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Updates in management of membranous nephropathy - Dr. Mohammed Kamal Nassar
This document discusses updates in the management of membranous nephropathy (MN). It begins by reviewing the current status and pathogenesis of MN, noting it is a common cause of nephrotic syndrome. It then discusses progress made in understanding MN, including identifying podocyte antigens and autoantibodies associated with MN. Rituximab therapy is emerging as a promising new treatment approach, targeting B cells and plasma cells to provide disease-specific therapy. Ongoing clinical trials are further evaluating rituximab compared to conventional immunosuppressive regimens. The conclusion emphasizes that evaluation of autoantibody levels and proteinuria can guide tailored treatment protocols, moving away from nonspecific toxic therapies towards safer disease
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Updates in management of membranous nephropathy - Dr. Mohammed Kamal Nassar
- 1. Updates in Managementof Membranous Nephropathy By Mohammed Kamal Nassar, MD Lecturer of Nephrology Mansoura University
- 2. Focus of thetalk •MN – The Current Status •MN – The Progress •MN – Changing Mind •MN – Towards Disease-Specific Therapy •MN - Conclusion
- 3. Focus of thetalk •MN – The Current Status •MN – The Progress •MN – Changing Mind •MN – Towards Disease-Specific Therapy •MN - Conclusion
- 4. Primary membranous nephropathy Akidney-specific, autoimmune glomerular disease that presents with increased protein in the urine associated with a pathognomonic pattern of injury in glomeruli
- 5. Epidemiology • Commonest causeof idiopathic nephrotic syndrome in nondiabetic adults worldwide. • Representing between 20 - 37% in most series. • Rising to as high as 40% in adults over 60. • 10%–20% of patients with PMN currently progress to ESRD. Cattran & Brenchley. Kidney Int 2017; 91:566–574.
- 6. Causes Clin J AmSoc Nephrol 2017;12: 983–997.
- 7. Pathogenesis Clinical and ExperimentalImmunology 2015; 183: 157–165
- 8. Primary vs secondaryMN Lancet 2015; 385: 1983–92
- 9. Exclude Malignancy Clin JAm Soc Nephrol 2014; 9: 609–616.
- 10. Treatment: Wait andSee Protocol Cattran D. JASN 2005; 16:1188-1194.
- 11. Treatment Clin J AmSoc Nephrol 2017;12: 983–997.
- 12. Treatment Clin J AmSoc Nephrol 2017;12: 983–997.
- 13. Focus of thetalk •MN – The Current Status •MN – The Progress •MN – Changing Mind •MN – Towards Disease-Specific Therapy •MN - Conclusion
- 17. The absence ofcirculating PLA2R autoantibody at the time of kidney biopsy does not rule out a diagnosis of PLA2R-related membranous nephropathy.
- 18. N Engl JMed 2014;371:2277-87
- 20. Target podocyte antigens Lancet2015; 385: 1983–92
- 21. Interpretation of serumanti-podocyte antibody and glomerular antigen staining in PMN Clin J Am Soc Nephrol 2017;12: 983–997.
- 22. Clinical and translationalcorrelates of circulating levels of anti-PLA2R Clin J Am Soc Nephrol 2017;12: 983–997.
- 23. Clinical and translationalcorrelates of circulating levels of anti-PLA2R Clin J Am Soc Nephrol 2017;12: 983–997.
- 24. Focus of thetalk •MN – The Current Status •MN – The Progress •MN – Changing Mind •MN – Towards Disease-Specific Therapy •MN - Conclusion
- 26. J Am SocNephrol 2017; 28: 421–430.
- 27.
- 28.
- 29. Therapeutic algorithm J AmSoc Nephrol 2017; 28: 421–430.
- 30. Focus of thetalk •MN – The Current Status •MN – The Progress •MN – Changing Mind •MN – Towards Disease-Specific Therapy •MN - Conclusion
- 31. Towards disease specifictherapy Nature Reviews Nephrology. 2017;13(9):563.
- 32. B cell andplasma cell-targeted protocols Nature Reviews Nephrology. 2017;13(9):563.
- 33. Rituximab Expert Review ofClinical Pharmacology 2016; 9(11):1463-1478
- 34. J Am SocNephrol 2017;28:348-358.
- 35. Outcome J Am SocNephrol 2017;28:348-358.
- 36. Changes in proteinuria JAm Soc Nephrol 2017;28:348-358.
- 37. Changes in albumin JAm Soc Nephrol 2017;28:348-358.
- 38. Changes in anti–PLA2R-Ablevels J Am Soc Nephrol 2017;28:348-358.
- 39. Efficacy at extendedfollow up J Am Soc Nephrol 2017;28:348-358.
- 40. Adverse effects J AmSoc Nephrol 2017; 28:348-358.
- 41. Ongoing trials The RI-CYCLOtrial • Rituximab vs cyclical steroid and cyclophosphamide MENTOR trial • Rituximab vs ciclosporin STARMEN trial • Rituximab + tacrolimus vs steroids plus cyclophosphamide.
- 42. Failure of rituximab 1.Changes in the CD20 antigen that prevent B cell–rituximab binding and B-cell depletion Nature Reviews Nephrology. 2017;13(9):563. Belimumab
- 43. Belimumab Nephrol. Dial. Transplant2015; 30, iii32–iii33.
- 44. 2. production bylong-lived memory plasma cells that do not express the CD20 antigen • Anti-CD38 monoclonal antibodies: daratumumab and isatuximab • Proteasome inhibitors: bortezomib, delanzomib and carfilzomib Failure of rituximab
- 45. Focus of thetalk •MN – The Current Status •MN – The Progress •MN – Changing Mind •MN – Towards Disease-Specific Therapy •MN - Conclusion
- 46. Conclusion • Evaluation ofserum autoantibody titre and proteinuria, together with serum albumin could guide diagnosis of MN and individually tailor treatment protocols. • Conventional, nonspecific, and toxic immunosuppressive regimens will become treatments of the past, to be replaced by more disease-specific and safer medications, such as B cell-targeting monoclonal antibodies and autoreactive plasma cell inhibitors.
- 47. • Treatment couldbe anticipated at earlier and milder stages of MN, even before the onset of nephrotic syndrome, to prevent chronic and potentially irreversible histological changes. • Patients who were previously left untreated, so as not to expose them to the toxicity of cyclophosphamide, might benefit from B cell-targeted therapy, which can prevent memory cell clone expansion associated with uncontrolled disease progression towards disease that is refractory to currently available therapy. Conclusion
- 48.
Editor's Notes
- #10 Investigations suggested to detect/exclude an underlying cancer in a patient with apparently idiopathic (primary) MN and repeatedly negative serologic tests for anti-PLA2R1 autoantibody and/or absence of PLA2R1 or IgG4 in glomerular deposits
- #16 A majority of patients with idiopathic membranous nephropathy have antibodies against a conformation-dependent epitope in PLA2R. PLA2R is present in normal podocytes and in immune deposits in patients with idiopathic membranous nephropathy, indicating that PLA2R is a major antigen in this disease.
- #22 (10%) who may: (1) develop detectable anti-PLA2R/THSD7A antibody later, (2) have diseasemediated by a different anti-podocyte antibody, or (3) develop another autoimmune disease to which the MN might be considered secondary. Over time, a threshold quantity of IgG4 and C5b-9 deposition is reached in some patients that is sufficient to cause enough podocyte injury/activation to increase urine protein excretion and lead to nephrotic syndrome (5–7,22,26). Just as appearance of proteinuria lags behind initial antibody production by weeks/months, so resolution of proteinuria (clinical remission) also lags behind antibody disappearance (immunologic remission) by week/months. This offset between immunologic and clinical remissions reflects the prolonged time required to form sufficient deposits to cause proteinuria initially and the time required to clear subepithelial deposits, repair podocyte and capillary wall damage, and restore glomerular permselectivity (5). Thus, proteinuria is a poor clinical biomarker for the pathogenetic disease processes that are targeted by current immunosuppressive therapies (IST).
- #23 Although the specificity of the anti-PLA2R assay for PMN is essentially 100%, this finding has somewhat blurred the distinction between primary and secondary disease because some patients with secondary diseases such as hepatitis B and C, cancer, and sarcoid have been found to be anti-PLA2R–positive suggesting the coincidental presence of PMN in some patients with an unrelated systemic disease rather than MN as a manifestation of, or secondary to, the systemic disease
- #28 Diagnostic algorithm. The diagnostic evaluation starts with a quantification of PLA2R Ab (ELISA; potentially superseded by ALBIA in the near future) and a screening for secondary disease, including antinuclear Abs, viral hepatitis serology, thyroiditis autoimmunity, chest x-ray (or computedtomography in patients at high risk formalignancy), andan evaluation for sarcoidosis in selected patients. The presence of PLA2R Ab and the absence of evidence for secondary disease confirm the diagnosis of a PLA2R Ab–associated MN, even without additional pathologic evidence. In patients with negative PLA2R Ab, staining for the PLA2R antigen on the biopsy identifies additional patients as PLA2R-associated MN. When both PLA2R Ab and antigen are negative, traditional immunopathologic characteristics, as delineated above, along with measurement of THSD7A Ab should be used to categorize MN as either primary or secondary. Patients without clear evidence of secondary disease butwith immunopathologic characteristics suggestive of secondaryMN may have an occult neoplasmand should be comprehensively screened for cancer. In view of the high prevalence of malignancy in THSD7A-associated MN, these patients should also undergo a thorough evaluation for occult malignancy. This algorithmwill likely change with the availability of newinformation. Recent data12 indicate that a substantial proportion of THSD7A-associated MN was IgG4 negative on biopsy, irrespective of whether a malignancy was present, suggesting that all patients who are PLA2R Ab/antigen negative, independent of the dominant IgG subtype in their renal biopsy, may need to be tested for THSD7A. We recognize that the diagnostic tools in this algorithm, in particular the measurement of THSD7A Ab and the specialized immunopathology studies, may not be widely or routinely available at present.
- #29 Prognostic algorithm. Although the temporal relationship between PLA2R Ab levels and disease activity is well established, a time lag of several months between immunologic and clinical response should be taken into account.Measurement of PLA2R Ab may obviate the need for a “wait and see” period of 6 months, as recommended by the Kidney Disease Improving Global Outcomes guidelines, and allow more rapid treatment decisions. Serial PLA2R Ab measurements may guide the decision to start IS. Patients with initial high PLA2R Ab titers should be followed monthly, whereas those with moderate to low PLA2R Abs should be re-evaluated bimonthly. This recommendation does not apply to patients with rapidly declining renal function, in whom prompt initiation of IS may be warranted. PLA2R Ab ELISA (Euroimmun): low =14–86 U/ml;moderate =87–204 U/ml; and high $204 U/ml.53 SCreat, serum creatinine.
- #30 Therapeutic algorithm. Patientswith aprompt androbust immunologic response may receive shorter than usual courses of IS. It is important to recognize that, for not only rituximab67 but also, cyclophosphamide,68 the stoppage of such therapies leaves sustained effects on B cell depletion for a variable period of time. A conversion to an alternative therapy should be considered in those who do not showa significant reduction in Ab titers. Patients with high baseline PLA2R Ab may require a longer duration of therapy to achieve immunologic remission and may need to be treated with more intensive and prolonged IS, possibly including plasma exchange.
- #32 Targets for monoclonal antibodies in B-cell lineages. B cells emerge from bone marrow stem cells as pro‑B cells and mature into pre‑B cells, immature B cells, mature B cells, and activated B cells. Eventually, they develop into antibody-secreting cells, including plasmablasts, plasma cells, and long-lived memory plasma cells that secrete IgA, IgE, IgG, and IgM antibodies. Autoreactive B‑cell clones can produce anti-M-type phospholipase A2 receptor (PLA2R) and anti‑thrombospondin type 1 domain containing 7A protein (THSD7A) antibodies and conceivably, autoantibodies against unknown antigens expressed on podocytes. As B cells mature, they develop various markers on the cell surface that can become targets for specific monoclonal antibodies. Anti‑CD20 monoclonal antibodies, such as rituximab and ofatumumab, bind and kill CD20‑expressing B cells (pre‑B cells, and immature, mature, and activated B cells), but not plasmablasts, mature plasma cells or memory plasma cells as they do not express this antigen. Plasma cells express CD38 and might, therefore, be a target for anti‑CD38 antibodies such as daratumumab and isatuximab. Immature, mature, and activated B cells express receptors for the B lymphocyte stimulator (BLyS, also known as BAFF) such as B cell activating factor receptor (BAFF‑R), B cell maturation antigen (BCMA), and the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI). The anti-BLyS monoclonal antibody belimumab might, therefore, prevent B-cell differentiation into plasma cells by blocking the interaction between this lymphocyte stimulator and its receptors. Proteasome inhibitors, such as bortezomib, can prevent antibody production by inducing plasma cell apoptosis, whereas anti‑CD38 monoclonal antibodies, such as daratumumab and isatuximab, can directly induce plasma cell cytolysis.
- #33 *Safe and well tolerated. Effectiveness of rituximab proven in randomized trials and observational studies. Preliminary observational evidence of efficacy for ofatumumab in rituximab-resistant forms of membranous nephropathy. ‡A second 375 mg/m2 dose of rituximab or a second dose of 300 mg of ofatumumab are administered 1 week after the first infusion if >5 circulating B cells per mm3 remain. §Preliminary evidence of efficacy from a small, randomized pilot study; no long-term data available. ||Preliminary observational evidence of efficacy in rituximab-resistant forms of membranous nephropathy; serious adverse effects. BLyS, B lymphocyte stimulator.
- #34 Small noncontrolled trials
- #35 Study design. After a pre-inclusion period of 6 months during which NIAT was optimized, patients were assigned either to NIAT plus Rituximab (375 mg/m2, two infusions at days 1 and 8) or to NIAT alone. Serum for anti-PLA2R-Ab determination was sampled at days 0 and 8, months 3 and 6, CD19 counts were determined at months 3 and 6; end points were assessed at month 6. The RCT was followed by an observational study during which follow-up was extended up to 24 months. IV, intravenous; R, rituximab.
- #39 The secondary end points are expressed as percentage changes in proteinuria, serum albumin, and PLA2R-Ab with time. Mean6SEM percentage changes from baseline in (A) proteinuria, (B) serum albumin, and (C) anti–PLA2R-Ab levels. Please note that C shows percentage changes of PLA2R antibodies in the subset of patients who had PLA2R-Ab at baseline. Bonferroni correction was applied; P value ,0.02 indicates statistical significance. NIAT is shown by blue lines, and NIAT-rituximab is shown by red lines. *P,0.02; **P,0.001; ***P,0.001.
- #43 The molecular configuration of the CD20 molecule. CD20 is a tetra-transmembrane protein that essentially remains on the membrane of B cells without dissociation or internalization upon antibody binding. CD20 has small and large extracellular loops. The binding sites of CD20 monoclonal antibodies, rituximab and ofatumumab, are indicated. Rituximab binds an epitope on the large loop only, whereas ofatumumab specifically recognizes an epitope encompassing both the small and large extracellular loops of the CD20 molecule.
- #44 Comparison of outcomes with belimumab or rituximab therapy. a | Percentage change in urinary protein to creatinine ratio (or 24 h proteinuria) versus baseline. b | Percentage change in anti-M-type phospholipase A2 receptor (PLA2R) antibody titre versus baseline. Data are from patients with membranous nephropathy and nephrotic syndrome treated with belimumab (n = 14) or rituximab (n = 132)61. Belimumab specifically targets the soluble form of B lymphocyte stimulator (BLyS, also known as BAFF)161. Changes in proteinuria and anti-PLA2R antibody titre after belimumab treatment seemed to parallel the changes observed after rituximab administration albeit with a delay in onset. Conceivably, the faster reduction in proteinuria and anti-PLA2R antibody titre after rituximab administration reflected the immediate B-cell lysis achieved by treatment, whereas the slower effect of belimumab might reflect the progressive ‘exhaustion’ of antibody-producing B cells secondary to BLyS binding and inhibition.
- #45 Whether early-stage membranous nephropathy is predominantly mediated by autoreactive B-cell clones sensitive to B‑cell targeted therapy, whereas more advanced disease is mediated by
- #49 could be instrumental in monitoring disease activity and guiding personalized therapy with conventional immunosuppressive protocols or specific B cell-targeting monoclonal antibodies78. Indeed, antibody levels provide a prompt and reliable indication of immunological status and an integrated evaluation of serology and proteinuria might accelerate therapeutic decision-making and address diagnostic uncertainties when proteinuria and antibody levels are discordant. Specifically, persistent proteinuria in the face of low antibody levels might reflect chronic damage, whereas high antibody levels in the absence of clinical symptoms could signal an impending relapse. This integrated approach to membranous nephropathy could increase diagnostic and prognostic accuracy, limit unnecessary exposure to immunosuppressive therapy, optimize efficacy of treatment, and minimize the risk or severity of recurrent disease in allotransplants78. These theories can now be addressed in prospective studies designed to test whether treatment titration to autoantibody titre will increase the probability of achieving remission from nephrotic syndrome and prevent relapse while decreasing the risk of treatment-related adverse effects. In antibody-negative patients, proteinuria and serum albumin levels remain the most sensitive markers of disease severity and outcome.