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Glomerulpathies: histology, possibilities of treatment

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Title: Otthoni v rnyom sm r s tapasztalatai Author: FBCS Last modified by: Tisl r Andr s Created Date: 11/20/2004 12:46:38 PM Document presentation format – PowerPoint PPT presentation

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Title: Glomerulpathies: histology, possibilities of treatment


1
Glomerulpathies histology, possibilities of
treatment
Dr. András Tislér November 2015
2
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3
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4
Clinical approach to glomerular diseases
5
Mechanisms of glomerular injury (bases for the
pathological classification)
  • Non-inflammatory (non-proliferative)
    glomerulopathy
  • Podocyte damage (MCN)
  • Subepithelial immune complexes (MN)
  • Inflammatory (proliferative) GN
  • Endothel (postinfectious GN)
  • Mesangial proliferative (IgA nephropathy)
  • Parietal epithelial cell proliferation (
    crescents, extracapillary)
  • Membranoprolierative GN

6
Summary
  • Proliferative (-itis)
  • Mesangial
  • Endocapillary
  • (postinfectious)
  • Membranoproliferative
  • Extracapillary proliferative
  • (crescents, necrosis)
  • May be
  • Focal/segmental
  • Diffuse proliferativ
  • (félholdképzodés)
  • Non-proliferative (-pathia)
  • Minimal change
  • FSGS
  • Membranous
  • Fibrillary
  • Diabetic nephropathy
  • Amyloidosis
  • Alport sy

7
  • Morphological
  • diagnosis
  • Postinfect. GN
  • Minimal change
  • Focal segmental GS
  • Membranous GN
  • Membranoprolif. GN
  • Crescens GN (necrotic)
  • Mesangial prolif GN
  • Diabetic nephropath
  • Amyloidosis
  • Myeloma
  • Acute tubular necrosis

Etiological diagnosis Primary
(unknown) Hepatatis C Hepatitis
B SLE Neoplasm Vasculitis Wegener gr. Goodpasture
sy. Diabetes Amyloidosis Myeloma Ischemia
  • Clinical diagnosis
  • Syndrome
  • Acute nephritis sy.
  • Nephrotic sy.
  • Isolated proteinuria,
  • haematuria sy.
  • Rapidly progressive
  • glomerulonephritis
  • Chronic renal failure sy.
  • Acute renal failure sy.

8
Hystology and clinical syndrome
9
Minimal change disease
  • Idiopathic nephrotic sy. (most frequently)
  • Secondary
  • M. Hodgkin
  • allergy (pollen, beesting, food, dust)
  • drugs NSAID, ampicillin, gold, penicillamine
  • Infections HIV, EBV, schistosomiasis
  • Immunisation
  • Dermatitis herpetiformis

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Minimal change nephropathy
  • T-cell dysfunction?
  • Podocyte effacement
  • ? Podocyte slit membrane damage
  • ? Non-immune permeability factor factor

12
Minimal change nephropathia
  • Clinically nephrotic syndrome
  • Management
  • Steroid (e.g. 1 mg/kg metylprednisolone tapered
    for 2-3 months
  • Diuretics
  • If needed anticoagulation

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15
Focal segmental glomerulosclerosis (FSGS)
  • Idiopathic nephrotic sy.
  • Secondary
  • HIV
  • Heroin
  • decreased nephrone number
  • Obstructive uropathy, vesicoureteral reflux
  • Obesitas
  • ageing

16
Treatment of FSGS
  • Induction
  • Prednisolon 1 mg/kg 8-12-(16) weeks, tapering
  • If steroid dependence (recurrence upon decreasing
    dose), frequent relapse or resistance
  • Cyclophosphamide 1,5-2 mg/kg 8-12 weeks
  • Chlorambucil 0,1-0,2 mg/kg
  • Alternatives
  • Cyclosporin-A 4-5 mg/kg prednisolon
  • Plasmapheresis in resistant FSGS (if perm.
    factor )
  • Newer alternatives
  • FK 506 (Prograf) 2x5 mg
  • Mycophenolate mofetil (CellCept) 2 x 0,75-1 g

17
Membranous glomerulopathy
  • Most frequent cause of adult nephrotic syndrome
  • Subepithelial immune complex
  • deposition
  • non proliferative GN
  • Norm complement level
  • urinary C5-C9 excretion

18
Membranous nephropathia
  • Idiopathic (most frequent)
  • Pathomechanism in humans antibody against a
    protein in the podocyte membrane (anti-)
    phospholipase A2 receptor
  • Neoplasms (solid tumors)
  • lung, gastrointestinal, breast, NHL, CLL,
    melanoma, hypernephroma
  • Infections
  • HBV, HCV, TBC, abscess, syphilis, malaria,
    scabies
  • Autoimmune diseases
  • SLE (type V)
  • Drugs
  • NSAID, penicillamine, gold, captopril

19
Primary membranosus glomerulopathy
  • Animal model Heymann nephritis
  • Antibody against a protein in the podocyte
    anti-megalin
  • Pathomechanism in humans
  • Antibody against a protein in the podocyte
    (anti-) phospholipase A2 receptor

20
Clinical course of MN
Spontaneous remission 20 Spontaneous partial
remission 25-40 End stage renal disease 5y
14 10y 35 15 y 41 Poor
prognostic factors tubulointerstitial
damage increased creatinine heavy
proteinuria glomerular sclerosis older
age Prognostic markes high urinary C5b-9,
IgG
21
Immunosupression in membranous nephropathy
Proteinuria ? 3,5 g/die no immunosupression, but
diuretics, ACEI, ARB, if needed
anticoagulation Proteinuria ? 3,5 g/d,
asymptomatic 6-12 mo conservative Rx, risk
assessment based on proteiuria - creatinine
change High risk Increased creatinine Severe
nephrosis ( ? 10 g/die) Thromboembolic
complication
Immunosuppression -Monthly alternating steroid
and cyclophosphamide -rituximab
22
Summary
  • Proliferative (-itis)
  • Mesangial
  • Endocapillary
  • (postinfectious)
  • Membranoproliferative
  • Extracapillary proliferative
  • (crescents, necrosis)
  • May be
  • Focal/segmental
  • Diffuse proliferativ
  • (félholdképzodés)
  • Non-proliferative (-pathia)
  • Minimal change
  • FSGS
  • Membranous
  • Fibrillary
  • Diabetic nephropathy
  • Amyloidosis
  • Alport sy

23
Postinfectious glomerulonephritis
  • Following Streptococcus, Klebsiella,Coxakie,
    Plasmodium, Aspergillus infection
  • Deposition if circulating immune complexes
  • Exudative inflammation (endocapillary
    proliferation)
  • Complement (alternatív) activation

24
Membranoproliferative glomerulonephritis
  • Type I.
  • Mesangial and subendothelial deposition of
    circulating immune complexes with proliferative
    inflammation, GBM doubling
  • Complement activation (classic)
  • Secundary forms
  • SLE, cryoglobulinemia, chronic HCV infection,
    abscesses, endocarditis, paraprotein deposition
    (MM Waldenström)
  • Type II. (dens deposit disease)
  • Continous alternative complement activation due
    to a activating antybody against C3 convertase
    (C3 nephritgen factor faktor) or other mechanisms
    (C4 is norm)

25
Membranoproliferativ glomerulonephritis
26
Membranoproliferative glomerulonephritis
27
Membranoproliferative GN prognosis, therapy
Spontaneous remission 10-20 10 ESRD in 15
years 60
Aspirin 500 mg/d dipyridamol 75 mg/d
3y Prednisolon po, alternate days x 2-3 y
(?) Prednisolon Azathioprin/cyclophosphamide
(?) Dens deposit disease eculizumab?
28
Cryoglobulinemia
  • Palpable purpura, myalgia, arthralgia (Meltzer
    triad)
  • Livedo reticularis, neuropathia
  • Hypocomplementemia
  • Renal disease usually with type II.
    cryoglobulinemia (seen in chronic HCV infection
    or CLL)
  • Membranoproliferative GN
  • hyalin thrombus
  • fingerprint pattern in the deposits

29
Cryoglobulinemia
30
IgA nephropathy
  • Most frequent primary GN
  • On microscopy mezangiál proliferative GN with
    predominant IgA deposition
  • Clinical presentation is usually isolated
    hematuria
  • As part of systemic disease Henoch-Schönlein
    purpura
  • increased IgA level
  • Measangial IgA deposition
  • Increased galactose-sialic acid content in the
    hinge region if IgA
  • ?clearance

31
IgA nephropathy
32
IgA nephropathy
  • Idiopathic Berger disease (IgA nephropathy)
  • Henoch Schönlein purpura
  • Alkoholic liver disease
  • Celiac disease
  • IBD Crohn, Colitis ulcerosa
  • Dermatitis herpetiformis
  • Mycosis fungoides
  • M. Bechterew

33
IgA clinical course
ESRD 5 y 10 10 y 15 15 y
25 20 y 33 Poor prognostic factors
Glomerular sclerosis Intersitialis
fibrosis crescent formation gt 3,5 g/d
proteinuria increased creatinin Hypertonsi
on older age ACE gene DD allele
34
Therapy of IgA nephropathy

Proteinuria lt 1 g /d, no major structural
damage BP control, ACEI/ARB Proteinuria gt 1 g
/d, no major structural damage Prednisolon
(18-36 hó) Fish oil Tonsillecomia (?) Increasin
creatinine (gt 2 ml/min/mo) Prednisolon mg/kg
2-3 mo tapered for 1-2 y Diffuse
crescents Metylprednisolon i.v. ? po.
Prednisolon Cyclophosphamide 2,5 mg /kg
35
RPGN is usually associated with crescent
formation (extracapillary proliferative GN)
  • Anti-GBM antibodies (linear deposition
  • on immunfluorescence)
  • Goodpasture syndr.
  • II. Immune complex mediated GN (granular
    deposition on IF)
  • Primary GN IgA GN, Membranoproliferative GN
  • Postinfectios sepsis, abscess, endocarditis,
    HBV,
  • Autoimmune SLE
  • III. ANCA associated GN (no immune deposition
    pauci-immune)
  • Wegeners granulomatosis
  • Microscopic polyangiitis
  • Churg Strauss syndr

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39
Goodpastures syndrome
  • Rare disease 1/1million/year
  • Pathogenesis
  • Antibody formation against the non-collagenous
    region of alpha 3 chain of type IV collagen found
    in the glomerulus and lung. This causes
    inflammation and proliferation
  • Pulmonary manifestation frequently after
    infection, or other pulmonary damage
  • In Alport syndrome after transplantation

40
Goodpastures syindrome
  • Pulmonary-renal syndrome
  • Pulmonary bleeding-RPGN
  • anti GBM antitbodies
  • Immunofluorescence, ELISA
  • Rx
  • Cyclophosphamide, steroid,
  • Plasma exchange

41
Small vessel vasculitis
uveitis
Wegener
42
Wegeners granulomatosis
43
ANCA positive glomerulonephritis
Wegeners granulomatosis (PAG) Microscopic polyangiitis (MPA) Churg Strauss syndrome
ANCA poz. 80-90 70 50
antigen PR3gtgtMPO MPOgtPR3 MPOgtPR3
Patology vasculitis vasculitis vasculitis
Renal pathology Necrotising, crescent formation, pauci immun on immunfluorescence Necrotising, crescent formation, pauci immun on immunfluorescence Necrotising, crescent formation, pauci immun on immunfluorescence
Upper airways Granuloma, necrosis Allergic rhinitis
Lungs Infiltration, granuloma, bleeding bleeding Asthma
other Vasculitis RPGN Neuropathia RPGN Eosinophilia RPGN
Rx Cyclo, steroid, TMP/SMX, PE, rituximab Cyclo, steroid, TMP/SMX, PE, rituximab Cyclo, steroid, TMP/SMX, PE, rituximab
44
SLE
45
Renal manifestations in SLE
  • WHO type I no renal change
  • WHO type II mesangial proliferative GN
  • WHO type III focal proliferative GN
  • WHO type IV diffuse proliferative GN
  • WHO type V membranous GN
  • WHO type VI chronic renal failure
  • Types II-V may be associated with crescent
    formation and necrosis indicating poor prognosis
    and necessitating agressive immunosuppression
  • Rx
  • Steroid i.v. p.o. tapering, cyclophosphamide i.v.
    500mg q2weeksx6
  • Mycophenolate mophetil
  • rituximab

46
Summary
  • Proliferative (-itis)
  • Mesangial
  • Endocapillary
  • (postinfectious)
  • Membranoproliferative
  • Extracapillary proliferative
  • (crescents, necrosis)
  • May be
  • Focal/segmental
  • Diffuse proliferativ
  • (félholdképzodés)
  • Non-proliferative (-pathia)
  • Minimal change
  • FSGS
  • Membranous
  • Fibrillary
  • Diabetic nephropathy
  • Amyloidosis
  • Alport sy
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