Membranoproliferative GN - Diagnosis & Management

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By: saikum37 (21 month(s) ago)

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Membranoproliferative GN r Road to Diagnosis & Management What is the evidence?:

Membranoproliferative GN r Road to Diagnosis & Management What is the evidence? Mohammed Abdel Gawad Nephrology Specialist Kidney & Urology Center (KUC) Alexandria CNE ESNT-CNE 3 rd Course, Cairo June 5-8, 2013

Definition:

Membranoproliferative glomerulonephritis (MPGN) is a glomerular disease . Alternative names: Mesangicapillary GN, Lobular GN MPGN may be idiopathic or secondary Definition

Epidemiology :

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) Zhou FD et al. Nephrol Dial Transplant 2009; 24:870-6. Briganti EM et al. Nephrol Dial Transplant 2001;16:1364-7.

Clinical Presentation :

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, 4 th edition, Chapter 21

Clinical Presentation :

Clinical Presentation Specific presentation for type II MPGN (DDD) (will be discussed later) F. Paolo Schena, Charles E. Alpers. Comprehensive Clinical Nephrology, 4 th edition, Chapter 21

Steps of Diagnosis & Management:

Steps of Diagnosis & Management To get through evaluation of secondary causes we have to discuss first classification of MPGN.

Classification:

MPGN is characterized by presence of deposits in different parts of the glomerulus (due to immunological abnormality) Classification Normal Glomerulus

Classification:

Classification MPGN Type I MPGN Type II MPGN Type III

Classification – Traditional: According to SITE of deposits::

Classification – Traditional: According to SITE of deposits: Endothelial Cells Epithelial Cells GBM www.nephrotube.blogspot.com

Classification – Traditional: According to SITE of deposits::

Classification – Traditional: According to SITE of deposits: Endothelial Cells Epithelial Cells GBM Mesangial Deposits MPGN I www.nephrotube.blogspot.com

Classification – Traditional: According to SITE of deposits::

Classification – Traditional: According to SITE of deposits: Endothelial Cells Epithelial Cells GBM Mesangial Deposits MPGN III www.nephrotube.blogspot.com

Classification – Traditional: According to SITE of deposits::

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

Classification – Traditional: According to SITE of deposits::

Classification – Traditional: According to SITE of deposits:

Classification:

Classification

Classification – New: According to TYPE of deposits::

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

Classification – New: According to TYPE of deposits::

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)

Classification – New: According to TYPE of deposits::

Classification – New: According to TYPE of deposits: Sanjeev Sethi et al. N Engl J Med 2012;366:1119-31.

Classification – New: According to TYPE of deposits::

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

Pathology - LM :

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

Pathology - LM :

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

Pathology - LM :

Pathology - LM www.nephropath.com

Pathology - LM :

Pathology - LM Fundamental of Renal Pathology, Section II, Chapter 2, Page 31,32

Pathology - LM :

Pathology - LM

Pathology - LM :

Pathology - LM Comprehensive Clinical Nephrology, 4 th edition, Chapter 21, Page 266

Pathology - LM :

Pathology - LM WebPath, http://library.med.utah.edu/WebPath/webpath.html

Pathology - LM :

Pathology - LM PAS-positive capillary walls thickening DDD - (arrows). (PAS stain, X400). www.kidneypathology.com

Pathology - LM :

Pathology - LM Comprehensive Clinical Nephrology, 4 th edition, Chapter 21, Page 267

Pathology - IF:

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.

Pathology - IF:

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.

Pathology - EM:

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.

Pathology - EM:

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.

Pathology - EM:

Pathology - EM

Pathology - EM:

Pathology - EM WebPath, http://library.med.utah.edu/WebPath/webpath.html#MENU

MPGN vs TMA:

MPGN vs TMA Table source: Glassock RJ. Oxford University Press: Oxford, UK, 2009.

MPGN vs TMA:

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.

MPGN vs TMA:

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.

MPGN vs TMA:

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.

MPGN vs TMA:

MPGN vs TMA www.renaldigest.com

MPGN – Diagnostic Algorithm:

MPGN – Diagnostic Algorithm No C3 no Ig chronic phase of TMA Always check the possibility of Infection

MPGN & Infection:

MPGN & Infection Always suspect infection whatever the type of the deposits

MPGN & Infection:

MPGN & Infection Suspect any organism as a cause of post infectious MPGN whenever there is an evidence of infection

Old classification & Complement:

Old classification & Complement (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 . 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) + MPGN I MPGN II MPGN III

Old classification & Complement:

MPGN CH50 I ↓ II (DDD) ↓ III ↓ C3 ↓ ↓ ↓ C4 ↓ N ? Old classification & Complement C3 nephritic factor activity: is more common in type II disease , namely 60–70% of patients, [1] compared to 20–25% of patients with type I or III disease . [1] Interestingly, this autoantibody is also detectable in up to 50% of patients with secondary forms of MPGN [1] and even in some healthy individuals [2] (1) Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 28, (2) F. Paolo Schena, Charles E. Alpers. Comprehensive Clinical Nephrology, 4 th edition, Chapter 21

MPGN Etiology (common & rare):

MPGN Etiology (common & rare) F. Paolo Schena, Charles E. Alpers. Comprehensive Clinical Nephrology, 4 th edition, Chapter 21

DDD Clinical Presentation:

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, 4 th edition, Chapter 21

DDD Clinical Presentation:

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, 4 th edition, Chapter 21

Steps of Diagnosis & Management:

Steps of Diagnosis & Management

Treatment of Idiopathic MPGN:

Treatment of Idiopathic MPGN With initial therapy limited to less than 6 months (2D) What is the Evidence?

Treatment of Idiopathic MPGN What is the evidence?:

Studies for treatment of Idiopathic MPGN Treatment of Idiopathic MPGN What is the evidence? Mainly small , observational S hort -term follow-up. M ostly in subjects with RPGN or In those with progressive kidney disease with severe nephrotic syndrome . W eak 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.

Research Recommendations :

RCT is needed to test corticosteroids in combination with an immunosuppressive agent in ‘‘idiopathic’’ MPGN with nephrotic syndrome. Research Recommendations

Treatment of Secondary MPGN HCV related GN:

Treatment of Secondary MPGN HCV related GN

Treatment of Secondary MPGN HCV related GN:

Treatment of Secondary MPGN HCV related GN Renal presentation Treatment CKD stage 1 or 2 Combined antiviral treatment ( pegylated interferon and ribavirin ) as in the general population. (2C) CKD stage 3 or 4 or 5 not on dialysis Monotherapy with pegylated interferon, With doses adjusted to kidney function. (2D) Mixed cryoglobulinemia (IgG/IgM) with: nephrotic proteinuria or evidence of progressive kidney disease or an acute flare of cryoglobulinemia plasmapheresis , or rituximab , or cyclophosphamide, in conjunction with i.v . methylprednisolone , and concomitant antiviral therapy. (2D) Titrate ribavirin dose according to patient tolerance and level of renal function. (Not Graded) What is the Evidence?

Treatment of Secondary MPGN HCV related GN:

Most studies are retrospective analyses with small sample sizes. The suggested doses in HCV infected patients with GFR <60 ml/min but not yet on dialysis are based on expert opinion , not evidence Case reports & very small observational studies have suggested remarkable reduction in proteinuria and stabilization of kidney function in response to rituximab in patients with cryoglobulinemic vasculitis Treatment of Secondary MPGN HCV related GN Very low–quality evidence

Natural History:

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 . Elevated creatinine Nephrotic proteinuria Severe hypertension 50% crescents marked I nterstitial fibrosis. Risk of progression increases with:

MPGN & Transplantation:

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 Choy BY et al. Am J Transplant 2006; 6:2535. Braun MC et al. J Am Soc Nephrol 2005; 16:2225.

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