Glomerulopathies

Dr. András Tislér

2013

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”

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

•Non-inflammatory (non-

proliferative) glomerulopathy

•Podocyta damage

•Subepithelial immune complexes

•Inflammatory (proliferative) GN

•Endothel (postinfectious GN)

•Mesangial proliferative (IgA

nephropathy)

•Parietal epithelial cell proliferation

( crescents)

•Membranoprolierative GN

Mechanisms of glomerular injury (bases for the

pathological classification)

Clinical approach to glomerular diseases

Clinical syndrome

Pathology Etiology

Nephrotic Non-proliferative Primary

nephritic Proliferative Neoplasia

RPGN

Acute renal failure sy

Autoimmune

Vasculitis

Isolated proteinuria

isolated hematuria

drugs

Infection

Nephrotic syndrome

• Proteinuria (usually>2-3 g/die)

• Hypalbuminemia

• Oedema

• Hyperlipoproteinemia

• Increased risk of thrombosis

• GFR may be norm.

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)

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 (?)

Management of nephrotic syndrome

• supportive management

• diuretics: Furosemide

Furosemide + thiazide

Furosemide + spironolactone

- ACE inhibitors/ ARBs

- Thrombosis profilaxis: heparin, oral anticoagulation

(if albumuin <20-25 g/L)

- Statins

• specific treatment: depends on pathology and ethiology

(e.g. immunsuppression)

Acute glomerulonephritis (nephritic) syndrome

• Hematuria

(dysmorphic RBCs, acanthocytes)

• Proteinuria

• Cylindruria

(cellular, RBCcasts)

• Hypertension

• Oedema

• Oliguria

• Decreased GFR

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)

Isolated hematuria syndrome

• Glomerular causes (non glomerular

causes – stone neoplasm, papillary

necrosis etc. should be excluded)

•Thin basement membrane disease

•IgA nephropathy

• Alport syndrome

• persistent microhematuria

•dysmorphic RBCs, acanthocytes

•Variable proteinuria (from minimal to

nephrotic range)

•Variable decrease in GFR

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

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

Clinical approach to glomerular diseases

Clinical syndrome

Pathology Etiology

Nephrotic Non-proliferative Primary

nephritic Proliferative Neoplasia

RPGN

Acute renal failure sy

Autoimmune

Vasculitis

Isolated proteinuria

isolated hematuria

drugs

Infection

•Non-inflammatory (non-

proliferative) glomerulopathy

•Podocyte damage

•Subepithelial immune complexes

•Inflammatory (proliferative) GN

•Endothel (postinfectious GN)

•Mesangial proliferative (IgA

nephropathy)

•Parietal epithelial cell proliferation

( crescents, extracapillary)

•Membranoprolierative GN

Mechanisms of glomerular injury (bases for the

pathological classification)

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

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)

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) + ++++

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

Minimal change nephropathy

• T-cell dysfunction?

• Podocyte effacement

• ? Podocyte slit membrane

damage

• ? Non-immune permeability

factor factor

Minimal change nephropathia

• Clinically nephrotic

syndrome

• Management:

– Steroid (e.g. 1 mg/kg

metylprednisolone

tapered for 2-3 months

– Diuretics

– If needed:

anticoagulation

Focal segmental glomerulosclerosis (FSGS)

• Idiopathic nephrotic sy.

•Secondary

•HIV

• Heroin

• decreased nephrone number

• Obstructive uropathy, vesicoureteral reflux

• Obesitas

• ageing

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 +)

Newer alternatives

•FK 506 (Prograf) 2x5 mg

•Mycophenolate mofetil (CellCept) 2 x 0,75-1 g

Membranous glomerulopathy

• Most frequent cause of adult nephrotic

syndrome

• Subepithelial immune complex

deposition

– non proliferative GN

– Norm complement level

– urinary C5-C9 excretion

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

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

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

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

Postinfectious glomerulonephritis

• Following Streptococcus,

Klebsiella,Coxakie, Plasmodium,

Aspergillus infection

• Deposition if circulating immune

complexes

• Exudative inflammation (endocapillary

proliferation)

• Complement (alternatív) activation

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

Membranoproliferativ glomerulonephritis

Membranoproliferative glomerulonephritis

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

Cryoglobulinemia

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

IgA nephropathy

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

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

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

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

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

Goodpasture’s syindrome

• Pulmonary-renal syndrome

– Pulmonary bleeding-RPGN

– anti GBM antitbodies

• Immunofluorescence, ELISA

• Rx

– Cyclophosphamide, steroid,

– Plasma exchange

ANCA positive glomerulonephritis

Wegener’s

granulomatosis

(PAG)

Microscopic

polyangiitis

(MPA)

Churg Strauss

syndrome

ANCA poz. 80-90% 70% 50%

antigen PR3>>MPO MPO>PR3 MPO>PR3

Patology vasculitis

Renal

pathology

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

Samll vessel vasculitis

Wegener

uveitis

Wegener’s granulomatosis

SLE

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

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)