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Glomerulpathies: histology, possibilities of treatment

This article discusses the histology of glomerulopathies and the various treatment options available. Topics covered include non-inflammatory and inflammatory glomerular diseases, clinical diagnosis, morphological diagnosis, and etiological diagnosis. Specific conditions such as minimal change disease, focal segmental glomerulosclerosis, and membranous glomerulopathy are also discussed.

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Glomerulpathies: histology, possibilities of treatment

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  1. Glomerulpathies: histology, possibilities of treatment Dr. András Tislér November 2015

  2. Clinical approach to glomerular diseases

  3. 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

  4. 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)

  5. Clinical diagnosis Syndrome Acute nephritis sy. Nephrotic sy. Isolated proteinuria, haematuria sy. Rapidly progressive glomerulonephritis Chronic renal failure sy. Acute renal failure sy. 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

  6. 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

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

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

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

  10. 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

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

  12. 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

  13. 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

  14. 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

  15. 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)

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

  17. 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)

  18. Membranoproliferativ glomerulonephritis

  19. Membranoproliferative glomerulonephritis

  20. 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?

  21. 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

  22. Cryoglobulinemia

  23. 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

  24. IgA nephropathy

  25. 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

  26. 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

  27. 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) • Wegener’s granulomatosis • Microscopic polyangiitis • Churg Strauss syndr

  28. 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

  29. Goodpasture’s syindrome • Pulmonary-renal syndrome • Pulmonary bleeding-RPGN • anti GBM antitbodies • Immunofluorescence, ELISA • Rx • Cyclophosphamide, steroid, • Plasma exchange

  30. Small vessel vasculitis uveitis Wegener

  31. Wegener’s granulomatosis

  32. ANCA positive glomerulonephritis

  33. SLE

  34. 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

  35. 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)

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