prognostic minimal change

7/26/2019 Prognostic Minimal Change

1/8

P ro gn o stic S ig n ifica n ce o f th e E ar ly C o u rse o f M in im a l

C h a n g e N ep h r otic S y n d ro m e: R ep o rt o f th e In ter n a tion a l

S tu d y of K id n ey D isea se in C h ild r en

P E N IN A T A R S H IS H ,* JO N A T H A N N . T O B IN ,t JA Y B E R N S T E IN , and

C H E S T E R M . E D E L M A N N , JR *

* D e p a r t,n en t o f P e d ia tr ic s , A lb e rt E in ste in C o lle g e o f M e d ic in e, B ro n x , N e w Y o rk; D ep a rtm e n t o f

E pidem io log y an d S oc ia l M ed icine , A lb ert E inste in C o lleg e o f M ed ic ine , B ronx , N ew Y o rk , and C lin ica l

D ire cto rs N e tw o rk , N e w Y o rk ; a n d W il ia m B ea u m o n t H o sp ita l R es ea rc h In stitu te , R o y a l O a k, M ic h ig a n .

A bs trac t . T he ab ility to p red ic t the co urse in ch ild ren w ith

new ly d iagn osed m in im a l change neph ro tic sy ndrom e

(M C N S ) m ay have sig n if ican t the rapeu tic im p lica tion s. P rev i-

ou s a ttem pts based on d a ta ava ilab le a t d isease onse t have n o t

been successfu l. T here fo re , it w as investiga ted w hether char-

acte r iza tion o f the in itia l re spo nse to ad reno co rtic a l s te ro ids

and the course during th e ea rly m on ths o f d isea se are p red ictiv e

o f the su bsequ en t o u tcom e . T hree hu ndred -e ig h ty -n ine ch il-

d ren w ith M C N S , d iagn osed at on se t, w ere trea ted w ith stan -

da rd p red n iso ne reg im en s and m on ito red fo r up to 1

7 yr (m ean ,

9 .4 y r). T h ey w ere cla ssif ied , a fte r 8 w k of the rapy , a s in itia l

re sp ond ers (com ple te rem ission ) o r in itia l n onre spo nde rs (con -

tinu ed pro te inu ria ) . S ub sequen t c las sific a tions in clu ded n onre -

lapse rs, in frequen t re lapse rs, and freq uen t re lapse rs. A t 8 yr o f

fo llow -up , 80% of p atien ts w ere in rem ission . T hree-four th s o f

in itia l respon ders w ho rem ained in rem iss ion during the f irst

6-m on th pe rio d a fter in itia l the rapy (no nrelapsers; 40 % of the

en tire se ries ) e ithe r con tinued in rem iss ion during the ir en tire

course or re lapsed ra re ly . In con trast, in itia l re lapse rs, bo th

frequen t and in frequen t, a ch ieved a n onre lap sing cou rse on ly

af te r an av erage o f 3 y r . U nrem itting p ro te inu ria du rin g the

in itia l 8 w k o f trea tm en t w as fo llow ed by pro gress ion to E S R D

in 21% . W hen pro teinu ria during the in itia l 8 w k con tinued

th roug h th e su bsequ en t 6 m on th s, p rog re ssion to rena l fa ilu re

occu rred fo r 35% . A ltho ugh 95% of ch ild ren w ith M C N S d o

w e ll, 4 to

5%

d ie fro m co m plica tions o r und ergo pro gres sion to

E S R D . D ocum en tatio n o f the ea r ly course a ids in id en tify ing

those a t inc rea sed risk fo r a poo r ou tcom e . M ore ag gress ive

the rapy m ay be ind ica ted fo r th ese ind iv idua ls. (J A m S oc

N eph ro l 8 : 769 -776 , 1997)

In 19 67 , th e In te rna tiona l S tudy o f K idney D isease in C h ild ren

(IS K D C ) began a m ultic en ter p rosp ec tive s tudy o f ch ildh ood

nephro tic syn drom e, to d e te rm ine c lin ica l and labora to ry char-

ac te ris tic s and to cond uc t a se ries o f con tro lled therapeu tic

trials ( 1-7). T h is repo rt ch arac te rizes the lon g-te rm cou rse and

ou tco m e o f m in im a l chang e neph ro tic synd ro m e (M C N S ),

w ith the dem on stra tio n tha t the p atte rn of s te ro id resp ons iv e-

ness du ring the first 6 m onths pred ic ts the su bsequ en t pa ttern

of re sp onse and re lapse .

M a te ria ls an d M eth od s

Patients

B etw een Janu ary 1967 and A pr il 19 76 , 52 1 ch ild ren w ith recen t-

on se t nephro tic sy ndrom e w ere en te red in to a prospec tiv e stud y tha t

invo lved 19 partic ipa tin g cen te rs in 12 cou n tries in N orth A m erica,

E u ro pe , and A sia . W ritten in fo rm ed consen t w as ob tain ed fro m a ll

par t icipan ts . C rite ria fo r adm iss io n w ere (1 ) h eavy pro te inuria , o f 40

m g /lvm 2 B S A (0 .9 6 g /daym 2 ), de te rm in ed w ith an o ve rn igh t cob -

lection: (2 ) hypo a lb um inem ia , o f 2 .5 g /dL (25 g/L) : (3 ) age of

R ece ived M ay 7 , 1996 . A ccep ted Sep tem ber 24 . 1996 .

C orrespondence to D r . C h ester M . E de lm ann . A lbe rt E ins tein C ollege of

M edicine . 1 300 M orris Park A v enue , B ronx , N Y 10461 .

I046-6673 /0805-0769$03 .00 /0

Journa l o f the A m erican Soc ie ty of N eph ro logy

C opyr ig h t U 199 7 by the A m erican S oc ie ty of N eph robog y

> 12 w k and < 16 yr; (4 ) no p rio r treatm ent w ith s tero ids or o ther

cy to tox ic or im m u nosu ppressive agen ts; and (5 ) no ev idence of u n-

derly ing sys tem ic d isease o r ex posure to agen ts kn ow n to be assoc i-

a ted w ith the n ephro tic synd rom e.

A ll p a tien ts un de rw en t rena l b iopsy afte r en try in to the stud y ,

be fore in itiat ion of the rap y.

O f th e

5 21 pa tien ts . 389 (74 .7% ) w ere

d iagnosed h istop atho bog ica lly b y the IS K D C cen tra l p atho lo g ists as

hav ing M C N S. T h is is in strik ing con tras t to the exp er ience w ith

adu lts, am ong w ho m m em brano us gbom eru lonephritis (a ra re d isease

am on g ch ild ren ) pr edo m inates.

P re d n iso n e R eg im e n s

T he in itia l tre a tm en t w as 60 m g/24 h m 2 predn iso ne (m ax im u m

da ily d osage , 80 m g /2 4 h m 2) in th ree d iv ided da ily doses fo r 4 w k ,

fo llow ed b y 4 0 m g /24 hm 2 (m ax im um da ily

do sage , 6 0 m g/24 hm 2)

in d iv id ed d oses on 3 consecu tive days o f 7 fo r 4 w k . T h e trea tm ent

o f re lapse w as 60 m g/24 hm 2 in d iv ided d oses un til respon se (m ax-

im um of 4 w k ), fo llow ed by 40 m g/24 hm 2 in d iv ided doses on 3

consecu tive day s of 7 fo r 4 w k.

R esponse w as defined as a reduc tion in th e ra te of u rina ry ex cretion

of pro te in to < 4 m g /lvm 2 (A lb ustix , 0 to trace) fo r 3 con secu tive d ays.

R e lapse inv o lved a reapp earance of p ro te in uria o f 40 m g / l v m 2

(A lbus t ix ,

+ +

or grea te r) fo r 3 con secu tive days . In itia l resp onders

w ere pa tien ts w ho respond ed during th e 8 w k of th e in itia l p red n ison e

reg im en . In itia l no nresp onders w ere pa tien ts w ho fa iled to respo nd

du ring the in itia l 8 w k of predn isone therapy .

S om e of the pa tien ts su bsequ en tly w ere en te red in to therapeu tic


2/8

7 70 Journ a l o f the A m erican So cie ty of N ep hro logy

su bsequ en t resp ond e r: lo ss o f p ro te inu ria

tria ls incorpo ra ting d if feren t dosag es of pred n ison e (5 ) a nd re gim en s

tha t in clud ed cycbop hospham ide ( 1 ) o r aza th ioprine (7 ). A fte r the

in itia l 2 y r o f inc lus ion in th e tria l, pa tien ts w ere trea ted as de term in ed

by the ir o w n phy sic ians. H ow ev er, excep t fo r those inc lu ded in these

tria ls , ve ry few patien ts rece ived drugs o ther than pred n ison e.

M eth ods u sed fo r d ata co lle c tion , cod in g , repo rting o f clin ica l and

laborato ry

exam ina tions , an d s tandard iza tio n of ag e- and g en der-

d ep en den t v a riab le s hav e been desc ribed p rev io usly (2 ,4 ) . V a lues o f

G F R w ere es tim a ted us ing th e S chw artz fo rm u la (8 ) .

T a b le 2 .

A nn ua l c la ss ific atio ns

N on re lap se r: no re lap se

In freq uen t re lap se r: one to th ree relap ses

F requen t relapser : fo u r o r m o re relapse s

N o nresp onder fo llow ed by rem ission : 8 w eeks of pro teinu ria

fo llo w ed by rem iss ion

N onrespon de r no t fo llow ed by rem is sion : u n rem ittin g

p ro teinu ria

A n a ly sis o f C lin ic a l C o u rse s

Fo r the pu rp ose o f ana lysis . th e co urses o f th e pa tien ts w ere d iv ided

in to th ree phases . as fo llow s: ( 1 ) the in itial 8 w k afte r en tran ce in to the

s tudy : (2 ) the 6 -m on th pe riod a fte r in itia l the rapy ; and (3 ) the sub se-

quen t course, c lass if ied ann ua lly on the bas is o f d a ta repor ted d uring

each 1 y r o f fo llow -up (T ab les I an d 2).

Fo r a sse ssing th e sta tu s o f pa tien ts o ve r tim e , a p eriod o f 2

consecu tive yr w ith th e sam e c lass ifica tion w as requ ired to ch arac -

ter iz e th e course o f the pa tien ts an d to iden tify clin ica lly s ign if ic an t

changes. T h is a llow ed tran sien t chan ges in the frequ en cy of re lapse s

to b e d isr eg ar de d.

H i s t o p a t h o l o g v

R ena l tissu e w as pro cessed , eva lua ted , and c lass ified in to h isto -

log ic sub group s as prev ious ly d esc ribed (2 .9 ). B ecause there w ere no

corre la tio ns be tw een h isto log ic su b types of M C N S and the long- te rm

clin ica l co urse , da ta fo r a ll pa tien ts w ere po o led for the presen t

ana lys is .

S ta tis tic a l M e th o d s

T he da ta w ere eva lua ted fo r ca tego rical m easu re s usin g prop ortio ns

an d for quan tita tive m easures us ing m eans and S D . T he 95% confl-

dence lim its w ere es tim ated to describe respo nse tim es and to assess

d iffe rences be tw een pa tien t subgro ups ( 1 0 ). P a tien ts w ere eva lu ated a t

irreg u la r in terva ls du rin g the fo llow -up pe riod . A n nua l a sse ssm en ts

w ere o b ta ined fo r a ll pa tien ts . an d the clin ica l co u rse s w ere c las sified

accord in g to the crite ria lis ted in T ab le 2. A nalys is o f the subsequen t

course s w as b ased on th e p ropo rtion o f p atien t rep o rts in each ann ua l

classification.

T a b le 1 .

In itia l and 6-m o n th c las sific a tions

Resul ts

C h a ra c te ris tic s a t O n se t

T he 3 89 p atien ts w ith M C N S in clu ded 6 6% m ale pa tien ts

and 34 % fem a le pa tien ts . A g e a t on se t w as 4 .8

2 .9 yr

( m ean

S D ). A ge at en try w as 4 .9 2 .9 y r . w ith a ran ge o f

0 .87 to 1 4 .8 . A f ig ure sh ow in g the ag e d istribu tion a t o nse t h as

been pub lished (4 ). A s p rev io usly repo rted (4 ) , ba se line c lin i-

ca l and labo ra to ry d ata d id n o t co rrelate w ith rena l h istop ath o-

log ic find ings , respon se to therapy , o r subsequen t cou rse and ,

th ere fo re , a re no t repo rted h ere . S im ila rly , n o co rre la tio ns w ere

foun d w ith m ic ro sco p ic h em atu ria , w h ich w as p re sen t at on se t

in o ne -th ird o f pa tien ts .

G e o g ra p h ic D istr ib u tio n

T h e ser ie s inc luded 47 .8 % p a tien ts from E u ro pe , 1 6 .5%

fro m Jap an and H on g K o ng , and 35 .7 % from N orth A m erica .

H istopa thob og ic su b types and th e 6-m o nth classifica tion s d id

no t d iffe r am on g these g roup s.

C o u r s e

F o llow -u p tim es av e raged 1 13

62 m onths , w ith a m axi-

m u m of 2 1 1 m onth s (17 .6 y r) . F o llow -up m on ito rin g inc luded

34 1 pa tien ts a t 2 yr from entry , 301 a t 5 yr. 26 2 a t 7 yr. 2 23 a t

10 y r. 1 86 a t 12 y r, and 6 0 a t 15 yr .

S ix -m on th c la ssif ica tion w as poss ib le fo r 363 of th e 38 9

ch ild ren (93% ) (T ab le 3). F or I 3 pa tien ts . the re w ere insu ffi-

c ien t da ta to cha rac te riz e th e cou rse s du ring the f irs t 6 m on ths;

fo r I 3 pa tien ts , the re w ere no fo llow -u p da ta b ey ond en tran ce.

O f the 3 63 p atien ts , 334 (92% ) w ere in itia l re sp ond ers and 29

(8% ) w ere in itia l nonrespon ders (T ab le 3). N e ith er G FR at

o nse t no r G F R

a t last fo llow -up exam ina tion correla ted w ith

In i t ia l respo n d er: atta inm en t o f com p le te rem issio n

cessa tion o f p ro te inu ria w ith in in itia l 8 w eeks o f

p redn isone the rap y

C ou rse d urin g

su b seq u en t 6 m o n th s

in itia l n onre lapse r: no re lapse

in itia l in freq uen t re lap se r: on e re lapse

in itia l f requen t re lapse r: tw o or m ore re lapses

su bsequ en t no nresp ond e r: p ro te in u ria fo r 8 w eeks

In it ia l n o nresp on d er: con tin u ou s p ro te in u r ia d u r in g th e

in it ia l 8 w eek s of th erap y

C o u rse d u r in g su b seq u en t 6 m o n th s

con tinued non re spo nde r: un rem ittin g p ro te inu ria

T a b le 3 . S ix -m on th c la ssific ation s

N o. % of T ota l % of

Subgroup

In itia l re spon de r (3 34 , 92% )

non re lapse r 148 40 .8 4 4 .3

in frequ en t relapser 7 3 20 .1 21 .8

frequen t re lap se r 102 28 .1 30 .6

subsequ en t non re spo nde r I 1 3 .0 3 .3

In itia l no nrespo nder (2 9 , 8% ) 100

w ith con tinu ed non respo nse 1 7

4 .7 58 .6

w ith su bsequ en t re spon se

1 2 3 .3 41 .4

T o ta l 36 3 1 00 100


3/8

S u b s e q u e n t A n n u a l

Classif icat ion:

R are R ela p s e

N o R ela p s e

In fr R e la ps e

F re q R ela p se

69

2 9

2

4 %

N o F u rth e r

Re la p s e

N o R ela p s e

R a re R elap se

:::: ln fre q R ela pse

F req R elap se

F igure 1 . S u bsequ en t c la ssif ic a tion o f 1 48 p atien ts w ho w ere no nrelapsers a t 6 m o n ths . T hree -fo u rth s relap sed rare ly o r n o t a t all. (R a re re lap se

is de fined as no 2 -yr p er io d w ith a t least one re lapse each year.) Th e percen t d is tribu tion of subsequen t ann ua l c lassifica tio ns of the in freq uen t

(In freq o r In fr) re lap se rs is p re sen ted in tabu la r fo rm , show ing , fo r ex am ple , th at the re w ere no re lapse s in 69% o f th e fo llow -u p yea rs . F req ,

frequen t .

Sign if icance of th e E arly C ourse of M C N S 771

c lass ific a tion at 6 m on th s o r w ith h is topa tho bog ic fin d ing s,

excep t fo r in itia l non re spo nd ers , w h o rem a ined n onre spon sive

th roug hou t the ir cou rse s (see be low ).

O f the 1 48 in itia l n on re la ps er s, 16% su sta in ed a n onre lap s-

ing pa tte rn th ro ugho u t the ir en tire cou rse an d 60% re lapsed

rarely , i.e.

,

no 2-y r p eriod w ith at le as t o ne relapse each y ea r

(F igu re 1

).

O nly six in itia l no nrelapse rs becam e frequ en t re-

lap sers , and ha lf o f the ir su bsequ en t annu al a sse ssm en ts w ere

a s n on re la ps er s.

A m o ng th e 73 in itia l in fre q u e n t re la p se rs , 70% becam e

n onre lap sers w ith in 0 .3 to 7 .7 y r (m ed ian , 2 .7 y r) (F igu re 2 ) .

O n ly seven in itia l in frequ en t re lap se rs (9 .6% ) w ere su bse -

q uen tly c la ssified as frequ en t re lap se rs .

O f

th e 102 in itia l fre q u en t re la p s ers , 63% b ecam e no nre -

lapse rs w ith in an av erage pe riod o f 3 y r; and an add itiona l 3 4%

of

in itia lfre q u e n t re la p ser s

becam e in freq uen t re lapse rs w ith in

2 yr (F igu re 3 ) . T h ere w as no s ign if ic an t d ifference in tim e to

n onre lap se o r in frequen t re lapse am on g tho se w ho rece ived

p redn ison e, azath iop rine , o r cyc lop hosp ham ide , sing ly o r in

com b ina tion . T h us, a ltho ugh cycbo pho sph am ide p lus p red -

n isone im p ro ved th e ea rly cou rse fo r freq u e n t r ela p se rs , co m -

p a red w ith p redn isone a lon e (1 ), a ll o f th ese p atien ts d id

eq ua lly w e ll w ith lon g-term m o nito r ing .

T h e pa ttern o f re sp onse fo r the en tire g ro up is show n in

F ig u re 4 . It c an be seen th at the p ropo rtio n o f n o n r e l a p s e r s

g radu a lly in creased , reach in g app rox im a te ly 80 % by 8 yr.


Classif icat ions:

Nevertheless , 5 to 10% o f pa tien ts con tinued to re lapse a t the

tim e of last fo llo w -up exam in a tion , a ltho ugh v e ry few w ere

frequ en t re lap se rs .

F if te en p atien ts w h o w ere in itia lly ste ro id -re spo nsiv e be -

cam e tran sien tly no nre sp ons ive ( i .e . ,o ve r a pe rio d of at le ast 8

w k) d uring the la tter yea rs o f fo llow -up m o nito r ing . T he

6-m o n th c las sific a tion o f the se pa tien ts con sisted o f tw o n o n -

relapsers ,

th ree

in fre q u e n t re la p se rs ,

tw o

fr eq u e n t re la p se rs ,

and e igh t su bsequ en t n o n r e s p o n d e r s . In add ition to p redn isone ,

seven w ere trea ted w ith cycbop hospham id e, one w ith aza th io -

p r im e , an d th ree w ith b o th o f th e se d ru gs; fou r rece ived p red -

n isone a lone . N one b ecam e pe rsis ten tly n onre spo nsive , ex cep t

fo r one frequen t re lapse r w ho rem a ined ste ro id -re sp onsiv e fo r

8 yr bu t u ltim ate ly becam e ste ro id -no nresp ons iv e and ex peri-

enced rena l fa ilu re .

T w en ty -n in e pa tien ts w ere

in itia l n on re sp on de rs

(T ab le 3 ).

F o r 12 of them (3 .3 % of to ta l) , th e p ro te inu ria w as reso lved

w ith in the sub seq uen t 6 m on th s. T rea tm en t o f th e se 1 2 p atien ts

a fte r the in itia l 8 w k of p redn iso ne adm in istra tion inc luded

predn iso ne alo ne (on e p atien t) , p redn iso ne p lus azath iop rine

( tw o p atien ts) , p redn ison e p lu s cyc loph osp ham ide (eig h t pa -

tien ts) , and all th ree d ru gs (o ne pa tien t). I t w as n o t p ossib le to

d ete rm ine w h e the r the ir rem is sions resu lted from co n tinu ed

the rap y or w ere sp on taneou s. H ow eve r, no bene ficia l e ffect

w as o bse rved am o ng n onrespo nd ers in th e tria l o f azath iop rine

(7 ) . In th e tria l o f cycbop hospham id e (1 ) , p ro tein u ria su bsided


4/8

N o R ela p se

ln fr R e la ps e

F re q R ela p s e

34 %

2 8%

32 %

21 %

5 7

00/

U /0

/0

12 %

90

,_,

/0

.

/0

/0

772 Journa l o f the A m erican S oc ie ty of N eph ro logy

S ubsequen t A nnua l

Classif ications:


Classif ications:

N o R ela pse

ln fr R ela ps e

F re q R ela p s e

T ra n sie n t N on -R esp on s e

I n t er m i tt e n t P r o t ei n u r ia

Subsequent Annual

Classifications:

N o R ela pse

ln fr R ela ps e

T ra n sie n t N on -R es p on se

Intermittent Proteinuria

N o R el ap se

lnfreq Relapse

F re q R ela p s e

F ig u re 2 . Su bsequ en t classification of 7 3 pa tien ts w h o w ere in frequ en t re lapse rs a t 6 m o nths. Th e c lassifica tion for 70% w as as a nonre lapser ,

and a sim ila r pe rcen tage o f the fo llow ing annu al c la ssif ica tio ns w as as a n onrelap ser . T h e sub sequen t c la ssific a tions o f in frequen t an d frequen t

re lapse rs a re show n in tabu la r fo rm . In te rm itten t p ro teinu ria re flec ts trans ien t p ro te in uria less than tha t requ ired to d efin e a re lapse .

ear lie r am o ng pa tien ts w h o rece iv ed cycbop hospham id e, com -

pa red w ith those w h o rece ived predn iso ne a lon e , bu t th e p ro -

po rtion s o f pa tien ts fo r w hom the p ro tein u ria w as re so lved

w ere sim ila r in the tw o trea tm en t g roup s. A m ong th ese 12

pa tien ts , o ne w ith n il d isea se d ied o f sep ticem ia 7 m on th s a fte r

on se t ( 1 1

).

S even b ecam e nonre lapsers w ith in 2 .3 y r o f en try .

O ne o the r b ecam e an

in frequen t

r e l a p s e r

a t 3 yr. an d th ree

becam e frequen t re lapsers w ith in 0 .6 to 3 .9 yr (m edian , 1 .5 yr) .

T h e 1 1 su rv iv ing pa tien ts w ere n onrebapse rs fo r 69% of the

fo llo w -up tim e of 6 to 1 3 y r. T he d istrib u tion o f h istopa th o -

lo g ic find in gs d id no t d iffer from tha t o f the rem ainder of the

ser ie s , and non e of th e se p atien ts dev elo ped E SR D .

S ev en teen pa tien ts (4 .7% of to tal) w e re

initial

an d

con t inued

nonresponders .

T h eir age and gende r d istrib u tion s w ere sim ila r

to th ose o f the en tire stu dy p opu la tion . T en o f them respo nded

subseq uen tly , w ith in 0 .5 to 3 .6 y r from en tran ce in to th e tr ia l

(m ed ian , 0 .8 y r) . and d id w e ll, w ith fo llo w -up pe rio ds o f 2 to

1 6 y r. T he ir tre a tm en t inc luded pred n iso ne a lone (on e pa tien t),

p red n ison e p lus azath iop rine (fo u r pa tien ts) , p redn isone p lu s

cy cb oph osp ham ide (tw o pa tien ts) , and all th ree d rug s (th ree

pa tien ts ). A ga in , it w as no t po ss ib le to re la te the ir u ltim ate

rem issions to an y p ar ticu la r fo rm of therapy . T he h is topa tho-

log ic c lass ifica tions inc lu ded n il d isease (th ree p atien ts) , m ild

m esang ia l th ick en in g (on e p a tien t), m ild m esang ia l h yp erp las ia

( th ree p atien ts ), an d focal gb om eru la r o bso le scence (th ree pa -

tients).

T he rem a in in g seven

initial

an d

co n tin ued no nrespond ers

(T ab le 4 ) inc luded on e w ho d ied from pn eum o co ccab pe rito -

n itis w ith in 6 m o nths o f en trance in to the study . T he o ther s ix

deve loped E S R D . O ne o f them respo nded to p redn isone from

tim e to tim e bu t u ltim ately re tu rned to a n onresp ond ing s tate

an d exp erienced E SR D b y y ea r 9 o f fo llow -u p m onito rin g . T he

o the r f ive m a in ta ined no nrespon sive cou rse s th roug hou t. H alf

o f the p atien ts rece ived cycbop hospham id e, an d ha lf receiv ed

p redn ison e a lon e .

F o llow -up b io psie s w ere p erfo rm ed at th e d isc re tion o f the

p atien ts phy sic ian s and w ere ava ilab le fo r on ly 65 pa tien ts.

C om p ared w ith the b aselin e read in gs, the c las sific a tions o f the

fo llo w -up b iop sie s , pe rfo rm ed by the IS K D C pa tho log ists ,

w e re d is co rd an t fo r 19 (2 9% ). F or 13 the b iop sy d iag nosis

chan ged to foca l gbom eru losc le ros is . N ine of the 1 3 con tinued

to do w e ll, w he rea s the o th er fou r (see ab ove ) deve loped

E S R D . T he fo u r pa tien ts w h o d ev e loped E S R D an d had fob -

low -up b iop sies sho w ed foca l g lo ba l g lom erub osc le ro sis o r

foca l segm enta l g lom eru loscle ros is (F S G S ); o ne of them la te r

d ev e loped p ro life ra tive g bom erub oneph ritis (T ab le 4 ).

Discuss ion

A m o ng th e d ifficu lt ta sks fac ing clin ician s trea ting ch ild ren

w ith M C N S are pred ic tin g bo th th e in itia l and subsequen t

cou rses and de te rm in in g th e progno sis. T h ese eva lua tion s are


5/8

1 )0 /

/0


Classif ications:

N o R e la p s e

ln fr R ela ps e

F re q R e la p s e 4

T ra n s ie n t N o n -R e s p o n s e 1

In te rm itte n t P ro te in uria

4

N o R ela p s e

l n f r eq R e l a ps e

- T ra ns ie nt N on -R es po ns e

S ign ific anc e of the E ar ly C o urse of M C N S 77 3


Classif ications:

59 %

N o R e la p s e 91

32 %

In fr R ela pse

9

F ig ure 3 . S ubsequen t c lass if ica tion of 102 pa tien ts w ho w ere frequen t

re lapse rs at 6 m on th s. T w o-th irds w ere cla ssif ied as non re lapse rs , and

91% of th e fo llow ing an nua l c la ssific a tion s w ere a s no nrelapsers .

N o te the sm all pe rcen tag e o f pa tien ts m ain ta in ing a frequen tly re lap s-

ing co urse.

used in co unse ling pa ren ts an d in m ak ing the rapeu tic d ec i-

s ions .

T he go als o f the IS K D C w ere to co ndu c t con tro lled c lin ica l

the rapeu tic tria ls and to id en tify ea r ly c lin ica l cha rac te ris tics

tha t p red ic t th e lo ng-te rm course . A s p rev io usly repo rted , few

clin ica l cha rac te ris tic s co rrela ted w ith h is topa tho bog ic ch arac-

te ris tic s and ou tcom e, excep t tha t in itia l s tero id -resp ons iv eness

pred icted M C N S w ith a h ig h degree o f accu racy (3 ,4 ) . S tero id -

n onre spo nsiveness w as h istopa tho bog ically n onsp ec if ic bu t in -

d icated gb om eru la r d iseases w ith p oo re r ou tco m es than th at

w ith M C N S . U nde te rm ined in the in itia l s tud ie s w ere the

ind ica to rs o f lo ng-te rm o utco m e w ith M C N S .

T h e curren t rep o rt is b ased on the o n ly large p ro spec tive

s tudy of an u nse lec ted , p rev io usly un trea ted se ries o f ch ild ren

w ith recen t-on set M C N S and ren al b io psy a t en try . B ecau se

rena l b iop sie s a re no lo nge r rou tine ly pe rfo rm ed fo r ch ild ren

th oug h t to h av e M C N S (o r, in ope ratio na l te rm s , w h o h av e

s te ro id -resp ons ive d is ea se ) , it is un like ly tha t such a stu dy w ill

ev er be d up lica ted .

O n th e basis o f p re lim in a ry da ta (3 ) , pa tien ts w ere c la ssif ied

acco rd ing to the ir cou rse du rin g th e 6 m on ths a f ter th e in itia l

8 -w k p eriod o f the rapy . B ecause o f the va riab ility in the

p atte rns o f re lapse s, a m e thod w as dev ised to cha rac te riz e the

sub sequen t cou rses. T h is app ro ach w as design ed to ig no re

trans ien t chang es and to base the lo ng-te rm an alyses on a

respon se /re lapse pa ttern (non re lapse r, in frequ en t re lap se r. etc . )

tha t p e rsis ted during a pe riod o f at le a st 2 con secu tive y r. T he

approach w as va lida ted by the find ing th at th ose w h o w ere

non re lapse rs fo r 2 consecu tive y r con tinued th e ir non re laps ing

cou rse s m ore than 86% of th e tim e , reg ard le ss o f the ir 6 -m o n th

c lass if ica tion . In con trast, those w ho w ere frequen t re lapse rs

fo r 2 co nsecu tive y r w ere non rebapsers on ly 3 4 to 47 % of the

tim e. Pa tien ts thu s can b e reassu red tha t a no nre lap sing co urse

fo r 2 co nsecu tive y r au gurs an ex cellen t p rogn osis , in ag ree -

m en t w ith the obse rva tion of H ab ib

e t a . (12 ,13). T h is is in

con tra st to th e f ind ings o f L ew is

et a .

(1 4 ) , w ho co nc lud ed th at

a 4-yr period w as req u ired to be pred ic tive of a subseq uen t

non re lapsin g co urse.

T hese ana lyses confirm ed an ea rly im pres sion (3 ) tha t the

6 -m on th c las sific a tion is h igh ly p red ic tive o f the sub sequen t

course . T hree-fou rths o f in itia l respond ers w ho rem ain ed in

rem iss io n dur in g the subsequen t 6 -m onth period (40% o f th e

en tire ser ies ) eithe r con tinued in rem iss io n th rough ou t th e ir

en tire co urse or re lapsed ra re ly . T hus , th is ea rly non rebapsing

pa ttern aug urs an exce llen t p rogn osis fo r ap pro x im a te ly on e -

th ird o f ch ild ren w ith M C N S .

In con tra st, in itia l re lapse rs ach ieved a no nrelaps ing course

on ly a f ter an ave rag e o f 3 y r . T he frequ en cy of sub sequen t

re lap se s an d the len g th o f tim e to ach ieve a n onre lap sing sta te

d id n o t d iffe r be tw een in itia l in frequ en t and frequ en t re lapse rs .

in con tras t to th e im press ion one ga the rs fro m the litera tu re.

T h e failu re to fin d such a d iffe rence can no t be exp lain ed b y the

treatm en t o f freq uen t re lapse rs w ith d ru gs o th er th an pred -

n ison e, becau se the tim e fram e fo r frequ en t relap sers to be -

com e in frequen t relapsers o r n onre lap sers d id no t co rrela te

w ith the d rug reg im en used .

T h e 80 % rem issio n ra te a t 8 y r (F ig u re 4 ) is so m ew h at be tte r

th an tha t repo rted in o th er se rie s , rang ing from 66% at 9 y r to

95 %

a t 1 5 to 2 0 yr (12 ,1 5 -1 7 ) . T h is m igh t be exp la ined by th e

en ro llm en t o f p atien ts be fo re b iopsy or treatm en t, av o id in g th e

b ias o f se lec ted re fe rra l o f pa tien ts w ith d isease tha t is d ifficu lt

to m an ag e.

M os t p atien ts w h o fail to re sp ond to an in itia l cou rse o f

p redn ison e u ltim a te ly atta in a fu ll rem ission , independ en t o f

th e trea tm en t reg im en . N eve rthe le ss , an in itia lly n onre spo nsive

sta te g rea tly inc rea se s the r isk o f po or o u tcom e . D esp ite the

sm all n um b er o f in itia l n onre spon de rs , un rem itting p ro te inu ria

d u ring th e in itia l 8 w k of p red n iso ne the rap y w as fo llo w ed by

p ro gress ion to E S R D in 21% . In ad d ition , 9 o f the 10 d ea ths

o ccu rred in p atien ts w ho w ere in itia lly no nrespon sive to p red -

n isone o r w h o re lapsed d uring the firs t 8 -w k p erio d of the rapy .

O ne-th ird o f 1 7 pa tien ts w h o h ad u nrem ittin g p ro te inu ria du r-

ing the in itia l 8 w k o f th erapy an d the su bsequ en t 6 m on ths

p rog re ssed to rena l fa ilu re, m ak ing th is an ev en m o re om in ous

p red icto r o f ou tcom e.

A s reported in 198 4 , a to ta l o f 10 p a tien ts in th is se ries d ied

w ith in 2 yr of d isease onse t (1 1 ), in clud in g fo ur of the p a tien ts

rep o rted he re . N ine o f the 10 re sp ond ed in itially on ly b rie f ly o r

no t at a ll. T he add itio na l fo llo w -up m onito rin g co nfirm s the

ea rlie r o bse rva tion th at ea r ly no nresp onse m arks a g ro up o f


6/8

7 74 Jou rna l of th e A m e rica n So cie ty of N eph ro bog y

10 0

(1 ) 80

U )

60

0

0

c:

40

a)

C .)

1.

ci )

Q 20

0

1 2 3 4 5 6 7 8 9 10 11 1 2 13 14-18

Year of Follow-up

F

L

Nonre lapse r

F re qu en t R ela ps er

In fre qu en t R ela ps er

LI

O th e r

F igure 4 .

A n nua l c la ssif ica tio n o f pa tien ts acco rd in g to re spo nse ca tego ry , d em on stra ting the p rog re ssiv e dec line in the in freq uen t an d

frequ en tly re lapsing categ o rie s .

T a b le 4 .

C lin ica l da ta an d co urse fo r th e sev en in itia l and con tinued no nre sp ond ers w ho deve loped E S R D or d ied

A ge at

O nset (y r)

G end e r A nnu al C la ssific a tion

In i t ial

Patho logy

F ollow -u p P atho bog y/

Y ea r

T o ta l Y ea rs

o f D a ta

3 .6 M

N ev er resp ond ed

F G O F G G S /0 .25 , F S G S /l,

M C G N /5 , D P G N /5

8

i .6 F O ccasion al re spo nses

fo llo w ed by

n onre spo nsive cou rse

FT C

9

1 .6

F

N ev er re spon ded ; d ied F T C

2

1 4 .6 M

N ev er re spon ded ; d ied F T C

1. 4

5 .6 F

N ever responded N IL FS G S /3

3

2 .6 M N ever respon ded

F G O FG G S w ith 8

tub u la r a troph y /3

3 .0 M N eve r re spon ded ; d ied from

pneum ococcal p er iton itis

N IL 0 .5

(4

N IL , n il d isea se ; F G O , foca l g lom eru la r o bso lescence ; F T C , fo cal tubu lar chan ges; F G G S , foca l g lo ba l gbo m eru bosc le ro sis ; M C G N ,

m esang ioc apillary gb om eru bon ep hntis; D PG N . d iffu se p roliferativ e g lom erubo nep hri tis.

S ee refe rence 1

1.

pa tien ts at risk o f ea rly death . T he death rate o f 2 .5% repo rted

he re is on th e lo w end of the ran ge of

2. 5

to 6 .7 % reported by

o the rs , w he rea s th e ren al failu re ra te is w ith in the 0 to 3 .5%

repo rted in o the r s tud ie s (12 ,14 -1 6 ,18 ) .

A lth oug h th is s tudy d id no t ad dres s th e rela tion sh ip be tw een

M C N S an d F S G S , the find ing o f fo ca l g lom eru la r le sio ns in 1 3

(2 0% ) of 65 seco nd b iops ies m ay re flec t the o pera tion of

com m on p ath ogene tic m echan ism s in the dev elo pm en t o f the se

tw o h isto pa thob og ic pa tterns (1 9 -22 ). F S G S in n ephro tic ch il-

d ren is n o t un ifo rm in h is topa tho bog ic seve rity o r c lin ica l onse t,

cou rse , and re spon siveness to ste ro id the rapy , and so m e of the

d iffe rences m ay rela te to the va riab le seve rity o f g iom eru la r


7/8

S ig n ifican ce of the E arly C ourse of M C N S 775

in ju ry (2 0 ) . A p prox im ate l, 3 0% of n ep hro tic ch ild ren w ith

in itia l F S G S respon d to s tero id therapy , and m ost o f them

con tin ue to do w e ll (1 9 ). N ine (69% ) of 1 3 ch ild ren w ith la te

F S G S and g lob al gb om eru bo scle rosis , af te r in itia l M C N S , d id

w ell. T hese gbom eru la r lesions m ay represen t a con tinu um

ra the r than sepa rate d is ea se en titie s .

C a re fu l docum en ta tion o f the ea r ly co urse o f p a tien ts w ith

M C N S can h elp in iden tify in g th ose at h igh est r isk o f a p oor

ou tco m e , nam e ly in itia l non re sp ond ers . C lose obse rva tion of

these pa tien ts is needed an d m ore in tens ive therapy m ay be

w arran ted fo r pa tien ts w ho a re in itia l and co n tinu ed no nre -

sp ond e rs a t 6 m on ths, becau se m o re th an one -th ird o f them

m ay eventu ally dev elo p E S R D . S uch the rap y m ig ht invo lv e the

u se of cycboph osp ham id e, cy clospor in , o r o ther the rap ies . C y -

cb ophospham ide w as found to ind uce rem ission in sev eral

u ncon tro lled and tw o con tro lled stud ies ( 1, 6 ,23 -26 ) , b u t th e

IS K D C tria l (1 ) , com parin g th is d rug w ith p redn ison e, sho w ed

th a t cycbop hosp ham id e on ly sh orten ed the tim e to re spo nse an d

d id no t chang e th e p rop ortion o f re spo nde rs . C y cb osp orin has

sh ow n som e e ffic acy in unco n tro lled stud ies (1 7 ,26 -30 ). In

tw o rep orts , N iau de t and co-w o rk ers (2 7 ,28 ) repo rted com ple te

rem ission in fiv e of e igh t pa tien ts and five o f six pa tien ts

trea ted w ith cycbo spo rin and predn isone , bu t n o t w ith cy cbo-

spo rin a lone . T he C ollabo ra tive G ro up of the F rench S oc ie ty o f

N ephrob ogy (3 0) , s tu dy in g ad u lts , rep o rted rem issio n in 14 of

21 p atien ts w ith s tero id -resis tan t M C N S (3 0). A lthoug h there

is no un iv ersa lly accep ted form of therapy for th is g rou p of

p atien ts , the o bse rv atio ns sug gest tha t th ese tw o d ru gs m ay be

o f b en ef it.

In conc lus ion , 9 5% of ch ild ren w ith M C N S d o w ell, w ith a s

m any as one -th ird m a in ta in in g a n onre lap sing or ra rely re laps-

ing s ta te th rou ghou t the ir en tire course. D esp ite these ov erall

exce llen t ou tcom es, 4 to 5% of pa tien ts m ay d ie fro m co m pli-

ca tions o r p rog re ss to E S R D .

A c k n o w l e d g m e n t s

P ar tic ipan ts in the IS K D C w ho co n tribu ted to th is study w ere as

fo llow s: C en tra l O ffice (N ew Y ork): H .L . B arn e tt and C M . E deb-

m ann , Jr . (D irec to rs ), I . G re ife r (A sso cia te D irecto r) , D I. G o ld sm ith

and A . S p itze r (D irecto rs o f C oo rd ina ting C en ter ), P . T arsh ish (D ata

C o ord ina to r), G . L ad dom ad a (P ro jec t A d m in istra to r) , and J. M assa ro

(S ecre ta ria l A ssis tan t); R eg io na l C oord ina to rs : lB . H o uston , R H .

K uijten , an d L B . T rav is ; D irec to rs o f Partic ip a ting C en ters: G . A rn eil

(G lasgow ), 0 . K ob ay ash i (T oky o). H . S ta rk (Is rae l), B . G au th ie r

(N ew Y o rk-D ow nsta te ), Y . T sao (H ong K o ng), B .S . A ran t (M em -

ph is ). G . G ord ilb o-P . (M exico C ity ). A .B . G ru sk in (P h ilad e lp h ia) . N .

H allm an and J. V ilska (H els ink i) , lB . H ousto n (M anch este r , U n ited

K ing dom ), R H . K uijten and H .A .W .M . T id dens (U trech t and A m -

ste rdam ), E . L eum ann (Z urich), I.E . L ew y an d M . K ap lan (N ew

Y ork -C orn ell) , J .-G . M ong eau (M on trea l), M i. S cho en em an and R .

W eiss (N ew Y ork-A lbert E inste in ), 0 . O e tlike r (B ern ), K .O . Sh arer

(H eid elberg ), I. S trauss (M iam i), L B . T rav is (G alves ton), C D . W est

(C inc inna ti), and R .H .R . W hite an d the ba te M . W in terborn (B irm in g-

ham , A lab am a) ; C onsu ltan ts : J. B erns te in , I. C hu rg , R . H ab ib , and

R .H .R . W hite (P a tho logy ) and I. F e rtig . K . F reem an , K . S u llivan . F .

H sieh , SM . W asserthe il-Sm olle r, and IN . T ob in (B iosta tistics ).

T h is w ork w as su pported by N ationa l Ins titu tes o f H ea lth R esearch

G ran t l-R O I-A M 18 234 , the N a tiona l K idney F ou nda tion of N ew

Y ork , th e K idn ey D isea se Institu te o f the S ta te o f N ew Y ork , the

W am

k e au m o n t l- io sp a ia t oog y i oJc cts

u f lC1. t c

io n Iatk

F ound ation . the N ationa l K idn ey R esearch Fo unda tion (U nited K in g-

d om ), an d the K id ney F ou nda tion of th e N e the rlan ds.

References

1

.

In terna tion a l S tudy of K idney D isease in C hild ren : P ro spec tive .

con tro lled tria l o fcy cb opho sph am ide therapy in ch ild ren w ith th e

n ephro tic synd rom e: R eport o f the In te rna tio na l S tudy of K idney

D isease in C h ild ren . L ance t 2: 4 23-4 27 , 1974

2.

In terna tion a l S tudy o f K id ney D isease in C hild ren : P rim ary

n ephro tic syndrom e in ch ild ren : C lin ica l sign ificance of h is -

topa thobo g ic varian ts o f m in im al change and o f d iffuse m esan-

g ia l hyperce llu la rity : A repo rt o f the In te rna tio na l S tudy of

K idney D isease in C hild ren . Kidne m t 20 : 765-771 , 198 1

3 . I nter na tio na l S tud y of K id ney D isea se in C h ild ren : E a rly iden -

tifica tion of f requ en t re lapse rs am o ng ch ild ren w ith m in im a l

change neph ro tic synd rom e: A repor t o f the In terna tio na l S tudy

of K idney D isease in C hild ren . J P ed ia tr 101 : 514-5 18 , 1982

4 . In terna tion a l S tu dy of K idney D isease in C hild ren : N ep hro tic

synd rom e in ch ild ren : P red iction of h istopa tho bogy fro m clin ica l

an d labo ra to ry charac te ris tic s at tim e o f d iagno sis: A report o f

the In te rna tiona l S tud y o f K id ney D isease in C hild ren .

K id n e y h it

1 3 : 1 5 9 1 6 5 1 9 78

5. In te rn ationa l S tu dy of K idney D isease in C hild ren : N ep hro tic

synd rom e in ch ild ren : A rando m ized trial com paring tw o pred -

n isone reg im ens in ste ro id -respon sive pa tien ts w ho re lapse early :

R ep o r t

of the In te rna tiona l S tudy of K id ney D isease in C hild ren .

J P ed ia tr 95 : 239-2 43 , 1 979

6 . In te rn ationa l S tudy of K idney D isease in C hild ren : T he prim ary

n ephro tic syndro m e in ch ild ren : Iden tifica tio n o f pa tien ts w ith

m in im al change nephro tic syn drom e from in itia l resp onse to

p redn iso ne : A rep ort o f the In te rn a tion al S tudy o f K idney D is-

ease in C h ild ren . J P ed ia tr 98 : 561-5 64 , 1981

7 . A bram ow icz M , B am ett H L , E de lm ann C M Jr. G re ife r I , K oba-

y ash i 0 , A rn e il G C , B arro n B A , G o rd ilbo-P G , H allm an N ,

T iddens H A : C ontro lled tria l o f aza th iopr in e in ch ild ren w ith

n ephro tic syn drom e: A report fo r the In te rna tiona l S tudy o f

K idney D isease in C hild ren . L ance t 2 : 959-9 61 , 197 0

8 . S chw ar tz G i, H aycock G B , E de lm ann C M Jr. S p itzer A : A

sim ple es tim ation of g lom eru la r filtra tio n ra te in ch ild ren derived

fro m b ody leng th and p lasm a crea tin in e. Pediatr ics 58 : 259 -263 .

1976

9 . C hurg I , H ab ib R . W h ite R H R : P a tho lo gy o f th e neph ro tic

synd rom e: A report fo r th e In te rna tio na l S tud y o f K idney D is-

ease in C hild ren . L ance t 1 : 1 299- 1 302 . 1970

10 . Z ar JH : B ios ta t i s t ica A na lys is , 2nd E d ., E n g lew oo d C liffs , N J,

P ren tice -H all, I 9 84

1 1

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