1

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

2

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

3

4

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

5

Signs of GlomerularDisease

Erythrocyte Casts

Deformed-Crenated Urinary RBC’s

Large amounts Albuminuria

( >3g/D )

6

7

8

• 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 )

9

1 0

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

1 1

1 2

1 3

1 4

1 5

1 6

1 7

1 8

1 9

2 0

2 1

2 2

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

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

2 4

2 5

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

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

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

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

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

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 .

3 2

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

3 4

3 5

L u p u s N e p h r i t i s C l a s s I V

3 6

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

3 8

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

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

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

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

4 3

4 4

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 )

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

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

)

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

)

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

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

5 1

5 2

5 3

5 4

5 5

5 6

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 +

5 8

5 9

6 0

6 1

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

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 . )

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

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