9 ± 5.0 | 35 ± 13.4 | <0.0001*** |
| Scr (mg/dL) | 1.0 ± 0.4 | 4.2 ± 2.5 | <0.0001*** |
| eGFR (mL/min/1.73 m2) | 85.5 ± 28.5 | 26.7 ± 22.2 | <0.0001*** |
| IgA (mg/dL) | 3.1 ± 1.1 | 3.0 ± 0.9 | 0.836 |
| IgG (mg/dL) | 12.3 ± 3.1 | 8.8 ± 4.1 | 0.008** |
| IgM (mg/dL) | 1.3 ± 0.7 | 1.0 ± 0.4 | 0.296 |
| C3 (mg/dL) | 1.1 ± 0.2 | 1.1 ± 1.8 | 0.873 |
| C4 (mg/dL) | 0.3 ± 0.1 | 0.3 ± 0.1 | 0.119 |
| CHO (mg/dL) | 205.1 ± 46.4 | 207.9 ± 46.4 | 0.740 |
| TG (mg/dL) | 150.5 ± 50.3 | 115.1 ± 53.1 | 0.835 |
| 24 hUP (mg/24h) | 1141 ± 1178 | 3813 ± 2303 | <0.0001*** |
| Oxford classification | |||
| M (M0/M1) | 0/62 | 0/7 | |
| E (E0/E1) | 58/4 | 7/0 | 0.496 |
| S (S0/S1) | 36/26 | 3/4 | 0.099 |
| T (T0/T1/T2) | 53/7/2 | 0/3/4 | <0.0001*** |
| C (C0/C1/C2) | 41/21/0 | 3/2/2 | 0.4525 |
| Tubular atrophy (%) | 13.87 ± 14.72 | 56.43 ± 13.45 | <0.0001*** |
| Hayline change (Y/N) | 56/6 | 6/1 | 0.707 |
Diastolic blood pressure, SBP: Systolic blood pressure, HGB: Serum hemoglobin, WBC: White blood cells, PLT: Serum platelets, ALB: Serum albumin, UA: Uric acid, BUN: Blood uric nitrogen, eGFR: estimated glomerular filtration rate, IgA: Immunoglubulin A, IgG: Immunoglobulin G, IgM: Immunoglobulin M, C3: Complement 3, C4: Complement 4, CHO: Total cholesterol, TG: Triglyceride, 24hUP: 24-Hour urinary total protein, M: Mesengial hypercellularity, E: Endocapillary hypercellularity, S: Segmental glomerulosclerosis, T: Tubular atrophy/interstitial fibrosis, C: Glomerular crescent, ESKD: End stage kidney disease. *p < 0.05, **p < 0.01,***p < 0.001.
- Significant differences in DSP, SBP, HGB, BUN, Scr, UA, IgG, eGFR, 24hUP, and tubular atrophy between ESKD and non-ESKD groups.
Discussion
Marked by IgA deposition in the mesangial area, IgAN is currently recognized as an autoimmune kidney disease. The deposition of antibodies like IgA, IgG, and IgM in the mesangium causes IgAN. These depositions in the mesangial region contribute to the development and progression of IgAN. Mesangial IgM deposition was an independent risk factor for poor renal outcomes in children with primary IgAN.13 C3 deposition was considered an independent risk factor for IgAN severity and progression.14 With the increasing intensity of C3 deposition, patients with IgAN are more likely to present with a high level of microscopic hematuria, fibrous crescents, interstitial inflammatory cell infiltration, and a higher score on segmental sclerosis lesions. IgM deposition is also reported to be associated with poorer outcomes. Mesangial IgM deposition was believed to be associated with histological activity, clinical severity, and renal outcome, and is considered an independent risk factor for poorer renal prognosis in IgAN.15 Combined mesangial IgM and C3 deposition might be associated with unfavorable histopathological features. However, the impact of the combination deposition of IgM and C3 on the severity and progression of IgAN remains uncertain.
IgM-positive deposition accounted for ∼68%, which is higher than the broader range mentioned in the literature. None of our patients had IgG deposition in IF, which was quite different from the 40% deposition mentioned in the literature. some research demonstrated that mesangial IgM deposition is independently associated with worse renal outcomes in patients with IgAN.16 Our data reveal IgM deposition associated with higher SBP and more severe proteinuria excretion. Blood pressure and proteinuria were both independent risk factors in IgAN. This confirms our findings of IgM+ patients with higher serum BUN and Scr levels, more severe proteinuria, and hypertension. Pathologically, these patients suffered from more severe tubular atrophy and significant vessel hyaline changes. Clinically or pathologically, IgM deposition indicated worse conditions. IgM-deposited patients had higher levels of serum IgM. The relationship between glomerular IgM and serum IgM should be further explored.
Research indicated that IgM deposition is a potential risk factor for ESKD in patients with advanced IgAN.17 Our IgM-deposited patients suffered from worse renal outcomes. More than 85% of our patients with ESKD had IgM depositions. Mesangial IgM deposition could be valuable in evaluating disease severity and renal prognosis in patients with IgAN.
Our data revealed that the co-deposition of IgM and C3 in IgAN indicated a worse renal outcome. IgM+C3+ deposition was associated with higher SBP and DBP. These patients suffered from more severe proteinuria and worse renal function. In pathology, patients with IgM+C3+ suffered from more severe tubular atrophy. Patients with positive IgM and C3 deposition had a higher percentage of experiencing disease progression. These suggest that the co-deposition of IgM and C3 in the glomerular membrane is associated with poor prognosis in IgAN. These findings emphasize the potential significance of kidney IgM and C3 co-deposition in the severity and progression of IgAN. They could be considered a prognostic factor. The co-deposition may accelerate the progression. Future prospective studies should provide more robust evidence on the impact of IgM and C3 deposition on kidney outcomes in patients with IgAN.
Additionally, >13% of IgM+C3+ staining patients reached ESKD in 32 months (mean) after renal biopsy, and >85% of patients with ESKD had co-deposition of IgM and C3. IgM+C3+ staining. ESKD patients had higher blood pressure, more severe proteinuria, and higher serum levels of BUN and Cr at the time of renal biopsy. They suffered from anemia and lower eGFR. Their serum IgG levels were lower than non-ESKD patients, which might indicate the immune abnormalities in IgM+C3+ patients with IgAN. Also, patients with IgM+C3+ ESKD had a higher percentage of tubular atrophy. Our data indicated that co-deposition of IgM and C3, higher blood pressure, elevated BUN, Scr, and UA, proteinuria, immune abnormality, and tubular atrophy were risk factors for renal progression to ESKD at the time of renal biopsy.
The complement system, particularly the lectin and alternative pathways of complement, has emerged as a key mediator of kidney injury in IgAN and a possible target for investigational therapy. Glomerular deposition of pattern-recognition molecules for the lectin pathway is associated with more severe glomerular damage and more severe proteinuria and hematuria.18 C3 deposition has been shown to correlate with IgAN progression, and the alternative complement (AP) pathway is considered the major complement cascade activator in IgAN.19 Serum C3 levels were normal in our study, but some studies indicated the C3 activation maakers were associated to kidney prognosis in IgAN. Factor B was also a crusial cofactor for C3 activation in IgAN in AP pathway. Consider as the a key driver of IgAN, selective AP inhibitions are being evaluated in IgAN.20 IgM might be trapped in the mesangium for its size and be damaging to renal tissues. IgM deposition was considered an independent risk factor for renal function progression in IgAN due to lectin pathway activation.21 IgM binding can cause complement deposition that finally lead to renal injury. Code position of C3 and IgM contributed to worse renal functions and more severe proteinuria might associated to complement pathway activation.
Patients with primary focal segmental glomerulosclerosis (FSGS) and IgM and C3 deposition showed unfavorable therapeutic responses and worse renal outcomes, which indicate that IgM and C3 deposition might involve disease progression via complement activation.22,23 The role of IgM and C3 deposition in both IgAN and FSGS might indicate some common mechanisms underlying their code position in the pathology of glomerular diseases.
We identified co-deposition of IgM and C3 as risk factor in IgAN. Our study has some limitations. Firstly, the number of patients was less, which may lead to a segmentary conclusion. A significant sample verification is necessary via multicenter and large-sample studies. Future prospective studies should address the limitations of small sample sizes and short follow-up periods to provide more robust evidence on the impact of IgM and C3 deposition on kidney outcomes in patients with IgAN.
Financial support and sponsorship
Project supported by the Research Fund of Traditional Chinese Medicine Bureau of Guangdong Province (20231304). Project supported by the Research Fund of Zhuhai Hospital of Integrated Chinese and Western Medicine (202203).
Conflicts of interest
There are no conflicts of interest.
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