Coexistence of anti-glomerular basement membrane disease and IgA nephropathy: an illustrative case and comprehensive literature review

Abstract

Anti-glomerular basement membrane (GBM) disease is a rare autoimmune condition characterized by the presence of positive anti-GBM autoantibodies, linear deposition of immunoglobulin G (IgG) along the GBM and severe kidney injury. In a limited number of cases, the association of anti-GBM disease with other glomerulonephritis has been reported. Herein, we present the case of a 66-year-old female patient with progressive worsen kidney function and decreased urine output. A renal biopsy revealed crescent glomerulonephritis with lineal IgG deposition along the GBM and mesangial IgA deposition, which supported the diagnosis of concurrent anti-GBM disease and IgA nephropathy (IgAN). In an extensive literature review, we identified a total of thirty-nine patients were reported anti-GBM disease combined with IgAN. The clinical characteristics of these patients demonstrate that the anti-GBM disease combined with IgAN tends to be milder with a more indolent course and a better prognosis than the classic anti-GBM disease, and its potential pathogenesis deserves to be further explored.

Keywords:

• Anti-glomerular basement membrane disease
• IgA nephropathy
• crescentic glomerulonephritis
• immunoglobulin G
• prognosis

Introduction

Anti-glomerular basement membrane (anti-GBM) disease is a rare autoimmune disorder characterized by the presence of positive anti-GBM autoantibodies and the linear deposition of immunoglobulin G (IgG) along specific basement membranes, such as the GBM and alveolar basement membrane [1,2]. Histologically, it is characterized by extensive crescent formation and clinically, it is associated with rapidly progressive glomerulonephritis (RPGN). Anti-GBM disease is mediated by serum circulating autoantibodies and its main autoantigen is the non-collagen domain of the α3 chain of type IV collagen [α3(IV)NC1)] [3–5]. Two conformational epitopes have been identified on α3(IV)NC1, specified as EA and EB [1,6,7].

In recent years, a growing number of atypical manifestations of anti-GBM disease have been reported, suggesting that it might be composed of heterogeneous subgroups [1, 8]. Concurrent presentations of two types of renal pathology are not rare findings in kidney biopsy. With progress in diagnostic technology, anti-GBM diseases with antineutrophil cytoplasmic antibody (ANCA) vasculitis and membranous nephropathy (MN) have been frequently reported [1,9,10]. However, cases of anti-GBM disease complicated by IgA nephropathy (IgAN) are uncommon. IgAN is the most prevalent glomerulonephritis worldwide, characterized by dominant IgA deposition in the glomerular mesangium [11]. The combination of anti-GBM disease with IgAN is usually a milder disease with a less aggressive pattern than typical anti-GBM disease. The underlying pathogenesis needs to be further elucidated [8].

Herein, we describe a case of concurrent anti-GBM disease and IgAN in our institute. In an extensive literature review, we identified a total of thirty-nine patients reporting anti-GBM glomerulonephritis combined with IgAN to better understand this disease.

Methods

We reviewed the literature for all papers on anti-GBM combined with IgAN published until September 30, 2023, searching the PubMed database of the National Center for Biotechnology Information. The following key words were used: ‘anti-GBM disease’ OR ‘anti-GBM nephritis’ OR ‘anti-GBM glomerulonephritis’ in combination with ‘IgA nephropathy’. Combined anti-GBM disease and IgAN were diagnosed using the following criteria. (i) Circulating anti-GBM antibodies were detected by a commercially available enzyme-linked immunosorbent assay with bovine α(IV)NC1 as solid-phase antigen. (ii) On kidney specimens, IgA staining (strength ≥2+) was identified in glomerular mesangium on immunofluorescence, and an electron-dense deposit was observed in the glomerular mesangial area on electron microscopy. (iii) Patients with combined other glomerular diseases or tumors, and patients with unavailable blood samples and missing data were excluded. Two readers (a nephrologist GX and a nephrology resident CZW) assessed the full text separately to extract the following data: gender, age, country, oliguria/anuria, hemoglobin, proteinuria, serum creatinine (SCr) on diagnosis, level of anti-GBM antibody, crescent ratio, immunofluorescence on GBM, hemodialysis on diagnosis, immunosuppressive therapy, follow-up time, and outcome. All variables are unified: (i) SCr (1 mg/dL =88.4 µmol/L). (ii) Hemoglobin (1 g/dL = 10 g/L). (iii) Proteinuria (24-h proteinuria quantification: ‘<0.15 g’ = ‘–’, ‘0.15–0.30g’ = ‘±’, ‘0.3–1.5 g’ = ‘1+’, ‘1.5–3 g’ = ‘2+’, ‘3–6 g’ = ‘3+’, ‘> 6 g’ = ‘4+’). Chi-square test was used to estimate the relationships between selected variables and renal revival in patients (SPSS 26.0 software). p < 0.05 was considered statistically significant.

Results

Case report

History of present illness

A 68-year-old female was admitted to the Kidney Institute of PLA (Changzheng Hospital, Shanghai, China) in October 2021 with complaints of fever and increasing SCr for one month. One month before this hospitalization, she developed symptoms such as fever, cough, fatigue, and nausea. Laboratory tests revealed a neutrophil rate of 80.9% with C-reactive protein (CRP) of 76.8 mg/L, as well as a Scr level of 116.1 µmol/L. Computed tomography (CT) scan showed normal signs of the lungs, with the exception of multiple small nodules. Then she received anti-infection treatment for two weeks. However, no improvement was detected in clinical symptoms, instead of decreased urine output, and a repeat laboratory test indicated progressive decreased kidney function with a SCr level of 496 µmol/L. Moreover, the anti-GBM antibody was positive, and urinalysis revealed urinary occult blood 3+ and urinary protein 3+. Subsequently, the patient was immediately transferred to our institute for further treatment.

Personal and family history

The patient denied having a family history and previous medical history of illness, such as hypertension, diabetes mellitus, arthritis, or chronic kidney disease.

Physical examination

On admission, the physical examination was unremarkable except for pallor, moderate bilateral pitting pedal edema and an elevated blood pressure of 153/82 mmHg.

Laboratory and imaging examinations

Urinalysis showed an erythrocyte level of 496.8/µL and 24-h urine protein quantification of 1.916 g. The SCr level had risen from 496 µmol/L to 1040 µmol/L during one week. In addition, the hemoglobin (Hb) level was 82 g/L and CRP was 162.92 mg/L. Serum immunoglobulin A (IgA) (5.08 g/L) and immunoglobulin G (IgG) (19.70 g/L) were increased, while complement C3 (1.110 g/L) and C4 (0.368 g/L) was normal. The level of serum anti-GBM antibody was 184.94 EU/ml (cat no. EA 1251-9601 G, EUROIMMUN, Medical Laboratory Diagnostics Co., Ltd, Luebeck, Germany). The antibody profile was negative for p-ANCA, c-ANCA and anti-double stranded DNA. Ultrasonogram showed normal signs of the kidneys.

Renal biopsy

Based on the above findings, rapidly progressive glomerulonephritis was diagnosed and an ultrasound-guided renal biopsy was immediately performed. Light microscopy showed 13 glomeruli, including 2 all-nodular sclerosing glomeruli, 7 spherical cellular crescents, 1 spherical fibrocellular crescent, and 1 segmental cellular crescent (Figure 1A). The glomerular mesangial cells and matrix were slightly proliferative. In addition, diffuse necrotic tubular epithelial and infiltration or inflammatory cells showed severe injury to the tubulointerstitium. Immunofluorescence staining revealed linear deposition of IgG (++) along the capillary wall, and the IgG subclass showed capillary lineal deposition of IgG3 (+) (Figure 1B and 1C). Granular and bolus-type deposits of IgA (++) were observed in the mesangial area (Figure 1D). Furthermore, electron microscopy revealed electron-dense mass deposits in the mesangial area.

Figure 1. Pathological results of kidney biopsy and clinical course. (A) Light microscopy showing the formation of large cellular crescents (PASM staining, × 200). (B) Immunofluorescence showing linear deposition of IgG along the GBM. (C) IgG subclass shows capillary lineal deposition of IgG3. (D) Immunofluorescence showing lumpy deposition of IgA in the mesangium. (E) Clinical course of patient. GBM, glomerular basement membrane; Ig, immunoglobulin; Scr creatinine; HD, hemodialysis; PE, plasma exchange; MethyI-PD, Methylprednisolone; IV, intravenous; CYC, cyclophosphamide; w. week; m, month.

Final diagnosis

A diagnosis of anti-GBM disease combined with IgAN was confirmed.

Treatment

After admission, the patient firstly received a pulse dose of intravenous methylprednisolone (IV Methyl-PD; Pfizer Ltd., Kent, UK) of 240 mg/day for 3 days followed by oral prednisolone acetate (Shanghai Xinyi Pharmaceutical Co., Ltd, Shanghai, China) of 50 mg/day, which was gradually tapered to 10 mg/day with a total of four months treatment duration. Intravenous cyclophosphamide (Baxter Oncology GmbH, German) of 400 mg/2 weeks was administered, with a cumulative dose of 2 g (end up with lung infection). In addition, she received plasmapheresis for 5 sessions during hospitalization, until the anti-GBM antibody was negative. Hemodialysis was performed simultaneously until urine output was restored (Figure 1E).

Outcome and follow-up

Throughout the 20-month follow-up, the anti-GBM antibody titer was persistently negative, the level of SCr was stabilized (170–212 µmol/L), and urinalysis showed no abnormalities. The patient was generally with a stable health condition.

Literature review

Patient characteristics

Thirty-nine cases of anti-GBM disease combined with IgAN were identified (including the present case) from 2005 to 2023 with an average age of 42.5 ± 17.1 years old, and 19/39 (48.7%) males (Table 1). A majority of patients were from China (29/39, 74.4%), flowed by India (4/39, 10.2%), Japan (3/39, 7.7%), Asia (2/39, 5.1%) and Korean (1/39, 2.6%). Oliguria or anuria was detected in 13/31 (41.9%) cases. The number of patients with proteinuria 1+, 2+, 3+, 4+ was 9 (23.7%), 11 (28.9%), 12 (31.6%), and 6 (15.8%), respectively. The average levels of hemoglobin and SCr were 9.4 ± 1.5 g/dL and 6.3 (3.3, 8.6) mg/dL, respectively. As expected, circulating anti-GBM antibodies were detected in all patients. The mean overall crescent ratio was 0.71 ± 0.22. As presented in Table 1, 34/38 (89.5%) patients were treated with IV Methyl-PD, and 12/38 (31.6%) patients required hemodialysis at presentation. A majority of patients (81.6%) received plasma exchange therapies. During the according follow-up, 25/39 (64.1%) patients had a significant renal revival, and 14/39 (35.9%) patients progressed to ESKD or remained on maintenance hemodialysis (MHD).

Table 1. Clinical characteristics of anti-GBM disease combined with IgAN (2005–2023).

Author		Gender	Age (yr)	Country	Oliguria/anuria	Hemoglobin (g/dL)	Proteinuria	Serum creatinine on diagnosis (mg/dL)	Level of anti-CBM antibody	Crescent ratio (%)	Immunofluorescence on GBM	Hemodialysis on diagnosis	Immunosuppressive therapy	Follow-up time (month)	Outcome – kidney
1	Our study	Female	68	China	Yes	8.2	2+	11.8	184.94 U/mL	69%	IgG 2+	Yes	IV Methyl-PD + oral PD + PE + IV CYC	22.0	Improved renal function
2	Takahiro Matsuno (2023) [2]	Male	76	Japan	NR	10.1	3+	5.2	485.7 U/mL	NR	NR	Yes	IV Methyl-PD + PE + IV CYC + oral PD + oral azathioprine	2.6	MHD
3	Yu Chen (2023) [13]Cong-rong Shen (2023) [8]	Female	35	China	Yes	10.6	3 +	4.7	Positive	55%	IgG 3+	No	IV Methyl-PD + PE + IV CYC + IV immunoglobulin + oral PD	3.0	Improved renal function
4		Female	49	China	Yes	6.8	2+	8.0	59 RU//mL	91%	IgG	Yes	IV Methyl-PD + PE + Immunosuppressant + oral PD	0.9	ESKD
5		Male	52	China	No	9.3	2+	8.5	142 RU//mL	79%	IgG, IgM	Yes	IV Methyl-PD + PE + Immunosuppressant + oral PD	19.6	ESKD
6		Female	49	China	No	8.3	3+	8.4	45 RU//mL	87%	IgG, IgM	No	IV Methyl-PD + PE + Immunosuppressant + oral PD	1.1	ESKD
7		Male	60	China	Yes	10.7	1+	10.1	200 RU//mL	86%	IgG, IgM	Yes	IV Methyl-PD + PE + Immunosuppressant + oral PD	1.1	ESKD
8		Male	16	China	No	12.8	4+	4.0	189 RU//mL	80%	IgG, IgM	No	IV Methyl-PD + PE + Immunosuppressant + oral PD	45.8	Improved renal function
9		Female	35	China	Yes	7.7	2+	9.3	86 RU//mL	90%	IgG	No	IV Methyl-PD + PE + Immunosuppressant + oral PD	1.0	ESKD
10		Male	58	China	No	9.3	3+	8.5	25 RU//mL	62%	IgG	No	IV Methyl-PD + PE + oral PD	1.2	ESKD
11		Male	70	China	No	8.8	4+	3.1	25 RU//mL	77%	IgG, IgM	No	PE + Immunosuppressant + oral PD	27.5	Improved renal function
12		Male	37	China	No	12.0	4+	6.0	200 RU//mL	91%	IgG	No	IV Methyl-PD + PE + Immunosuppressant + oral PD	24.4	Improved renal function
13		Female	31	China	No	9.9	3+	2.5	200 RU//mL	52%	IgG, IgM	No	IV Methyl-PD + PE + Immunosuppressant + oral PD	17.6	Improved renal function
14		Female	43	China	No	9.9	1+	1.7	29 RU//mL	53%	IgG, IgM	No	IV Methyl-PD + PE + Immunosuppressant + oral PD	16.3	Improved renal function
15		Female	54	China	No	10.4	3+	5.1	200 RU//mL	93%	IgG	No	IV Methyl-PD + PE + Immunosuppressant + oral PD	15.5	Improved renal function
16		Male	76	China	No	8.3	2+	9.6	148 RU//mL	78%	IgG	No	IV Methyl-PD + PE + Immunosuppressant + oral PD	9.6	Improved renal function
17		Male	54	China	No	7.8	1+	6.2	160 RU//mL	77%	NR	No	IV Methyl-PD + PE + Immunosuppressant + oral PD	0.9	ESKD
18		Male	17	China	No	8.4	2+	2.2	200 RU//mL	86%	IgG	No	IV Methyl-PD + PE + Immunosuppressant + oral PD	2.9	Improved renal function
19	Chuan Guo (2022) [14]	Male	49	China	No	10.8	2+	1.5	68 RU//mL	70%	IgG 3+	No	IV Methyl-PD + IV CYC + oral PD	7.0	Improved renal function (Scr, 1.19–1.39 mg/dL)
20	Huihui Chen (2022) [15]	Female	40	China	No	9.9	1+	3.6	192.4 IU//mL	77%	IgG 3+	No	PE + oral CYC + oral PD	12.0	Improved renal function (1.17 mg/dL)
21	Fu Shaojie (2022) [16]	Female	26	China	NR	NR	3+	1.9	142 RU/ mL	48%	IgG	No	IV Methyl-PD + PE + IV CYC + oral PD	12.0	Remain within the normal range
22	Varun Bajaja (2022) [17]	Female	13	India	Yes	7.4	2+	3.4	Positive	56%	IgG1 (2 ∼ 3+), IgG4 (1 ∼ 2+)	Yes	IV Methyl-PD + PE + IV CYC + oral PD	NR	Improved renal function (Scr, 1.26 mg/dL)
23	Manyu Zhang (2021) [18]	Female	41	China	Yes	9.1	2+	4.6	100.8 RU/mL	> 50%	NR	Yes	IV Methyl-PD + PE + IV CYC + IV rituximab + oral PD	6.5	Scr level fluctuated from 1.33–2.05 mg/dL
24	Candice Khor (2021) [19]	Female	66	Australia	NR	10.0	1+	3.6	79 U/mL	40%	IgG 3+	No	IV Methyl-PD + PE + IV CYC + oral PD	12.0	Improved renal function
25	Malviya PB (2021) [20]	Male	29	India	Yes	11.0	3+	12.7	Positive	100%	IgG	Yes	IV Methyl-PD + PE + IV CYC + oral PD	NR	ESKD
26	Kwang-Sun Suh (2019) [21]	Female	38	Korean	NR	NR	1+	5.5	187.2 U/mL	69%	IgG	No	IV Methyl-PD + IV CYC + oral PD	3.0	Improved renal function (Scr, 2.08 mg/dL)
27	Tadasu Kojima (2019) [22]	Female	66	Japan	Yes	11.3	4+	4.5	116 IU/mL	58%	IgG 2+	Yes	IV Methyl-PD + PE + oral PD	NR	MHD
28	Longano Anthony (2019) [10]	Male	22	Australia	No	9.0	1+	0.9	Positive	18%	IgG	No	PE + oral PD + oral CYC + oral azathioprine	4.0	Scr remained within the normal range
29	Yashita Gupta (2019) [23]	Male	20	India	Yes	NR	3+	13.1	Positive	100%	IgG (3 ∼ 4+)	No	IV Methyl-PD + PE + IV CYC + oral PD	NR	Nondialysis-dependent chronic renal failure
30	Jing Shan (2018) [24]	Male	40	China	No	9.1	2+	4.7	141 RU/mL	NR	NR	No	IV Methyl-PD + PE + IV immunoglobulin + IV CYC + oral PD	1.0	Improved renal function (Scr, 1.48 mg/dL)
31	Ishwarya Annamalai (2017) [25]	Female	22	India	Yes	8.6	3+	3.2	96 U/mL	70%	IgG 2+	No	IV Methyl-PD + oral PD	NR	Improved renal function
32	Dechao Xu (2016) [26]	Female	50	China	No	9.9	1+	2.62	258.3 EU/mL	89%	IgG 3+	No	IV Methyl-PD + oral mycophenolate + oral PD	20.0	Scr remained within the normal range
33	Yating Ge (2015) [27]	Male	24	China	Yes	8.2	4+	15.7	Positive	58%	IgG	Yes	IV Methyl-PD + PE + IV CYC + oral PD	2.9	MHD
34	Weifeng Shang (2015) [28]	Female	54	China	Yes	8.1	3+	10.0	Positive	19%	IgG	Yes	IV Methyl-PD + PE + IV immunoglobulin + IV CYC + oral PD	3.0	MHD
35	Hiroshi Yamaguchi (2013) [29]	Male	46	Japan	NR	11.9	1+	6.6	214 EU/mL	94%	IgG	No	IV Methyl-PD + oral PD	NR	MHD
36	Aifeng Wang (2012) [30]	Female	31	China	NR	NR	3+	3.3	93.5 RU/mL	82%	IgG 3+	No	IV Methyl-PD + oral CYC + oral PD + PE	1.0	Improved renal function
37	Bixia Gao (2009) [31]	Female	38	China	No	6.1	2+	6.6	237.6 EU/mL	28%	IgG 2+	No	IV Methyl-PD + oral PD + IV CYC	4.0	Improved renal function (Scr, 2.19mg/dL)
38	Zhao Cui (2006) [32]	Male	27	China	NR	NR	NR	15.2	Positive	100%	IgG +	NR	NR	NR	MHD
39	Yan Wang (2005) [33]	Male	34	China	NR	11.4	4+	8.6	Positive	63%	IgG 3+	Yes	oral mycophenolate	NR	ESKD

Abbreviations: GBM, glomerular basement membrane; IgAN, IgA nephropathy; Scr, serum creatinine; HD, hemodialysis; PE, plasma exchange; Methyl-PD, Methylprednisolone; IV, intravenous; CYC, cyclophosphamide; MHD, maintained hemodialysis; ESKD, end-stage kidney disease; NR, not reported.

Correlated factors with renal survival of patients

To explore the potential clinical factors associated with the renal survival, we divided the patients into ESKD group and non-ESKD group based on the clinical outcomes (Table 2). Statistical analysis shows that the SCr level above 4 mg/dL (p < 0.001) and hemodialysis at diagnosis (p = 0.002) were significantly associated with ESKD. However, the factors of age, country, oliguria/anuria, anemia, proteinuria, and crescent ratio were not associated with ESKD.

Table 2. Factors associated with renal survival of patients.

Variables	Non-ESKD (24)	ESKD (15)	p value
Age (yr)	39.3 ± 17.8	47.5 ± 15.1	0.612
Country	24	15	0.597
China, n (%)	18 (75.0%)	11 (73.3%)
Foreign country, n (%)	6 (25.0%)	4 (26.7%)
Oliguria/anuria	20	11	0.069
Yes, n (%)	6 (30.0%))	7 (63.6%)
No, n (%)	14 (70.0%)	4 (36.4%)
Hemoglobin (g/dL)	20	14	0.643
<9 g/dL, n (%)	13 (65.0%)	8 (57.1%)
≥9 g/dL, n (%)	7 (35.0%)	6 (42.9%)
Proteinuria	24	14	0.789
1+, n (%)	6 (25.0%)	3 (21.4%)
2+, n (%)	8 (33.3%)	3 (21.4%)
3+, n (%)	7 (29.2%)	5 (35.7%)
4+, n (%)	3 (12.5%)	3 (21.4%)
Serum creatinine on diagnosis (mg/dL)	24	15	<0.001
<4 mg/dL, n (%)	13 (54.2%)	0 (0.0%)
≥4 mg/d, n (%)	11 (45.8%)	15 (100.0%)
Crescent ratio (%)	23	14	0.362
<50%, n (%)	4 (17.4%)	1 (7.1%)
≥50%, n (%)	19 (82.6%)	13 (92.9%)
Hemodialysis on diagnosis	24	14	0.002
Yes, n (%)	3 (12.5%)	9 (64.3%)
No, n (%)	21 (87.5%)	5 (35.7%)

Abbreviations: Scr, serum creatinine; ESKD, end-stage kidney disease. Bold values are statistically significant.

Discussion

In our present study, a rare case of concurrent anti-GBM disease and IgAN was reported. Since the first report of a recurrent anti-GBM disease with IgAN in 1998 [12], the coexistence of anti-GBM disease and IgAN has been documented sporadically in several studies. A literature review for Anti-GBM disease and IgAN was performed resulting in a total of thirty-nine cases (Table 1) [2, 8–10, 13–33]. The current therapy involves a combination of plasmapheresis and immunosuppressive therapy to quench active inflammation and weaken cellular reaction and antibody production. Based on the analysis of the collected cases, we discovered that most of patients were treated with a combination of steroids, cytotoxic immunosuppressive therapy and plasmapheresis. Among 39 cases, we found that more than half (64.1%) of patients had favorable renal recovery. However, the clinical presentations of anti-GBM diseases with ANCA-associated vasculitis were often severe, and the majority manifested acute renal failure with low renal survival rates [34]. Moreover, a latest article reported on 28 patients who were diagnosed with concurrent anti-GBM disease and MN, and their prognosis was very poor despite prompt plasmapheresis and immunosuppression [35]. The combination of anti-GBM disease with IgAN tends to be a milder disease with a less aggressive pattern than typical anti-GBM disease.

Anti-GBM disease presents with severe and abrupt symptoms, with about 90% of patients having rapidly progressive glomerulonephritis. A study found that patients with 100% crescents on renal biopsy who receive dialysis and show renal failure at presentation have a terrible kidney survival rate of 8% at 1 year of follow-up [1]. Previous studies revealed that advancing age, low glomerular filtration rate (GFR), low hemoglobin, high crescent ratio, and high SCr level were significant negative risk factors associated with the prognosis of typical anti-GBM disease [36–39]. In our study, the chi-square test showed that ESKD was related to high SCr level (p < 0.001) and hemodialysis on admission (p = 0.002). A prospective study reported that in-hospital dialysis was an indicative factor of short-term renal survival [38]. However, the limited number of cases and incomplete clinical information prevented us from conducting a multivariate Cox regression analysis to further explore the risk factors in our patients.

In addition to the above clinical characteristics, an increasing number of studies have focused on the pathogenesis of the disease. In accordance with previous case reports, IgAN was diagnosed prior to or synchronously with anti-GBM disease, rather than as a subsequent event. Pathogenesis of IgAN is characterized by IgA-containing immune complexes passing through the glomerular capillary walls and depositing extensively in the mesangium [11]. It has been suggested that epitopes are isolated under normal circumstances and exposed following some physicochemical disruption, which then allows the initiation of immune response [17]. There was one hypothesis that IgA-related immune complexes might promote immunologic and inflammatory activities, leading to conformational changes and exposure of GBM antigens resulting in the development of anti-GBM autoantibodies [22]. In addition, abnormalities in IgA molecules might be another factor. Deposits of IgA1 with aberrant polysaccharide chains along GBM and anti-GBM IgG detected in patients with anti-GBM disease combined with IgAN led us to speculate that the deposition of abnormal IgA1 along GBM might induce novel antigen formation and consequently cause the production of anti-GBM antibodies [32]. Takahiro Matsuno [2] has reported a male patient who developed anti-GBM disease after being diagnosed with IgAN. Despite this, it is challenging to determine whether anti-GBM disease is an incidental complication of IgAN or a secondary manifestation, since there is no established marker that may differentiate primary from secondary anti-GBM disease.

There is one hypothesis concerning epitopes on GBM. In natural conditions, the type IV collagen of human GBM is composed of five subclasses of α chains (α1, α2, α3, α4 and α5), and the main target antigen of anti-GBM antibodies recognizes conformational epitopes within the α3 chain of type IV collagen. Dissociation of the α3 monomer from the hexamer structure leads to exposure of cryptic epitopes (Ea and Eb) to the host immune system [5, 40]. Juan Zhao et al. [41] found that the level of autoantibodies against α3 (IV) NC1 was a significant independent risk factor for a higher SCr level on diagnosis by regression analysis. It suggested that autoantibodies against α3 (IV) NC1 were vital in the pathogenesis of renal damage in anti-GBM disease, and autoantibodies against α1, α2, α4 and α5 chains caused less kidney damage than α3 chain. A similar study also reported that the level of antibodies against α3 (IV) NC1 is an independent risk factor for renal damage. A new study in IgAN revealed that α5 (IV) NC1 was characterized by a strong linear pattern on the vertical cut surface of GBM, and in the glomeruli with cellular crescents, the α5 (IV) expression in the GBM was disrupted, indicating rupture of the GBM [42]. The above information suggests that different epitopes of α chains might explain partly the better prognosis of anti-GBM disease combined with IgAN.

Another popular explanation suggested that the distribution of anti-GBM autoantibody IgG subclasses was associated with disease severity. IgG is categorized into four subclasses (IgG1, IgG2, IgG3, and IgG4) according to their heavy chains, which elicit different immunological and inflammatory responses. Anti-GBM antibodies subclasses detected in the normal human serum belong to IgG2 and IgG4 [43]. IgG1 and IgG3 are the most dominant IgG subclass in typical anti-GBM disease, while the proportion of IgG2 and IgG4 seem to be greater than IgG1 and IgG3 in anti-GBM disease combined with IgAN [8]. In our case, we found that IgG3 was deposited along the GBM, which might explain a severe renal dysfunction on admission. It suggested that during the progression of anti-GBM disease, IgG1 and IgG3 subclasses against target GBM were also the most crucial contributors to the severity of renal function [43–45]. It should be mentioned that autoantibodies of the IgG1 and IgG3 subclasses might have had an evident role in pathogenesis, as these two subclasses were known to activate the complement. Once activated, complement chemotactic factors may then attract effector cells such as macrophages and neutrophils, which are known to contribute to glomerulonephritis [46]. Complement activation has been shown to have a pathogenic role in accelerated nephrotoxic nephritis models and involving the pathogenesis of anti-GBM disease [47, 48]. In addition, both IgG2 and IgG4 are weak activators of the complement system, likely explaining their less aggressive process. Another mechanism for IgG including tissue damage lies in its high affinity binding to Fc receptors (FcR) on phagocytic cells to mediate opsonization. The IgG-FcR interaction in glomeruli could also mediate macrophage accumulation to induce renal injury [49, 50]. Weak classical complement pathway activation and weak binding to IgG Fc receptors on mononuclear cells by IgG4 make it less likely to cause an aggressive inflammatory reaction [51, 52]. Further research is needed to determine whether the IgG subclass contributes to a better prognosis in patients with anti-GBM glomerulonephritis in combination with IgAN.

In the case of anti-GBM disease complicated with IgAN, whether GBM damage is mediated by IgG or IgA also raised our attention. Literature review revealed linear IgG deposition on the glomerular basement membrane by renal biopsy in most cases. The high diagnostic accuracy of commercial assays to detect only IgG antibodies against anti-GBM antibodies could be limited to typical anti-GBM disease, and generate a negative result for serum containing non-IgG anti-GBM antibodies. Previous studies found undetectable circulating anti-GBM antibodies such as IgA and IgM on enzyme linked immunosorbent assay (ELISA), indirect immunofluorescence (IF), and western blot (WB) in patients with non-typical anti-GBM disease [1]. Some patients have high affinity antibodies trapped in the kidneys with a low circulation titer. The low titer is not detectable in conventional detection assays, resulting in false negative results. Intriguingly, while Marilina Antonelou [53] described a case of anti-GBM disease combined with IgA nephropathy mediated by IgA anti-GBM antibodies not detected by standard serological tests, however, whether the IgA deposited along GBM or the IgA in mesangium in patients with combined diseases are homologous merits further exploration.

In conclusion, we describe a case of concurrent anti-GBM disease and IgAN, and review the cases published in the literature to better understand the disease. An in-depth examination of the underlying pathogenic relationship between anti-GBM disease and IgAN needs to be conducted in more cases.

Authors’ contributions

Zewei Chen, Dechao Xu, and Fangzheng Cui were involved in the patient case, collected the necessary data, and drafted and finalized the manuscript. Xiang Gao and Huihui Hou was involved in the patient case, delivered the necessary data, and critically revised the manuscript for intellectual content. Xiang Gao and Zhiguo Mao were accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved. All authors contributed to the article and approved the submitted version.

Acknowledgements

The authors appreciate the patient for her patience and cooperation in the diagnostic work-up and follow-up.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by research Grants 20234Y0175 from the Clinical Research Project of Shanghai Municipal Health Commission, 22Y11905500 from the Science and Technology Innovation Plan of Shanghai Science and Technology Commission, 82070705 from the National Natural Science Foundation of China.