c p c : g l o m e r u l o n e p h r i t i s · pdf file23 serum complement in gn • low...
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C P C :
G l o m e r u l o n e p h r i t i s
G e r a l d B A p p e l , M D
V i v e t t e D ’ A g a t i , M D
C l a s s i fi c a t i o n o f R e n a l
G l o m e r u l a r D i s e a s e s
• M o r p h o l o g i c a l
• I m m u n o l o g i c a l
• E t i o l o g i c a l
• C l i n i c a l
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V u l n e r a b i l i t y o f G l o m e r u l u s
t o I C I n j u r y
1 . 2 0 - 2 5 % C a r d i a c O u t p u t
2 . H i g h g l o m e r u l a r c a p i l l a r y p r e s s u r e
3 . F e n e s t r a t e d e n d o t h e l i u m
4 . C o n c e n t r a t i o n ( s i e v i n g e f f e c t )
M e c h a n i s m s o f I m m u n o l o g i c
I n j u r y t o t h e G l o m e r u l u s
1 . G l o m e r u l a r d e p o s i t i o n o f
c i r c u l a t i n g A g - A b c o m p l e x e s
2 . B i n d i n g o f C i r c u l a t i n g A b t o
s t r u c t u r a l g l o m e r u l a r A g ( i . e . a n t i -
G B M A b )
3 . I n s i t u i m m u n e c o m p l e x f o r m a t i o n
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G l o m e r u l a r P r o l i f e r a t i o n
1 . E n d o c a p i l l a r y
2 . E x t r a c a p i l l a r y
( c r e s c e n t i c )
P a t t e r n s o f G l o m e r u l a r D i s e a s e
G l o b a lV s2 .
S e g m e n t a l
D i f f u s eV s1 . F o c a l
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Signs of GlomerularDisease
Erythrocyte Casts
Deformed-Crenated Urinary RBC’s
Large amounts Albuminuria
( >3g/D )
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• 7 y o W M c / o x s e v e r a l d a y s b a d s o r e
t h r o a t + l o w g r a d e t e m p e r a t u r e ; h e i s
g i v e n a c e t a m i n o p h e n , a n d r e c o v e r s
u n e v e n t f u l l y . 2 w k s l a t e r d e v e l o p s d a r k ,
c o c a - c o l a c o l o r e d u r i n e a n d n o t e s
u r i n a t i n g l e s s . O n P x p e d a l e d e m a a n d
a n e l e v a t e d b l o o d p r e s s u r e .
• L a b s :
– U / A r b c ’ s , r b c c a s t s , 2 + p r o t .
– C r e a t i n i n e 2 . 4 m g / d l
– C o m p l e m e n t 2 2 ( n o r m a l 5 0 - 1 5 0 )
– C 3 l e v e l l o w
– A S L O 1 2 5 0 ( n o r m a l < 2 5 0 )
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N e p h r i t i c S y n d r o m e
• D e c r e a s e d G F R
• O l i g u r i a
• E d e m a
• H y p e r t e n s i o n
• A c t i v e u r i n a r y s e d i m e n t
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P o s t - S t r e p t o c o c c a l G N
• F o l l o w s c e r t a i n s e r o t y p e s t r e p t o c o c c a l
i n f e c t i o n s – s o r e t h r o a t s , i m p e t i g o , e t c .
• C h i l d r e n m o r e c o m m o n t h a n a d u l t s
• T i m e l a g b e t w e e n i n f e c t i o n & k i d n e y
d i s e a s e
• N e p h r i t i c p i c t u r e c o m m o n
• S e r o l o g i c t e s t s f o r s t r e p t i n f e c t i o n s +
• L o w c o m p l e m e n t a n d C 3 l e v e l s
• E x c e l l e n t p r o g n o s i s c h i l d r e n , + / - i n a d u l t s
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2 3
Serum Complement in GN
• Low Levels
Post-infectious GN
SLE
Cryoglobulinemia
Idiopathic MPGN
• Normal Levels
MCD, FSGS, Memb Neph, Amyloidosis,
IgA, DM, ANCA + RPGN, Goodpastre’s,
HSP, etc.
• A 1 6 y o h i g h s c h o o l j u n i o r n o t i c e s
d a r k b r o w n u r i n e a f t e r p l a y i n g
b a s k e t b a l l . U r i n a r y s e d i m e n t h a s
r b c ’ s a n d r b c c a s t s .
• L a b s :
– C r e a t i n i n e 1 . 1 m g / d l
– C r e a t i n i n e c l e a r a n c e 1 2 8 c c / m i n
– 6 6 0 m g p r o t e i n u r i a / d a y
– S e r o l o g i c t e s t s a r e n o r m a l o r
n e g a t i v e
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2 5
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2 6
D e m o g r a p h i c s o f I g A
N e p h r o p a t h y
A g e s 4 – 8 0 ( m e a n 2 5 ) y e a r s
( 6 5 % o f p a t i e n t s i n 2 n d / 3 r d d e c a d e )
M / F = 2 / 1
R a r e i n b l a c k s
I n c i d e n c e ( % p r i m a r y g l o m e r u l o p a t h i e s )
5 - 1 0 % N . A m e r i c a
U . K .
S c a n d i n a v i a
2 0 - 3 0 % E u r o p e
A u s t r a l i a
2 5 - 4 5 % A s i a
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2 7
C l a s s i fi c a t i o n
• P r i m a r y
– I g A N e p h r o p a t h y
– H e n o c h - S c h o n l e i n P u r p u r a
• S e c o n d a r y
– L i v e r C i r r h o s i s
– I n fl a m m a t o r y B o w e l D i s e a s e
P a t h o g e n e s i s
1 . D e f e c t i v e h e p a t i c c l e a r a n c e
– L i v e r c i r r h o s i s
2 . I n c r e a s e d I g A p r o d u c t i o n
– A s s o c i a t i o n w i t h e l e v a t e d s e r u m I g A
– O n s e t m a y f o l l o w U R I o r G a s t r o e n t e r i t i s
3 . D e f e c t o f a n t i g e n e x c l u s i o n a t t h e
m u c o s a l s u r f a c e
– U R I
– G a s t r o e n t e r i t i s
– C e l i a c d i s e a s e
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2 8
S t r u c t u r e o f H u m a n
S e c r e t o r y I g A ( s i g A )
IgA Nephropathy
• M o s t c o m m o n i d i o p a t h i c G N i n w o r l d
• D e fi n e d b y I g A d e p o s i t i o n i n
m e s a n g i u m
• P r e s e n t s - Y o u n g – g r o s s h e m a t u r i a
A d u l t s – P r o t e i n u r i a +
h e m a t u r i a
• N o t b e n i g n h e m a t u r i a ( B e r g e r ’ s D i s
)
• 2 0 - 3 0 % p r o g r e s s E S R D o v e r 2 0
y e a r s
• R x – A C E i n h i b . + S t d s , F . O . , M M F
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2 9
C o r t i c o s t e r o i d s i n I g A N : a
c o n t r o l l e d t r i a l
8 6 P t s U p r o t 1 - 3 . 5 g / D P c r e a t < 1 . 5 m g / d l
R x c y c l i c P u l s e S M + Q O D s t d s v s P B O x 6 m o .
E n d p o i n t 5 0 % r i s e i n P c r e a t . F o l l o w 6 y r s
E n d p o i n t 9 / 4 3 R x v s . 1 4 / 4 3 P B O ( p < . 0 5 )
H i g h r i s k P t s : v a s c u l a r s c l e r o s i s , m a l e s ,
n o S t e r o i d R x
N o m a j o r s i d e e f f e c t s
P o z z i e t a l . L a n c e t 3 5 3 : 8 8 3 , 1 9 9 9
I g A N e p h r o p a t h y : A
C o n t r o l l e d T r i a l o f S t e r o i d s
( P o z z i , e t a l )
0
5
10
15
20
25
Control Steroids
Doubled Scr
ESRD
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3 0
C o n t r o l l e d T r i a l o f F i s h O i l s i n
I g A N
1 0 6 P t s 7 8 M / 2 8 F a g e 3 6 y o
U p r o t > 1 g / D H B P 6 0 %
R x M a x E P A 1 2 g / D ( 5 8 ) v s O l i v e o i l ( 5 1
)
R x 2 y r f o l l o w 5 y r
E n d p o i n t 5 0 % i n c r e a s e P c r e a t .
E n d p o i n t 6 % R x E P A v s 3 3 %
P B O
C h a n g e P c r e a t . 0 3 m g / d l v s . 1 4
m g / d l
D D T 1 0 % v s
4 0 %
D o n a d i o e t a l N E n g J M e d
1 9 9 4
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3 1
I m m u n o s u p p r e s s i v e R x f o r I g A N
C h a n g e i n P r o t e i n u r i a
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Proteinuria
(g/24hr)
0 12 24 36 48
Trial Entry (Months)
Treatment
Controls
B a l l a r d i e , F W , R o b e r t s , I D . J A m S o c N e p h , 1 3 : 1 4 2 - 1 4 8 , 2 0 0 2 .
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3 2
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3 3
• A 2 9 y o s a l e s w o m a n d e v e l o p s a r t h r i t i s
o f m u l t i p l e j o i n t s , f e v e r ,
l y m p h a d e n o p a t h y , a n d a m a l a r r a s h .
• L a b s :
– U r i n a l y s i s 3 + p r o t e i n , c r e n a t e d r b c ’ s
– C r e a t i n i n e 1 . 2 m g / d l
– 2 4 h r . p r o t e i n 1 . 8 g / d l
– C o m p l e m e n t 1 8 % ( n o r m a l 5 0 - 1 5 0 % )
– A N A p o s i t i v e , A n t i - D N A a n t i b o d y p o s i t i v e
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3 4
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3 5
L u p u s N e p h r i t i s C l a s s I V
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3 6
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3 7
L u p u s N e p h r i t i s W H O C l a s s i fi c a t i o n
C L A S S E S
I M i n i m a l m e s a n g i a l
I I M e s a n g i a l P r o l i f e r a t i v e
I I I F o c a l S e g m e n t a l P r o l i f e r a t i v e
I V D i f f u s e P r o l i f e r a t i v e
V M e m b r a n o u s
L u p u s N e p h r i t i s C l a s s I I
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3 8
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3 9
Treatment of Lupus Nephritisby Class
• Class I and II – Treat extra-renal findings
• Class III -FPLN – Vigorous Rx if necrotizingfeatures, crescents, extensiveproliferation.
• Class IV – DPLN – Vigorous Rximmunosuppressives
• Class V – Memb LN – Treat to induce remitproteinuria – Nephrotic syndrome
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4 0
Predictors of Progression of LupusNephritis in Three Ethnic Groups
N e w Y o r k C i t y C o h o r t :N e w Y o r k C i t y C o h o r t :
1 2 9 p t s - 5 1 H , 2 2 A A , 5 5 C C l a s s I I I - I V
L N
P r e d i c t o r s ( a g e - a d j u s t e d h a z a r d r a t i o )
H i s p a n i c e t h n i c i t y ( 3 . 7 )
A f r i c a n – A m e r i c a n r a c e ( 3 . 1 )
L i v i n g i n n e i g h b o r h o o d w i t h h i g h p o v e r t y ( 2 . 9 )
G o v e r n m e n t i n s u r a n c e – M e d i c a r e ( 3 . 2 )
E l e v a t e d c r e a t i n i n e ( 4 . 3 )
P r o t e i n u r i a ( 3 . 8 )
H y p e r t e n s i o n ( 3 . 2 )
W H O C l a s s I V ( 3 . 3 ) B a r r … A p p e l e t a l ,
2 0 0 3
Impact of Race on RenalPrognosis – NYC n= 129
0
20
40
60
80
100
5 15 25 35 45 55 65
Follow-up, months
Pro
ba
bil
ity
o
f n
ot
do
ub
lin
g
cre
ati
nin
e,
%
White
Black
Hispanic
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4 1
I m p a c t o f P o v e r t y o n R e n a l
P r o g n o s i s - N Y C
0
20
40
60
80
100
5 15 25 35 45 55 65
Follow-up, months
Pro
ba
bil
ity
o
f n
ot
do
ub
lin
g
cre
ati
nin
e,
%
Others
Poverty
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4 2
0
20
40
60
80
100
220200180160140120100806040200
P r o b a b i l i t y o f D e v e l o p i n g E n d - S t a g e R e n a l
D i s e a s e : C o m p a r i s o n A m o n g L u p u s N e p h r i t i s
T r e a t m e n t R e g i m e n s
C Y C = c y c l o p h o s p h a m i d e ; A Z A = a z a t h i o p r i n e .
S t e i n b e r g A D , S t e i n b e r g S C . A r t h r i t i s R h e u m . 1 9 9 1 ; 3 4 : 9 4 5 - 9 5 0 .
M o n t h s
P r o b a b i l i t y
o f
E n d - S t a g e
R e n a l
D i s e a s e
I V C Y C
O r a l C Y C + A Z A
O r a l C Y C
A Z A
P r e d n i s o n e
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4 3
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4 4
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4 5
M u l t i c e n t e r T r i a l o f M M F v s I V C y c
f o r I n d u c t i o n T h e r a p y o f S e v e r e
L N
• M u l t i c e n t e r , r a n d o m i z e d , n o n b l i n d e d t r i a l
o f i n d u c t i o n R X f o r s e v e r e a c t i v e L N
• D e s i g n e d a s e q u i v a l e n c e t r i a l
• C a l c u l a t e d s a m p l e s i z e : 6 4 / R x a r m
• H y p o t h e s i s : M M F h a s e q u i v a l e n t e f fi c a c y
w i t h s u p e r i o r t o x i c i t y / t o l e r a b i l i t y p r o fi l e
v s . I V C
A C R G i n z l e r e t a l 2 0 0 3 , A S N A p p e l e t a l 2 0 0 3
B a s e l i n e P a t i e n t C h a r a c t e r i s t i c s
3 3 . 2 ± 1 1 5 . 5
1 0 . 3 ± 1 7 . 3
2 4 . 1 ± 5 0 . 3
1 2 . 6 ± 2 3 . 5
U r i n e s e d i m e n t
R B C / h p f
W B C / h p f
4 . 4 1 ± 3 . 5 14 . 0 6 ± 3 . 1 4U r i n e p r o t e i n , g / 2 4 h r
1 . 0 8 ± 0 . 4 91 . 0 6 ± 0 . 5 2S c r e a t i n i n e , m g / d L
5 8 . 7 0 ±
8 0 . 6 4
4 3 . 7 2 ±
6 6 . 8 8
D u r a t i o n o f S L E , m o .
3 6 ( 5 2 % )4 3 ( 6 1 % )B l a c k
2 . 6 9 ± 0 . 5 62 . 8 1 ± 0 . 9 5S a l b u m i n , g / L
6 5 ( 9 4 % )6 1 ( 8 6 % )F e m a l e
3 1 . 0 ± 9 . 03 2 . 5 ± 1 0 . 0A g e ( y r s )
I V C ( n = 6 9 )M M F
( n = 7 1 )
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4 6
W H O R e n a l B i o p s y C l a s s i fi c a t i o n
o f S t u d y P o p u l a t i o n
8 7M i x e d
1 3 1 4M e m b r a n o u s ( V )
3 7
1 1
3 9
1 1
P r o l i f e r a t i v e
C l a s s I V
C l a s s I I I
I V C
( n = 6 9 )
M M F
( n = 7 1 )
R e m i s s i o n R a t e s : M M F v s . I V C
0
10
20
30
40
50
60
Complete Remission Partial Remission Complete + Partial
Remission
MMF IVC
1 6 / 7
14 / 6
9
2 1 / 7
1
1 7 / 6 9
3 7 / 7 1
2 1 / 6
9
I n t e n t - t o - T r e a t
A n a l y s i s
P = N S
P = 0 . 0 0 5
P = 0 . 0 0 9
Pe
rc
en
t R
es
po
nd
ing
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4 7
C h a n g e i n P r e d n i s o n e D o s e
0
10
20
30
40
50
60
0 4 8 12 16 20 24
Weeks
MMF IVC
P = 0 . 0 6
4
Pr
ed
nis
on
e (
mg
/d
ay
)
0
1
2
3
4
5
0 4 8 12 16 20 24
Weeks
C h a n g e i n S e r u m C r e a t i n i n e
a n d
U r i n e P r o t e i n E x c r e t i o n
0.8
0.9
1
1.1
1.2
0 4 8 12 16 20 24
Weeks
MMF IV CYC
S e r u m
C r e a t i n i n e
U r i n e
P r o t e i n
Se
ru
m C
re
at
inin
e (
mg
/d
L)
Ur
ine
Pr
ot
ein
(m
g/
dL
)
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4 8
0
3
6
9
12
15
0 4 8 12 16 20 24
Weeks
C h a n g e i n U r i n e S e d i m e n t
0
10
20
30
40
0 4 8 12 16 20 24
Weeks
R B C W B C
M M F I V C
RB
C/
hp
f
WB
C/
hp
f
10
15
20
25
0 4 8 12 16 20 24
Weeks
C h a n g e i n C o m p l e m e n t
C o m p o n e n t s
70
80
90
100
110
0 4 8 12 16 20 24
Weeks
C 3 C 4
M M F I V C
C3
(m
g/
dL
)
C4
(m
g/
dL
)
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4 9
2
2.5
3
3.5
4
0 4 8 12 16 20 24
Weeks
MMF IV CYC
C h a n g e i n A n t i - d s D N A a n d
S e r u m A l b u m i n
0
0.5
1
1.5
2
0 4 8 12 16 20 24
Weeks
A n t i - d s D N A S e r u m A l b u m i n
An
ti-
ds
DN
A s
co
re
Se
ru
m A
lbu
min
(m
g/
dL
)
MMF vs IVCY Induction - 24Wk Remission Rates: AA vs Others
C o m p l e t e R e m i s s i o nC o m p l e t e R e m i s s i o n
M M FM M F B l a c k B l a c k
M M FM M F O t h e r O t h e r
I V C YI V C Y B l a c k B l a c k
I V C YI V C Y O t h e r O t h e r
C o m p l e t e + P a r t i a lC o m p l e t e + P a r t i a l
M M FM M F B l a c k B l a c k
M M FM M F O t h e r O t h e r
I V C YI V C Y B l a c k B l a c k
I V C YI V C Y O t h e r O t h e r
A p p e l e t a l , A S N 2 0 0 3A p p e l e t a l , A S N 2 0 0 3
0 25 50 75
NIH 100 86
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5 0
• A 5 8 y o i n s u r a n c e s a l e s m a n d e v e l o p s
s i n u s i t i s , w e i g h t l o s s , m a l a i s e a n d a d r y
c o u g h o v e r t h r e e w e e k s . H i s s i n u s fi l m s
s h o w o p a c i fi c a t i o n o f t h e l e f t m a x i l l a r y
s i n u s , a n d h e i s f o u n d t o h a v e a c a v i t a r y
l e s i o n o n h i s c h e s t X - r a y .
• L a b s :
– U r i n a l y s i s : r b c ’ s , w b c ’ s , a n d r b c c a s t s
– C r e a t i n i n e 2 . 7 m g / d l
– S e r u m c o m p l e m e n t i s n o r m a l
– A n t i - G B M a n t i b o d i e s a r e a b s e n t
– A N C A i s p o s i t i v e
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5 1
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5 2
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5 3
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5 4
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5 5
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5 6
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5 7
P u l m o n a r y - R e n a l V a s c u l i t i c
S y n d r o m e
• P a u c i - i m m u n e ( u s u a l l y A N C A -
a s s o c i a t e d )
– W e g e n e r ’ s g r a n u l o m a t o s i s
– M i c r o s c o p i c P o l y a n g i i t i s
• I m m u n e C o m p l e x D e p o s i t s ( g r a n u l a r )
– S L E
– C r y o g l o b u l i n e m i c v a s c u l i t i s
• A n t i - G l o m e r u l a r B a s e m e n t M e m b r a n e
A n t i b o d y D e p o s i t s ( l i n e a r )
– G o o d p a s t u r e ’ s S y n d r o m e
C i r c u l a t i n g a n t i - G B M
a n t i b o d i e s w i t h l i n e a r
g l o m e r u l a r I F s t a i n i n g
C i r c u l a t i n g A N C A w i t h
p a u c i t y o f g l o m e r u l a r I F
i m m u n o g l o b u l i n s t a i n i n g
G l o m e r u l a r i m m u n e
c o m p l e x l o c a l i z a t i o n w i t h
g r a n u l a r I F s t a i n i n g
A N T I B O D Y M E D I A T E D G L O M E R U L O N E P H R I T I S
> 8 0 % A N C A +
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5 8
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5 9
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6 0
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6 1
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6 2
R a p i d l y P r o g r e s s i v e
G l o m e r u l o n e p h r i t i s
A s e v e r e f o r m o f G N l e a d i n g t o R F i n d a y s
t o m o n t h s
R P G N = C r e s c e n t i c G N
S e c o n d a r y R P G N ( S L E , H S P , P o s t -
i n f e c t i o u s , e t c . )
P r i m a r y R P G N - a n t i - G B M d i s e a s e
- i m m u n e c o m p l e x
G N
- p a u c i - i m m u n e G N
R x a n d C o u r s e d e p e n d o n e t i o l o g y a n d
s t a g e
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6 3
T r e a t m e n t o f R P G N
• A n t i - G B M d i s e a s e – S t e r o i d s ,
c y t o t o x i c s , a n d p l a s m a p h e r e s i s
• I m m u n e C o m p l e x G N – T r e a t
u n d e r l y i n g d i s e a s e
• P a u c i - i m m u n e R P G N ( A N C A + ) –
C y t o t o x i c s ( I v o r P . O . )
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6 4
A n t i - N e u t r o p h i l C y t o p l a s m i c
A n t i b o d i e s
• C - A N C A c y t o p l a s m i c a g a i n s t s e r i n e
p r o t e i n a s e 3 ( P R 3 )
• P - A N C A p e r i n u c l e a r a g a i n s t
m y e l o p e r o x i d a s e ( M P O )
• P - A N C A i s a n a r t i f a c t o f a l c o h o l
fi x a t i o n
A N C A i s t o R P G N a s A n t i - D N A i s t o
S L E
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6 5
R e n a l P u l m o n a r y S y n d r o m e s
• G o o d p a s t u r e ’ s S y n d . A n t i G B M A b s
• S L E l u n g d i s . + L N a D N A + C H 5 0
• R P G N , W e g . G . , P A N A N C A
•
• P u l m o n a r y e m b o l i R V T ( m e m b N S
)
• P n e u m o n i a I m m u n e
c o m p l e x G N
• U r e m i c L u n g C H F + R e n a l
f a i l u r e