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Centrul de Medicina Interna –Nefrologie
Institutul Clinic Fundeni
Prof. Dr. M. Voiculescu
Sindromul Goodpasture
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Definitie
- Boala Goodpasture (BGP):- depozite tisulare formate din ac ANTI-MBG
- Sindromul Goodpasture:- BGP + glomerulonefrita si/sau hemoptizie
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Celula mezangiala
Membrana bazala
Celula endoteliala
Celula epiteliala
Lumen
Afectarea celulelor mezangialeNefropatia IgA
Nefropatia IgM
GN mezangioproliferativa
Nefrita lupica clasa II OMS
Nefropatia diabetica
Leziuni de celule epitelialeNefropatia membranoasa
GN cu leziuni minime
GSFS
Nefrita lupica clasa V OMS
Nefropatia diabetica
Leziuni de celule endotelialeGN asociata infectiilor
GN mezangiocapilara
GN cu Atc. anti MBG
Nefrita lupica clasa III si IV OMS
Vasculite
Crioglobulinemii
Sindromul hemolitic uremic
Prezenta unei cantitati anormale de proteine sau celule sugereaza patologie glomerulara
Sediul celular al leziunilor in glomerulonefrite
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Glomerulopatii rapid progresiva
- entitate morfologica- etiologie variata- caracterizata prin leziuni inflamatorii si fibroase
glomerulare severe cu aspect de semilune- instalarea rapida a insuficientei renale
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Anatomie patologica
- Elementul histologic caracteristicestereprezentat de formarea
excrescentelor cuaspect semilunar
• excrescentele sunt formate din: • celule
- epiteliale rezidente din capsula Bowman
- mononucleare sistemice → macrofage epitelioide • material acelular
- fibrina- colagen
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Anatomie patologica
- In raport cu mecanismul patogenic se
descriutrasaturi histologice specifice:
• GMP mediate de CIC predomina: • hipercelularitate • influx leucocitar crescut
• peretii capilari ingrosati
• GMP mediata de ANCA si de Ac. anti-MBG: • necroza fibrinoida bine exprimata
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Clasificarea patogenica
- Tipul I: Ac. anti MBG
-Tipul II: CI
- Tipul III: ANCA (necrotizanta, pauciimuna)
- Tipul IV: ANCA + Ac. anti MBG
- Tipul V: primitiva (fara ANCA sau Ac. anti MBG)
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Patogeneza
- Debutul: leziuni capilare glomerularenecrotizante
severe
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Patogeneza
- Evolutia:
leziune necrotizanta capilara
extravazare sangvina
depunere de fibrina, acumulare
celularaexcrescente celulare +/- ruperea capsuleiBowman
excrescentefibrocelulareexcrescente
fibroasescleroza
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GMN rapid progresiva
- Clasificare nonhistologica:
• GMN cu anticorpi anti-MBG: • 2 – 20%
•
aspect IF: neted • anticorpi anti-lant alfa 3a fibrelor de colagentip IV
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Patogeneza
CIC Ac. anti MBG
ANCARuperea peretelui capilar
Transvazeaza in spatiul Bowman
• polimorfonucleare • monocite
• trombocite • proteine plasmatice • complement seric
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Eliberarea din:
• celule rezidente (endoteliale si mezangiale)
• celule sistemice (PMN, monocite,trombocite) • citokine (TGF.TNF-α )
• prostaglandine • leukotriene
• molecule de adeziune celulara
Imobilizare Hyalunoninat CytokineChemotactism
fixare polimerizare proliferare infiltrare
PMN FBG in fibrina celularaleucocitara
Proliferare epiteliala + invazie
monocitara
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Epidemiologie
- Incidenta - 0.1 cazuri / 1.000.000 loc
- 1-2% din totalul PBR
- Sex: - F / B ≈ 1 (usoara preponderenta la B)
- Varsta: - distributie bimodala cu 2 varfuri: 30 ani; 60ani
- Rasa: - frecvent la maorii din Noua Zeelanda- mai frecvent la rasa alba vs negrii
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Patogeneza:
- Tipul IV de colagen din MBG, plaman, plexcoroid,
- lanturi ∝ 1 ,∝ 2
- lanturi aditionale ∝ 3 non-colagenice (NC1 )
-Ac anti-MBG = Ac anti lant ∝3NC1 colagentip IV
- Epitopul Goodpasture = ultimii 36 aa ailantului ∝3 NC1
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GMB
Celule
epitelialePodocite
Celule endoteliale
Retea de
colagentip IV
Fibre decolagen
tip IV
7s
Promotor
NC1
Dimer
Hexamer
Monomer
α 3(IV)NC
1
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Sindromul Goodpasture
Tipuri de colagen IV
Lant α Gena Locus Distributie tisulara Observatii
α 1 (IV) COL4A1 13q34 Toate membranele bazale
α 2 (IV) COL4A2 13q34 Toate membranele bazale Impreuna cu α 1 (IV)
α 3 (IV) COL4A3 2q36 Ureche, capsula cristalin,rinichi (MBG, mici cant. In
MBT distala si capsula
Bowman).
Autoantige in s.Goodpasture.
Mutatii in formele
autosomale ale s.Alport
α 4 (IV) COL4A4 2q36 Ureche, capsula cristalin,rinichi (MBG, mici cant. In
MBT distala si capsulaBowman).
Impreuna cu α 3 (IV)
α5(IV) COL4A5 xq22 Piele, capsula cristalin, m.neted, rinichi (MBG, MBT
distala .Mutatii in formeleX-link-ate ale s.
Al ort
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Susceptibilitat egenetica (HLA)
Sindromul Goodpasture
Reactivitate incrucisatacu
epitopi exogeni /
expunerela antigene criptice prin
lezarea MBG de catre:- infectii, toxine
- ischemie, neoplazii - GN membranoasa
Fenotip
+
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Manifestari clinice (1)
- Manifestari sistemice- febra
-rash
- mialgii- stare generala alterata- cefalee- scadere ponderala
- Afectare pulmonara (1/2 -3/4 mod de pr ezentare)- clinic
- tuse- infectii ale cailor aeriene superioare
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Manifestari clinice (2)
- Afectare pulmonara (1/2 -3/4 mod de pr ezentare)
- clinic- hemoragie pulmonara
precede cu ani instalarea GN sau urmeaza afectariirenalemanifeste
sputa cu striuri sanghinolente → hemoptizie fatala(sau doar
sputa cu macrofage incarcate cu hemosiderina)- radiologie
- infiltrate alveolare- opacitati nodulare- infiltrate segmentale
- functia pulmonara- poate fi ↓
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Manifestari clinice (3)
- Afectare renala- proteinurie (rar in domeniul nefrotic)- sediment urinar cu
-
hematii dismorfice- cilindrii hematici
Inexistenta modificarilor urinare → reconsiderarea altor boli
- Functia renala - normala
- alterata rapid in sapt / luni = GN rapidprogresiva- in ≤ 3 luni
- ↓ RFG la ½ sau- ↑ 2x creatinina serica
- Rinichi normali ecografic
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Manifestari clinice (4)
- Hipertensiunea arteriala
- rar valori crescute- de obicei carsteri usoare, corelate cu varsta
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Date de laborator
Conditia in sine qua non pentru diagnosticul (+) =
prezenta complexelor imune glomerulare sau Acanti-MBG
- Metode de detectie (1) - decelarea Ac anti-MBG circulanti (IgG, ocazitionalIgA, IgM)
imunofluorescenta indirecta (10% fals (-), ≤ 1% fals (+),ieftin) RIA < 5% fals (-)
ELISA < 1% fals (+)
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Date de laborator
- Metode de detectie- punctie biopsie renala de urgenta la toti pacientiisuspecti in
prezenta / absenta Ac anti-MBG circulanti.
Sindromul Goodpasture
Timpul este decisiv(durata bolii)
Prognostic Raspuns la tratament
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Morfopatologie1. Renal:
- MO:
-Necroza fibrinoida-Proliferare focala si segmentara-Proliferare epiteliala cu formare desemilune
- IF:-Depozite liniare de IgG dispuse de-a lungul MBG-in 70% cazuri depozitele contin si C3
-In 70% cazuri exista depozite liniare
concomitente la nivelul MB tubulare- ME:
-Ingrosari si fragmentari ale MBG-Fuziunea segmentara a podocitelor
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Morfopatologie2. Pulmonar:
- MO:
- Alveolita hemoragica
-
Depozite liniare de IgG de-a lungul MBalveolare
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MO: S Goodpasture
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Sindromul Goodpasture
MBG discontinua + fibrina
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IF: IgG anti MBG cu dispozitie lineara (S. Goodpasture )
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Evolutie si prognostic:
- Prognosticul:- bolii netratate / tratate este sever.
-Tratament imunosupresiv :
- pulsterapia cortizon: fara -
- 89% evolutie spre:- deces- dializa
- 10% ameliorare
- Plasmafereza - 50% ameliorare
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Evolutie si prognostic:
-
Oliguricii / dializatii nu raspund dupa- schimb de plasma
- metilprednisolon pulsterapie- alte metode
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Factori de prognosticnegativ:
-HLA-DRW 2 , HLA-B7
- Prezenta de semilune > 50%
- Afectarea tubulointestitiala
-Glomeruloscleroza
- Creatinina serica ≥ 6mg/dl
- Oligurie / anurie
-
Dializa
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Tratament
Etiologic: nu este cunoscut - Patogenic:
- imunosupresie:
- corticosteroizi:- in faza acuta: exclusiv iv, mega doze (1 g/zi, 3 zile), 6
luni - in faza cronica: metilprednisolon, 80 → 100 mg / zi), 12
– 24 luni
- ciclofosfamida: 0,8 – 1,4 g iv / luna, 3 – 6 luni,
- plasmafereza: asociata imunosupresiei -Transplantul renal: in conditii de nivel nedetectabil al
Ac.antiMBG cel putin un an-Recurenta 30%
- Complicatii:- infectii
- Insuficienta Renala Acuta / Cronica: dializa,transplant renal
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Tratament
B. Plasmafereza
- Introdusa de Lockwood (1976)- studiul lui Pusey (1991):
- beneficiaza de plasmafereza:• GMP cu anticorpi anti-MBG (S. Goodpasture)• GMP ANCA+• GMP severe cu excrescente > 70%
- obligatori asociata cu tratament imunosupresiv
- efecte adverse:
• infectii • moarte subita
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