IgA Vasculitis With Nephritis Research Articles

Outcome of immunosuppression in children with IgA vasculitis-related nephritis.

IgA vasculitis with nephritis (IgAVN) is the most common vasculitis in children. Treatment recommendations are, due to a lack of evidence, based on expert opinion resulting in variation. The aim of this study was to describe clinical presentation, treatment and outcome of an extremely large cohort of children with biopsy proven IgAVN to identify prognostic risk factors and signals of treatment efficacy. Retrospective data were collected on 1148 children with biopsy proven IgAVN between 2005 and 2019 from 41 international paediatric nephrology centres across 25 countries and analyzed using multivariate analysis. The primary outcome was estimated glomerular filtration rate (eGFR) and persistent proteinuria at last follow up. The median follow up was 3.7 years (IQR 2-6.2). At last follow up, 29% of patients had an eGFR<90ml/min/1.73m2, 36% had proteinuria and 3% had chronic kidney disease stage 4-5. Older age, lower eGFR at onset, hypertension and histological features of tubular atrophy and segmental sclerosis were predictors of poor outcome. There was no evidence to support any specific second line immunosuppressive regimen to be superior to others, even when further analysing subgroups of children with reduced kidney function, nephrotic syndrome or hypoalbuminemia at onset. Delayed start of immunosuppressive treatment was associated with a lower eGFR at last follow up. In this large retrospective cohort, key features associated with disease outcome are highlighted. Importantly there was no evidence to support that any specific immunosuppressive treatments were superior to others. Further discovery science and well-conducted clinical trials are needed to define accurate treatment and improve outcomes of IgAVN.

Long-term outcome of combination therapy with corticosteroids, mizoribine and RAS inhibitors as initial therapy for severe childhood IgA vasculitis with nephritis.

Patients with severe IgA vasculitis with nephritis (IgAVN) typically receive aggressive therapy as an initial approach. We have consistently performed combination therapy including corticosteroids and immunosuppressants as initial therapy for severe IgAVN over a 20-year-plus period, with only minor changes to the treatment protocol. This study seeks to reveal the efficacy of combination therapy for severe IgAVN. We retrospectively studied 50 Japanese children diagnosed between 1996 and 2019 with clinicopathologically severe IgAVN who were defined as ISKDC classification grade IIIb-V and/or serum albumin < 2.5g/dL. The median age at the onset of IgAVN was 8.0years (IQR: 6.0-10.0). At biopsy, 44% of patients had nephrotic syndrome and 14% had kidney dysfunction. All patients were treated with combination therapy after biopsy. Abnormal proteinuria resolved after initial therapy in all 50 patients. However, eight patients (16%) had recurrence of proteinuria. Abnormal proteinuria was again resolved in three of these patients with additional treatment. At the last follow-up (median 59.5months; IQR, 26.2-84.2), the median urine protein-to-creatine ratio was 0.08g/gCr (IQR, 0.05-0.15), and only one patient had kidney dysfunction. Combination therapy provided good kidney outcomes for Japanese children with severe IgAVN. Even including recurrent cases, the degree of proteinuria was slight, and kidney function was good at the last follow-up. A higher resolution version of the Graphical abstract is available as Supplementary information.

Comparative proteomic analysis of glomerular proteins in IgA nephropathy and IgA vasculitis with nephritis

BackgroundIgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN) are related glomerular diseases characterized by marked similarities in immunological and histological findings. We herein performed a comparative proteomic analysis of glomerular proteins in IgAN and IgAVN.MethodsWe used renal biopsy specimens from 6 IgAN patients without nephrotic syndrome (NS) (IgAN-I subgroup), 6 IgAN patients with NS (IgAN-II subgroup), 6 IgAVN patients with 0–8.0% of glomeruli with crescent formation (IgAVN-I subgroup), 6 IgAVN patients with 21.2–44.8% of glomeruli with crescent formation (IgAVN-II subgroup), 9 IgAVN patients without NS (IgAVN-III subgroup), 3 IgAVN patients with NS (IgAN-IV subgroup), and 5 control cases. Proteins were extracted from laser microdissected glomeruli and analyzed using mass spectrometry. The relative abundance of proteins was compared between groups. An immunohistochemical validation study was also performed.ResultsMore than 850 proteins with high confidence were identified. A principal component analysis revealed a clear separation between IgAN and IgAVN patients and control cases. In further analyses, 546 proteins that were matched with ≥ 2 peptides were selected. The levels of immunoglobulins (IgA, IgG, and IgM), complements (C3, C4A, C5, and C9), complement factor H-related proteins (CFHR) 1 and 5, vitronectin, fibrinogen chains, and transforming growth factor-β inducible gene-h3 were higher (> 2.6 fold) in the IgAN and IgAVN subgroups than in the control group, whereas hornerin levels were lower (< 0.3 fold). Furthermore, C9 and CFHR1 levels were significantly higher in the IgAN group than in the IgAVN group. The abundance of some podocyte-associated proteins and glomerular basement membrane (GBM) proteins was significantly less in the IgAN-II subgroup than in the IgAN-I subgroup as well as in the IgAVN-IV subgroup than in the IgAVN-III subgroup. Among the IgAN and IgAVN subgroups, talin 1 was not detected in the IgAN-II subgroup. This result was supported by immunohistochemical findings.ConclusionsThe present results suggest shared molecular mechanisms for glomerular injury in IgAN and IgAVN, except for enhanced glomerular complement activation in IgAN. Differences in the protein abundance of podocyte-associated and GBM proteins between IgAN and IgAVN patients with and without NS may be associated with the severity of proteinuria.

Association of the clinicopathological characteristics and proteinuria remission of pediatric IgAV with nephrotic-range proteinuria: A retrospective cohort study.

IgA vasculitis (IgAV) combined with nephrotic-range proteinuria is uncommon, and nephrotic-range proteinuria is considered a risk factor for poor prognosis in children with IgAV. There are few clinical studies with large samples. Children with IgAV and nephrotic-range proteinuria who were hospitalized at the Department of Nephrology, Rheumatology and Immunology, Hunan Children's Hospital, from March 2008 to January 2020 were retrospectively studied; the patients were aged ≤18 years and were followed up for ≥12 months. We analyzed clinical characteristics, pathological changes, treatment responses, and their relationships in patients with IgAV combined with nephrotic-range proteinuria. Two hundred seventy-seven children with an average age at onset of IgAV with nephritis (IgAVN) of 8.0 years (interquartile range (IQR), 6.0-10.0) were enrolled; 65.7% were aged 6-10 years. The male-to-female ratio was 1.35:1. All children had both nephrotic-range proteinuria and hematuria, 49 (17.7%) had hypoalbuminemia, and 9 (3.2%) had estimated glomerular filtration rate < 90 (mL/min/1.73 m2). All included children were followed up for at least 1 year. At 3, 6, and 12 months of follow-up, the remission rates of proteinuria in children with IgAV combined with nephrotic-range proteinuria were 27.8%, 62.1%, and 83.0%, respectively, and the remission rates of hematuria were 1.4%, 8.7%, and 35.7%, respectively. In addition, children with age at onset of IgAV with nephrotic-range proteinuria ≥10 years, who were female, who had proteinuria ≥100 mg/kg/24 h, and who had a pathological grade III or above had lower remission rates of hematuria and proteinuria (P < 0.05). Multivariate factor analysis was performed by logistic regression and showed age at onset of IgAVN ≥ 10 years and crescents to be risk factors for nonremission of proteinuria at 12 months of follow-up (P < 0.05). Age at onset of IgAVN, sex, proteinuria level, pathological grade, and crescents significantly affect proteinuria remission in children with IgAV combined with nephrotic-range proteinuria.

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

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. 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. 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). 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.

Neutrophil-to-lymphocyte ratio as an independent inflammatory indicator for poor renal prognosis in adult IgA vasculitis with nephritis

BackgroundSkin-limited IgAV patients usually present self-limiting disease and good prognosis, while adult IgA vasculitis with nephritis (IgAV-N) present severe phenotype and poor prognosis. Previous studies showed that neutrophil-to-lymphocyte ratio (NLR) was an inflammatory indicator for predicting systemic involvement in children IgAV patients. In this study, we focused on adult IgAV-N patients to explore the relationship of NLR with disease phenotype and long-term renal prognosis. MethodsIn this study, 245 IgAV-N patients, 1151 IgAN patients and 251 healthy controls were recruited. Composite endpoint was defined as 30% eGFR declined or end stage kidney disease. ResultsIgAV-N patients presented increased white blood cells (WBC), neutrophils (NE), platelet-to-lymphocyte ratio (PLR), and NLR levels, while decreased lymphocyte (LY) than healthy controls. When compared to clinical and pathological features matched IgAN patients, IgAV-N patients still showed higher WBC, NE, and NLR levels. NLR showed the best performance for the diagnosis of IgAV-N with the highest area under the ROC curves (0.738). IgAV-N patients in high NLR group (>2.41) presented with sever baseline manifestations and more acute pathological lesions than low NLR group (≤2.41). 77 patients with regular follow-up were used for survival analysis. After adjusting some well-known risk factors, NLR levels remained as an independent risk factor for poor renal outcome in adult patients with IgAV-N (HR, 1.913; 95% CI, 1.314 to 2.787, P = 0.001). ConclusionsNLR levels were associated with the clinical and pathological phenotypes, and NLR may serve as an independent risk factor for poor renal outcome in adult IgAV-N patients.

Fluctuation of R2* values in blood oxygenation level-dependent MRI during acute and remission phases of IgA vasculitis with nephritis in children.

Noninvasive assessment of the kidney using blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) has progressed remarkably; indications have expanded to include the evaluation of glomerulonephritis. However, no longitudinal measurements from acute to post-treatment remission phases have been reported. Hence, this study aimed to investigate spin relaxation rate (R2*) values during acute and remission phases in children with glomerulonephritis. All pediatricpatients with IgA vasculitis with nephritis (IgAVN) diagnosed between January 2014 and October 2021 and requiring renal biopsy were retrospectively reviewed; four patients who were observed from onset to remission were included in this study. In total, eight MRIs were performed in the acute and remission phases, and R2* values and fluctuations induced by low-dose oxygen administration were determined from 10 echoes using a 1.5T MRI system with 4.76-47.6ms echo times and a 153ms repetition time. The median age of patients undergoing MRI was 8.5years in the acute phase and 13.9years in the remission phase. R2* values of the acute phase were higher than those of the remission phase; however, the difference was not significant (cortex; p = 0.32 and medulla; p = 0.052). Oxygen administration did not cause fluctuations in the R2* values in the cortex or medulla during the acute phase (cortex; p = 0.67 and medulla; p = 0.76); however, in the remission phase, the R2* values in the cortex and medulla significantly decreased due to low-dose oxygen administration (cortex; p < 0.01 and medulla; p < 0.01). The fluctuation in R2* values observed during different phases of IgAVN indicates that BOLD MRI may be used to assess disease activity. Therefore, we propose BOLD MRI with low-dose oxygen administration as a noninvasive method to evaluate the activity of glomerulonephritis.

The Usefulness of Vanin-1 and Periostin as Markers of an Active Autoimmune Process or Renal Fibrosis in Children with IgA Nephropathy and IgA Vasculitis with Nephritis-A Pilot Study.

This study aimed to evaluate the usefulness of vanin-1 and periostin in urine as markers of the autoimmune process in kidneys and renal fibrosis in IgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN). From a group of 194 patients from the Department of Pediatrics and Nephrology, who were included in the Polish Pediatric Registry of IgAN and IgAVN, we qualified 51 patients (20 with IgAN and 31 with IgAVN) between the ages of 3 and 17, diagnosed based on kidney biopsy, for inclusion in the study. All of the patients received glucocorticosteroids, immunosuppressive drugs, or renoprotective therapy. The control group consisted of 18 healthy individuals. The concentration of vanin was significantly higher in the IgAN and IgAVN groups than in the control group. The concentration of vanin/creatinine correlates positively with the level of IgA and negatively with the serum level of C3 at the end of the observation. Urinary vanin-1 concentration may be useful as a marker of the active autoimmune process in IgAN and IgAVN in children, but the study needs confirmation on a larger group of children, along with evaluation of the dynamics of this marker. Urinary periostin is not a good marker for children with IgAN and IgAVN, especially in stage 1 and 2 CKD.

Lipid metabolism contribute to the pathogenesis of IgA Vasculitis

Background and objectivesThe underlying mechanism of IgA vasculitis (IgAV) and IgA vasculitis with nephritis (IgAVN) remains unclear. Therefore, there are no accurate diagnostic methods. Lipid metabolism is related to many immune related diseases, so this study set out to explore the relationship of lipids and IgAV and IgAVN.MethodsFifty-eighth patients with IgAV and 28 healthy controls were recruited, which were divided into six separate pools to investigate the alterations of serum lipids according to the clinical characteristics: healthy controls group (HCs) and IgAV group (IgAVs), IgAVN group (IgAV-N) and IgAV without nephritis group (IgAV-C), initial IgAV group (IgAV0) and IgAV in treatment with glucocorticoids group (IgAV1).Results31 identified lipid ions significantly changed in IgAVs with p < 0.05, variable importance of the projection (VIP) > 1 and fold change (FC) > 1.5. All these 31 lipid ions belong to 6 classes: triacylglycerols (TG), phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine, ceramide, and lysophosphatidylcholine. TG (16:0/18:1/22:6) +NH4 over 888875609.05, PC (32:1) +H over 905307459.90 and PE (21:4)-H less than 32236196.59 increased the risk of IgAV significantly (OR>1). PC (38:6) +H was significantly decreased (p < 0.05, VIP>1 and FC>1.5) in IgAVN. PC (38:6) less than 4469726623 conferred greater risks of IgAV (OR=45.833, 95%CI: 6.689~341.070).ConclusionWe suggest that lipid metabolism may affect the pathogenesis of IgAV via cardiovascular disease, insulin resistance, cell apoptosis, and inflammation. The increase of TG(16:0/18:1/22:6) + NH4, and PC(32:1) + H as well as PE (21:4)-H allow a good prediction of IgAV. PE-to-PC conversion may participate in the damage of kidney in IgAV. PC (38:6) + H may be a potential biomarker for IgAVN.

Lectin and alternative complement pathway activation in cutaneous manifestations of IgA-vasculitis: A new target for therapy?

IgA-vasculitis is a systemic small-vessel leucocytoclastic vasculitis and is associated with a high morbidity. The disease can progress to IgA-vasculitis with nephritis (IgAVN) which can result in chronic renal failure. Complement activation is involved in the pathogenesis of IgA-vasculitis. A recent study has shown that cutaneous C3c deposition in IgA-vasculitis is associated with a higher risk to develop IgAVN. In the current study we investigated the different complement pathways that are activated in cutaneous IgA-vasculitis in order to reveal potential targets for intervention. In addition, we analyzed the association of complement factors with IgAVN and the clinical course of the disease.In this retrospective study, the clinicopathological features of 17 patients with IgA-vasculitis were compared with 25 non-IgA-vasculitis cases. Deposition of immunoglobulins and complement was analyzed by direct immunofluorescence for IgA, IgG, IgM, C1q, C4d, properdin, mannan-binding lectin (MBL), ficolin-2 (FCN2), MBL-associated serine protease 1/3 (MASP1/3), MASP2 and C3c. The vascular intensity and positive area was scored on a nominal scale and cumulative score was calculated by multiplying the intensity x area.Properdin was positive in 82% of IgA-vasculitis cases, reflecting alternative pathway activation. C4d was positive in 88% of IgA-vasculitis cases reflecting classical and/or lectin pathway activation, although only 12% of cases were positive for C1q. Lectin pathway activation was demonstrated by deposition of MBL (47%), MASP1/3 (53%) and MASP2 (6%) while FCN2 was found negative. Significantly more deposition of MASP1/3 was found in IgA-vasculitis versus non-IgA-vasculitis.This study demonstrates for the first time activation of lectin and alternative pathways in cutaneous manifestations of IgA-vasculitis. Hence, drugs that intervene in these complement pathways may be an interesting more targeted alternative to the current drugs, in reducing local cutaneous symptoms of the disease, with potentially less side-effects. No association was found between complement activation and IgAVN and/or response to therapy. Therefore, it is unlikely that intervention in complement activation will lead to a better clinical course of the disease.

IgA Vasculitis with Nephritis in Adults: Histological and Clinical Assessment.

Patients with IgA vasculitis (IgAV), an immune complex-mediated disease, may exhibit kidney involvement—IgAV with nephritis (IgAVN). The kidney-biopsy histopathologic features of IgAVN are similar to those of IgA nephropathy, but little is known about histopathologic disease severity based on the interval between purpura onset and diagnostic kidney biopsy. We assessed kidney histopathology and clinical and laboratory data in a cohort of adult patients with IgAVN (n = 110). The cases were grouped based on the interval between the onset of purpura and kidney biopsy: Group 1 (G1, <1 month, n = 14), Group 2 (G2, 1–6 months, n = 58), and Group 3 (G3, >6 months, n = 38). Glomerular leukocytes were more common in G1 than in the other groups (p = 0.0008). The proportion of neutrophils among peripheral-blood leukocytes was the highest in the patients biopsied within a month after onset of purpura (G1: 71 ± 8%). In the patients with an interval >6 months, the neutrophil proportion was lower, 60%. Moreover, the glomerular mesangial proliferation score correlated with the serum total IgA concentration (p = 0.0056). In conclusion, IgAVN patients biopsied <1 month from purpura onset showed an elevated percentage of blood neutrophils and glomerular leukocytes, consistent with an acute-onset inflammatory reaction. In all IgAVN patients, the mesangial proliferation score correlated with the serum IgA level.

Serum Bilirubin Is Correlated With the Progression of IgA Vasculitis With Nephritis.

Background: Bilirubin has been identified as an endogenous antioxidant and cellular protectant. The present study was performed to clarify the potential influence of serum bilirubin on IgA vasculitis with nephritis (IgAV-N).Methods: One hundred and eighty-nine IgAV-N patients over 14 years old were enrolled. The patients were divided into two groups by the optimum cut-off value calculated by ROC curve. The composite endpoints were defined as a 60% decline in estimate glomerular filtration rate (e-GFR), end-stage renal disease (ESRD) and/or death. Kaplan-Meier (K-M) analysis and multivariate Cox analysis were carried out to determine the predictors for renal outcomes. In order to eliminate the influence of different baseline data, a 1:2 propensity score (PS) match was performed to make the results comparable and convictive.Results: The baseline data suggested that patients in low serum bilirubin group had significantly higher levels of systolic blood pressure, proteinuria, serum creatinine and crescent formation ratio and lower levels of serum albumin and hemoglobin. Renal survival analysis indicated that lower serum bilirubin levels were significantly correlated with a poorer prognosis. Multivariate Cox analysis demonstrated that the higher level of serum bilirubin was an independent protective factor for renal survival (HR, 0.172; 95% CI, 0.030–0.991; P = 0.049). After PS matching, the baseline characters of two groups had no statistical differences. Similar outcomes were demonstrated in K-M curve and the multivariate Cox analysis.Conclusion: Elevated bilirubin levels might be related to the favorable renal outcomes.

IgA vasculitis with nephritis: update of pathogenesis with clinical implications.

IgA vasculitis with nephritis (IgAVN) shares many pathogenetic features with IgA nephropathy (IgAN). The purpose of this review is to describe our current understanding of the pathogenesis of pediatric IgAVN, particularly as it relates to the four-hit hypothesis for IgAN. These individual steps, i.e., hits, in the pathogenesis of IgAN are (1) elevated production of IgA1 glycoforms with some O-glycans deficient in galactose (galactose-deficient IgA1; Gd-IgA1), (2) generation of circulating IgG autoantibodies specific for Gd-IgA1, (3) formation of pathogenic circulating Gd-IgA1-containing immune complexes, and (4) kidney deposition of the Gd-IgA1-IgG immune complexes from the circulation and induction of glomerular injury. Evidence supporting the four-hit hypothesis in the pathogenesis of pediatric IgAVN is detailed. The genetics, pediatric outcomes, and kidney histopathologic features and the impact of these findings on future treatment and potential biomarkers are discussed. In summary, the evidence points to the critical roles of Gd-IgA1-IgG immune complexes and complement activation in the pathogenesis of IgAVN. Future studies are needed to characterize the features of the immune and autoimmune responses that enable progression of IgA vasculitis to IgAVN.

Immunoglobulin A Glycosylation and Its Role in Disease.

Human IgA is comprised of two subclasses, IgA1 and IgA2. Monomeric IgA (mIgA), polymeric IgA (pIgA), and secretory IgA (SIgA) are the main molecular forms of IgA. The production of IgA rivals all other immunoglobulin isotypes. The large quantities of IgA reflect the fundamental roles it plays in immune defense, protecting vulnerable mucosal surfaces against invading pathogens. SIgA dominates mucosal surfaces, whereas IgA in circulation is predominately monomeric. All forms of IgA are glycosylated, and the glycans significantly influence its various roles, including antigen binding and the antibody effector functions, mediated by the Fab and Fc portions, respectively. In contrast to its protective role, the aberrant glycosylation of IgA1 has been implicated in the pathogenesis of autoimmune diseases, such as IgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN). Furthermore, detailed characterization of IgA glycosylation, including its diverse range of heterogeneity, is of emerging interest. We provide an overview of the glycosylation observed for each subclass and molecular form of IgA as well as the range of heterogeneity for each site of glycosylation. In many ways, the role of IgA glycosylation is in its early stages of being elucidated. This chapter provides an overview of the current knowledge and research directions.

Global Glomerulosclerosis and Segmental Glomerulosclerosis Could Serve as Effective Markers for Prognosis and Treatment of IgA Vasculitis With Nephritis.

Background: This study was aimed at investigating the clinical significance and curative effect of global glomerulosclerosis (GS) and segmental glomerulosclerosis (S) in adult-onset IgA vasculitis with nephritis (IgAV-N) patients since there was no consensus pathological grading method for adult IgAV-N.Methods: A total of 188 biopsy-proven IgAV-N patients were prospectively identified. Patients were separately assigned to GS0/GS1/GS2 group and S0/S1/S2 based on the scores of global glomerulosclerosis and segmental glomerulosclerosis (0% /0–15% />15%, respectively).Results: GS0, GS1, and GS2 occurred in 56.4, 29.2, and 14.4% of the adult-onset IgAV-N, respectively. Patients in GS2 group tended to have the most serious renal deterioration and the highest levels of blood pressure. IgAV-N patients were also divided into S0 group (64.4%), S1 group (20.7%), and S2 group (14.9%), where no obvious differences in baseline data were noted. K–M curves indicated that GS2 group had the worst renal outcome (P = 0.05) while there seemed to be no significant differences between GS0 group and GS1 group. In addition, no remarkable differences in primary outcome were found among S0 group, S1 group, and S2 group though the prognosis of S2 group tended to be the worst. However, the prognosis of S0/S1 group was markedly better than that of S2 (P = 0.04). The discrimination of poor prognosis could be improved by adding the pathological indicators of global glomerulosclerosis and segmental glomerulosclerosis. Most importantly, immunosuppressive treatment might be a superior alternative in IgAV-N patients without sclerosis scores or with lower level of sclerosis scores. But addition of immunosuppression was not recommended in patients with higher sclerosis scores.Conclusions: Global glomerulosclerosis and segmental sclerosis might be used for management and treatment of adult-onset IgAV-N.

Serum levels of galactose-deficient IgA1 in Chinese children with IgA nephropathy, IgA vasculitis with nephritis, and IgA vasculitis.

IgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAV-N) are related diseases. Galactose-deficient IgA1 (Gd-IgA1) plays an important role in the pathology of IgAV-N and IgAN, so we aim to compare the serum levels of Gd-IgA1 in Chinese pediatric patients with IgAN, IgAV-N, and IgAV. We retrospectively enrolled 52 patients with IgAN, 57 patients with IgAV-N, 26 patients with IgAV, and 40 healthy children. The serum levels of Gd-IgA1 were measured at the time of biopsy using a lectin-based ELISA method. Gd-IgA1 levels in IgAV-N patients and IgAN patients were higher than in healthy controls (303.94 ± 39.37 U/ml, 314.91 ± 47.79 U/ml vs. 273.57 ± 48.29 U/ml, P < 0.001), and Gd-IgA1 levels in IgAV-N patients were higher than in IgAV patients (303.94 ± 39/ml vs. 286. 21 ± 38.81 U/ml, P = 0.059), but the latter result is not statistically significant. The Gd-IgA1 levels in IgAV patients were comparable with those in healthy controls (286.21 ± 38.81 U/ml vs. 273.57 ± 48.29 U/ml, P = 0.267). Among the four groups, we did not observe significant correlations of Gd-IgA1 levels with eGFR, proteinuria, or the MEST-C score. Serum Gd-IgA1 maybe involved in the pathogenesis of the IgAV-N and IgAN. However, we found no statistically significant correlation between Gd-IgA1 levels and clinical and pathological features.

Glomerular galactose-deficient IgA1 expression analysis in pediatric patients with glomerular diseases

Galactose-deficient IgA1 (Gd-IgA1) is important in the pathogenesis of IgA nephropathy (IgAN). A Gd-IgA1-specific monoclonal antibody (KM55) has revealed glomerular Gd-IgA1 deposition solely in patients with IgAN and IgA vasculitis with nephritis (IgAV-N). However, this specificity is controversial and has not been demonstrated in pediatric patients. Here, we conducted double-immunofluorescence staining of IgA and Gd-IgA1 in 60 pediatric patients with various glomerular diseases. We divided patients into four groups: (1) patients with IgAN and IgAV-N (n = 23); (2) patients with immunocomplex-mediated glomerulonephritis accompanied by IgA deposition, including lupus nephritis, membranoproliferative glomerulonephritis, and membranous nephropathy (n = 14); (3) patients with other glomerular diseases involving IgA deposition, including idiopathic nephrotic syndrome (INS), oligomeganephronia, Alport syndrome, dense deposit disease, and crescentic glomerulonephritis (n = 11); and (4) patients with IgA-negative diseases including INS, membranoproliferative glomerulonephritis, membranous nephropathy, oligomeganephronia, Alport syndrome, C3 glomerulonephritis, poststreptococcal acute glomerulonephritis, and hemolytic uremic syndrome (n = 12). KM55 staining revealed Gd-IgA1-positive findings in 23/23 patients in Group 1 and 13/14 patients in Group 2, but not in patients in Groups 3 or 4. Therefore, KM55 may detect incidental IgA deposition in pediatric patients. Gd-IgA1 may be involved in the pathogenesis of these immune-related diseases; alternatively, KM55 may recognize IgA-related immunocomplexes in a non-specific manner.

P0347COMPLEMENT FACTOR BB AND FACTOR C4D IN IGA NEPHROPATHY AND IGA VASCULITIS

Abstract Background and Aims IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. IgAN and IgA Vasculitis with nephritis (IgAVN) are thought to have related pathogenesis characterized by IgA-containing renal immune complexes contributing to chronic kidney disease (CKD) and renal failure. In both diseases, IgA1 immune complexes and complement factors have been shown to be involved, indicating complement activation. However, the individual contribution of the alternative and lectin pathway has of yet not been fully elucidated. Plasma Bb is a marker of the alternative pathway activity and plasma C4d of the mannan-binding lectin pathway. We aimed to investigate the association between circulating plasma Bb and C4d at diagnosis and potential correlates with clinical features, renal histopathology and renal outcome in patients with IgAN and IgAVN. Method A prospective study of 98 patients undergoing renal biopsy was performed. Median age was 43 years, 52% males, 88% were caucasians, Sixty-six patients were diagnosed with IgAN, 15 IgAVN and 17 controls with “non-immunocomplex driven disease including Thin membrane disease, Diabetic Nephropathy, Minimal change disease or renal failure due to hyperfiltration. Blood samples were analyzed for complement factors C4d and Bb (both ELISA, Termo Fisher ScientificTM). Oxford classification of the renal biopsy was done at baseline and creatinine, estimated glomerular filtration rate (eGFR-CKD-EPI formula) were measured annually. Continuous data are expressed as median (25th to 75th percentile) and nominal or ordinal data as percentage. Comparisons between groups were assessed with the non-parametric Wilcoxon test/ Kruskal-Wallis ANOVA-test for continuous variables and Chi-square test for nominal variables. Results Patients with IgAN and IgAVN were significantly younger than the control group. There were no significant differences between the three groups for gender distribution and eGFR. Complement factor Bb for patients with IgAN and IgAVN was significantly increased (figure 1) as compared to the control group, whereas there was was no statistical difference for complement factorsC4d between groups. Estimated GFR decreased significantly only in patients with IgAN after 24 months of follow-up (56.6 ± 3.8 ml/min/1,73m2 as compared to IgAVN 83.8 ± 8.5 and controls 90.2 ± 8.9). Patients with IgAN had more severe histopathological changes in T-score (T-score 0, 1, 2 in IgAN 51 %, 37 % and 12 % respectively) compared to IgAVN. In the IgAN group a more severe T-score was significantly associated with increased levels of complement factor Bb (p=0.005) but did not reach significance for complement factor C4d (p=0.097). No other difference or correlations were found with regards to M, E, S and C % scores. Conclusion Patients with IgAN were younger and had increased levels of complement factor Bb and after 24 months follow-up significantly reduced eGFR. The increase in factor Bb was also associated with more severe histopathological changes in T-score. These findings suggest that the alternative complement pathway contributes to the pathogenesis in IgAN and chronic kidney damage. Our findings should motivate studies in a larger population to further clarify the role of complement activity in IgAN and IgAVN.

Histological prognostic factors in children with Henoch-Schönlein purpura nephritis.

The management of IgA vasculitis with nephritis (IgAVN) remains controversial because of the difficulty to identify prognostic factors. This study reports the prognosis of children with IgAVN in relation to histological parameters. All children with IgAVN diagnosed between 2000 and 2015 in three pediatric nephrology centers were included. The following histological parameters were analyzed: mesangial proliferation (MP), endocapillary proliferation (EP), crescents, active, or chronic tubular and interstitial lesions (TIa lesions/TIc lesions), and segmental glomerulosclerosis (GS). Clinical and biological data were collected at the time of renal biopsy. The primary endpoint was IgAVN remission defined as a proteinuria < 200mg/l without renal failure. One hundred fifty-nine children were included with a median age of 7.6years. Acute glomerular or TI lesions including MP, EP, crescents, and TIa lesions were observed, respectively, in 81%, 86%, 49%, and 21% of patients. Chronic glomerular lesions including GS and TIc lesions were observed in 6 and 7% of patients. Median initial proteinuria was 330mg/mmol, albuminemia 32g/l, and eGFR 110ml/min/1.73m2. One hundred twelve (70%) patients were in remission at the end of a median follow-up of 37.4months. Chronic lesions were significantly associated with the absence of remission in multivariate analysis, whereas EP, crescents and TIa were not associated with a poor prognosis. Of children with IgAVN, 30% present a persistent renal disease at the end of a 3-year follow-up. Chronic histological lesions, but not EP or crescents, are associated with a bad prognosis and must be evaluated in IgAVN histological classification.

Gastrointestinal bleeding is associated with renal prognosis in adult patients with IgA vasculitis with nephritis.

BackgroundAlthough the prediction of renal prognosis in patients with IgA vasculitis with nephritis (IgAVN) is important, the association between gastrointestinal bleeding (GIB) and its renal prognosis is unknown. This study investigated the effect of GIB on the progression to end‐stage kidney disease (ESKD) in patients with IgAVN.MethodsWe compared the clinicopathological findings at diagnosis, therapy, and clinical outcomes between 10 patients with GIB and 20 patients without GIB in 30 patients with IgAVN aged ≥18 years at the renal biopsy. The primary outcome was the incidence of ESKD. Secondary outcomes included clinical remission and all‐cause mortality. The outcomes and factors affecting the progression to ESKD were evaluated using the Kaplan‐Meier method with log‐rank test and Cox proportional hazards models.ResultsEnd‐stage kidney disease, clinical remission, and deaths from any related cause occurred in 6, 17, and 2 patients, respectively. In Kaplan‐Meier analyses, the GIB group showed a higher incidence of ESKD (50% vs 5%, P = .003) and a lower incidence of clinical remission (20% vs 75%, P = .003). Although the numbers were not statistically significant, this group tended to have a greater number of deaths than the non‐GIB group (7% vs 0%, P = .07). In a multivariable Cox model adjusted for hypertension and urinary proteinuria, GIB could not demonstrate a significant association with ESKD (hazard ratio, 4.51; 95% confidence interval, 0.39‐52.7; P = .23).ConclusionIgAVN with GIB has worse renal outcome, but GIB does not have a statistically significant association with progression to ESKD.