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.

Effect of Telitacicept on Circulating Gd-IgA1 and IgA-Containing Immune Complexes in IgA Nephropathy.

Introduction: Telitacicept, a transmembrane activator and cyclophilin ligand interactor (TACI) fusion protein targeting B cell activating factor and a proliferation-inducing ligand (APRIL), has proven efficacy in treating Immunoglobulin A (IgA) nephropathy (IgAN). However, serum biomarkers that could predict the clinical response during the treatment remain unclear. Methods: Plasma samples from 24 participants in the phase 2 clinical trial were collected at baseline and after 4, 12, and 24 weeks; with 8 participants in the placebo group, 9 in the 160 mg group, and 7 in the 240 mg group. We measured the levels of galactose-deficient-IgA1 (Gd-IgA1), IgA-containing immune complexes, C3a, C5a, and sC5b-9. The association between the changes in these markers and proteinuria reduction was analyzed. Results: After 24 weeks of treatment, Gd-IgA1 decreased by 43.9% (95% confidence interval: 29.8%, 55.1%), IgG-IgA immune complex by 31.7% (14.4%, 45.5%), and poly-IgA immune complex by 41.3% (6.5%, 63.1%) in the 160 mg group; Gd-IgA1 decreased by 50.4% (38.6%, 59.9%), IgG-IgA immune complex decreased by 42.7% (29.5%, 53.4%), and poly-IgA immune complex decreased by 67.2% (48.5%,79.1%) in the 240 mg group. There were no significant changes in the circulatory C3a, C5a, or sC5b-9 levels during telitacicept treatment. Decreases in both plasma Gd-IgA1 and IgG-IgA or poly-IgA immune complexes were associated with proteinuria reduction. In turn, IgG-IgA or poly-IgA immune complexes showed a dose-dependent effect, consistent with proteinuria reduction during telitacicept treatment. Conclusion: Telitacicept lowered both circulating Gd-IgA1 and IgA-containing immune complexes, whereas IgA immune complex levels were more consistent with decreased proteinuria.

Examining the association between serum galactose-deficient IgA1 and primary IgA nephropathy: a systematic review and meta-analysis.

BACKGROUND: IgA nephropathy (IgAN) is a common primary glomerular disease. The O-glycosylation status of IgA1 plays a crucial role in disease pathophysiology. The level of poorly-O-galactosylated IgA1, or galactose-deficient IgA1 (Gd-IgA1), has also been identified as a potential biomarker in IgAN. We sought to examine the value of serum Gd-IgA1 as a biomarker in IgAN, by investigating its association with clinical, laboratory, and histopathological features of IgAN. METHODS: The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and was registered in PROSPERO (CRD42021287423). The literature search was conducted in PubMed, Web of Science, Cochrane, and Scopus, and the selected articles were evaluated for eligibility based on predefined criteria. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. Statistical analysis was performed to calculate effect sizes and assess heterogeneity among the studies. RESULTS: This review analyzed 29 out of 1,986 studies, conducted between 2005 and 2022, with participants from multiple countries. Gd-IgA1 levels were not associated with age and gender, while associations with hypertension, hematuria, and proteinuria were inconsistent. In the meta-analyses, a correlation between serum Gd-IgA1 and estimated glomerular filtration rate was identified, however, the relationships between Gd-IgA1 levels and chronic kidney disease (CKD) stage and progression to kidney failure were inconsistent. CONCLUSIONS: Serum Gd-IgA1 levels were not associated with validated prognostic risk factors, but were negatively correlated with kidney function. Further research in larger studies using standardized assays are needed to establish the value of Gd-IgA1 as a prognostic risk factor in IgAN.

IgA nephropathy: gut microbiome regulates the production of hypoglycosilated IgA1via the TLR4 signaling pathway.

BACKGROUND: IgA nephropathy (IgAN) is a major cause of primary glomerulonephritis characterized by mesangial deposits of galactose-deficient IgA1 (Gd-IgA1). Toll-like receptors (TLRs), particularly TLR4 are involved in the pathogenesis of IgAN. The role of gut microbiota on IgAN patients was recently investigated. However, whether gut microbial modifications of Gd-IgA1 through TLR4 play a role in IgAN remains unclear. METHODS: We recruited subjects into four groups, including 48 patients with untreated IgAN, 22 treated IgAN patients (IgANIT), 22 primary membranous nephropathy (MN), and 31 healthy controls (HCs). Fecal samples were collected to analyze changes in gut microbiome. Gd-IgA1 levels, expression of TLR4, B-cell stimulators, and intestinal barrier function were evaluated in all subjects. C57BL/6 mice were treated with a broad-spectrum antibiotic cocktail to deplete the gut microbiota and then gavaged with fecal microbiota transplanted fromclinical subjects of every group. Gd-IgA1 and TLR4 pathway were detected in peripheral blood mononuclear cells (PBMCs) from IgAN and HCs co-incubated with Lipopolysaccharide (LPS) and TLR4 inhibitor. RESULTS: Compared with other three groups, different compositions and decreased diversity demonstrated gut dysbiosis in un-treated IgAN, especially the enrichment of Escherichia -Shigella. Elevated Gd-IgA1 levels were found in un-treated IgAN patients and correlated with gut dysbiosis, TLR4, B-cell stimulators, indexes of intestinal barrier damage, and proinflammatory cytokines. In vivo, mice colonized with gut microbiota from IgAN and IgANIT patients, copied the IgAN phenotype with the activation of TLR4/MyD88/NF-κB pathway, B-cell stimulators in the intestine, and complied with enhanced proinflammatory cytokines. In vitro, LPS activated TLR4/MyD88/NF-κB pathway, B-cell stimulators and proinflammatory cytokines in the PBMCs from IgAN patients, which resulted in overproduction of Gd-IgA1 and inhibited by TLR4 inhibitor. CONCLUSIONS: Our results illustrated that gut-kidney axis was involved in the pathogenesis of IgAN. Gut dysbiosis could stimulate the overproduction of Gd-IgA1 by TLR4 signaling pathway production and B-cell stimulators.

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.

Serum galactose-deficient immunoglobulin A1 in recurrent immunoglobulin a nephropathy after kidney transplantation: A meta-analysis.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is a main cause of end stage renal disease (ESRD). Many IgAN patients with ESRD accept kidney allograft for renal replacement. However, disease recurrence occurs after transplantation. Galactose-deficient immunoglobulin A1(Gd-IgA1) has been proved to be a crucial biomarker in the primary IgAN population. METHODS: This meta-analysis aimed to explore the association between serum Gd-IgA1 and IgAN recurrence after renal transplantation and was registered on PROSPERO: CRD42022356952; A literature search was performed and relevant studies were retrieved from the PubMed, Embase and Cochrane library databases from inception to April 27, 2023. The inclusion criteria were: 1) full-text studies; 2) patients with histological diagnosis of IgAN of their native kidneys who underwent kidney transplantation; 3) studies exploring the relationship between serum Gd-IgA1 and IgAN recurrence after kidney transplantation. The exclusion criteria were: 1) reviews, case reports, or non-clinical studies. 2) studies with insufficient original data or incomplete data. 3) studies with duplicated data. Study quality was assessed using Newcastle Ottawa Scale (NOS). Data were pooled using a random-effects model. RESULTS: 8 full-text studies including 515 patients were identified. The Newcastle-Ottawa Scale (NOS) score ranged from 6 to 8. The standard mean difference (SMD) of the level of Gd-IgA1 was significantly higher in recurrence group than in non-recurrence group (SMD = 0.50，95%CI = 0.15-0.85, p = 0.005). Furthermore, Gd-IgA1 levels were higher in recurrence patients than in non-recurrence in both Europe subgroup (SMD 0.45, 95%CI: 0.08-0.82, p = 0.02) and Asia subgroup (SMD 0.90, 95%CI: 0.10-1.70, p = 0.03). However, pretransplant Gd-IgA1 levels showed no significant difference between recurrence and non-recurrence group (SMD 0.46, 95%CI: 0.06-0.99, p = 0.08) in anther subgroup analysis while posttransplant Gd-IgA1 levels were significantly higher in recurrence population than in non-recurrence (SMD 0.57, 95%CI 0.21 to 0.92, p = 0.002). CONCLUSIONS: This meta-analysis showed that posttransplant serum Gd-IgA1 levels are associated with IgAN recurrence after kidney transplantation; however, pretransplant serum Gd-IgA1 levels are not.

Optimized synthesis, polymer conjugation, and proof-of-concept studies of the gd-IgA1 epitope for antibody-scavenging therapies in IgA nephropathy.

IgA nephropathy (IgAN) is the most common glomerular autoimmune disease and has severe long-term consequences for patients, with 40% of the patients eventually progressing to end-stage renal disease. Despite the severity, no causal treatment is currently available. While the pathogenesis of IgAN is complex, disease severity is linked to autoantibodies against the gd-IgA1 epitope, a stretch in the hinge region of IgA1 that lacks O-glycans and is found in the characteristic immune complexes deposited in the kidneys of IgAN patients. One elegant, causal approach would be to remove the anti-gd-IgA1 autoantibodies and consequently reduce the immune complex burden on the kidneys. The administration of synthetic polymers that present autoantigens in a multivalent manner have been established as promising therapeutic strategies in other autoimmune diseases and may be applied to IgAN. We here present an improved protocol for the synthesis of the gd-IgA1 epitope, its successful coupling to a poly-L-lysine polymer and proof-of-concept experiments that the polymer-bound synthetic glycopeptide is able to capture the IgAN autoantibodies, making this approach a promising way forward for developing a targeted treatment option for IgAN patients.

Zonulin, as a marker of intestinal permeability, is elevated in IgA nephropathy and IgA vasculitis with nephritis.

Background: Immunoglobulin A nephropathy (IgAN) and IgA vasculitis with nephritis (IgAV-N) are considered related diseases and share some similar clinicopathologic phenotypes. Elevated circulating galactose-deficient IgA1 (Gd-IgA1)-containing immune complexes and mucosal immunity were associated with the pathogenesis of IgAN and IgAV-N. Recently, studies have identified that the zonulin level, as a modulator of intestinal permeability, is significantly elevated in several inflammatory and autoimmune-related diseases. However, whether zonulin also plays a role in IgAN and IgAV-N is not clear. Methods: A total of 73 IgAV-N patients, 68 IgAN patients and 54 healthy controls were assessed for circulating zonulin and Gd-IgA1 levels by enzyme-linked immunosorbent assay. The diagnostic efficiency of the combination of zonulin with Gd-IgA1 was evaluated by the area under the receiver operating characteristic curve (AUC) and integrated discrimination improvement (IDI) analysis. Results: Compared with healthy controls, we found that both IgAV-N and IgAN patients had elevated zonulin and Gd-IgA1 levels (P < .001). Additionally, patients with IgAV-N presented with even higher circulating zonulin levels than patients with IgAN (P = .020). The addition of zonulin to Gd-IgA1 showed better predictive performance than Gd-IgA1 alone in the diagnosis of both IgAN and IgAV-N, as illustrated by a significantly increased AUC (IgAN: 0.805 versus 0.708, P = .0021; IgAV-N: 0.886 versus 0.673, P < .001) and significant IDI (IgAN: IDI 0.136, P < .001; IgAV-N: IDI 0.281, P < .001). Conclusion: Elevated circulating zonulin levels were detected in both patients with IgAV-N and those with IgAN. Combined detection of circulating zonulin and Gd-IgA1 is recommended as a noninvasive diagnostic biomarker for IgAV-N and IgAN.

IgA Nephropathy: Current Understanding and Perspectives on Pathogenesis and Targeted Treatment.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with varied clinical and histopathological features between individuals, particularly across races. As an autoimmune disease, IgAN arises from consequences of increased circulating levels of galactose-deficient IgA1 and mesangial deposition of IgA-containing immune complexes, which are recognized as key events in the widely accepted "multi-hit" pathogenesis of IgAN. The emerging evidence further provides insights into the role of genes, environment, mucosal immunity and complement system. These developments are paralleled by the increasing availability of diagnostic tools, potential biomarkers and therapeutic agents. In this review, we summarize current evidence and outline novel findings in the prognosis, clinical trials and translational research from the updated perspectives of IgAN pathogenesis.

COSMC expression as a predictor of remission in IgA nephropathy.

PURPOSE: The impact of core 1,3-galactosyltransferase-specific molecular chaperon (COSMC) gene expression and methylation profile on clinical progression of IgA nephropathy (IgAN) is unclear. The aim of this study was to determine the clinical significance and the relation of the COSMC gene expression and methylation pattern with the progression of IgAN. METHODS: Thirty-nine biopsy-confirmed IgAN patients, 11 healthy relatives and 20 healthy controls were recruited. The COSMC mRNA levels and methylation profile of COSMC gene promoter were measured using the quantitative real-time PCR. The galactose-deficient IgA1 (Gd-IgA1) levels were measured using ELISA in serum and cell culture supernatant. The effect of IL-4 and AZA on COSMC expression and methylation and the correlation of COSMC gene expression and methylation levels with baseline kidney function tests, histology and long-term outcomes were examined. RESULTS: The mean COSMC mRNA level was significantly lower, and serum Gd-IgA1 level was higher in IgAN patients compared with the control groups (p < 0.001, and p = < 0.001, respectively). The COSMC mRNA levels were correlated with intensity of hematuria (r = - 0.41, p = 0.009), serum creatinine level (r = - 0.37, p = 0.002) and eGFR (r = 0.36, p = 0.002). The COSMC methylation levels were correlated with age (r = 0.25, p = 0.04) and baseline eGFR (r = - 0.326, p = 0.006). Twenty IgAN patients (51.3%) reached to complete (5, 12.8%) or partial remission (15, 38.5%) after a median of 34.5 months (IQR, 13.75-71). In multivariable Cox regression analysis, COSMC mRNA expression (adjusted HR (aHR) 1.871, 95% CI 1.287-2.722, p = 0.001) and Oxford T score (aHR 0.355, 95% CI 0.146-0.859, p = 0.022) predicted the remission. CONCLUSION: COSMC mRNA level is a novel biomarker candidate to predict the remission in IgAN patients.

Gut Dysbiosis and Intestinal Barrier Dysfunction Promotes IgA Nephropathy by Increasing the Production of Gd-IgA1.

Background: Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerular disease in adults worldwide. Several studies have reported that galactose-deficient IgA1 (Gd-IgA1) is involved in the pathogenesis of IgAN. Methods: Thirty-five patients with IgAN diagnosed with renal biopsy for the first time served as the experimental group, who were hospitalized in our department. Twenty normal healthy cases in the physical examination center of our hospital served as the control group. Then the levels of Gd-IgA1 in serum and urine, and intestinal mucosal barrier injury indexes [diamine oxidase (DAO), serum soluble intercellular adhesion molecule-1 (sICAM-1), D-lactate (D-LAC), and lipopolysaccharide (LPS)] and inflammatory factors [interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α)] in the serum samples were detected. Fecal samples were collected to detect intestinal microbiota using 16 s rDNA sequencing. Then, we assessed possible correlations among clinical and laboratory findings. Results: In patients with IgAN, the levels of Gd-IgA1 both in the serum and urine were higher than that of the healthy control. Furthermore, urine Gd-IgA1 level was positively correlated with the serum creatinine level, 24 h urine protein, and M, S, and T parameters in the Oxford classification. ROC curve analysis showed that urine Gd-IgA1 has a greater diagnostic value (AUC = 0.9714, 95% CI, 0.932-1; P < 0.0001) for IgAN. The best cutoff value for urine Gd-IgA1 was 0.745 ng·l/ml·µmol (sensitivity, 94%; specificity, 95%). The intestinal mucosal barrier damage indexes (DAO, sICAM-1, D-LAC, and LPS) were increased in the patients with IgAN, which were positively correlated with Gd-IgA1 levels (P < 0.05) both in serum and urine. The levels of inflammatory factors in the patients with IgAN were increased. 16 s rDNA analysis showed that the intestinal microbiota in these patients was disordered compared to that observed in the healthy subjects. Actinobacteria, Bifidobacterium, Blautia, Bifidobacteriaceae, and Bifidobacteriales were decreased and Shigella was increased in IgAN. The decreased populations of these flora were negatively and significantly correlated with urine Gd-IgA1 and the levels of DAO, sICAM-1, D-LAC, and LPS. Conclusion: The urine Gd-IgA1 levels may be a non-invasive biological marker for evaluating kidney injury in IgAN. Gut flora dysbiosis and intestinal barrier dysfunction may be involved in Gd-IgA1 expression.

Glomerular deposition of galactose-deficient IgA1-containing immune complexes via glomerular endothelial cell injuries.

BACKGROUND: Galactose-deficient immunoglobulin A1 (Gd-IgA1) plays a crucial role in the development of IgA nephropathy (IgAN). However, the pathological role of Gd-IgA1-containing immune complexes (ICs) and the mechanism of deposition in the mesangial region remain unclear. METHODS: To examine the deposition of Gd-IgA1-containing ICs in the mesangial region through glomerular endothelial cell injury, we evaluated the alteration of renal microvascular endothelial glycocalyx in nude mice injected with Gd-IgA1-IgG ICs. Human renal glomerular endothelial cells (HRGECs) were used to assess the potential capacity of Gd-IgA1-IgG ICs to activate endothelial cells. RESULTS: Nude mice injected with Gd-IgA1-containing ICs showed podocyte and endothelial cell injuries, with IgA, IgG and C3 depositions in glomerular capillaries and the mesangium. Moreover, albuminuria and hematuria were induced. Real-time glycocalyx imaging showed that renal microvascular glycocalyx was decreased immediately after injection of Gd-IgA1-containing ICs and then mesangial IgA deposition was increased. After coculture of Gd-IgA1-containing ICs with HRGECs, messenger RNA expression levels of endothelial adhesion molecules and proinflammatory mediators were upregulated significantly. CONCLUSION: Gd-IgA1-IgG ICs had a high affinity for glomerular endothelial cells, which resulted in glomerular filtration barrier dysfunction mediated by glycocalyx loss. Furthermore, Gd-IgA1-IgG ICs accelerated the production of adhesion factors and proinflammatory cytokines in glomerular endothelial cells. The glomerular endothelial cell injury induced by Gd-IgA1-containing ICs may enhance the permeability of Igs in the mesangial region and subsequent inflammatory responses in the pathogenesis of IgAN.

IL-6 and its role in IgA nephropathy development.

IL-6 is considered one of the well characterized cytokines exhibiting homeostatic, pro- and anti-inflammatory activities, depending on the receptor variant and the induced intracellular cis- or trans-signaling responses. IL-6-activated pathways are involved in the regulation of cell proliferation, survival, differentiation, and cell metabolism changes. Deviations in IL-6 levels or abnormal response to IL-6 signaling are associated with several autoimmune diseases including IgA nephropathy (IgAN), one of most frequent primary glomerulonephritis worldwide. IgAN is associated with increased plasma concentration of IL-6 and increased plasma concentration of aberrantly galactosylated IgA1 immunoglobulin (Gd-IgA1). Gd-IgA1 is specifically recognized by autoantibodies, leading to the formation of circulating immune complexes (CIC) with nephritogenic potential, since CIC deposited in the glomerular mesangium induce mesangial cells proliferation and glomerular injury. Infection of the upper respiratory or digestive tract enhances IL-6 production and in IgAN patients is often followed by the macroscopic hematuria. This review recapitulates general aspects of IL-6 signaling and summarizes experimental evidences about IL-6 involvement in the etiopathogenesis of IgA nephropathy through the production of Gd-IgA1 and regulation of mesangial cell proliferation.

A case of pathologically confirmed streptococcal infection-related IgA vasculitis with associated glomerulonephritis and leukocytoclastic cutaneous vasculitis.

We report the case of an 80 year-old woman who developed bilateral lower extremity purpura and renal impairment with proteinuria a few days after a transient fever (day 0). High levels of both anti-streptolysin-O antibody (ASO) and anti-streptokinase antibody (ASK), as well as low levels of coagulation factor XIII in serum were noted. Skin biopsy was performed and showed a leukocytoclastic vasculitis with deposition of IgA and C3 in the cutaneous small vessels, indicating IgA vasculitis in the skin. After initiation of oral prednisolone, the skin lesions showed significant improvement. However, renal function and proteinuria gradually worsened from day 12. Kidney biopsy was performed on day 29, which demonstrated a necrotizing and crescentic glomerulonephritis with mesangial deposition of IgA and C3. In addition, the deposition of galactose-deficient IgA1 (Gd-IgA1) was positive on glomeruli and cutaneous small vessels, indicating that the purpura and glomerulonephritis both shared the same Gd-IgA1-related pathogenesis. In addition, the association between the acute streptococcal infection and the IgA vasculitis was confirmed by the deposition of nephritis-associated plasmin receptor (NAPlr) in glomeruli. The patient was treated with steroid pulse and intravenous cyclophosphamide, in addition to the oral prednisolone treatment. Renal function and proteinuria gradually improved, but did not completely recover, as is typically seen with courses of IgA vasculitis in the elderly. In this case, the streptococcal infectionrelated IgA vasculitis was confirmed pathologically by the deposition of both NAPlr and Gd-IgA1 in glomeruli, as well as Gd-IgA1 in the cutaneous small vessels.

Relationship between Gd-IgA1 and TNFR1 in IgA nephropathy and IgA vasculitis nephritis in children - multicenter study.

AIM OF THE STUDY: To evaluate the relationship between serum Gd-IgA1 (sGd-IgA1) and serum and urine TNFR1 (sTNFR1, uTNFR1) levels as possible prognostic factors in IgA nephropathy (IgAN) and IgA vasculitis nephritis (IgAVN). MATERIAL AND METHODS: From 299 patients from the Polish Registry of Pediatric IgAN and IgAVN, 60 children (24 IgAN and 36 IgAVN) were included in the study. The control group consisted of 20 healthy children. Proteinuria, haematuria, serum creatinine as well as IgA and C3 levels were measured and glomerular filtration rate (GFR) was calculated at onset and at the end of the follow-up. Kidney biopsy findings were evaluated using the Oxford classification. Serum Gd-IgA1 and serum and urine TNFR1 levels were measured at the end of follow-up. RESULTS: Serum Gd-IgA1 level was significantly higher in IgAN and IgAVN patients in comparison to the control group. Urine TNFR1 was significantly higher in IgAN than in IgAVN and the control group. We did not observe any differences in sTNFR1 level between IgAN, IgAVN and control groups. We found a positive correlation between Gd-IgA1 and creatinine (r = 0.34), and negative between Gd-IgA1 and GFR (r = -0.35) at the end of follow-up. We observed a negative correlation between uTNFR1/creatinine log and albumin level and protein/creatinine ratio. We did not find any correlations between Gd-IgA1 and TNFR1. CONCLUSIONS: The prognostic value of sGd-IgA1 in children with IgAN and IgAVN has been confirmed. TNFR1 is not associated with Gd-IgA1 and is not a useful prognostic marker in children with IgAN/IgAVN and normal kidney function.

Immune characteristics of renal allograft donors with mesangial IgA deposition.

BACKGROUND: There are few studies describing the prevalence and immune features of people with subclinical mesangial immunoglobulin A (IgA) deposition in the Chinese population. We sought to investigate the prevalence of mesangial IgA deposition among kidney donors and the immune characteristics of donors with mesangial IgA deposition. METHODS: Fifty blood-related living donors with zero-hour allograft biopsies obtained at Peking University First Hospital were enrolled. Galactose-deficient IgA1 (Gd-IgA1) in glomerular deposits was examined by double immunofluorescent staining using the specific monoclonal antibody KM55. Plasma IgA, IgA1, Gd-IgA1 and antibodies directed against Gd-IgA1 were measured using enzyme-linked immunosorbent assay. RESULTS: Thirteen of 50 (26%) donors had mesangial IgA deposition, which was confirmed by both immunofluorescence and electron microscopy. The levels of plasma IgA, IgA1 and Gd-IgA1 were all increased in donors with IgA deposition compared with those without IgA deposition (mean ± SD, 3.54 ± 0.505 versus 2.356 ± 0.265 mg/ml, p = 0.049; 3.003 ± 0.4048 versus 2.356 ± 0.265 mg/ml, p = 0.057; and 4.719 ± 0.4357 versus 3.356 ± 0.4707 ug/ml, p = 0.0440, respectively). Colocalized IgA1 and Gd-IgA1 indicated that there were galactose-deficient IgA1 deposits in the glomerular mesangium. While donors with IgA deposition showed lower levels of IgG anti-glycan antibodies than patients with IgA nephropathy (37.71 ± 8.886 versus 78.86 ± 5.155 units/ml, p = 0.001). CONCLUSIONS: The immune features of donors with IgA deposition, including IgA1 and Gd-IgA1 deposition, were similar to those of patients with IgA nephropathy, but donors with IgA deposition had lower levels of antiglycan antibodies, which may explain the subclinical status of IgA deposition in donors. Mesangial IgA deposition was common in the Chinese blood related donors cohort, further large study with both living and cadaveric donor kidneys was still needed to confirm these findings.

Tonsillar immunology in IgA nephropathy.

As one of the most common types of primary glomerulonephritis, IgA nephropathy (IgAN) is often characterized by the immunoprecipitation of IgA1 in mesangial area. In clinical terms, IgA nephropathy can be treated with tonsillectomy or conservative treatment, basing on modern immunology knowledge in which the mucosa immune system (MIS), especially the widely distributed mucosa-associated lymphoid tissue (MALT) is focused accordingly In terms of basic research, IgAN has been shown correlated with multiple factors, including serum Gd-IgA1 level, IgA-IgG immunity, tonsil-associated bacteria,GADD34, CX3CR1, FOXP3 and the expression of other related intrinsic immune antibody. Therefore, it is reasonable there could be mutual correlation among IgAN-associated factors. The purpose of this study is to review the new progress on the treatment and prevention of IgAN diseases and related mechanisms of IgAN tonsils, which will be of great significance for the therapy of IgAN patients.

Crescentic IgA nephropathy after administration of human monoclonal interleukin-12/23p40 antibody in a patient with Crohn's disease: a case report.

Ustekinumab (UST), an interleukin (IL)-12/IL-23-blocking monoclonal antibody, is a novel therapeutic option for Crohn's disease (CD). We describe a 24-year-old man with CD who showed an abrupt decline in renal function after administration of UST. Twenty-nine months previously, the patient was diagnosed with CD, and abnormal urinalysis findings in health checkup were coincidentally found at that time. Three months previously, treatment for CD was switched from infliximab to UST because of therapy-resistant severe diarrhea and bloody stools. A single dose of UST (260 mg) was initially intravenously administered, followed by single subcutaneous administration (90 mg) 2 months later. Thereafter, the patient exhibited rapid renal dysfunction with significant urinary abnormalities, although his gastrointestinal symptoms had completely disappeared. He was admitted to our hospital for further examination and treatment. Renal pathologic findings were compatible with crescentic glomerulonephritis consisting of almost fibro-cellular crescents. Immunofluorescent study showed IgA and C3 deposition in the glomerular mesangial area and IgA subclass staining revealed predominant IgA1 with concomitant mild IgA2 deposition. Furthermore, galactose-deficient IgA1 (Gd-IgA1) was also positive in the mesangial area. In addition, serum-Gd-IgA1 level was moderately increased. UST treatment was stopped and he responded to intensive steroid therapy with a parallel reduction of serum creatinine and Gd-IgA1 levels without flare of gastrointestinal symptoms. To our knowledge, this is the first case of immunoglobulin A nephropathy (IgAN) in patient with CD that might be aggravated by UST treatment. We presume that inhibition of IL-12/23 signaling with UST may cause to form crescentic IgAN by enhancing Gd-IgA1 production.

Higher serum galactose-deficient immunoglobulin A1 concentration is associated with stronger mesangial cellular inflammatory response and more severe histologic findings in immunoglobulin A nephropathy.

BACKGROUND: Galactose-deficient immunoglobulin A1 (Gd-IgA1) is known to play a key role in the pathogenesis of IgA nephropathy (IgAN). We aimed to evaluate whether serum Gd-IgA1 is associated with in vitro activation of mesangial cells in individual patients and how this affects the clinical and histologic parameters. METHODS: Serum samples and clinical and histologic data were collected in the University Hospital Basel and Hammersmith Hospital, London. Serum levels of IgA1 and Gd-IgA1 were measured by enzyme-linked immunosorbent assay (ELISA) and lectin-binding assay using lectin Helix aspersa (HA). Primary human mesangial cells were stimulated with IgA1 isolated from serum from individual patients and the concentrations of monocyte chemoattractant protein-1 and interleukin-6 were measured in cell culture supernatant by ELISA. RESULTS: Thirty-three patients were enrolled. A significant correlation was observed between serum Gd-IgA1 levels and the concentration of MCP-1 in the culture supernatant in individual patients (Spearman r = 0.5969, P = 0.0002). There was no significant correlation between serum Gd-IgA1 levels and proteinuria or estimated glomerular filtration rate at diagnosis. However, the serum Gd-IgA1 level was significantly higher in patients with segmental glomerulosclerosis (S0 versus S1, P = 0.0245) and tubular atrophy/interstitial fibrosis (T0 versus T1 and T2, P = 0.0336; T0 versus T2, P = 0.0225). CONCLUSIONS: Higher serum Gd-IgA1 concentration is associated with stronger mesangial cell inflammatory response with production of a greater amount of MCP-1 in vitro. This in turn is associated with severe histologic changes. The disease progression with worse renal outcome in patients with higher serum Gd-IgA1 may be therefore mediated by more pronounced mesangial cell inflammatory response leading to more severe histologic changes.