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694 PED IATR ICS Vo l. 83 N o . 5 M ay 1989

Da ily S ing le -D ose and D a ily R educed -D oseP redn isone The rapy fo r C h ild ren W ith th eN eph ro tic S ynd rom eB a rry L . W arshaw , M D , and L eo na rd C . H ym es , M DF rom the D epa rtm en t o f P ed ia trics , Em o ry U n ive rs ity S choo l o f M ed ic ine , A tlan ta

ABSTRACT . M o s t cu rren t re fe ren ce sources recomm endtha t in itia l the rap y fo r m in im al le sion n ephro tic sy n -drom e cons ist o f p redn isone , 60 m g/rn 2 p er 24 hours or 2m g /kg pe r 2 4 hou rs, g iv en in d iv ided doses, an d tha t th isreg im en b e repeated fo r each re lap se . T he n eed for d i-v id ed -d ose da ily -adm in iste red p red n iso ne is p red icatedon anecdo ta l ob serva tions tha t sing le -do se da ily adm in-is tratio n is no t e ffectiv e. B ecause sin g le -d ose da ily -ad -m in istered an d red uced -d ose da ily -adm in is tered p redn i-son e h as b een used to trea t th is con d ition fo r sev era lyears , ex perien ce w ith these reg im ens in nephro tic ch il-then w as ana lyzed . Fo rty -one pa tien ts w ere s tu d ied , in -c lud ing 22 trea ted from the on se t o f the ir d isea se . O fthese 22 , 1 7 (7 7% ) responded to sing le -d ose da ily -adm in-is te red p redn isone (2 m g /kg); af te r subseq uen t b iospy ,each of th e no nre sp ond ers p rov ed to have le sio ns o th erthan m in im a l change d isease. The m ean re sp onse tim ew ith sin g le -d ose d aily -adm in iste red p redn isone (9 .6 daysfo r trea tm en t o f the in itia l o nse t o f neph ro tic sy ndrom eand 11 .1 days fo r trea tm ent o f re lapses) w as com parab leto th a t p rev io usly rep orted w ith d iv ided-dose reg im ens.In 14 pa tien ts w ith frequen t re lapses, a s ing le reduced-do se da ily -adm in is tered dose o f p redn isone (0 .2 to 1 .5m g /kg /d ) successfu lly ind uced rem ission s in 5 5 of 63re lapse ep iso des. It is conc luded tha t a s ing le m o rn ingdo se o f p red n iso ne e ffec tive ly indu ces rem is sion in ch il-then w ith m in im a l le sion neph ro tic sy ndrom e. Am ongse lected p atien ts w ith freq uen t re lapse s, add itio na l ste -ro id spa rin g m ay be ach iev ed by th e u se o f th is reg im enw ith red uced doses d uring trea tm en t o f re lap se s. Ped ia t -rics 1989 ;83 :694-699 corticoste ro id , p red n ison e , n ep hro ticsyndrome .

Co rticos tero ids a re e ffectiv e in the trea tm en t o fm inim a l le s ion neph ro tic synd rom e and rep resen tth e m a instay of cu rren t the rapy . D esp ite the ir e f-ficacy as in itia l th erapy to induce rem iss ion , how -

Rece ived for pub lica tion D ec 8 , 1987 ; accep ted M ay 20 , 1988 .R eprin t requests to (B .L .W .) D epartm en t o f Ped ia tric s, Em oryU niversity Schoo l o fM ed icine , 2040 R idgew ood D r, N E , A tlan ta ,G A 30322 .PED IATR IC S (ISSN 0031 4005). C opy rig h t 1989 by theAm erican A cadem y of Ped ia tric s.

eve r , s tero id reg im ens have n o t b een iden tified tha tca n preven t sub sequen t re lapse once treatm ent isd iscon tinu ed . A cco rd ing ly , i t h as b ecom e appa ren ttha t treatm ent w ith stero ids should b e reg a rded aspa llia tiv e rath e r than cu rative .2 97

M ost refe rence so urce s cu rren tly recom m endtha t in itia l the rapy fo r m in im a l le sion n ephro ticsyndrom e con sis t o f predn isone , 60 m g/rn2 per 24hours o r 2 m g/kg pe r 24 h ours, g iven in d iv id eddo ses fo r 4 w eeks2 9 35 and tha t th is reg im en berepeated fo r each relapse ep isod e , de fin ed as recu r-ren t pro teinu ria (qu alitative d ip stick v alue 2+ org rea ter) fo r th ree con secu tive days. B ecause 4 0%o r m o re o f pa tien ts w ith m in im a l les io n neph ro ticsyndrom e have frequen t re lapses , th e po ten tia l fo rs ig n ifican t s te ro id tox icity is w ell recogn ized .

A lth ough som e have obse rved th at p redn isoneadm in is tered as a sin g le d aily -adm in istered do se isno t effec tive in induc ing nephro tic synd rom e re-m ission ,6 7 com para tive da ta a re no t ava ilab le todocum ent the need for d iv ided da ily do ses , no r h asthe quan tity o f the da ily do se n ecessa ry to inducerem iss io n been ana lyzed . S im p lified dosing sched-u le s w ou ld h av e obvious advan tag es w ith re spec t tocom plian ce and conven ien ce, and low er to tal do sesm ight reduce the lik elihood of s te ro id tox ic ity andth e a ttendan t need fo r cy to to x ic drug therapy .

W e have used sin g le -do se d aily -adm in iste red an dredu ced-dose d aily -adm in is tered p redn isone reg i-m en s fo r the m anagem en t o f n ep hro tic synd rom efo r seve ral y ears . In th is report , w e have ana lyzedou r experien ce w ith th ese reg im en s in neph ro ticch ild ren and com pared the re sponse tim es to tho sein p rev iously p ub lish ed tr ia ls in w h ich d iv ided -do sedaily -adm in istered predn ison e reg im ens w ere used .

MATER IA LS AND METHODSW e retrosp ec tiv ely rev iew ed the reco rd s o f a ll

ch ild ren w ith n ep hro tic syn drom e in ou r ca re a t the

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A R T I C L E S 69 5

Emor y C lin ic o r th e H enrietta E g le ston H o sp ita lfo r Child ren du ring the 3-y ea r pe riod from 1984through 1986 . T he d iagno sis of neph ro tic synd rom ew as m ade on the b asis o f p ro tein uria (d ip stickurinary pro te in concen tration 2+ or greate r fo r a tleas t th ree consecu tive days), h ypoa lbum inem ia(se rum album in concen tration

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696 PREDN ISONE AND NEPHROT IC SYNDROM E

T A B L E 1 . S ta n da rd (2 m g/kg /d ay) S in g le-D ose D aily P redn iso ne T rea tm ent R esp onseTreatm en t N o. of Patien ts N o. of Episod es M ean R espon se N o. of Resistan t H isto log ic F in din gs in R esis tan t

G roup Responding/TotalN o. of P atien ts

(% )Responding/TotalN o. of Episod es

(% )Time

( d [ ra ng e] )Patien ts /TotalN o. of P atie nts

(% )Patients

(N o. o f P atie nts )

In itia l O n se t 17 /22 (77 ) 1 7 /22 (77) 9 .6 (4 -23) 5 /2 2 (2 3) F oca l segm enta l g lom eru loscle ros is,(2) , 1gM m esang ia l p ro life ra tiv eg lom eru lonephr itis (2 ), m esan -g ia l p ro li fe ra ti ve g lo m er ul on ep h-n tis (1 )R e lapse 31 /32 (97 )* 81 /83 (98) 11 .1 (5 -26)t 2 /3 2 (6 )* M in im al lesion nephro tic sy n-d rom e (1), 1 gM m esang ial gb-m eru lo nephritis (1 )

* One pa tien t w ho in itia lly responded to treatm ent fo r re lapse la te r ex perienced a resis tan t re lap se and is coun ted as bo th respond inga nd r es is ta nt .t Calcu la tion of response tim e for relapses w as based on da ta from 37 re lapses inv o lv ing 18 pa tien ts from w hom suffic ien t d e ta ilsw er e a va il ab le .

pe riod . R e lapses w ere , th ere fore , ob serv ed in a to ta lof 16 pa tien ts , 13 o f w hom exp erienced th ree o rm ore ep iso des du rin g the f irs t yea r. N in e p atien tsw ith frequen t re lapses receiv ed cy cbopho spham ideor ch lo ram bu cil b etw een 5 and 51 m onths fo llow ingonse t. C y to tox ic the rapy w as p re sc rib ed fo r recu r-ren t an asarca in one pa tien t, s te ro id tox icity in f ive ,an d stero id re sis tance (la te no nre sp onsiv eness) intw o . B io psy find in gs in th e b ate non re sp ond ersshow ed 1gM rnesangia l p ro lifera tiv e gbom erubo -n ephrit is in one and m in im al ch ange in the o the r.C a ta rac ts d ev elop ed in only one patien t. L inearg row th rem a in ed no rm a l in 13 of 15 pa tien ts fo rw hom da ta w ere av ailab le du ring a m ean fo llow -upin te rva l of 3 .4 years (range 9 m on ths to 8 yea rs);tw o p atien ts expe rien ced transien t dece lera tion o fg row th . R enal fun ction rem ained norm al a t thetim e of fin al fo llow -up in all pa tien ts .T rea tm en t o f N eph ro tic S ynd rom e R elapses

N ine teen pa tien ts w ere re fe rred fo r m anagem en tof re lapsin g nephro tic synd rom e. D e tails o f the irin itia l m anagem ent va ried , bu t a ll had prev iouslyre sponded to predn ison e w ith the ex cep tion of on eboy w ho h ad re spo nded on ly pa rtia lly to d iv ided -dose d aily the rapy . C yto tox ic the rapy w ith chbor-am buc il o r cycbophospham id e had been adm in is-te red to eigh t of these p a tien ts prio r to refe rral . O fth e 19 , 17 w ere trea ted by u s on at b east o ne o ccasionfo r nephro tic syndrom e re lap se w ith stand ard sin -g le -dose d aily -adm in iste red p redn isone . T he re -m ain ing tw o rece iv ed on ly reduced sing le -d osed aily -adm in iste red trea tm en t. A ll pa tien ts w ith theexcep tio n o f th e one w ho had prev iously been re-s is tan t re sponded to treatm ent. W e eva lua ted theresp onses of a ll re lapse ep iso des am ong the 16re sponding pa tien ts in th is group plus 16 o f the 17resp ond ing pa tien ts w hom w e trea ted from the on-se t o f d isease and w ho subsequen tly had re lap ses(T ab le 1). A to ta l o f 81 re lapses w ere successfu lly

tre a ted , w he rea s th e ep iso des o f tw o pa tien ts w ereres is tan t (late nonresponders). S uffic ien t d e tailsw ere ava ilab le to de te rm ine the response tim es fo r37 relap ses invo lv ing 18 pa tien ts . T h e m ean re -spon se tim e fo r each patien t hav ing m o re than onerelapse w as calcu lated , and th is v a lue w as used tocom pu te the m ean tim e fo r th e en tire g rou p . T hus ,w e foun d a m ean re spo nse tim e fo r trea tm en t o frelapse o f 11 .1 d ay s, w ith a range o f fiv e to 26 days.

In 1 4 ste ro id -sensitive pa tien ts w ith freq uen t re-lap ses , w e a ttem p ted to induce rem iss ion s w ithreduced sing le -do se da ily -adm in is te red p redn isone .A s prev iously d esc rib ed , redu ced -dose the rapy w asused du ring ea rly re lapse a fte r p ers is ten t p ro te in -uria w as do cum en ted b u t p r io r to th e on se t o f sev ereed em a ; m o reove r, the reduced-do se reg im en w asab andoned in favor of h igh er standa rd predn ison edo ses if ed em a developed or p rogressed o r if p ro-te inu ria did not re so lv e w ith in 14 days. A ccord ing ly ,the failu re rate fo r the reduced -do se reg im en w ash ighe r, w he reas the m ean response tim e w as sho rterthan fo r stand ard d oses. E ach of the 14 ste ro id -sensitive pa tien ts w ith re lapses re sponded on a tlea s t on e occasio n to redu ced -dose p redn isone . O f63 re lap se ep isod es, 5 5 w ere successfu lly treatedw ith a m ean p redn ison e dose o f 0 .8 m g/k g (range0 .2 to 1 .5 m g/kg). T he m ean respon se tim e, ca lcu-b a ted on the basis o f 36 ep isod es invo lv ing 12 pa -tien ts from w hom suff ic ien t de ta ils w ere ava ilab le ,was 7.3 days, w ith a range o f th ree to 14 day s. T here sponses to va rio us doses a re d elineated in T ab le2 . N o c lear rela tio nsh ip w as appa ren t be tw een th epredn ison e dose and e ith er the re spon se tim e or thesu ccess ra te oftreatm ent. F ive pa tien ts , al l o f w homh ad success fu l re sp onses to redu ced -d ose trea t-m ent, also experienced redu ced-dose trea tm en t fa il-ures invo lv ing a to tal o f e igh t re lapse s. T hese pa -tien ts w ere rece iv ing a m ean pred n ison e do se o f 0 .7m g /kg (range 0 .2 to 1 .2 m g /kg) fo r a m ean dura tio no f e igh t days (range th ree to 1 4 d ay s) p rio r to

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A R T I C L E S 697

con ve rs ion to h igh e r do ses , to w hich all p atien tssubsequ en tly re spo nded . F ou r pa tien ts fa iled to re -spond to redu ced-dose trea tm en t on one occasioneach and one on four o ccasio ns . T he batter p atien t,w ho had frequ en t relap ses of neph ro tic syndrom edesp ite th ree p rev iou s course s o f cy to tox ic d rugthe rapy , h ad becom e m arked ly cush in go id duringtrea tm en t o f re lapses w ith stand ard p redn ison edo ses. R em iss ions w ere su ccessfu lly in duced on 14occasion s w ith d aily reduced doses . W hen a reg im enof c on tinuo us bow -dose a lte rna te-d ay p redn ison ewas used as m ain tenance the rap y an d reduced -dosedaily p redn ison e w as u sed fo r relapses , cu sh ingo idchanges w ere m arked ly am e lio rated and linea rg row th p rese rved desp ite p ro longed ste ro id depend -ence (h eig h t w as in the 75 th to 90 th p ercen tile a t 5yea rs o f age , d ec reased to th e 50 th by 8 yea rs , andrem a in ed stab le in the 50 th p e rcen tile th rough 13yea rs of ag e).DISCUSS ION

W e found th at s in g le -do se d aily -adm in is te redp redn isone th erapy is e ffec tive for th e in itia l m an -agem en t o f nephro tic sy ndrom e in ch ild ren . Am ongth e 22 pa tien ts trea ted from the o nse t o f the ird isease, none o f th e five w ho fa iled to respondp rov ed to h av e m in im al les io n pa tho log ic find ing sf rom subsequen t b iop sy . H is tobog ic fin d ings fromthe le s ion s of each of th e re s is tan t p atien ts m di-cated a bow lik elihood o f s te ro id re sponsiv en ess ,0and the ir subsequen t re s is tan ce to po ten t im m u -nosuppressive agen ts suggests tha t failu re to re-spond to stero ids w as not lik e ly reb a ted to thesin g le -do se da ily -adm in is te red reg im en . T he m eanrespon se tim e a t d isease onse t w as 9 .6 d ay s andtha t fo r trea tm en t of sub sequen t re lapses w as 11 .1day s. T hese re sp onse tim es com pare favo rab ly tothose prev iously reported for da ily d iv ided-dosep redn isone reg im ens. T he In tern ation al S tudy o fK idn ey D isease in C hild ren reported a m ean re-sponse tim e a t d isease onset o f 13 .3 d ay s and fortre atm en t o f re lap se 11 .4 day s. It is th us apparen ttha t the sin g le-dose d aily adm in is tra tion p ro to co l

induces rem iss ion s in a sim ila r tim e fram e co rn-pa red to da ily d iv id ed doses and offe rs prac tica ladvan tages in te rm s of com plian ce and conven-ience. W hile adm in is trat ion o f the en tire da ily dosein th e m orn ing a lso has po ten tial fo r red uced tox -ic ity ,2 stero id sid e effec ts are c learly no t obviated .A contro lled study is requ ired to d e term in e w he the rs te ro id tox ic ity is b ess seve re th an w ith d iv ided-doseprotocols .W e a lso obse rved tha t reduced sing le d aily pred-n ison e do ses as low as 0 .2 m g /kg /d w ere o ftene ffec tive in induc ing rem iss ion of ea rly re lapse ofn ep hro tic syn drom e (ie, pe rs is ten t p ro te inu ria w ithm in im a l to n o ed em a). In a m in ority o f relapses(eig h t o f 63), how ever, ea rly trea tm en t w ith reduceddoses failed to p reven t the on set o r p rog re ssio n ofed em a. Subsequen t convers io n to standa rd do sesre su lted in good re sp onses in a ll c a se s an d no ap -p a ren t u n tow ard effec ts from the in itia l u se o f thelow er do se. W he the r m ore pro longed reduced -do setrea tm en t a lso w ould have induced rem ission can-no t be dete rm ined from ou r da ta . B ecau se th e m eane ffec tive reduced dose w as slig h tly le ss than h a lf o fth e s tan da rd d ose , th is reg im en can re su lt in sig -n ific an t stero id spa ring , p ar ticu la rly fo r the p a tien tw ith ch ron ic frequ en t re lap ses . In su ch patien ts ,th e re fo re , w e w ou ld recom m end th at one ha lf thes tand ard p redn isone do se b e g iv en for early relap seas p rev ious ly de fined . T he standa rd dose sho u ld bere sum ed if s ig n ifican t edem a deve lop s . If the re-sp onse to the reduced dose is sa tisfacto ry , fu r the rin d iv idua lized do se reduc tion can be a ttem p ted form anag em en t o f su bsequ en t re lap se s usin g do ses a slow as 0 .2 m g /kg /d .

A lth ough the m echan ism by w hich predn isonein du ces rem ission in pa tien ts w ith the neph ro ticsy ndrom e h as neve r b een e luc ida ted , ea r lie r inves-t iga to rs susp ec ted tha t s tero ids m ight have a sp e-c if ic actio n to erad ica te th e underly in g cause o f thed isease.2 A ccord ing ly , re lative ly h igh-dose andlong -te rm reg im ens w ere deve loped w ith a goa l o fno t on ly suppressing pro te inu ria bu t a lso e ffec tin ga bong-te rm cure . U nfo rtun a tely , w hen th e In ter-

T A B L E 2. Sing le R educed -Do se D aily P redn isone T rea tm ent in P a tien ts W ith F requen t R elapses*P redn isone N o. of T o ta l N o . o f M ean R espon se To ta l N o . o f M ean T rea tm ent

D ose P a tien ts R e lapses T im e R elapses T im e for(m g/kg /d ) R espond ing (d [R ange]) F a iling F a ilu res

( d [ Ra ng e] )1 .2 -1 .5 5 8 8 .3

(4 -14)1 7

0 .8 -1 .0 9 23 7 .0(3 -14 )

2 6(5 -7 )

0 .2 -0 .5 6 24 6 .0(4 -10 )

5 9(3 -14 )

* Reduced dose w as cons idered to h av e fa iled if p ro teinu ria pers isted fo r 14 days or if sign if ican t ed em a deve lop ed ; a llsu ch ep isod es subseq uen tly resp ond ed to s tandard doses .

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698 PREDN ISONE AND NEPHROT IC SYNDROME

na tio na l S tudy of K idn ey D isease in C hild ren co rn-pa red a h igh er cum u la tive predn ison e do sag e reg i-m en , adm in is tered afte r a firs t re lapse , w ith a low ercum ula tiv e do se reg im en , the frequency o f subse -qu en t relap se w as no t favorab ly influ en ced by theh ighe r do sag es . B ecau se th e tw o reg im en s d iffe redprim arily in th e du ration o f da ily d iv ided-dose th er-apy (on e g roup rece ived such trea tm ent fo r a m eano f 12 days and the o the r for 8 w eeks), th e find ing ssuggest tha t d aily d iv ided-dose predn ison e treat-m ent cannot a rres t the unde rly in g d isease process .R ecen tly , U eda e t al4 reported fo r th e firs t tim etha t the stero id reg im en used a t the onse t o f d iseasem ight im pac t on the long -term course . T hese in-vestig ato rs s tud ied tw o trea tm en t reg im ens, w hichinc lud ed id en tica l d aily d iv ided -dose predn isobonefo r the firs t 4 w eek s but d iffe red in th e dura tio n ofin term itten t (th ree trea tm en t day s ou t o f seven for1 m on th) o r altern ate-d ay (ev ery 48 hours fo r 6m onths) trea tm en t. B ecause the g roup rece iv ingbong -term a lte rna te-d ay trea tm en t h ad a bow er in -cidence of re lap se du ring the 6 m on ths fo llow ingdiscon tin ua tion of p redn isobone , these fin d ings sug -g est tha t the dura tio n of trea tm en t at th e on set ofd isease ra the r than th e frequen cy o f do se adm in is-tra tion m ight in fluence the cou rse of th e d iseaseafter trea tm ent is d iscon tinued . A lthough ou r ownbong-te rm resu lts show a high in cid ence o f frequ en tre lapses , th is is la rge ly accounted fo r by se lec tio nb ias , because the m a jority o f our pa tien ts w ereiden tified b ecause o f a re lapsin g cou rse . A lth oughw e cannot exc lud e th e possib ility tha t the sin g le-do se d aily adm in istratio n p ro to co l pred isposes tom o re frequen t relapses a fter trea tm en t is d iscon tin -ued , the in it ia l efficacy o f th is reg im en , com bin edw ith th e ob se rv atio ns cited b e fo re , suggest th atd a ily d iv ided -dose predn ison e trea tm ent h as noproven advan tag e for in itia l trea tm en t of th is con -dit ion.

Am ong patien ts w ith frequ en t relapses , s te ro idtox ic ity rem a in s a p rob lem fo r w hich im p rovedtreatm ent s tra teg ie s are needed . P rev iou s reportsh ave show n tha t low -dose m ain tenance stero id reg -im ens, su ch as low -dose altern ate-d ay -adm in is te redpredn ison e6 9 o r low -do se d aily -adm in is te red hyd ro-co rtison e,5 can be help fu l in preven ting frequ en tre lapses w hile m in im iz ing stero id tox ic ity . D esp itesu ch m ain tenance the rapy , how eve r, som e pa tien tsexpe rien ce b reak through re lapses resu lting in fre -quen t exposure to h igh dosages of s te ro id if conven-tion ab p ro to co ls are fo llow ed . O ur d ata ind ica te th atm any of these relap ses can be con tro lled w ith con -s id erab ly low er da ily p redn isone do ses th an havep rev iously been recomm ended .

B ecau se th e m echanism of ac tio n of p redn isonein pe rson s w ith the neph ro tic syndrom e rem a in s

unknow n, specific ph arm acokin etic stud ies to de -fin e th e du ra tio n of ac tion h av e not been po ssib le .O ur obse rva tion th at a s ing le da ily predn ison e do seis su ffic ien t to in duce rem issio n w ou ld no t havebeen p red ic ted on th e basis of v alues for p la sm ahalf-life , w hich only slig h tly ex ceed tw o hours anda re no t d iffe ren t in n ephro tic ch ild ren com pared too the r p atien t g roups.6 S im ila rly , the dura tio n o fp redn iso lone -induced dec rease in the lym phocytere spon se to m itogen is re lative ly sho rt, w ith recov-e ry occurrin g w ith in 24 hou rs .6 O th er ob se rva tio ns ,h ow eve r, a re in acco rdance w ith a m ore p ro longeddu ra tion o f p redn iso ne ac tion . F o r ex am ple , sk indelayed -typ e hype rsensit iv ity re spon ses a re sup -p re ssed when p redn isone is adm in is tered onced aily , w he reas p rese rva tion o f norm a l re spon sesrequ ires p ro longation of the dose in te rva l to 48hou rs.7 S im ila r find ings d is tingu ish the e ffect o fonce d aily and altern ate -d ay treatm ent w ith pred-n ison e on plasm a cortiso l con cen tratio ns .7 U ntilp ha rm acolog ic s tu d ie s can be targ eted m ore d irectlya t a de fined m ode of ac tio n of p redn ison e in pa -tien ts w ith the neph ro tic syndrom e , fu rthe r clin ica le ffo rts to iden tify trea tm ent schedu le s w ith reducedtox ic ity a re w arran ted .

REFERENCES1 . In te rn ation al S tudy of K idney D isease in Child ren : N e-

phro tic synd rom e in ch ild ren : A random ized tria l com paringtw o p redn iso ne reg im ens in ste ro id .re sp onsiv e pa tien ts w hore lap se early . J P ed ia tr 1979 ;95 :239 -2432. G lasso ck R J, A d le r SG , W ard H J, e t a l: P rim ary g lom eru la rd iseases , in B ren ner BM , R ec to r FC Jr (ed s ): Th e Kid n e y .Ph ilad elp hia , W E Saunders C o, 1986

3. B arn ett H L , Seho enem an M , B ern ste in J , et a !: M in im alchange neph ro tic syn drom e, in E de lm ann CM Jr (ed ): Pe -d ia tric K id ney D ise ase . Boston , L ittle, B row n, & Co , 1978 ,p 695

4 . B arra tt TM , G eary D F, H olland PC , e t a l: T herapy ofg lom eru la r d isease, in H o llid ay M A , B arra tt TM , V ern ie rR L (ed s): P ed ia tric N ep hro log y. B altim ore , W illiam s & W il.k ins, 1987 , p 5 32

5 . T rav is LB : The nephro tic sy ndrom e, in Rudolph AM , H off-m an JIE , A xe lrod S (ed a ): Ped ia tr ic s . N orw alk , C T , App le -to n & Lange , 19 87 , p 1 176

6 . M cEnery PT , S trife C F: N eph ro tic synd rom e in ch ildhood .Ped ia tr GUn N orth Am 1982 ;89 :875- .894

7. T he n eph ro tic synd rom e (n ep hros is), in B eh rm an RE ,Vaughn VC III, N e lson W E (eds): N eLson Tex tbook o f Pe -diatrics. Ph ila de lph ia , W B Saunders C o , 1987 , p 11298 . S oyka LF , S axena KM : A lte rna te -day ste ro id therapy forn ephro tic ch ild ren . JAMA 1965;192:125-130

9 . A rbe itsgem einsch af t f#{252}rad iatriache N ephro log ie : A lte r-n a te -thy predn isone is m o re effec tive than in te rm itten tp redn isone in frequ en tly re lapsin g nephro tic syn drom e. Eu rJ P ed ia tr 1 98 1;1 35 :2 29 -2 37

10 . C hurg J, H ab ib R , W hite RHR : P ath o log y o f th e n eph ro ticsynd rom e in ch ild ren : A rep ort fo r th e In te rna tiona l S tudyo f K idney D isease in Child ren . L ance t 1970 ;1 :1299-1302

11 . In te rna tio na l S tudy of K idn ey D isease in Child ren : P rim aryn ephro tic syndrom e in ch ild ren : C lin ica l s ign ifican ce ofhis topathobogic varian ta of m in im al ch ange and o f d iffuse

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m es an gi al h yp er ce ll ul ar it y. Kidney m t 1981;20:765-77112 . Thorn GW : C lin ical co nsidera tions in the use o f cor ticos ter -

o ids . N E ngI J M ed 1966;274:775-78113 . A rn e il G C : M anagem ent o f the nephro tic synd rom e in th e

ch ild , in L ieberm an E (ed): C lin ica l P ed ia tric N eph ro log y.Philad elp h ia, JB L ipp in co tt C o , 1976 , p 159

14 . U eda N , Chihara M , K aw aguch i 5 , e t a l: In term itten t versuslong -term tap erin g predn iso lone for in itia l the rap y in ch il-d ren w ith id iop ath ic nephro tic sy ndrom e. J P ed ia tr1988;112 : 122 - 126

15 . Schoenem an M J: M in im al ch ange nephro tic syndrom e:T reatm ent w ith low do ses of hydrocortiso ne . J P edia tr1983;102:791-793

16 . G reen OC , W in ter R b , K aw ahara FS , e t a ): P harm acok ine ticstud ies o f p red n isobone in ch ild ren . J P ed ia tr 1978 ;93 :299-30 3

17 . M acG rego r RR , Sheagren JN , L ipse tt M B , et a l: A lte rna te -day predn isone the rapy : Evalua tion of d elayed hypersens i-tiv ity responses, con tro l o f d isease an d s te ro id side effec ts .N EngI J Med 1969;280:1427-1431

FACULTY SCHO LARS AW ARD

E ach yea r th e W illiam T . G ran t foundation m akes aw ard s to up to fiv ere sea rch wo rke rs in th e field o f ch ild rens m en ta l health . A w ards a re for 5 yea rsto ta ling $175 ,000 , w hich inc lud es ind irec t costs fo r th e in stitu tion w here theScho la rs w o rk .

The goal of the Facu lty Scho la rs P rogram is to p rom ote ch ild ren s m en ta lhea lth by su ppo rting inv es tiga to rs in the f ield o f p rob lem behav io rs in scho o l-aged ch ild ren . A pp lican ts should be estab lish ed investiga to rs w ith a reco rd ofpublica tion s bu t no t ye t in tenu re positio ns . Aw ard recip ien ts w ill b e calledW illiam T . G ran t Facu lty S chola rs .

A pplican t ins ti tu tions and ind iv idua ls should obta in the b rochu re ou tl in in gthe app lication p rocedure from

Robert J . H agge rty , M DPresidentW ill iam T . G ran t F ounda tio n515 M adison A venueN ew Yo rk , NY 10022 -5403

D ead line for app lica tio ns for 1990 aw ards is Ju ly 1 , 1989 .