Complement system is overactivated in patients with IgA nephropathy after COVID-19.

IgA nephropathy (IgAN), which has been confirmed as a complement mediated autoimmune disease, is also one form of glomerulonephritis associated with COVID-19. Here, we aim to investigate the clinical and immunological characteristics of patients with IgAN after COVID-19. The level of plasma level of C5a (p < 0.001), soluble C5b-9 (p = 0.018), FHR5 (p < 0.001) were all significantly higher in Group CoV (33 patients with renal biopsy-proven IgAN experienced COVID-19) compared with Group non-CoV (44 patients with IgAN without COVID-19), respectively. Compared with Group non-CoV, the intensity of glomerular C4d (p = 0.017) and MAC deposition (p < 0.001) and Gd-IgA1 deposition (p = 0.005) were much stronger in Group CoV. Our finding revealed that for IgAN after COVID-19, mucosal immune responses to SARS-CoV-2 infection may result in the overactivation of systemic and renal local complement system, and increased glomerular deposition of Gd-IgA1, which may lead to renal dysfunction and promote renal progression in IgAN patients.

Characterization of patients with IgA nephropathy with and without associated minimal change disease.

Introduction: Immunoglobulin A nephropathy (IgAN) presents various clinical manifestations and pathological phenotypes. Approximately 5% of patients with IgAN present with early onset nephrotic syndrome, mild mesangial lesions, and diffuse foot process effacement of podocytes, which resemble minimal change disease (MCD). These patients are defined as MCD-IgAN. Whether MCD-IgAN is a special type of IgAN or simply MCD accompanied by IgA deposition remains controversial. Methods: A total of 51 patients diagnosed with MCD-IgAN at Beijing Anzhen Hospital from January 2010 to September 2022 were recruited. The clinical and pathological characteristics of IgA-MCD were analyzed. Patients with IgAN but without MCD (non-MCD-IgAN) and healthy participants were enrolled as controls. Galactose-deficient immunoglobulin A1 (Gd-IgA1) and complement C3 were detected both in the circulation and in renal tissues. Results: We found that the levels of serum Gd-IgA1 were lower in participants with MCD-IgAN than in those with non-MCD-IgAN, but higher than in healthy participants. Gd-IgA1 was rarely deposited in the glomeruli of participants with MCD-IgAN, with a positive rate of only 13.7% (7/51); in contrast, the positive rate in participants with non-MCD-IgAN was 82.4% (42/51). Among renal Gd-IgA1-positive patients, Gd-IgA1 and immunoglobulin A (IgA) colocalized along the glomerular mesangial and capillary areas. Interestingly, we found that the circulating levels of complement C3 were significantly higher in participants with MCD-IgAN than in participants with non-MCD-IgAN. In addition, the intensity of C3c in glomeruli in participants with MCD-IgAN was significantly weaker than in participants with non-MCD-IgAN. Conclusions: Our study suggests that, in MCD-IgAN, most of the IgA that is deposited on glomeruli is not the same pathogenic Gd-IgA1 as found in general IgAN. Complement activation both in the circulation and in the renal locality was much weaker in MCD-IgAN than in non-MCD-IgAN. Our study suggests that IgAN with MCD might be MCD with coincidental IgA deposition.

Overactivation of the complement system may be involved in intrarenal arteriolar lesions in IgA nephropathy.

Introduction: IgA nephropathy (IgAN) encompasses a wide range of clinical and histology features. Some patients present without hematuria, with or without hypertension, still rapidly progress in renal function. Renal pathology of this part of patients were predominant intrarenal arteriolar lesions, rarely presented glomerular proliferative lesions. We aim to investigate the clinical and pathological characteristics and prognosis of these IgAN patients and initially explore whether the abnormal activation of complement is involved in the intrarenal arteriolar lesions of IgAN. Methods: A total of 866 patients with renal biopsy-proven IgAN diagnosed at Beijing Anzhen Hospital were recruited. IgAN patients without intrarenal arteriolar lesions and proliferative lesions were excluded (n = 115), the rest were divided into arteriolar lesions group (n = 202) and proliferative lesions group (n = 549). Among them, 255 patients were regularly followed up for at least 1 year. Renal biopsy tissues of 104 IgAN patients were stained for complement components by immunohistochemistry and immunofluorescence. Results: Compared with proliferative lesions group, the arteriolar lesions group experienced high percentage of hypertension (p = 0.004), low percentage of gross hematuria (p = 0.001), microscopic hematuria (p < 0.001) and less initial proteinuria (p = 0.033). Renal survival between the two groups was not significantly different (p = 0.133). MBL, C4d, FH and FHR5, C3c, and MAC deposited on intrarenal arteriole in arteriolar lesions group. Compare with the proliferative lesion group, the arteriolar lesions group exhibited a higher intensity of C3c deposition on the intrarenal arterioles (p = 0.048). C3c and CD31 co-deposited on intrarenal arterioles area in patients with intrarenal arteriolar lesions. Conclusion: Renal survival of the IgAN patients in arteriolar lesions group was not better than those in proliferative lesions group. Abnormal activation of complement may be involved in the pathogenesis of arteriolar damage through the injury of endothelial cells in this clinical phenotype of IgAN.

Association of TLR9 gene polymorphisms with lupus nephritis in a Chinese Han population.

OBJECTIVES: Although increasing data have supported the possible role of TLR-9 in the pathogenesis of lupus nephritis (LN), the effect of TLR-9 on the lupus phenotype remains controversial. The aim of this study was to associate common variants in the TLR9 gene with susceptibility to lupus nephritis in the Chinese population to further ascertain whether it is a susceptible locus for SLE, especially its likely role in LN from a comparatively large population. METHODS: Two previously reported SLE associated single nucleotide polymorphism (rs352139, rs352140) were investigated in a case-control study comprised of 315 patients with biopsy proven lupus nephritis and 338 matched healthy controls. Single nucleotide polymorphisms (SNPs) were typed by TaqMan allele discrimination assays. RESULTS: Both rs352139 (p=0.040, OR: 0.713, 95%CI: 0.516-0.985) and rs352140 (p=0.048, OR: 0.723, 95%CI: 0.525-0.997) were associated with LN in dominant model. A trend for an association between genotypes and the disease activity indexes was observed. However, no significance was achieved. CONCLUSIONS: The present study suggested that TLR9 gene have a role in establishing an autoimmune background and pathogenesis in human LN.