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.

Clinicopathological and prognostic characteristics of idiopathic membranous nephropathy with dual antigen positivity.

Background: Idiopathic membranous nephropathy (IMN) is the most common pathological type in adults with nephrotic syndrome. Many target antigens have been discovered. However, dual antigen-positive IMN patients are very rare, with only a few such cases being briefly described in various studies. There is no specific study on the clinicopathological and prognostic characteristics of dual antigen-positive IMN patients, and the disease characteristics of such patients remain unclear. Methods: Immunohistochemical staining of PLA2R, THSD7A, and NELL-1 was conducted on kidney tissue samples obtained from patients diagnosed with IMN. Simultaneously, the presence of corresponding serum antibodies was determined. Patients exhibiting positivity for dual antigens were included in the study, identified either through tissue staining or serum antibody detection. We retrospectively collected their clinical, pathological, and follow-up data and measured their serum antibody levels at multiple time points. Additionally, the same type of dual antigen-positive IMN cases reported in the literature were reviewed to extract clinical, pathological, and prognostic information. We compared the data for all of the above dual antigen-positive and PLA2R single-positive IMN cases at our center. Results: We identified 6 IMN patients with dual antigen positivity at our center, approximately 0.7% of whole MN series; the previous literature reports 43 IMN patients with dual antigen positivity, the proportion ranged from 0.2% to 2.8%. The IgG1 positivity rate in the renal tissue of the dual antigen-positive patients at our center was significantly lower than that of dual antigen-positive patients previously reported (16.7% vs. 100.0%, p=0.015), but there was no significant difference in clinical or prognostic aspects. Patients with dual antigen positivity reported at our center and in the literature were combined and compared with PLA2R single-positive IMN reported at our center. Compared with PLA2R single-positive IMN patients, dual antigen-positive IMN patients had a higher renal tissue IgG1 positivity rate (58.3% vs. 22.3%, p=0.016), and the time required to achieve remission was longer [13.5 (3.3,35.0) vs. 3.0 (1.0,8.0), p=0.052]. Overall, The changes in urine protein were consistent with the changes in serum PLA2R antibody levels in dual antigen-positive IMN patients. Conclusions: For patients with primary membranous nephropathy who did not attain remission following prolonged treatment, multiple target antigen staining should still be actively performed, even with positivity for the PLA2R target antigen.

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.

Glomerular Galactose-Deficient IgA1(KM55) Positive May Predict Poorer Prognosis in Coexisting Primary Membranous Nephropathy and IgA Nephropathy Patients.

Primary membrane nephropathy (PMN) and IgA nephropathy (IgAN) are the most common glomerular diseases in China. Because of different pathogenesis, prognosis is significantly different. When the two diseases coexist (PMN/IgAN), the clinicopathological manifestations and prognosis remain unclear. In the present study, we analyzed the clinicopathological characteristics of PMN/IgAN patients, with only IgA deposition (PMN/IgA deposition) patients as controls. Galactose-deficient IgA1(KM55) and M-type Phospholipase A2 Receptor(PLA2R), both in circulation and renal tissues, were detected. Furthermore, prognosis of PMN/IgAN was explored. We found that PMN/IgAN also had some clinical features of IgAN in addition to PMN, such as higher serum albumin, along with a similar heavy proteinuria and lower titers of serum anti-PLA2R antibody. The positive rate of glomerular KM55 in PMN/IgAN was 23.5% (20/85), and 0% (0/29) in PMN/IgA deposition. Among those glomerular KM55 positive patients, KM55 and IgA colocalized mainly along the glomerular mesangial and capillary areas. Unfortunately, there was no significant difference in serum level of Gd-IgA1 between KM55+ and KM55- subgroups in PMN/IgAN patients, similar to the PMN/IgA deposition group. Notably, glomerular KM55 positive may predict a poorer prognosis in PMN/IgAN patients. In conclusion, our study suggested that, when glomerular KM55 staining was positive, this special coexisting PMN/IgAN disorder was prone to have more characteristics of IgAN besides PMN, and may predict poorer prognosis, while the mechanism requires further investigation.

Neural Epidermal Growth Factor-Like 1 Protein-Positive Membranous Nephropathy in Chinese Patients.

BACKGROUND AND OBJECTIVES: The neural EGF-like 1 (NELL-1) protein is a novel antigen in primary membranous nephropathy. The prevalence and clinical characteristics of NELL-1-positive membranous nephropathy in Chinese individuals with primary membranous nephropathy are unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 832 consecutive patients with biopsy-proven primary membranous nephropathy were enrolled. The glomerular expression of phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A) was screened. Glomerular immunohistochemistry staining for NELL-1 was performed in 43 patients with PLA2R- and THSD7A-negative membranous nephropathy, 31 patients with PLA2R-positive membranous nephropathy, and two patients with PLA2R and THSD7A double positivity. The NELL-1 antibody was also detected in the sera of patients with NELL-1-positive membranous nephropathy by western blot. Clinical and pathologic features were comparable between patients with isolated NELL-1-positive, isolated PLA2R/THSD7A-positive, and triple antigen-negative membranous nephropathy. RESULTS: Among the 832 patients with primary membranous nephropathy, 11 of 54 (20%) patients with PLA2R-negative membranous nephropathy had THSD7A-positive membranous nephropathy. NELL-1-positive membranous nephropathy accounted for 35% (15 of 43) of all patients with PLA2R- and THSD7A-negative membranous nephropathy. One patient was double positive for NELL-1 and PLA2R in glomerular deposits and positive for only the PLA2R antibody in the serum. Most patients with NELL-1-positive membranous nephropathy were women. No tumors were found. There were significant differences in the prevalence of IgG subtypes between patients with different antigen positivity. Among patients with isolated NELL-1-positive membranous nephropathy, although 80% (12 of 15) were IgG4 staining positive, the proportion of IgG4 dominance was only 67% (ten of 15). CONCLUSIONS: About one third of patients who were PLA2R and THSD7A negative were NELL-1 positive in Chinese patients with primary membranous nephropathy. NELL-1-positive membranous nephropathy was more common than THSD7A-positive membranous nephropathy in PLA2R-negative membranous nephropathy.

Cutaneous mucormycosis in a patient with lupus nephritis: A case report and review of literature.

RATIONALE: Mucormycosis is a rare fungal infection but life-threatening, especially in lupus nephritis (LN). Mucormycosis may manifest as rhino-orbital-cerebral, pulmonary, cutaneous, gastrointestinal, renal, or disseminated forms. PATIENT CONCERNS: We report a case of a 52-year-old woman with cutaneous mucormycosis infection who was admitted because of LN. DIAGNOSES: Histopathological analysis of the lesion confirmed the Rhizopus microspores from the family Mucoraceae. INTERVENTIONS AND OUTCOMES: The mortality of mucormycosis remains unacceptably high. Our patient died at last even with standard therapy (aggressive surgical debridement and anti-mucormycosis drugs). LESSONS: It is difficult to diagnose because lacking of specific clinical features, it is necessary to identify the susceptible patients, and then make diagnosis rapidly through tissue biopsy. Despite the outcome is poor, aggressive surgical debridement and Amphotericin B/Posaconazole can be effective.

Polymorphisms in the nonmuscle myosin heavy chain 9 gene (MYH9) are associated with the progression of IgA nephropathy in Chinese.

BACKGROUND: IgA nephropathy (IgAN) is the leading cause of end-stage renal disease (ESRD) in China considering different compositions of ESRD causes in different ethnicities. A recent genome-wide association study (GWAS) indicated that the MYH9 gene was significantly associated with non-diabetic ESRD in African-Americans and also influenced kidney function in Europeans. Thus, in the present study, we aim to clarify whether MYH9 confers a shared mechanism among different causes of ESRD and to seek possible further insight into our understanding of IgAN by applying GWAS data from ESRD to IgAN. METHODS: One thousand one hundred and sixteen Chinese, including 527 patients with renal biopsy-proven IgAN and 589 healthy controls, were enrolled in the present study. Four single neucleotide polymorphisms (SNPs) (rs3752462, rs4821480, rs11089788 and rs2413396) reported to be associated with ESRD with the most significance were genotyped by TaqMan assay or a restriction fragment length polymorphism assay for a further case-control study. RESULTS: None of the four SNPs was associated with the susceptibility to IgAN or clinical and pathological characters at the time of renal biopsy. However, estimated glomerular filtration rate decline rate was associated with rs11089788 in the dominant model (P = 0.021). Cox regression showed that rs11089788 (hazard ratio, 3.95; 95% confidence interval, 1.23-12.63; P = 2.1 × 10(-2)) was an independent predictive factor for renal survival. CONCLUSIONS: Based on a large Chinese IgAN cohort, we found an association between rs11089788 and prognosis of IgAN, adding to the mounting evidence of MYH9 as an important gene in IgAN to ESRD.

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.