![SECONDARY MN
Infections
HBV, HCV, HIV, parasites (filariasis,
schistosomiasis, malaria), leprosy,
syphilis, hydatid disease, sarcoid
Malignancy
Solid tumors (lung 26%, prostate
15%, hematologic [plasma cell
dyscrasias, non-Hodgkin
lymphoma, CLL] 14%, colon 11%),
mesothelioma, melanoma,
pheochromocytoma; some benign
tumors](https://image.slidesharecdn.com/membranousnephropathy-201227155515/85/Membranous-nephropathy-4-320.jpg)
Membranous nephropathy
- 2. INTRODUCTION • The term membranous refers to thickening of the glomerular capillary wall on light microscopy of a renal biopsy • Membranous nephropathy is defined by immunofluorescence and electron microscopy (EM). • Immune deposits of immunoglobulin G (IgG) and complement components beneath podocytes on the subepithelial surface of the glomerular capillary wall • Most common cause of primary nephrotic syndrome in older (>60 years)
- 3. PRIMARY MN • Anti-PLA2R associated (70%-80%) • Idiopathic (20%-30%) • Anti-THSD7A (up to 5%)
- 4. SECONDARY MN Infections HBV, HCV, HIV, parasites (filariasis, schistosomiasis, malaria), leprosy, syphilis, hydatid disease, sarcoid Malignancy Solid tumors (lung 26%, prostate 15%, hematologic [plasma cell dyscrasias, non-Hodgkin lymphoma, CLL] 14%, colon 11%), mesothelioma, melanoma, pheochromocytoma; some benign tumors
- 5. Autoimmune diseases SLE (class V), thyroiditis, diabetes, rheumatoid arthritis, Sjogren syndrome, dermatomyositis, mixed connective tissue disease, ankylosing spondylitis, retroperitoneal fibrosis, renal allografts Anti-GBM disease, IgAN, ANCA-associated vasculitis IgG4 disease Membranous-like glomerulopathy with masked IgG κ deposits
- 6. Alloimmune diseases Graft versus host disease, autologous stem cell transplants, de novo MN in transplants/transplant glomerulopathy Fetometernal alloimmunization to neutral endopeptidase Drugs/toxins NSAIDs and cyclooxygenase-2 inhibitors, gold, d-penicillamine, bucillamine, captopril, probenecid, sulindac, anti-TNFα, thiola, trimetadione, tiopronin Mercury, lithium, hydrocarbons, formaldehyde, environmental air pollution (China) Miscellaneous Cationic Bovine Serum Albumin (infants) Sarcoidosis
- 7. Experimental Membranous Nephropathy • Heymann nephritis model of MN in rats - late 1970s • Subepithelial immune deposits form in situ when circulating antibodies bind to an intrinsic antigen in the glomerular capillary wall • Antigen was subsequently identified as megalin,(internsic) • A large (~600 kD) transmembrane receptor of the low-density lipoprotein receptor family expressed on the basal surface of rat podocytes • Capping and shedding of the antigen-antibody complexes, where they bind to the underlying GBM, resist degradation, and persist for weeks or months as immune deposits characteristic of MN • Sublethal podocyte injury induced by the complement membrane attack complex C5b-9
- 8. • Podocyte foot process effacement is likely the result of the collapse of the actin cytoskeleton and loss of cell-GBM adhesion complexes, and the loss and displacement of slit diaphragms are associated with the onset of severe, nonselective proteinuria • ECM proteins that are laid down between and around the immune deposits, giving rise to the characteristic “spikes” and GBM thickening that are hallmarks of MN • Planted antigens - ainimal models immunized with cationized bovine serum albumin (cBSA). The cBSA binds to negatively charged residues in the GBM where it serves as a target for circulating anti-BSA antibodies
- 11. Human Membranous Nephropathy • First demonstration of an intrinsic podocyte antigen -by an unusual case of antenatal MN induced by the transplacental passage of alloantibodies to neutral endopeptidase (NEP), a known podocyte protein • The mother of the affected child was found to be deficient in NEP and had been immunized during a previous pregnancy • Same mechanism seen in • de novo MN after renal transplantation and • MN in the setting of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation
- 13. •AUTOANTIBODIES •PLA2R • autoantibodies directed at the M-type phospholipase A2 receptor (PLA2R) on podocytes • 75% to 80% of patients with primary MN • IgG4 •THSD7A • thrombospondin type 1 domain–containing 7A • 5% of cases of primary MN
- 14. • Planted antigen mechanism in MN • children with MN who have been exposed to cBSA, presumably in bottled milk • class V (membranous) lupus nephritis and • hepatitis B virus (HBV)–associated MN
- 15. Serum Antibody (±) Glomerular Antigen (±) Percent of Patients Who Underwent Biopsy, % Diagnosis Anti-PLA2R (+) PLA2R (+) 70 PLA2R-mediated PMN (active) Anti-PLA2R (−) PLA2R (+) 15 PLA2R-mediated PMN (inactive) Anti-THSD7A (+) THSD7A (+) 3–5 THSD7A-mediated PMN (active) Anti-THSD7A (−) THSD7A (+) Unknown THSD7A-mediated PMN (inactive) Anti-PLA2R/THSD7A (−) PLA2R/THSD7A (−) 10 Non-PLA2R/THSD7A– mediated (pathogenesis unknown)a
- 16. Pathology • STAGE I • Characteristic changes in MGN are in the glomerular capillary walls. • The initial phase of the glomerulopathy is marked by subepithelial granular deposits • Seen with light microscopy • Trichrome stain-fuchsinophilic • Methenamine-silver stain, -mottled aspect or very small orifices (“holes”) • Can be missed if we do not have immunofluorescence (IF) or electron microscopy (EM); these deposits are immune and will be positive for IgG and, in most of cases, for C3, in addition, they are electron-dense
- 18. • STAGE II • Glomerular architecture is preserved and the capillary walls appear thickened with routine stains • Cellularity usually is not increased (if present it suggests a secondary MGN) • Projections perpendicularly to this GBM: “spikes” are seen • Spikes are originated in reaction to the deposits and go progressively surrounding them (type IV collagen)
- 21. • STAGE III • Forming thus new layers of GBM leaving the deposits immersed • Deposits are seen intramembranous and with silver stain capillary walls can take an aspect in “chain” or “rosary” • Positive with the immunostaining (IF), although progressively they are less electron-dense
- 23. •STAGE IV •The GBM is irregularly thickened •Without the presence of electron-dense deposits or holes. •In this phase it is considered that the deposits have been resorpted leaving this irregular aspect.
- 25. IMMUNOFLUORESCENCE • Granular parietal IgG positivity • C3 deposits in approximately 75% of cases. • The IgG immunostaining usually is more intense than C3. • IgG4 sub-class is the most frequent
- 27. Primary Secondary Immunofluorescence Microscopy IgG4 > IgG1, IgG3 IgG1, IgG3 > IgG4 IgA, IgM absent IgA, IgM may be present Mesangial Ig staining absent Mesangial Ig staining may be present C1q negative or weak C1q positive PLA2R positive and co-localizes with IgG PLA2R negative Electron Microscopy Subepithelial deposits only ± mesangial rarely Subepithelial deposits ± mesangial and subendothelial deposits
- 28. ELECTRON MICROSCOPY • Electron-dense deposits in the epithelial aspect (external) of the GBM, between this one and the epithelial cell: subepithelials or epimembranous • Spikes are demonstrated as irregular projections of the GBM
- 31. CLINICAL FEATURES • Rare in children: Less than 5% of total cases of nephrotic syndrome • Common in adults: 15% to 50% of total cases of nephrotic syndrome, depending on age; increasing frequency after 40 • Males > females in all adult groups • Nephrotic syndrome in 60% to 70% • Normal or mildly elevated blood pressure at presentation • Benign urinary sediment • Nonselective proteinuria • Tendency to thromboembolic disease • Other features of secondary causes: Infection, drugs, neoplasia, systemic lupus erythematosus
- 32. Clinical features-correlating to Anti PLA2R • 70%–80% of patients with PMN have anti-PLA2R/THSD7A antibody • Anti-PLA2R antibody is about 80% sensitive and 100% specific for PMN • Anti-PLA2R antibody can be present for many months before proteinuria appears • In non-nephrotic patients, low, or declining, anti-PLA2R levels predict spontaneous remission and high levels predict progression to nephrotic syndrome • Anti-PLA2R–negative patients can become positive later • High antibody levels (before and after treatment) correlate with proteinuria, response to therapy, and (after therapy) long-term outcomes
- 33. • Patients with higher antibody levels require more prolonged immunosuppression to achieve remission rates comparable to those with lower levels • Expansion of the specificity of anti-PLA2R antibody to include additional epitopes (epitope spreading) correlates with a worse prognosis • Anti-PLA2R levels go down in remission and return with relapse • Elevated anti-PLA2R levels after treatment predict relapse • Elevated anti-PLA2R levels at the time of transplantation predict recurrence • Disappearance of anti-PLA2R antibodies (immunologic remission) precedes renal remission (disappearance of proteinuria) by weeks to months
- 34. • ELISA assay for PLA2R • Cell-based ALBIA assay (Mitogen Advanced Diagnostics Laboratory, Calgary, Canada) ELISA assay, levels >20 RU/ml are considered positive
- 35. Predictors of Poor Outcome Factors Predictor PPV (%) Clinical Features Age Older > younger 43 Gender Male > female 30 HLA type HLA/B18/DR 3/Bffl present 71 Hypertension Present 39 Serum Levels Albumin <1.5 g/dL 56 Creatinine Above normal 61
- 36. Urine Protein Nephrotic syndrome Present 32 Proteinuria >8 g for >6 months 66 IgG excretion >250 mg/day 80 β2-Microglobulin excretion >54 µg/mmol creatinine <54 79 C5b-9 excretion >7 mg/mg creatinine 67 Biopsy Changes Glomerular focal sclerosis Present 34 Tubulointerstitial disease Present 48
- 37. TORANTO RISK SCORE Low Risk Medium Risk High Risk Normal serum and creatinine plus proteinuria over 6 mo of Normal or near- creatinine clearance persistent proteinuria 8 g/day over 6 mo maximum treatment Deteriorating renal function (>30%decline GFR)and/or persistent proteinuria >8 g/day (up to 6) months of observation
- 40. OUTCOME Clinical Response Definition Complete remission Proteinuria <0.3 g/d Partial remission >50% reduction from baseline and between 0.3 and 3.5 g/d With stable GFR No remission <50% reduction or >3.5 g/d Relapse Recurrence of >3.5 g/d after remission ESRD GFR<15 ml/min or requirement for dialysis/transplant
- 41. • Relapse from a complete remission occurs in approximately 25% to 40% • Relapse rate is as high as 50% in those achieving only a partial remission • Review of 348 nephrotic patients with MN documented a 10-year renal survival • complete remission of 100% • partial remission, 90% • no remission, only 45%. • A recent update suggested durability of remission, whether complete or partial, drug-induced or spontaneous, is closely related to the long- term outcome. • Thus goal of therapy is Complete and partial remission
- 42. ST Regimen Drug, Dose Comments Cytotoxic drugs KDIGO first choice Modified Ponticelli Months 1, 3, 5: 1 g methylprednisolone iv on days 1, 2, and 3 followed by oral prednisone, 0.5 mg/kg daily for 27 d Monitor Uprotein and WBC weekly ×8, then every 2 mo; daily oral prednisone and cyclophosphamide may have similar efficacy. Increased risk of malignancy above 36 g Months 2, 4, 6: 2.0–2.5 mg/kg oral cyclophosphamide daily Relapse rate 20%–30% Dutch protocol Months 1, 3, 5: 1 g MP days 1–3 followed by oral prednisone, 0.5–1.0 mg/kg for 6 mo, then taper Same as above Oral cyclophosphamide, 1.5–2.0 mg/kg daily for 12 mo
- 43. CNIs KDIGO second choice Cyclosporin 3.5–5.0 mg/kg daily in divided doses adjusted to level of 120–200 μg/L for 12–18 mo and tapered Used in patients resistant to cytotoxic drugs but can be used as initial therapy. Taper slowly Prednisone 5–10 mg daily or alt days Discontinue at 6 mo if no response Relapse rate 40%–50% Tacrolimus 0.05–0.075 mg/kg daily in two divided doses adjusted to level of 3–5 μg/L for 12–18 mo and taper slowly Same as above Prednisone 5–10 mg/kg per day daily or alt days Preferable in young women B cell depletion Used for patients resistant to cytotoxic drugs or CNIs Utility as initial therapy not yet established by RCTs Rituximab 375 mg/M2 weekly times 4 Follow CD20 counts and repeat dose if counts rise before remission in proteinuria or relapse occurs 375 mg/M2 once and follow CD20/19 counts 1000 mg on days 1 and 15 ACTH Tetracosactrin (Synacthen) (synthetic) 1 mg IM every 2 wk for 6–12 mo Corticotropin (ACTHAR) (purified) 80 U IM every 2 wk for 6–12 mo
- 44. • MULTIDRUG THERAPY • Rituximab with low-dose cyclophosphamide and an accelerated taper of steroids reported a 100% remission rate over a mean follow-up of 37 months • Rituximab and CSA, achieved remissions in 92% and antibody depletion in 100% in 9 months • A combination of rituximab and plasma exchange showed promise in a third small study
- 45. Transplantation in PMN • In anti-PLA2R–positive patients, subepithelial deposits can appear in the allograft within 6 days • Proteinuria is seen within 13–15 months in about 40%–50% of allografts and can diminish allograft survival • Recurrence rate of subepithelial deposits in patients positive for anti- PLA2R antibodies at the time of transplantation may approach 90% • Anti-PLA2R–negative de novo MN is also a common cause of transplant nephrotic syndrome, affecting about 2% of all renal transplant recipients whose original disease was not MN
- 46. • Because patients with recurrent subepithelial deposits do not all go on to manifest clinical recurrence, treatment for recurrent MN is usually considered only when protein excretion reproducibly exceeds 1 g/d in patients with PMN or 4 g/d in patients with de novo MN • Rituximab is usually added to regular immunosuppressive protocols, which often already include CNIs -one dose of 200 mg
- 47. NEW THERAPY • Belimumab, an inhibitor of B cell activation, in 11 anti-PLA2R–positive patients reported a 90% reduction in anti-PLA2R levels and a (delayed) 70% reduction in proteinuria in patients receiving monthly iv doses of the drug over a period of 28 weeks
- 48. THANK U…