B Cell Therapy in Nephrotic Syndrome.pptx

B Cell Therapy in Nephrotic Syndrome

1. B Cell Therapy in Nephrotic Syndrome

2. Introduction to Nephrotic Syndrome Nephrotic syndrome is a clinical constellation characterized by massive proteinuria, hypoalbuminemia, and edema Affects approximately 3-5 per 100,000 adults annually with significant morbidity and mortality Traditional management focused on corticosteroids and immunosuppressive agents Recent evidence highlights the critical role of B cells in disease pathogenesis B cell-targeted therapies represent a paradigm shift in treatment approach Understanding B cell biology is crucial for optimal therapeutic outcomes Kidney Int. 2022;101(4):680-695

3. Definition Proteinuria : ≥3.5 g/day or protein/creatinine ratio >3.5 g/g Hypoalbuminemia : Serum albumin <3.0 g/dL (30 g/L) Edema : Typically bilateral, starting in dependent areas Hyperlipidemia : Elevated cholesterol and triglycerides Lipiduria : Presence of lipid casts and oval fat bodies May be associated with thromboembolism and increased infection risk Kidney Int. 2022;101(4):680-695

4. Etiology in Adults In adults, the etiology of nephrotic syndrome encompasses both primary (idiopathic) and secondary causes. Primary causes include minimal change disease (MCD), which accounts for 10-15% of adult cases, focal segmental glomerulosclerosis (FSGS) representing 35-40%, and membranous nephropathy (MN) comprising 25-30% of cases. Secondary causes include diabetic nephropathy, systemic lupus erythematosus, amyloidosis, and drug-induced nephropathy Kidney Int. 2022;101(4):680-695

5. Etiology in Adults Infectious causes: Hepatitis B, hepatitis C, HIV, malaria Malignancy-associated: Hodgkin's lymphoma, solid tumors Drug-induced: NSAIDs, gold, penicillamine, interferon Hereditary nephritis: Alport syndrome, congenital nephrotic syndrome Kidney Int. 2022;101(4):680-695

6. Etiology in Adults Kidney Int. 2022;101(4):680-695 Normal and damaged glomerular filtration barrier in nephrotic syndrome, illustrating proteinuria due to barrier disruption

7. Clinical Features of Nephrotic Syndrome Fluid retention: Peripheral edema, ascites, pleural effusion Cardiovascular: Increased risk of atherosclerosis and thromboembolism Infectious complications: Increased susceptibility due to immunoglobulin loss Metabolic disturbances: Protein malnutrition, vitamin D deficiency Renal manifestations: Progressive kidney function decline Systemic effects: Fatigue, muscle weakness, growth retardation in children J Am Soc Nephrol. 2021;32(11):2671-2689

8. Pathophysiology of Nephrotic Syndrome and Role of B Cells 1. Traditional Perspective: T Cell-Mediated Disease Historically, nephrotic syndrome was primarily regarded as a T cell-driven disorder. This view was supported by several clinical observations: infections such as measles, which suppress cellular immunity, were associated with temporary symptom remission; and immunosuppressive drugs like cyclosporine, which selectively inhibit T cell activation, showed significant therapeutic benefit. These findings led to the long-standing belief that dysregulated T cell activityrather than autoantibody productionwas central to disease pathogenesis. J Am Soc Nephrol. 2021;32(11):2671-2689

9. Pathophysiology of Nephrotic Syndrome and Role of B Cells 2. Modern Insights: Pivotal Role of B Cells Recent advances in immunopathology have shifted focus toward the critical role of B cells in the development and progression of nephrotic syndrome. B cells contribute through multiple mechanisms: They produce pathogenic autoantibodies that directly target podocyte-associated proteins, disrupting the glomerular filtration barrier. They secrete cytokines such as IL-4 and IL-13, which induce structural and functional podocyte injury, thereby promoting proteinuria. Dysregulated B cell homeostasis contributes to a broader immune imbalance, affecting both adaptive and innate responses. These insights have helped explain the observed efficacy of B cell-depleting therapies like rituximab in steroid-dependent and frequently relapsing cases. J Am Soc Nephrol. 2021;32(11):2671-2689

10. Pathophysiology of Nephrotic Syndrome and Role of B Cells 3. Integrated View: Dual Immunologic Dysregulation Emerging evidence supports a combined role of T and B cell abnormalities in nephrotic syndrome. Biomarkers such as soluble CD25 (sCD25, a marker of T cell activation) and soluble CD23 (sCD23, a marker of B cell activation) have been shown to rise synchronously during disease relapse and decline during remission. This parallel activation suggests a coordinated immunologic mechanism rather than isolated T or B cell involvement. Therefore, nephrotic syndrome is increasingly understood as a complex immune disorder involving cross-talk between T cells, B cells, and podocytes, necessitating more comprehensive and targeted immunomodulatory strategies. J Am Soc Nephrol. 2021;32(11):2671-2689

11. J Am Soc Nephrol. 2021;32(11):2671-2689

12. Anti-Nephrin and Anti-Podocin Antibodies Anti-Nephrin Antibodies Anti-nephrin autoantibodies represent a crucial pathogenic mechanism in nephrotic syndrome. These antibodies were initially detected in 29% of patients with minimal change disease, with levels increasing during acute phases and decreasing during remission, closely correlating with disease progression . Recent multicenter studies using novel assay techniques have detected anti-nephrin autoantibodies in approximately 65-90% of children with idiopathic nephrotic syndrome and up to two-thirds of adult patients with minimal change disease and active nephrotic syndrome. Nat Rev Nephrol. 2021;17(11):748-763

13. Anti-Nephrin Antibodies The mechanism of action involves disruption of the slit diaphragm structure through multiple pathways. Anti-nephrin antibodies interact with Neph1 and disrupt the interaction between Neph1 and ZO-1, leading to rapid reduction in glomerular ZO-1 levels and disordered glomerular filtration function. Additionally, these antibodies interact with ephrin-b1, promoting JNK phosphorylation and leading to structural destruction of the slit diaphragm Nat Rev Nephrol. 2021;17(11):748-763

14. Anti-Podocin Antibodies Anti-podocin antibodies, while less extensively studied than anti-nephrin antibodies, play an important role in steroid-resistant nephrotic syndrome. Research has investigated the presence of anti-podocin antibodies in patients with NPHS2 mutations, particularly in recurrent nephrotic syndrome following kidney transplantation. However, extensive searches for anti-podocin antibodies using indirect Western blot with recombinant podocin have often yielded negative results, suggesting that other unknown pathogenetic mechanisms may be involved in podocin-related disease recurrence. Nat Rev Nephrol. 2021;17(11):748-763

15. Detailed diagram of the nephron's glomerulus and glomerular filtration barrier showing cellular and molecular components relevant to nephrotic syndrome pathophysiology

16. Need for B Cell Depletion Therapy The rationale for B cell depletion therapy in nephrotic syndrome stems from multiple lines of evidence demonstrating the central role of B cells in disease pathogenesis. The success of rituximab, a CD20-targeting monoclonal antibody, in treating steroid-dependent and frequently relapsing nephrotic syndrome has provided clinical proof of concept for B cell-targeted therapy. The effectiveness of rituximab in maintaining remission in 70-95% of patients with steroid-dependent nephrotic syndrome, the correlation between B cell recovery and disease relapse, and the observation that memory B cells play a crucial role in disease recurrence. Kidney Int. 2022;101(4):680-695

17. Need for B Cell Depletion Therapy Mechanistic rationale includes: B cells serve as antigen-presenting cells providing co-stimulatory signals to T cells, they produce cytokines that modulate T cell differentiation, and they are the source of pathogenic autoantibodies targeting podocyte proteins. The depletion of B cells may restore regulatory T cell function and reduce production of permeability factors Kidney Int. 2022;101(4):680-695

18. B Cell Development and Proliferation Pathway and Site of Action of Various Drugs B cell development follows a well-defined pathway from hematopoietic stem cells in the bone marrow through multiple stages of differentiation. The process begins with pro-B cells in the bone marrow, where functional rearrangement of immunoglobulin gene fragments occurs. These cells progress through pre-B cells and immature B cells expressing surface IgM, before migrating to secondary lymphoid organs Nat Rev Drug Discov. 2021;20(4):287-306

19. B Cell Development and Proliferation Pathway and Site of Action of Various Drugs In the periphery, B cells differentiate into several distinct populations: follicular B cells (the predominant population requiring T cell help for activation), marginal zone B cells (providing first-line defense against pathogens), and B1 cells (rapidly differentiating into short-lived plasma cells secreting natural IgM). Upon antigen stimulation, mature B cells can differentiate into plasma cells producing large quantities of antibodies or memory B cells providing long-term immunity Nat Rev Drug Discov. 2021;20(4):287-306

20. B Cell Development and Proliferation Pathway and Site of Action of Various Drugs Drug targeting sites along this pathway include: CD20 (expressed on immature, mature, and memory B cells but not plasma cells), CD19 (expressed throughout B cell development including plasmablasts and some plasma cells), CD22 (B cell-specific adhesion molecule), and CD38 (highly expressed on plasma cells). BAFF and APRIL pathways regulate B cell survival and can be targeted with specific inhibitors Nat Rev Drug Discov. 2021;20(4):287-306

21. Rituximab Rituximab is a chimeric mouse/human IgG1 monoclonal antibody targeting the CD20 antigen expressed on B cells. Its mechanism of action involves three primary pathways: complement-dependent cytotoxicity (CDC) through C1q binding and complement activation, antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer cells and macrophages, and direct apoptosis induction . The standard dosing regimen involves 375 mg/m² weekly for 4 weeks, with B cell depletion occurring within 1-2 weeks and lasting 6-12 months Nat Rev Rheumatol. 2020;16(2):101-11

22. Obinutuzumab - Second Generation Anti-CD20 Humanized antibody: Reduced immunogenicity compared to rituximab Enhanced ADCC: Improved antibody-dependent cellular cytotoxicity Type II mechanism: Different binding epitope and effector functions Clinical studies: Ongoing trials in nephrotic syndrome Potential advantages: Superior B cell depletion and prolonged effect Safety profile: Similar to rituximab with possible infusion reactions Nat Rev Rheumatol. 2020;16(2):101-11

23. Ofatumumab - Humanized Anti-CD20 Fully humanized: Minimal immunogenicity potential Distinct epitope: Binds different CD20 epitope than rituximab Enhanced CDC: Superior complement-dependent cytotoxicity Clinical experience: Limited data in nephrotic syndrome Subcutaneous formulation: Convenient administration route Potential applications: Rituximab-resistant or refractory cases MAbs. 2020;12(1):1685349

24. Anti-CD38 Therapy (Daratumumab) CD38 expression: High expression on plasma cells and activated B cells Mechanism of action: ADCC, CDC, and direct apoptosis Deep B cell depletion: Targets both B cells and plasma cells Clinical rationale: Addresses antibody-producing plasma cells Preliminary studies: Case reports showing efficacy in refractory cases Future directions: Ongoing clinical trials in glomerular diseases Clin J Am Soc Nephrol. 2022;17(3):398-407

25. BAFF and APRIL Inhibitors Belimumab is a human IgG1 monoclonal antibody that neutralizes B cell activating factor (BAFF), a critical cytokine for B cell survival and differentiation. The drug reduces B cell numbers and autoantibody production while preserving memory responses . Atacicept is a recombinant fusion protein targeting both BAFF and APRIL (A Proliferation Inducing Ligand), providing broader B cell pathway inhibition. Clinical trials have demonstrated dose-dependent reductions in immunoglobulin levels and autoantibody titers Nat Rev Rheumatol. 2021;17(8):463-478

26. Nat Rev Rheumatol. 2021;17(8):463-478 Structure, epitope binding, and mechanisms of action of anti-CD20 monoclonal antibodies Rituximab, Ocrelizumab, Ofatumumab, and Ublituximab in B cell therapy

27. Monitor Therapy Monitoring B cell therapy requires a comprehensive approach encompassing laboratory parameters, clinical assessments, and safety surveillance. Laboratory monitoring includes CD19+ B cell counts (primary endpoint for assessing depletion efficacy), immunoglobulin levels (IgG, IgM, IgA) to detect hypogammaglobulinemia, and autoantibody titers to assess therapeutic response Clin J Am Soc Nephrol. 2021;16(8):1252-1261

28. Monitor Therapy Clinical monitoring focuses on proteinuria levels, serum albumin, renal function parameters, and infection surveillance. The timing of B cell recovery correlates with relapse risk, with studies showing that CD19 B cell percentages at 90 days correlate with relapse probability . Safety monitoring is crucial given the immunosuppressive effects of B cell depletion. Key parameters include infection rates, vaccination responses, and long-term immunologic consequences. Pre-existing low IgG levels have been identified as a risk factor for severe infections following rituximab therapy Clin J Am Soc Nephrol. 2021;16(8):1252-1261

29. Clin J Am Soc Nephrol. 2021;16(8):1252-1261

30. Guideline Recommendations The KDIGO 2021 guidelines for glomerular diseases have incorporated B cell-targeted therapies as important treatment options. For membranous nephropathy, rituximab is recommended for moderate to high-risk patients, with anti-PLA2R antibody levels used to guide therapy decisions . The KDIGO 2025 pediatric guidelines include updated recommendations for rituximab use in steroid-dependent nephrotic syndrome, reflecting the growing evidence base for B cell-targeted therapy in pediatric populations . European and national guidelines increasingly recognize rituximab as an important steroid-sparing agent, with specific recommendations for dosing, monitoring, and patient selection. The German pediatric nephrology guidelines provide detailed protocols for rituximab use in frequently relapsing and steroid-dependent nephrotic syndrome.

31. Future Therapies CAR-T Cell Therapy Chimeric antigen receptor (CAR) T cell therapy represents a revolutionary approach to autoimmune disease treatment. Anti-CD19 CAR-T cells have shown remarkable efficacy in systemic lupus erythematosus and lupus nephritis, with studies demonstrating sustained remission and immune reset . CAAR-T cells (chimeric autoantibody receptor T cells) represent a precision medicine approach, designed to specifically eliminate pathogenic B cells producing disease-specific autoantibodies while sparing normal B cell populations Nat Rev Nephrol. 2022;18(5):296-312

32. Future Therapies - Novel Approaches Bispecific antibodies: Dual targeting of B cells and T cells Antibody-drug conjugates: Targeted delivery of cytotoxic agents Epigenetic modulators: Targeting B cell differentiation pathways Checkpoint inhibitors: Modulation of B cell regulatory mechanisms Personalized medicine: Biomarker-guided therapy selection Combination therapies: Synergistic approaches targeting multiple pathways Nat Rev Nephrol. 2022;18(5):296-312

33. Conclusions B cell therapy has emerged as a transformative approach in nephrotic syndrome management, offering new hope for patients with difficult-to-treat disease. The clinical efficacy of rituximab and newer-generation B cell-targeted therapies has established this approach as a cornerstone of modern nephrotic syndrome treatment. Future directions include the development of more precise targeting strategies, combination therapies, and personalized medicine approaches based on individual patient characteristics and biomarker profiles.