INTRODUCTION:Nephrotic syndrome (NS), a common glomerular disease in children, is classified based on response to corticosteroid therapy as either steroid-sensitive nephrotic syndrome (SSNS), or steroid-resistant nephrotic syndrome (SRNS). However, there are no current reliable predictors of therapy response at initial clinical presentation. METHODS:To evaluate predictors, we conducted genome-wide association studies, developed polygenic risk scores (PRS) for therapy response and analyzed classical HLA alleles in 1,997 children (994 discovery and 1,003 replication/validation cohorts) previously unstudied children with NS and 3,558 ancestry-matched control individuals. RESULTS:A significant association with HLA loci defined by variants in HLA-DQB1, HLA-DRB1, and HLA-DQA1 were found for SSNS (but not SRNS), along with a second immune-related SSNS locus: CLEC16A. A PRS that discriminates between SSNS and SRNS was validated in two independent cohorts. The HLA haplotype HLA- DRB1∗07:01∼DQA1∗02:01∼DQB1∗02:02 was associated with about four times the risk of developing SSNS. A model incorporating HLA haplotype, PRS score, and age at disease onset was the best predictor of steroid responsiveness with an area under the curve of 0.68-0.70 and an overall classification accuracy of SSNS versus SRNS of 67-71%. CONCLUSIONS:Our findings confirm that SSNS, unlike SRNS, is an immune-mediated HLA-associated disorder. The PRS for therapy response and HLA haplotype can serve as biomarkers, provide a foundation for more accurate diagnoses and tailored individualized treatment.

BACKGROUND:Approximately 50% of patients with chronic kidney disease due to C3 glomerulopathy (C3G) or primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN) will require dialysis and/or kidney transplantation (KTx) within the first 10 years of disease onset. Currently, there are no guidelines regarding the indications for KTx or post-transplant management. METHODS:We therefore initiated an international online survey via Survey Monkey on C3G and IC-MPGN in children with CKD stage 5. All KTx centers of the European Society for Paediatric Nephrology (ESPN) were invited to participate in the survey, which was conducted from August 23 to November 25, 2023. RESULTS:Sixty-five (63%) of the centers (n = 103) participated. Twenty-six percent had made at least one decision against living donation for a child with C3G or IC-MPGN. The main reason for 88.2% of these decisions was concern about the recurrence of the underlying disease in any potential transplant. Eighty-eight percent indicated deceased donation as an option; 12% decided not to proceed with transplantation at all. Regarding KTx decision-making or management, none of them referred to an existing recommendation by any national or regional guideline. For the recurrence of C3G or IC-MPGN post-transplant, eculizumab treatment was suggested by 60% of respondents. CONCLUSION:This survey shows a considerable reluctance of pediatric nephrologists to list patients with CKD stage 5 due to C3G or IC-MPGN for living donor kidney transplantation. This decision is mainly based on the fear of recurrence of the underlying disease combined with the lack of reliable treatment options. This limited access of affected patients to the best treatment option for kidney failure requires further action.

Background:Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis, requiring a kidney biopsy for diagnosis. This study aimed to estimate the prevalence of primary IgAN within the European Union (EU) and investigate the potential impact of the coronavirus disease 2019 (COVID-19) pandemic on kidney biopsy rates and IgAN diagnosis frequency. Methods:We conducted four comprehensive literature searches to identify data on the IgAN prevalence and incidence, native kidney biopsy rates and COVID-19 impact on these metrics. We calculated country-specific prevalence estimates based on a combination of published and modeled data, incorporating biopsy frequency and the Healthcare Access and Quality Index (HAQI). The EU IgAN prevalence was derived from country-specific prevalence estimates weighted by population size. Results:The estimated prevalence of IgAN in the EU was 4.31 per 10 000 population, with large geographic variation among countries, ranging from 0.16 to 14.4 per 10 000 population. A strong correlation was observed between the IgAN incidence and biopsy rate (R2 = 0.96). Countries with a higher HAQI mostly exhibited higher biopsy rates and IgAN incidences. The COVID-19 pandemic resulted in a notable decrease in kidney biopsy rates for most European countries with available information in 2020 compared with both pre- and post-pandemic periods. However, the long-term implications of this reduction on biopsy rates and subsequent IgAN incidence remain to be determined. Conclusion:Our findings confirm the rarity of IgAN, albeit the most common type of glomerulonephritis. They underscore a robust correlation between biopsy rates and IgAN incidence, influenced by healthcare access and quality. The COVID-19 pandemic's temporary suppression of biopsy rates in 2020 suggests potential delays in IgAN diagnosis, warranting further investigation into the long-term effects.

The complement system, consisting of three initiating pathways—classical, lectin and alternative, is an important part of innate immunity. Dysregulation of the complement system is implicated in the pathogenesis of several autoimmune and inflammatory diseases. Therapeutic inhibition of the complement system has been recognized as a viable approach to drug development and has been successful with the approval of a small number of complement inhibitors for diseases such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, neuromyelitis optica, myasthenia gravis and geographic atrophy. More recently, therapies selectively targeting the alternative pathway (AP), which drives the amplification of the complement responses, are being evaluated for these complement-mediated diseases. Complement Factor B, a serine protease, is a unique component of the AP that is essential for the catalytic activity of AP C3 convertase and AP C5 convertase. Inhibition of Factor B blocks the activity of the alternative pathway and the amplification loop, and subsequent generation of the membrane attack complex downstream; however, it has no effect on the initial activation mediated by the classical and lectin complement pathways. Therefore, Factor B is an attractive target for diseases in which the AP is overactivated. In this review, we provide an overview of Factor B and its critical role in the AP, discuss the benefit-risk of Factor B inhibition as a targeted therapeutic strategy, and describe the various Factor B inhibitors that are approved and/or in clinical development.

Introduction: C3 glomerulopathy (C3G) is a complex, chronic, ultra rare, progressive primary glomerulonephritis, resulting from alternative complement pathway overactivation, leading to kidney failure in most patients, and frequent recurrence in transplants. Iptacopan (LNP023) is an oral, proximal complement inhibitor specifically targeting factor B, that selectively inhibits the alternative complement pathway. Methods: This was a phase 2 extension study of 26 adult patients with native kidney (cohort A), or recurrent C3G (post kidney transplantation; cohort B) receiving open label iptacopan. Results: At 12 months, patients in cohort A had a significant reduction in 24-hour urine protein-to-creatinine ratio (UPCR; 57%; P < 0.0001; confidence interval [CI]: 0.31-0.59), an improvement in estimated glomerular filtration rate (eGFR; 6.83 ml/min per 1.73 m(2); P = 0.0174; CI: 1.25-12.40), and an increase in serum C3 levels (geometric mean ratio to baseline: 3.53; P < 0.0001; CI: 3.01-4.15). In cohort B, most patients had normal urinary protein excretion at baseline (mean [range] 24-hour UPCR: 121 [9-445]), which was slightly lower by 12 months (21% reduction; CI: 0.48-1.31; P = 0.3151). In cohort B at 12 months, mean eGFR was at baseline values (mean change from baseline: -0.96 ml/min per 1.73 m(2); P = 0.7335; CI: -6.60 to 4.69). Cohort B patients had significantly higher serum C3 values at 12 months compared with baseline (ratio:1.96; CI: 1.70-2.27; P < 0.0001). In cohorts A + B combined, the median difference in C3 deposit score on renal biopsy from baseline was -7.00 (CI: -12.00 to 4.00;) at 9 to 12 months treatment with iptacopan. Conclusion: These data provide a clinical rationale for further evaluation of long-term treatment of C3G with iptacopan.

BACKGROUND:C3 glomerulopathy is an ultra-rare, severe form of glomerulonephritis caused by overactivation of the alternative complement pathway. We aimed to assess efficacy and safety of iptacopan (LNP023), an oral, proximal complement inhibitor that targets factor B to selectively inhibit the alternative pathway of the complement cascade. METHODS:APPEAR-C3G was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study of iptacopan versus placebo (both in addition to supportive care [renin-angiotensin-aldosterone system (RAAS) inhibitors] and immunosuppression). Adult participants (aged 18-60 years) with biopsy-confirmed C3 glomerulopathy were enrolled from 35 hospitals or medical centres in 18 countries. Inclusion criteria included reduced serum C3 concentration (ie, <77 mg/dL [defined as <0·85 × lower limit of the central laboratory normal range]) at screening, urine protein-creatinine ratio (UPCR) of 1·0 g/g or higher at day -75 and day -15 before randomisation, estimated glomerular filtration rate (eGFR) of 30 mL/min per 1·73 m2 or higher at screening and day -15, and vaccination against Neisseria meningitidis and Streptococcus pneumoniae. All eligible participants were randomised 1:1 via interactive response technology to either the iptacopan or the placebo group, stratified by treatment with corticosteroids, mycophenolic acid, or both (yes or no). During the 6-month double-blind period, participants orally received either iptacopan 200 mg twice daily or placebo; this was followed by a 6-month open-label period in which all participants received iptacopan 200 mg twice daily. The primary endpoint was relative reduction in proteinuria (measured by log-transformed ratio to baseline in UPCR sampled from a 24-h urine collection) at 6 months. The primary analyses were done in the full analysis set (ie, all participants to whom study treatment was assigned by randomisation); all participants who received at least one dose of study treatment were included in the safety analysis. This trial was registered with ClinicalTrials.gov (NCT04817618) and the adult cohort has been completed. FINDINGS:Between July 28, 2021, and Feb 15, 2023, 132 participants were screened, of whom 58 did not complete the screening period and 74 (64% male; 69% White) were randomised 1:1 to receive either iptacopan (n=38) or placebo (n=36). One participant in the placebo group discontinued treatment during the open-label period. The 24-h UPCR percentage change relative to baseline at 6 months was -30·2% (95% CI -42·8 to -14·8) in the iptacopan group and 7·6% (-11·9 to 31·3) in the placebo group. In the iptacopan group, the geometric mean of 24-h UPCR was 3·33 g/g (95% CI 2·79 to 3·97) at baseline and 2·17 g/g (1·62 to 2·91) at 6 months; in the placebo group, this was 2·58 g/g (2·18 to 3·05) at baseline and 2·80 g/g (2·37 to 3·30) at 6 months. The primary endpoint was met with a relative reduction in 24-h UPCR at 6 months for iptacopan versus placebo of 35·1% (13·8 to 51·1; p=0·0014). 30 (79%) of 38 participants in the iptacopan group had treatment-emergent adverse events, compared with 24 (67%) of 36 participants in the placebo group; most of these were of mild or moderate severity. There were no deaths, no treatment discontinuations due to treatment-emergent adverse events, and no meningococcal infections. Serious adverse events were reported in three (8%) participants in the iptacopan group and one (3%) participant in the placebo group. INTERPRETATION:Iptacopan showed a statistically significant, clinically meaningful proteinuria reduction in addition to RAAS inhibitors and immunosuppression at 6 months. Iptacopan was well tolerated with an acceptable safety profile in patients with C3 glomerulopathy. FUNDING:Novartis Pharma.

Introduction: C3 glomerulopathy (C3G) and immune-complex membranoproliferative glomerulonephritis (ICMPGN) are rare disorders that frequently result in kidney failure over the long-term. Presently, there are no disease-specific treatments approved for these disorders, although there is much interest in the therapeutic potential of complement inhibition. However, the limited duration and necessarily small size of controlled trials means there is a need to quantify how well short-term changes in estimated glomerular filtration rate (eGFR) and proteinuria predict the clinically important outcome of kidney failure. Methods: We address this using longitudinal data from the UK Registry of Rare Kidney Diseases (RaDaR) involving retrospective and prospective data collection with linkage to hospital laboratories via automated feeds of 371 patients. Analyses of kidney survival were conducted using Kaplan-Meier and Cox regression with eGFR slope estimated using linear mixed models. Results: In a median of 11.0 (inter quartile range 7.4-15.1) years follow-up, 148 patients (40%) reached kidney failure. There was no significant difference in progression to kidney failure between C3G and IC-MPGN groups. Baseline urine protein-creatinine ratio (UPCR), although high, was not associated with kidney failure in either group. Two-year eGFR slope had a modest association with kidney failure. In contrast, both 20%.50% and 50 mg/mmol reductions in UPCR between 0-12 months were associated with lower kidney failure risk in both groups. Notably, those with a UPCR under 100 mg/mmol at 12 months had a substantially lower risk of kidney failure (hazard ratio 0.10 (95% confidence interval 0.03-0.30). Conclusions: Overall, proteinuria a short time after diagnosis is strongly associated with long-term outcomes and a UPCR under 100 mg/mmol at one year is associated with a substantially lower kidney failure risk.

Introduction: Immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) is an ultra-rare, fast-progressing kidney disease that may be idiopathic (primary) or secondary to chronic infection, autoimmune disorders, or monoclonal gammopathies. Dysregulation of the alternative complement pathway is implicated in the pathophysiology of IC-MPGN; and currently, there are no approved targeted treatments. Iptacopan is an oral, highly potent proximal complement inhibitor that specifically binds to factor B and inhibits the alternative pathway (AP). Methods: This randomized, double-blind, placebo-controlled phase 3 study (APPARENT; NCT05755386) will evaluate the efficacy and safety of iptacopan in patients with idiopathic (primary) IC-MPGN, enrolling up to 68 patients (minimum of 10 adolescents) aged 12 to 60 years with biopsy-confirmed IC-MPGN, proteinuria >= 1 g/g, and estimated glomerular filtration rate (eGFR) >= 30 ml/min per 1.73 m(2). All patients will receive maximally tolerated angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and vaccination against encapsulated bacteria. Patients with any organ transplant, progressive crescentic glomerulonephritis, or kidney biopsy with >50% interstitial fibrosis/tubular atrophy, will be excluded. Patients will be randomized 1:1 to receive either iptacopan 200 mg twice daily (bid) or placebo for 6 months, followed by open-label treatment with iptacopan 200 mg bid for all patients for 6 months. The primary objective of the study is to evaluate the efficacy of iptacopan versus placebo in proteinuria reduction measured as urine protein-to-creatinine ratio (UPCR) (24-h urine) at 6 months. Key secondary end points will assess kidney function measured by eGFR, patients who achieve a proteinuria-eGFR composite end point, and patient-reported fatigue. Conclusion: This study will provide evidence toward the efficacy and safety of iptacopan in idiopathic (primary) IC-MPGN.

Complement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare chronic kidney diseases with an overall poor prognosis, with approximately 40–50

Abstract Background and Aims Complement 3 glomerulopathy (C3G), due to dysregulation of the alternative complement pathway (AP), is an ultra-rare primary glomerulonephritis. Iptacopan (LNP023) is an oral, proximal complement inhibitor that specifically binds factor B and inhibits the AP. We previously reported the primary endpoint data from the Phase (Ph) 2 extension study (NCT03955445), showing proteinuria reduction (57% [p &lt; 0.0001]) and estimated glomerular filtration rate (eGFR) improvement (by +6.83 mL/min/1.73 m2 [p = 0.0174]) from baseline, following 12 months (M) of treatment with iptacopan in patients with C3G. Here we present further long-term efficacy and safety data from patients with C3G and recurrent C3G (post-kidney transplantation), who completed 33M of treatment with iptacopan (NCT03955445). Method Adults with C3G disease (Cohort A) or C3G recurrence post-transplantation (Cohort B) received iptacopan 200 mg twice-daily (bid) for at least 12 weeks in the Ph2 study (NCT03832114) before entering the open label extension study (NCT03955445). Long-term efficacy was assessed by a number of renal endpoints, including a 2-component composite renal endpoint (eGFR stability [≤10% reduction] and ≥50% proteinuria reduction). Long-term safety and tolerability of iptacopan was continually monitored. Results Of 27 patients completing the Ph2 study (NCT03832114), 26 (16 Cohort A, 10 Cohort B) entered the extension study treatment with iptacopan 200 mg bid; 22 patients (14 Cohort A, 8 Cohort B) completed the 33M visit (i.e., 3M in the Ph2 study and 30M in the extension study). In Cohort A, 42.9% of patients met the 2-component composite renal endpoint criteria at 33M. Proteinuria (first morning void [FMV] urine protein–creatinine ratio [UPCR]) was reduced by 41% (p = 0.0097) compared to baseline. eGFR stabilized or improved in most patients (13/16) over time and change from baseline at the 33M time-point was −3.18 mL/min/1.73 m2 (p = 0.3512). C3 levels increased by 275% (p &lt; 0.0001) from baseline. In Cohort B, eGFR change from baseline at the 33M time-point was −6.34 mL/min/1.73 m2 (p = 0.0571), and C3 levels increased by 102%. Baseline proteinuria values (FMV UPCR) were within the normal range for most participants in Cohort B and remained so during iptacopan treatment. Iptacopan was generally well-tolerated, and most adverse events were of mild severity in both cohorts. Biomarkers demonstrated substantial AP inhibition. Conclusion Long-term treatment with iptacopan was associated with sustained reduction in proteinuria in patients with C3G (Cohort A), and preservation of eGFR. These improvements in kidney function were associated with substantial inhibition of the AP leading to normalization of serum C3. Iptacopan was well-tolerated with no new safety findings in the long term, in patients with C3G, including those with recurrence post-transplantation on top of broad triple immunosuppression. The ongoing Ph3 APPEAR-C3G study (NCT04817618) is evaluating the efficacy and safety of iptacopan in patients with C3G.

Abstract Background and Aims Primary membranoproliferative glomerulonephritis (MPGN), is a rare kidney disorder which can be further divided into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G) based on relative complement and immunoglobulin staining on biopsy specimens. There is limited literature on the natural history and long-term outcomes of this disorder. The aims of this study were to: Method Adult and paediatric patients with diagnostic biopsy reports that could be classified or reclassified as C3G or IC-MPGN within RaDaR were included. RaDaR contains data on MPGN patients from kidney units across the UK, with automated collection of retrospective and prospective laboratory data. Follow-up time was from diagnosis, defined by biopsy date, until KF, death or last available test result. Kidney failure was defined as initiation of dialysis, kidney transplantation or sustained eGFR ≤15 mL/min/1.73 m2 for ≥4 weeks. Annualized rate of eGFR loss (eGFR slope) was calculated for the first 24 months and over full duration of follow-up. A linear mixed model was used to estimate each patient's intercept and slope of eGFR using a minimum of four observations. Analyses of time to KF were conducted using Kaplan–Meier estimates with log-rank tests for comparisons and Cox regression. The latter was used to investigate the association of early (within 24 months of diagnosis) changes in urine protein:creatinine ratio (UPCR), eGFR and eGFR slope with KF events over maximum of 20 years. Results Our cohort included 135 patients with C3G and 152 patients with IC-MPGN diagnosed between 1987 and 2020. At the time of diagnosis 153/287 (53%) of the cohort were paediatric (<18 years old). Both groups had significant proteinuria at baseline (Table 1). Median eGFR was 70 mL/min/1.73 m2 (IQR 30-92) and 58 mL/min/1.73 m2 (IQR 40-110) for C3G and IC-MPGN respectively. Median time to KF was 9.3 years for C3G and 12 years for IC-MPGN but the difference was not statistically significant (p = 0.31). KF was significantly associated with changes in UPCR between 0-12 months and 6-12 months (HRs adjusted for eGFR) (Fig. 1). Similarly, a 50 mg/mmol reduction in time-averaged UPCR between 0-12 months and 6-12 months was also strongly associated with a lower risk of KF (HR adjusted for eGFR [95% Confidence Interval] 0.66 [0.53-0.83] and 0.71 [0.59-0.85] respectively). Both annualized 24 month eGFR slope, and percentage change in eGFR at 24 months were also significantly associated with KF events (Fig. 1). Conclusion We present one of largest studies describing the demographics, clinical characteristics, and long-term outcomes of 287 UK patients with IC-MPGN and C3G. Consistent with other studies we found no statistically significant difference in time to KF for C3G and IC-MPGN patients. We also demonstrate the value of short-term changes in proteinuria and eGFR (within 24 months of biopsy diagnosis), for predicting long-term risk of kidney failure.

IC-MPGN is an ultra-rare, fast-progressing complement-mediated kidney disease characterized by immunoglobulin deposits in the kidneys, which may be idiopathic (primary) or secondary to chronic infections, autoimmune disorders, or monoclonal gammopathies. The clinical presentation and disease course are comparable to complement 3 glomerulopathy, also characterized by membranoproliferative histology. Dysregulation of the alternative pathway (AP) is strongly implicated in the pathogenesis of both glomerulonephritis entities including children and adults.