Membrano-Proliferative       Glomerulonephritis    Diagnostic Road for Etiology    Mohammed Abdel Gawad1
Searching for a cause of GN is like ……..2
OBJECTIVES Introduction before we drive on the road to etiology:     Epidemiology     Pathogenesis & Types     Renal P...
OBJECTIVES Introduction before we drive on the road to etiology:     Epidemiology     Pathogenesis & Types     Renal P...
Epidimiology     MPGN accounts for 5% to 10% of primary renal     causes of nephrotic syndrome in children and adults5   ...
OBJECTIVES Introduction before we drive on the road to etiology:     Epidemiology     Pathogenesis & Types     Renal P...
Pathogenesis7         Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 262
Pathogenesis8         Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 261
Pathogenesis9         Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 261
Pathogenesis10    Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis-a new look      at an old entity. N Engl ...
Pathogenesis – Nephritic Factors        Nephritic factors are IgG or IgM autoantibodies          that bind to and stabili...
Pathogenesis12     Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis-a new look       at an old entity. N Eng...
Causes13          Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 261
OBJECTIVES  Introduction before we drive on the road to etiology:      Epidemiology      Pathogenesis & Types      Ren...
Presentation                                         F                                         k         m          Micro...
Presentation          From benign and slowly progressive to rapidly progressive         m          Microscopic hematuria...
OBJECTIVES  Introduction before we drive on the road to etiology:      Epidemiology      Pathogenesis & Types      Ren...
Classification Type I:      Discerte immune deposits in the mesangium and subendothelial       space. Type II (Dense De...
Classification               Endothelial Cells     GBM                Epithelial Cells19
Classification                                   Mesangial                                   Deposits               Endoth...
Classification                                   Mesangial                                   Deposits               Endoth...
Classification                                    Mesangial                                    Deposits               Endo...
Classification23
Classification24
Classification25
Classification26
Pathology – LM27
Pathology – LM – MPGN I      Glomeruli show:       subendothelial deposits, resulting in a thickened capillary wall and ...
Pathology – LM – MPGN I29
Pathology – LM – MPGN I30
Pathology – LM – MPGN I31
Pathology – LM – MPGN I     Diffuse lobular simplification of glomeruli in membranoproliferative     glomerulonephritis ty...
Pathology – LM – MPGN I33            Fundamental of Renal Pathology, Section II, Chapter 2, Page 31,32
Pathology – LM – MPGN I34                               www.nephropath.com
Pathology – LM – MPGN I35            Fundamental of Renal Pathology, Section II, Chapter 2, Page 31,32
Pathology – LM – MPGN I36           Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 266
Pathology – LM – MPGN I37           Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 266
Pathology – LM – MPGN I38         WebPath, http://library.med.utah.edu/WebPath/webpath.html#MENU
Pathology – LM – MPGN I39         WebPath, http://library.med.utah.edu/WebPath/webpath.html#MENU
Pathology – LM – MPGN I40         Fundamental of Renal Pathology, Section II, Chapter 2, Page 31,32
Pathology – LM – MPGN I41                 AJKD, Atlas of Kidney Disease, www.ajkd.org
Pathology – LM – MPGN I     See the irregularities of the capillary walls with methenamine-silver stain. In some     capil...
Pathology – LM – MPGN I     In some cases it is possible to identify subendothelial deposits. In this case, with the     t...
Pathology – LM – MPGN I     In this image we can see very well the irregular aspect of the capillary wall: the original   ...
Pathology – LM – DDD45
Pathology – LM – DDD     Known as type II MPGN, although this name does not seem right since it is     physiopathogenicall...
Pathology – LM – DDD      Endocapillary proliferation is present.      The   basement membranes are thickened and highly...
Pathology – LM – DDD  In dense deposit disease the capillary walls appear rigid, thickened, and with a more   intensely P...
Pathology – LM – DDD        PAS-positive capillary walls thickening (arrows). (PAS stain, X400).49                       ...
Pathology – LM – DDD a)      1-µm thickness stained with     toluidine blue. The linear material     following the baseme...
Pathology – LM – MPGN III                                                                Mesangial                        ...
Pathology – LM      MPGN may present with crescents      Fibrosis in chronic cases52                 Fundamental of Rena...
Pathology – LM – MPGN I53        Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 266
Pathology – LM – MPGN I                   Cellular Crescent54        Comprehensive Clinical Nephrology, 4th edition, Chapt...
Pathology – IF55
Pathology – IF – MPGN I, III       deposition of IgM, IgG, and C3 in a granular capillary wall        distribution      ...
Pathology – IF – MPGN I57           Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 263
Pathology – IF – MPGN I       Segmental, coarsely granular-to-globular or elongated capillary wall       IgG deposits in m...
Pathology – IF – DDD      C3         C3 staining outlines the capillary wall, and may be          smooth, granular, or d...
Pathology – IF – DDD       Here is intense staining for C3, typically with almost no staining for        immunoglobulin. ...
Pathology – IF – DDD       The bright deposits scattered along capillary walls and in the mesangium by       immunofluores...
Pathology – IF – DDD62                            www.renaldigest.com
Pathology – IF – DDD63
Pathology – EM64
Mesangial                                Deposits           Endothelial Cells     GBM            Epithelial Cells   Tubule...
Pathology – EM – MPGN I66
Pathology – EM – MPGN I                                    Mesangial                                    Deposits          ...
Pathology – EM – MPGN I68         Fundamental of Renal Pathology, Section II, Chapter 2, Page 33-35
Pathology – EM – MPGN I      numerous dense deposits in subendothelial and mesangial areas69             Comprehensive Cl...
Pathology – EM – MPGN I     Membranoproliferative glomerulonephritis type 1 with multiple, small-to-     medium subendothe...
Pathology – EM – MPGN I     Membranoproliferative glomerulonephritis type 1. The marked endocapillary     proliferation (p...
Pathology – EM – MPGN I     Membranoproliferative glomerulonephritis type 1 with multiple, large subendothelial     deposi...
Pathology – EM – MPGN I     Membranoproliferative glomerulonephritis type 1. Mesangial interposition is illustrated     at...
Pathology – EM – DDD      In DDD, electron microscopy shows replacement of      large sections of the GBM with an extreme...
Pathology – EM – DDD      In DDD, electron microscopy shows replacement of                                          Mesan...
Pathology – EM – DDD76
Pathology – EM – DDD77                            www.kidneypathology.com
Pathology – EM – DDD78           WebPath, http://library.med.utah.edu/WebPath/webpath.html#MENU
Pathology – EM – DDD79          Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 266
Pathology – EM – DDD            shows GBM as well as mesangial deposits80                                              ww...
Pathology – EM – MPGN III                                        Mesangial                                        Deposits...
Pathology – EM – MPGN III82                                 www.renaldigest.com
Pathology – EM – MPGN III83                                 www.renaldigest.com
Pathology – C3GN C3GN has mesangial, subendothelial,     and sometimes subepithelial           and     intramembranous de...
OBJECTIVES  Introduction before we drive on the road to etiology:      Epidemiology      Pathogenesis & Types      Ren...
Pathology Tips – Main Scheme86      Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis-a new look        at an...
Pathology Tips – Main Scheme87      Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis-a new look        at an...
Pathology Tips – Main Scheme                I made some             modifications in this                  algorithm88    ...
Pathology Tips – Main Scheme      1ry   2ry       other                    diseases                     present           ...
Pathology Tips – Main Scheme                                     No C3                                     no Ig          ...
Pathology Tips – Main Scheme                                                                     No C3                    ...
Pathology Tips – Main Scheme                                                                                    No C3     ...
Pathology Tips – Tip 1           Idiopathic MPGN                     Secondary MPGN     proliferation is typically uniform...
Pathology Tips – Tip 1             Idiopathic MPGN                              Secondary MPGN     proliferation is typica...
Pathology Tips – Tip 2     Cryoglobulinemia      Cryoglobulinemic MPGN:        Intracapillary:          globular accumu...
Pathology Tips – Tip 2     Cryoglobulinemia - LM96            Comprehensive Clinical Nephrology, 4th edition, Chapter 21, ...
Pathology Tips – Tip 2     Cryoglobulinemia - LM      See the hypercellularity and diminution of capillary lumens, one of ...
Pathology Tips – Tip 2     Cryoglobulinemia - LM98                              www.renaldigest.com
Pathology Tips – Tip 2     Cryoglobulinemia - LM99              Fundamental of Renal Pathology, Section II, Chapter 2, Pag...
Pathology Tips – Tip 2      Cryoglobulinemia - EM         Vague wormy or microtubular or finely fibrillar consisting of t...
Pathology Tips – Tip 2      Cryoglobulinemia - IF                                       MPGN                        HCV   ...
Pathology Tips – Tip 2      Cryoglobulinemia - IF                                        MPGN                       HCV   ...
Pathology Tips – Tip 2      Cryoglobulinemia - IF            Globular accumulations of cryoglobulin in the capillary lumen...
Pathology Tips – Tip 3      Autoimmune & Rheumatologic disease                                       MPGN                A...
Pathology Tips – Tip 3      Autoimmune & Rheumatologic disease                                       MPGN                A...
106
Appendix A      -IF: 1ry is uniform diffuse, 2ry is irregular      - Cryoglobulins:           -a: LM: hyaline thrombi     ...
Pathology Tips – Main Scheme                                                                  No C3                       ...
Pathology Tips – Main Scheme                                                                  No C3                       ...
Pathology Tips – Tip 4      Paraproteinemias                                       MPGN                  Monoclonal       ...
Pathology Tips – Tip 4      Paraproteinemias                                       MPGN                  Monoclonal       ...
Pathology Tips – Tip 4                                                                             Plasma Cell Dyscriasis ...
Pathology Tips – Tip 4      Paraproteinemias – Fibrillary GN               approximately 20 nm diameter fibrils113        ...
Pathology Tips – Tip 4Paraproteinemias – Immunotactoid GN114            http://www.uncnephropathology.org/jennette/tutoria...
Pathology Tips – Tip 5      Postinfectious GN - LM  Both disorders give global and diffuse glomerular hypercellularity, a...
Pathology Tips – Tip 5      Postinfectious GN - LM116            Handbook of Renal Biopsy Pathology, 2nd Edition, Chapter ...
Pathology Tips – Tip 5      Postinfectious GN - IF                                   MPGN                 Postinfectious  ...
Pathology Tips – Tip 5      Postinfectious GN - IF                                   MPGN                 Postinfectious  ...
Pathology Tips – Tip 5      Postinfectious GN - IF119            Handbook of Renal Biopsy Pathology, 2nd Edition, Chapter ...
Pathology Tips – Tip 5      Postinfectious GN - EM        Electron microscopy confirms the distribution of        immune ...
Pathology Tips – Tip 5      Postinfectious GN - EM121            Handbook of Renal Biopsy Pathology, 2nd Edition, Chapter ...
Pathology Tips – Tip 6      IgA Nephropathy         IgA nephropathy may present pathologically as                        ...
123
Appendix B      - Paraprotinemia:          -IF: monoclonal or very rare          polyclonal Ig, Kappa, Lambda light       ...
Appendix B      - Paraprotinemia:          -IF: monoclonal or very rare          polyclonal Ig, Kappa, Lambda light       ...
Pathology Tips – Main Scheme                                                                  No C3                       ...
Pathology Tips – Main Scheme                                                                    No C3                     ...
Pathology Tips – Main Scheme                              Appendix C                                                      ...
Pathology Tips – Tip 7      Thrombotic Microangiopathy - LM        In the acute phase:          endothelial swelling, an...
Pathology Tips – Tip 7      Thrombotic Microangiopathy - LM        In the acute phase:          endothelial swelling, an...
Pathology Tips – Tip 7      Thrombotic Microangiopathy - LM        In the acute phase:          endothelial swelling, an...
Pathology Tips – Tip 7      Thrombotic Microangiopathy - LM        In the acute phase:          endothelial swelling, an...
Pathology Tips – Tip 7Thrombotic Microangiopathy – IF & EM                                      MPGN                    TM...
Pathology Tips – Tip 7Thrombotic Microangiopathy – IF & EM                                      MPGN                    TM...
Pathology Tips – Tip 7      Thrombotic Microangiopathy135                               www.renaldigest.com
Pathology Tips – Tip 7      Thrombotic Microangiopathy136                               www.renaldigest.com
Pathology Tips – Tip 7      Thrombotic Microangiopathy137                               www.renaldigest.com
Other MPGN Like Pathologies138            Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 267
Pathology Tips – Tip 8      Pathology & Outcome       The extent of the basement membrane broadening,        (due to mesa...
Pathology Tips – Main Scheme                                                                  No C3                       ...
Pathology Tips – Main Scheme                                                                  No C3                       ...
142
Always suspect       secondary causes      especially if there is          an evidence143
OBJECTIVES  Introduction before we drive on the road to etiology:       Epidemiology       Pathogenesis & Types       ...
Age & Sex        MPGN Type I:         Idiopathic in children and young adults (primary          kidney disease without s...
OBJECTIVES  Introduction before we drive on the road to etiology:       Epidemiology       Pathogenesis & Types       ...
Causes147           Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 261
Causes148      Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 28, Page 250
History       Blood transfusion       Drug abuse       Dry eye & mouth       Photosensitivity       Traveling to trop...
Examination      HCV & Mixed Cryoglobulinemia         Meltzer Triad           Arthralgia           Myalgia & weakness  ...
Examination      HCV & Mixed Cryoglobulinemia       The arthralgias:         rarely accompanied by arthritis,         u...
Examination      HCV & Mixed Cryoglobulinemia152           Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Pag...
Examination      HCV & Mixed Cryoglobulinemia       Other manifestations may include:         ulcerative, vasculitic les...
Examination      HCV & Mixed Cryoglobulinemia154           Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Pag...
Examination - DDD       It may precede the renal disease by many years.       Partial lipodystrophy:         preferenti...
Examination - DDD       It may precede the renal disease by many years.       Partial lipodystrophy:         preferenti...
Examination - DDD       Partial lipodystrophy:         preferentially involves the face and upper body may be present   ...
Examination - DDD       Partial lipodystrophy:          preferentially involves the face and upper body may be present  ...
Examination - DDD   Some patients with DDD will have:         mild visual field         color defects         prolonge...
Examination       Examine all lymph node groups       Auscultate the heart for new murmur       Search for drug injecti...
Examination       Examine all lymph node groups       Auscultate the heart for new murmur       Search for drug injecti...
OBJECTIVES  Introduction before we drive on the road to etiology:       Epidemiology       Pathogenesis & Types       ...
Causes163           Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 261
Causes164      Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 28, Page 250
Investigations         1- detection of infections:           blood, urine, sputum cultures           HCV Ab           ...
Investigations         1- detection of infections:           blood, urine, sputum cultures           HCV Ab           ...
Investigations         1- detection of infections:           blood, urine, sputum cultures           HCV Ab           ...
Investigations         1- detection of infections:                  13- CXR           blood, urine, sputum cultures    ...
Investigations         1- detection of infections:                  13- CXR           blood, urine, sputum cultures    ...
Investigations         1- detection of infections:                13- CXR           blood, urine, sputum cultures      ...
Investigations Hypocomplementemia          MPGN       CH50    C3      C4             I        ↓     ↓ or N   ↓          I...
Investigations Hypocomplementemia                       Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page ...
Investigations Hypocomplementemia                                         Comprehensive Clinical Nephrology, 4th edition,...
Investigations      HCV & Mixed Cryoglobulinemia174           Comprehensive Clinical Nephrology, 4th edition, Chapter 21, ...
Investigations175
Investigations       Suspect any organism         as a cause of post          infectious MPGN          whenevr there is   ...
Investigations – Alternative Pathway177
Follow On      www.nephrotube.blogspot.com                  &            Facebook Group              NephroTube178
Hope that it is clear now ….                               Thank                                You                       ...
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Membranoproliferative Glomerulonephritis - Diagnostic Road for Etiology

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Membranoproliferative Glomerulonephritis - Diagnostic Road for Etiology

  1. 1. Membrano-Proliferative Glomerulonephritis Diagnostic Road for Etiology Mohammed Abdel Gawad1
  2. 2. Searching for a cause of GN is like ……..2
  3. 3. OBJECTIVES Introduction before we drive on the road to etiology:  Epidemiology  Pathogenesis & Types  Renal Presentation  Pathology Diagnostic Road for Etiology of MPGN:  Step 1: Pathology Tips  Step 2: Age & Sex  Step 3: History &Examination3  Step 4: Investigations
  4. 4. OBJECTIVES Introduction before we drive on the road to etiology:  Epidemiology  Pathogenesis & Types  Renal Presentation  Pathology Diagnostic Road for Etiology of MPGN:  Step 1: Pathology Tips  Step 2: Age & Sex  Step 3: History &Examination4  Step 4: Investigations
  5. 5. Epidimiology  MPGN accounts for 5% to 10% of primary renal causes of nephrotic syndrome in children and adults5 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 263
  6. 6. OBJECTIVES Introduction before we drive on the road to etiology:  Epidemiology  Pathogenesis & Types  Renal Presentation  Pathology Diagnostic Road for Etiology of MPGN:  Step 1: Pathology Tips  Step 2: Age & Sex  Step 3: History &Examination6  Step 4: Investigations
  7. 7. Pathogenesis7 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 262
  8. 8. Pathogenesis8 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 261
  9. 9. Pathogenesis9 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 261
  10. 10. Pathogenesis10 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis-a new look at an old entity. N Engl J Med. 2012;366(12):1119-31
  11. 11. Pathogenesis – Nephritic Factors  Nephritic factors are IgG or IgM autoantibodies that bind to and stabilize the C3 convertase of the alternative (C3bBb) or classical (C4b2b) pathway thus resulting in continued complement activation.11 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 260
  12. 12. Pathogenesis12 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis-a new look at an old entity. N Engl J Med. 2012;366(12):1119-31
  13. 13. Causes13 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 261
  14. 14. OBJECTIVES  Introduction before we drive on the road to etiology:  Epidemiology  Pathogenesis & Types  Renal Presentation  Pathology  Diagnostic Road for Etiology of MPGN:  Step 1: Pathology Tips  Step 2: Age & Sex  Step 3: History &Examination14  Step 4: Investigations
  15. 15. Presentation F k m  Microscopic hematuria and non-nephrotic proteinuria (35%),  Nephrotic syndrome with minimally depressed renal function (35%),  Chronically progressive GN (20%),  RPGN: rapidly deteriorating renal function with proteinuria and red cell casts (10%). S I I b15 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 263
  16. 16. Presentation  From benign and slowly progressive to rapidly progressive m  Microscopic hematuria and non-nephrotic proteinuria (35%),  Nephrotic syndrome with minimally depressed renal function (35%),  Chronically progressive GN (20%),  RPGN: rapidly deteriorating renal function with proteinuria and red cell casts (10%).  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.16 S I Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 263
  17. 17. OBJECTIVES  Introduction before we drive on the road to etiology:  Epidemiology  Pathogenesis & Types  Renal Presentation  Pathology  Diagnostic Road for Etiology of MPGN:  Step 1: Pathology Tips  Step 2: Age & Sex  Step 3: History &Examination17  Step 4: Investigations
  18. 18. Classification Type I:  Discerte immune deposits in the mesangium and subendothelial space. Type II (Dense Deposit Disease – DDD):  Dense ribbon-like deposits along the basement membranes of the glomeruli, tubules, and Bowmans capsule & mesangium Type III:  Similar to MPGN type I + subepithelial deposits18 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 265, 266
  19. 19. Classification Endothelial Cells GBM Epithelial Cells19
  20. 20. Classification Mesangial Deposits Endothelial Cells GBM Epithelial Cells MPGN I20
  21. 21. Classification Mesangial Deposits Endothelial Cells GBM Epithelial Cells MPGN III21
  22. 22. Classification Mesangial Deposits Endothelial Cells GBM Epithelial Cells Tubules & Bowman’s Capsule Deposits MPGN II (DDD)22
  23. 23. Classification23
  24. 24. Classification24
  25. 25. Classification25
  26. 26. Classification26
  27. 27. Pathology – LM27
  28. 28. Pathology – LM – MPGN I  Glomeruli show:  subendothelial deposits, resulting in a thickened capillary wall and a double contour (tram track) of the glomerular basement membrane (GBM) (This appearance results from so-called 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)  Endocapillary proliferation  increased mesangial cellularity and matrix  Lobular appearance  Sometimes associated to abundant monocytes and neutrophils28 Fundamental of Renal Pathology, Section II, Chapter 2, Page 31,32
  29. 29. Pathology – LM – MPGN I29
  30. 30. Pathology – LM – MPGN I30
  31. 31. Pathology – LM – MPGN I31
  32. 32. Pathology – LM – MPGN I Diffuse lobular simplification of glomeruli in membranoproliferative glomerulonephritis type 1, caused by extensive endocapillary proliferation (Jones silver stain; original magnification, x100)32 AJKD, Atlas of Kidney Disease, www.ajkd.org
  33. 33. Pathology – LM – MPGN I33 Fundamental of Renal Pathology, Section II, Chapter 2, Page 31,32
  34. 34. Pathology – LM – MPGN I34 www.nephropath.com
  35. 35. Pathology – LM – MPGN I35 Fundamental of Renal Pathology, Section II, Chapter 2, Page 31,32
  36. 36. Pathology – LM – MPGN I36 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 266
  37. 37. Pathology – LM – MPGN I37 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 266
  38. 38. Pathology – LM – MPGN I38 WebPath, http://library.med.utah.edu/WebPath/webpath.html#MENU
  39. 39. Pathology – LM – MPGN I39 WebPath, http://library.med.utah.edu/WebPath/webpath.html#MENU
  40. 40. Pathology – LM – MPGN I40 Fundamental of Renal Pathology, Section II, Chapter 2, Page 31,32
  41. 41. Pathology – LM – MPGN I41 AJKD, Atlas of Kidney Disease, www.ajkd.org
  42. 42. Pathology – LM – MPGN I See the irregularities of the capillary walls with methenamine-silver stain. In some capillaries the lumen becomes imperceptible and in others they demonstrate clearly the double contours (arrows). Between the GBM and the “new GBM-like” there are immune42 deposits or “interposed” mesangial cells (Methenamine-silver, X400). www.kidneypathology.com
  43. 43. Pathology – LM – MPGN I In some cases it is possible to identify subendothelial deposits. In this case, with the trichrome stain, we can see those (fuchsinophilic: red) in the internal aspect of the capillary wall, demonstrating that they are subendothelial (arrows). These deposits can also be identified, in some cases, with methenamine-silver stain. (Masson’s trichrome,43 X1000). www.kidneypathology.com
  44. 44. Pathology – LM – MPGN I In this image we can see very well the irregular aspect of the capillary wall: the original GBM (green arrows), the neosynthesized GBM-like material in the internal aspect (blue arrows) and an interposed nucleus of mesangial cell (red arrow). The cytoplasm of the mesangial cell is located between both contours in a variable extension (Methenamine-44 silver, X1000). www.kidneypathology.com
  45. 45. Pathology – LM – DDD45
  46. 46. Pathology – LM – DDD Known as type II MPGN, although this name does not seem right since it is physiopathogenically and morphologically a different disease46 (Walker PD, et al. Dense deposit disease is not a membranoproliferative glomerulonephritis. Mod Pathol. 2007;20(6):605-16)
  47. 47. Pathology – LM – DDD  Endocapillary proliferation is present.  The basement membranes are thickened and highly refractile and eosinophilic, with involved areas with strings of deposits looking like a string of sausages.  Mesangial Deposits are also present.  Thickening also affects tubular basement membranes and Bowman’s capsule.47 Fundamental of Renal Pathology, Section II, Chapter 2, Page 31,32
  48. 48. Pathology – LM – DDD In dense deposit disease the capillary walls appear rigid, thickened, and with a more intensely PAS stained center, also observed with trichrome (sometimes fuchsinophilic) (arrows). In some cases there is slight cellularity increase and in others it can be mesangial48 (as in this case) www.kidneypathology.com
  49. 49. Pathology – LM – DDD  PAS-positive capillary walls thickening (arrows). (PAS stain, X400).49 www.kidneypathology.com
  50. 50. Pathology – LM – DDD a) 1-µm thickness stained with toluidine blue. The linear material following the basement membrane of the capillary wall is also evident in Bowmans capsule (bottom). b) A higher magnification of a portion of the field in (a). The reflection of the dense material into Bowmans capsule is seen on the left (arrow). Breaks in the continuity of the material within the basement membrane of the capillary wall can also be seen. Original magnification50 Oxford Text Book of Clinical Nephrology, Section III, Chapter 8, Page 527
  51. 51. Pathology – LM – MPGN III Mesangial Deposits Endothelial Cells GBM Epithelial Cells  Type I and type III MPGN form a morphologic continuum and thus are not always separable by light microscopy.51 Fundamental of Renal Pathology, Section II, Chapter 2, Page 31,32
  52. 52. Pathology – LM  MPGN may present with crescents  Fibrosis in chronic cases52 Fundamental of Renal Pathology, Section II, Chapter 2, Page 31,32
  53. 53. Pathology – LM – MPGN I53 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 266
  54. 54. Pathology – LM – MPGN I Cellular Crescent54 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 266
  55. 55. Pathology – IF55
  56. 56. Pathology – IF – MPGN I, III  deposition of IgM, IgG, and C3 in a granular capillary wall distribution  Staining for immunoglobulin is usually scanty.  Staining for C3 is more frequent and constant and present also in mesangium.  Often they are elongated and smooth in their external edge because they are subendothelial and they are molded to the GBM.  Staining for classical pathway complement components (C1q, C4) may also be seen in MPGN type I.56 Fundamental of Renal Pathology, Section II, Chapter 2, Page 33
  57. 57. Pathology – IF – MPGN I57 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 263
  58. 58. Pathology – IF – MPGN I Segmental, coarsely granular-to-globular or elongated capillary wall IgG deposits in membranoproliferative glomerulonephritis type 1 (immunofluorescence with anti-IgG; original magnification, x200).58 AJKD, Atlas of Kidney Disease, www.ajkd.org
  59. 59. Pathology – IF – DDD  C3  C3 staining outlines the capillary wall, and may be smooth, granular, or discontinuous.  Mesangial bright granular C3 staining can be present.  Neither classical complement pathway components nor immunoglobulins are detected; this helps distinguish it from other types of injury with an MPGN pattern. However, segmental IgM or less often IgG and very rarely IgA have been reported59 Fundamental of Renal Pathology, Section II, Chapter 2, Page 31,32
  60. 60. Pathology – IF – DDD  Here is intense staining for C3, typically with almost no staining for immunoglobulin. The capillary wall staining is usually linear or bilinear. There often are spherical or ring-shaped mesangial deposits that correspond to the mesangial dense deposits observed by electron60 microscopy. www.kidneypathology.com
  61. 61. Pathology – IF – DDD The bright deposits scattered along capillary walls and in the mesangium by immunofluorescence microscopy with antibody to complement component C3 are typical for membranoproliferative glomerulonephritis, type II.61 WebPath, http://library.med.utah.edu/WebPath/webpath.html#MENU
  62. 62. Pathology – IF – DDD62 www.renaldigest.com
  63. 63. Pathology – IF – DDD63
  64. 64. Pathology – EM64
  65. 65. Mesangial Deposits Endothelial Cells GBM Epithelial Cells Tubules & Bowman’s Capsule Deposits65
  66. 66. Pathology – EM – MPGN I66
  67. 67. Pathology – EM – MPGN I Mesangial Deposits Endothelial Cells GBM67 Epithelial Cells
  68. 68. Pathology – EM – MPGN I68 Fundamental of Renal Pathology, Section II, Chapter 2, Page 33-35
  69. 69. Pathology – EM – MPGN I  numerous dense deposits in subendothelial and mesangial areas69 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 266
  70. 70. Pathology – EM – MPGN I Membranoproliferative glomerulonephritis type 1 with multiple, small-to- medium subendothelial deposits (transmission electron microscopy; original magnification, x14,000)70 AJKD, Atlas of Kidney Disease, www.ajkd.org
  71. 71. Pathology – EM – MPGN I Membranoproliferative glomerulonephritis type 1. The marked endocapillary proliferation (proliferating endothelial and mesangial cells) appears to occlude the capillary lumen. Numerous large subendothelial and occasional mesangial-dense immune complex-type deposits (bottom middle) are present (transmission electron microscopy; original magnification, x4,700).71 AJKD, Atlas of Kidney Disease, www.ajkd.org
  72. 72. Pathology – EM – MPGN I Membranoproliferative glomerulonephritis type 1 with multiple, large subendothelial deposits (transmission electron microscopy; original magnification, x10,000)72 AJKD, Atlas of Kidney Disease, www.ajkd.org
  73. 73. Pathology – EM – MPGN I Membranoproliferative glomerulonephritis type 1. Mesangial interposition is illustrated at higher magnification, without evident deposits. These changes result in a "tram- track," double contour of the basement membrane by light microscopy (see Fig 2) (transmission electron microscopy; original magnification, x54,000)73 AJKD, Atlas of Kidney Disease, www.ajkd.org
  74. 74. Pathology – EM – DDD  In DDD, electron microscopy shows replacement of large sections of the GBM with an extremely electron- dense (sausge like, ribbon like, band like) band of homogeneous material, the identity of which remains unknown.  Involvement of mesangial regions, Bowman’s capsules, and tubular basement membranes by the deposits is common.74 Fundamental of Renal Pathology, Section II, Chapter 2, Page 33-35
  75. 75. Pathology – EM – DDD  In DDD, electron microscopy shows replacement of Mesangial large sections of the GBM with an extremely electron- Deposits Endothelial Cells dense (sausge like, ribbon like, band like) band of homogeneous material, the identity of which remains unknown.GBM  Involvement of Epithelial Cells mesangial regions, Bowman’s capsules, Tubules & and tubular basement membranes by Bowman’s the deposits is common. Capsule Deposits75 Fundamental of Renal Pathology, Section II, Chapter 2, Page 33-35
  76. 76. Pathology – EM – DDD76
  77. 77. Pathology – EM – DDD77 www.kidneypathology.com
  78. 78. Pathology – EM – DDD78 WebPath, http://library.med.utah.edu/WebPath/webpath.html#MENU
  79. 79. Pathology – EM – DDD79 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 266
  80. 80. Pathology – EM – DDD  shows GBM as well as mesangial deposits80 www.kidneypathology.com
  81. 81. Pathology – EM – MPGN III Mesangial Deposits Endothelial Cells GBM Epithelial Cells81 www.renaldigest.com
  82. 82. Pathology – EM – MPGN III82 www.renaldigest.com
  83. 83. Pathology – EM – MPGN III83 www.renaldigest.com
  84. 84. Pathology – C3GN C3GN has mesangial, subendothelial, and sometimes subepithelial and 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.84 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis--a new look at an old entity. N Engl J Med. 2012;366(12):1119-31
  85. 85. OBJECTIVES  Introduction before we drive on the road to etiology:  Epidemiology  Pathogenesis & Types  Renal Presentation  Pathology  Diagnostic Road for Etiology of MPGN:  Step 1: Pathology Tips  Step 2: Age & Sex  Step 3: History &Examination85  Step 4: Investigations
  86. 86. Pathology Tips – Main Scheme86 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis-a new look at an old entity. N Engl J Med. 2012;366(12):1119-31
  87. 87. Pathology Tips – Main Scheme87 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis-a new look at an old entity. N Engl J Med. 2012;366(12):1119-31
  88. 88. Pathology Tips – Main Scheme I made some modifications in this algorithm88 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis-a new look at an old entity. N Engl J Med. 2012;366(12):1119-31
  89. 89. Pathology Tips – Main Scheme 1ry 2ry other diseases present pathologically like MPGN89
  90. 90. Pathology Tips – Main Scheme No C3 no Ig other diseases present pathologically like MPGN 1ry 2ry other diseases Think of present chronic pathologically phase of like MPGN TMA90
  91. 91. Pathology Tips – Main Scheme No C3 no Ig other diseases present pathologically like MPGN 1ry 2ry other diseases Think of present chronic pathologically phase of like MPGN TMA91 Always check the possibility of secondary cause
  92. 92. Pathology Tips – Main Scheme No C3 no Ig other diseases present pathologically like MPGN 1ry 2ry other diseases Think of present chronic pathologically phase of like MPGN TMA Pathology Tips 1, 2, 392 Always check the possibility of secondary cause
  93. 93. Pathology Tips – Tip 1 Idiopathic MPGN Secondary MPGN proliferation is typically uniform and injury may be more irregular. diffuse93
  94. 94. Pathology Tips – Tip 1 Idiopathic MPGN Secondary MPGN proliferation is typically uniform and injury may be more irregular. diffuse Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 26694 AJKD, Atlas of Kidney Disease, www.ajkd.org
  95. 95. Pathology Tips – Tip 2 Cryoglobulinemia  Cryoglobulinemic MPGN:  Intracapillary:  globular accumulations of eosinophilic material representing cryoprecipitate.  more pronounced infiltration of macrophages within capillary lumina.95 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 266
  96. 96. Pathology Tips – Tip 2 Cryoglobulinemia - LM96 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 267
  97. 97. Pathology Tips – Tip 2 Cryoglobulinemia - LM See the hypercellularity and diminution of capillary lumens, one of them completely occluded by a “hyaline thrombus” (arrow). Hyaline thrombi can be seen green, bluish or reddish depending on the technique used for the trichrome stain and, probably, on its composition (Masson’s trichrome, X1000).97 www.kidneypathology.com
  98. 98. Pathology Tips – Tip 2 Cryoglobulinemia - LM98 www.renaldigest.com
  99. 99. Pathology Tips – Tip 2 Cryoglobulinemia - LM99 Fundamental of Renal Pathology, Section II, Chapter 2, Page 31,32
  100. 100. Pathology Tips – Tip 2 Cryoglobulinemia - EM  Vague wormy or microtubular or finely fibrillar consisting of the precipitated cryoglobulins100 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 267
  101. 101. Pathology Tips – Tip 2 Cryoglobulinemia - IF MPGN HCV C3 C3 ± + IF IgM, IgG IgM, IgG + kappa & lambda chains http://www.kidneypathology.com101 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis--a new look at an old entity. N Engl J Med. 2012;366(12):1119-31
  102. 102. Pathology Tips – Tip 2 Cryoglobulinemia - IF MPGN HCV C3 C3 ± + IF IgM, IgG IgM, IgG + kappa & lambda chains http://www.kidneypathology.com102 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis--a new look at an old entity. N Engl J Med. 2012;366(12):1119-31
  103. 103. Pathology Tips – Tip 2 Cryoglobulinemia - IF Globular accumulations of cryoglobulin in the capillary lumens. These can be seen by light microscopy as hyaline thrombi.103 http://www.uncnephropathology.org/jennette/tutorial.htm
  104. 104. Pathology Tips – Tip 3 Autoimmune & Rheumatologic disease MPGN Autoimmune & Rheumatologic diseases C3 multiple IF ± immunoglobulins and  autoimmune diseases IgG IgM, complement proteins IgG, IgM, IgA, C1q, C3, and kappa and lambda light chains104 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis--a new look at an old entity. N Engl J Med. 2012;366(12):1119-31
  105. 105. Pathology Tips – Tip 3 Autoimmune & Rheumatologic disease MPGN Autoimmune & Rheumatologic diseases C3 multiple IF ± immunoglobulins and  autoimmune diseases IgG IgM, complement proteins IgG, IgM, IgA, C1q, C3, and kappa and lambda light chains105 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis--a new look at an old entity. N Engl J Med. 2012;366(12):1119-31
  106. 106. 106
  107. 107. Appendix A -IF: 1ry is uniform diffuse, 2ry is irregular - Cryoglobulins: -a: LM: hyaline thrombi -b: EM: vague wormy microtubules -c: IF: bright ppt in the capillaries -1ry: C3, IgM, IgG -HCV IF: C3, IgG, IgM, Kappa, Lambda -Autoimmune: C3, C1q, IgG, IgM, IgA, Kappa, Lambda107
  108. 108. Pathology Tips – Main Scheme No C3 no Ig other diseases present pathologically like MPGN 1ry 2ry other diseases Think of present chronic pathologically phase of like MPGN TMA108 Always check the possibility of secondary cause
  109. 109. Pathology Tips – Main Scheme No C3 no Ig other diseases present pathologically like MPGN 1ry 2ry other diseases Think of present chronic pathologically phase of like MPGN TMA Pathology Tips 4, 5, 6109 Always check the possibility of secondary cause
  110. 110. Pathology Tips – Tip 4 Paraproteinemias MPGN Monoclonal Gammopathy C3 monotypic IF ± immunoglobulin with IgM, IgG kappa or lambda light chain restriction.110 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis--a new look at an old entity. N Engl J Med. 2012;366(12):1119-31
  111. 111. Pathology Tips – Tip 4 Paraproteinemias MPGN Monoclonal Gammopathy C3 monotypic IF ± immunoglobulin with IgM, IgG kappa or lambda light chain restriction.111 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis--a new look at an old entity. N Engl J Med. 2012;366(12):1119-31
  112. 112. Pathology Tips – Tip 4 Plasma Cell Dyscriasis (increase number & activity of plasma cells) Paraproteinemias Monoclonal Gammopathy Polyclonal Gammopathy (paraproteinemia) (deposition of polyclonal Ig) (deposition of monoclonal Ig) Light Chain Light Chain Light Chain Light Chain Heavy Chain IgG, C3, , IgG, C3, , or or Mainly Mainly Cast formation in Amyloid fibril tubules LCDD HCDD Fibrillariy transformation Glomerulopathy (cast nephropathy) Immunotactoid GN (granular deposits) (granular deposits) (fibrils 8-15 nm) (fibrilis 12-22 nm)(Crystalline deposits) (glomerulonephritis with organized monoclonal microtubular immunoglobulin deposits GOMMID) (microtubules HLCDD >30nm) AL (granular deposits) (primary amyloidosis) My Own Plasma Cells Classification > 10 % < 10%112 Myeloma Multiple Clonal Cell Proliferation
  113. 113. Pathology Tips – Tip 4 Paraproteinemias – Fibrillary GN approximately 20 nm diameter fibrils113 http://www.uncnephropathology.org/jennette/tutorial.htm
  114. 114. Pathology Tips – Tip 4Paraproteinemias – Immunotactoid GN114 http://www.uncnephropathology.org/jennette/tutorial.htm
  115. 115. Pathology Tips – Tip 5 Postinfectious GN - LM  Both disorders give global and diffuse glomerular hypercellularity, and both may have an infiltrate of neutrophils in the tuft at early stages  appearance of glomerular basement membranes on sections stained by periodic acid-methenamine silver:  In acute postinfective glomerulonephritis, these appear single,  in subendothelial membranoproliferative glomerulonephritis, these appear double.  The glomerular tuft in subendothelial membranoproliferative glomerulonephritis may appear in distinct lobules115 Handbook of Renal Biopsy Pathology, 2nd Edition, Chapter 6, Page 121, 122
  116. 116. Pathology Tips – Tip 5 Postinfectious GN - LM116 Handbook of Renal Biopsy Pathology, 2nd Edition, Chapter 6, Page 72
  117. 117. Pathology Tips – Tip 5 Postinfectious GN - IF MPGN Postinfectious GN particularly of particularly of Deposits complement and complement but often sometimes of IgG of IgG and IgM as well mainly on the outside on the inner aspect of Site of glomerular capillary loops capillary loops117 Handbook of Renal Biopsy Pathology, 2nd Edition, Chapter 6, Page 121, 122
  118. 118. Pathology Tips – Tip 5 Postinfectious GN - IF MPGN Postinfectious GN particularly of particularly of Deposits complement and complement but often sometimes of IgG of IgG and IgM as well mainly on the outside on the inner aspect of Site of glomerular capillary loops capillary loops118 Handbook of Renal Biopsy Pathology, 2nd Edition, Chapter 6, Page 121, 122
  119. 119. Pathology Tips – Tip 5 Postinfectious GN - IF119 Handbook of Renal Biopsy Pathology, 2nd Edition, Chapter 6, Page 133
  120. 120. Pathology Tips – Tip 5 Postinfectious GN - EM  Electron microscopy confirms the distribution of immune deposits, and shows whether glomerular basement membranes are single or double.120 Handbook of Renal Biopsy Pathology, 2nd Edition, Chapter 6
  121. 121. Pathology Tips – Tip 5 Postinfectious GN - EM121 Handbook of Renal Biopsy Pathology, 2nd Edition, Chapter 6, Page 135
  122. 122. Pathology Tips – Tip 6 IgA Nephropathy  IgA nephropathy may present pathologically as MPGN type I pattern  Differentiate with IF, IgA predominates in IgA nephropathy122 Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 27, Page 243
  123. 123. 123
  124. 124. Appendix B - Paraprotinemia: -IF: monoclonal or very rare polyclonal Ig, Kappa, Lambda light chains - EM: characteristic appearance -Postinfectious: - LM: - no double contour - no lobulation -IF: IgG, IgM on the inner aspect on capillary wall -EM: sybepithelial deposits - IgA nephropathy: IF of IgA deposits124
  125. 125. Appendix B - Paraprotinemia: -IF: monoclonal or very rare polyclonal Ig, Kappa, Lambda light chains - EM: characteristic appearance -Postinfectious: - LM: - no double contour - no lobulation -IF: IgG, IgM on the inner aspect on capillary wall -EM: sybepithelial deposits - IgA nephropathy: IF of IgA deposits125
  126. 126. Pathology Tips – Main Scheme No C3 no Ig other diseases present pathologically like MPGN 1ry 2ry other diseases Think of present chronic pathologically phase of like MPGN TMA126 Always check the possibility of secondary cause
  127. 127. Pathology Tips – Main Scheme No C3 no Ig other diseases present pathologically like MPGN 1ry 2ry other diseases Think of present chronic pathologically phase of like MPGN TMA Pathology Tip 7127 Always check the possibility of secondary cause
  128. 128. Pathology Tips – Main Scheme Appendix C No C3 no Ig other diseases present pathologically like MPGN 1ry 2ry other diseases Think of present chronic pathologically phase of like MPGN TMA Pathology Tip 7128 Always check the possibility of secondary cause
  129. 129. Pathology Tips – Tip 7 Thrombotic Microangiopathy - LM  In the acute phase:  endothelial swelling, and fibrin thrombi are present in the glomerular capillaries.  In the chronic phase:  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. How129
  130. 130. Pathology Tips – Tip 7 Thrombotic Microangiopathy - LM  In the acute phase:  endothelial swelling, and fibrin thrombi are present in the glomerular capillaries.  In the chronic phase:  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. How130
  131. 131. Pathology Tips – Tip 7 Thrombotic Microangiopathy - LM  In the acute phase:  endothelial swelling, and fibrin thrombi are present in the glomerular capillaries.  In the chronic phase:  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. How131
  132. 132. Pathology Tips – Tip 7 Thrombotic Microangiopathy - LM  In the acute phase:  endothelial swelling, and fibrin thrombi are present in the glomerular capillaries.  In the chronic phase:  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 deferntiate chronic phase from MPGN?132
  133. 133. Pathology Tips – Tip 7Thrombotic Microangiopathy – IF & EM MPGN TMA (Chronic Phase) C3 IF ± IgM, IgG Dense deposits EM In mesangium & along capillary walls133 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis--a new look at an old entity. N Engl J Med. 2012;366(12):1119-31
  134. 134. Pathology Tips – Tip 7Thrombotic Microangiopathy – IF & EM MPGN TMA (Chronic Phase) C3 IF ± NO complement or Ig IgM, IgG Dense deposits EM In mesangium NO dense deposits & along capillary walls134 Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis--a new look at an old entity. N Engl J Med. 2012;366(12):1119-31
  135. 135. Pathology Tips – Tip 7 Thrombotic Microangiopathy135 www.renaldigest.com
  136. 136. Pathology Tips – Tip 7 Thrombotic Microangiopathy136 www.renaldigest.com
  137. 137. Pathology Tips – Tip 7 Thrombotic Microangiopathy137 www.renaldigest.com
  138. 138. Other MPGN Like Pathologies138 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 267
  139. 139. Pathology Tips – Tip 8 Pathology & Outcome  The extent of the basement membrane broadening, (due to mesangial interposition into the basement membrane), may be a marker of disease severity, in type I MPGN: focal changes may represent an early manifestation of the disease and explain the more favorable outcome in response to treatment. *  Crescents  tubulointerstitial lesions.139 * Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 28, Page 251
  140. 140. Pathology Tips – Main Scheme No C3 no Ig other diseases present pathologically like MPGN 1ry 2ry other diseases Think of present chronic pathologically phase of like MPGN TMA140 Always check the possibility of secondary cause
  141. 141. Pathology Tips – Main Scheme No C3 no Ig other diseases present pathologically like MPGN 1ry 2ry other diseases Think of present chronic pathologically phase of like MPGN TMA141 Always check the possibility of secondary cause
  142. 142. 142
  143. 143. Always suspect secondary causes especially if there is an evidence143
  144. 144. OBJECTIVES  Introduction before we drive on the road to etiology:  Epidemiology  Pathogenesis & Types  Renal Presentation  Pathology  Diagnostic Road for Etiology of MPGN:  Step 1: Pathology Tips  Step 2: Age & Sex  Step 3: History &Examination144  Step 4: Investigations
  145. 145. Age & Sex  MPGN Type I:  Idiopathic in children and young adults (primary kidney disease without systemic manifestations).  DDD:  females : males (3:2).  between 5 and 15 years old.145 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 263
  146. 146. OBJECTIVES  Introduction before we drive on the road to etiology:  Epidemiology  Pathogenesis & Types  Renal Presentation  Pathology  Diagnostic Road for Etiology of MPGN:  Step 1: Pathology Tips  Step 2: Age & Sex  Step 3: History &Examination146  Step 4: Investigations
  147. 147. Causes147 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 261
  148. 148. Causes148 Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 28, Page 250
  149. 149. History  Blood transfusion  Drug abuse  Dry eye & mouth  Photosensitivity  Traveling to tropic areas  Surgical history: Ventriculoarterial shunt.  Drugs:  Graulocyte colony stimulating factor.  Interferon α therapy  Family history of GN149
  150. 150. Examination HCV & Mixed Cryoglobulinemia  Meltzer Triad  Arthralgia  Myalgia & weakness  Skin vasculitis (purpura)  Liver disease  Cirrhosis  Portal hypertension  Other manifestations150 Cattran. Am J Kidney Dis 1999; 33:1174
  151. 151. Examination HCV & Mixed Cryoglobulinemia  The arthralgias:  rarely accompanied by arthritis,  usually symmetric,  classically involve the knees, hips, and shoulders.  The purpura:  usually painless,  palpable,  nonpruritic;  occurs in “crops” that last 4 to 10 days  preferentially localizes to the extremities.151 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 264
  152. 152. Examination HCV & Mixed Cryoglobulinemia152 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 264
  153. 153. Examination HCV & Mixed Cryoglobulinemia  Other manifestations may include:  ulcerative, vasculitic lesions that classically involve the lower extremities and buttocks,  Raynaud’s phenomenon,  digital necrosis,  peripheral neuropathy,153 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 264
  154. 154. Examination HCV & Mixed Cryoglobulinemia154 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 265
  155. 155. Examination - DDD  It may precede the renal disease by many years.  Partial lipodystrophy:  preferentially involves the face and upper body may be present155 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 263, 264
  156. 156. Examination - DDD  It may precede the renal disease by many years.  Partial lipodystrophy:  preferentially involves the face and upper body may be present156 Oxford Text Book of Clinical Nephrology, Section III, Chapter 8, Page 530
  157. 157. Examination - DDD  Partial lipodystrophy:  preferentially involves the face and upper body may be present Family photographs of a normal young boy (left) who developed partial lipodystrophy (right) following an attack of measles. He went on to have mesangiocapillary glomerulonephritis and renal failure. Oxford Text Book of Clinical Nephrology, Section III, Chapter 8, Page 530157
  158. 158. Examination - DDD  Partial lipodystrophy:  preferentially involves the face and upper body may be present Family photographs of a normal young boy (left) who developed partial lipodystrophy (right) following an attack of measles. He went on to have mesangiocapillary glomerulonephritis and renal failure. Oxford Text Book of Clinical Nephrology, Section III, Chapter 8, Page 530 Hereditary deficiencies of the classical pathway of complement (C1q, C2, C4) and of C3 are associated with the development of MPGN in addition to predisposing to lupus and158 bacterial infections. Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 260
  159. 159. Examination - DDD Some patients with DDD will have:  mild visual field  color defects  prolonged dark adaptation  mottled retinal pigmentation (drusen bodies)  sometimes deterioration of vision. Eye examinations should be performed on first presentation and annually thereafter including:  dark adaptation,  electroretinography,  electro-oculography. Indocyanine green angiography of the retina may reveal dense deposits in the ciliary epithelial basement membrane (abnormal fluorescent dots) and choroidal neovascularization.159 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 263, 264
  160. 160. Examination  Examine all lymph node groups  Auscultate the heart for new murmur  Search for drug injection marks on hands & thighs.  Search for malar rash, discoid rash  Search for oral ulcers160
  161. 161. Examination  Examine all lymph node groups  Auscultate the heart for new murmur  Search for drug injection marks on hands & thighs.  Search for malar rash, discoid rash  Search for oral ulcers  Don’t miss FEVER even the low grade one161
  162. 162. OBJECTIVES  Introduction before we drive on the road to etiology:  Epidemiology  Pathogenesis & Types  Renal Presentation  Pathology  Diagnostic Road for Etiology of MPGN:  Step 1: Pathology Tips  Step 2: Age & Sex  Step 3: History &Examination162  Step 4: Investigations
  163. 163. Causes163 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 261
  164. 164. Causes164 Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 28, Page 250
  165. 165. Investigations  1- detection of infections:  blood, urine, sputum cultures  HCV Ab  HBsAg  HIV Ab  Polymerase-chain reaction  serologic tests for viral, bacterial, and fungal infections.165
  166. 166. Investigations  1- detection of infections:  blood, urine, sputum cultures  HCV Ab  HBsAg  HIV Ab  Polymerase-chain reaction  serologic tests for viral, bacterial, and fungal infections.  2- Cryoglobulins  3- Rheumatoid factor  4- C3, C4  5- anti dsDNA  6- ANA  7- Anti Ro  8- Anti La166
  167. 167. Investigations  1- detection of infections:  blood, urine, sputum cultures  HCV Ab  HBsAg  HIV Ab  Polymerase-chain reaction  serologic tests for viral, bacterial, and fungal infections.  2- Cryoglobulins  3- Rheumatoid factor  4- C3, C4  5- anti dsDNA  6- ANA  7- Anti Ro  8- Anti La  9- ESR  10- CRP  11- CBC167  12- Blood film
  168. 168. Investigations  1- detection of infections:  13- CXR  blood, urine, sputum cultures  14- US abdomen & pelvis (searching  HCV Ab abscess or RCC)  HBsAg  HIV Ab  15- CT (searching abscess or RCC)  Polymerase-chain reaction  serologic tests for viral, bacterial, and fungal infections.  2- Cryoglobulins  3- Rheumatoid factor  4- C3, C4  5- anti dsDNA  6- ANA  7- Anti Ro  8- Anti La  9- ESR  10- CRP  11- CBC168  12- Blood film
  169. 169. Investigations  1- detection of infections:  13- CXR  blood, urine, sputum cultures  14- US abdomen & pelvis (searching  HCV Ab abscess or RCC)  HBsAg  HIV Ab  15- CT (searching abscess or RCC)  Polymerase-chain reaction  serologic tests for viral, bacterial, and fungal infections.  16- ECHO  2- Cryoglobulins  3- Rheumatoid factor  4- C3, C4  5- anti dsDNA  6- ANA  7- Anti Ro  8- Anti La  9- ESR  10- CRP  11- CBC169  12- Blood film
  170. 170. Investigations  1- detection of infections:  13- CXR  blood, urine, sputum cultures  14- US abdomen & pelvis (searching  HCV Ab abscess or RCC)  HBsAg  15- CT (searching abscess or RCC)  HIV Ab  Polymerase-chain reaction  serologic tests for viral, bacterial,  16- ECHO and fungal infections.  17- detection of monoclonal gammopathy:  2- Cryoglobulins  serum and urine electrophoresis  3- Rheumatoid factor  Immunofixation studies  4- C3, C4  free light-chain assays  5- anti dsDNA  Positive results necessitate bone  6- ANA marrow studies for a more precise  7- Anti Ro diagnosis..  8- Anti La  9- ESR  10- CRP  11- CBC170  12- Blood film
  171. 171. Investigations Hypocomplementemia MPGN CH50 C3 C4 I ↓ ↓ or N ↓ II (DDD) ↓ ↓ N III ↓ ↓171
  172. 172. Investigations Hypocomplementemia Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 261172
  173. 173. Investigations Hypocomplementemia Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 261 C3 nephritic factor activity is more common in type II disease, namely 60–70% of patients, compared to 20–25% of patients with type I or III disease. 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]173 [1] Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 28, Page 251 [2] Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 260
  174. 174. Investigations HCV & Mixed Cryoglobulinemia174 Comprehensive Clinical Nephrology, 4th edition, Chapter 21, Page 265
  175. 175. Investigations175
  176. 176. Investigations Suspect any organism as a cause of post infectious MPGN whenevr there is evidence of infection176
  177. 177. Investigations – Alternative Pathway177
  178. 178. Follow On www.nephrotube.blogspot.com & Facebook Group NephroTube178
  179. 179. Hope that it is clear now …. Thank You Gawad179

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