Primary IgA Nephropathy Research Articles

The humanistic burden of immunoglobulin A nephropathy on patients and care-partners in the United States.

This cross-sectional survey study quantified the humanistic burden of immunoglobulin A nephropathy (IgAN), in terms of physical and mental health-related quality of life (HRQoL) and work productivity, among adults with primary IgAN and their care-partners. HRQoL was assessed (01/31/22 - 05/31/23) with validated tools including the KDQoL-36 (with SF-12), GAD-7 (anxiety), PHQ-9 (depression), and WPAI: SHP (work productivity). Participant characteristics and total/domain scores were summarized; selected outcomes were compared to an external, kidney disease-free cohort. 117 adults with IgAN and their care-partner pairs, and one adult without a care-partner, were included. The mean ages of patients and care-partners were 38.0 (SD: 8.6) and 40.2 (11.8) years, respectively; 55.9% and 43.6% were female. Mean physical and mental SF-12 scores for patients were 46.7 (SD: 8.0) and 41.9 (9.2), respectively, and 50.7 (7.3) and 43.7 (10.24) for care-partners. Both SF-12 components for patients, and the mental component for care-givers, were significantly worse compared to the US general population. Among patients, 27.1% had moderate/severe anxiety and 49.2% reported at least moderate depression. Compared to external controls, patients experienced significantly higher severity of anxiety (6.6 vs. 5.4) and depression (8.1 vs. 6.6; both p < 0.0001). Among care-partners, 13.7% experienced moderate anxiety and 37.8% experienced moderate/moderately-severe depression. Among employed individuals, both groups reported IgAN-related absenteeism (8.8-9.4%), presenteeism (25.1-25.9%), and overall work impairment (30.4-30.5%). US adults with IgAN and their care partners experience impairments to mental and physical HRQoL and heightened levels of depression and anxiety, underscoring the need for effective IgAN therapies and care-partner support.

Efficacy and Safety of Nefecon in Patients with Immunoglobulin A Nephropathy from Mainland China: 2-Year NefIgArd Trial Results.

Immunoglobulin A nephropathy (IgAN), an immune-mediated kidney disease, is particularly prevalent among individuals of East Asian ancestry. Nefecon is a novel, oral, targeted-release budesonide formulation designed to inhibit galactose-deficient-IgA1 formation underlying IgAN pathophysiology. We present findings in patients with IgAN from mainland China participating in the 2-year, multicenter, randomized, double-blind, phase 3 NefIgArd trial of Nefecon. Patients (aged ≥18 years) with primary IgAN (estimated glomerular filtration rate [eGFR] 35-90 ml/min per 1.73 m2, persistent proteinuria [urine protein-creatinine ratio ≥0.8 g/g or proteinuria ≥1 g/24 h] despite optimized renin-angiotensin system blockade) received Nefecon or placebo over 9 months, followed by a 15-month follow-up phase on supportive care alone. The primary efficacy end point was time-weighted average of eGFR over 2 years. Sixty-two patients from mainland China were included in this prespecified analysis. The primary efficacy end point was 9.6 ml/min per 1.73 m2 (95% confidence interval [CI], 2.0 to 19.8) in favor of Nefecon versus placebo. This was consistent with (and numerically greater than) that of the global study population. Time to confirmed 30% eGFR reduction or kidney failure from baseline was substantially delayed with Nefecon (patients with an event: 9%) versus placebo (30%; hazard ratio, 0.21; 95% CI, 0.04 to 0.73]). No deaths were reported in the China cohort. In the Nefecon group, treatment-emergent serious adverse events were reported by one patient during treatment and two patients during follow-up (versus no patients and seven patients, respectively, in the placebo group). No severe infections requiring hospitalization were reported. Nefecon treatment for 9 months showed greater preservation of eGFR over 2 years compared with placebo. The efficacy outcomes were consistent with global study results, with a numerically greater treatment benefit observed in patients from China. Nefecon was well tolerated, with no unexpected safety signals.

Safety, Tolerability, and Efficacy of Mezagitamab (TAK-079) as Add-On to Standard of Care Therapy in Individuals with Primary IgA Nephropathy: Interim Results from an Open-Label Phase 1b Study

Safety, Tolerability, and Efficacy of Mezagitamab (TAK-079) as Add-On to Standard of Care Therapy in Individuals with Primary IgA Nephropathy: Interim Results from an Open-Label Phase 1b Study

A Multicenter Study on the Related Factors of Pathological Classification in Patients with Primary IgA Nephropathy

A Multicenter Study on the Related Factors of Pathological Classification in Patients with Primary IgA Nephropathy

C4d Is an Independent Predictor of the Kidney Failure in Primary IgA Nephropathy.

Background: C4d deposits are present in a substantial proportion of patients with IgA nephropathy (IgAN), indicating the activation of the lectin pathway (LP) of the complement system. It seems that patients with activated LP have worse renal prognosis. The aim of this study was to investigate the prevalence and prognostic significance of C4d in our cohort of patients with primary IgA nephropathy (pIgAN). Methods: Patients with pIgAN were recruited from a hospital register of kidney biopsies of the Department of Nephrology and Dialysis, Dubrava University Hospital, Zagreb. Additional immunohistochemistry staining for C4d was performed on paraffin-embedded kidney tissue, and patients were stratified into being C4d positive or C4d negative. The clinical and histologic features of patients were analyzed and compared regarding C4d positivity. The primary outcome was defined as kidney failure (KF), and predictor variables of KF and renal survival were analyzed. Results: Of a total of 95 patients with pIgAN included in the study, C4d was present in 43 (45.3%). C4d-positive patients had a higher value of systolic (p = 0.039) and diastolic (p = 0.006) blood pressure at diagnosis as well as higher 24 h proteinuria (p = 0.018), serum urate (p = 0.033), and lower eGFR (p < 0.001). C4d-positive patients had worse renal survival (p < 0.001), higher rates of disease progression to KF (p < 0.001), and higher proteinuria (p < 0.001) and lower eGFR (p < 0.001) at the last follow-up. Glomerular C4d was an independent predictor of disease progression to KF (HR = 5.87 [0.95 CI 1.06-32.44], p = 0.032). Conclusions: C4d is an independent predictor of disease progression in patients with pIgAN. C4d may be used as an additional marker of progressive disease course in IgAN. The therapeutic implications of C4d status in IgAN, particularly in terms of complement inhibitors application, are not yet known.

Correlation analysis of cofilin-1 with renal prognosis in primary IgA nephropathy

PurposeThe purpose of this study was to investigate the correlation between podocyte related biomarker cofilin-1 and renal function, and explore the value of cofilin-1 in predicting the risk of renal adverse prognosis in IgA nephropathy (IgAN).MethodsPatients with primary IgAN diagnosed by initial renal biopsy performed in our hospital from January 2019 to February 2022 were included. This study was a prospective cohort study. All IgAN patients were detected the expression of cofilin-1 and other related biomarkers (RhoA, NGAL) in urine by enzyme-linked immunosorbent assay (ELISA) and follow-up at least 6 months. We also collected baseline clinicopathologial data of IgAN. The decreased renal function group was defined as baseline eGFR < 60 ml/min/1.73m2. Logistic and Cox regression model were used to analyze the correlation among cofilin-1 and renal prognosis.Results133 IgAN patients were included, with a male-to-female ratio of 1.25:1 and an age of 37.67 ± 13.78 years, as well as an average of eGFR was 71.63 (40.42,109.33) ml/min/1.73m2. 56 patients (42.1%) had decreased renal function at baseline, with the average of eGFR was 34.07 (16.72, 49.21) ml/min/1.73 m2. 12 of which developed to renal adverse prognosis. The average of follow-up time was 22.035 ± 8.992 months. The multivariate regression analysis showed that increased urinary cofilin-1 was an independent risk factor associated with baseline renal function decline and renal adverse prognosis in IgAN patients (P < 0.05). ROC curves showed great efficacy of urinary cofilin-1 levels in diagnosing baseline renal function decline and predicting renal adverse prognosis (the area under the ROC curve was 0.708 and 0.803).ConclusionCofilin-1 as a novel biomarker of podocyte lesion is closely related to renal function decline in IgAN. Cofilin-1 has certain clinical value in predicting the risk of renal adverse prognosis. Podocyte fusion affects the renal prognosis of IgAN.

Immunosuppression, tonsillectomy and remissions in high-risk IgA-nephropathy

To evaluate the efficacy of immunosuppressive therapy (IST) and tonsillectomy (TE) in patients with high-risk IgA nephropathy (IgAN). Materials and мethods. The retrospective study cohort included cases with primary IgAN (n=213, age 34±11 years, male 52%) at high risk of progression with clinical and morphological data collected. The follow-up was 26 (10; 61) months. The association of IST without TE (IST; n=141) or with TE (IST+TE; n=72) with the development of complete (PR), partial (PR) and overall (PR or PR, OR) remissions was investigated. The incidence of achieving early PR or OR in the IST and IST+TE groups was 65.2% and 86.1%, respectively (p=0.002). The probability of early PR or OR was significantly increased in the IST+TE group compared to IST [HR 1.714 (1.214-2.420) and HR 3.410 (1.309-8.880), respectively]. IST+TE was associated with a 3- to 4-fold increase in the likelihood of PR or OR at the end of follow-up [HR 2.575 (1.679-3.950) and HR 4.768 (2.434-9.337), respectively]. Analyses using pseudorandomisation methods yielded similar results. TE may be effective for remission induction in high-risk IgAN.

The role of antibody glycosylation in autoimmune and alloimmune kidney diseases.

Immunoglobulin glycosylation is a pivotal mechanism that drives the diversification of antibody functions. The composition of the IgG glycome is influenced by environmental factors, genetic traits and inflammatory contexts. Differential IgG glycosylation has been shown to intricately modulate IgG effector functions and has a role in the initiation and progression of various diseases. Analysis of IgG glycosylation is therefore a promising tool for predicting disease severity. Several autoimmune and alloimmune disorders, including critical and potentially life-threatening conditions such as systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and antibody-mediated kidney graft rejection, are driven by immunoglobulin. In certain IgG-driven kidney diseases, including primary membranous nephropathy, IgA nephropathy and lupus nephritis, particular glycome characteristics can enhance in situ complement activation and the recruitment of innate immune cells, resulting in more severe kidney damage. Hypofucosylation, hypogalactosylation and hyposialylation are the most common IgG glycosylation traits identified in these diseases. Modulating IgG glycosylation could therefore be a promising therapeutic strategy for regulating the immune mechanisms that underlie IgG-driven kidney diseases and potentially reduce the burden of immunosuppressive drugs in affected patients.

Insights on Nefecon®, a Targeted-Release Formulation of Budesonide and Its Selective Immunomodulatory Effects in Patients with IgA Nephropathy.

Immunoglobulin A nephropathy (IgAN) is a chronic, immune-mediated kidney disease characterized by the deposition of galactose-deficient immunoglobulin A1 (Gd-IgA1) in the kidneys. Excess Gd-IgA1 production in patients with IgAN is located within the mucosa-associated lymphoid tissue, particularly within the lamina propria in the distal ileum. Nefecon® is a targeted-release formulation of the corticosteroid budesonide, which became the first treatment approved by the US Food and Drug Administration (FDA; brand name, TARPEYO®) and European Medicines Agency (EMA; KINPEYGO®) for patients with primary IgAN at risk of rapid disease progression, after demonstrating clinically significant reduction of proteinuria in an interim analysis of the Phase III NefIgArd trial. After showing a significant reduction in estimated glomerular filtration rate decline in the full 2-year analysis of the trial, Nefecon was granted full approval by the FDA to reduce the loss of kidney function. Nefecon was specifically designed to deliver budesonide to the distal ileum, selectively targeting excess Gd-IgA1 production in the gut-associated lymphoid tissue. In this review, we describe the properties of Nefecon and the evidence to date that confirms its localized treatment effect. We also present unpublished evidence from Phase I trials investigating the pharmacokinetics and cortisol suppression effects of Nefecon in healthy participants. These studies demonstrated that Nefecon has a distinct pharmacokinetic profile from other budesonide products, allowing for targeted, localized action in the distal ileum. When considered alongside existing clinical trial data showing the effect of Nefecon on gut-associated biomarkers, available evidence indicates that Nefecon has a selective immunomodulatory mechanism of action and a direct disease-modifying effect in patients with IgAN, while having low systemic exposure and adverse effects.

Crohn's disease-associated IgA nephropathy may prone to better renal outcome.

Renal involvement in Crohn's Disease (CD) was rare in the population. Little was known between IgA nephropathy and CD. This study aimed to investigate the differences in clinical and outcome features of CD-associated IgA nephropathy (CD-IgAN)and primary IgA nephropathy (PIgAN). Clinical data of patients diagnosed with IgAN by kidney biopsy were collected in the Sixth Affiliated Hospital of Sun Yat-sen University from January 1st, 2016 to June 1st, 2023. 17 patients with CD-IgAN and 87 patients with PIgAN were enrolled in this retrospective study. Compared with PIgAN patients, CD-IgAN patients had lower levels of urinary protein excretion (1.57g per 24h vs. 0.33g per 24h, p < 0.01), but higher levels of estimated glomerular filtration rate (77.63 ± 40.11ml per min per 1.73m2 vs. 104.53 ± 32.97ml per min per 1.73m2, p = 0.008). From the point of renal pathology of PIgAN, patients with CD-IgAN had a less incidence of tubular atrophy or interstitial fibrosis (p = 0.001). CD-IgAN patients had a higher incidence of complete remission of proteinuria (45.8% vs. 81.8%, p = 0.031) or hematuria (10.4% vs. 45.4%, p = 0.019) than PIgAN patients after twelve-month treatments. CD-IgAN manifests a milder progression of renal function than those PIgAN. After the treatment, proteinuria or hematuria are more prone to remit in patients with CD-IgAN.

#2042 Efficacy and safety of telitacicept in IgA nephropathy: a retrospective study

Abstract Background and Aims Telitacicept is a novel fusion protein composed of a recombinant transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) receptor fused with the fragment crystallizable (Fc) region of human immunoglobulin G (IgG). Telitacicept inhibits the differentiation of immature B cell and survival of long-lived plasma cells by neutralizing the activity of B Lymphocyte Stimulator (BlyS) and A Proliferation-Inducing Ligand (APRIL). It was approved for the treatment of patients with Systemic Lupus Erythematosus (SLE) in China in March 2021. Given that BlyS/APRIL overexpression has also been identified in IgA nephropathy (IgAN), telitacicept is in clinical trials for the treatment in IgAN. In this study, we aim to retrospectively evaluate the efficacy and safety of telitacicept in patients with IgAN. Method In this retrospective study, 27 patients with primary IgAN were enrolled from Nephrology Department of Renmin hospital of Wuhan university in China from February 2022 to March 2023. Patients were administered 160 mg telitacicept by subcutaneous injection based on the previous treatment once a week at least 4 weeks, and were followed up. Adults 20–75 years of age who met the following criteria were included: biopsy-proven primary IgAN and 24-hour proteinuria &amp;gt;0.75 g. Patients were excluded if they had secondary causes of IgAN, 24 h proteinuria &amp;lt;0.75 g or immunocompromised state. Changes in proteinuria, serum creatinine, estimated glomerular filtration rate (eGFR), serum immunoglobulins, complement protein (in blood serum), albumin, urine erythrocyte, blood leukocyte and hemoglobin were analyzed during treatment. Key assessment time points were at 2, 4, 8, 12, 16 and 24 weeks after the first administration. Results In this study, duration of telitacicept exposure ranged from 4 weeks to 32 weeks, the median of which was 16 weeks. After administration of telitacicept, baseline 24 h proteinuria of 3.37 g/d decreased to 1.05 g/d at the Week 24 (z = −4.46, p &amp;lt; 0.05), with reductions statistically significant by Week 4. During telitacicept treatment, the median eGFR showed stable trend without sudden decline. Compared to the baseline eGFR of 68.34 ml/(min 1.73 m2), the eGFR at Week 24 was 72 ml/(min 1.73 m2). Changes in immunoglobulin A (IgA), immunoglobulin G (IgG) and immunoglobulin M (IgM) all showed downward trend while complement protein 3 (C3) and complement protein 4 (C4) maintained stable trend. Specifically, IgA decreased from 2.51 g/L at baseline to 1.41 g/L at Week 24, there was a significant reduction by Week 4 (P = 0.001). The median of IgG decreased from 8.31 g/L at baseline to 6.71 g/L at Week 24, with reductions statistically significant by Week 4 (P = 0.008). IgM decreased significantly at Week 2 from baseline of 1.13 g/L to 1.05 g/L (P = 0.017) and was 0.64 g/L at Week 24. The median C3 was stable from baseline to Week 24 (0.92 g/L, 0.87 g/L, respectively), and C4 were 0.22 g/L and 0.23 g/L, in order. Patients had a significant increase in albumin from baseline to Week 2 (P = 0.009) and the Week 24. (36.7 g/L, 37.1 g/L and 41.8 g/L, respectively). Conversely, there was a continuous reduction in urine erythrocyte, from baseline of 62.46/μL to 7.68/μL at Week 24. There remained stable in blood leukocyte from baseline to Week 24 (8.48 × 109/L, 8.67 × 109/L, respectively), with no significant changes. By the end of the study, 10/27 patients was in complete remission (CR) and 8/27 patients had achieved partial remission (PR). The overall remission rate of primary IgAN with telitacicept treatment reached 67%. Telitacicept was generally well tolerated in patients with IgAN in this study. No treatment-emergent adverse events (AEs) occurred in all 27 patients, such as respiratory tract infection, urinary tract infections and injection site allergic. Conclusion In conclusion, based on the retrospective analysis with a small sample, telitacicept, a novel BLyS/APRIL dual inhibitor, effectively decreases proteinuria in IgAN with stable renal function. In addition, it demonstrates a favorable safety profile in patients. The data are supportive of further study with telitacicept in IgAN.

#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 &amp;gt;1.1 g/g), and urinary protein excretion (% with urinary protein excretion &amp;gt;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 &amp;lt; 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.

#1444 Albuminuria and subsequent risk of kidney events in patients with IgA nephropathy: a nationwide cohort study

Abstract Background and Aims KDIGO recommends proteinuria &amp;lt;1 g/d as a treatment target in patients with immunoglobulin A nephropathy (IgAN) because of high-risk of progression to kidney failure. However, long-term kidney outcomes in patients with low-grade proteinuria remain poorly studied. Method We enrolled patients with biopsy-proven primary IgAN from the Swedish Renal Registry and analyzed associations between first-recorded urinary albumin-to-creatinine ratio (uACR, in categories &amp;lt;0.3, 0.3-0.5, 0.5-1.0, 1.0-1.5, 1.5-2.0 and &amp;gt;2.0 g/g) and the occurrence of major adverse kidney events (MAKE, a composite of kidney replacement therapy [KRT] and &amp;gt;30% decline in eGFR). We also explored the risk of MAKE associated with the fold-change in uACR within a year. Results We enrolled 1269 patients with primary IgAN (74% men, median 53 years, mean eGFR 33 mL/min/1.73 m², median uACR 0.7 g/g). Compared to patients with uACR &amp;lt;0.3 g/g, those with higher uACR levels were younger, more often men, had a higher prevalence of hypertension, diabetes, acute kidney injury, lower eGFR and serum albumin level, and were less often prescribed RASi. Over median follow-up of 5.5 [2.8;9.2] years, 667 MAKE and 517 KRT events occurred, and 528 patients experienced &amp;gt; 30% eGFR decline. In multivariable analyses, and compared with uACR &amp;lt;0.3 g/g, any higher uACR category strongly and incrementally associated with the risk of MAKE (Figure), with Hazard Ratios (HR) ranging from 1.56 [95% CI 1.14-2.14] in patients with uACR 0.3-0.5 g/g to 4.53 [3.36-6.11] in patients with uACR&amp;gt;2g/g. Similar graded relationships were observed for KRT (HR ranging from 1.39 to 4.65), and for &amp;gt;30% decline in eGFR (HR ranging from 1.76 to 3.47). In the 785 patients who had repeated uACR measurements within a year, and compared with stable uACR, the risk of kidney events was lower if uACR decreased by 2-fold (HR ranging from 0.47 to 0.49), and higher if uACR increased by 2-fold (HR from 1.18 to 2.56), irrespective of baseline uACR. Conclusion Our findings show substantial risk of adverse kidney outcomes among patients with IgAN and uACR between 0.3 and 1.0 g/g, a population currently considered at low-risk of CKD progression. Reduction in uACR is associated with better kidney outcomes, irrespective of baseline uACR.

#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 &amp;lt; 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.

#145 Subgroup and secondary endpoint evaluation of a phase 2 randomized placebo-controlled trial of ravulizumab in IgA nephropathy

Abstract Background and Aims The pathogenesis of IgA nephropathy (IgAN) involves immune complex deposition and activation of the complement system, causing formation of the terminal pathway components C5a and C5b-9, leading to inflammation and glomerular damage. Elevated levels of activated C3 in plasma are associated with proteinuria and renal function decline in patients with IgAN [1]; mesangial C3 deposition is also associated with progression of disease [2]. Ravulizumab is a humanized monoclonal antibody that immediately and completely inhibits complement component C5. Primary endpoint (week 26) data from the phase 2 randomized controlled trial (RCT) (NCT04564339) were previously reported and demonstrated a 30% and 33% treatment effect of ravulizumab compared to placebo on 24-hour urine protein and 24-hour urine protein-to-creatinine ratio (UPCR) reduction, respectively [3]. This analysis reports prespecified subgroup and secondary endpoints as well as post hoc exploration of treatment response by baseline serum C3 and C4 quartiles through week 26. Method The SANCTUARY RCT evaluated ravulizumab (IV; weight-based dosing Q8W) vs placebo in adults with primary IgA nephropathy. Randomized patients (2:1) were stratified by mean proteinuria (1–2 vs &amp;gt;2 g/day). Patients (18–75 years) with biopsy-confirmed IgA nephropathy, proteinuria ≥1g/day, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, and on stable maximally tolerated renin angiotensin inhibition were enrolled. The primary endpoint was proteinuria reduction at week 26 based on 24-hour urine collection. Secondary endpoints at week 26 included the proportion of patients with &amp;gt;50% reduction in proteinuria (absolute urine protein) and the percentage with &amp;lt;1g/day proteinuria. The percentage change in proteinuria (absolute urine protein) among subgroups of sex, race, duration of disease, baseline proteinuria and eGFR, and baseline serum C3 and C4 levels were also evaluated, as were safety data. Results 66 patients entered the 26-week initial evaluation period (n = 43, ravulizumab arm; n = 23, placebo arm); 71.2% were White and 21.2% were Asian. Overall, 41.5% and 18.2% of ravulizumab- and placebo-treated patients, respectively, achieved &amp;gt;50% proteinuria reduction (Fig. 1). Proteinuria reduction to &amp;lt;1g/day was achieved in 26.8% and 18.2% in the ravulizumab and placebo arms, respectively. Subgroup analysis indicated a treatment effect across subgroups of sex, race, disease duration, and baseline proteinuria and eGFR (Fig. 2). With ravulizumab, there were reductions of 41.9% and 41.0% in proteinuria for those with the lowest quartile of baseline serum C3 and C4, respectively. Similarly, reductions of 40.4% and 40.8% were observed in those with baseline serum C3 and C4 levels above the lowest quartile. In the ravulizumab arm, two patients had low serum C3 at baseline and there were no patients with low serum C4 at baseline; there was no change in mean serum C3 and C4 levels over time. Treatment with ravulizumab was well-tolerated. Conclusion In this phase 2 trial of ravulizumab in IgAN, proteinuria was significantly reduced with ravulizumab vs placebo through week 26. A reduction in proteinuria was also observed across subgroups of patients. As is typical in IgAN, serum C3 and C4 levels at baseline were normal, and there was no difference in proteinuria reduction by baseline serum C3 and C4 levels with ravulizumab through 6 months.

#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.

#2740 Pregnancy outcomes in patients with IgA nephropathy and the impact of pregnancy on the renal disease

Abstract Background and Aims IgA nephropathy (IgAN), the predominant primary glomerulonephritis in adults,, frequently affects women in childbearing age. There is a dearth of information about the impact of pregnancy on the outcome in IgAN especially in the Indian population where it is known to have an aggressive disease phenotype. This retrospective cohort study examines pregnancy outcomes in women with biopsy-proven IgAN and the impact on renal outcome. Method In a retrospective cohort study, we assessed the medical records of women in child bearing age (18-40 years) diagnosed with biopsy proven primary IgAN from 2012-2022. Patients with end stage kidney disease (ESKD) at the time of biopsy and/or at time of conception and those who had undergone kidney transplantation were excluded. Maternal (pre-eclampsia, relapse, renal disease progression, etc.) and fetal outcomes (neonatal death, preterm delivery, intra-uterine growth retardation-IUGR, etc.) were recorded. Relapse was defined as increase in proteinuria to ≥1 g/day during pregnancy and renal disease progression as &amp;gt;40% sustained decline in eGFR and/or ESKD. Results Of 75 women assessed, 25 were lost to follow up. 34 did not conceive after biopsy. 20 pregnancies were documented in 14 patients. Three (15%) were medically terminated, 7 (35%) resulted in spontaneous abortions, and 10 (50%) culminated in live births. There was one neonatal death. 6/20(30%) pregnancies occurred while the patient was on ACEi/ARBs of which 5 pregnancies resulted in live births. 7/10 (70%) births were premature, 5 being moderate preterm (34-37 weeks) and 2 late preterm (32-34 weeks). IUGR below the 5th percentile affected 7/10(70%) of births. The mode of delivery was evenly split between vaginal (5, 50%) and Caesarian (5, 50%). From a maternal perspective, preeclampsia affected 3/10 (30%) patients. 5/10(50%) patients who delivered had a relapse during pregnancy with 2 developing nephrotic range proteinuria. 4 of them receiving steroids during pregnancy. All relapsed patients had persistent proteinuria &amp;gt;1 g/day postpartum. In 2 (20%) pregnancies, relapse developed during immediate post-partum period. In 4 patients, eGFR decreased by &amp;gt; 40 percent compared to their baseline (at biopsy) following the pregnancy. Conclusion Pregnancy is associated with adverse maternal and fetal outcomes in women with IgA nephropathy. eGFR, estimated glomerular filtration rate. IUGR, Intra-uterine growth restriction (based on birth weight percentile, adjusted for gender and gestational age). *Serum creatine of one patient during pregnancy is not available, analysis is done using values of other 9 patients. **Urine Protein of one patient is not available at the latest follow-up, analysis is done using values of 9 other patients.

#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 (&amp;lt;2 g/g vs ≥2 g/g), eGFR (&amp;lt;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 &amp;lt;1 g/g and &amp;lt;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.

Indirect Markers of Intestinal Damage in IgA Nephropathy

Introduction: Presence of subclinical intestinal inflammation has repeatedly been shown in IgA nephropathy (IgAN) and the degree of histological inflammation has correlated with abnormal urinary findings. There is lack of noninvasive biomarkers evaluating the presence of subclinical intestinal damage in IgAN. We conducted this study hypothesizing that selected biomarkers regarded as indirect markers of intestinal damage could be elevated in IgAN. Methods: Eighty-five primary IgAN patients (median age 55 years, 54% men) participated in this single-center study in Tampere, Finland. None had end-stage kidney disease or previously diagnosed enteropathies. Celiac disease was excluded with serum transglutaminase 2 antibody (TG2Ab) and endomysial antibody tests and inflammatory bowel disease with fecal calprotectin. Intestinal damage was evaluated from sera with analyses of intestinal fatty-acid binding protein (I-FABP), soluble cluster of differentiation molecule 14 (sCD14), and lipopolysaccharide binding protein. Fourteen people suffering from dyspepsia and 15 healthy people served as controls. Results: I-FABP levels among IgAN patients were higher than in the healthy controls (median 830 pg/mL vs. 289 pg/mL, p < 0.001). Also, sCD14 was increased in IgAN patients compared to dyspepsia controls. Although TG2Ab levels were within the normal range among IgAN patients, they were higher than in the healthy controls (median 1.3 U/mL vs. 0.6 U/mL, p < 0.001). Conclusions: Elevated serum levels of I-FABP were present in primary IgAN patients without known enteropathies. Serum I-FABP may indicate the presence of subclinical intestinal damage. These findings encourage further investigation into the role of the intestine in the pathophysiology of IgAN.

Albuminuria predicts kidney events in IgA nephropathy.

KDIGO recommends proteinuria <1g/d as a treatment target in patients with immunoglobulin A nephropathy (IgAN) because of high-risk of progression to kidney failure. However, long-term kidney outcomes in patients with low-grade proteinuria remain insufficiently studied. We enrolled patients with biopsy-proven primary IgAN from the Swedish Renal Registry and analyzed associations between urine albumin-to-creatinine ratio (uACR, in categories<0.3, ≥0.3-0.5, ≥0.5-1.0, ≥1.0-1.5, ≥1.5-2.0 and≥2.0g/g) and the occurrence of major adverse kidney events (MAKE, a composite of kidney replacement therapy [KRT] and>30% decline in eGFR). We also explored the risk of kidney events associated with change in uACR within a year. We included 1269 IgAN patients (74% men, median 53 years, mean eGFR 33mL/min/1.73m², median uACR 0.7g/g). Over median follow-up of 5.5 [2.8;9.2] years, 667 MAKE and 517 KRT events occurred, and 528 patients experienced>30% eGFR decline. Compared with uACR<0.3g/g, any higher uACR category was strongly and incrementally associated with the risk of MAKE (adjusted HR ranging from 1.56 [95%CI 1.14-2.14] if uACR 0.3-0.5g/g to 4.53 [3.36-6.11] if uACR≥2.0g/g), KRT (HR ranging from 1.39 to 4.65), and eGFR decline>30% (HR ranging from 1.76 to 3.47). In 785 patients who had repeated uACR measurements within a year, and compared with stable uACR, the risk of kidney events was lower if uACR decreased by 2-fold (HR ranging from 0.47 to 0.49), and higher if uACR increased by 2-fold (HR from 1.18 to 2.56), irrespective of baseline uACR. There is substantial risk of adverse kidney outcomes among patients with IgAN and uACR between 0.3 and 1.0g/g, a population currently considered at low-risk of CKD progression. Reduction in uACR is associated with better kidney outcomes, irrespective of baseline uACR.