1 Relax your eyes with the nature: It time for Glomerular Diseases

2 This lecture will deal with the Glomerular Diseases These diseases poses Important Medical problems. Lecture by: Dr. Amitabha Basu MD

3 The Glomerular Diseases We will learn it in following order Normal Glomeruli (LM and EM) Diagnosis of glomerular disease Etiology and pathogenesis of various glomerular diseases

4 The Normal Glomerulus : light microscopy) It consists of a tuft of anastomosing capillaries. Mesangium: mesengial cells.

5 Electron microscopy Foot processes Basement membrane Mesangial cells RBC

6 Terminologies to understand glomerular diseases Glomerulonephritis Diffuse Focal Segmental Membranous Proliferative Sclerosis

7 The Diseased Glomerulus Terminology The preferred terminology to define diseases of the glomerulus is glomerulitis. If secondary changes are induced in adjacent tubules, one may use the term glomerulonephritis.

8 Diffuse When all glomeruli of the kidney is involved in disease process.

9 Focal When some glomeruli of the kidney is involved in disease process.

10 Segmental When part of a glomerulous is involved in disease process.

11 Proliferative Where there are increased number of cells in glomeruli…may die to infiltration of PMNs. Will result in loss of bowman space and less GFR/urine output- commonly result in acute renal failure.

12 MEMBRANOUS GLOMERULONEPHRITIS (thickened basement mem.)

13 Sclerosis (Trichrome stain) Increased collagen, blue colored in this stain.

14 Duration Acute eg: Acute Diffuse Proliferative glomerulonephritis. Chronic eg. Chronic Glomerulonephritis

15 D. Sclerosis (Trichrome stain) Increased collagen, blue colored in this stain.

16 Glomerular disease Types: –Primary –Secondary ( due to other systemic disease) –Hereditary Clinical syndromes Pathophysiology Pathogenesis Discussion of individual disease

17 Diagnosis of glomerular disease Disease of the glomeruli can be identified by three syndromes: 1.Nephrotic syndrome 2.Acute Nephritic syndrome 3.Recurrent hematuria ( red or smoky urine).

18 Glomerular diseases Nephrotic syndrome Acute nephritic syndrome/ RPGN Recurrent Hematuria

19 The Nephrotic Syndrome 1.Massive Proteinuria (3.5 g or more/day/1.73 m 2 ) 4+ protein in urine ( usually frothy) 2.Hypoalbuminemia ( plasma protein< 3g/dL) 3.Generalized Edema (Anasarca) 4.Hyperlipidemia and Lipiduria

20 Pathophysiology of Nephrotic Syndrome Damaged Capillary or Epithelium ↓ increased capillary permeability ↓ loss of albumin: Protenuria ↓ Hypoalbuminemia ↓ Decreased osmotic Pressure ↓ Transudation in the interstitial spaces, peritoneum, pleural cavity etc : pitting edema Protenuria produce foamy white foam after urination.

21 Hyperlipidimia and Lipiduria Decreased albumin in Blood triggers lipoprotein synthesis. ↓ Cause high cholesterol ↓ Part of which passes through urine. ↓ Lipid in the urine is seen as “oval fat Body”. ↓ Some lipid is accumulated in the tubular epithelial cells as hyaline droplet.

22 The Nephrotic Syndrome Complications 1. Infections Patients are unusually susceptible to some infections due to protein loss. 2. Increased Cholesterol = Arthrosclerosis. 3. Blood clotting - which may cause venous thrombosis ( due to increase viscosity of blood).

23 Acute Nephritic syndrome Anuria or oliguria. Onset: weeks-months –Moderate protenuria (< 3.5 gm/day) [ +2, +3]. –Hematuria –Azotemia –Hypertension Rapidly progressive Glomerulonephritis –Similar features but onset is quicker (weeks to months )→ ARF.

24 Parthenogenesis of glomerulonephritis Three mechanisms: 1.Deposition of soluble antigen-antibody Complex in glomeruli. 2.Antibody reacting to in-situ antigen in the Glomeruli (Glomerular Basement Membrane antigen). 3.Cell mediated immune Nephritis.

25 Circulating immune complex nephritis: Type III hypersensitivity reaction Diseases this is seen are: 1.SLE 2.Streptococcal 3.Hepatitis B 4.Treponema pallidum 5.Malaria So IF will show granular deposit

26 Antibody reacting to in-situ antigen in the Glomeruli Antibodies (anti GBM antibody) are directed to the fixed antigen in the GBM. Examples –Good pasture syndrome –Heymann nephritis( experimental) So IF will show smooth linear deposit

27 Two Patterns of Deposit (IF) Granular Circulating immune complex Linear, smooth In situ disease

28 Individual Diseases 1.Minimal change disease 2.Membranous glomerulonephritis 3.Acute glomerulonephritis 4.Crescentic glomerulonephritis 5.Berger's disease (IgA nephropathy) 6.Membrenoproloferative GN 7.Alport syndrome All are primary glomerular diseases

29 Important !!! For all Glomerular disease: Study 1.Light microscopic features (LM) 2.Electron microscopic features (EM) 3.Immunofuroscence feature ( this detect immune deposit)= IF 4.Syndromes

30 Minimal change disease ( lipoid nephrosis) Syndrome: Nephrotic syndrome –Type of protenuria: selective (only albumin comes out). –Due to loss of the normal charge barrier of GBM –Pathogenesis: Lymphokine production by T cells Most common cause of nephrotic syndrome in children ( 2-6 years). Light Microscopy : –Normal glomeruli. –Lipid droplet in proximal tubular epithelium

31 Minimal change disease ( lipoid nephrosis) IF: no deposit EM: –Effacement of epithelial ( podocytes) foot process. Treatment : excellent result with corticosteroid: stops protenuria quickly. Majority recover completely.

32 RBC Effacement of foot processes due to loss of foot process (giving the appearance of fusion of the epithelial cell) (giving the appearance of fusion of the epithelial cell)

33 Lipoid Nephrosis( Minimal Change Disease) Urine Analysis and laboratory Urine: –Color Yellow –Appearance Slightly Cloudy –Protein 4+ ( massive) –Oval fat body +++ –All others are negative Laboratory: –Serum Cholesterol: High –Complement : normal

34 Membranous nephropathy (GN) Syndrome: Nephrotic syndrome Most common nephrotic syndrome in ADULT. Etiology: –Idiopathic or genetic –Drug ( penicillamine), renal transplantation, Heymann nephritis. –SLE, Diabetes mellitus –Adenocarcinoma of lung and colon.

35 Morphology LM: –H&E stain: diffuse thickening of the capillary wall. –Silver stain: spikes IF: granular deposit of IgG and C3. EM: Sub epithelial deposit along Basement membrane.

36 m Membranous GN Silver stain: spikes H&E stain: diffuse thickening of the capillary wall.

37 Sub epithelial deposit Granular deposit of IgG and C3

38 Characteristic urinalysis findings and laboratory Urine: –Protein 4+ –WBC/hpf = <2/hpf Laboratory: –low complements

39 Membranous GN Clinical Features and Prognosis Some patient develop hypertension and hematuria. It has a variable and indolent course. 40% patient progress to renal failure or end stage renal disease after 2-20 years % with partial or complete remission of proteinuria. No or infrequent effect with steroid.

40 Acute Glomerulonephritis Acute Post-streptococcal Glomerulonephritis Non-streptococcal causes

41 Acute Post-streptococcal glomerulonephritis AKA: proliferative GN, Post infectious GN Syndrome: Acute nephritic syndrome ASO titer: very high. Age:: 2-4 years. Etiology: –beta hemolytic group A streptococci infection of throat and skin (type 12,4,1).. –This organism has M protein on cells wall.

42 Other Acute Glomerulonephritis Non-streptococcal causes –Pneomococcal pneumonia –Hepatitis B, C –SLE, PAN –Malaria. Morphological features of these disease are similar to that of acute post streptococcal GN, only prognosis would be different.

43 Morphology of Acute Post-streptococcal Glomerulonephritis LM: Hyper cellular, large glomeruli contain Neutrophils. Tubules: RBC cast IF: granular deposit of IgG, IgM, C3 in all glomerulous. EM: sub epithelial humps.

44 ASO titer elevate- in poststreptococcal case. Urine : Smoky (due to hematuria), Dysmorphic RBC. Serum complement level- Low Sub epithelial humps Hyper cellular glomeruli

45 Clinical Course Past History: Throat or skin (impetigo ) infection. Abrupt onset, Malaise, slight fever, nausea. Self recovery in child >95% case. Adult : –may progress to crescentic GN. –May progress to chronic Glomerulonephritis.

46 Crescentic Glomerulonephritis (CrGN) Aka: –Rapidly Progressive Glomerulonephritis ( RPGN) :: because it quickly (months/weeks) develops acute renal failure. Syndrome: Acute nephritic syndrome. Three types: –LM of all types show glomerular crescent.

47 Crescent Three types Crescent is formed by proliferation of epithelial cells and monocytes and fibrin.

48 Type I CrGN 1.AKA Anti-GBM DISEASE 2.AKA: G ood pasture syndrome. 1.Presence of Anti GBM antibody in serum: this react with alveolar capillary → pulmonary alveolar hemorrhage. 2.Present as hematuria and hematemesis. 3.IF: Linear and smooth deposit of IgG, and C3 on GBM.

49 Type II (CrGN) Etiology: mainly SLE IF: Granular deposit Clinical : progress to renal failure. Serum: ANA present

50 Type III (CrGN) Aka: Pauci-immune ( no immune reaction) Diseases: –Wagner Granulomatosis, polyarteritis Nodosa Serum: –Normal complements –Positive ANCA (c or p) LM: glomerular crescent IF and EM: no deposit

51 Crescentic Glomerulonephritis C/F and Prognosis Present with the features of Nephritic Syndrome (RPGN) → acute renal failure. Prognosis depends upon the number of Crescent in kidney: so biopsy is indicated.

52 Any Question ?

53 Berger's disease Or, IgA nephropathy

54 Lung infection GI disease IgA elevation Deposit in Kidney Deposit in dermis Deposit in blood vessels

55 Berger's disease (IgA nephropathy); Please correct your PPT Age : Children and Young adult Syndrome: recurrent hematuria –This hematuria occur 1-2 days after upper respiratory tract infection. –May progress to Chronic renal Failure(25%-50%). –IgA deposit in skin –Gluten enteropathy. LM: focal proliferation of mesangial cells IF: IgA is deposited mainly in mesangium.

56 Variant of Berger's disease (IgA nephropathy) Disease name: Henoch-Schönlein Purpura: It is associated with 1.Skin purpuric Rash 2.Abdominal Pain 3.Arthritis 4.And Kidney change Q: What is the similarity? A: Both are caused by IgA deposition in Mesangium and skin deposit of IgA.

57 Berger's disease and Henoch-Schönlein Purpura Focal proliferation of mesangial cells IgA deposit is in mesengium

58 Membranoproliferative Glomerulonephritis (MPGN) Are divided into types I and II.

59 Membranoproliferative glomerulonephritis (MPGN I) Syndrome: Nephrotic syndrome Etiology: Hepatitis B and C, HIV, SLE, chronic liver diseases, chronic Bacterial Infection. LM: –H&E: hyper cellular glumeruli ( but no PMNs) and thick GBM. –Silver stain : Tram track IF: Granular deposit. Serum: low complements ( particularly C3)

60 H&E: Glomerular cellularity and thickening in the basement membrane “Tram-tracking”: Double basement membranes, Why? = Basement membrane splitting

61 MPGM type II Syndrome: Hematuria / chronic renal failure –40% progress to end stage renal failure IF: Dense deposit in GBM. –Aka dense deposit diseases. Serum: C3NeF (C3 Nephritic Factor) autoantibody is Present.

62 Dense depositEM: note the deposit These bright deposits are of C3 in capillary walls and in the mesangium.

63 Focal segmental Glomerulosclerosis (FSGS).

64 Focal segmental Glomerulosclerosis (FSGS). Age: child and adult Syndrome: Nephrotic syndrome. –Develop non-selective proteinuria Morphology: –H&E: Sclerosis of some glomeruli, with partial involvement. –Trichrome: Blue

65 Focal, segmental Glomerulosclerosis Trichrome stain demonstrates blue, collagen deposition.

66 FSGS A.Etiology: A.HIV infection, Heroin addiction B.Inherited congenital disease C.start as a Primary disease B.Clinical: A.Poor response to corticosteroid B.Hematuria, Hypertension C.Progression to chronic renal failure D.50% develop End stage Renal failure within 10 years.

67 SECONDARY GLOMERULONEPHRITIS (SYSTEMIC ): more common 1. Diabetes Mellitus 2. Systemic Lupus Erythematosus. 3. Amyloidosis 4. Goodpasture Syndrome 5. Wagner granulomatosis 6. Henoch-Schönlein Purpura 7. Bacterial Endocarditis

68 Glomerular disease with:- Systemic lupus erythematosus: Nephrotic syndrome Diabetes mellitus: Nephrotic syndrome Amyloidosis: Nephrotic syndrome

69 Glomerular changes in SLE: positive dsDNA 1.Crescentic GN = RPGN 2.Focal proliferative GN : 25% case = ANS 3.Membranous GN (Wire loop thickening)* = NS 4.Mesangial lupus GN = NS 5.Normal glomerulous ( rare) = NS

70 SLE: LM: wire loop IF: C1q deposit C1q deposit EVERYWHERE Serum complement low ( typically C1q)

71 Diabetic kidney Kimmelstiel-Wilson disease or Nodular glomerulosclerosis Hyaline arteriolosclerosis Nodular hyaline deposit- PAS positive

72 Amyloidosis of Kidney Gross: waxy pale surface LM: –Pink hyaline like deposit in mesangium Cogored –LM: brick red –Polarized light: apple green birefrenges Type of amyloid: –Primary: Amyloid light chain ( Multiple myeloma) –Secondary (reactive): AA

73 We will now start Alport syndrome (hereditary)

74 Alport syndrome Syndrome: recurrent hematuria –Family history of Chronic renal failure –Sex: Male child > Female child –Early onset of renal failure –Nerve deafness –Cataract, lens dislocation, corneal dystrophy. Inheritance: ‘X- Linked’ autosomal Recessive or Dominant.

75 Alport syndrome Defective gene (alfa5) produce abnormal Collagen Type IV. LM: irregular thickening of glomeruli LM: foamy cells in tubules

76 Key words of clinical features & disease Acute Nephritic syndrome Nephrotic syndrome Acute Glomerulonephritis -Post streptococcal -Non post streptococcal Minimal change disease Membranous GN, MPGN 1 Focal segmental glomerulosclerosis (FSGS). Systemic diseases : diabetes, SLE, Amyloidosis.

77 Key words of clinical features & disease Recurrent HematuriaRapidly progressive Glomerulonephritis IgA nephropathy ( Berger's disease) Henoch-Schönlein Purpura Cresentic GN 1.Good pasture syndrome 2.Wegner Granulomatosis 3.Polyarteritis nodosa 4.SLE Alport syndrome (+ family history of hematuria)

78 Chronic Glomerulonephritis.

79 Clinical: Increasing BUN and creatinine, uremia Hypertension

80 “Chronic glomerulonephritis“ % of all patient needs hemodialysis and Renal Transplantation. Gross: cortical atrophy LM: Non specific ( biopsy not useful) –Scarring of Glomeruli, bowmen’s space –Hyalinization of glomeruli. –Interstitial fibrosis. –Tubular atrophy –Thickening of the small and medium sized arteries.

81 Symmetrically Contracted SMALL Kidney coarse Granular Surface Note the hyalinized glomeruli Some are still viable!

82 Remember !! Chronic glomerulonephritis → End stage kidney. End stage kidney (renal) disease: GFR is < 5% of the normal. –All glomeruli: sclerosed. –Patient cannot live without transplantation or regular dialysis.

83 End stage kidney: no normal glomeruli !!!!

84 Progression of glomerular disease Complete recovery ARF Chronic GN Coarsely granular Kidney Death Chronic Renal failure/ Ure8484mia ESRD- all glomeruli sclerosed Any other kidney diseases

85 Diagnosis of glomerular disease 24 hour urine 4+ 2, 3+ Nephrotic syndrome Child Adult Child Adult Rapid ↑BUN/ Creatinine and rapid oliguria/ hematuria Nephritic syndrome RPGN Hematuria

86 End of the Primary Diseases of Kidney THANK YOU YOU ARE WELCOME TO ASK ANY QUESTION ANY TIME