Anti-glomerular basement membrane disease(Anti-GBM disease) is an autoimmune disease in which the target antigen is present within a specific basement membrane, such as GBM and/or alveolar basement membrane. About 80 to 90 percent of patients will develop features of rapidly progressive glomerulonephritis. Pulmonary hemorrhage occurs in 40% to 60% of patients, and isolated lung disease may occur in a very small number of patients (1). Anti-GBM disease is rare, with an incidence of about 1.64 per million population per year (2). However, anti-GBM glomerulonephritis accounts for 10%–15% of all crescentic glomerulonephritis (3). This makes anti-GBM one of the most aggressive glomerular diseases.

Anti-GBM diseases with IgA deposition in the mesangial region are rarely described. Since 1998, when Trpkov, K. et al. first reported IgA deposition in the mesangial region with anti-GBM disease (4), 23 isolated case reports (4–26) and one case-control study (n=15) have been published (27). Some scholars believe that their kidney lesions are milder and their renal prognosis is significantly better than that of classical patients. However, due to the limited number of reported cases and the variable duration of follow-up, we still need to collect more cases to better understand the clinical, pathological, and prognostic data of anti-GBM disease combined with mesangial IgA deposition. The factors influencing renal prognosis in patients with anti-GBM disease combined with mesangial IgA deposition are unknown. So we searched the pathological reports of the First Affiliated Hospital of Zhengzhou University from 2015 to 2023 and found that a total of 72 patients with the anti-GBM disease and 25 patients combined with mesangial IgA deposition, accounted for 34.72%. We studied the clinical and pathological features, renal prognosis, and the factors affecting renal prognosis in patients with anti-GBM disease combined with mesangial IgA deposition.

Our results suggest that patients with anti-GBM disease combined with mesangial IgA deposition have higher 24-hour urine protein excretion at diagnosis (p=0.02), less incidence of oliguria or anuria (p=0.03), lower SCr levels at diagnosis(p=0.002), and better renal prognosis (p<0.001) than patients with classical anti-GBM disease. After adjustment for hypertension, oliguria or anuria, and crescents%, IgA deposit in the mesangial was still an independent protective factor (p=0.003) for ESRD in anti-GBM patients. Hypertension (0.026), and SCr level at diagnosis (0.004) were risk factors for renal prognosis in patients with anti-GBM disease combined with mesangial IgA deposition.

It seems paradoxical that patients with anti-GBM disease combined with IgA deposition in the mesangial region have higher urinary protein excretion at diagnosis but better renal outcomes. Our results showed that patients with anti-GBM disease combined with IgA deposition in the mesangial region have no statistical difference in the treatment of classical anti-GBM patients (Initial dialysis treatment: p=0.06; Number of plasma exchanges:p=0.537; Plasmapheresis: p = 0.665; pulse methylprednisolone:p=0.119; Oral steroid:p=0.504; Cyclophosphamide: p = 0.394; Rituximab, p = 0.24; Mycophenolate mofetil:p=1). We think that this may be related to better response to treatment in patients combined with mesangial IgA deposition, which is also suggested by the case report of F. Shaojie et al. (22), and the clinical study of C. R. Shen et al. (27). We followed up the 24-hour urinary protein excretion between the two groups, and the results showed no statistical difference in the mean 24-hour urinary protein excretion between the two groups from 0 to 3 months, 3 to 6 months, 6 to 12 months, and 12 months to the end of follow-up. We found that the median and quartile of the mean 24-hour urinary protein excretion from 0 to 3 months after diagnosis decreased compared with the 24-hour urinary protein excretion at diagnosis in patients with anti-GBM disease combined with IgA deposition in the mesangial region. The median and quartile of the mean 24-hour urinary protein excretion from 0 to 3 months after diagnosis increased compared with the 24-hour urinary protein excretion at diagnosis in patients with classical anti-GBM disease. However, due to the absence of data and the failure of the normality test, we could not conduct a T-test or ANOVA of repeated measurement design to obtain statistically significant conclusions. According to the follow-up results, we think patients with anti-GBM disease combined with IgA deposition in the mesangial region may achieve good alleviating proteinuria at the early stage of treatment, while patients with classical anti-GBM disease still have proteinuria progression at the early stage of treatment. The kidney survival curves of the two groups also supported this conclusion. We can observe that there is a large gap in renal survival between the two groups at the early stage of follow-up, and the renal survival rate of patients with anti-GBM disease combined with mesangial IgA deposition is significantly higher than that of classical anti-GBM disease. We speculate that this may be one of the characteristics of the anti-GBM disease combined with IgA deposition in the mesangial region. As for the mechanism of high urinary protein excretion at diagnosis, we hypothesize that it may be related to renal injury due to pathogenic immune complex deposition in the mesangium (28). One of the known pathogenesiss of IgA nephropathy is the aggregation of circulating immune complexes in the mesangium of the glomerulus, which induces cellular inflammation and damage, leading to increased urinary protein excretion (29). It may be that basal membrane inflammation caused by anti-GBM disease combined with mesangial inflammation caused by IgA nephropathy leads to higher urinary protein excretion. The inflammation could be reversed after treatment initiation, which may explain the decreased urinary protein excretion in patients with anti-GBM disease combined with mesangial IgA deposition at the early stage of treatment.

Patients with anti-GBM disease combined with mesangial IgA deposition have less incidence of oliguria or anuria, lower SCr levels at diagnosis, and better renal outcomes than patients with the classical anti-GBM disease, which indicates less impairment of kidney function. Zhao J et al. thought that IgG1 and IgG3 subclasses may play a crucial role in the pathogenesis of anti-GBM diseases (30). C. R. Shen et al. suggested that the lower prevalence of circulating anti-α3 (IV)NC1 IgG1 and IgG3 subclasses in patients with anti-GBM disease combined with IgA nephropathy(IgAN) may be associated with milder renal disease (27). We studied the subclasses of IgG antibodies deposited along the glomerular basement membrane between patients with anti-GBM disease combined with mesangial IgA deposition and patients with the classical anti-GBM disease and found that there was no statistical difference in the deposition of each subclass (IgG1: p=0.382; IgG2: p=0.842; IgG3: p=0.726; IgG4:p=0.237). Whether the presence and action of IgG1 and IgG3 anti-GBM antibodies are related to better renal prognosis in patients with mesangial IgA deposition needs further experimental verification.

It is not clear whether mesangial IgA deposition or anti-GBM disease occurs first, or whether it occurs simultaneously so far. We hypothesize that IgA deposition in the mesangial region precedes anti-GBM disease. Current research results suggest that pathogenic circulating IgA1-IgG immune complexes in patients with IgA nephropathy enter the renal circulation and are deposited in the mesangium of the glomeruli, resulting in mesangial cell proliferation and expansion of extracellular matrix components. This immune complex has a high affinity for fibronectin, the extracellular matrix components in the mesangium, and type IV collagen (28). The main target antigen of anti-GBM autoantibodies is the non-collagen domain (NC1) of the α3 chain of type IV collagen [α3(IV)NC1], and the content of a3 (IV) in the basement membrane is tissue-specific, with the highest content of a3 (IV) in the basement membrane of patients with anti-GBM (31). We hypothesize that the pathogenesis of patients with anti-GBM disease and IgA deposition in the mesangial region may be as follows: the patient begins with IgA deposition in the mesangial region, and the pathogenic circulating immune complex binds to type IV collagen in the mesangium of the glomeruli, changing the conformation of type IV collagen, exposing the α3 chain, and the patient produces anti-a3 (IV) antibodies, i.e., anti-GBM antibodies, which leads to the development of anti-GBM disease. Matsuno et al. observed that the titer of anti-GBM antibodies changed from negative to positive in the patient with IgA nephropathy during the disease, suggesting the possibility of our view (26). In addition, two patients in the cohort of Shen, C. R., et al. had IgA nephropathy before the onset of anti-GBM disease (27). However, whether the anti-GBM disease in these patients is an incidental complication or secondary to IgA deposition in the mesangial region remains difficult to prove. More researches are needed.

We also summarized all cases of anti-GBM disease combined with mesangial IgA deposition published in Pubmed (http://www.ncbi.nlm.nih.gov/pubmed) to date (including our cohort, a total of 61 cases, since 1998), as shown in Table 5 (4–26).

The median age of all reported patients with anti-GBM disease combined with mesangial IgA deposition was 44.5 years, and 63.93% of patients were female ( Table 5 ). The age distribution of patients showed an unimodal distribution, as shown in Supplementary Figure S2 . The unimodal age distribution may suggest the order in which the disease occurs. The male-to-female ratio was approximately 1:1.77, suggesting that estrogen levels may be related to the occurrence of the anti-GBM disease combined with mesangial IgA deposition. Of the 61 patients, 48 were in China, 4 in Japan, 3 in India, 2 in the United States, 2 in Australia (1 in Asian, 1 Caucasian), 1 in South Korea, and 1 in Canada. This suggests that the incidence of anti-GBM disease combined with mesangial IgA deposition may vary greatly from region to region.

18% of patients smoked ( Table 5 ). Precursor infection precedes onset in 43% of patients. Gross hematuria occurs in 45% of patients( Table 5 ). Oliguria or anuria occurs in 45% of patients ( Table 5 ). 2 patients (3.28%) developed pulmonary hemorrhage ( Table 5 ). 3 patients (4.91%) had ANCA-associated vasculitis ( Table 5 ). The 24-hour urine protein excretion, SCr level, median serum C3, and hemoglobin values were 2.45 g/24 h, 400.45 μmol/L, 1.21 g/L, and 93 g/L, respectively ( Table 5 ). The median anti-GBM antibody titer was 200 U/mL ( Table 5 ). In all cases, pathological findings showed mesangial IgA deposition. The median rates of glomerular sclerosis and crescent formation were 3% and 77.07%, respectively. In addition, 86.67% of the patients had tubular atrophy, 65.22% had renal interstitial fibrosis, and 81.63% had electron-dense deposition ( Table 5 ). Of all patients, 52.73% received initial dialysis therapy, 85% received plasmapheresis, 98.33% received pulse methylprednisolone, 84.75% received immunosuppressants, and 6.82% received rituximab ( Table 5 ). In the end, 22 (39.39%) of patients progressed to ESRD, and 1 (1.64%) patient died (died of sepsis) ( Table 5 ). This suggests that anti-GBM disease combined with mesangial IgA deposition may have a better renal prognosis.

There are certain limitations to our study. As our study is retrospective, we were unable to obtain sera samples from patients for investigation of IgG subclasses. Because the disease we studied is so rare, our sample size is small and we may not be able to draw very accurate conclusions. We hope that there will be more prospective studies with larger sample sizes in the future.

In summary, we report the largest cohort of the currently known anti-GBM disease combined with mesangial IgA deposition (n=23). We found that patients with anti-GBM disease combined with mesangial IgA deposition may have less kidney damage, better renal outcomes, and better response to treatment than patients with the classical anti-GBM disease. Anti-GBM patients combined with IgA deposition in the mesangial region need early detection and treatment to expect a better renal prognosis.

Patients with anti-GBM disease combined with mesangial IgA deposition have less kidney damage and better renal prognosis than patients with classic anti-GBM disease.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

The studies involving humans were approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

WN: Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing. Y-FZ: Data curation, Investigation, Writing – review & editing. Y-RL: Data curation, Investigation, Writing – review & editing. Y-YQ: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review & editing. Z-ZZ: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review & editing.