Glomerular IgA Research Articles

Immunoglobulin A-dominant membranoproliferative glomerulonephritis-like pattern of injury as a possible paraneoplastic nephropathy in a breast cancer patient.

A middle-aged woman was found to have proteinuria during a health check-up. About sixteen months later, she was diagnosed with stage IIA invasive ductal carcinoma of the right breast. Her proteinuria progressed to nephrotic syndrome with significant hematuria. Hormone therapy was initiated for her estrogen and progesterone receptor-positive breast cancer. A kidney biopsy performed 47days after starting the therapy revealed an IgA-dominant membranoproliferative glomerulonephritis-like pattern of injury. Electron microscopy showed subendothelial-dominant electron-dense deposits (EDD), with small amounts of mesangial EDD and a single occurrence of subepithelial hump-like EDD, along with occasional mesangial interpositions. Similar pathology can be caused by IgA vasculitis with nephritis, IgA-dominant infection-associated glomerulonephritis, and liver disease-associated glomerulopathy, but all of these were ruled out. The deposited IgA was found to be galactose-deficient IgA1. Thus, IgA nephropathy with glomerular capillary IgA deposition was considered. She underwent a right partial mastectomy and sentinel lymph node biopsy in the right axilla 75days after starting hormone therapy, followed by adjuvant radiation. Proteinuria and hematuria tended to decrease after the treatment, and this trend continued even after corticosteroid therapy for glomerulonephritis, which was administered 156days after starting hormone therapy. Approximately 15months after starting hormone therapy, her proteinuria had reduced to around 1.0g/g of creatinine, and her hematuria was negative. IgA nephropathy with glomerular capillary IgA deposition is known to be resistant to corticosteroid therapy. The favorable clinical course of the rare glomerulopathy following breast cancer treatment suggested a diagnosis of paraneoplastic glomerulopathy secondary to breast cancer in our patient.

Glomerular Injury and Differences in Colocalization of Glomerular IgA, IgG, and Complement C3 in Patients with IgA Vasculitis with Nephritis

Glomerular Injury and Differences in Colocalization of Glomerular IgA, IgG, and Complement C3 in Patients with IgA Vasculitis with Nephritis

Predictors of glomerular IgA immunostaining patterns and disease progression in IgA nephropathy patients; a 13-year study of clinical and morphological features of renal biopsies

Introduction: IgA nephropathy (IgAN) is a common primary glomerulonephritis with highly heterogeneous clinical and histopathological features. The MEST-C scoring system has been developed to improve prognostic assessment but lacks elements related to immunostaining study. Objectives: This study aimed to investigate the association between the immunofluorescence (IF) deposits’ patterns of IgA (mesangiocapillary versus pure mesangial) with demographic, clinical, biochemical, and morphological parameters of MEST-C classification in IgAN patients. Patients and Methods: This retrospective, cross-sectional study was conducted on 268 biopsy-proven cases of IgAN from July 2009 to July 2022 at a single laboratory in Isfahan in Iran. The demographic, clinical, and laboratory data including age, gender, serum creatinine, and proteinuria were collected from the biopsy request forms. The morphological parameters of MEST-C classification and IF study patterns were collected from the biopsy reports. Results: The average age of all patients was 37.7 ± 13.47 years, with 67% being males. The mean serum creatinine and proteinuria levels were 1.43 mg/dL and 1730.94 mg/day, respectively. MEST-C score analysis revealed that 171 patients (63.8%) had mesangial expansion (M1), while 105 patients (39.2%) exhibited endocapillary hypercellularity (E1). Additionally, segmental glomerulosclerosis (S1) and tubular atrophy/interstitial fibrosis (T1 and T2) was observed in 160 biopsy samples (59.7%). Moreover, crescent (C) formation was noted in 76 (28.4%) of biopsies. Data analysis using univariate logistic regression demonstrated that E, T, and C on morphology, complement C3, IgG, IgM deposits on IF, and the total MEST score were all associated with an increased risk for mesangiocapillary deposits of IgA. However, using the multivariate method, the results indicated that only the total MEST score (OR: 2.4), presence of crescent (OR: 3.22), presence of endocapillary hypercellularity (OR: 4.86), tubular atrophy/interstitial fibrosis grade II (OR: 34.4), and IgG deposition (OR: 3.37) were independent risk factors for mesangiocapillary deposits of IgA. Conclusion: The total MEST score is significantly higher in mesangiocapillary patterns. Furthermore, the presence of E1, T2, and C1-2 morphological parameters of the updated Oxford classification in renal biopsies are independent risk factors for IgA mesangiocapillary deposits. Hyperactivation of immunoglobulins and the complement system appears to contribute to mesangial-capillary proliferation.

#1307 Glomerular galactose-deficient IgA1 (KM55) positive may be associated with poor prognosis in DKD patients

Abstract Background and Aims Diabetic kidney disease (DKD) and IgA nephropathy (IgAN) are prevalent renal diseases with a high incidence rate, and the prognosis is notably poorer when these two diseases coexist. However, it remains uncertain whether the pathological changes associated with DKD combined with IgA deposition (DKD-IgA deposition) are linked to a worsened prognosis. Method To address this question, we conducted an analysis comparing the clinicopathological characteristics and prognosis of DKD-IgA deposition patients to DKD patients as controls (Fig. 1). Results The results revealed that DKD-IgA patients exhibited higher cholesterol levels compared to DKD patients (6.2 ± 2.0 vs. 5.4 ± 1.9 mmol/L, p = 0.042). The group with DKD-IgA deposition had a significantly shorter follow-up duration (10.9 ± 10.6 months) compared to the control group (20.4 ± 18.7 months, p = 0.029). However, they exhibited higher levels of serum creatinine at the end of the follow-up period (343.8 ± 328.0 μ mol/L vs. 182.1 ± 124.6 μmol/L, p = 0.031). Kaplan-Meier analysis showed a higher cumulative incidence of poor events in the DKD-IgA deposition group (p = 0.036) (Fig. 2). In addition, we also detected galactose deficient IgA1 (KM55) in the kidneys and serum of patients with DKD-IgA deposition. Of the 24 patients with DKD-IgA deposition, 54.5% (24/44) showed positive glomerular KM55 results. Immunofluorescence analysis revealed that KM55 and IgA were predominantly colocalized in the mesangial and capillary regions (Fig. 3). Furthermore, the subgroup with KM55 positivity had a shorter disease duration compared to the KM55 negative subgroup (66.0 vs. 120.0 months, p = 0.048). The serum levels of galactose-deficient IgA1 (Gd-IgA1) (6296.4 ± 1535.4 vs. 4057.4 ± 1082.0 ng/mL, p = 0.010) and C4 (0.4 ± 0.1 vs. 0.3 ± 0.1 g/L, p = 0.020) were significantly higher in the KM55 positive subgroup than in the KM55 negative subgroup. Furthermore, it was observed that the KM55 positive subgroup exhibited a considerably higher incidence of reaching the renal endpoint compared to the control group (64.3% vs. 20.0%, p = 0.047). Conclusion These study results suggest that individuals with DKD who display glomerular IgA deposition alongside KM55 positivity may experience a more unfavorable prognosis.

Heterozygous mutations in factor H aggravate pathological damage in a stable IgA deposition model induced by Lactobacillus casei cell wall extract.

Activation of complement through the alternative pathway (AP) has a key role in the pathogenesis of IgA nephropathy (IgAN). We previously showed, by intraperitoneal injection of Lactobacillus casei cell wall extract (LCWE), C57BL/6 mice develop mild kidney damage in association with glomerular IgA deposition. To further address complement activity in causing glomerular histological alterations as suggested in the pathogenesis of IgAN, here we used mice with factor H mutation (FHW/R) to render AP overactivation in conjunction with LCWE injection to stimulate intestinal production of IgA. Dose response to LCWE were examined between two groups of FHW/R mice. Wild type (FHW/W) mice stimulated with LCWE were used as model control. The FHW/R mice primed with high dose LCWE showed elevated IgA and IgA-IgG complex levels in serum. In addition to 100% positive rate of IgA and C3, they display elevated biomarkers of kidney dysfunction, coincided with severe pathological lesions, resembling those of IgAN. As compared to wild type controls stimulated by the same high dose LCWE, these FHW/R mice exhibited stronger complement activation in the kidney and in circulation. The new mouse model shares many disease features with IgAN. The severity of glomerular lesions and the decline of kidney functions are further aggravated through complement overactivation. The model may be a useful tool for preclinical evaluation of treatment response to complement-inhibitors.

Distribution spectrum and clinical significance of glomerular exostosin (EXT1) deposits in PLA2R-positive membranous nephropathy.

The discovery of antigen phospholipase A2 receptor (PLA2R) in 2009 ushered in the antigen-based study of membranous nephropathy. Thefurther putative antigen exostosin 1/2 (EXT1/2) was described in 2019. However, the distribution spectrum of glomerular EXT1 deposits in membranous nephropathy has not been fullyelucidated. We conducted a retrospective cohort study of biopsy-proven membranous nephropathy patients. Patients with complete baseline data and adequate tissue specimens were included in this study. Tests for glomerular expression of PLA2R and EXT1 and circulating anti-PLA2R antibodies were performed. Clinicopathological and outcome data were reviewed. We included 626 patients, namely, 487 (77.8%) PLA2R-positive patients and 54 (8.6%) EXT1-positive patients; 32 (5.1%) patients were dual-positive for PLA2R and EXT1 (PLA2R + /EXT1 +). A higher percentage of dual-positive patients had low C3 levels (P < 0.001) and were more likely to have autoimmune diseases (P = 0.013) than PLA2R-positive and EXT1-negative (PLA2R + /EXT1-) patients. Kidney biopsy findings revealed that there was a higher percentage of glomerular IgG1, IgG2, IgA, C4, and C1q deposits (P < 0.05), "full-house" staining (P < 0.001), and stronger intensity of C1q staining (P = 0.002) in PLA2R + /EXT1 + patients. Based on Kaplan-Meier analysis, a higher percentage of PLA2R + /EXT1 + patients exhibited partial or complete remission of proteinuria. Furthermore, EXT1-positive expression was a favourable predictor for proteinuria remission, whereas interstitial fibrosis/tubular atrophy was an unfavourable predictor. A complement C3 level < 0.79g/L was independently associated with EXT1 positivity in PLA2R-positive membranous nephropathy. We describe a subgroup of PLA2R and EXT1 dual-positive patients. Patients in this subset exhibited more signs of autoimmunity and morefrequent clinical remission. In PLA2R-positive membranous nephropathy, a complement C3 level < 0.79g/L was independently associated with EXT1 positivity, which was a favourable predictor for proteinuria remission.

Dioscin Mediated IgA Nephropathy Alleviation by Inhibiting B Cell Activation In Vivo and Decreasing Galactose-Deficient IgA1 Production In Vitro.

The increase of circulating galactose-deficient IgA1 (Gd-IgA1) is caused by excessive activation of IgA-positive secretory cells in the process of mucosal immune responses, which is a critical link in the pathogenesis of IgA nephropathy (IgAN). Peyer's patch, the prominent place where B lymphocytes are transformed into IgA-secreting plasma cells, is the primary source of IgA. In addition, the lower expression of core 1β-1,3-galactosyltransferase (C1GalT1) and its molecular chaperone, C1GalT1-specific molecular chaperone (Cosmc), is related to abnormal glycosylation of IgA1 in IgAN patients. Our clinical experience shows that Dioscoreae Nipponicae Rhizoma's (DNR) herbal medicine can relieve proteinuria and hematuria and improve renal function in IgAN patients. Dioscin (DIO) is one of the main active ingredients of DNR, which has various pharmacological activities. This study explores DIO's possible mechanism in treating IgAN.The IgAN model mouse was established by mucosal immune induction. The mice were divided into the control, model, and DIO gavage groups. The glomerular IgA deposition in mice, renal pathological changes, and B cell markers CD20 and CXCR5 expression in Peyer's patch were detected by immunofluorescence and immunohistochemistry. After lipopolysaccharide (LPS) stimulation, DIO's effects on DAKIKI cells proliferation, IgA and Gd-IgA1 secretion, C1GalT1, and Cosmc expression were studied by cell counting kit-8 (CCK-8) assay, enzyme-linked immunosorbent assay (ELISA) test, quantitative real-time polymerase chain reaction (QRT-PCR), and western blotting (WB). In in vivo studies, IgA deposition accompanied by glomerular mesangial hyperplasia and increased expression of CD20 and CXCR5 in Peyer's patch in the IgAN model mouse was alleviated by DIO. In vitro studies showed 0.25 µg/mL to 1.0 µg/mL DIO inhibited LPS-induced DAKIKI cell proliferation, IgA and Gd-IgA1 secretion, and up-regulated the mRNA and protein expression of C1GalT1 and Cosmc. This study demonstrates that DIO may reduce Gd-IgA1 production by inhibiting excessive activation of IgA-secreting cells and up-regulating C1GALT1/Cosmc expression.

Current Understanding of Complement Proteins as Therapeutic Targets for the Treatment of Immunoglobulin A Nephropathy.

Immunoglobulin Anephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a frequent cause of kidney failure. Currently, the diagnosis necessitates a kidney biopsy, with routine immunofluorescence microscopy revealing IgA as the dominant or co-dominant immunoglobulin in the glomerular immuno-deposits, often with IgG and sometimes IgM or both. Complement protein C3 is observed in most cases. IgANleads to kidney failure in 20-40% of patients within 20 years of diagnosis and reduces average life expectancy by about 10 years. There is increasing clinical, biochemical, and genetic evidence that the complement system plays a paramount role in the pathogenesis of IgAN. The presence of C3 in the kidney immuno-deposits differentiates the diagnosis of IgAN from subclinical glomerular mesangial IgA deposition. Markers of complement activation via the lectin and alternative pathways in kidney-biopsy specimens are associated with disease activity and are predictive of poor outcome. Levels of select complement proteins in the circulation have also been assessed in patients with IgAN and found to be of prognostic value. Ongoing genetic studies have identified at least 30 loci associated with IgAN. Genes within some of these loci encode complement-system regulating proteins that can interact with immune complexes. The growing appreciation for the central role of complement components in IgAN pathogenesis highlighted these pathways as potential treatment targets and sparked great interest in pharmacological agents targeting the complement cascade for the treatment of IgAN, as evidenced by the plethora of ongoing clinical trials.

The nucleotide-sensing Toll-Like Receptor 9/Toll-Like Receptor 7 system is a potential therapeutic target for IgA nephropathy

The progression determinants of IgA nephropathy (IgAN) are still not fully elucidated. We have previously demonstrated that the mucosal activation of toll-like receptor (TLR) 9, which senses microbial unmethylated CpG DNA, influences progression by producing aberrantly glycosylated IgA. However, numerous recent reports of patients with IgAN presenting with gross hematuria after the mRNA vaccination for coronavirus disease 2019 suggest that the RNA-sensing system also exacerbates IgAN. Here, we investigated whether TLR7, which recognizes microbial RNA, is also involved in IgAN progression using a murine model and tonsil tissue from 53 patients with IgAN compared to samples from 40 patients with chronic tonsillitis and 12 patients with sleep apnea syndrome as controls. We nasally administered imiquimod, the ligand of TLR7, to IgAN-prone ddY mice and found that TLR7 stimulation elevated the serum levels of aberrantly glycosylated IgA and induced glomerular IgA depositions and proteinuria. Co-administered hydroxychloroquine, which inhibits TLRs, canceled the kidney injuries. Invitro, stimulating splenocytes from ddY mice with imiquimod increased interleukin-6 and aberrantly glycosylated IgA levels. The expression of TLR7 in the tonsils was elevated in patients with IgAN and positively correlated with that of a proliferation-inducing ligand (APRIL) involved in the production of aberrantly glycosylated IgA. Mechanistically, TLR7 stimulation enhanced the synthesis of aberrantly glycosylated IgA through the modulation of enzymes involved in the glycosylation of IgA. Thus, our findings suggest that nucleotide-sensing TLR9 and TLR7 play a crucial role in the pathogenesis of IgAN. Hence, nucleotide-sensing TLRs could be reasonably strong candidates for disease-specific therapeutic targets in IgAN.

MTMR3 risk alleles enhance Toll Like Receptor 9-induced IgA immunity in IgA nephropathy

Multiple genome-wide association studies (GWASs) have reproducibly identified the MTMR3/HORMAD2/LIF/OSM locus to be associated with IgA nephropathy (IgAN). However, the causal variant(s), implicated gene(s), and altered mechanisms remain poorly understood. Here, we performed fine-mapping analyses based on GWAS datasets encompassing 2762 IgAN cases and 5803 control individuals, and identified rs4823074 as the candidate causal variant that intersects the MTMR3 promoter in B-lymphoblastoid cells. Mendelian randomization studies suggested the risk allele may modulate disease susceptibility by affecting serum IgA levels through increased MTMR3 expression. Consistently, elevated MTMR3 expression in peripheral blood mononuclear cells was observed in patients with IgAN. Further mechanistic studies invitro demonstrated that MTMR3 increased IgA production dependent upon its phosphatidylinositol 3-phosphate binding domain. Moreover, our study provided the invivo functional evidence that Mtmr3-/- mice exhibited defective Toll Like Receptor 9-induced IgA production, glomerular IgA deposition, as well as mesangial cell proliferation. RNA-seq and pathway analyses showed that MTMR3 deficiency resulted in an impaired intestinal immune network for IgA production. Thus, our results support the role of MTMR3 in IgAN pathogenesis by enhancing Toll Like Receptor 9-induced IgA immunity.

Long noncoding RNA FGD5-AS1 alleviates childhood IgA nephropathy by targeting PTEN-mediated JNK/c-Jun signaling pathway via miR-196b-5p

This paper studied lncRNA FGD5 antisense RNA 1 (FGD5-AS1)-associated mechanisms in immunoglobulin A nephropathy (IgAN). FGD5-AS1, miR-196b-5p, and PTEN in the serum of children with IgAN were assessed. MES-13 cells were stimulated by p-IgA1 to construct an in vitro model of IgAN. After plasmid intervention, cell proliferation, cell cycle, apoptosis, and inflammatory response were correspondingly evaluated. An IgAN mouse model was established to define FGD5-AS1/miR-196b-5p/PTEN axis-mediated alternations of 24-h proteinuria, blood urea nitrogen, serum creatinine, glomerular IgA deposition, renal fibrosis, and glycogen content in renal tissue. The changes in JNK/c-Jun pathway activation in the cell model were also tested. Our results discovered that FGD5-AS1 and PTEN were down-regulated and miR-196b-5p was up-regulated in children with IgAN. Overexpression of FGD5-AS1 or silencing of miR-196b-5p impeded the proliferation and inflammatory response and induced apoptosis of p-IgA1-stimulated MES-13 cells, and improved pathological conditions in IgAN mice. Inhibition of PTEN rescued the therapeutic effects of overexpression of FGD5-AS1 or inhibition of miR-196b-5p on IgAN. FGD5-AS1/miR-196b-5p/PTEN axis inhibited the activation of the JNK/c-Jun pathway. Taken together, FGD5-AS1 attenuates IgAN by targeting PTEN-mediated JNK/c-Jun signaling via miR-196b-5p. Therefore, FGD5-AS1 may be a new therapeutic target for IgAN.

The Diagnostic Conundrum of Glomerular Crescents With IgA Deposits

Glomerulonephritis (GN) with crescents and IgA deposits in kidney biopsy poses a frequent diagnostic and therapeutic dilemma because of multiple possibilities. Native kidney biopsies showing glomerular IgA deposition and crescents (excluding lupus nephritis) were identified from our biopsy archives between 2010 and 2021. Detailed clinicopathologic features were assessed. One-year clinical follow-up on a subset of cases was obtained. A total of 285 cases were identified, and these clustered into IgA nephropathy (IgAN, n= 108), Staphylococcus or other infection-associated GN/infection-related GN (SAGN/IRGN, n= 43), and antineutrophil cytoplasmic antibody-associated GN (ANCA-GN, n= 26) based on a constellation of clinicopathologic features, but 101 cases (group X) could not be definitively differentiated. The reasons have been elucidated, most important being atypical combination of clinicopathologic features and lack of definitive evidence of active infection. Follow-up (on 72/101 cases) revealed that clinicians' working diagnosis was IgAN in 43%, SAGN/IRGN in 22%, ANCA-GN in 28%, and others in 7% of the cases, but treatment approach varied from supportive or antibiotics to immunosuppression in each subgroup. Comparing these cases as "received immunosuppression" versus "non-immunosuppression," only 2 features differed, namely C3-dominant staining, and possibility of recent infection (both higher in the no-immunosuppression group) (P< 0.05). Renal loss was higher in the non-immunosuppression subgroup, but not statistically significant (P= 0.11). Diagnostic overlap may remain unresolved in a substantial number of kidney biopsies with glomerular crescents and IgA deposits. A case-by-case approach, appropriate antibiotics if infection is ongoing, and consideration for cautious immunosuppressive treatment for progressive renal dysfunction may be needed for best chance of renal recovery.

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.

Paraneoplastic Nephropathy with Peculiar Immunofluorescence Pattern: Report of a Rare Case

Abstract Introduction/Objective Hematolymphoid neoplasms are commonly associated with medical renal disease; however, association of renal cell carcinoma and nephrotic/nephritic syndrome is exceedingly rare. Paraneoplastic nephropathy in setting of renal cell carcinoma can manifest as membranous nephropathy, IgA nephropathy, or minimal change disease. The purpose of this report is to describe a rare case of clear cell renal cell carcinoma with associated membranous nephropathy with concurrent glomerular IgG and IgA deposition. Methods/Case Report A 68-year-old male presented with a penile mass. Diagnostic work up reveled an 11cm renal mass. Urinalysis demonstrated nephrotic range proteinuria (&amp;gt;5 g/d). Subsequently, the patient underwent nephrectomy and penectomy. Pathologic evaluation showed clear cell renal carcinoma with sarcomatoid component and metastasis to penis. Nonneoplastic kidney workup revealed membranous glomerulopathy, with 3+ granular IgG predominantly within glomerular capillaries and 2+ IgA and 1+ C3 in a similar pattern. Electron microscopy demonstrated numerous subepithelial and intramembranous immune deposits, and few small mesangial deposits. Concurrent membranous and IgA nephropathy has been reported, but the IgA in that case is typically mesangial. The peculiar pattern of IgG and IgA deposition in this case can be seen with membranous nephropathy secondary to lupus or neoplasia. Lupus was excluded based on patient’s history, serology, and absence of significant C1q staining. Therefore, the findings were consistent with membranous glomerulopathy secondary to patient’s cancer. Patient’s proteinuria improved after nephrectomy. He is alive and disease-free 10months after nephrectomy, with proteinuria in 0.1-0.6 g/d range. Results (if a Case Study enter NA) NA Conclusion This case highlights the importance of thorough evaluation of non-neoplastic kidney in nephrectomy specimens for cancer, thus guiding the type of surgical intervention. Non-orthodox presentation of immunoglobulin deposition may be the herald of neoplasia in select cases.

Genetic Variants of the COL4A3 , COL4A4 , and COL4A5 Genes Contribute to Thinned Glomerular Basement Membrane Lesions in Sporadic IgA Nephropathy Patients.

Thinned glomerular basement membrane (tGBM) lesions are not uncommon in IgA nephropathy (IgAN). Type IV collagen-built of α 3, α 4, and α 5 chains, encoded by COL4A3 / COL4A4 / COL4A5 genes-is the major component of glomerular basement membrane (GBM). In recent years, mutations in type IV collagen-encoding genes were also reported in patients with a histologic diagnosis of FSGS. Pathogenic COL4A3 / COL4A4 / COL4A5 variants were recently identified in familial cases of IgAN, but the contribution of these variants to sporadic IgAN is still unclear. We compared 161 patients with sporadic IgAN with tGBM lesions (IgAN-tGBM) to matched patients with IgAN without tGBM lesions and matched patients with thin basement membrane nephropathy (TBMN). Variants of COL4A3 / COL4A4 / COL4A5 genes were screened and evaluated after whole-exome sequencing. GBM thickness was measured, and levels of circulating galactose-deficient IgA1 (Gd-IgA1) were assessed by ELISA. The patients with IgAN-tGBM manifested milder disease than did patients with IgAN without tGBM but had more severe features than the patients with TBMN. Exome sequence analysis of the 122 patients with IgAN-tGBM identified 37 diagnostic variants of the COL4A3 / COL4A4 / COL4A5 genes among 38 patients (31.1%). Furthermore, patients with IgAN-tGBM who had diagnostic variants had higher proportions of GBM thickness <250 nm and milder glomerular injury, whereas patients with IgAN-tGBM who did not have diagnostic variants showed more characteristic features of IgAN, including higher intensity of glomerular IgA deposits and elevated Gd-IgA1 levels. These findings suggest different mechanisms in patients with versus without diagnostic variants of these collagen genes. COL4A3 / COL4A4 / COL4A5 variant detection is essential in evaluating patients with sporadic IgAN with tGBM lesions.

Associations of left renal vein entrapment with IgA nephropathy and Henoch–Schönlein purpura nephritis

Objectives The aims of the study were to identify whether left renal vein (LRV) entrapment was more prevalent in IgA nephropathy (IgAN) and Henoch–Schönlein purpura nephritis (HSPN) compared with other types of renal diseases, and the association of LRV entrapment with glomerular incidental IgA and galactose-deficient-IgA1 (Gd-IgA1) deposition. Methods A total of 797 patients with biopsy-proven kidney diseases have been screened for LRV entrapment by color Doppler ultrasound, and the prevalence of LRV entrapment in different types of renal diseases were then analyzed. Propensity score matching analysis was used to adjust for age, gender, and body mass index. Immunostaining of Gd-IgA1 with KM55 was performed in paraffin-embedded sections of renal biopsy specimens. Results LRV entrapment was diagnosed in 47 patients (6%) with several kinds of renal diseases in our cohort. A total of 32 (68%) LRV entrapments were combined with expanded IgAN (idiopathic IgAN and HSPN). The prevalence of LRV entrapment in expanded IgAN was significantly higher than that in non-expanded IgAN (17 vs. 2%, p < 0.001), even after adjustment for age, gender, and body mass index by propensity score matching analysis (13 vs. 2%, p < 0.001). Removing expanded IgAN and LN, glomerular incidental IgA deposition was observed to be significantly more common in patients with LRV entrapment compared with patients without it (43 vs. 9%, p < 0.001). Furthermore, in glomerular diseases with incidental IgA deposits, significantly much larger proportion of patients with LRV entrapment were positive for glomerular Gd-IgA1 in contrast to patients without LRV entrapment (5/5 vs. 5/17, p = 0.01). Conclusions LRV entrapment coexisted with several kinds of renal diseases, with a significantly higher prevalence in patients with idiopathic IgAN and HSPN. In patients of LN and IgAN-unrelated disease with LRV entrapment, glomerular IgA and Gd-IgA1 deposition was more common compared with patients without LRV entrapment.

C1q or IgA deposition in glomeruli of children with primary membranous nephropathy

Objective: To assess the correlation of glomerular C1q or IgA deposition with clinical and pathological features of primary membranous nephropathy (PMN) in children. Methods: The clinical and pathological manifestations including (phospholipase A2 receptor, PLA2R) and IgG subclasses staining in renal biopsies, serum anti-PLA2R antibody and therapeutic response of 33 children diagnosed with PMN in Peking University First Hospital from December 2012 to December 2020 were retrospectively summarized and analyzed. According to results of PLA2R test and findings renal pathological, the patients were divided into PLA2R-related group and non-PLA2R-related group, typical MN group and atypical MN group, C1q deposit group and non-C1q deposit group, as well as IgA deposit group and non-IgA deposit group respectively. T-test, Mann-Whitney U test and Fisher's exact probability test were used for comparison between the groups. Results: Among the 33 children with PMN, there were 20 males and 13 females, of that the age of onset was 11 (8, 13) years, and 32 patients had nephrotic level proteinuria. Renal biopsies were performed at 4.6 (2.1, 11.6) months after onset, and 28 patients (85%) received glucocorticoid or immunosuppressive therapy prior to renal biopsy. There were 20 cases (61%) with PLA2R-related MN and 13 cases (39%) with non-PLA2R-related MN. Compared with the non-PLA2R-related group, the PLA2R-related group had an older age of onset (12 (10, 13) vs. 7 (3, 12) years, Z=-2.52, P=0.011), a lower preceding infection rate (45% (9/20) vs. 11/13, P=0.032) and lower spontaneous remission rate (0 vs. 4/13, P=0.017). Renal PLA2R positivity was significantly associated with predominant or co-deposition of IgG4 (13/17 vs. 5/15, P=0.031) and low albumin levels at renal biopsy ((25±6) vs. (29±7) g/L, t=2.14, P=0.041). There were 12 patients with typical PMN and 21 patients with atypical PMN, and no significant difference in clinical and pathological manifestations was found between these 2 groups (all P>0.05). There were 10 cases (32.3%) with glomerular C1q deposition, and their disease course before renal biopsy was significantly shorter than those without C1q deposition (1.8 (0.8, 5.9) vs. 6.0 (2.5, 22.3) months, Z=-2.27, P=0.023). Twelve cases (36.4%) had glomerular IgA deposition, and their course of disease,clinical and pathological manifestations were not significantly different from those without IgA deposition (all P>0.05). Conclusion: Glomerular C1q or IgA deposition may not affect the clinical manifestations, glomerular PLA2R and IgG subclasses staining pattern, or the response to treatment of PMN in children.

Clinical relevance of glomerular C4d deposition in children with early IgA nephropathy or Henoch-Schönlein purpura nephropathy.

Both IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephropathy (HSPN) are characterized by glomerular mesangial IgA deposition. Several large studies on adults have suggested that glomerular C4d deposition has prognostic value in IgAN. However, there are few relevant studies on the clinical value of C4d deposition in children with IgAN or HSPN. We performed a retrospective cohort study in pediatric patients with IgAN or HSPN. Clinicopathological data were collected at the time of kidney biopsy. Kidney C4d deposition was analyzed by immunohistochemistry. The end point was defined as a ≥ 20% decrease in estimated glomerular filtration from baseline. We enrolled 75 children, including 36 children with IgAN and 39 with HSPN. The prevalence of C4d deposition was 36% (27/75). C4d deposition was more abundant in children with proteinuria ≥ 50mg/kg/day (51.9% versus 20.8%, P = 0.006) or nephrotic syndrome (37.0% versus 10.4%, P = 0.006). Mesangial hypercellularity (hazard ratio [HR], 5.745, 95% confidence interval [CI], 1.670-19.761, P = 0.006) and IgM deposition (HR, 4.522, 95% CI, 1.321-15.478, P = 0.016) were associated with C4d deposition. After a median follow-up of 22months, seven (19.4%) IgAN patients and one (2.6%) HSPN patient had decreased kidney function. In children with IgAN, positive C4d was associated with decreased kidney function (P = 0.047). Glomerular C4d deposition was associated with mesangial hypercellularity and glomerular IgM deposition in IgAN and HSPN. Glomerular C4d deposition may be a risk factor for eGFR decline in children with IgAN. A higher resolution version of the Graphical abstract is available as Supplementary information.

MO261: Sparsentan, The Dual Endothelin Angiotensin Receptor Antagonist (DEARA), Attenuates Albuminuria and Protects from the Development of Renal Injury to a Greater Extent Than Losartan in the GDDY Mouse Model of IGA Nephropathy: A 16-Week Study

Abstract BACKGROUND AND AIMS gddY mice are an IgA nephropathy (IgAN)-prone mouse model that develops albuminuria by 8 weeks (wks) of age with glomerular IgA, IgG and C3 deposits and progressive mesangioproliferative glomerulonephritis. We have previously shown that sparsentan (SP), a novel, highly selective, first-in-class, single-molecule dual endothelin angiotensin receptor antagonist (DEARA) being developed for the treatment of focal segmental glomerulosclerosis and IgAN, protected gddY mice from the development of albuminuria and glomerulosclerosis in an 8-week study. Here we compare the impact of SP and losartan (LS), an angiotensin II subtype 1 receptor antagonist (AT1R), on albuminuria, % of sclerotic glomeruli (GS), podocyte number, and glycocalyx damage in gddY mice treated for 16 weeks. METHOD gddY mice at 4 weeks of age were treated for 8 or 16 weeks either with chow as a control (C) (n = 10) or containing SP at 900 ppm (SP900) (n = 12) or with control chow and LS in drinking water to deliver 30 mg/kg of LS (LS30) (n = 12). Systolic blood pressure (BP) was measured by tail-cuff plethysmography at 8, 12 and 18 weeks of age. Albuminuria/creatinine ratio (ACR) was assessed every 2 weeks until 20 weeks of age. Kidney biopsies (n = 4–5 per group) were taken from a subset of mice sacrificed at age 12 weeks and at the end of the study at 20 weeks of age (5–7 per group) and processed for determination of GS, the number of podocytes assessed by immunohistochemistry using an anti-WT-1 antibody (30 glomeruli per animal), and measurement of the glycocalyx area using FITC-labeled lectin (10 glomeruli per animal). RESULTS gddY mice treated with SP900 or LS30 had an equivalent and significant (P &amp;lt; .01) reduction in BP compared with C mice at 12 and 18 weeks of age (18 weeks of age mean BP ± SD mmHg: C, 147 ± 28; SP900, 100 ± 6; LS30, 101 ± 8). Despite similar systemic hemodynamic effects, SP900 treatment resulted in a greater and more rapid reduction in ACR from baseline compared with either mice treated with C or LS30 during the first 4 weeks of treatment (Fig. 1). Development of GS was significantly attenuated in mice at 20 weeks of age treated with SP900 (P &amp;lt; .001) compared with C mice, but not in those treated with LS30 (mean sclerosis score ± SD: C, 28 ± 17; SP900, 3 ± 1; LS30, 19 ± 21). Compared with C mice at 20 weeks of age, SP900 (P &amp;lt; .0001) and LS30 (P &amp;lt; .05) significantly prevented the reduction in WT-1 immunoreactivity (WT-1 positive cells/glomerulus, mean ± SD: C, 7.3 ± 0.5; SP900, 10.0 ± 0.5; LS30 8.1 ± 0.8). Notably, SP900-treated mice had significantly greater WT-1 staining (P &amp;lt; .0001) and glycocalyx area (Fig. 2) than LS30 mice. CONCLUSION gddY mice treated from 4–20 weeks of age with sparsentan demonstrated a more rapid attenuation of ACR and greater protection from GS than mice treated with losartan. Sparsentan protected the glomeruli from loss of podocytes and glycocalyx to a greater extent than losartan despite equivalent lowering of BP. These results suggest that the ability of sparsentan to protect gddY mice from progression of IgAN nephropathy may go beyond effects mediated through reduction in blood pressure and antagonism of AT1R alone and may be attributed to its dual mechanism of action. If translated to the clinic, these data may support sparsentan as a new approach to the treatment of IgAN.

Comparison of Complement Pathway Activation in Autoimmune Glomerulonephritis

IntroductionStudies on complement activation have implicated a combination of the classical pathway (CP), lectin pathway (LP), and alternative pathway (AP) in triggering the terminal pathway (TP) for each common autoimmune glomerulonephritis (GN). Evaluating different pathways simultaneously may help identify whether one is preferentially activated and, consequently, which is best to target for each disease.MethodsWe followed 112 patients with focal segmental glomerular sclerosis (FSGS), membranous nephropathy (MN), IgA nephropathy (IgAN), lupus nephritis (LN), and antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) for a median duration of 22 (12–52) months. At the time of greatest clinical activity, we simultaneously evaluated urinary C3a (C3 convertase activity), C5a and sC5b-9 (TP), MASP-1 and MASP-2 (LP), C1q (CP), C4a (CP/LP), and Ba and Bb (AP). We evaluated the relation between activation fragments of the AP and CP/LP with the TP.ResultsUrinary complement biomarkers for each pathway were associated with the severity of proteinuria. Fragments of the TP were higher among patients with FSGS and MN compared with patients with IgAN, LN, and AAV. For the AP, urinary Ba level was lower in those with IgAN and LN compared with those with FSGS. For the CP/LP, urinary C4a, MASP-1, and MASP-2 levels were similar between diseases whereas urinary C1q levels were lower in those with LN. For each GN, independent associations existed between the activation markers of the AP and CP/LP with the degree of TP activation, except for the AP in AAV, although perhaps underpowered.ConclusionThe AP and CP/LP contribute individually to the TP activation in autoimmune GN, and both seem to be valid potential therapeutic targets.