1

C PC :G lom eru lonephrit is G era ld B A ppe l, M D V ivette D ’A gati, M D

C lass ification o f Rena lG lom eru la r D iseases

• M orpho log ica l• Im m uno log ica l• Etio log ica l• C lin ica l

V u lne rab ility o f G lom eru lusto IC In ju ry

1 . 20 -25% Card iac O utput2 . H igh g lom eru la r cap illa ry p ressu re3 . Fenestrated endothe lium4 . Concentrat ion (s iev ing e ffect)

M echan ism s o f Im m uno log icIn ju ry to the G lom eru lus

1 . G lom eru la r depos it ion o fc ircu lat ing A g-A b com p lexes

2 . B ind ing o f C ircu lat ing A b tostructu ra l g lom eru la r A g ( i.e . anti-GBM A b )

3 . In s itu im m une com p lex fo rm ation

2

G lom eru la r P ro life rat ion

1 . Endocap illa ry

2 . Extracap illa ry(c rescentic )

Patte rns o f G lom eru la r D isease

G loba lV s2 .Segm enta l

D iffuseV s1 . Foca l

Signs of GlomerularDisease

Erythrocyte Casts

Deformed-Crenated Urinary RBC’s

Large amounts Albuminuria

( >3g/D )

3

• 7 y o W M c/o x severa l days bad so reth roat + low g rade tem peratu re ; he isg iven acetam inophen , and recoversuneventfu lly . 2 w ks late r deve lops dark ,coca-co la co lo red u rine and notesu rinat ing less . O n P x peda l edem a andan e levated b lood p ressu re .

• Labs:– U/A rbc’s , rbc casts , 2+ p rot .– C reatin ine 2 .4 m g/d l– Com p lem ent 22 (no rm a l 50 -150)– C3 leve l low– A SLO 1250 (no rm a l < 250)

4

N ephrit ic Synd rom e

• D ecreased GFR

• O ligu ria

• Edem a

• Hypertens ion

• A ctive u rinary sed im ent

5

6

7

8

Post-S treptococca l GN

• Fo llow s certa in se ro type streptococca lin fections – so re th roats , im petigo , etc .

• Ch ild ren m ore com m on than adu lts• T im e lag betw een in fection & k idney

d isease• N ephrit ic p ictu re com m on• Sero log ic tests fo r s trept in fections +• Low com p lem ent and C3 leve ls• Exce llent p rognos is ch ild ren , + /- in adu lts

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 16 y o h igh schoo l jun io r noticesdark b row n u rine a fte r p lay ingbasketba ll. U rinary sed im ent hasrbc ’s and rbc casts .

• Labs:– C reatin ine 1 .1 m g/d l– C reatin ine c learance 128 cc/m in– 660 m g p rote inu ria/day– Sero log ic tests a re no rm a l o r

negative

9

D em ograph ics o f IgAN ephropathy

A ges 4 – 80 (m ean 25 ) years(65% o f patients in 2 n d/3 rd decade)

M /F = 2/1Rare in b lacks

Inc idence (% p rim ary g lom eru lopath ies)5 -10% N . A m erica

U .K .S cand inav ia

20 -30% EuropeA ustra lia

25 -45% A sia

C lass ification

• Prim ary– IgA N ephropathy– Henoch-S chon le in Pu rpura

• Secondary– L ive r C irrhos is– Inflam m ato ry Bow e l D isease

Pathogenes is

1 . D efective hepatic c learance– L ive r c irrhos is

2 . Increased IgA p roduction– A ssoc iat ion w ith e levated se rum IgA– O nset m ay fo llow UR I o r Gastroenterit is

3 . D efect o f antigen exc lus ion at the m ucosa l su rface

– UR I– Gastroenterit is– Ce liac d isease

1 0

S tructu re o f Hum anSecreto ry IgA (s igA )

IgA Nephropathy

• M ost com m on id iopath ic GN in w orld• D efined by IgA depos it ion in

m esang ium• Presents- Young – g ross hem aturia A du lts – P ro te inu ria +

hem aturia• N ot ben ign hem aturia ( Berger’s D is

)• 20 -30 % p rog ress ESRD over 20

years• Rx – A CE inh ib . + S tds , F .O ., M M F

Cort icoste ro ids in IgA N : acontro lled tria l

86 Pts U p rot 1 -3 .5g/D P creat < 1 .5 m g/d lRx cyc lic Pu lse SM + Q O D stds v s PBO x 6 m o .Endpo int 50% rise in P creat. Fo llow 6 y rs

Endpo int 9 /43 Rx vs . 14/43 PBO ( p< .05 )H igh r isk P ts : vascu la r sc le ros is , m a les , no S te ro id RxN o m ajo r s ide e ffects

Pozz i e t a l. Lancet 353 :883 , 1999

IgA N ephropathy : AContro lled T ria l o f S te ro ids

(Pozz i, e t a l)

Contro lled T ria l o f F ish O ils inIgA N

106 Pts 78M /28F age 36yo U p rot > 1 g/D HBP 60%Rx M ax EPA 12g/D ( 58 ) v s O live o il ( 51

)Rx 2yr fo llow 5 y r Endpo int 50% increase P creat.

Endpo int 6% Rx EPA v s 3 3%PBO

Change Pcreat .03 m g/d l v s .14m g/d l

D D T 10% v s40%

D onad io et a l N Eng J M ed1994

1 1

Im m unosuppress ive Rx fo r IgA NChange in P ro te inu ria

Ba lla rd ie , FW , Roberts , ID . J A m Soc N eph, 13 :142 -148 , 2002 .

• A 29 y o sa lesw om an deve lops a rth rit iso f m u lt ip le jo in ts , fever,lym phadenopathy, and a m a la r rash .

• Labs:– U rina lys is 3+ p rote in , c renated rbc ’s– C reatin ine 1 .2 m g/d l– 24 h r. p ro te in 1 .8 g/d l– Com p lem ent 18% (no rm a l 50 -150% )– A N A pos it ive , A nti-D N A antibody pos it ive

1 2

Lupus N ephrit is C lass IV

1 3

Lupus N ephrit is W HO C lass ification

CLA SSESI M in im a l m esang ia lII M esang ia l P ro life rat iveIII Foca l Segm enta l P ro life rat iveIV D iffuse P ro life rat iveV M em branous

Lupus N ephrit is C lass II

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

1 4

Predictors of Progression of LupusNephritis in Three Ethnic Groups

N ew Yo rk C ity Cohort:129 pts -51 H , 22 A A , 55 C C lass III - IVLNPred icto rs (age-ad justed hazard rat io )

H ispan ic ethn ic ity (3 .7 )A frican – A m erican race (3 .1 )L iv ing in ne ighborhood w ith h igh poverty (2 .9 )Governm ent insu rance – M ed icare (3 .2 )E levated c reatin ine (4 .3 )P rote inu ria (3 .8 )Hypertens ion (3 .2 )W HO C lass IV (3 .3 ) Barr… A ppe l e t a l,2003

Impact of Race on RenalPrognosis – NYC n= 129

Im pact o f Poverty on Rena lP rognos is- N YC

Probab ility o f D eve lop ing End -Stage Rena lD isease : Com parison A m ong Lupus N ephrit is

T reatm ent Reg im ens

CYC = cyc lophospham ide ; A ZA = azath iop rine .S te inberg A D , S te inberg SC . A rth rit is Rheum . 1991 ;34 :945 -950 .

M onths

Probab ilityo f

End -StageRena l

D isease

IV CYCO ra l CYC + A ZA

O ra l CYC

A ZA

Predn isone

1 5

M u lt icenter T ria l o f M M F vs IV Cycfo r Induction Therapy o f Severe

LN• M u lt icenter, random ized , nonb linded tria l

o f induction RX fo r severe active LN• D es igned as equ iva lence tria l

• Ca lcu lated sam p le s ize : 64/ Rx a rm• Hypothes is : M M F has equ iva lent e fficacy

w ith superio r tox ic ity/to le rab ility p rofi levs. IV C

A CR G inz le r et a l 2003 , A SN A ppe l e t a l 2003

Base line Patient Characte rist ics

33 .2 ± 115 .510 .3 ± 17 .3

24 .1 ± 50 .312 .6 ± 23 .5

U rine sed im entRBC/hpfW BC/hpf

4 .41 ± 3 .514 .06 ± 3 .14U rine p ro te in , g/24 h r1 .08 ± 0 .491 .06 ± 0 .52Screatin ine, m g/dL58 .70 ±80 .64

43 .72 ±66 .88

D uration o f SLE , m o .36 (52% )43 (61% )B lack

2 .69 ± 0 .562 .81 ± 0 .95Sa lbum in , g/L

65 (94% )61 (86% )Fem a le31 .0 ± 9 .032 .5 ± 10 .0A ge ( y rs)IV C (n=69)M M F

(n=71)

1 6

W HO Rena l B iopsy C lass ificationo f S tudy Popu lat ion

8 7M ixed 13 14M em branous ( V )

37 11

39 11

Pro life rat ive C lass IV C lass III

IV C(n=69)

M M F(n=71)

Rem iss ion Rates: M M F vs . IV C

16/71

4/69

21/71

17/69

37/71

21/69

In tent-to -T reatA na lys is

P=N SP=0 .005

P=0 .009

Perc

ent

Resp

ondi

ng

C hange in P redn isone D ose

P = 0 .064

Pred

niso

ne (

mg/

day)

C hange in Serum C reatin ineand

U rine P ro te in ExcretionSerum

Creatin ineU rine

P rote in

Seru

m C

reat

inin

e (m

g/d

L)

Uri

ne P

rote

in (

mg/

dL)

C hange in U rine Sed im entRBC W BC

M M F IV C

RBC

/hpf

WB

C/h

pf

C hange in Com p lem entCom ponents

C3 C4

M M F IV C

C3

(m

g/dL

)

C4

(m

g/dL

)

1 7

C hange in A nti-d sD N A andSerum A lbum in

A nti-d sD N A Serum A lbum in

Ant

i-dsD

NA

sco

re

Seru

m A

lbum

in (

mg/

dL)

MMF vs IVCY Induction - 24Wk Remission Rates: AA vs Others

Com p lete Rem iss ionM M F B lackM M F O therIV CY B lackIV CY O therCom p lete + Part ia lM M F B lackM M F O therIV CY B lackIV CY O ther

A ppe l e t a l, A SN 2003

• A 58 y o insu rance sa lesm an deve lopss inus it is , w e ight loss , m a la ise and a d rycough over th ree w eeks. H is s inus fi lm sshow o pac ification o f the le ft m ax illa rys inus, and he is found to have a cav ita ryles ion on h is chest X -ray .

• Labs:– U rina lys is : rbc’s , w bc ’s , and rbc casts– C reatin ine 2 .7 m g/d l– Serum com p lem ent is no rm a l– A nti-GBM antibod ies a re absent– A N CA is pos it ive

1 8

1 9

Pu lm onary -Rena l V ascu lit icSyndrom e

• Pauc i- im m une (usua lly A N CA -assoc iated)

– W egener’s g ranu lom atos is– M icroscop ic P o lyang iit is

• Im m une Com p lex D epos its (g ranu la r)– SLE– C ryog lobu linem ic v ascu lit is

• A nti-G lom eru la r Basem ent M em braneA ntibody D epos its ( linear)

– Goodpastu re ’s Syndrom e

C ircu lat ing a nti-GBMantibod ies w ith linearg lom eru la r IF sta in ing

C ircu lat ing A N CA w ith pauc ity o f g lom eru la r IFim m unog lobu lin sta in ing

G lom eru la r im m unecom p lex loca lizat ion w ith

g ranu la r IF sta in ing

A N T IBO D Y M ED IA TED GLO M ERULO N EPHR IT IS

>80% A N CA +

2 0

2 1

R ap id ly P rog ress iveG lom eru lonephrit is

A severe fo rm o f GN lead ing to RF in daysto m onths

RPGN = C rescentic GNSecondary RPGN ( SLE , HSP , Post-

in fectious, e tc . )P rim ary RPGN - anti-GBM d isease - im m une com p lex

GN - pauc i- im m une GNRx and Course depend on et io logy and

stage

T reatm ent o f RPGN

• A nti-GBM d isease – S te ro ids ,cytotox ics , and p lasm apheres is

• Im m une Com p lex GN – T reatunderly ing d isease

• Pauc i- im m une RPGN ( A N CA + ) –Cytotox ics ( Iv o r P .O . )

2 2

A nti-N eutroph il C ytop lasm icA ntibod ies

• C -A N CA cytop lasm ic aga inst se rine p ro te inase 3 ( PR3 )• P-A N CA perinuc lear aga inst m ye loperox idase ( M PO )• P-A N CA is an a rt ifact o f a lcoho l

fixation

A N CA is to RPGN as A nti-D N A is toSLE

Rena l Pu lm onary Syndrom es

• Goodpastu re ’s Synd . A nti GBM A bs• SLE lung d is . + LN aD N A + CH50• RPGN , W eg.G ., PA N A N CA•• Pu lm onary em bo li RV T ( m em b N S

)• Pneum on ia Im m une

com p lex GN• U rem ic Lung CHF + Rena l

fa ilu re