Membranoproliferative GN - Road to Diagnosis & Management - What is the evidence? - Dr. Gawad
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Membranoproliferative glomerulonephritis (MPGN) is a significant type of glomerular disease accounting for 7-10% of biopsy-confirmed cases, often linked to hypertension. The document discusses the classification and pathogenesis of MPGN, highlighting the transition from traditional to new classification systems based on the type of deposits in the glomeruli. It also reviews the challenges in treatment and the limited evidence for the effectiveness of immunosuppressive therapies in idiopathic MPGN.
Membranoproliferative GN - Road to Diagnosis & Management - What is the evidence? - Dr. Gawad
- 1. Membranoproliferative GN Road to Diagnosis & Management What is the evidence? Mohammed Abdel Gawad Nephrologist – Alexandria – Egypt Founder & Chairman of NephroTube [email protected]
- 2. Membranoproliferative glomerulonephritis (MPGN) is a glomerular disease. Alternative names: Mesangicapillary GN, Lobular GN MPGN may be idiopathic or secondary Definition
- 3. Epidemiology MPGN accounts for 7 to 10% of all cases of biopsy confirmed glomerulonephritis. (1) MPGN ranks as the third or fourth leading cause of ESRD among the primary glomerulonephritides. (2) (1) Zhou FD et al. Nephrol Dial Transplant 2009; 24:870-6. (2) Briganti EM et al. Nephrol Dial Transplant 2001;16:1364-7.
- 4. Clinical Presentation Systemic hypertension: It is resent in 50% to 80% of patients, It may occasionally be so severe that the presentation may be confused with that of malignant hypertension. F. Paolo Schena, Charles E. Alpers. Comprehensive Clinical Nephrology, 5th edition,
- 5. Clinical Presentation Specific presentation for type II MPGN (DDD) (will be discussed later) F. Paolo Schena, Charles E. Alpers. Comprehensive Clinical Nephrology, 4th edition, Chapter 21
- 6. Steps of Diagnosis & Management To get through evaluation of secondary causes we have to discuss first classification of MPGN.
- 7. MPGN is characterized by presence of deposits in different parts of the glomerulus (due to immunological abnormality) Classification Normal Glomerulus
- 9. Classification MPGN Type I MPGN Type II MPGN Type III
- 10. Classification – Traditional: According to SITE of deposits: Endothelial Cells Epithelial Cells GBM www.nephrotube.blogspot.com
- 11. Classification – Traditional: According to SITE of deposits: Endothelial Cells Epithelial Cells GBM Mesangial DepositsMPGN I www.nephrotube.blogspot.com
- 12. Classification – Traditional: According to SITE of deposits: Endothelial Cells Epithelial Cells GBM Mesangial DepositsMPGN III www.nephrotube.blogspot.com
- 13. Classification – Traditional: According to SITE of deposits: Endothelial Cells Epithelial Cells GBM Mesangial Deposits Tubules & Bowman’s Capsule Deposits MPGN II )DDD( www.nephrotube.blogspot.com
- 14. Classification
- 15. To get through NEW classification we have to discuss first pathogenesis of MPGN. Classification – New: According to TYPE of deposits: Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31
- 16. Classification – New: According to TYPE of deposits: (1) Kai H et al. J Nephrol. 2006: 19:215–219 (2) Williams DG. Pediatr Nephrol. 1997: 11:96–98 (3) Braun MC et al. Pediatric nephrology. 2004:Elsevier, Philadelphia, pp147–155 (4) Image 1 source: Nalini S. Seminars in Immunopathology. 2008: 30: Issue 2. (5) Image 2 source: Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31. Regulatory proteins _
- 17. Classification – New: According to TYPE of deposits: (1) Kai H et al. J Nephrol. 2006: 19:215–219 (2) Williams DG. Pediatr Nephrol. 1997: 11:96–98 (3) Braun MC et al. Pediatric nephrology. 2004:Elsevier, Philadelphia, pp147–155 (4) Image 1 source: Nalini S. Seminars in Immunopathology. 2008: 30: Issue 2. (5) Image 2 source: Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31. C3 nephritic factor )C3NeF(: an IgG or IgM autoantibody that binds and prevents the inactivation of C3 convertase (2) + Regulatory proteins _ Nephritic factor of the terminal pathway )NeFt( (3) + chronic antigenemia and the generation of nephritogenic immune complexes (1) + C4 nephritic factor )C4NeF( +
- 18. Classification – New: According to TYPE of deposits: (1) Kai H et al. J Nephrol. 2006: 19:215–219 (2) Williams DG. Pediatr Nephrol. 1997: 11:96–98 (3) Braun MC et al. Pediatric nephrology. 2004:Elsevier, Philadelphia, pp147–155 (4) Image 1 source: Nalini S. Seminars in Immunopathology. 2008: 30: Issue 2. (5) Image 2 source: Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31. C3 nephritic factor (C3NeF): an IgG or IgM autoantibody that binds and prevents the inactivation of C3 convertase (2) + Regulatory proteins _ Mutation or autoantibodies (2) Nephritic factor of the terminal pathway (NeFt) (3) + chronic antigenemia and the generation of nephritogenic immune complexes (1) + C4 nephritic factor (C4NeF) + Ig + Complement
- 19. Classification – New: According to TYPE of deposits: (1) Kai H et al. J Nephrol. 2006: 19:215–219 (2) Williams DG. Pediatr Nephrol. 1997: 11:96–98 (3) Braun MC et al. Pediatric nephrology. 2004:Elsevier, Philadelphia, pp147–155 (4) Image 1 source: Nalini S. Seminars in Immunopathology. 2008: 30: Issue 2. (5) Image 2 source: Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31. C3 nephritic factor (C3NeF): an IgG or IgM autoantibody that binds and prevents the inactivation of C3 convertase (2) + Regulatory proteins _ Mutation or autoantibodies (2) Nephritic factor of the terminal pathway (NeFt) (3) + chronic antigenemia and the generation of nephritogenic immune complexes (1) + C4 nephritic factor (C4NeF) + Ig + Complement Complement (DDD or C3 GN)
- 20. Classification – New: According to TYPE of deposits: Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31.
- 21. Classification – New: According to TYPE of deposits: Algorithm source: Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31. Table source: Glassock RJ. Oxford University Press: Oxford, UK, 2009.
- 22. Classification – New: According to TYPE of deposits: DDD C3 Nephropathy + mesangial, tubular, bowman’s space deposits + mesangial deposits Algorithm source: Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31. Table source: Glassock RJ. Oxford University Press: Oxford, UK, 2009.
- 23. Why New Classification is Better? Old Classification Old Classification MPGN Type IMPGN Type I MPGN Type IIMPGN Type II MPGN Type IIIMPGN Type III EM IF Subendothelial Subendothelial + Subepithelial Intra membranos C3 onlyC3+Ig C3 only C3 only C3+Ig C3 GN DDD C3 GN Ig +veIg +ve C3 GlomerulopathyC3 Glomerulopathy Ig +veIg +ve Modified From D’Agati & Bomback. Kidney International (2012) 82, 379–381 New Classification New Classification
- 24. Classification – New: According to TYPE of deposits: DDD C3 Nephropathy + mesangial, tubular, bowman’s space deposits + mesangial deposits MPGN like pathologies When to suspect 2ry causes? Algorithm source: Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31. Table source: Glassock RJ. Oxford University Press: Oxford, UK, 2009.
- 25. Classification – New: According to TYPE of deposits: DDD C3 Nephropathy + mesangial, tubular, bowman’s space deposits + mesangial deposits MPGN like pathologies When to suspect 2ry causes? Algorithm source: Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31. Table source: Glassock RJ. Oxford University Press: Oxford, UK, 2009. Pathological features of MPGN
- 26. Pathology - LM Normal Glomerulus GBM deposits, resulting in a thickened capillary wall Endocapillary proliferation Increased mesangial cellularity and matrix A double contour (tram track) of the glomerular basement membrane (GBM) (This appearance results from circumferential mesangial interposition, whereby mesangial cells, infiltrating mononuclear cells, or even portions of endothelial cells interpose themselves between the endothelium and the basement membrane, with new, inner basement membrane being laid down) Lobular appearance Fundamental of Renal Pathology, Section II, Chapter 2
- 27. Pathology - LM Diffuse lobular simplification of glomeruli in membranoproliferative glomerulonephritis (Jones' silver stain; original magnification, x100) caused by endocapillary proliferation AJKD, Atlas of Kidney Disease, www.ajkd.org
- 29. Pathology - LM Fundamental of Renal Pathology, Section II, Chapter 2, Page 31,32
- 30. Pathology - LM
- 31. Pathology - LM Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 266
- 32. Pathology - LM WebPath, http://library.med.utah.edu/WebPath/webpath.html
- 33. Pathology - LM PAS-positive capillary walls thickening DDD - (arrows). (PAS stain, X400). www.kidneypathology.com
- 34. Pathology - LM Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 267
- 35. Pathology - IF Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31.
- 36. Pathology - IF Immune complex mediated Complement mediated C3 (more prominent than Ig) C3 IgM, IgG, Rarely IgA Scanty Ig staining Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31.
- 37. Pathology - IF Disorder IF Monoclonal gammopathy monotypic immunoglobulin with kappa or lambda light chain HCV IgM, IgG, C3, and kappa and lambda light chains Autoimmune diseases multiple immunoglobulins and complement proteins Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31.
- 38. Pathology - EM Fundamental of Renal Pathology, Section II, Chapter 2, Page 33-35 • Electron microscopy cannot distinguish between immune- complex–mediated MPGN and C3GN • C3GN: • mesangial • subendothelial • sometimes subepithelial & intramembranous deposits • On the basis of the morphologic characteristics of C3GN on electron microscopy, C3GN is most likely to be termed MPGN I or MPGN III according to the older classification.
- 39. Pathology - EM www.renaldigest.com • Electron microscopy cannot distinguish between immune- complex–mediated MPGN and C3GN • C3GN: • mesangial • subendothelial • sometimes subepithelial & intramembranous deposits • On the basis of the morphologic characteristics of C3GN on electron microscopy, C3GN is most likely to be termed MPGN I or MPGN III according to the older classification.
- 40. Pathology - EM
- 41. Pathology - EM WebPath, http://library.med.utah.edu/WebPath/webpath.html#MENU
- 42. MPGN vs TMA Table source: Glassock RJ. Oxford University Press: Oxford, UK, 2009.
- 43. In the acute phase of TMA: endothelial swelling, and fibrin thrombi are present in the glomerular capillaries. In the chronic phase of TMA: As the process evolves into a reparative and chronic phase, there are no active thrombotic lesions BUT mesangial expansion and remodeling of the glomerular capillary walls, including double-contour formation, take place. How to differentiate chronic phase from MPGN? MPGN vs TMA Goldberg RJ et al. Am J Kidney Dis 2010;56:1168-74.
- 44. MPGN vs TMA MPGN TMA )Chronic Phase( IF C3 + IgM, IgG EM Dense deposits In mesangium & along capillary walls Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31.
- 45. MPGN vs TMA MPGN TMA )Chronic Phase( IF C3 + IgM, IgG NO complement or Ig EM Dense deposits In mesangium & along capillary walls NO dense deposits Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31.
- 47. MPGN – Diagnostic Algorithm No C3 no Ig chronic phase of TMA Always check the possibility of Infection
- 48. MPGN & Infection
- 49. MPGN & Infection Always suspect infection whatever the type of the deposits
- 50. MPGN & Infection
- 51. MPGN & Infection Suspect any organism as a cause of post infectious MPGN whenever there is an evidence of infection
- 52. It may precede the renal disease by many years. Partial lipodystrophy: preferentially involves the face and upper body. DDD Clinical Presentation Image 1: Oxford Text Book of Clinical NeAphrology, Section III, Chapter 8 Image 2: F. Paolo Schena, Charles E. Alpers. Comprehensive Clinical Nephrology, 4th edition, Chapter 21
- 53. Some patients with DDD will have: color defects prolonged dark adaptation mottled retinal pigmentation (drusen bodies) sometimes deterioration of vision. Indocyanine green angiography of the retina may reveal dense deposits in the ciliary epithelial basement membrane (abnormal fluorescent dots) and choroidal neovascularization. DDD Clinical Presentation F. Paolo Schena, Charles E. Alpers. Comprehensive Clinical Nephrology, 4th edition, Chapter 21
- 54. Steps of Diagnosis & Management
- 55. Treatment of Idiopathic MPGN With initial therapy limited to less than 6 months (2D) What is the Evidence?
- 56. Studies for treatment of Idiopathic MPGN Treatment of Idiopathic MPGN What is the evidence? • Mainly small, observational • Short-term follow-up. • Mostly in subjects with RPGN or • In those with progressive kidney disease with severe nephrotic syndrome. Weak experimental design. Benefits of immunosuppressive therapy combined with high dose i.v. or oral steroids have never been demonstrated in RCTs. Few number of patients. There is very low–quality evidence to suggest the benefit of an immunosuppressive agent plus corticosteroids in the treatment of idiopathic MPGN with nephrotic syndrome and/or deteriorating kidney function.
- 57. RCT is needed to test corticosteroids in combination with an immunosuppressive agent in ‘‘idiopathic’’ MPGN with nephrotic syndrome. Research Recommendations
- 58. Treatment of Secondary MPGN HCV related GN
- 59. Studies of rituximab treatment in idiopathic MPGN Rituximab seems to be effective in immunoglobulin-associated MPGN, particularly in those cases associated with: •monoclonal gammopathy •chronic lymphocytic leukemia •cryoglobulinemia with or without HCV Biomed Res Int. May 9; 2017: 2180508.
- 60. Studies of rituximab treatment in idiopathic MPGN Biomed Res Int. May 9; 2017: 2180508.
- 61. Reports on rituximab treatment in C3GN and DDD Biomed Res Int. May 9; 2017: 2180508.
- 64. Mixed cryoglobulinemia syndrome + one or more of the following = immunosuppressive therapy (to rapidly improve TOD, rather than therapy directed at the underlying etiology alone) Glomerulonephritis associated with either a rapidly progressive course and/or nephrotic range proteinuria Severe digital ischemia threatening amputation Gastrointestinal vasculitis associated with abdominal pain and/or gastrointestinal bleeding Rapidly progressive neuropathy Central nervous system vasculitis that may present as a stroke or acute cognitive impairment Pulmonary vasculitis associated with diffuse alveolar hemorrhage or respiratory failure Heart failure Glomerulonephritis associated with either a rapidly progressive course and/or nephrotic range proteinuria Severe digital ischemia threatening amputation Gastrointestinal vasculitis associated with abdominal pain and/or gastrointestinal bleeding Rapidly progressive neuropathy Central nervous system vasculitis that may present as a stroke or acute cognitive impairment Pulmonary vasculitis associated with diffuse alveolar hemorrhage or respiratory failure Heart failure © 2018
- 65. Rituximab for Severe Mixed Cryoglobulinemia N Engl J Med. 2013 Sep;369(11):1035-45 Autoimmun Rev. 2011 Jun;10(8):444-54 Nephron Clin Pract. 2011;119(2) Immunosuppressive therapy including rituximab or, if unavailable, cyclophosphamide After disease stabilization, patients should receive concurrent therapy for the underlying disorder Exceptions to this general principle include mixed cryoglobulinemia due to HIV or HBV infections; (antiviral therapy should always be initiated before or at the same time as immunosuppressive therapy)
- 66. 5 years after biopsy, 50% of patients either die or need renal replacement therapy (dialysis or transplantation). Natural History Schmitt H et al. Nephron. 1990;55:242-250. This proportion increases to 64% after 10 years. Risk of progression increases with:
- 67. In patients with primary MPGN, the recurrence rate is: 20% to 30% in those with type I. (1) 50% to 100% in those with type II. (2) In those with secondary disease, the recurrence is directly linked to control of the underlying illness. MPGN & Transplantation (1) Choy BY et al. Am J Transplant 2006; 6:2535. (2) Braun MC et al. J Am Soc Nephrol 2005; 16:2225.
- 68. Thank You