1. Kidney Lecture 1 – Normal, Function, Glomerulonephritis

2. Learning Objectives Describe the clinical and pathologic features of: –Infection-related glomerulonephritis –Crescentic Glomerulonephritis –Membranous Nephropathy –Membranoproliferative Glomerulonephritis –IgA Nephropathy

3. Lecture Outline Lecture 1 –Normal Kidney –Glomerulonephritis Lecture 2 –Non-immune glomerular disease –Systemic diseases involving glomeruli –Infections –Vascular diseases Lecture 3 –Obstructive and cystic diseases – Acute Tubular Necrosis –Renal Transplant

4. Normal Renal Anatomy

6. Anatomic A. Glomerulus B. Tubules C. Interstitium D. Vasculature E. Pelvis

7. Structure of Normal Glomerulus Light microscopy outer to inner: 1.Bowman’s capsule – urinary and vascular poles 2.Parietal epithelium – single layer 3.Bowman’s (urinary) space 4.Visceral epithelium 5.Capillary loop 6.Basement membrane 7.Endothelium 8.Mesangium 1 2 3 4 5 6 7878

8. View of basement membrane similar to region shown in box magnified in next slide Electron Microscopy of Glomerulus 1.Visceral epithelium 2.Capillary loop 3.Basement membrane 4.Endothelium 5.Mesangium 6.Foot processes 7.Slit diaphragms 8.Endothelial fenestrations 1 2 7 8 3 4 5 6

9. Normal Glomerulus 1.Foot processes 2.Slit diaphragms 3.Endothelial fenestrations 4.Lamina densa 5.Lamina lucida 1 25 4 3

10. Glomerular Disease Topics Definitions Clinical syndromes Immune mediated types –Infection related glomerulonephritis –Crescentic glomerulonephritis –Membranous nephropathy –IgA nephropathy –Membranoproliferative glomerulonephritis Non immune and systemic (next lecture)

11. Glomerular Terminology DiffuseFocalGlobalSegmental

12. Clinical Nephritic Syndrome Rapidly Progressive Glomerulonephritis Nephrotic Syndrome Often overlap Can not always predict which disease the patient has based on nephrotic or nephritic presentation alone –Serology, consideration of coexisting diseases, and/or biopsy usually needed

13. ACUTE NEPHRITIC SYNDROME 1. Hematuria and red cell casts a.Also known as active sediment b.Casts – clumps of cells and/or protein molded by interior of tubules – thus proves that blood originate in kidney and not elsewhere in urinary tract 2. Mild-moderate proteinuria 3. Hypertension 4. Azotemia a.Definition - Elevated BUN and Creatinine b.Moderate elevation in typical nephritic syndrome

14. Rapidly Progressive Glomerulonephritis (RPGN) Clinical Rapid rise in creatinine over days or weeks RBCs and casts in urine sediment Signs and symptoms associated with acute renal failure (nausea, vomiting, oliguria) and if applicable, specific systemic disease Requires aggressive treatment, including immunosuppression

15. NEPHROTIC SYNDROME 1. Edema 2. Proteinuria > 3gm/24 hours (N 150mg or, after exercise, 300mg) 3. Hypoalbuminemia 4. Hypercholesterolemia 5. Oval fat bodies in urine 6. Thrombosis risk

17. Nephrotic – Foot process alterations Nephritic – Thrombosis and Inflammation

18. Mechanisms of Immune Mediated Glomerulonephritis Antigen-antibody reactions 1. Deposition of circulating immune complexes Passively trapped. By EM either in mesangium, subendothelial or subepithelial. 2. In situ antigen-antibody combinations. Anti-GBM and foot process antibodies. Circulating antibody to GBM antigen fixes to native antigenic site within GBM. Anti-GBM and foot process antibodies. Circulating antibody to GBM antigen fixes to native antigenic site within GBM. 3. Planted antigens. Circulating antigens bind ot glomerular wall components. Subsequent antibody binding and/or complement fixation

19. 1.Subepithelial 2.Epimembranous 3.Subendothelial 4.Mesangial 5.Intramembranous

20. Immunofluorescence Microscopy In situ deposition Immune complex Fluorescent label Anti-human Ig monoclonal Patient Anti-GBM Antibody GBM Antigen (Collagen IV) Glomerular basement Membrane Glomerular loop as seen by microscopy (linear) Patient Immune complex antigen Glomerular loop As seen by microscopy (granular or lumpy) Patient Immune complex antibody Immune complex

21. Acute Infection –Related (Post Infectious or Post Streptococcal) Glomerulonephritis (AIRGN)

22. Histologic. Diffuse proliferative GN; IFL Complement 3 (C3) and IgG, granular; EM subepithelial lumps Clinical –Nephritic syndrome. Follows nephritogenic strep or other infection of any site, notoriously pharynx or skin. Usually recover. –More common in developing countries Pathogenesis. In situ assembly of immune complexes based on plated bacterial antigens

23. Normal Glomerulus Infection Related Glomerulonephritis

24. Streptococcal Skin Lesion (Impetigo)

25. Subepithelial Humps

26. Immunofluorescence IgG –AIRGN Coarse Granular – “Lumpy Bumpy”

27. Question 1 What is the characteristic immunoflurescent pattern of infection-related glomerulonephritis? – –Coarsely granular IgG deposition on the glomerular basement membrane – –Granular IgA deposition in the mesangium – –No immunofluorescent findings – –Finely granular IgM deposition on the glomerular basement membrane – –Linear IgG deposition on the glomerular basement membrane

28. Question 1 What is the characteristic immunoflurescent pattern of infection-related glomerulonephritis? – –Coarsely granular IgG deposition on the glomerular basement membrane – –Granular IgA deposition in the mesangium – –No immunofluorescent findings – –Finely granular IgM deposition on the glomerular basement membrane – –Linear IgG deposition on the glomerular basement membrane

29. Crescentic Glomerulonephritis

30. Clinical manifestation is Rapidly Progressive Glomerulonephritis (RPGN) Signs and symptoms associated with renal failure and if applicable, specific systemic disease (Wegener-sinusitis, Goodpasture- hemoptysis, Lupus - rash, etc)

31. Crescentic Glomeruolnephritis

32. Three Subtypes of RPGN Type I –In situ IgG deposition – linear IgG by IF, because of even distribution of IgG along GBM –Anti GBM antibodies by serology –No abnormality by EM –Anti GBM disease - Kidney only – Goodpasture Kidney and lung – renal failure and hemoptysis Type II – Immune mediated –Defined by underlying glomerular disease (e.g. rapidly progressive IgA nephropathy, AIRGN, lupus, MPGN, etc)

33. RPGN Type I IgG-IF Linear Pattern

34. Subtypes of RPGN – Type III Pauci –immune – No immune deposits by EM, IF Most common type of RPGN Anti-nuclear cytoplasmic antibody (ANCA) by serology – myeloperoxidase–ANCA idiopathic, microscopic PAN – proteinase 3 ANCA– Wegener granulomatosis Mechanism –ANCA encourages vascular destruction by PMN –GBM destruction releases fibrin in urinary space –Reactive proliferation by parietal epithelium

35. p-ANCA c-ANCA (Myeloperoxidase) (Proteinase3)

36. Question 2 The glomerular abnormality associated with rapidly progressive glomerulonephritis is referred to as – –Crescent – –Spikes – –Kimmelsteil-Wilson nodule – –Foot process effacement – –Fenestrated endothelium

37. Question 2 The glomerular abnormality associated with rapidly progressive glomerulonephritis is referred to as – –Crescent – –Spikes – –Kimmelsteil-Wilson nodule – –Foot process effacement – –Fenestrated endothelium

38. Membranous Nephropathy

40. Normal Glomerulus Current Case for Comparison

41. Silver Stain Basement Membrane Spikes

42. IgG Immunofluorescence

44. Membranous Glomerulopathy Pathology - Thick GBM (by LM); granular (by IFL); saw-toothed thickening with subepithelial spikes and dense deposits (by EM) Clinical — Massive proteinuria, nephrotic +/– nephritic syndromes. PLA2R (50%) Idiopathic (30%) or secondary (20%, hepatitis B, cancer) Pathogenesis: Injury mediated by C5b-C9 membrane attack complex of complement Pathogenesis: Autoantibodies against podocyte cell membrane antigen M-type phospholipase A2 receptor (PLA2R),Injury mediated by C5b-C9 membrane attack complex of complement Prognosis - May respond to steroids, immunosuppression

45. Membranoproliferative Glomerulonephritis

46. Membranoproliferative Glomerulopathy Club shaped lobules, mesangial hypercellularity, excess mesangial matrix, double basement membranes (LM). Club shaped lobules, mesangial hypercellularity, excess mesangial matrix, double basement membranes (LM). Two principal types defined by EM: –Type I - Immune Complex Mediated)-subendothelial deposits, IF -granular IgG, Early complement pathway - C 1q and C 4 –Dense Deposit Disease/ C3 Glomerulopathy – Rare. Clinical — Primary or secondary, nephritic or nephrotic. Type I often hepatitis C related.

47. Membranoproliferative Glomerulonephritis

48. Double Contour Basement Membrane

49. Membranoproliferative GN – Type I Double Contour Basement Membrane

50. IgA Nephropathy

51. IgA Nephropathy Berger Disease Defined by IgA in the mesangium. Light microscopy: assorted possibilities including mesangial lesions, crescentic, focal glomerulonephritis or sclerosis, normal or obsolete glomeruli. EM: electron dense deposits in the mesangium.

52. IgA Nephropathy Berger Disease (continued) Clinical-. Gross or microscopic hematuria especially coincident with URI. Other: asymptomatic hematuria; proteinuria; nephrotic syndrome; fulminant renal failure, chronic renal failure. –Related to Henoch-Schonlein-purpura (lower extremety purpuric rash, more severe renal disease) –Most common primary glomerulonephritis in the world –Course variable: benign to slow chronic renal failure –Etiology related to abnormal glycosylation of hinge region of IgA molecule

53. IgA Nephropathy Focal Glomerulonephritis

54. IgA Nephropathy Mesangial Hypercellularity

55. IgA IF – Mesangial Pattern

56. EM – Mesangial Deposits

57. Henoch Schoenlein Purpura IgA nephropathy with lower extremity purpura Renal disease often more severe

58. Diagnosis of Glomerular Disease Nephrotic, nephritic, or RPGN does not identify the specific disease, only steers you in direction toward a glomerular differential Examples of isolated hematuria –IgA, thin basement membrane disease Examples of nephritic presentation –Post infectious, IgA, lupus Examples of nephrotic presentation –Membranous, IgA, MPGN, lupus There can be overlap Bottom line – Biopsy required for final diagnosis of many glomerular diseases –Treatment depends on diagnosis of specific disease entity