Updates on Glomerular Diseases: A Summary of Inaugural GlomCon Hawaii 2024

Glomerular diseases have long captivated the attention of nephrologists. However, recent advances and ongoing clinical trials resulting in available therapies have brought renewed focus and heightened interest to this intricate area of kidney pathology [1]. Effective management of glomerular diseases often requires a collaborative, multidisciplinary approach that integrates a comprehensive understanding of disease pathogenesis, accurate clinical assessment, and the appropriate use of immunosuppressive therapies, in addition to considering the potential for significant adverse effects of the therapies [1, 2]. In August 2024, GlomCon launched its 1st international hybrid conference on glomerular diseases in Maui, HI. The 4-day event, GlomCon Hawaii, offered a comprehensive program focused on deepening the understanding of glomerular disease pathogenesis, management, and clinical trials. The GlomCon Hawaii Conference showcased a distinguished and diverse faculty of 52 members, achieving an intentional and balanced gender representation of 50% male and 50% female. The event reached a total of 619 registrations. During the conference, GlomCon Hawaii recorded 5,292 posts from 512 contributors, including 4,420 reposts. This activity resulted in a total of 26,155,121 impressions using the #GlomConHawaii hashtag on X. This summary provides the latest update on glomerular diseases discussed during the GlomCon Hawaii Conference (Fig. 1).The treatment landscape for IgA nephropathy (IgAN) has been evolving rapidly with a growing array of therapeutic options and ongoing clinical trials. In December 2021, delayed-release budesonide received accelerated FDA approval for reducing proteinuria in adults with IgAN, followed by full approval in December 2023 for its efficacy in slowing kidney function decline [3, 4]. In February 2023, the FDA granted accelerated approval for sparsentan to reduce proteinuria in adults with IgAN. Full approval was subsequently granted in September 2024 based on the PROTECT Study, which demonstrated its effectiveness in significantly slowing kidney function decline over 2 years as a non-immunosuppressive treatment option [5, 6]. Additionally, based on the APPLAUSE-IgAN study, iptacopan received accelerated FDA approval on August 8th, coinciding with the GlomCon Hawaii conference [7]. The conference featured discussions on IgAN, emphasizing navigating treatment options with biopsy interpretation, estimated glomerular filtration rate (eGFR), urine protein-to-creatinine ratio (UPCR), and other patients’ individualized factors to guide personalized treatment approaches. Historically, patients with crescents on biopsy would have been treated with IV corticosteroids; however, iptacopan, an alternative complement pathway, is emerging as a potential treatment option [8]. According to the new draft of Kidney Disease Improving Global Outcomes (KDIGO) guidelines, it is now recommended to initiate supportive treatments for chronic kidney disease, such as renin-angiotensin-aldosterone-system inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and sparsentan, simultaneously with IgAN-specific drivers for nephron loss medications such as nefecon or systemic glucocorticoids for patients deemed high risk. Iptacopan was not mentioned in the draft of guidelines as its approval coincided with the time of KDIGO draft online publication [9].MEST-C score was discussed as a prognostic factor; however, it is not validated as a tool for guiding treatment. Hematuria as a marker of active disease was also discussed; however, its role remains a subject of ongoing debate, warranting further research to establish its correlation with disease activity. Furthermore, the need for biomarkers to assess treatment response or guide repeat kidney biopsies was a key topic of discussion. The consensus was that repeat kidney biopsies would likely remain necessary until reliable biomarkers become readily available for clinical use. The Risk Evaluation and Mitigation Strategies (REMS) program for sparsentan in the USA, designed to monitor liver enzymes and pregnancy, was identified as a potential barrier to practical implementation. Similarly, the REMS program requires vaccination prior to initiating iptacopan, which is essential but highlights the need for further educational efforts, as nephrologists may be unfamiliar with the protocol. Clinical trial enrollments might become more challenging due to the multitude of FDA-approved medications for IgAN. Guidelines remain under review, and the final report has yet to be published.Lupus nephritis (LN) affects approximately 60% of patients with systemic lupus erythematosus (SLE) [10]. While a kidney biopsy is not essential for diagnosis, it is critical for identifying the specific class of LN, the activity score, and the extent of chronic damage in the kidneys. Maintaining a low threshold for performing a kidney biopsy in patients with lupus is important to determine LN class and monitor response to treatment [11]. The BLISS-LN study showed some promising outcomes, particularly in achieving a sustained renal response, which was higher with belimumab than with placebo through week 104 (hazard ratio 1.58; 95% CI, 1.08–2.31). Additionally, belimumab attenuated the GFR decline by 30–40% compared to the standard of care (SoC) [12]. The AURORA trial had a different primary endpoint focused on the renal response at 52 weeks, defined by a reduction in proteinuria to <0.5 g/g. In the group receiving voclosporin plus SoC (with mycophenolate mofetil [MMF]), 73 out of 179 (41%) patients achieved a renal response, compared to 40 out of 178 (23%) patients in the standard care group (odds ratio, 2.65; 95% CI, 1.64–4.27; p < 0.0001) [13]. A study assessed the eGFR slope over 2 years, finding a change of −0.2 mL/min/1.73 m2 (95% CI, −3.0 to 2.7) in the voclosporin group, compared to −5.4 mL/min/1.73 m2 (95% CI, −8.4 to −2.3) in the control group. However, the voclosporin group demonstrated a sustained reduction in proteinuria and a higher rate of complete renal response at 36 months (50.9% vs. 39.0%; odds ratio, 1.74; 95% CI, 1.00–3.03) [14]. The availability, cost, and contraindications of voclosporin during pregnancy must be carefully considered. The conference highlighted the need for clinical trials to define standardized markers for renal response and identify new biomarkers that can aid in individualized therapy. KDIGO released a guideline update on LN in 2024 following the approval of new therapeutic agents [15]. The updates recommend induction therapy for class 3 and 4 LN, with or without a membranous component, using combination therapy that includes glucocorticosteroids plus one of the following: (a) mycophenolic acid analogs (MPAAs), (b) low-dose cyclophosphamide (as per the Euro-lupus protocol [16]), (c) calcineurin inhibitors (CNIs) (voclosporin if eGFR >45 mL/min per 1.73 m2 or tacrolimus with serum Cr <3.0 mg/dL) in combination with MPAA (especially in patients with nephrotic range proteinuria due to extensive podocyte injury), or (d) belimumab in combination with MPAA or low-dose cyclophosphamide, particularly in patients with a high risk of LN flare and non-nephrotic range proteinuria [15]. The discussion also encompassed the role of B-cell depletion in LN. Rituximab has been used in some cases of refractory LN; however, its overall efficacy remains a topic of debate due to mixed results from clinical trials and clinical practice [17‒20]. Obinutuzumab, a novel therapeutic agent with enhanced B cell-depleting capabilities, has shown significant promise in the phase 2 NOBILITY trial [21]. In this study, 38% of patients receiving obinutuzumab in combination with SoC achieved a renal response, compared to 16% of patients receiving placebo plus SoC at week 76 while receiving 7.5 mg or less prednisone daily (p < 0.01) [21]. Additionally, obinutuzumab was associated with a 57% reduction in LN flares and a slower eGFR slope decline with an annualized eGFR slope advantage of 4.1 mL/min/1.73 m2 per year (95% confidence interval, 0.14–8.08) [21]. A German study introduced CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy to 12 patients, including 8 with severe LN. The study reported clinical remission in these patients after 6 months, underscoring the potential impact of deep B-cell depletion in the modulation of autoimmune diseases like LN [22]. These findings are particularly noteworthy as CAR-T and obinutuzumab highlight the role of deep B-cell depletion, distinguishing them from rituximab, which primarily targets peripheral B cells. This distinction suggests that CAR-T and obinutuzumab may offer improved outcomes for patients with refractory LN [22].During the discussion regarding membranous nephropathy (MN), the conference sparked the evolution of understanding its pathophysiology, particularly in light of the discovery of numerous antigenic targets over the past decade [23, 24]. These antigens were found to be associated with specific clinical entities, increasing their utility in diagnosing underlying triggers for MN. Autoimmune diseases have been linked to several antigens, including exostosin-1/2 (EXT-1/2), neural cell adhesion molecule 1 (NCAM-1), and protocadherin 7, while antigens such as neural epidermal growth factor-like 1 (NELL-1) and thrombospondin type-1 domain-containing 7A (THSD7A) have been associated with malignancy [24, 25]. Although these antigens are mainly detected in the biopsy specimen, many antibodies have been detected in the serum of patients with what was formerly classified as “primary MN,” including anti-phospholipase A2 receptor (PLA2R), anti-NELL-1, anti-protocadherin-7 (PCDH7), thrombospondin type-1 domain-containing 7A (THSD7A), and anti-netrin G1 (NTNG1) antibodies. Except for PLA2R-antibody and THSD7A circulating autoantibody testing, which are commercially available as well as available for kidney biopsy staining, the clinical utility of the other antibodies and their correlation with disease activity remain to be fully established [24, 26, 27]. Antigens may also carry prognostic implications. For instance, EXT-1/2 positivity supports lesser disease activity and better prognosis in patients with membranous LN [28]. Collectively, the clinical associations, prognostic implications, and potential of using antibodies against the recently discovered antigens for serological follow-up of disease activity supported transitioning to a novel antigen-based classification for MN with hopes that mass spectrometry would be readily available in more centers in the future [24, 29]. The discussion was later followed by the presentation of a clinical case of biopsy-proven PLA2R-positive MN with profound nephrotic syndrome and severe hypoalbuminemia (1.3 g/dL). This case triggered a fruitful discussion on the role of kidney biopsy in diagnosing PLA2R-positive MN. While most experts supported the KDIGO guideline recommendation that a kidney biopsy is not required for the diagnosis of PLA2R MN, a few supported the utility of a kidney biopsy to establish a histological baseline, diagnose coexisting pathologies, and to initiate treatment promptly, especially in centers where PLA2R-antibody titers take up to 2 weeks to result [30]. Many therapeutic options for high-risk patients with severe MN were proposed, including rituximab, cyclophosphamide, and a combination of both. The MENTOR trial compared rituximab versus cyclosporine for the management of MN. One hundred and thirty patients with proteinuria ≥5 g/day were randomized to receive rituximab and cyclosporine therapy. Rituximab was non-inferior to cyclosporine in achieving partial/complete remission of proteinuria and superior to cyclosporine in maintaining remission [31]. The STARMEN trial showed that alternating treatment with cyclophosphamide and steroids was superior to sequential treatment with tacrolimus and rituximab in PLA2R-positive MN [32]. A 2-year follow-up of 60 patients with MN who were treated with low-dose cyclophosphamide, rituximab, and steroids showed a complete and partial remission rate of 83% and 100%, respectively [33]. Other experts suggested rituximab or cyclophosphamide with steroids as alternative therapeutic options for high-risk patients, highlighting the variation in clinical approaches among nephrologists in managing high-risk MN. They also discussed the possible utility of neutrophil margination in kidney biopsy of patients with MN and serum albumin in raising suspicion for underlying hypercoagulability and initiating prophylactic anticoagulation [34].The discussion on podocytopathies began with a lecture on the pathology of minimal change disease and focal segmental glomerulosclerosis (FSGS). The lecture included recent updates in the pathophysiology of podocytopathies, including the role of anti-nephrin antibodies in minimal change disease [35]. Then, recent advances in the understanding of genetic forms of FSGS, including apolipoprotein-1 (APOL1) mediated kidney disease (AMKD), and the possible role of genetically inhibiting the pore-forming function of APOL1 in preventing AMKD were covered [36]. More recently, inaxaplin, an APOL1 channel inhibitor, was discovered to be effective in ameliorating proteinuria and podocyte damage in patients with AMKD [37]. Currently, there is an ongoing multicenter, double-blind, placebo-controlled phase 2/3 trial to study the effect of inaxaplin in patients with AMKD [38]. Toward the discussion of clinical management of podocytopathies, the faculty speakers, panelists, and audience reviewed treatment options for steroid-resistant FSGS, highlighting CNIs as the considered usual the first-line therapy and rituximab and MMF as subsequent options [39]. During the GlomCon Hawaii conference, it was recommended starting tacrolimus with a target trough level of 4–6 ng/mL for 2 years in patients with steroid-resistant or relapsing FSGS or those with a UPCR greater than 3 g/g after 6 months. If there is no response to tacrolimus, a 2-year trial of rituximab may be considered, followed by alternative options, including other B-cell-depleting agents, combination therapies, or enrollment in a clinical trial. The discussion concluded with a focus on genetic FSGS, emphasizing the potential underdiagnosis of coexisting genetic abnormalities, such as collagen-4A-1 (COL4A-1) mutations, in patients with FSGS [40].The promising outcomes of the VALIANT study were highlighted in discussions surrounding C3 glomerulopathy (C3G) and immune complex glomerulonephritis [41]. During the GlomCon Hawaii conference, we had a press release on Aug 8th as phase 3 VALIANT Study of Pegcetacoplan a targeted C3 inhibitor in C3G and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) had met the primary endpoint, achieving statistically significant 68% (p < 0.0001) reduction in proteinuria compared to placebo by week 26 [41]. Importantly, disease-specific activity was demonstrated, with histological improvement in C3 staining over the course of treatment [42]. The results of the open-label extension are highly anticipated. 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