IgA Nephropathy Research Articles

#2365 Spectrum and prevalence of renal pathologies: a retrospective analysis of biopsy data from a tertiary care center in India

Abstract Background and Aims Renal biopsy remains a cornerstone in diagnosing various nephropathies, providing vital insights into disease etiology and guiding therapeutic strategies. In India, where the burden of renal diseases is on the rise, characterizing the spectrum of renal pathologies through biopsy can significantly influence clinical outcomes. Despite increasing global data on kidney diseases, regional variations exist, and localized data from tertiary care centers in India are sparse. The primary objective of this study was to delineate the spectrum of renal diseases diagnosed via biopsy at a tertiary care center in New Delhi, India, over a seven-year period. Method This retrospective study analyzed records from a tertiary care center in New Delhi, India, from 2015 to 2022. Data were extracted from paper-based records and electronic medical records (EMR). The study included patients who underwent native kidney biopsy during this period. Graft biopsies and biopsies with inadequate samples were excluded. Biopsies were evaluated by nephropathologists, and diagnoses were categorized based on standardized criteria. Results Between 2015 and 2022, 1,174 renal biopsies were analyzed from patients aged 1.3 to 82 years, with an average age of 40.5 years, showing a male predominance (60%). Chronic Interstitial Nephritis was the most prevalent diagnosis at 14.58%, followed by Diffuse Global Glomerulosclerosis at 13.13%, and IgA Nephropathy at 12.77% (Table 1). In IgA Nephropathy patients (n = 141), the majority exhibited microhematuria (53.9%) and subnephrotic proteinuria (56.02%), while 24.82% presented with nephrotic range proteinuria. Lupus Nephritis was the most common secondary glomerular disease (6.34%). Within the Lupus Nephritis subgroup (n = 70), Class IV (34.29%) and Class V (24.28%) were the most observed classes, with a notable presence of combined Class III+V (10%) and Class IV+V (8.57%). Within the cohort, the most common primary glomerulonephritis diagnosed in the age group of 18-30 years was IgA Nephropathy. For the 30-60 years demographic, Membranous nephropathy was most frequently identified, while in those older than 60 years, Diabetic Glomerulosclerosis was predominant. In cases presenting with hematuria (n = 417), IgA Nephropathy was identified in 17.74%. Among those with rapidly progressive renal failure (n = 79), Pauci immune GN accounted for 46.83% of diagnoses, followed by IgA Nephropathy at 15.18%. For patients with nephrotic range proteinuria (n = 139), IgA Nephropathy, Membranous nephropathy, and FSGS were leading diagnoses, each accounting for 12.94%, 12.23%, and 12.23% respectively. Conclusion The analysis revealed IgA Nephropathy as the most common histopathological finding in renal biopsies. The primary indication for biopsy is nephrotic range proteinuria. In this category, IgA Nephropathy is also the most prevalent diagnosis. For patients with rapidly progressive renal failure, Pauci immune GN is the most frequent finding. Additionally, IgA Nephropathy is the leading cause in patients presenting with hematuria. Lupus Nephritis is the most common secondary glomerular disease with class IV being the most common biopsy finding. The study underscores the necessity for continued surveillance of renal pathology trends to inform healthcare strategies in India.

#1261 A small-molecule inhibitor of Bruton's tyrosine kinase reduces production of galactose-deficient IgA1 in IgA nephropathy

Abstract Background and Aims IgA nephropathy (IgAN) is a chronic kidney disease characterized by glomerular immunodeposits that contain aberrantly glycosylated IgA1, i.e., IgA1 with some hinge-region O-glycans deficient in galactose (galactose-deficient IgA1; Gd-IgA1). These immunodeposits originate from circulating immune complexes that contain Gd-IgA1 bound by IgG autoantibodies. Consistent with this hypothesis, serum levels of Gd-IgA1 and IgG autoantibodies independently predict disease progression in IgAN patients. Biochemical studies using IgA1-secreting cell lines derived from peripheral blood of IgAN patients and healthy controls have revealed that Gd-IgA1 production is driven by altered biosynthetic pathways of IgA1 O-glycans. Specifically, cell lines from IgAN patients have altered expression and activity of several glycosyltransferases, C1GalT1 and ST6GalNAc2, and a C1GalT1-specific chaperone, C1GalT1C1. Genetic studies have shown that serum levels of Gd-IgA1 are genetically co-determined and genome-wide association studies (GWAS) identified genetic variations that impact the expression C1GALT1 and C1GALT1C1 genes. Moreover, macroscopic hematuria during an upper-respiratory-tract infection is common at the clinical onset of IgAN and during episodes of accentuated disease activity, indicating a connection between IgAN and mucosal inflammation. Notably, a pro-inflammatory cytokine interleukin-6 (IL-6), enhances production of Gd-IgA1 exclusively in the cell lines derived from IgAN patients. Leukemia inhibitory factor (LIF) has similar effects. LIF-induced effects are mediated by abnormal STAT1 signaling and pathways that include Lyn, a Src-family kinase. The corresponding gene, LYN, was recently identified in one of the 16 new IgAN-associated GWAS loci. Lyn, together with spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk), is involved in B-cell-receptor (BCR)-signaling pathways that include activation and inhibitory signals. The aim of this study was to assess if Btk may be involved in Gd-IgA1 production in IgAN. Method IgA1-producing cell lines were cloned by limiting dilution of Epstein-Barr-virus-immortalized peripheral-blood B cells from patients with IgAN (n = 5) and healthy controls (n = 5). Cell signaling, induced by LIF or by BCR crosslinking with anti-IgA antibody, was assessed by flow cytometry or SDS-PAGE/immunoblotting using antibodies for specific phosphorylated sites of selected proteins. Data were normalized using antibodies for specific proteins. Total IgA and Gd-IgA1 were quantified in cell-culture medium using standard ELISA and lectin-ELISA, respectively. Gd-IgA1, normalized to IgA, was expressed in Units (U) of standard Gd-IgA1 protein. Results IgA1-producing cell lines from patients with IgAN and healthy controls secreted similar amounts of total IgA (17.2 ± 9.3 ug/ml vs. 14.6 ± 9.5 ug/ml), but the cells from IgAN patients secreted more Gd-IgA1 (24.2 ± 7.5 U vs. 15.5 ± 2.7 U; p < 0.05). Baseline phosphorylation of Btk (Y223), but not Syk (Y551), was higher in the cells from patients with IgAN than in those from healthy controls. We used an IgA1-secreting cell line from an IgAN patient to confirm that BCR crosslinking with F(ab’)2 anti-IgA antibody in IgA + CD19+ cells lines induced phosphorylation of Btk (Y223). Conversely, anti-IgM antibody, used as a negative control, did not activate Btk. LIF stimulation did not affect phosphorylation of Btk or Syk. A Btk inhibitor, PCI-32765 (ibrutinib), reduced Gd-IgA1 production in a dose-dependent fashion exclusively in the IgAN-derived cells. Notably, 1 uM PCI-32765 reduced Gd-IgA1 production to that for healthy controls (25.7 ± 1.2 U to 17.3 ± 1.8 U; p < 0.01). Conclusion Inhibition of Btk with a small-molecule inhibitor normalized Gd-IgA1 production in IgA1-secreting cells from patients with IgAN, revealing a previously unknown role of Btk in aberrant O-glycosylation of IgA1. Btk may thus represent a potential new target for disease-specific therapy of IgAN.

#2615 Altered peroxidasin expression pattern in IgA nephropathy

Abstract Background and Aims PXDN is a multifunctional heme peroxidase responsible for the crosslinking of type IV collagen protomers at basement membranes, playing a crucial role in the extracellular matrix dynamics. In renal pathophysiology, increased PXDN expression has been associated with pro-fibrotic and pro-carcinogenic mechanisms and we have shown that PXDN is expressed throughout all kidney compartments since the early stages of nephrogenesis. However, the role of PXDN in kidney health and disease remains largely unknown. In this work we performed a comparative analysis of PXDN expression between renal biopsy samples from IgA nephropathy (IgAN) patients and healthy kidney biopsy samples. IgAN was the selected CKD model due to its straightforward diagnosis by standard protocols for histopathological evaluation of kidney biopsies, and to the fact that the renal outcomes are consistently associated with several key pathologic features, including tubular atrophy and interstitial fibrosis. Correlations between PXDN expression and IgAN disease and kidney function parameters as well as with ECM proteins were also explored. Method Fluorescence immunohistochemistry for PXDN was performed in biopsy samples from IgAN patients (n = 20) and in biopsies from healthy kidney donors (n = 7). Proximal tubules were assessed by anti-CD15 fluorescent staining. Collagen III (COLIII) deposition was investigated in IgAN samples (n = 7) by immunofluorescence. Brightfield images were manually segmented into glomeruli, proximal and distal tubules, and interstitium, using QuPath software, and the fluorescence intensity measurements were obtained with ImageJ/Fiji. Results Results showed that, in comparison with healthy kidney samples, PXDN is significantly decreased in proximal and distal tubules of IgAN patients (P < 0.001 and P < 0.05, respectively) whereas it is increased in IgAN interstitium (P < 0.001). When IgAN samples were stratified by the presence or absence of chronic lesions (glomerular sclerosis and interstitial fibrosis) we observed that in the proximal tubules, PXDN is decreased even in areas without lesions while in the distal tubules the expression is compromised only in the lesioned areas. In the interstitium, PXDN shows a tendency of increase from healthy tissue to IgAN in areas without and with tubulointerstitial fibrosis, presenting a significant increase in the lesioned areas (P < 0.001). Concerning ECM deposition, results showed a significant correlation between the expression of PXDN and COLIII in sclerotic glomeruli (R = 0.8214; P = 0.0341) and in the tubulointerstitial fibrotic areas (R = 0.93; P = 0.0067). Moreover, although no differences were observed in the glomerular expression of PXDN between healthy and IgAN samples, when considering eGFR, a significant increase of PXDN was observed in both non-lesioned and sclerotic glomeruli from IgAN patients with eGFR bellow 60 ml/min/1,73 m2. In the interstitium, the expression of PXDN was also increased in tubulointerstitial fibrotic areas of IgAN patients with eGFR bellow 60 ml/min/1,73 m2, in comparison with the same areas in patients with higher eGFR values. Conclusions Overall, our study shows a differential expression of PXDN in IgAN, with loss in the tubular region that relates with the state of interstitial fibrosis, and gain in the glomerular and interstitial region where it correlates with COLIII compartment-specific deposition and with kidney function as assessed by eGFR. These data support, for the first time, the enrollment of PXDN in the topographic mechanism of IgA-mediated kidney lesion that deserves further investigations. Given that sclerosis and fibrosis are a common pathogenic mechanism of CKD, irrespective of the underlying etiology, we postulate that PXDN may serve as a novel therapeutic target for this disease.

#873 Membranous nephropathy has higher all-cause mortality rate in comparison to focal segmental glomerulosclerosis and IgA nephropathy: a long-term study

Abstract Background and Aims Membranous nephropathy, focal segmental glomerulosclerosis (FSGS) and IgA nephropathy are the most frequent types of primary glomerulonephrites in the adulthood. Glomerulonephritides may progress into end-stage renal disease despite appropriate treatment. Both the manifestations of the glomerulonephritides and medications for treatment might yield cardiovascular events such as venous thromboembolism, coronary artery disease and stroke. The purpose of this study is to compare three different types of primary glomerulonephritides in terms of all-cause mortality, kidney-related and cardiovascular outcomes. Method All patients who underwent kidney biopsy between 01.01.2000 and 01.06.2022 in Hacettepe University Hospital were screened and cases with primary glomerulonephritis and follow-up data were enrolled. Data regarding baseline demographics, laboratory and kidney pathology reports and outcomes were obtained. The primary end-point was defined as all-cause mortality. Kidney related and cardiovascular outcomes were determined as secondary end-points. Results population was 39 (18-81) years. Membranous nephropathy was present in 36.5% (n = 172), focal segmental glomerulosclerosis was present in 25.9% (n = 122) and IgA nephropathy was present in 37.6% (n = 177) of the cases. Age (p < 0.001), frequency of diabetes (p = 0.004) and smoking history (p = 0.020) were significantly higher in patients with membranous nephropathy than both FSGS and IgA nephropathy. Serum albumin levels were lower (p < 0.001), while total cholesterol (p < 0.001), LDL cholesterol (p < 0.001) and proteinuria levels (p < 0.001) were higher both in patients with membranous nephropathy than the other two groups and in patients with FSGS than IgA nephropathy. Median duration of follow-up was 120.2 (1.7-273.3) months (Table 1). All-cause mortality rate was significantly higher in patients with membranous nephropathy than the other two groups (p = 0.005); however the type of glomerulonephritides was not found to be related to all-cause mortality (HR: 1.07; 95% CI: 0.65-1.77; p = 0.770). Age (HR: 1.079; 95% CI: 1.05-1.10; p < 0.001), serum creatinine (HR: 1.35; 95% CI: 1.10-1.66; p = 0.003) and serum albumin (HR: 0.60; 95% CI: 0.38-0.95; p = 0.030) levels were found to be associated with all-cause mortality in patients with primary glomerulonephritides. The rates of ischemic stroke, atrial fibrillation and steroid induced diabetes were similar between all of the glomerulonephritides subgroups. Acute coronary syndrome (p = 0.015), coronary revascularization (p = 0.021) and venous thromboembolic events were more frequent in patients with membranous nephropathy than IgA nephropathy. There was no difference in terms of cardiovascular outcomes between the patients with FSGS and IgA nephropathy (Table 1). Although the remission rate was significantly higher in patients with membranous nephropathy than the other two groups (p < 0.001); there was not a distinct difference in relapse rates. Progression to end-stage renal disease was prominently lower in patients with membranous nephropathy than the other groups (p = 0.003) and loss of glomerular filtration rate per year was significantly higher in cases with FSGS compared to other groups (p = 0.021). Conclusion All-cause mortality risk was higher in patients with membranous nephropathy because of higher age at diagnosis and accompanying higher burden of comorbidities including diabetes and dyslipidemia. FSGS had a worse prognosis in terms of kidney related outcomes compared to other glomerulonephritides due to higher loss of glomerular filtration rate per year and increased rates of progression to end-stage renal disease. Intensive cardiovascular risk reduction strategies should be applied especially in patients with membranous nephropathy due to increased mortality rates.

#1258 Moderate-severe intrarenal arteriosclerosis and circulating GDF-15 levels may influence the cardiac-renal prognosis of IgAN patients

Abstract Background and Aims The cardiovascular risk among patients with IgA nephropathy (IgAN) is gradually garnering increased attention. The KDIGO guidelines explicitly emphasize the importance of evaluating cardiovascular risk in the management of IgAN patients and implementing appropriate interventions when necessary. The aim of this study was to investigate the risk factors affecting cardiac-renal prognosis in patients with IgAN. Method This is a retrospective study. A total of 353 IgAN patients with regular follow-up for at least 1 year at Beijing Anzhen Hospital were recruited. Patients were divided into group A (n = 85, yes) and group B (n = 268, no) according to the occurrence of cardio-renal composite endpoint events. Clinical and pathological characteristics of the two groups were compared and analyzed. The risk factors affecting the cardiac and renal prognosis in IgAN patients were analyzed by univariate and multivariate Cox models. In addition, serum GDF-15 of IgAN patients were detected. Results Approximately 14.7% (52/353) of IgAN patients presented with cardiovascular diseases at the time of renal biopsy. 55.8% (197/353) patients presented with hypertension. Prognostic analysis showed that hypertension (HR, 1.810; 95% confidence interval, 1.073 to 3.053; P = 0.026), 24-hour urinary protein (24 hUTP) (HR, 1.081; 95% confidence interval, 1.006 to 1.162; P = 0.033), eGFR (HR, 0.980; 95% confidence interval, 0.973 to 0.987; P<0.001), the presence of endocapillary proliferation (E1) (HR, 1.697; 95% confidence interval, 1.079 to 2.669; P = 0.022), tubular atrophy/interstitial fibrosis (T2) (HR, 3.757; 95% confidence interval, 1.959 to 7.203; P < 0.001), and moderate-severe intrarenal arteriosclerosis (HR, 3.320; 95% confidence interval, 1.289 to 8.548; P = 0.013) are independent risk factors affecting the cardiac-renal prognosis of IgAN. In IgAN patients with moderate-severe intrarenal arteriosclerosis, 24-hour urinary protein (24 hUTP) (HR, 1.131; 95% confidence interval, 1.014 to 1.261; P = 0.028), eGFR (HR, 0.982; 95% confidence interval, 0.971 to 0.993; P = 0.001) and E1 (HR, 2.583; 95% confidence interval, 1.379 to 4.841; P = 0.003) are independent risk factors affecting the cardiac-renal prognosis of IgAN patients. The serum GDF-15 level is positively correlated with 24 hUTP (r = 0.405, P < 0.001) and negatively correlated with eGFR (r = −0.606, P < 0.001). Compared with those with benign cardio-renal composite outcome, the serum level of GDF-15 in IgAN with poor cardio-renal composite outcome were significantly higher (1591.69 (1001.65, 2546.36) pg/ml vs 775.85 (546.82, 1310.29) pg/ml, P < 0.001). Conclusion The occurrence of cardiovascular diseases in patients with IgAN is frequently observed. In addition to the conventional risk factors associated with IgAN, including hypertension, initial proteinuria, eGFR, E1 and T2 lesion, moderate-severe intrarenal arteriosclerosis also contributes to the cardiac-renal prognosis of individuals with IgAN. In IgAN patients with moderate-severe intrarenal arteriosclerosis, Oxford-E lesion is an independent risk factor affecting the cardiac-renal prognosis of IgAN patients. This study suggested that the impairment of endothelial cells could potentially serve as a link between heart and kidney disease. The circulating levels of GDF-15 might contribute to the cardiac-renal prognosis of IgAN.

#2389 Enhancing immunoglobulin A nephropathy management: insights from the IGAN-MIC project

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) comprises a substantial proportion of primary glomerulonephritis cases in China, yet comprehensive nationwide data regarding its diagnosis and treatment are lacking. The Immunoglobulin A Nephropathy Management Quality Improvement Initiative Project in China (IGAN-MIC) seeks to establish an IgAN cohort collaboration network to comprehend real-world IgAN management practices in China. Method The IGAN-MIC project convened 15 Chinese experts from 14 regions to form an expert committee to develop a registry of IgAN patients to evaluate regional differences in IgAN management from 2015 to 2024. The registry will involve comprehensive data collection from electronic medical records, encompassing key aspects including demographic and clinical characteristics, renal biopsies, diagnoses, comorbidities, laboratory findings, and treatment modalities, facilitating a detailed analysis of disease progression and changes in treatment strategies from initial diagnosis through subsequent follow-up periods. Results The IGAN-MIC project has garnered applications from 78 healthcare institutions, with 7 of them already incorporated into the initiative and initiated data collection. As of January 1, 2024, the project has enrolled 543 pathologically confirmed IgAN patients diagnosed between 2015 and 2023 from these 7 centers. At the time of diagnosis, the median (IQR) of age was 38.00 (30.00, 48.00) years; 54.51% were females; the median (IQR) of eGFR was 75.41 (51.93, 104.09) mL/min/1.73 m2 and the median (IQR) 24-hour urinary protein was 1263.50 (645.30, 2362.64) mg/day. For these patients, the utilization rates of RAS inhibitors (RASi), SGLT2 inhibitors (SGLT2i) and glucocorticoids at initial treatment were 53.41%, 3.51%, and 42.73% respectively. The utilization rate of SGLT2i from 2022 to 2023 was 9.90%, as the first indication for SGLT2i in CKD was approved in China in September 2022. A detailed outline of patient baseline characteristics is presented in Table 1 below. Conclusion These initial findings in the registry showed that the Chinese IgAN patients were young, had mildly reduced renal function, and with massive proteinuria at the time of initial diagnosis. For initial treatment, only half of the patients received RASi, and only one tenth received SGLT2i. More education needs to be focused on promoting guideline-directed medical therapies in the future. Given that nationwide data on Chinese IgAN patients are limited, the IGAN-MIC project is anticipated to broaden its registry to include more healthcare institutions and Chinese IgAN patients in the future, with the aim of providing a more in-depth understanding of the changing clinical presentations and ongoing follow-up scenarios among IgAN patients, contributing crucial insights to the clinical management of IgAN.

#1993 Analysis of the characteristics of IgA nephropathy patients using real-world data from five European countries

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally; it has a significant health burden and a highly variable disease course. As IgAN is a heterogeneous disease, it is important to appreciate the associated patient characteristics in order to understand disease progression and how best to implement individualised treatment regimens. To determine the patient characteristics associated with IgAN, a physician questionnaire and patient chart audit were conducted. Method From 21 December 2022 to 6 February 2023, physicians from five European countries (France, Germany, Spain, Italy and the UK) completed a questionnaire and patient chart review of their IgAN patients. Physicians were required to have ≥50 patients with stage 1–4 chronic kidney disease (CKD); at least four of these were required to be non-dialysis IgAN patients. Patients whose charts were included were required to be aged 12 years or older, non-dialysis IgAN patients and have an estimated glomerular filtration rate of ≥15 mL/min/1.72 m2. The charts included were required to be from patients who had seen a participating physician within the prior 6 months. Results 261 physicians answered the questionnaire and completed chart audits on 473 of their most recently seen patients. Patient charts audited were largely from male (71%) Caucasian (78%) patients from 31–49 years of age (38%). 22% of patients were referred to their current physician within the past year. Most patients (70%) were referred by a primary care physician and 9% by another nephrologist. Of those referred by a nephrologist, 32% were referred for specialised care. Participating physicians perceived that close to 30% of patients were referred to them late or extremely late, with contributing factors including lack of engagement from patients with annual follow-ups and patients remaining asymptomatic for a long time. At the most recent visit, 24.3% had CKD stage 1 or 2, 26.6% of patients had CKD stage 3a, 30.4% had stage 3b and 18.6% had stage 4 disease. Nephrologists characterised 53% of their CKD stage 4 patients as having severe IgAN. The symptoms reported with greatest frequency at the most recent visit included fatigue (59%), blood in the urine (41%) and increased weight gain (41%). In total, 71% of patients had proteinuria >0.5 g/day (8% had no values available) and 8% of patients had nephrotic syndrome (urine protein >3.5 g/day and low serum albumin). In total, 28% of patients had no co-morbid conditions. More than half (54%) of the patients whose charts were audited had comorbid hypertension. Other comorbidities included hyperlipidaemia (22%), obesity (17%), type 2 diabetes (15%) and peripheral oedema (7%). Counterintuitively, when asked about the overall health of their patients, physicians perceived the majority (98%) of patients to be in good or excellent overall health. Patients were prescribed five medications on average, with most (92%) taking an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, or both. The number of medications prescribed increased after the age of 50. Two-thirds (66%) of physicians felt that patients completely adhered to their treatment regimen. However, 54% of physicians reported some form of dissatisfaction with the response of their patients to their overall treatment regimen; though, levels of satisfaction varied between individual treatment options. Conclusion Despite high rates of proteinuria and patients often in late-stage CKD at referral, physicians perceived the majority of patients to be in good or excellent overall health, revealing a potential gap in physicians’ perceptions of patients’ health and their risk of progression to kidney failure. As a result, patients were often diagnosed or referred late and their perception of their own health may have led to a lack of engagement with physicians. These data indicate that there is an unmet need for early diagnosis and treatment of IgAN to ensure that patients receive appropriate care.

#456 Efficacy and safety of iptacopan in patients with primary IgA nephropathy: interim analysis results of the Phase 3 APPLAUSE-IgAN study

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis. An unmet need for targeted disease-modifying treatments addressing its pathophysiology remains. There is compelling evidence for involvement of the alternative complement pathway (AP) in IgAN. Iptacopan binds to Factor B and specifically inhibits the AP. The APPLAUSE-IgAN trial is evaluating the efficacy and safety of iptacopan vs placebo, on top of optimized supportive therapy, in patients with IgAN. Here we present the results of the pre-specified interim analysis (IA) with a focus on the results for key subgroups. Method APPLAUSE-IgAN (NCT04578834), a Phase 3, multicentre, randomised, double-blind, placebo-controlled trial, enrolled adults with biopsy-confirmed IgAN with proteinuria ≥1 g/g by urine−protein creatinine ratio from 24-hour urine collection (UPCR-24h) despite being on a stable dose of maximally tolerated renin-angiotensin-system inhibition (RASi) for 3 months, with or without other background therapy such as sodium-glucose transport protein 2 inhibition (SGLT2i). Patients were randomized 1:1 to iptacopan 200 mg or placebo twice daily for 24 months while remaining on stable supportive therapy. The primary objective of the prespecified IA was to demonstrate superiority of iptacopan vs placebo in reducing UPCR-24h at Month 9 (M9) in the main study population (estimated glomerular filtration rate [eGFR] ≥30 mL/min/1.73 m2 at baseline). Subgroup analyses included baseline age, sex, Asia vs non-Asia region, proteinuria, eGFR, and SGLT2i use. Efficacy analyses were performed on the first 250 patients (n = 125 each for iptacopan and placebo) who reached the M9 visit or discontinued from the study. Safety analyses included all patients of the main population who had received treatment by the time of the IA (iptacopan, n = 222; placebo, n = 221). Results Baseline demographics and disease characteristics were similar between the two arms (Table) and indicative of patients at high risk of IgAN disease progression. Iptacopan was superior to placebo in reducing proteinuria, with reduction in UPCR-24h at M9 relative to baseline of 38.3% (95% CI: 26.0%, 48.6%; 1-sided p < 0.0001) vs placebo (Figure). Subgroup analyses showed that treatment effect consistently favoured iptacopan regardless of baseline age, sex, Asia vs non-Asia region, UPCR-24h or eGFR levels, or SGLT2i use as part of the supportive care (Figure). Treatment-emergent adverse events (TEAEs) occurred in 138 (62.2%) iptacopan vs 153 (69.2%) placebo patients, with the majority being of mild to moderate severity. Treatment-emergent serious AEs were reported in 18 (8.1%) and 11 (5.0%) patients in the iptacopan and placebo arms, respectively. TEAEs leading to treatment discontinuation occurred in 6 patients (2.7%) in each arm. No deaths were reported. Iptacopan treatment did not lead to clinically relevant differences in total cholesterol, low-density lipoprotein cholesterol, and serum triglycerides compared with placebo. Conclusion APPLAUSE-IgAN, the first Phase 3 study confirming the relevance of the AP in IgAN, demonstrated superiority of iptacopan vs placebo, with a significant reduction in proteinuria at M9 (38.3%) that was consistent across key subgroups evaluated. Iptacopan was well tolerated with a favourable safety profile.

#1425 Anemia in patients with IgA nephropathy: an impact on the prognosis of IgA nephropathy

Abstract Background and Aims Immunoglobulin A Nephropathy (IgAN) has several well-known predictors of renal outcomes, including persistent proteinuria, hypertension, and baseline eGFR at the time of diagnosis. However, the effect of hemoglobin (Hb) levels on the progression of IgAN is rarely reported. This study aims to evaluate the impact of Hb levels on the prognosis of IgAN and to identify risk factors for anemia in patients with IgAN. Method A retrospective analysis of the data of 855 patients diagnosed with IgAN at Kyungpook National University Hospital between January 2002 and December 2021 was performed. We obtained the data on clinical parameters and pathological findings according to the Oxford classification at the time of the kidney biopsy. Univariate and multivariate logistic regression analyses were used to evaluate the risk factors for anemia, and a Cox proportional hazard model was used to estimate the effects of anemia on the development of end-stage kidney disease (ESKD). Results Lower serum albumin, lower eGFR, severe interstitial fibrosis, and tubular atrophy were associated with anemia in patients with IgAN. The Kaplan-Meier survival curve revealed that patients with anemia had worse renal survival than those without anemia. The multivariable Cox analysis showed that anemia was an independent risk for the progression to ESKD (HR 2.86, confidence interval 1.58–5.17, p = 0.001). In a sex-specific analysis, only the female sex showed a significant and higher risk for ESKD (hazard ratio 4.07, confidence interval 1.53–10.8, p = 0.005). Conclusion A low Hb level at the time of biopsy, even if subclinical, was an independent risk factor for the development of ESKD in patients with IgAN. Therefore, it is necessary to monitor Hb levels at the time of diagnosis and take proactive measures to reduce the risk of disease progression.

#887 Complement biomarkers in IgA nephropathy and IgA vasculitis with renal involvement: can urine rather than blood be the answer?

Abstract Background and Aims IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. Dysregulation of the complement system is considered a part of the pathogenesis and can occur both in the circulation and locally in the kidney. Despite this, most studies have focused on complement biomarkers in the blood, rather than in urine. Our aim was to evaluate a wide range of complement-related proteins in blood and urine at diagnosis and their association with disease activity in biopsy findings, proteinuria, and outcome. We added PTX-3, a protein expressed in activated endothelial cells, which can be both produced by and activate mesangial cells in IgAN and has a function in all three complement pathways. Adult-onset IgA vasculitis with renal involvement (IgAVN) shares many similarities with IgAN and cannot currently be distinguished by kidney biopsy or any established biomarker. We therefore also aimed to compare the same biomarkers between these two disorders. Method In a Swedish cohort of 96 patients with IgAN (n = 65) and IgAVN (n = 31), who had been followed prospectively for a median of 10.8 years, we performed the following analysis in plasma and urine in samples stored at the time of kidney biopsy. Analyses in plasma (p-) included C3bc, C4c, C5b-9, MASP2, MASP3, MAP1, FCN 1-3, MBL, CL11 and PTX-3 and in urine (u-) C3bc, C4c, C5b-9, MASP3, FCN2, FCN3, MBL and PTX-3. An in-house developed sandwich ELISA was used for all analyses. Kidney biopsies were classified according to the Oxford MEST-C score, describing (simplified for this small cohort) the presence vs absence (1 vs 0) of mesangial proliferation (M), endocapillary proliferation (E), segmental sclerosis (S), tubular atrophy/interstitial fibrosis (T) and crescents (C). Severe outcome was defined by a combination of an eGFR slope > 2.5 ml/min/1.73 m2 per year or end stage kidney disease. For statistical analysis, Mann-Whitney U test was performed for comparison between independent groups, Chi squared test and Fisher's test for categorical variables and Spearman's ranks test for correlation analysis. Median values are presented without IQR for this abstract. Results Urine samples were available in 59 patients (IgAN n = 39, IgAVN n = 20). Patients with detectable u-MBL (28.9%) and u-C5b-9 (27.1%) had higher levels of proteinuria than those with undetectable levels (1.5 g/d vs 0.71g/d; p = 0.009 and 2.3 g/d vs 0.7 g/d respectively; p < 0.001). Lower eGFR (71 ml/min/1.73 m2 vs 88 ml/min/1.73 m2; p = 0.034) were observed if u-C5b-9 was measurable. Detectable levels of u-PTX-3 and u-MBL were more often found in the presence of M1 vs M0 (53% vs 20%; p = 0.022 and 47% vs 12.5%; p = 0.011), E1 vs E0 (55% vs 14%; p = 0.001 and 40% vs 11%; p = 0.020) and C1 vs C0 (56% vs 11%; p = 0.003 and 44% vs 11%; p = 0.012). No differences in proteinuria or eGFR were seen in patients with or without detectable u-PTX-3. The degree of proteinuria was positively correlated to the levels of u-C3bc (r = 0.33; p = 0.011) and u-C4c (r = 0.39; p < 0.001). U-C4c levels were higher in patients with M1 vs M0 (54.4 Au/mL vs 23.8 Au/mL; p = 0.037) and T1 vs T0 (53.2 Au/mL vs 23.8 Au/mL; p = 0.034). Concerning the analyses in plasma (n = 95), lower p-MASP3 and p-CL11 levels were correlated with lower eGFR (r = 0.29; p = 0.004 and r = 0.31, p = 0.002). Moreover, lower p-MASP3 levels were detected in patients with E1 vs E0 (2918 ng/mL vs 3404 ng/mL; p = 0.002) and C1 vs C0 (3053 ng/mL vs 3427 ng/mL; p = 0.015). Both p-C5b-9 (13.3 Au/mL vs 8.2 Au/mL; p = 0.001) and p-FCN 1 (395 ng/mL vs 289 ng/mL; p = 0.001) were higher in patients with C1 vs C0. No single complement-related protein was associated with severe outcome, and no statistically significant differences in plasma or urine levels between patients with IgAN and IgAVN were observed. Conclusion Increased urinary levels of MBL and PTX-3 could be potential biomarkers of disease activity in both IgAN and IgAVN, whereas excretion of C5b-9 might be more unspecific and associated with chronic damage. However, these results need to be confirmed in larger and more ethnically diverse cohorts. The impact of treatment on these potential biomarkers for disease activity need to be evaluated in longitudinal studies.

#1940 Plasma complement activation profile in kidney transplant recipients with IgAN supports the importance of the complement alternative pathway in IgAN

Abstract Background and Aims The alternative complement and lectin pathways are key players in IgA nephropathy (IgAN). However, the precise dynamics of complement activation in IgAN remain poorly understood. Non-invasive complement biomarkers are urgently needed in view of the evolving landscape of complement-targeting therapies under evaluation in IgAN. Method We analyzed plasma complement activation biomarkers in a cohort of 87 kidney transplant recipients (KTR) with IgAN and 30 controls consisting of autosomal dominant polycystic kidney disease (ADPKD) KTR (NCT05234463, DC-2013-1990). Patients were excluded if 1) they had a biological inflammatory syndrome at the time of sampling or 2) they had experienced a cellular/humoral rejection in the year prior to or after sampling. We simultaneously measured a large panel of complement activation and regulation fragments (C3a, C5a, C4a, sC5b-9, Ba, Bb) and intact proteins (C3, C4, FI, FH, properdin) in plasma using multiplex ELISA (Quidel Ortho®, A900), nephelometry and in-house ELISA. Results There was no consumption of C3 and C4 proteins in IgAN patients. However, C3a and Bb concentrations were elevated in IgAN patients compared to ADPKD patients (161 [98-227] vs. 102 [66-172] ng/mL, p = 0.007; 3.0 [2.6-4.0] vs. 2.5 [2.0-2.8] µg/mL, p < 0.0001). Overall, 70/87 IgAN patients (80.5%) had elevated Bb levels. The plasma concentration of C5a was elevated in IgAN patients compared to ADPKD patients (6.3 [3.8-9.2] vs. 4.9 [2.8-6.3] ng/mL, p = 0.0274), with values within the reference range in 92.0% of IgAN patients. There was no difference in plasma levels of sC5b-9 between the two groups (p = 0.186). The combined analysis of C3a, C5a and sC5b-9 allowed us to distinguish 4 clusters of patients (Fig. 1). A total of 48 patients (55.2%) show evidence of C3 convertase activity in plasma (clusters 3 and 4), including 16 patients (18.4%) with the highest plasma concentrations of sC5b-9, C3a and Bb. In contrast, 15 patients (17.2%, cluster 1) have no (or very low) complement activation. The last group (n = 32, 36.8%, cluster 2) shows an isolated increase in sC5b-9 without evidence of plasma C3 convertase activity. Proteinuria was significantly increased in groups 3 and 4, which had the highest C3a concentrations, compared to groups 1 and 2 (p = 0.0051). Conclusion This study provides insights into the mechanisms of complement activation in IgAN, with a pivotal role for the activity and regulation of the alternative C3 pathway convertase. In addition, the combined analysis of complement biomarkers identified, for the first time, clusters of patients who may benefit from complement targeting therapies.

#1271 Risk of primary infections in patients with IgA nephropathy: a Swedish population-based cohort study

Abstract Background and Aims IgA nephropathy (IgAN) is the most common global kidney disease with a highly variable clinical presentation. Diagnosis IgAN requires a biopsy, and the immunohistologic examination is dominated by depositions of aberrant IgA1 antibodies. Since IgA antibodies are mainly produced by the mucosal associated lymphoid tissue the relationship between the mucosal immune system and IgAN has long been considered. The current theories on the origin of the disease involve genetic and environmental factors, with mucosal infections potentially playing a role. In some IgAN patients gastrointestinal and/or upper respiratory infections can aggravate the disease with episodic macrohematuria and/or increased proteinuria. Coincidently, these infections are also more common among patients with selective IgA deficiency. The aim of this study was to investigate whether the presence of IgAN confers an increased risk of infections in general to the IgAN patient. Method IgAN was defined by a computerized biopsy record from 1997 to 2011 in Sweden. Each IgAN patient was matched with up to five reference individuals based on age, sex, calendar year, and county of residence. Exclusions included those with organ transplants, HIV, immunodeficiency, or end-stage kidney disease before study entry, and follow-up data were censored for subsequent occurrences. Linear and Cox regressions, adjusted for age, sex, and education, were performed to analyze total infections and antimicrobial treatments in both patient and reference groups. Sibling analyses were also performed, adjusted for baseline age, sex and educational attainment. Results The linear regression analysis revealed a significant association between IgA nephropathy (IgAN) and the overall frequency of infections compared to the general population (β = 0.45; 95% CI: 0.37–0.54), women (β = 0.35; 95% CI: 0.19–0.50), men (β = 0.50; 95% CI: 0.40–0.60), and siblings (β = 0.37; 95% CI: 0.25–0.49) for women (β = 0.24; 95% CI: 0.06–0.41) and men (β = 0.43; 95% CI: 0.27–0.60). Similarly, a significant association was found for the frequency of prescribed antimicrobial agents compared to the general population (β = 0.66; 95% CI: 0.51–0.82), women (β = 0.92; 95% CI: 0.56–1.27), men (β = 0.55; 95% CI: 0.39–0.71), with similar estimates in the sibling analyses. The subtypes with the strongest association were urinary tract infections (β = 0.09; 95% CI: 0.07–0.11), ENT (ear, nose, and throat) infections (β = 0.08; 95% CI: 0.04–0.12), muscular infections (β = 0.08; 95% CI: 0.05–0.12), and infections in the GI (gastrointestinal) tract (β = 0.06; 95% CI: 0.04–0.09). Infections in the lower respiratory tract, skin and mycoses also had a significant positive association, however, no associations to infections in the central nervous system or infections caused by helminths and protozoans were identified. Cox regression showed an elevated risk of any infection with an adjusted hazard ratio (HR) of 2.05 (95% CI: 1.88–2.23), especially for sepsis (aHR = 3.13; 95% CI: 2.14–4.59), and time to the first prescription of antimicrobials with an aHR of 1.37 (95% CI: 1.30–1.45). Linear regression of prescribed antimicrobial treatments showed an overall β = 0.67; 95% CI: 0.51–0.82, and specifically for antibiotics (β = 0.64; 95% CI: 0.49–0.78). Conclusion Our study demonstrates an increased prevalence of infections and antibiotic prescriptions in IgAN patients compared to the general population and their siblings. Further studies on the potential impact of IgAN and its immunological aberrations on overall infection susceptibility is warranted.

#1257 Complement system is overactivated in patients with IgA nephropathy after COVID-19

Abstract Background and Aims Since the coronavirus disease of 2019 (COVID-19) pandemic swept across the world, the flare of immune-mediated disease following SARS-CoV-2 infection has emerged rapidly. IgA nephropathy (IgAN), which has been confirmed as a complement mediated autoimmune disease, is also one of the common glomerulonephritis associated with COVID-19. Here, we aim to investigate the clinical and immunological characteristics of patients with IgAN after COVID-19. Method From December 2022 to April 2023, 33 patients with renal biopsy-proven IgAN (Group CoV) at Beijing Anzhen hospital who had experienced COVID-19 before renal biopsy were enrolled. Meanwhile, 44 patients with IgAN (Group non-CoV) diagnosed from December 2018 to April 2019 (the same period in the previous year, with no COVID-19) were enrolled as control. Plasma FHR-5, MBL, C5a, soluble C5b-9, serum Gd-IgA1 and IgA immune complex were detected by enzyme-linked immunosorbent assay. Glomerular staining for FHR-5, C3c, MAC and Gd-IgA1 were detected by immunofluorescence. SARS-CoV-2 nucleocapsid was detected by immunohistochemistry. Clinicopathological and immunological features between the two groups were analyzed. Results The median time between onset of COVID-19 symptoms and the time of renal biopsy was 12 (6, 18) weeks, ranging from 1 to 26 weeks. SARS-CoV-2 nucleocapsid antigen expression in the renal tubular epithelial cells were observed in 11/33 (33.3%) patients. Compared with Group non-CoV, the level of eGFR was significantly lower in Group CoV[67.30 (52.94, 96.43) ml/min per 1.73 m2 vs. 101.04 (74.35, 120.98) ml/min per 1.73 m2, p = 0.010]. Histologically, compared with Group non-CoV, Group CoV presented with more percentages of segmental glomerulosclerosis/adhesion (p = 0.003) and less percentages of mesangial hypercellularity (p = 0.017). The level of plasma level of C5a [16.45 (10.48, 22.07) ng/ml vs. 3.68 (2.70, 4.47) ng/ml], soluble C5b-9 [614.43 (481.66, 770.02) ng/ml vs. 358.08 (304.83, 471.77) ng/ml], FHR5 [4.01 (3.51, 4.48) ug/ml vs. 2.73 (2.25, 3.21) ug/ml]were all significantly higher in Group CoV compared with Group non-CoV, respectively (p < 0.001). Although the plasma level of MBL showed no difference in Group CoV and Group non-CoV, the proportion of high levels of MBL in Group CoV was higher than in Group non-CoV (p = 0.025). Compared with Group non-CoV, the intensity of glomerular MAC deposition was much stronger in Group CoV. There were no significant differences in serum levels of IgA, Gd-IgA1, IgA immune complex between two Groups. However, a greater intensity of Gd-IgA1 deposition in glomerular mesangial and capillary areas has been exhibited in Group CoV than those in Group non-CoV (p = 0.005). Conclusion 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, which is the first hit, and increased glomerular deposition of Gd-IgA1 is the second hit. We think that these two hits may lead to renal dysfunction and promote renal progression in IgAN patients. It is crucial to emphasize the necessity for long term follow-up in these patients of IgAN after COVID-19. Additionally, we propose that inhibitors targeting the mediators of complement activation might be a promising therapy for these IgAN patients after SARS-CoV-2 infection.

#177 Assessment and comparison of physician gaps related to clinical knowledge of IgA nephropathy

Abstract Background and Aims Understanding physician gaps related to IgA nephropathy (IgAN) can inform development of tools to improve physician knowledge and competence related to both diagnosis and treatment. Additionally, comparisons among specialists (nephrologists) and generalists (primary care physicians, PCPs) can segment educational needs for combined or customized education to close identified gaps. Method A survey instrument of 25 multiple choice, knowledge- and case-based questions allowed participants to assess their clinical knowledge related to IgAN. The survey was available online to physicians without monetary compensation or charge. Respondent confidentiality was maintained and responses were de-identified and aggregated prior to analyses. Initial data collection occurred from March 16, 2023 to May 19, 2023. Results In total, 98 nephrologists and 57 PCPs completed the full assessment within the data collection period. Conclusion This assessment of physicians’ clinical knowledge yielded important insights into gaps related to IgAN. Both nephrologists and PCPs need education on pathophysiology of IgAN and emerging treatment pathways, role of proteinuria and risk correlations to ESRD with IgAN, clinical use of the International IgAN Prediction Tool, and KDIGO recommendations for managing IgAN. PCPs need additional education on basic IgAN prevalence as well as clinical strategies for diagnosis. Further studies are planned to assess the effect of medical education on decreasing these clinical practice gaps.

#1805 Renal progenitor cells isolated from urine of IgA nephropathy patients formed renal spheroids that can recapitulate the typical IgA1 deposition

Abstract Background and Aims Recent developments in stem cell biology have made it possible to create spheroids and kidney organoids from human and mouse pluripotent stem cells and renal stem cells. Spheroids are a suitable in vitro model for studies of drug studies and can transform into organoids whose rapidly developing field has proven useful in simulating nephrotoxicity, kidney disorders, and kidney development. However, to date in all studies the generation of organoids and tubuloids required the use of sophisticated and complex differentiation protocols involving external administration of several growth factors and needs compliance with a precise and specific timescale. Here we showed for the first time that human adult renal progenitor cells (ARPCs) can be isolated from urines of healthy subjects (HS) or IgA Nephropathy (IgAN) patients and can form spheroids generating very long tubule-like structures naturally, without the external use of chemokines or growth factors to artificially induce the process and recapitulating the IgA1 deposition that is the typical characteristic of the disease. Method Spheroids and tubule-like structures were characterized by whole-mounting and frozen section immunofluorescence (IF) assays and by Flow Cytometry Analysis using CD133, NanoG, Oct3/4, GATA-3, SSEA4, CD249, Aminopepidase N, ZO-1, Uromodulin, and Lotus Tetragonolobus Lectin (LTL) antibodies. ELISA was used to determine the renin secretion and CAM assays to determine ARPCs and ARPC-derived Spheroids angiogenic properties. PKH-26 labeling was used for their in vitro and in vivo tracking. Serum of HS and IgAN patients in culture with spheroids was used to recapitulate the disease and IgA1 deposits were measured by IF. Results ARPC-derived spheroids reflected the renal progenitor properties and recapitulated organoids generating very long tubule-like structures that expressed structural and functional renal tubule markers such as CD249, Aminopepidase N, ZO-1, Uromodulin, and LTL and in some cases shared many structural similarities with some regions of nephrons, such as the distal convoluted tubule, the loop of Henle and proximal convoluted tubules. Moreover, ARPC-derived spheroids secreted elevated levels of renin and, as the cellular counterpart, showed angiogenic properties. To study the proof of concept that ARPC-derived spheroids can be used to establish in vitro models recapitulating renal diseases, we generated IgAN patient-specific renal spheroids using the ARPC mixed cell population method. ARPC-derived spheroids of IgAN patients showed deposits of IgA1 already after four days of culture with patient serum (p = 0.004) and, with a different pattern, after 8 and 15 days (p = 0.0029 and p = 0.0012, respectively). The IgA1 deposition resembled that in the glomeruli of patients diagnosticated with IgAN. In contrast, no positive signal was detected in either IgAN spheroids in culture with FBS, or with inactivated IgAN serum, as well as in spheroids derived from urine of HS in culture with IgAN serum. Conclusion The ability of ARPCs to form spheroids and differentiate into tubular-like structures without the need for external chemokines or growth factors is a significant advancement in the field, even more considering that these cells can be isolated from the urine of patients. These findings open up new possibilities for the regenerative medicine in studying kidney development, disease mechanisms, and regenerative therapy development for renal disorders.

#162 Single-nucleus RNA-seq of biopsy-confirmed IgA nephropathy reveals cell-specific transcriptomic alteration

Abstract Background and Aims Single-nucleus RNA-seq (SnRNA-seq) is a valuable method for identifying cell-specific transcriptomic alterations in kidney cells. Our objective was to investigate SnRNA-seq data from biopsy-confirmed IgA nephropathy (IgAN) cases and identify cell-specific alterations in the transcriptome. Method We collected snap-frozen kidney biopsy tissues from 6 cases of IgA nephropathy (IgAN) and 7 nephrectomy control cases. The disease control group included 3 cases of diabetic kidney disease, 6 cases of minimal change disease, and 6 PLA2R-Ab positive membranous nephropathy cases. SnRNA-seq was performed on the kidney tissues, and kidney cells were identified in the dataset through UMAP clustering. We investigated differences in the proportion of kidney cell types and identified differentially expressed genes (DEGs). Additionally, we searched for representative gene loci previously reported in a multiethnic genome-wide association study (GWAS). Results We successfully collected transcriptomic profiles of >50 000 cells from IgAN, with a considerable enrichment of intraglomerular cells. The DEG analysis revealed a high number of DEGs in mesangial cells, fibroblasts, and vascular smooth muscle cells in the IgAN transcriptome compared to the nephrectomy and disease control cases. In the gene set enrichment analysis, the epithelial-mesenchymal transition pathway was enriched in the glomerular cells of IgAN. Furthermore, among various GWAS loci, ETS1 was the gene significantly highly expressed in the mesangial cells of IgAN, consistent across the compared control groups. Conclusion This investigation represents the largest SnRNA-Seq profiling of IgAN kidney cells to date. We identified notable enriched cell-specific pathways in IgAN. ETS1 may be a kidney-indwelling causal factor for IgAN pathophysiology, considering its notable significance in both previous GWAS results and the current SnRNA-Seq data.

#425 Felzartamab (anti-CD38) in patients with IgA Nephropathy—interim results from the IGNAZ study

Abstract Background and Aims Most patients with IgA nephropathy (IgAN) will progress to kidney failure within 10-15 years of diagnosis. Sustained proteinuria is the best predictor of adverse long-term kidney outcomes and is a surrogate marker for efficacy. CD38+ plasma cells are likely the main source of pathogenic Gd-IgA1, and the related autoantibodies in IgAN. Felzartamab (felza; HIB202) is a recombinant purified human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to CD38 on plasma cells and is being studied across immune-mediated kidney diseases such as IgAN, Primary Membranous Nephropathy, Lupus Nephritis, and Antibody Mediated Rejection. The primary aims of the IGNAZ study were to assess: 1) efficacy of felza compared to placebo on urine protein:creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR) change from baseline, and 2) the relationship between exposure, safety, and efficacy in each of 3 dose groups vs. placebo. Interim results with 15 months of follow-up from this 24-month trial are presented. Method In Part 1, 48 IgAN subjects were randomized in a 1:1:1:1 ratio across a placebo and 3 active arms in this multicenter, double-blind placebo-controlled, phase IIa trial. The M1, M2, and M3 active arms received 2 doses in 15 days, 5 doses in 2 months, and 9 doses in 5 months, respectively. In Part 2, 6 Japanese subjects received the M3 regimen, open-label, and have been followed for 9 months. Key inclusion criteria included ages 18-80 years, biopsy confirmed diagnosis of IgAN within the past 8 years, proteinuria at screening ≥1.0 g/d, eGFR ≥30 ml/min/1.73 m2 (by CKD-EPI), and background stable and maximally tolerated renin angiotensin system inhibitors. Results 48 randomized subjects were enrolled at 28 sites in the US and in 14 different countries in Europe and in Asia, of which 46 completed the treatment phase. Mean (SD) baseline characteristics (Parts 1 and 2 combined): age 41.6 (12.3) yrs, UPCR 1.67 (1.0) g/g, eGFR 74.6 (30.3) ml/min/1.73 m2. 67% of subjects were male. Intention-to-treat with felza demonstrated rapid, clinically meaningful reductions in UPCR with the maximal treatment effect being observed in the M3 9-dose regimen. In Part 1, percentage change from baseline in UPCR was −14% for placebo and −25% for M3 9-dose arm at month 3, and +9% for placebo and −35% for M3 at month 6 (Fig. A). Reductions in proteinuria observed at month 6 persisted until Month 15, 10 months after the last dose: +6% and −38% mean UPCR change from baseline for placebo and the M3 9-dose arm, respectively (Fig. B). Relatively stable eGFR values were observed for the felza arms compared to loss of eGFR in the placebo arm. Rapid, durable reductions in IgA and Gd-IgA1 levels were seen across the dosing arms, with reductions lasting 10 months after the last dose (Fig. C). IgG recovery occurred faster off-treatment than IgA. Results in the Part 2 subjects were similar to the Part 1 M3 cohort through 9 months. There were no apparent dose-dependent adverse events and no exposure-safety relationship. Treatment-emergent adverse events (TEAEs) were generally of mild or moderate intensity or toxicity grade. The most common TEAE assessed as related by study investigator was infusion related reactions (IRR), most of which occurred on the first infusion. There was one treatment-related serious AE due to an IRR. Five subjects discontinued treatment due to IRRs or drug hypersensitivity; for four of the five subjects, the infusion rate was higher than protocol-specified or had an error in pre-medication. TEAE infections were comparable between placebo and felza arms: Placebo (33.3%), M1 (33.3%), M2 (36.4%), M3 (38.5%), Part 2 (50.0%); all were Grades 1 or 2, and non-serious. Conclusion This proof-of-concept study highlights the potential for disease modification in IgAN with the anti-CD38 mAb felza and supports continued research as a potential treatment for high-risk IgAN patients. Felza treatment resulted in clinically meaningful, prolonged UPCR reductions and eGFR stabilization sustained ≥10 months after dosing was completed. Felza was generally well tolerated with rapid recovery of IgG with durable reductions in IgA and pathogenic Gd-IgA1 levels.

#1021 A phase 3 randomized controlled trial of ravulizumab in adult patients with IgA nephropathy

Abstract Background and Aims The pathogenesis of IgA nephropathy (IgAN) includes the deposition of immune complexes in the kidney and activation of the complement system. Complement components, including C5a (anaphylatoxin) and C5b-9 (membrane attack complex), are generated leading to mesangial inflammation and glomerular injury [1]. Ravulizumab, a humanized monoclonal antibody, is a long-acting complement C5 inhibitor that provides immediate, complete, and sustained inhibition of the terminal complement pathway, thereby targeting a key component of the pathophysiology of IgAN. A phase 2 study of ravulizumab (NCT04564339) demonstrated a rapid effect and significant reduction in proteinuria compared with placebo at week 26 (change from baseline in 24-hour urine protein to creatinine ratio [UPCR] –40.3% vs –10.9%), and treatment was well-tolerated [2]. This abstract describes the study design of the planned phase 3 trial of ravulizumab in adult patients with IgAN. Method This phase 3, randomized, double-blind, placebo-controlled trial (I CAN) will evaluate the efficacy and safety of ravulizumab (IV; weight-based dosing Q8W) in adults with IgAN. Eligibility criteria include a diagnosis of primary IgAN based on kidney biopsy at any point, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 at screening, and UPCR ≥0.75 g/g or urine protein ≥1.0 g/day (Table 1). The study consists of a 6-week screening period, followed by randomization (1:1) of participants to ravulizumab or placebo and a 2-year blinded treatment period (Fig. 1); all patients receive a stable and maximally tolerated dose of renin-angiotensin system inhibitor therapy. Approximately 450 patients will be randomized, stratified by proteinuria (<2 g/g vs ≥2 g/g), eGFR (<45 vs ≥45 mL/min/1.73 m2), and SGLT2i use (yes/no). The co-primary endpoints are change from baseline to week 34 in 24-hour UPCR evaluated on the log scale and the annualized total eGFR slope over 106 weeks. The sample size for the proteinuria endpoint of n = 204 will provide ∼90% power to detect a 35% relative treatment effect in UPCR at week 34 at a one-sided significance level of 0.005. The total sample size of n = 450 for the eGFR endpoint will provide ∼90% power to detect a difference in total annualized eGFR slope of 2.2 mL/min/1.73 m2 at week 106 at a one-sided significance level of 0.025. An open-label exploratory cohort (n = 20) with eGFR 20-29 mL/min/1.73 m2 and with kidney biopsy within 6 months of or during screening will be enrolled and analyzed separately from the main cohort. At completion of the blinded treatment period, all study participants will have the option to enter an open-label ravulizumab access period for up to 2 years. Results The co-primary endpoints are the change in 24-hour UPCR at week 34 and the annualized total eGFR slope over 106 wks. Secondary and exploratory endpoints include change in 24-hour UPCR at weeks 10, 26, 50, and 106, a composite kidney failure endpoint over 106 weeks, reduction in 24-hour UPCR ≥50% from baseline, time to UPCR <1 g/g and <0.3 g/g, and patient reported outcomes on fatigue, quality of life, and work-related productivity. Safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics will be evaluated. Conclusion Through immediate, complete, and sustained inhibition of C5, ravulizumab targets the pathophysiology of IgAN and has the potential to provide a disease modifying treatment option. This pivotal phase 3 study (I CAN) will evaluate the efficacy of ravulizumab in patients with IgAN who are at high risk of disease progression. The trial will evaluate effects on proteinuria and eGFR that may translate to long term kidney function preservation and provide a rapidly acting treatment option for patients living with IgAN.

#2663 Assessment of in situ alternative and classical convertases as indicators of ongoing glomerular complement activation in IgA nephropathy

Abstract Background and Aims Complement activation is involved in IgA nephropathy (IgAN), opening up new avenues for complement-targeting therapies. However, precise patient selection and optimal timing for these therapies are essential. Current diagnostic methods of complement activation in IgAN, based on immunostaining, lack precision in identifying specific pathway(s) involved and distinguishing ongoing from past complement activation. Method Complement deposition analysis was conducted on kidney biopsy samples from 53 patients with primary IgAN at diagnosis (NCT05234463). Glomerular complement deposition was assessed through immunohistochemistry for C4d and C5b-9 and immunofluorescence for C3b/iC3b and C1q. In situ detection of C3/C5 convertases complexes from complement classical/lectin (C4b2b) and alternative pathways (C3bBb) was performed on paraffin-embedded kidney biopsies from 33 patients using a proximity ligation assay (Duolink®, Sigma). Kidney biopsies from patients with lupus nephritis (LN) and C3 glomerulopathy (C3G) were used as positive controls for classical/lectin and alternative convertases staining, respectively. The signals corresponding to the convertases were quantified using QuPath® Software and correlated with clinical parameters, MEST-C score and C5b-9 staining. Results At diagnosis, all 53 IgAN patients (100%) exhibited C3 mesangial deposition. Additionally, 51.2% were positive for C4d, 16.5% had C1q deposition and 62.7% had C5b-9 deposition. In situ analysis of C3/C5 convertases revealed the presence of glomerular C3bBb convertases in 20/33 (60.6%) patients, with a median positive area of 14.9 [2.5-26.5]%o of glomerular surface. C4b2b convertases were detected in 21/33 patients (63.6%), with a median glomerular positive area of 8.1 [3.4-12.1]%o. Both C3bBb and C4b2b convertases were detected in 13/33 (39.4%) patients (Fig. 1). By contrast, no convertases were detected in 5/33 (15.2%) patients despite positive C3b/iC3b deposition. The intensity of C3bBb staining positively correlated with terminal pathway C5b-9 glomerular deposits (p = 0.0011, r2 0.29). Patients with MEST-C score S1 lesions and/or interstitial fibrosis/tubular atrophy (T1-2) exhibited a more pronounced intensity of C3bBb at diagnosis (p = 0.0093). Conclusion Our study, for the first time, presents evidence of ongoing complement activation at the tissue level in IgA nephropathy (IgAN), showing variable intensities among patients. The visualization of in situ C3/C5 convertases could enhance the functional aspect of pathological examination, helping identify patients with ongoing complement activation, making them potential candidates for complement inhibitors. Further research is necessary to investigate the kinetics of this staining over the natural course of IgAN and its implications for IgAN progression.

#2459 Matching-adjusted indirect comparison of eGFR in patients with immunoglobulin A nephropathy treated with Nefecon (TRF budesonide) or sparsentan

Abstract Background and Aims Primary immunoglobulin A nephropathy (IgAN) is an immune-mediated disease that can lead to kidney failure, need for dialysis and kidney transplantation, and early death. IgAN is the most common type of primary glomerulonephritis globally, with an estimated worldwide incidence of 2.5 per 100 000 individuals per year. Estimated glomerular filtration rate (eGFR) is a measure of renal function and is accepted as a surrogate endpoint for clinical trials evaluating kidney function deterioration. In December 2023, the US Food and Drug Administration (FDA) granted full approval to Nefecon (marketed as Tarpeyo® by Calliditas Therapeutics), a targeted-release formulation of budesonide, to reduce the loss of kidney function in adults with IgAN at risk of disease progression, based on the Phase 3 NefIgArd clinical trial. In February 2023, sparsentan (marketed as Filspari™ by Travere Therapeutics) was granted accelerated approval by the FDA to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression, generally a urine protein–creatinine ratio (UPCR) ≥1.5 g/g, based on the Phase 3 PROTECT study. Matching-adjusted indirect comparison (MAIC) is a widely accepted and relevant methodology for comparing treatments across trials in the absence of head-to-head comparisons. In this analysis, we aimed to compare the effects of Nefecon and sparsentan on kidney function deterioration in patients with IgAN, as assessed by eGFR. Method An anchored MAIC was performed to estimate the relative effect of Nefecon and sparsentan on the absolute eGFR change from baseline at 9, 12 and 24 months, with common comparators of optimized renin–angiotensin system inhibition for NefIgArd and irbesartan for PROTECT. Patient-level data from NefIgArd were used to select a population matched to PROTECT, and the following baseline characteristics were used to determine the weights: mean age (years), sex (% male), race (% white), mean eGFR (mL/min/1.73 m2), mean UPCR (g/g), urine albumin–creatinine ratio (UACR) (% with UACR >1.1 g/g), and urinary protein excretion (% with urinary protein excretion >1.8 g/day). Absolute change in eGFR was analyzed using a mixed model for repeated measures (MMRM) method, including baseline, 3-, 6-, 9-, 12-, 18- and 24-month data, baseline eGFR, baseline eGFR-by-time interaction, treatment, and treatment-by-time interaction. The MAIC weights were incorporated into the MMRM. A Bayesian fixed-effects network meta-analysis was performed on the relative effect from PROTECT and the weighted relative effect from NefIgArd, measured by the estimated absolute change from baseline in eGFR. Results The matching-adjustment of the NefIgArd patient population to the PROTECT population is shown in Table 1. The weighted NefIgArd population exhibits very similar baseline characteristics to the PROTECT population. The effective sample size of the weighted NefIgArd population is 208. Results from the anchored MAIC showed statistically and clinically significant favorable effects of Nefecon versus sparsentan on eGFR for all time points analyzed (Fig. 1). Mean differences in the absolute change in eGFR of 5.68 mL/min/1.73 m2 (95% credible interval [Crl] 3.14, 8.20; p < 0.001), 3.48 mL/min/1.73 m2 (95% Crl 0.97, 5.97; p = 0.006) and 3.28 mL/min/1.73 m2 (95% Crl 0.02, 6.51; p = 0.048) were observed when comparing Nefecon with sparsentan at 9 months vs 36 weeks, 12 months vs 48 weeks, and 24 months vs 106 weeks, respectively. Conclusion After accounting for differences in the patient populations from the NefIgArd and PROTECT trials, the anchored MAIC showed that treatment with Nefecon 16 mg/day for 9 months was associated with greater eGFR benefit compared with continuous treatment with sparsentan 400 mg/day over 2 years, with significant differences observed as early as 9 months after treatment initiation and sustained up to 2-years of follow-up.