1. Primary Glomerular Disease SHOKOUFEH SAVAJ ASSOCIATE PROFESSOR OF MEDICINE FIROOZGAR HOSPITAL,IUMS

6. Albumin has a negative charge with a physical radius of 3.6 nm. GBM and slit-pore membranes have a radius of 4 nm Albumin is reabsorbed in proximal tubule Normal urine albumin :8-10 mg/d.

8.  Glomerulonephritis : Glomerular Injury with Inflammation ( Leukocyte infiltration, Complement activation & Antibody deposition )  Primary :Limited to kidney  Secondary : Part of Systemic disorder  Acute :Injury occur in days or weeks  Subacute or rapidly progressive : in Weeks or months  Chronic : Injury in years

9.  Nephrotic syndrome : > 3.5gr proteinuria in 24 hours/1.73 M 2  Nephritic syndrome : proteinuria,decrease in GFR, hypertension,hematuria and cellular casts  Proliferative : Increase in glomerular cell number ( intracapillary & Extracapillary )  Sclerosis :Deposition of homogenous non fibrillar material  Fibrosis :Deposition of collagen type I and III

10. Nephrotic Syndrome  Proteinuria  Hypoalbuminemia  Hyperlipidemia  hypercoagulable state  Hypertension  Decrease in GFR

11. Minimal Change Disease

12. Pathogenesis  T cell dysfunction  Permeability Factor : immune origin (IL 13 )  Genetic ??

13.  70–90% in childhood &10–15% of nephrotic syndrome in adults.  Acellular urinary sediment  Hypertension (30% in children, 50% in adults)  Microscopic hematuria (20% in children, 33% in adults)  Atopy or allergic symptoms (40% in children, 30% in adults)  Decreased renal function (<5% in children, 30% in adults).

15. Causes of minimal change disease  Allergy : bee stings, house dust, pollens..  Cancer :Lymphoma,leukemia  Infection : syphilis, tuberculosis, HIV, Hepatitis C virus, and Echinococcus  Drugs : NSAID, Lithium, ampicillin,rifampin pamidronate

16. Membranous Nephropathy

18.  Neutral endopeptidase expressed by podocytes  Hepatitis antigens B/C  Helicobacterpylori antigens  Tumor antigens.  Autoantibodies against the M-type phospholipase A 2 receptor (PLA 2 R) circulate and bind to a conformational epitope present in the receptor on human podocytes

21. Primary/idiopathic membranous glomerulonephritis Secondary membranous glomerulonephritis Infection : Hepatitis B and C, syphilis, malaria, schistosomiasis, leprosy, filariasis Cancer : Breast, colon, lung, stomach, kidney, esophagus, neuroblastoma Drugs : gold, mercury, penicillamine, nonsteroidal anti-inflammatory agents, probenecid Autoimmune diseases : systemic lupus erythematosus, rheumatoid arthritis, primary biliary cirrhosis, dermatitis herpetiformis, bullous pemphigoid, myasthenia gravis, Sjögren's syndrome, Hashimoto's thyroiditis Other systemic diseases : Fanconi's syndrome, sickle cell anemia, diabetes, Crohn's disease, sarcoidosis, Guillain-Barré syndrome, Weber- Christian disease, angiofollicular lymph node hyperplasia

22.  30% of nephrotic syndrome Adult  The male to female ratio :2 to 1  80% nephrotic syndrome  Microscopic hematuria in 50%  Highest incidence of renal vein thrombosis

23. Focal segmental Glomerulosclerosis

24.  Primary focal segmental glomerulosclerosis  Secondary focal segmental glomerulosclerosis  Viruses: HIV/Hepatitis B/Parvovirus  Hypertensive nephropathy  Reflux nephropathy  Cholesterol emboli  Drugs: Heroin/analgesics/pamidronate  Oligomeganephronia  Renal dysgenesis  Alport's syndrome  Sickle cell disease  Lymphoma  Radiation nephritis  Familial podocytopathies  NPHS1 mutation/nephrin  NPHS2 mutation/podocin  TRPC6 mutation/cation channel  ACTN4 mutation/actinin  -Galactosidase A deficiency/Fabry's disease  N -acetylneuraminic acid hydrolase eficiency/nephrosialidosis

26. Collapsing glomerulosclerosis

27. Clinical Presentation  Hematuria  Hypertension  A level of proteinuria  Renal insufficiency  African-American raceare associated with a poor outcome, with 50% of patients reaching renal failure in 6–8 years

28. Alport Syndrome  The most common hereditary nephrits  Genetic defect of α5 chain of type IV collagen  Gene on long arm of chromosome X  Males presented with :  Hematuria, Proteinuria, Progressive renal insufficiency

31. Immune Mechanisms of Glomerular Injury Podocyte Non inflammatory Neutrophil, Monocyte Proliferating glomerular cells Inflammatory

32. Inflammatory Mechanisms of Immune Glomerular Injury

33. Antibody – Mediated Injury  1- Reactivity of circulatory autoantibodies with intrinsic autoantigens  2-Insitu formation of immune Complex ( with extrinsic antigens )  3- Intraglomerular trapping of immune complex

34.  Generation of nephritogenic Antibodies : 1. Similarity with foreign antigen 2. Expression MHC II ( which were invisible) 3. Problem in tolerance  Deposition of Nephritogenic antibodies within Glomerus

35. Site of antibody deposition  Size  Charge  Quantity  Site of antigen  Local hemodynamics factor  Problem in clearance mechanisms for immune complexes

37. Mechamism of glomerular Damage

38. Post Streptococcal Glomerulonephritis

39. Pathogenesis  Children 4-12  Decreased incidence rate  Throat infections infection:1-3 weeks after with M types of streptococci (nephritogenic strains) antedate glomerular disease and M types 1, 2, 4, 3, 25, 49, and 12 with pharyngitis  Skin: 2-6 weeks after infection ; M types 47, 49, 55, 2, 60, and 57 are seen following impetigo.

43. IgA nephropathy

44. Pathogeneis  Immune complex mediated GN with diffuse mesangial IgA deposit  Abnormal IgA production  Abnormal IgA clearance (liver,mesangial )  O-glycosylation of hinge region of IgA

45. Clinical Presentation  Microscopic hematuria  Subnephrotic proteinuria  Nephrotic syndrome (rare)  Gross hematuria  Acute renal failure  Rapidly progressive GN

46. Membranoproliferative GN type I lobular appearance of the glomerular tuft with focal areas of increased glomerular cellularity (large arrows), mesangial expansion (*), narrowing of the capillary lumens, and diffuse thickening of the glomerular capillary walls

49. Electron Microscopy In MPGN I

50. Membranoproliferative Type II Basement membrane thickening, double contour, mesangial interposition C3 deposition on capillary wall and mesangium

51. Electron microscopy in MPGN II DDD

52. Pathogensis  Type I MPGN : secondary to glomerular deposition of circulating immune complexes or their in situ formation  Types II and III MPGN :"nephritic factors," (autoantibodies that stabilize C 3 convertase).

53. Clinical Findings  Proteinuria, hematuria, and pyuria (30%)  Systemic symptoms of fatigue and malaise  An acute nephritic picture with RPGN and a Speedy deterioration in renal function in up to 25% of patients.  Low serum C 3 levels are common

54. Prognosis  50% with MPGN develop ESRD in10 years after diagnosis,  90% have renal insufficiency after 20 years.  Nephrotic syndrome, hypertension, and renal insufficiency all predict poor

55. Rapidly Progressive Glomerulonephriris