Glomerulopathies. Dr. András Tislér 2013

Transcription

1 Glomerulopathies Dr. András Tislér 2013

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3 Glomerular diseases may be classified as: Primary renal disease vs. renal manifestation of a systemic disease (i.e. secondary) Immune vs. non-immune mechanism mediated Proliferative vs. non-proliferative glomerular pathology Different pathatological entities Clinical syndromes Isolated hematuria, nephrotic sy., nephritic sy., RPGN Acute, subacute, chronic, acute-on-chronic

4 Immune mechanisms in glomerular diseases Antibody against a local antigen Podocyte antigen (membranous GN: phospolipase A2 receptor) Glomerular basement menbrane antigen (Goodpasture s) planted antigen (e.g. in membranous SLE) Deposition of circulating immune complexes with inflammation E.g. IgA nephropathy, cryoglobuliemia, SLE Without immune complexes ( pauci immun ), but with immune mechanism ANCA associated diseases

5 Mechanisms of glomerular injury (bases for the pathological classification) Non-inflammatory (nonproliferative) glomerulopathy Podocyta damage Subepithelial immune complexes Inflammatory (proliferative) GN Endothel (postinfectious GN) Mesangial proliferative (IgA nephropathy) Parietal epithelial cell proliferation ( crescents) Membranoprolierative GN

6 Clinical approach to glomerular diseases Clinical syndrome Pathology Etiology Nephrotic Non-proliferative Primary nephritic Proliferative Neoplasia RPGN Acute renal failure sy Isolated proteinuria isolated hematuria Autoimmune Vasculitis drugs Infection

7 Nephrotic syndrome Proteinuria (usually>2-3 g/die) Hypalbuminemia Oedema Hyperlipoproteinemia Increased risk of thrombosis GFR may be norm.

8 Most frequent pathology behind the nephrotic syndrome in adults Primary renal disease Minimal change glomerulopathy Focal segmental GN Membranous glomerulopathy Fibrillary (immunotactoid) GN Systemic disease Diabetes Amyolidosis SLE (type V)

9 Frequent complications of nephrotic syndrome Thrombosis (renal vein, deep venous) Frequent infections Acute prerenal renal failure Heavy proteinuria in itself contributes to the progression of renal disease Accelerated atherosclerosis (?)

10 Management of nephrotic syndrome supportive management diuretics: Furosemide - ACE inhibitors/ ARBs Furosemide + thiazide Furosemide + spironolactone - Thrombosis profilaxis: heparin, oral anticoagulation (if albumuin <20-25 g/l) - Statins specific treatment: depends on pathology and ethiology (e.g. immunsuppression)

11 Acute glomerulonephritis (nephritic) syndrome Hematuria (dysmorphic RBCs, acanthocytes) Proteinuria Cylindruria (cellular, RBCcasts) Hypertension Oedema Oliguria Decreased GFR

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13 Frequent pathologies behind the acute nephritic syndrome (but may present in other syndromes as well) Post-streptococcal GN acute diffuse proliferative endocapillary proliferative IgA nephropathy Mesangial proliferative Membranoproliferative GN SLE: focal vs. diffuse proliferative GN (types II-IV)

14 Alport syndrome Isolated hematuria syndrome persistent microhematuria dysmorphic RBCs, acanthocytes Variable proteinuria (from minimal to nephrotic range) Variable decrease in GFR Glomerular causes (non glomerular causes stone neoplasm, papillary necrosis etc. should be excluded) Thin basement membrane disease IgA nephropathy

15 Rapidly progressive GN syndrome (crescentic GN) Progressive loss of GFR (weeks, months) Active urinary sediment RBCs, cellular and granular casts Variable proteinuria Frequent systemic symptoms vasculitis upper-lower airway Pulmonary (bleeding) Arthritis fever

16 Causes of rapidly progressive GN syndrome I. 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) Wegener s granulomatosis Microscopic polyangiitis Churg Strauss syndr

17 Clinical approach to glomerular diseases Clinical syndrome Pathology Etiology Nephrotic Non-proliferative Primary nephritic Proliferative Neoplasia RPGN Acute renal failure sy Isolated proteinuria isolated hematuria Autoimmune Vasculitis drugs Infection

18 Mechanisms of glomerular injury (bases for the pathological classification) Non-inflammatory (nonproliferative) glomerulopathy Podocyte damage Subepithelial immune complexes Inflammatory (proliferative) GN Endothel (postinfectious GN) Mesangial proliferative (IgA nephropathy) Parietal epithelial cell proliferation ( crescents, extracapillary) Membranoprolierative GN

19 Clinical diagnosis Syndrome Morphological diagnosis Etiological diagnosis Acute nephritis sy. Nephrotic sy. Isolated proteinuria, haematuria sy. Rapidly progressive glomerulonephritis Chronic renal failure sy. Acute renal failure sy. Postinfect. GN Minimal change Focal segmental GS Membranous GN Membranoprolif. GN Crescens GN (necrotic) Mesangial prolif GN Diabetic nephropath Amyloidosis Myeloma Acute tubular necrosis Primary (unknown) Hepatatis C Hepatitis B SLE Neoplasm Vasculitis Wegener gr. Goodpasture sy. Diabetes Amyloidosis Myeloma Ischemia

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

21 Hystology and clinical syndrome Nephrosis Nephritis Minimal change dis Membranous GN Diabetic gl.sclerosis Amyloidosis FSGS Fibrillary GN Mesangioproliferative Membranoproliferative Proliferative (foc./diff.) Extrakapillaris (RPGN)

22 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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24 Minimal change nephropathy T-cell dysfunction? Podocyte effacement? Podocyte slit membrane damage? Non-immune permeability factor factor

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

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

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28 Treatment of idiopathic nephrotic sy. (MCD, 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 +) FK 506 (Prograf) 2x5 mg Newer alternatives Mycophenolate mofetil (CellCept) 2 x 0,75-1 g

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

30 Membranous nephropathia Idiopathic (most frequent): anti-phospholipasea2 antibodies 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

31 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

32 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

33 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

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

35 Membranoproliferative glomerulonephritis Type I. Mesangial and subendothelial deposition of circulating immune complexes with proliferative inflammation, GBM doubling Complement activation (klasszikus) 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) Partial lypodystrophy

36 Membranoproliferativ glomerulonephritis

37 Membranoproliferative glomerulonephritis

38 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

39 Cryoglobulinemia

40 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 IgA nephropathy increased IgA level Measangial IgA deposition Increased galactose-sialic acid content in the hinge region if IgA clearance

41 IgA nephropathy

42 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

43 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 > 3,5 g/d proteinuria increased creatinin Hypertonsion Kor ACE gene DD allele

44 Therapy of IgA nephropathy Proteinuria < 1 g /d, no major structural damage: BP control, ACEI/ARB Proteinuria > 1 g /d, no major structural damage: Prednisolon (18-36 hó) Fish oil Tonsillecomia (?) Increasin creatinine (> 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

45 RPGN is usually associated with crescent formation (extracapillary proliferative GN) I. 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) Wegener s granulomatosis Microscopic polyangiitis Churg Strauss syndr

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49 Goodpasture s 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

50 Goodpasture s syindrome Pulmonary-renal syndrome Rx Pulmonary bleeding-rpgn anti GBM antitbodies Immunofluorescence, ELISA Cyclophosphamide, steroid, Plasma exchange

51 ANCA positive glomerulonephritis Wegener s granulomatosis (PAG) Microscopic polyangiitis (MPA) Churg Strauss syndrome ANCA poz % 70% 50% antigen PR3>>MPO MPO>PR3 MPO>PR3 Patology vasculitis Renal pathology Upper airways Lungs Necrotising, crescent formation, pauci immun on immunfluorescence Granuloma, necrosis Infiltration, granuloma, bleeding bleeding Allergic rhinitis Asthma other Vasculitis Neuropathia Eosinophilia RPGN RPGN RPGN

52 Samll vessel vasculitis uveitis Wegener

53 Wegener s granulomatosis

54 SLE

55 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 Non-blomerular manifestation Vasculitis Intestitial nephritis

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