IgAN Patients Research Articles

Single-cell RNA-sequencing reveals distinct immune cell subsets and signaling pathways in IgA nephropathy

BackgroundIgA nephropathy (IgAN) is the most common primary glomerulonephritis globally. Increasing evidence suggests the importance of host immunity in the development of IgAN, but its dynamics during the early stage of IgAN are still largely unclear.ResultsHere we successfully resolved the early transcriptomic changes in immune cells of IgAN by conducting single-cell RNA-sequencing (scRNA-seq) with peripheral blood mononuclear cells. The differentially expressed genes (DEGs) between control and IgAN were predominantly enriched in NK cell-mediated cytotoxicity and cell killing pathways. Interestingly, we discovered that the number and cytotoxicity of NK cells are significantly reduced in IgAN patients, where both the number and marker genes of NK cells were negatively associated with the clinical parameters, including the levels of urine protein creatinine ratio (UPCR), serum galactose-deficient IgA1 and IgA. A distinctive B cell subset, which had suppressed NFκB signaling was predominantly in IgAN and positively associated with disease progression. Moreover, the DEGs of B cells were enriched in different viral infection pathways. Classical monocytes also significantly changed in IgAN and a monocyte subset expressing interferon-induced genes was positively associated with the clinical severity of IgAN. Finally, we identified vast dynamics in intercellular communications in IgAN.ConclusionsWe dissected the immune landscape of IgAN at the single-cell resolution, which provides new insights in developing novel biomarkers and immunotherapy against glomerulonephritis.

Transmembrane signaling molecules play a key role in the pathogenesis of IgA nephropathy: a weighted gene co-expression network analysis study

BackgroundImmunoglobulin A nephropathy (IgAN) is one of the most common primary glomerulonephritis and a serious health concern worldwide; though still the underlying molecular mechanisms of IgAN are yet to be known and there is no efficient treatment for this disease. The main goal of this study was to explore the IgAN underlying pathogenic pathways, plus identifying the disease correlated modules and genes using the weighted gene co-expression network analysis (WGCNA) algorithm.ResultsGSE104948 dataset (the expression data from glomerular tissue of IgAN patients) was analyzed and the identified differentially expressed genes (DEGs) were introduced to the WGCNA algorithm for building co-expression modules. Genes were classified into six co-expression modules. Genes of the disease’s most correlated module were mainly enriched in the immune system, cell–cell communication and transmembrane cell signaling pathways. The PPI network was constructed by genes in all the modules and after hub-gene identification and validation steps, 11 genes, mostly transmembrane proteins (CD44, TLR1, TLR2, GNG11, CSF1R, TYROBP, ITGB2, PECAM1), as well as DNMT1, CYBB and PSMB9 were identified as potentially key players in the pathogenesis of IgAN. In the constructed regulatory network, hsa-miR-129-2-3p, hsa-miR-34a-5p and hsa-miR-27a-3p, as well as STAT3 were spotted as top molecules orchestrating the regulation of the hub genes.ConclusionsThe excavated hub genes from the hearts of co-expressed modules and the PPI network were mostly transmembrane signaling molecules. These genes and their upstream regulators could deepen our understanding of IgAN and be considered as potential targets for hindering its progression.

Identification of miRNA-mRNA network and immune-related gene signatures in IgA nephropathy by integrated bioinformatics analysis

BackgroundIgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, and its diagnosis depends mainly on renal biopsy. However, there is no specific treatment for IgAN. Moreover, its causes and underlying molecular events require further exploration.MethodsThe expression profiles of GSE64306 and GSE93798 were downloaded from the Gene Expression Omnibus (GEO) database and used to identify the differential expression of miRNAs and genes, respectively. The StarBase and TransmiR databases were employed to predict target genes and transcription factors of the differentially expressed miRNAs (DE-miRNAs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to predict biological functions. A comprehensive analysis of the miRNA-mRNA regulatory network was constructed, and protein–protein interaction (PPI) networks and hub genes were identified. CIBERSORT was used to examine the immune cells in IgAN, and correlation analyses were performed between the hub genes and infiltrating immune cells.ResultsFour downregulated miRNAs and 16 upregulated miRNAs were identified. Forty-five and twelve target genes were identified for the upregulated and downregulated DE-miRNAs, respectively. CDKN1A, CDC23, EGR1, HIF1A, and TRIM28 were the hub genes with the highest degrees of connectivity. CIBERSORT revealed increases in the numbers of activated NK cells, M1 and M2 macrophages, CD4 naive T cells, and regulatory T cells in IgAN. Additionally, HIF1A, CDC23, TRIM28, and CDKN1A in IgAN patients were associated with immune cell infiltration.ConclusionsA potential miRNA-mRNA regulatory network contributing to IgAN onset and progression was successfully established. The results of the present study may facilitate the diagnosis and treatment of IgAN by targeting established miRNA-mRNA interaction networks. Infiltrating immune cells may play significant roles in IgAN pathogenesis. Future studies on these immune cells may help guide immunotherapy for IgAN patients.

The relationship between glomerular IgG staining and poor prognostic findings in patients with IgA nephropathy: the data from TSN-GOLD working group

BackgroundGalactose-deficient IgA1 (Gd-IgA1) has an increased tendency to form immunocomplexes with IgG in the serum, contributing to IgAN pathogenesis by accumulating in the glomerular mesangium. Several studies showed that glomerular IgG deposition in IgAN is an important cause of mesangial proliferation and glomerular damage. This study aims to determine the association of the positivity of IgG and the intensity of IgG staining with a poor renal prognosis.MethodsA total of 943 IgAN patients were included in the study. Glomerular IgG staining negative and positive patients were compared using Oxford classification scores, histopathological evaluations, proteinuria, eGFR, albumin, blood pressures. IgG positive patients were classified as (+), (++), (+++) based on their staining intensity, and the association with the prognostic criteria was also evaluated.Results81% (n = 764) of the patients were detected as IgG negative, while 19% (n = 179) were positive. Age, gender, body mass index, blood pressure, proteinuria, eGFR, uric acid values were similar in IgG positive and negative patients who underwent biopsy (p > 0.05). Intensity of glomerular IgG positivity was not found to be associated with diastolic and systolic blood pressure, urea, uric acid, age, eGFR, albumin, proteinuria (p > 0.05 for all, r = − 0.084, r = − 0.102, r = − 0.006, r = 0.062, r = 0.014, r = − 0.044, r = − 0.061, r = − 0.066, r = 0.150, respectively). There was no difference for histopathological findings between IgG (+), IgG (++), IgG (+++) groups (for all, p > 0.05).ConclusionGlomerular IgG negativity and positivity detected by routine IFM in IgAN patients is not associated with poor renal prognostic risk factors.

Differential Cell Cycle and Kinase Activation in IgA1-Producing Cells from IgAN Patients and Healthy Controls Mediated by Cytokine Stimulation

Differential Cell Cycle and Kinase Activation in IgA1-Producing Cells from IgAN Patients and Healthy Controls Mediated by Cytokine Stimulation

Traditional Chinese Medicine in Treating IgA Nephropathy: From Basic Science to Clinical Research.

IgA nephropathy (IgAN) is a major cause of chronic kidney disease (CKD) and end-stage renal disease worldwide. Currently, clinical interventions for IgAN are limited, and many patients seek out alternative therapies such as traditional Chinese medicine (TCM). In the last several years, TCM has accumulated ample application experiences and achieved favorable clinical effects. This article summarizes high-quality research from basic science to clinical applications aimed to provide more evidence-based medicine proof for the clinical treatment of IgAN. In summary, qi and yin deficiency accounted for the largest proportion in IgAN patients, and the treatment of IgAN should be based on supplementing qi and nourishing yin. Further, for patients with severe IgAN, the treatment combination of Chinese and Western medicines is better than pure Chinese medicine or hormone therapy. In addition, the pharmacological mechanism of Chinese herbal medicines is mostly based on restoring the immune function, relieving the inflammation damage, and inhibiting proliferation of the glomerular mesangial cells.

Serum complement factor B is associated with disease activity and progression of idiopathic membranous nephropathy concomitant with IgA nephropathy.

Few studies have reported the roles of the complement system in concomitant idiopathic membranous nephropathy and IgA nephropathy (IMN-IgAN). Complement factor B (CFB) is a crucial factor that involved in the alternative complement pathway. We aimed to evaluate the association between disease activity (eGFR, anti-PLA2R antibody levels and 24h urinary protein excretion), progression and serum CFB levels of IMN-IgAN patients. In total, 39 IMN-IgAN patients (median follow-up, 46.6months), 99 IMN patients and 92 IgAN patients participated in this study. The disease progression event was defined as end-stage renal disease (ESRD) or a 30% decline in estimated glomerular filtration rate (eGFR). The serum CFB concentration was measured by enzyme-linked immunosorbent assay. Serum CFB levels were lower in IMN-IgAN patients than in patients with IgAN only (P < .001). Serum CFB levels correlated positively with serum creatinine levels, anti-PLA2R antibody levels and 24h urinary protein excretion (P < .05). Kaplan-Meier analysis revealed that IMN-IgAN patients with high serum CFB levels had a significantly lower cumulative renal survival rate than patients with low levels (log-rank test, P = .009). Multivariate Cox regression analysis showed that high baseline serum CFB levels were significantly associated with poor renal outcome in patients with IMN-IgAN (HR: 2.727, 95% CI 1.076-6.913, P = .034). High serum CFB levels correlated with increased serum creatinine, anti-PLA2R antibody and urinary protein excretion as well as poor renal prognosis in patients with IMN-IgAN, indicating that serum CFB may be a marker of disease activity and progression.

Epidemiology and risk factors for progression in Chinese patients with IgA nephropathy

BackgroundIgA nephropathy (IgAN) is one of the main causes of primary glomerulonephritis worldwide, and it is also the main primary disease leading to chronic kidney disease. The purpose of this study is to evaluate the epidemiology and risk factors for progression in Chinese patients with IgAN. MethodsIn this retrospective study, 246 patients with renal biopsy-proven IgAN were enrolled from January 2012 to June 2018. The patients’ data were divided into two groups according to eGFR at the end of follow-up: a high-eGFR group (eGFR≥60ml/min) and a low-eGFR group (eGFR<60ml/min). ResultsAt the end of the study, we identified 49 (19.92%) patients with low-eGFR from 246 IgAN patients. Renal function, represented by serum creatinine, urea nitrogen and cystatin-C, was significantly decreased in the low-eGFR group (P<0.001 for all) at the time of renal biopsy. Compared with the high-eGFR group, the age, mean arterial blood pressure (MAP), proteinuria, cholesterol, triglycerides and serum uric acid were significantly higher (P<0.05 for all). According to the Oxford evaluation, the proportion of S1-2 (59.2%) and T1-2 (65.3%) was significantly increased (P<0.001 for both) and the proportion that had a MEST-C score ≥3 was statistically increased in the low-eGFR group (83.7%, P=0.001). ConclusionsMale, MAP, haematuria, Scr, cholesterol, hemoglobin, Lee classification more than 3 and C1-2 are independent risk factors for low-eGFR in Chinese IgAN patients.

The predictive value of Oxford MEST-C classification to immunosuppressive therapy of IgA nephropathy.

To analyze the efficacy of immunosuppressive therapy in IgA nephropathy and investigate the value of all clinicopathologic indicators. One hundred and one eligible IgA nephropathy patients were retrospectively studied. All the patients received immunosuppressive treatment and were then grouped according to the treatment outcome. The endpoint was a composite outcome (halving eGFR, end-stage renal disease (ESRD) or death due to kidney disease). The outcomes of immunosuppressive therapy were evaluated, and the factors influencing the outcomes of immunosuppressive therapy were analyzed by logistics regression. The independent significance of clinicopathologic indicators on renal outcome was then analyzed by multivariable Cox regression. Multivariate logistic regression analysis showed that S1 and M1 were the risk factors for the immunosuppressive treatment effect in IgAN patients, and eGFR was the protective factor for the immunosuppressive treatment effect in IgAN patients. Kaplan-Meier analysis revealed that outcomes of immunosuppressive therapy were significantly associated with poor renal outcomes. Multiple Cox regression analysis further confirmed that M1, T2, and the initial level of eGFR were independent predictive factors for poor renal outcomes. M, S scores and initial eGFR are independent predictors of outcomes of immunosuppressive therapy. Only M, T scores can effectively predict poor renal outcomes after immunosuppressive therapy. Nonetheless, stable eGFR and low proteinuria can protect renal outcomes.

Lipidomics reveals association of circulating lipids with body mass index and outcomes in IgA nephropathy patients.

IgA nephropathy (IgAN) is a leading cause of chronic kidney disease (CKD), which are commonly accompanied by dyslipidemia. Obesity is also associated with dyslipidemia and risk of CKD, but the relation of the dyslipidemia patterns with obesity and disease progression in IgAN patients remains unknown. Traditional Chinese medicine (TCM) and the combined treatment with corticosteroids and TCM have been shown to be of benefit for IgAN patients, but predictive markers for guiding these treatments are lacking. Here, we quantified 545 lipid species in the plasma from 196 participants, including 140 IgAN patients and 56 healthy volunteers, and revealed an altered plasma lipidome in IgAN patients as compared to healthy participants. Association analysis showed that a subgroup of glycerides, particularly triacylglycerols (TGs) containing docosahexaenoic acid, were positively associated with high body mass index (BMI) in under- or normal-weight IgAN patients, while several free fatty acids and sphingomyelins were positively associated with high BMI in overweight or obese IgAN patients. Further, our study suggested that elevated levels of eight lipids, mainly TG species containing linolenic acid, were independent risk factors for IgAN progression and also reported the prospective association of circulating lipids with treatment outcomes in IgAN. Taken together, our findings may not only help to achieve precision medicine but also provide a knowledge base for dietary intervention in the treatment of IgAN.

Positive renal familial history in IgA nephropathy is associated with worse renal outcomes: a single-center longitudinal study

BackgroundIgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Although most IgAN cases are sporadic, few show a familial aggregation. However, the prevalence and prognosis of IgAN individuals with positive familial history (FH) of renal disorders remains uncertain. To address these issues, we conducted a longitudinal observational study on a single-institution cohort of patients with biopsy-proven IgAN.MethodsA total of 467 IgAN patients who underwent renal biopsy during 1994 to 2019 were ascertained to have positive- or negative-FH by history taking and were followed for an average of 8.9 years. We compared the clinical and pathological features of the two subgroups. The primary outcome, a composite of a hard endpoint (end-stage renal disease [ESRD]) and surrogate endpoint (a 50% or more reduction in the estimated glomerular filtration rate [eGFR] from baseline), was evaluated. To estimate the risk for progression to ESRD, a Cox proportional hazards analysis was performed for a subset of patients who underwent follow-up for > 2 years and had an eGFR > 30 mL/min/1.73 m2 at baseline (n = 389; observation, 8.7 years).ResultsPositive-FH subtype accounted for 11.6% (n = 54) of all IgAN patients. At baseline, there were no significant differences between the positive- and negative-FH subgroups regarding age, sex, comorbid disease, MEST-C score, observation period, and therapeutic interventions. However, the eGFR value at baselines was significantly lower in the positive-FH subgroup than in the negative-FH subgroup (P < 0.01). On multivariate analysis, positive-FH emerged an independent determinant of poorer renal outcomes (odds ratio, 2.31; 95% confidence interval, 1.10–4.85; P = 0.03), after adjusting for confounding factors. eGFR at follow-up was significantly lower in the positive-FH subgroup than in the negative-FH subgroup after adjustment for age and observation period.ConclusionsPositive-FH was found in 11.6% of all IgAN patients, consistent with the incidence seen in previous literature. A significantly lower eGFR at baseline and last follow-up and unfavorable renal outcomes in the positive-FH subgroup suggest that certain genetic risk factors predisposing to renal failure may exist in a fraction of our IgAN cohort. (331 words).

Precision medicine in immunoglobulin Anephropathy: still a journey ahead.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease worldwide and since its first description extensive research has identified a number of key central pathogenetic contributors, including genetic, immunological and environmental factors. Along with its multifaceted pathophysiology, the clinical presentation of IgAN varies, ranging from mild forms with only minor urinary findings and preserved renal function to cases that rapidly progress to end-stage renal disease. Because of this, early identification of patients at risk for a progressive course is urgently needed. The search for valid and easily accessible biomarkers showed urinary Dickkopf-3 as a promising candidate to predict the course of kidney function. In addition, a recently established IgAN risk prediction tool derived from an international cohort of IgAN patients allows estimation of the risk of a 50% loss of kidney function over several years upon diagnosis. This might serve as a significant tool to individually predict the course of renal function by combining biometric, clinical, histological and treatment information at the time of diagnosis. Today there is no doubt that a comprehensive supportive treatment regimen is the main pillar for all IgAN patients. The value of an additional immunosuppressive treatment in IgAN patients at risk for disease progression is less clear. Early risk stratification and individualized therapies would be desirable for IgAN patients to facilitate the choice of treatment strategies, which is still a matter of ongoing discussion.

The Role of Renal Macrophage, AIM, and TGF-β1 Expression in Renal Fibrosis Progression in IgAN Patients.

ObjectiveTo analyze the expression of macrophages, AIM, TGF-β1 in the kidney of IgAN patients, and to explore the role of macrophages, AIM, TGF-β1 in the progression of renal fibrosis in IgAN patients.MethodsThe paraffin specimens of renal tissue from 40 IgAN patients were selected as the observation group. At the same time, paraffin specimens of normal renal tissue from 11 patients treated by nephrectomy were selected as the normal control group. We observed the distribution of macrophages, the expression of AIM and TGF-β1 by immunohistochemical staining and/or immunofluorescence.ResultThe number of M0, M1, M2 macrophages could be found increased in IgAN patients. M0 macrophages are mainly polarized towards M2 macrophages. The expression of AIM and TGF-β1 were significantly higher in IgAN patients than in NC. M2 macrophage, AIM and TGF-β1 were positively correlated with serum creatinine and 24-hour proteinuria, but negatively correlated with eGFR. M2 macrophages, AIM, TGF-β1 were positively correlated with fibrotic area.ConclusionM2 macrophages, AIM and TGF-β1 play important roles in the process of IgAN fibrosis, and the three influence each other.

Reduced fecal short-chain fatty acids levels and the relationship with gut microbiota in IgA nephropathy

BackgroundIgA nephropathy(IgAN)) is the common pathological type of glomerular diseases. The role of gut microbiota in mediating “gut-IgA nephropathy” has not received sufficient attention in the previous studies. The purpose of this study was to investigate the changes of fecal short-chain fatty acids(SCFAs), a metabolite of the intestinal microbiota, in patients with IgAN and its correlation with intestinal flora and clinical indicators, and to further investigate the role of the gut-renal axis in IgAN.MethodsThere were 29 patients with IgAN and 29 normal control subjects recruited from January 2018 to May 2018. The fresh feces were collected. The fecal SCFAs were measured by gas chromatography/mass spectrometry and gut microbiota was analysed by16S rDNA sequences, followed by estimation of α- and β-diversity. Correlation analysis was performed using the spearman’s correlation test between SCFAs and gut microbiota.ResultsThe levels of acetic acid, propionic acid, butyric acid, isobutyric acid and caproic acid in the IgAN patients were significantly reduced compared with control group(P < 0.05). Butyric acid(r=-0.336, P = 0.010) and isobutyric acid(r=-0.298, P = 0.022) were negatively correlated with urea acid; butyric acid(r=-0.316, P = 0.016) was negatively correlated with urea nitrogen; caproic acid(r=-0.415,P = 0.025) showed negative correlation with 24-h urine protein level.Exemplified by the results of α-diversity and β-diversity, the intestinal flora of IgAN patients was significantly different from that of the control group. Acetic acid was positively associated with c_Clostridia(r = 0.357, P = 0.008), o_Clostridiales(r = 0.357, P = 0.008) and g_Eubacterium_coprostanoligenes_group(r = 0.283, P = 0.036). Butyric acid was positively associated with g_Alistipes (r = 0.278, P = 0.040). The relative abundance of those were significantly decreased in IgAN group compared to control group.ConclusionsThe levels of fecal SCFAs in the IgAN patients were reduced, and correlated with clinical parameters and gut microbiota, which may be involved in the pathogenesis of IgAN, and this finding may provide a new therapeutic approach.

MO246ESTIMATING DELAY IN TIME TO ESKD FOR TREATMENT EFFECTS ON PROTEINURIA IN IGA NEPHROPATHY AND FSGS*

Abstract Background and Aims Reduction in proteinuria is associated with lower risk of end-stage kidney disease (ESKD) in IgA nephropathy (Thompson et al, 2019) and focal segmental glomerulosclerosis (FSGS) (Troost et al, 2017). Sparsentan, a dual endothelin receptor and angiotensin II receptor antagonist, is in phase 3 clinical trials in IgA nephropathy (PROTECT) and FSGS (DUPLEX), that are powered to detect a treatment benefit on proteinuria-based endpoints versus standard of care angiotensin receptor blockade (irbesartan). In this study, we aim to estimate the delay in time to ESKD conferred by the hypothesized treatment effect of sparsentan on proteinuria in these phase 3 trials; for PROTECT, a 30% reduction in urine protein to creatine ratio (UP/C) vs irbesartan in IgA nephropathy patients, and for DUPLEX, 30% more patients achieving the new FSGS Partial Remission Endpoint (UP/C &amp;lt;1.5 g/g associated with a 40% reduction in UP/C) versus irbesartan. Methods We analysed individual patient level data from two UK registries: the first is provided by Leicester General Hospital, UK and consists of IgAN patients, and the second is the UK National Registry of Rare Kidney Disease (RaDaR) Nephrotic Syndrome cohort, with access provided by the University of Bristol, UK, including FSGS patients. IgAN patients with urine total protein value ≥1.0 g/day or UP/C ≥1.0 g/g and eGFR &amp;gt;30 mL/min at the initiation of renin-angiotensin system blockade (RASB) were identified, as were patients with primary or genetic FSGS with UP/C ≥1.5 g/g and eGFR ≥30 mL/min. The time to ESKD (eGFR &amp;lt;15 mL/min, initiation of dialysis, transplantation) or death from any cause over the patient follow-up period was analysed using accelerated failure time modelling; Weibull, Log Logistic and Log Normal distributions were applied with the fitted survivor function reported from the model with the lowest AIC. The time gained for a given reduction in risk in ESKD/death and 5-year survival was estimated under proportional hazards. Results A 30% reduction in proteinuria in IgAN patients confers a 50% lower risk of ESKD, extending the median time to ESKD by 10.7 years, from 12.4 to 23.1 years; 5-year ESKD free survival rate is also increased, from 77.7% to 88.1%. Similarly, ongoing analysis in FSGS patients indicates 30% more patients achieving the FSGS Partial Remission Endpoint confers lower risk for ESKD and increase in 5-year ESKD free survival. Conclusion The data from the Leicester General Hospital, UK and RaDaR provide invaluable insight into the longer-term natural history of IgAN and FSGS patients and time to ESKD. Therapeutic interventions that reduce proteinuria and the risk of ESKD can confer important and clinically meaningful extensions in the time patients are alive and free from ESKD.

MO286DESIGN OF A PH1, MULTICENTER TRIAL TO INVESTIGATE THE SAFETY, TOLERABILITY, PK/PD OF BION-1301 IN HEALTHY VOLUNTEERS AND ADULTS WITH IGAN AND A MULTICENTER, OPEN-LABEL EXTENSION STUDY FOR IGAN PATIENTS WHO PARTICIPATED IN A PRIOR TRIAL OF BION-1301

Abstract Background and Aims IgA nephropathy (IgAN), the leading cause of primary glomerulonephritis, is an autoimmune disease with no approved treatments.1 Progression to end-stage-renal disease occurs in up to 45% of IgAN patients, requiring dialysis or kidney transplant to manage.2-4 A critical step in IgAN pathogenesis is the production of galactose-deficient IgA1 (Gd-IgA1) leading to the generation of anti-Gd-IgA autoantibodies and the formation of immune complexes that result in kidney inflammation and damage.5 A Proliferation-Inducing Ligand (APRIL), a soluble factor that regulates B cell differentiation, proliferation and survival of plasma cells, and IgA class-switching is elevated in patients with IgAN6, 7. IgAN patients with high plasma APRIL levels are reported as having higher levels of Gd-IgA1 and proteinuria and lower estimated glomerular filtration rates compared to those with lower plasma APRIL levels.7 BION-1301 is a novel humanized blocking antibody targeting APRIL. The primary objective of Study ADU-CL-19 is to assess the short-term safety and tolerability of BION-1301 in Healthy Volunteers (HV) and IgAN patients and to secondarily assess the short-term pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary clinical activity of BION-1301. The primary objective of Study ADU-CL-24 is to characterize the long-term safety of BION-1301 in IgAN patients who completed treatment in ADU-CL-19 while secondarily assessing the long-term PK, PD, immunogenicity, and preliminary clinical activity of BION-1301. Method The Phase 1 study (ADU-CL-19; NCT03945318) comprises 3 parts. Parts 1 and 2 are double-blind, randomized, placebo-controlled single and multiple ascending dose designs in HV; both parts have been completed. Part 3 is an ongoing multicenter (US and UK), multiple-dose, two cohort design in approximately 20 patients with IgAN (10/cohort). Key eligibility criteria for Part 3 includes: (1) urine protein ≥0.5 g/24h or baseline UPCR ≥0.5 g/g, (2) stable/optimized dose of ACE-I/ARB or intolerant to ACE-I/ARB, and (3) biopsy-verified diagnosis of IgAN within the past 10 years. In Part 3, patients in Cohort 1 are receiving BION-1301 at 450mg every 2 weeks for 3 months. The dose and schedule for Cohort 2 will be determined by the Safety Review Team (SRT) based on data from the first 5 patients. After 3 months of treatment, patients continue safety follow-up for approximately 6 months unless deciding to enroll in the open-label extension (OLE) study, withdraw from the study, or are lost to follow up. Study ADU-CL-24 (NCT04684745) is a Phase 2 Open-Label Extension (OLE) of Study ADU-CL-19. Eligibility for the OLE study is restricted to those patients who completed at least 75% of their intended doses as well as the End of Treatment (EOT) visit in Study ADU-CL-19. Patients who enroll directly from the ADU-CL-19 EOT visit are not required to attend an additional screening visit. This is encouraged to maintain un-interrupted dosing. Once enrolled in the OLE, patients receive BION-1301 at the same dose and regimen as assigned in the parent study for up to 2 years. The dose, route, and regimen of BION-1301 may change after review of emergent safety, PK, PD and efficacy data by the SRT. Results Parts 1 and 2 of the Phase 1 study in HV are complete and the data were presented at ASN in 20208 Part 3 of the Phase 1 and the Phase 2 OLE study are ongoing, and interim results from the first dose cohort in IgAN patients are being presented in a separate poster at this meeting. Conclusion The design of the Phase 1 and Phase 2 OLE studies described in HVs and IgAN patients have enabled the generation of short- and long-term safety, PK, PD, immunogenicity and preliminary efficacy data for BION-1301. The Phase 1 short-term data will guide the design of future later-stage trials of BION-1301, while the long-term data from OLE will enable a greater understanding of the potential long-term risk/benefit profile of BION-1301 in IgAN patients.

MO276TOTAL AND SPECIFIC IGE IN PATIENTS WITH IGA NEPHROPATHY

Abstract Background and Aims IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis characterized by impaired immunological tolerance. One of possible trigger factors for IgAN initiation and development are allergens which have been described to form IgA complexes deposited in the mesangium. Previous studies reported that serum immunoglobulin class E (IgE) levels are elevated and suggested as a prognostic indicator in glomerular diseases. However, mechanisms of IgE/IgG4-mediated allergic reactions involvement in IgAN as well as specific allergens and their clinical significance have poorly been investigated. The aim of the study was to assess the total serum IgE and IgG4 level and to determine the allergoprofile in IgAN patients. Method The peripheral blood was obtained from 21 IgAN patients (aged of 32.0 (27.0 ÷ 36.0) y.o., male/female ratio as 14/7) and 18 donors (aged of 38.0 (30.0 ÷ 46.0) y.o., male/female ratio as 10/8). IgAN diagnosis was confirmed in patients’ biopsy materials according to the Oxford classification (MEST-C score). The concentrations of total IgE and IgG4 were determined using «IgE total-ELISA-BEST» kit («Vector-Best», RF) and «Human IgG4 Platinum ELISA» kit («eBioscience», Austria)». Allergen-specific IgE to 55 inhalation (domestic, epidermal, fungal, plant) or food allergens were measured using «EUROLINE Atopy Screen IgE» immunoblot kit («Euroimmun», Germany). Statistical analysis was done in Statistica 8.0. Results The increased level of total IgE (in 47,4% of cases) but not IgG4 was established in sera of IgAN patients as compared to donors (p=0.004). Moreover, proteinuria was lower in IgAN patients with a high IgE level as compared to normal one (610 (220 ÷ 910) mg/day vs 1545 (600 ÷ 2200) mg/day, p=0.01) as well as there were no any crescent formation. The investigation of allergen-specific IgE in IgAN patients revealed a strong positive reaction to dust mite allergens of Dermatophagoides pter. (22,75 (16,72 ÷ 35,69) IU/ml – in 29% of cases) and Dermatophagoides farinae (38,24 (12,19 ÷ 65,88) IU/ml – in 43% of cases) correlated with the total IgE (R=0,57, p=0,03) and IgM (R=0,54, p=0,04). The more concentration of specific IgE to dust mite allergens was the lower the severity of segmental glomerulosclerosis (R= -0.55, p=0.04), crescent formation (R= -0.56, p=0.03), proteinuria (R= -0.65, p=0.01) and haematuria (R = -0.55, p = 0.04) were reported. A weak positive reaction was established to other domestic (house dust, honey bee venom, common wasp venom, cockroach), epidermal (cat), plant (sweet vernal grass, orchard grass, timothy grass, cultivated rye, alder, birch, hazel, oak, common ragweed, mugwort, plantain) and food (carrot, sesame, hazelnut, apple) allergens in 9–18% of IgAN patients. Conclusion The prevailing of specific IgE to dust mite allergens of Dermatophagoides pter. and Dermatophagoides farinae but not to food or plant allergens was determined in IgAN patients. The obtained data demonstrated that IgAN pathogenesis in patients with latent sensibilization to dust mite allergens is characterized by a milder disease course what allows to identify this cohort as possible secondary form of IgAN.

FC 040INTERIM RESULTS OF PHASE 1 AND 2 TRIALS TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND CLINICAL ACTIVITY OF BION-1301 IN PATIENTS WITH IGA NEPHROPATHY

Abstract Background and Aims IgA nephropathy (IgAN), the leading cause of primary glomerulonephritis, is an autoimmune disease with no approved treatments.1 Progression to end-stage-renal disease occurs in up to 45% of IgAN patients, requiring dialysis or kidney transplant to manage.2-4 A critical step in IgAN pathogenesis is the production of galactose-deficient IgA1 (Gd-IgA1) leading to the generation of anti-Gd-IgA1 autoantibodies and the formation of immune complexes that result in kidney inflammation and damage.5 A Proliferation-Inducing Ligand (APRIL), a soluble factor that regulates B cell differentiation, proliferation and survival of plasma cells, and IgA class-switching is elevated in patients with IgAN6, 7. IgAN patients with high plasma APRIL levels are reported as having higher levels of Gd-IgA1 and proteinuria and lower estimated glomerular filtration rates compared to those with lower plasma APRIL levels.7 BION-1301 is a novel humanized blocking antibody targeting APRIL that has been evaluated in a Phase 1 study of healthy volunteers (HV). In Parts 1 and 2 of the Phase 1 study in HV, we previously reported that BION-1301 was well-tolerated with no serious adverse events (SAEs), a pharmacokinetic (PK) half life &amp;gt;30 days and demonstrated dose-dependent pharmacodynamic (PD) effects characterized by durable reductions in serum levels of free April (fAPRIL), IgA and Gd-IgA1, IgM, and to a lesser extent IgG8. Here we present interim results from Part 3 of the Phase 1 and the Phase 2 Open-Label Extension (OLE) trials that characterize the safety, PK and PD profile, and preliminary efficacy of BION-1301 in patients with IgAN. Method The Phase 1 study (NCT03945318) comprises 3 parts. Parts 1 and 2 assessed single- and multiple ascending doses of BION-1301 in HV from 10mg to 1350mg and 50mg to 450mg once every 2 weeks for one month, respectively. Part 3 is an ongoing, open-label, two cohort design in approximately 20 IgAN patients with BION-1301 at a starting dose and regimen of 450mg once every 2 weeks for a total of 3 months. Key eligibility criteria for Part 3 include: (1) urine protein ≥0.5 g/24h or baseline UPCR ≥0.5 g/g, (2) stable/optimized dose of ACE-I/ARB or be intolerant to ACE-I/ARB, and (3) biopsy-verified diagnosis of IgAN within the past 10 years. Patients completing Part 3 are eligible to enroll in the Phase 2 OLE study (NCT04684745) to receive BION-1301 for up to an additional 2 years. To evaluate PK and PD effects of BION-1301, serum levels of BION-1301, free APRIL (fAPRIL), anti-drug antibodies (ADA), neutralizing antibodies (NAbs), and Gd-IgA1 were quantitated using ELISA-based immunoassays. Serum levels of IgA, IgG, and IgM were measured by immunoturbidimetry. UPCR was assessed from 24-hour urine collections. Results In Part 3 of Phase 1 and the Phase 2 OLE trial to date, BION-1301 has been well tolerated in IgAN patients receiving a 450mg dose every two weeks for 12+ weeks with no SAEs observed. Consistent with PD responses previously reported in HVs, durable reductions in serum levels of fAPRIL and immunoglobulins were also observed in IgAN patients. Clinically meaningful reductions in proteinuria were observed as early as 12 weeks and were associated with the reduction in IgA. Additional data from patients receiving long-term treatment will be updated. Conclusion BION-1301 is a novel humanized anti-APRIL monoclonal antibody being developed as a potential treatment for patients with IgAN. BION-1301 offers disease modifying potential by directly targeting the underlying multi-hit immune pathogenesis of IgAN, which is not addressed with the current standard of care treatment. Promising early biomarker and clinical activity responses support the continued development of BION-1301 in IgAN.

MO230A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY OF ATRASENTAN IN PATIENTS WITH IGA NEPHROPATHY (THE ALIGN STUDY)

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis globally and an important cause of chronic kidney disease (CKD). Up to 40% of IgAN patients are at risk of progressing to end-stage kidney disease (ESKD) and proteinuria is the strongest predictor of progression. There are no approved therapies for IgAN, leaving an important need for new strategies to lower proteinuria and preserve kidney function in high-risk patients. Endothelin A (ETA) receptor activation drives proteinuria, along with kidney inflammation and fibrosis. Atrasentan, a potent and selective ETA antagonist, has been studied extensively in &amp;gt;5,000 patients with type 2 diabetes and kidney disease (DKD), demonstrating clinically significant and sustained reductions in proteinuria when administered on top of a maximum tolerated dose of RAS inhibitor (RASi). In a global Phase 3 outcome study in DKD (SONAR), atrasentan demonstrated a 35% reduced risk of the primary composite outcome of doubling of serum creatinine or end stage kidney disease (95% CI: 0.49, 0.88; P = 0.005). The most common adverse event was fluid retention. Selective ETA blockade represents a promising approach to reduce proteinuria and preserve kidney function in high risk IgAN patients. This is a presentation of a global, phase 3, double-blind, placebo-controlled trial to determine the effect of atrasentan in IgAN patients at high risk of kidney function loss. Method Approximately 320 patients across North America, South America, Europe, and Asia-Pacific with biopsy-proven IgAN will be randomized to receive 0.75 mg atrasentan or placebo daily for 132 weeks. Patients will continue receiving a maximally tolerated and stable dose of a RAS inhibitor as standard of care. The study will also include patients that are unable to tolerate RAS inhibitor therapy. Additional eligibility criteria include urine protein creatinine ratio (UPCR) ≥1 g/g and eGFR ≥30 mL/min/1.73 m2. Participants will have study assessments over two and a half years with options for remote study visits using telemedicine and home health visits. The primary objective is to evaluate the effect of atrasentan versus placebo on proteinuria at Week 24. Secondary objectives include evaluating the change from baseline in eGFR, safety, and tolerability, and quality of life. Results N/A Conclusion N/A

MO148A MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, PARALLEL GROUP, PHASE III STUDY TO EVALUATE THE EFFICACY AND SAFETY OF LNP023 IN PRIMARY IGA NEPHROPATHY PATIENTS

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is an autoimmune disease characterized by deposits of IgA1-containing immune complexes in the glomerular mesangium leading to local inflammation and subsequent decline in kidney function. Currently, there are no targeted therapies for IgAN. The KDIGO guidelines (2012) recommend optimized long-term supportive care including inhibition of the RAS (ACEi or ARB) as well as lifestyle modification for blood pressure control and proteinuria reduction. Patients who remain at high risk of progressive CKD despite maximal supportive care might be considered for high-dose corticosteroids or immunosuppressants. In recent years, mounting evidence has supported an important role for complement activation in disease onset and progression of IgAN. The alternative complement pathway (AP) and lectin complement pathway (LP) are found to be activated in 75-90% and 17-25% of IgAN patients, respectively (Floege et al 2014, Maillard et al 2015). Factor B (FB) is an essential component of C3- and C5-convertases. Iptacopan (LNP023) is an oral, first-in-class, highly potent selective inhibitor of FB and thereby blocks the activity of AP C3 and C5 convertases, inhibiting the AP as well as the amplification of the classic and lectin complement pathways. Currently, iptacopan is being evaluated in an ongoing adaptive seamless double-blind and placebo-controlled dose-ranging Phase 2 study (CLNP023X2203, Part 1 and Part 2) in patients with biopsy-confirmed IgAN and elevated proteinuria [urine protein to creatinine ratio (UPCR) ≥ 0.75 g/g]. An interim analysis (IA) at 90 days of treatment in the Part 1 study showed that iptacopan administered up to 200 mg b.i.d for 90 days was safe, well tolerated and may be effective in reducing proteinuria. A further IA combining participants in Part 1 and Part 2 will be completed in early 2021 and the pivotal phase 3 trial is to start in early 2021. Aim APPLAUSE-IgAN (NCT04578834; CLNP023A2301) is a multicenter, randomized, double-blind, placebo-controlled parallel-group Phase 3 study which aims to evaluate the efficacy and safety of iptacopan (LNP023) compared with placebo in addition to supportive therapy on proteinuria reduction and slowing kidney disease progression in primary IgAN patients. Method Adult patients diagnosed with primary IgAN (based on kidney biopsy and elevated proteinuria [UPCR ≥ 1 g/day]) will be recruited. A run-in period will ensure that patients have received ACEi/ARB at a maximally tolerated dose for at least 90 days and receive required vaccinations at least 2 weeks prior to first dosing. Patients will be randomized in a 1:1 ratio to either iptacopan 200 mg b.i.d or matching placebo for a 24-month treatment period. The trial will enroll approximately 450 participants, aiming for 430 with eGFR ≥30 mL /min/1.73m2 (main study population). About 20 participants with eGFR 20 to &amp;lt;30 mL/min/1.73m2 (severe renal impairment population) will also be enrolled to explore PK and safety of iptacopan in this group, but will not be included in the efficacy analyses. Primary objectives 1) At IA (when approximately 250 patients have completed the 9 months visit): To demonstrate superiority of iptacopan vs. placebo in the reduction of proteinuria. The IA results may be submitted to support accelerated/conditional approval. 2) At final analysis (when approximately 430 patients have completed 24 months of active treatment): to demonstrate superiority of iptacopan vs. placebo in slowing kidney disease progression measured by the annualized total slope of eGFR decline over 24 months. Results Recruitment will start in Q1 2021. Conclusion This trial will evaluate the efficacy of iptacopan, a promising new therapy for IgAN, in reducing proteinuria and slowing loss of kidney function over 2 years.