Pediatrics 1950 BARNESS 486 503

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1950;5;486PediatricsLEWIS A. BARNESS, GRETCHEN H. MOLL and CHARLES A. JANEWAY

NEPHROTIC SYNDROME: I. Natural History of the Disease

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1950;5;486PediatricsLEWIS A. BARNESS, GRETCHEN H. MOLL and CHARLES A. JANEWAY

NEPHROTIC SYNDROME: I. Natural History of the Disease

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48 6

N E P H R O T IC S Y N D R O M E

I. N atu ra l H is to ry of the D isease

B y L E w is A .

B A R N E S S , M. D . ,

G R E T C H E N H. M O L L ,

M. D . ,

A N D C H A R L E S A . J A N E W A Y , M . D .

Bos ton

T H E nep hro tic synd rom e, w h ich occurs m ain ly in ch ild ren , is m an ifes ted by edem a,

a lbu m in uria , lipem ia and hyp opro te inem ia , u sua lly w ith re la tive ly n orm al leve ls o f

nonpro tein n itrogen in th e b lood and re la tiv ely no rm al b lood pressu re , and is charac ter -

ized by a chron ic cou rse w ith exacerba tions , rem issio ns and , in m any instances , even tua l

recovery . It is the purpose of th is paper to rev iew the n atu ral h is to ry of th is d isease , as it

has been ob se rv ed in th is clin ic, a s a backg rou nd fo r p re sen t and pro jec ted stud ie s on its

p ath ogenesis an d trea tm en t. P a rticu lar em ph as is has been p laced o n estab lish in g crite ria

w hich m igh t assist p rogn osis and o n iden tify ing the facto rs w hich con tribu te to an u n-

favorab le ou tcom e.

A lthoug h sim ilar s tu d ies have been m ade in o th er c lin ics,14 the ex tens iv en ess o f th is

m ate ria l, possib le geograph ic d ifferen ces , and an im press ion tha t the prog nos is had

changed cons iderab ly w ith th e adv en t o f an tibac te ria l chem otherap y led us to und ertak e

th is ana lys is. T w o recen t a rtic les5 {176}ave rev iew ed the lite ra tu re con cern ing th is im p or-

tan t

ch ron ic d isease of ch ildho od .

M E T h O D

T he reco rds of a ll C h ild ren s and In fan ts H osp ita l pa tien ts w ith th e nephro tic syn drom e ad m itted

d uring the period 19 26 to 19 48 w e re e xam ine d . L et ters w ere w rit ten to the p are n ts or p hys icia ns

o f pa tien ts la st k no w n to b e aliv e bu t no t und er act ive trea tm ent , ask ing th e pa tien ts to retu rn to the

h osp ita l fo r a fo llow -up visit. W hen th is w as n ot p os sib le , the p are n ts an d phy sic ian s w e re a ske d to

d escribe the hea lth sta tus o f the ch ild ren and to

give

the resu lts o f recen t u r in e and b lo od pressu re

exam ina tions w hen p oss ib le . If the ch ild h ad d ied , the p aren ts w e re ask ed to re cord th e cau se of

death .

T he ana ly sis o f the d ata in th e

rec ord s w a s car ried out in the fo l low ing m ann er : C har ts o f eac h

ca se w e re m ad e, show in g the f luc tua tion s in w e igh t, p ro tein uria , he m a tur ia , b lo od p res sure an d

nitrog en reten t ion o ver the y ears. T he se find ings w ere c orrela ted w ith th e o ccu rre nce of in fec tio ns an d

var iou s thera pe u tic pro ced ure s. C r iter ia fo r a fav orab le pro gno sis w e re e stab lished b y s tud y of the

records of

pa tien ts k no w n to b e liv in g an d w e ll. T he cou rse a nd find ing s in th is group w ere com -

p are d w ith the co urse and fin d in gs in a g rou p of sim ila r ca ses w hic h h ad e nde d in de ath , a nd in

w h ich the d iagn osis of lip o id ne phrosis w as m a de a t au top sy . S e veral o f th ese au top sie s h ave bee n

reported by W olbach and B lack fan7 as exam ples o f lipo id nephros is.

C riter ia fo r an un favorab le p rogn osis w ere es tab lished by a s tudy of the records o f pa tien ts w h o

die d a rena l fa ilu re an d in w ho m autop sy sho w e d de fin i te g lorneru lo nep hri tis .

F rom th e D ep ar tm en t o f P ed iatric s, H arvard M edica l Schoo l an d T he C hild ren s M edica l C en ter ,

B os to n , M ass.

S up po rted by a gra n t, rec om m e nde d by the P an el on H em ato log y , fro m the N atio na l In sti tu te o f

H e alth o f th e U n ite d S ta tes P ub lic H eal th S erv ice , and also b y a gra n t from the M e ad Joh nso n

C o m p a n y .

P resen ted in ab brev ia ted form at the E a ste rn A re a! M e etin g o f the A m er ican A ca dem y o f P ed i-

atrics , B u ffa lo , N .Y ., A pril 2 9-30 , M ay 1-2 , 19 48 .

(R ece ived fo r

pub lica tio n A pril 1 3 , 194 9 .)

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N E P H R O T IC S Y N D R O M E 4 87

T h e d is tin gu ish in g fea tu res o f each o f th ese g roup s of cases w ere de te rm in ed by an ana lys is o f

the frequ en cy and d ura tion of such sig ns as he m a tur ia , n i tro gen reten t ion an d hyp ertens ion . A study

w as m ade o f the ca use s o f de ath in o rde r to see w h at step s m ight b e tak en to red uce the m o rtal ity in

the fu tu re. A n effo rt w as a lso m ad e to de te rm ine w hat

type

of ep iso de appeared to in itia te rem is -

sio ns or ex ace rba tion s.

D E F I N m 0 N 5

F or the pu rpo se s of th is rep ort , th e fo llow ing d efin itions a re u sed :

1. A c ut e g lo m er ul on ep h ri ti s- an acu te rena l d isease, w ith acu te o r abru p t onse t u sua lly fo llow in g

a py oge nic in fec tio n , in w hic h he m aturia a lon e or assoc iate d w ith ede m a , hy pe rten sio n , azo tem ia and

pro tein uria are

presen t fo r a sh ort

per iod of t im e, the n gra du ally sub sid e o r sub seq ue n tly progress

i nt o c hr on ic g lo m er ul on ep hr it is .

T A B L E I

N E W C A S E S

O F N E P H R O SIS A N D

N E P H R IT IS A D M IT T E D T O C H IL D R E N S A N D

IN FA NT S H OS P IT AL S 1926-1946

1 92 6-1 938 193 9-1 94 8 T ota l

L ip oid n eph ros is

N eph ro t ic stage of g lom eru lon eph ritis

52

11

10 9

36

16 1

47

T o ta l nephro tic syndro m e

63

14 5

20 8

A c ut e g lo m e ru lo ne ph ri ti s

C h ro ni c g lo m e ru lo ne ph ri ti s

52

24

13 1

34

18 3

58

T o ta l acu te and chron ic

76

16 5

24 1

T ota l cases adm itted

13 9

31 0

44 9

2.

C h ro ni c g lo m er ul on ep h ri ti s- a chron ic ren a l d isease fo llow in g e ith e r acu te g lom eru loneph ritis

or a

py og enic in fec tio n o r de velop ing in sid ious ly , m anifes ted

b y p ro te inuria , hem atu ria on occas ion

and u ltim ate ly b y azo tem ia and e lev ated b lood pressu re . E dem a m ay or m ay no t b e presen t, b u t is no t

the o u tstand ing sym ptom exc ep t in tho se cases w hich a re clas sif ied as th e

n ep hro tic sy ndrom e.

3. N ep hro tic synd ro m e (se e first pa rag rap h)-

a. C h ron ic g lom eru lon ep hritis in the neph ro tic s ta ge -A fo rm of the ne phro tic synd rom e w ithou t

k no w n an tece de n t h is to ry of a cu te g lo m e ru lone ph ritis* or pyo ge nic in fec tion , w ith pe rsisten t pro -

te inu ria and ede m a as the pre sen tin g sign s, a nd w ith o the r ev ide nce s o f chron ic g lo m e ru lo ne phr itis

in itia lly ob scu red , b u t u ltim ately be com in g m a nifest.

b.

L ipo id

nephros is -A fo rm of th e n eph ro t ic syn dro m e m a nife ste d by ed em a, pro teinur ia , lip em ia,

es sen tia l ly n orm al b lood p res sure a nd li ttle , if any , h em atu ria or n itro gen rete n tion at an y tim e.

In som e cases the tru e na tu re o f th e d isease pro cess becom es apparen t on ly a t au topsy ; in o th ers ,

b y lab orato ry and clin ic al ev id en ce de velo p ing d uring the co urse of th e d isease . F or the purposes of

a nalysis, patien ts w ho sho w e d glom eru lar sca rrin g at au to psy w e re class ifie d as in stan ces of the

n ep hro tic stage of chro n ic g lom eru lo nephritis regard less o f the c lin ica l d iagnos is. A lso fo r th e

pur -

p ose s o f a nalysis , p atien ts w h o a re n ow pu rsu ing norm a l ac tiv i ty , b u t w ho h ave pe rsis ten t alb um i-

nu ria , h ype rte nsion o r a zo tem ia, h av e be en class ifie d (as lipo id n eph ros is or the ne phro tic stage of

ch ron ic g lom eru lo nep hri tis) . ac cord in g to the d iag nos is

w hich

w as app rop ria te d uring the e dem atous

p hase o f the d isease .

* S inc e th is stud y w as in itia ted o rig ina lly in an atte m p t to find ou t ho w to differen t ia te lipo id

ne ph rosis fro m c hro n ic g lom eru lon eph rit is , cases o f th e

nephro tic synd rom e fo llow ing acu te

glo m e ru lo ne phr itis w ere arb it rari ly exc lud ed , s inc e in th em th e d istinction se em ed cle ar. H ow eve r,

o cca sio nal c ase s o f acu te g lo m eru lo nep hr itis m ay p rog res s in to the n ep hro tic synd rom e.

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-

N EPH R OSI S

-

A C U T E N E P H R IT IS

C H R O N IC N E P H R ITIS

{149 }.4 N E PH R O T IC S T A G E O F

C HR ON IC G LO ME RU LO NE PH RIT IS

6 1 C A S E S

83

C A S E S

58 C A S E S

47 CASES

I

I

a

.4 .)

0

0

z

I 2 3 4 5 6 7 9

IC II a

488 L . A. BARNESS, G . H . M O L L A N D C . A . JA N E W A Y

R E S U L T S

Incidence

In th e

23

year pe rio d , from 1 926 to

194 8 , 20 8 ch ild ren

w ho en te red th e C h ild ren s

an d In fan ts H o sp ita l w ere d iag nosed as hav ing th e nephro tic sy ndrom e (T ab le I) . O f

these, 148 have been fo llow ed , 29 have re tu rned q uestion na ire s an d

31

cou ld no t be

reached fo r fo llow -u p . O ne hun dred six ty -o ne o f the 20 8 pa tien ts fu lf ill the c rite r ia fo r

a d iagno sis o f lip o id n ep hrosis an d 47 fo r the n ephro tic stage o f ch ron ic g lo m eru lo -

n ep hritis . T h e reco rd s o f 58 p a tien ts w ith chron ic g lom eru lo nephritis and of 183 w ith

acu te g lo m eru loneph ritis w ho w ere adm itted to th is hosp ita l d u ring th e sam e pe riod w ere

u sed fo r sta tis tica l con tro ls .

Y E A R S

C H A R T 1 . A ge o f on set of d iffere n t fo rm s of rena l d ise ase in c h ildho od .

A ge of O n se t

In lipo id n ep hros is , the ag e of onse t, a s show n in C hart 1 , averages 3 .5 years , w h ile

the ave rage age o f o nse t fo r th e neph ro tic stag e o f- ch ro n ic g lom eru lon ep hritis is 4 .6

years in th is se ries. T he average age of o nse t in the co n tro l se ries o f ch ild ren w ith chron ic

g lom eru lo nephritis is 7 .6 years, and 6 .3 years in acu te g lom eru lon ephritis .*

S ym ptom ato log y an d C ou rse

in itia l sy rn pto rn s.-T he onset in a lm ost a ll in stances o f lipo id neph ro sis an d the

* In l ipo id ne ph ros is th e ave rag e a ge of onset is 3 .5 yr. w ith a stand ard de v ia tio n o f 2. 1 yr . ;

in the nephrotic stage of c hro n ic g lom eru lon eph ritis , th e av erag e is 4 .6 yr. 3 .0 yr . S in ce th e

s tan dard error of the d ifferen ce of the se 2 m e ans is 0 .4 73 , an d th e d iffe ren ce of the 2 m e ans is 1.1 yr.

or

2.3 times

th e s tand ard e rro r, the d ifferen ce in ag e o f on set of ne phrosis a nd the nep hro tic s tage

of o m e ru lone ph ritis is sig n ifican t.

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*

A v era ge no . o f rem issions p er pa tie n t.

N E PH R O T IC S Y N D R O M E 489

T A B L E II

O N SE T O F D IS EA S E-F IR ST S Y M P T O M N O TE D

S y m p tom L ip oid N eph ro sis

N ep hro tic S tage o f C hro n ic

Glomeru lonephr i t is

Total

L iv in g D ead

L o st T o tal

%

L iv ing D ead L os t T o tal %

U pp er res pira to ry

infect ion 2 2 14 4 40 2 5 4 7 1 12 2 5 52

E d e m a o f ev es 4 4 14 9

6 7 42 6 5 3 14 3 0 81

%Vt.g ain 12 14 11 37 23 6 8 0

14 30 51

Pallor 1

0 1 2 1 1 0 1 2 4 4

G ene ral ized ra sh 3 1 1 5 3 1 0 0

1 2 6

Enuresis 0 1 0 1 1 0 0 0 0 0 1

Diarrhea

0 0 2 1

0 0 0 0 0 2

Other

6 1 0 7

4 2 2 0 4 9 11

Total 90 45 26 161

20 2 2

20 8

nephro tic s tage of nephr itis w as ins id ious . T he firs t sym ptom s no ted w ere e ith e r edem a

around th e eyes (81 cases), rap id inc rease in w eig h t (51 cases) o r an up per resp ira to ry

in fec tion tw o or th ree day s befo re th e appearance of ed em a (52 cases ) . A b reak d o w n

of fir st sym pto m s reported is show n in T ab le II. T h e figures ind ica te tha t n o s tatis tica lly

sig n ifican t d if fere nce ex ists b etw ee n

the frequ en cy of f irs t sym ptom s in lip o id neph ro sis

and in the nephro tic stage of chron ic g lo m eru lonephritis.

T A B L E III

S P O N T A N E O U S R EM IS S IO N S

(R em is sion s n o t asso cia ted w ith ob vio us in fec tion s)

.

Nephrosis

N ep hro tic S tage of C hro n ic

.

Glomeru lonephr i t is

L iv ing D e ad T o tal L iv in g D ea d T ota l

T o t a l

T ota l patien ts 90 45 1 35

20 2 2 5 2 17 7

P a tie n ts w ith re m issions :

1 . W ith in 2 m o. of on set 5 2 22 7 4 (5 5% ) 1 4 ii 2 5 (60 % ) 9 9(56% )

2 . M ore th an 2 m o. af ter

onset

4 6 11 5 7(42% ) 4 7 11(26% )

6 8 ( 3 8 %)

T o tal pa tien ts h av ing at leas t

1 sp on t. rem ission

6 4 2 6 9 0 ( 67% ) 14 1 3 27 (64 % ) 1 17 (6 6% )

P atien ts hav ing m ore th an 1

spo nt. rem is sio n

3 8 9 4 7 (35% ) 6 5 1 1 (2 6% )

58 (33 % )

T o tal n um ber of spo nt. re-

missions

1 25 44 1 69(1.3)* 20 21 4 (1.0)*

2 10 ( 1. 2) *

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49 0 L . A . B A R N E S S , G . H . M O L L A N D C . A . JA N E W A Y

Se x

inc idence .-N ine ty -n in e o f the 161 ch ild ren w ith lipo id nep hros is w ere b oys and

62 w ere g irls . T w en ty -n in e o f the 4 7 ch ild ren w ith the neph ro tic s tag e of ch ron ic

g lom eru lo nephritis w ere boys and 18 w ere g irls. T here w as , thus , a som ew h at h igh er in -

c idence of these rena l d iseases am o ng m ales .

R em iss io ns and exacerba tions .-A ll

cases

of the neph ro tic syn drom e h ad edem a. S o-

called sp on taneo us rem ission s are com m on w ith in tw o

m onths of the onse t. A s ind ica ted in

T ab le III , 7 4 of 1 35 ch ild ren w ith lipo id neph ros is and 25 of 42 ch ild ren w ith th e

neph ro tic stage o f ch ron ic g lo m eru loneph ritis d em on stra ted th is type o f rem ission .

T A B L E

IV A)

R E S P O NS E T O IN F E C T IO N

Nephro t ic

.

Nephrosis

Stageof

.

Chronic

.

I

otal

Nephr i t is

T otal pa tien ts 16 1 4 7 2 08

P atien ts w ith no infe ctio ns reco rde d

45 1 3

58

T otal pa tien ts w ith in fect ion s rec ord ed

11 6 34

15 0

T otal no . in fec tions 2 98

85 38 3

N o. No . % N o.

In fe ctions fo llow ed by re m is sio ns*

75

2 5 18 2 1 9 3

In fec tio ns fo llow ed b y ex ace rba tio n* 14 6 4 9 4 4 52

19 0

Infe ctions fo llow ed by n o cha ng e

77

26 2 3 27 100

*

R em ission o r ex ace rba tion w ith in

1 5 days of onse t.

A s the d isease p rogresses , spo n taneous rem iss ions app aren tly occur less f requen tly fo r

any ind iv idua l p a tien t. T h is is no t in d icated by T ab le III , h ow ev e r, w h ich sho w s on ly

tha t the rem ission s no t rela ted to an y app aren t in fec tion occurred a fte r tw o m onth s in

68 ins tances am ong

17 7

fo llow ed cases .

R espon se to in fec tion .-A ny rem iss ion occurr ing w ith in 1 5 days of an in fec tion w as

cons id e red a resp onse to in fec tion , sin ce , in a se ries o f 19 pa tien ts w ho had in fec tion s

w hile observed in

th e

hosp ita l, 18 ex perienced a d iu res is be tw een

1

an d 1 5 days fo llow in g

in fec t ion .

R em iss io ns, ex acerba tions o r no change in th e pa tien ts s ta tu s m ay occur lo llow ing

in fec tio n , and no m arked d iffe rence in th is respec t ex ists b etw een the tw o group s of

p a tien ts (T ab le IV (A )

)

. O f 1 61 ch ild ren w ith n ep hrosis , th ere w ere 2 98 instances o f

k now n infec tions .

S even ty -five (25 % ) of these in fec tion s w ere fo llow ed by rem iss io ns w ith in 1 5 d ay s,

146 (49% ) by ex acerba tions and 77 (26% ) by no chan ge in sta tus o f the p atien t.

In th e 47 ch ild ren w ith th e nephro tic s tage of g lom eru lonephritis, the re w ere 85 k now n

in fec tion s ; 21 w ere fo llow ed by rem ission s, 52% by exacerba tions and 27 % by no

change .

In T ab le IV (B ), th e resp onse to d iffe ren t typ es of in fection is co n trasted . It is q u ite

appa ren t tha t up pe r resp ira to ry in fectio ns are se ldom fo llow ed by rem is sions an d usu ally

by exacerba tions , w hereas the ra te o f rem iss io n is rough ly 4 0% afte r m ost o the r typ es

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N E P H R O T IC S Y N D R O M E 49 1

of in fec tion . A g a in th ere is no sign if ican t d iffe rence in response be tw een the tw o fo rm s

of the nephro tic syndrom e. It is in te res tin g to specu la te w he th er fever, w h ich is se ldom

h ig h in up pe r re sp irato ry in fec tions, accoun ts fo r the m ore favorab le respon se to o the r

typ es o f in fec tion .

R ecov ery fro m lip o id neph ro sis in th is se rie s o f pa tien ts occu rred a fter a s few as one

ep iso de of edem a or af te r as m any as 1 6 exace rba tions . R ecov e ry occurred in seve ra l

ch ild ren even th oug h the re w ere no rem issio ns fro m one ep iso de of ed em a fo r a s lo ng as

12 m on ths, th oug h m ore frequen tly rem is sions o ccu rred a fter one to tw o m onth s o f the

ed em atou s p hase .

T A B L E IV (B )

R E L A T IO N O F R E S P O N S E T O T Y P E O F IN FE CT IO N

T y pe of

In fec t ion

L ip oid N eph ros is

N e phro tic S tage o f C h ron ic N ep hrit is

R em is- E xacer - N o

sio n ba tion C ha nge

% R e-

missions

R em is- E x acer- N o

s ion b ation C h ang e

% R e-

missions

U pp er resp ira to ry in-

fect ion

P n e u m o c o c c u s

Streptococcus*

O ther

16 96 4 9

2 3 23 10

8 6 3

28 21 1 5

10

41

47

44

2 34 6

3 6 3

5 2 4

8 2 10

5

25

45

40

* A lm ost a ll

i3

S tr . h e m ol yt ic us .

D eath occurred a fte r 1 to 1 4 exacerba tio ns. T he ed em atou s p hase w ithou t rem ission

pe rs is ted fro m

1

to 1 5 m on ths p rio r to dea th . A ppa ren tly , the re is no corre la tion be tw een

th e n um ber and du ra tion of exacerba tio ns and u ltim ate ou tcom e.

L abo ra to ry F in d ing s

T he inc idence o f h ype rten sion , azo tem ia , and hem a tu ria is in d ica ted in C ha rt 2 . H yper-

tension w as co nsid ered to ex ist w h en the b lood pressu re de term in ed w ith a cu ff o f

appropria te size w as ab ove th e b lo od pres su re o f s tan da rd p re ssu re -ag e grap hs

;

azo t em i a

w hen the N P N w as ove r 40 m g./1 00 cc . ; and h em atu ria w h en m ore than on e red

b lo od ce ll pe r h igh pow er fie ld w as fou nd in spun u rina ry sed im en t. B ecause n ep hro tic

ch ild ren w ith in fec tions m ay tem porarily show hem a tu ria , h yp ertension or eleva tio n of

b lo od N P N , these sig ns w ere c la ssif ied as pe rs is ten t on ly if th ey w ere p re sen t fo r a pe rio d

of on e m o n th or lo nge r .

It w ill be seen th at in d iffe ren tia tin g b etw een lip o id nephrosis an d the n ep hro tic stage

o f ch ron ic g lom eru lon ep hritis , pe rsis ten t hy pe rtens ion is ev idence ag ain st neph ro sis . O n ly

one of the 1 61 ch ild ren w ith lipo id nephrosis had hyp ertension fo r lo nge r th an o ne

m on th w hile seen a t th is h osp ita l, 3 3 had tran sien t hy pe rtens ion an d 1 27 had n o hyp er-

tension w hile un der ob serva tion . O f th e 47 ch ild ren w ith the n ep hro tic s tag e of chro n ic

g lo m eru lo neph ritis , no rm a l b lood p re ssu re w as fo und in

14 , trans ien t hypertens io n in 12

an d pe rsis ten t hy pe rtensio n in

21 .

A zo tem ia w as trans ien t in

28 nephro tics, pe rsis ted lo nger than one m onth in 1 3 and

w as absen t in 1 20 , w hereas it w as trans ien t in n ine n ep hro tics in the nephro tic s tage ,

pe rs is ten t in 2 2 and absen t in 16 .

P ersis ten t hem a tu ria w as foun d in 41 ch ild ren w ith lipo id n ephrosis , transien t hem a-

8/10/2019 Pediatrics 1950 BARNESS 486 503

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49 2 L .

A . B A R N E S S , G . H . M O L L A N D C . A . JA N E W A Y

tuna in 43 an d no hem atu ria in

77 .

G ross h em atu r ia w as no ted in

f ive

of these pa tien ts

w h o are liv in g , o ne of w hom is w ell an d fou r o f w ho m now have a lbu m inu ria as th e

so le abno rm al f ind ing ; in fo ur w h o d ied , and in fo ur w ho have been lo st f rom o ur

reco rds . T w en ty -fo u r ch ild ren in the neph ro tic stage o f g lo m eru lo neph ritis had p er-

s is ten t hem atu ria , 1 0 had transien t h#{2 35}m atu ria and in 1 3 no hem atu ria w as no ted . G ross

h em a tur ia w as no ted in on e c h ild w ho is liv in g , in tw o w h o are no long er in ou r record s

and in four w ho have d ied . T hus hem atu ria has been th e leas t h elp fu l sign in d if feren tia t-

ing be tw een these tw o d iseases, thoug h g ross h em atu r ia is ra re in lipo id neph rosis . T h is is

SIG N IF IC AN C E O F S IG N S

N E PH R O SIS (LE F T C O LU M N S ) 161 C A SE S ( 4 4 L w .45 A LB U M IN U R IC , I H Y PE R TE N SIO N

4 5D E 4 0 2 6L O S T )

10 N E PH R IT IS (R IG H T C O LU M N S) 47 C A SE S (2O L IV IN G , 2 2 D E A D 5 LO ST )

80 H YP E R T E N S IO N N IT R ET E N T IO N M IC H E M A TU R IA

5% 46

50 z

1

26 20 21Z

C

0 T R A N SI EN T

(

M O N T H )

C H A R T 2. D iag no stic sig n ifican ce of m ajo r sig ns of re na l d isea se .

at variance w ith the experience of m os t o th e r studen ts o f the d isease and m ay b e cx -

p lained in p ar t b y ou r a rb itra ry exc lusion of cases b eg inn ing as acu te g lom eru lon ep hritis

from the group of cases o f chron ic g lo m eru lonephr itis in th e nephro tic s tag e .

Serum cho les tero l va ried from 17 0 to 1 ,3 00 m g ./1 00 c c. in lip o id n eph ros is w ith m ore

than 275 m g./100 cc . in 79 ou t o f 8 8 ca ses in w hic h the ch ole ste ro l w as repor ted .

C hole ste ro l in

19 cases o f g lom eru loneph ritis in the n ephro tic s tage varied from 204 to

700 m g./100 cc ., w ith m ore than 2 75 m g ./10 0 cc . in 16 of these 1 9 . In severa l ch ild ren

of b o th groups , cho les tero l w as be low 27 5 m g./10 0 cc . w h en firs t m easu red , bu t rose

abo ve th is leve l one to th ree m onths afte r the onset o f the d isease.

V a lues fo r the serum pro te in in the ch ild ren w ith lipo id nephro sis ran ged fro m 2 .1 to

7 .4 gm ./100 cc . and w ere less than 4 .5 gm ./1 00 cc . in 119 of 153 pa tien ts in w hom

m easurem en ts w ere m ade . In ch ild ren in the nephro tic s tage of chron ic nephritis, th e

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N E P H R O T IC S Y N D R O M E 4 93

se ru m pro te in ranged from 3.5 to 7 .2 gm ./1 00 cc . w ith 23 of 44 pa tien ts show ing leve ls

be low 4 .5 gm ./1 00 cc . O f 19 7 pa tien ts in w hom serum pro te in leve ls w ere rep orted ,

edem a w as p resen t in 18 6 w hen the se rum p ro te in w as be lo w 4 .5 g m ./100 cc ., and w as

absen t w hen abo ve th is leve l. H ow ev er , in n ine nephro tic s and seven n ep hritic s edem a

wa s presen t a t lev els o f 5 to 6 gm ./100 cc . an d in th ree nephro tics an d th ree nephr itic s

edem a w as absen t at leve ls o f 3 to 4 gm ./1 00 cc.

P rev ious H is to ry

T he re w as no constan t f ind in g of an y prev iou s d isease in e ithe r g ro up of ch ild ren .

A p pro x im a te ly on e ha lf o f each group o f ch ild ren had b een breast fed and the rem ain de r

artific ia lly fed . A b ou t th ree fourths had rece ived adequa te supp lem en ts o f v itam ins A

and D , and approx im ate ly o ne fou rth had received none . T w en ty o f th e ch ild ren are

rep orted to h av e had frequen t co lds. F ifteen had h ad tons illec tom ies befo re th e onse t

o f neph rosis . lit genera l, h ow ev er , ex cep t fo r the usua l ch ild hood d iseases, th e ch ild ren

h ad b een in g ood h ea lth p rio r to the onse t o f nephrosis o r ch ron ic g lom eru loneph ritis .

F am ily H isto ry

A n a ttem pt w as m ad e to find a com m on h ered ita ry back groun d in these ch ild ren .

A fam ily h isto ry o f a llergy w as fo und in 43 of the 161 nephro tic s , and in 1 6 o f th e

4 7 c hro n ic g lo m e ru lone ph ritic s in the neph ro tic stage . T he s ign if ican ce o f these f igu re s

is

d ifficu lt to de term in e due to the vary in g es tim ates o f a lle rg y in the genera l p opu la tio n .

A

fam ily h is to ry o f ren al d isea se w as foun d in

23 pa tien ts, o f tubercu los is in 2 0 a nd of

d iabe tes in 23 of the 20 6 pa tien ts.

T rea tmen t

T ab le V lists 64 m etho ds of trea tm en t w hich have been u sed fo r the 2 08 pa tien ts w hile

u nder ob serva tion in the h osp ita l. T he large num b er o f m etho ds of trea tm en t ind ica tes

tha t few have been g ood en ough to w iths tan d the test o f tim e ; u ndoub ted ly m any h av e

no t b een ev a lua ted ca re fu lly .

D iet-S even varia tions in d ie t have been used , b u t none has proved therapeu tically

strik in g . W e now favo r a h igh p ro te in low -sa lt d iet w ith less th an 0 .5 gm . sod ium

ch lo ride pe r day , bu t th is is im poss ib le to ach ieve , u n le ss th e ch ild w ill d r ink salt- free

m ilk .* M ixed v itam ins a re g iven em pir ica lly d uring the edem a tou s p hase .

R em ova l o f focus o f in fec tion -F our teen of th e 20 8 edem atous ch ild ren h ad o titis

m ed ia requ ir in g m yrin go tom y. E lev en had ce llu litis req u iring dra inage . T w o had car io us

te eth ex trac ted . O n e m asto idec tom y , o ne rib re sectio n fo r em py em a , o ne an tro tom y fo r

sinus itis , and one p e lv ic abscess d ra in ag e w ere p erfo rm ed . S ev en teen tons illec tom ies and

adeno idec tom ies w ere carr ied ou t. T h is has no t been a rou tine pro cedu re and has been

p erfo rm ed on ly w hen the cu stom ary ind ica tions ex ist. W hen a ton sillec tom y is necessary ,

an a ttem p t is m ad e to perfo rm the opera tion w hen ed em a is m in im al. T he anesthes ia de-

p artm en t o f th is hosp ita l recom m end s cyc loprop an e as th e anesthe tic o f cho ice in th e

presen ce of rena l dam age .

Diure t ic s -No

d iu re tic has been fou nd cons isten t in ac tion . M ercuria l d iu re tics have

*

L on alac (sod iu m -f ree m ilk) (M ead Joh nso n) .

It

ha s prove d u sefu l, if the ch ild can b e ind uce d

to su bs titu te it fo r ord in ary m ilk . W ith L ona lac , s alt -fre e bre ad and salt- fre e bu tter , a n in ta ke o f 0 .5

g m . so d iu m c hlo rid e per d ay can be ac h ie ved , w h ich is s till m o re sal t th an is ex creted b y m an y

nep hro tic ch i ld re n .

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494 L . A . B A R N E S S , G . H . M O L L A N D C . A . J A N E W A Y

T A B L E V

D R U G S A N D P R O C E D U R E S U S E D IN T R E A T M E N T O F N E P H R O S IS IN C H IL D R E N S

A N D IN F A N T S H O S P ITA L S , 1926-1948

B loo d and B lood Subs titu te s

H i g h

pro te in low sa lt B lood transfus io n

H igh pro tein P lasm a

L ow sa lt C o nce n tra ted serum a lbu m in , s alt -po or

Lo w

pro tein C o nce n trate d hu m a n seru m

L o w fa t Im m u ne g lob u lin

L im ited flu ids A c acia

Forced f lu id s A m in o ac ids

B o vin e seru m album in

R e m o v a l o f I nf ec ti on

. . In fec tio ns Indu ced

T on sillecto m y an d a den oid ectom .y

C arious teeth re m o ved V ac cin ia

M as to idec tom y M e asle s

R ib r es ec ti on

. .

C hem o the rap eutic D ru gs

P elv ic abscess d ra ined

A ntro to m y P en ici llin

M yringo tom y S ulfad iaz ine

C ellu litis d ra ined Su lfath iazo le

. .

Sulfapyr id ine

Diure t ic s Sulfan i lamide

Mercupur in

# {174 } S trep tom ycin

Salyrgan #{174}

. .

O t h e r D rugs an d Procedures

Diuret in #{174}

A m m onium chlo ride P yram idon

H y perton ic g lu cose P aracen tes is

H yperton ic sucrose T h yro id ex tract

Aminophyll in

# {174 } D ecapsu la tion of k idney

Theophyllne

#{ 174} A sco rb ic acid

T h e o b r o m i n e #{17 4} T es to ste rone p rop ion ate

U rea R utin

M a gn esiu m su lfa te V ita m in

A

an d M azo la o il

J ava tea C arb ohy drate frac tion o f p n eu m o co c cu s

P o tass ium c hlo rid e P a rathorm o ne

P otass ium n itra te L ive r, in tram uscu lar

P o tass ium c itra te H orse an t ise rum

C a lciu m ch lor ide U rina ry an tise p tics

Dig i ta l is

M ix ed vita m ins

C hol ine

Pyridoxine

S w e a t s

been used in six ch ild ren . A m m o nium ch lo rid e w as u sed in six ch ild ren and in n o in -

stance w as the re a d iu res is . H y pe rton ic g lucose and suc rose w ere used e igh t tim es w ith -

o u t no tab le e ffec t. A m in oph y llin , theop hy llin e an d theob ro m ine w ere used in five . M ag -

n esiu m su lfate w as g iven to

14 ch ild ren w ith ou t con sis ten tly dem o nstrab le e ffec t. Java

te a (K um is k uch ing , an he rb used ch ie f ly in the O rien t is a d iu re tic ) w as u sed in

th ree ch ild ren w ith equ ivoca l re su lts , a lthou gh it repea ted ly p ro duced a d iu re sis in o ne

ch ild over a p erio d of n ear ly a year a t hom e. P o tass ium sa lts w ere g iven to six an d ca lc iu m

sa lts to tw o c hild re n.

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N E P H R O T IC S Y N D R O M E 495

B lood , b lood d eriva tive s a nd b loo d subs titu te s.-F ifty -o ne of th e 2 08 ch ild ren w ere

g iven tran sfu sion s fo r anem ia and as sup portive th erapy during in fec tion s, be fo re the

era of chem otherap y . T h irty -on e ch ild ren in bo th gro ups rece ived no rm al h um an serum

albu m in in an a ttem pt to in itia te d iu resis and increase th e c ircu la ting se rum album in . S a lt-

poo r serum a lbu m in h as p rod uced a d iu re sis in app ro x im a te ly ha lf th e cases w itho u t

inc rea sing th e serum a lb um in leve l ap prec iab ly , a s repo rted els ew here.8 S ix ch ild ren w ere

g iven h um an seru m , four w ere g iven p lasm a and six w ere g iven im m une serum glob u lin ;

th ree rece iv ed am in o ac ids , o ne acac ia an d one b ov ine a lb um in . T h e effec ts o f these sub -

s tan ces w ere v ar iab le .

in fec tk rn s ind uced .-B ecau se spon tan eous d iu re sis frequen tly fo llow s in fec tion , espe -

c ially m eas les , 17 ch ild ren w ere inocu la ted w ith m eas les v irus . Success fu l inocu la tion has

been ach iev ed by in tran asal in stilla tion of ap prox im ate ly 1 to 2 cc . o f th roa t w ash ing s

ob ta ined from ind iv id ua ls w ith K oplik s spo ts in th e oropharyn x . T hese are co llec ted by

hav ing th e p atien t ga rg le and rinse th e th roa t w ith bac te rio log ic b ro th . T he w ash ings are

frozen a t -

70 #{1 76} C . n til ready fo r use, th en thaw ed at 3 7#{ 176 }C ., nd 100,000

u . each o f

pen ic illin and strep tom y cin a re add ed to

2 cc . be fo re inocu la tion .

T h is m e tho d of inocu la tio n w as used in

12

ch ild ren w ith neph ro sis an d in five in th e

nep hro tic s tag e o f ch ron ic g lom eru lo nephritis . F ourteen ch ild ren dev elo ped a ty p ical

m acu la r e rup tio n 7 to

17

days a fte r in ocu la tion an d th ree fa iled to d ev elo p m eas les in

sp ite o f repea ted in ocu lation s. T he ch ild ren have been g iv en chem otherapy to prev en t

secondary bac teria l in fec tions th ro ughou t the ir a ttack of ac tive m eas les .

O f th e 14 ch ild ren w ho deve lop ed m eas les , 1 1 experienced a lm ost com p le te d isap pear-

ance of edem a an d a lbum inuria 1 to 1 2 d ays af te r onse t o f the rash . T hree ch ild ren , a ll

ch ro n ic n ep hritics in the n ep hro tic stage , h ad no d iu re sis ; tw o of the ch ron ic n ep hritic s

in the neph ro tic stag e re spon ded w ith a d iu re sis sim ila rly to the n in e ch ild ren w ith

neph ros is . T hree of these 1 1

ch ild ren h ave rem ain ed essen tia lly edem a free fo r tw o

y ears . In th e rem ain ing eig h t, p ro te inuria and edem a hav e recurred from o ne m o nth to

one yea r a f ter th e d iu re sis .8

{ 149 }

Paracen te s i s . -Seven ty - four of the 2 08 ch ild ren req u ired abdo m ina l pa racen te sis . O f

these p aracen te sis w as p e rfo rm ed m o re than on e tim e in 43 . It ha s been n o ted tha t

parace n te sis is o fte n m ore ef fec tive

la te in the d isea se . O ne possib le ex p lana tion is tha t

ea r ly in th e d isease th e ab dom ina l w a ll is th ick and ed em a tous, and the ed em a flu id is

sp read over the bo dy . L a te r in th e d isease , the abd om ina l w all is th in , edem a flu id co l-

lec ts m o re eas ily in the abdom ina l cav ity th an in o ther parts o f th e bo dy , and conse-

quen tly is m ore read iiy relea sed by pa racen te sis .

O ther dru gs an d procedures.-D es icca ted

th y ro id g lan d w as g iven in the ho sp ita l to

11

ch i ld ren ; severa l o the rs rece iv ed it a t hom e. E ven though these ch ild ren app aren tly to lerate

thyro id g land adm in is tra tion w ell, its u se has b een abando ned because of lack of bene-

f ic ial re su lts . D ig italis w as u sed in fiv e ch ild ren w itho u t ap pa ren t effec t. T he o th er m eas-

u re s lis ted in th e la st sectio n of T ab le V have been tr ied on ly o ne tim e and , because no

strik ing im p rovem ent w as no ted , w ere d iscon tinu ed . T he use of chem otherapeu tic d rug s

is d iscussed b elow .

C ause o f D eath

T he causes o f death , w hen th e ch ild d ied in the h osp ital, a re sho w n in C h art 3 . In the

p resen t stud y of 161 pa tien ts d iag nosed lip o id nephrosis , 13 6 have been fo llo w ed an d ,

o f the se , 4 5 pa tien ts

( 3 2 %) have d ied . S ev en teen e ithe r d ied a t hom e, o r the cause

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49 6

L . A . B A R N E S S , G . H . M O L L A N D C . A . JA N E W A Y

C A U S E S O F D E A T H

IN N E P H R O T IC S Y N D R O M E

N E PH R O S IS N E PH R O T IC S T A G E O F

C HR ON IC G LO ME RU LO NE PH RIT IS

29

C A S E S 1 9 C A S ES

7 m T n h l _

AC C I D EN T S

5,,

. I O F T H ER A PY

O -C AR D IA C F A ILU R E

-3

R E N A L

._-

63 7

FAILURE

83

f- IN F E C T IO N -4

27 Z

C H A R T 3 . C om pa rative inc ide nce of d if fere n t ca use s o f d ea th in 2 form s o f ne phro tic synd rom e.

N o te pre do m in an t ro le of in fect ion in lip o id ne phrosis.

of d ea th w as no t asce rta ined . O f th e rem ain ing

28

pa t ien ts ,

23

d ied o f in fec tion , th ree

of ca rd iac decom p en sa tion , o ne of anu ria fo llo w ing su lfapyrid ine and one fo llow in g to nsil-

lectomy.

T w enty -tw o of the ch ild ren in th e neph ro tic stage of chron ic g lo m eru lonephritis a re

kno w n to have d ied . T he cause of dea th has been ascerta ined in

1 9 . O f th ese , five d ie d

of in fec tion , o ne of ca rd iac deco m pensation , o ne of pu lm onary edem a fo llow in g th e

ad m in istra tion of alb um in a nd 1 2 in urem ia.

T he causes o f death acco rd ing to ty pe of in fec tion am o ng the p a tien ts w ith lipo id

nep hro sis a re sh ow n in C har t 4 . P ne um oco cce m ia or pn eum oc occ al p eriton itis w as p resen t

in 16 , w h ile the s trep tococcus w as im plica ted in tw o an d E . co li in tw o of th e 23 cases

in w h ich infect ion w a s presen t a t the tim e of dea th . In th ree cases , the o rgan ism s w ere

n o t iden tif ied . It is seen tha t since the adv en t o f the libe ra l u se o f su lfad iaz ine in

1 9 4 2 ,

few dea ths h av e b een accom p an ied b y in fec tion w hen the pa tien t Jied in the ho sp ita l.

O f th e f ive h osp ita l death s in ch ild ren w ith n ep hro sis since 19 42 , tw o w ere circu lato ry

d eaths, tw o fo llow ed in fec tion and o ne dea th fo llo w ed tons illec tom y .

O ne po ssib le exp lan a tio n fo r recen t inc rea se in the num ber o f dea ths at hom e m ay

be th e inc rea se in th e n um be r of p atien ts w ho h ave com e fro m c ons ide rab le d istan ce s.

T his is show n in T ab le V I w hich a lso ind ica tes the h ig her m or ta lity rate bo th befo re and

af ter 194 2 a m o ng c hild ren liv ing a d ista nce a nd he nc e presu m a bly h av ing les s read y

access to p rom pt m ed ica l and ho sp ita l ca re .

P rognos is

T h e prog nos is o f these d iseases is b ased on the da ta from ch ild ren fo llow ed to da te .

T he sta tus o f th ese pa tien ts is b rie fly sum m arized in T ab les V II and V III. T he d a ta

regard in g the pa tien ts w ith ac u te a nd ch ron ic g lom eru lon eph ritis in T ab le V II are

w eig h ted , as no spec ia l a ttem pt w as m ade to fo llow these pa tien ts a fte r d ischarge from

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24

.-.N E W C AS E S

..-

A SE L O A D

0

S U L F O N A M ID E S [PEN LL IN

I S A 1 S P 1S . T1 S D . j,

D EA T H S

E E l P N E U M O C O C C U S

D S T R E P T O C O C C U S

t i E S C H E R IC H I C O L I

0

O T H E R IN F E C T IO N

Q D IE D A T H O M E

. C I R C U L A T O R Y

0 A C C ID E N T O F T H E R A P Y

16 2 8

Y E A R

NEPHROTIC SYNDROME 49 7

.4 ,)

w

U)

a

.4)

U.

0

2

N E W C A S ES O F N EP H R O S IS A N D D EA T H S IN N EP H R O S IS 1926-1948

C H A R T 4 . C auses o f de ath in 1 61 ca ses o f lip o id n ep hro sis w ith 4 5 d ea ths. N o te failu re o f m ortality

to ris e sin ce in tro du ctio n of su lfa d ia zin e in 19 42 , d esp ite stead ily in crea sin g case loa d . A lso n ote

tha t m os t de ath s in rec en t yea rs h ave oc curred a t h om e a nd tha t pn eum oc occ us w hich w as form er ly

re spo nsib le for m os t fa ta litie s has n o t c aused dea th since 19 42 .

the hosp ita l. T he cr ite ria used fo r cons id er in g a pa tien t w ell a re freedom from edem a for

on e year , no rm a l b lood pre ssu re , no rm a l se rum N P N , an d urine free o f p ro te in and

abnormal fo rm ed e lem en ts . T he ch ild ren have b een su bd iv ided in to th ree g roups fo r pur-

p oses o f ana lysis : those w ith on set be fo re 1 938 -th e prechem o th erap y era ; th ose w ith

onse t in the pe riod 193 9 to 19 42 w hen su lfonam ides w ere in troduced fo r the trea tm en t

o f in fec tio ns ; th ose w ith onse t a fte r 1942 , w hen su lfad iazine began to b e used fo r the

t reatment .

F . 3L E V I

R E L A TIO N O F D O M IC IL E O F P A T IE N T S T O M O R T A LIT Y IN 16 1 C A S E S O F L IP O ID N E P H R O S IS

Date of Onset 192 6 -1942

1943-1948

C ase s fro m T otal C ases

D e aths M orta lity

T o tal C a ses D ea ths M o rtal ity

GreaterBoston

49 (61 % ) 1 7 3 5%

27 (33 % )

3 11 %

E l se w h e r e

3 1 (39 % ) 15 48 % 5 4 (67 % ) 10 19 %

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49 8

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8/10/2019 Pediatrics 1950 BARNESS 486 503

16/20

N E P H R O T IC S Y N D R O M E 49 9

O f 1 61 ch ild ren w ith lipo id n ephrosis , 4 5 (2 8% ) have d ied . In the p re su lfonam id e

p eriod 1 926 to 1938, the av e rage case load* w as 1 4 .6 p atien ts pe r y ea r and the re w ere

13 death s, a rela tive m o rta lity o f 6 .8 p atien ts/1 00 /y ear . In th e su lfonam id e pe riod

1939 to 194 2 , the ave rage case lo ad w as 39 pa tien ts pe r y ea r , w ith 1 6 dea ths, a re la tive

m orta lity o f 10 .3 pa tien ts /100 /year. In the su lfad iaz ine -pen ic illin p er io d 1 943 to 194 8 ,

th e ave rage case lo ad w as 64 w ith 1 5 d ea th s, a rela tive m orta lity o f 3 .9 /10 0 /yea r.

O ne hun dred sev en ch ild ren w ith lipo id nephros is have b een fo llow ed tw o o r m ore

yea rs : 4 5 (42 % ) have d ied ; 4 4 (41 % ) are liv ing and w e ll ; 18 ( 1 7% ) a re liv ing w ith

ev idence of rena l d isea se . O f these la tte r 1 8 , ho w ev er , 10 a re am on g th e cu rren t pa tien ts ,

and approx im ate ly o ne ha lf o f th ese m ay b e ex pected to recove r .

T A B L E V III

S T A T U S O F 62 L IV IN G P A T IE N T S W IT H L n oID N E P H R O S IS W H O H A V E B E E N

F O L L O W E D

2

O R M O R E Y E A R S

F ollo w ed fo r

T o tal N o .

Patients

N o. P atien ts w ith M a jor S ign s

_ _ _ _ _ _ _ _ _

P ro teinur ia E de m a

H yper-

tension

A z ote m ia H e m a tur ia

16-22yr .

9 3 0 2 0 0

11-lS yr. 9

0 0

1 0

0

6-lO y r. 1 2

0 0 0 0 0

4-5yr . 1 0 1 0 0 0 0

3yr. 1 0 6 3

0 0 0

2yr. 12 7 7 0 0 0

T w en ty -n in e ch ild ren in the neph ro tic stag e o f ch ron ic n ep hritis have been fo llo w ed

tw o or m ore years : 22 (7 6% ) are dead , an d sev en (24% ) a re liv in g.

T hus, it is seen th at the ov er-a ll p rogn osis in lipo id neph ro sis be fo re ch em othe rap y

w as favorab le in app ro x im a te ly 40 % o f th e cases . S ince the in trod uc tion of su lfad iaz ine

and the new er an tib io tic s , the m orta lity rate h as been red uced fu rth er (from 6 .8 to 3. 1

pat ien ts/100 /year)

.

P resum ab ly , in a long e r fo llow -u p , ac tua l m ortality w ill a lso be

sh ow n to be red uced . A lm ost a ll o f the neph ro tic ch ild ren w ho have d ied since 1942

h av e d ied a t ho m e . P e rhaps, had ce rta in supp ortive m easu res , su ch as a re av ailab le a t the

h osp ital, b een used , th ese pa tien ts m ig h t h av e to le ra ted w ha teve r cr is is cau sed the ir

death .

It rem a ins im p ossib le, h ow eve r, to g ive a favorab le p rog nosis in e ithe r ch ro n ic g lo m er-

*

C a se

load is the num b er of liv ing pa tien ts fo llow ed dur in g the year p lu s th e n um ber of new

p atien ts fo r th at yea r w ith e v id enc e of ac tiv e rena l d isease . T h irty -th ree ch ron ic nephritics have been

fo l low ed (76% m o rta lity ). O f 1 83 pat ien ts w ith acu te g lo m e ru lone ph ritis , 81 ha ve bee n fo l low ed

longer

than

2 y r. T he m ajo rity o f the 10 2

others

ar e

p r e su m e d

to be w ell as o n ly those w ith sub-

seq u en t

dif f icu l ty

are like ly to retu rn to the h osp ita l.

Fif ty - th ree

o f the 81

are k no w n

to be w e ll, 25

h ave b ec om e

ch ro n ic and

3 died

o f c ard ia c

d e c o m p e n sa1 on d uring

the acu te illne ss .

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500 L . A . B A R N E S S, G . H . M O L L A N D C . A . JA N E W A Y

ulone phr itis o r th e n eph ro t ic sy nd rom e of chron ic g lom eru lo nephritis, thou gh ch ild ren

w ith the la tter m ay live 10 yea rs

or longer w ith the ir d isease .

Duration of Di sease

In the se ries o f 62 ch ild ren w ho have been fo llow ed tw o or m ore years w ith recov ery ,

the co urse of nephro sis has pers isted from 6 to 96 m onths . In a ll bu t a few , ac tiv e d isease

las ted be tw een o ne an d th ree years (2 1 .2 years ) . O f th ose n ep hro tic s w ho d ied , d ea th

occurred be tw een 2 and 95 m o nths a fte r onset, b u t usua lly w ith in tw o years.

G row th and D ev elop m en t

G row th and deve lopm ent usua lly a re de lay ed during th e active ph ase of n ep hros is, bu t

fo llow ing reco very , the p atien t assum es h is norm al g row th channe l as p lo tted on s tand ard

h eigh t-w e igh t an th ropom etric charts. O n ly one pa tien t has show n m enta l re ta rda tion . T he

ch ild ren app aren tly do average sch oo l w o rk , and no a ttem p t has b een m ade to do ro u tine

psy ch om etric e xam ina tio ns.

D I S C U S S I O N

O u r ob serva tion s a re sim ila r to th ose repo rted by S chw arz ,1 M urphy ,2 H eym an ,3 and

B lock .4 T he m o rta lity am on g ou r pa tien ts a s w e ll as th e labo ra to ry and clin ica l find ings

are co m parab le to th ose recorded in the ir se ries.

Using

the c rite ria fo r d iffe ren tia l d iagnos is as ou tlined , the d iffe ren tiation be tw een

lipo id nephrosis and the neph ro tic stage of chron ic g lom eru loneph ritis has been d ifficu lt,

bu t po ss ib le. F our teen d iag noses am ong 208 cases have h ad to be changed , eithe r as a

resu l t

o f au top sy repor ts o r the ap pearan ce o f such sym ptom s and s ig ns as h em atu r ia ,

hy pe rten sion or n itro gen reten tio n . H o w eve r , m an y pa tien ts had to be fo llow ed fo r a

consid e rab le tim e , even up to one yea r, be fo re a d efin ite d istin ctio n co u ld be m ade .

G lom eru la r chang es h av e b een n o ted a t au topsy in 5 of 17 p atien ts in w h om a clin ic al

d iagn osis o f lipo id n ephrosis h ad been m ad e. H o w eve r , in a ll o f the se five , tub u la r

degenerat ion

predom ina ted , and in fou r o f the five a typ ica l signs an d sym p to m s h ad been

no ted at som e tim e. T h is is no t th e p lace to d iscuss w he ther lip o id nephrosis and the

nep hro tic stage of ch ron ic g lom eru lo nep hri tis are actual ly tw o d iffe ren t d isea ses or tw o

differen t var ian ts of the sam e fun dam en tal pa tho lo g ic p ro cess. It is c lea r tha t ce rta in

in stances of the nephro tic syndro m e w hich w e c lassify as lipo id n ep hros is h av e a re la -

t ively

go od pro gno sis , w h ile th ose in w h ich the fea tu re s o f ch ro n ic g lo m eru loneph ritis

predom ina te have a po or p ro gnos is. It is qu ite possib le tha t in ce rta in cases, g lom eru lo -

nephritis m ay be sup erim po sed o n an orig ina l lip o id neph ro sis , g iv ing a m ixed p ic tu re ,

just a s py elo nep hri tis o r v asc u la r sclero sis m a y com plicate o th er fo rm s o f re nal d isea se .

M o re ex ac t in fo rm a tion con ce rn ing the p hysio log ic and ana tom ic de ran gem en ts in the

n ep hro tic synd ro m e can co m e on ly from th e corre la tio n of ca re fu l stud ies o f rena l fun c-

tion by the n ew er m etho ds w ith the c lin ical course and u ltim ate au topsy f in d ings in those

pa tien ts w h o succum b to in te rcu rren t in fec tion o r to the d isease itse lf. S uch s tud ies a re

und er w ay in our o w n as w ell as in a num b er of o ther c lin ics.9 U nfo rtuna te ly , the ren al

fun ctio n te sts used in the past d id n o t y ie ld in fo rm atio n w hich cou ld a llo w o ne to de -

term ine w h eth er

som e cases o f so -ca lled lipo id n ephros is w ith c lin ica l o r apparen t

recov ery actu ally ended up w ith redu ced rena l func tion . Fo r th e purpo ses o f th is in itia l

fo llo w -up stud y , w e h av e h ad to re ly on ord ina ry c lin ica l ex am ina tion w ith rou tine un -

n alys is. T h e fac t th at, in the group o f n in e p atien ts fo llo w ed fo r 16 or m ore years, p ro -

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N E P H R O T IC S Y N D R O M E 5 01

te inun ia

has been found in th ree , an d hy perten sion in tw o , su ggests tha t c lin ica l recovery

from ne ph rosis in

ch ild hood d oes no t alw ays im ply com p le te res to ra tio n of the k idney to

norm al. T h is w ou ld be in line w ith R enn ie s observa tions .10

B eca use of the d ifficu lty in d is tin gu ish in g be tw een the tw o types of cases and becau se

lipo id neph ros is appears to be re la tive ly com m on in ch ildhoo d , a ll pa tien ts w ith edem a,

lipem ia , low serum p ro te in s and a lbum inun ia shou ld b e trea ted w ith a reasonab le degree

of op tim ism . T he d isea se w ill nun a ch ron ic cou rse w ith rem ission s and exace rba tions,

bu t u ltim ate recovery w ill occur in m any ch ild ren , pa rticu la rly if o ne can pro tec t th e

p a tien t fro m infec tion , w h ich h as been the m ajo r cau se o f dea th in the p as t. T h ose pa-

tien ts w ho deve lop frank ev iden ce of g lom eru la r invo lv em en t, how ever, u sua lly assu m e

the poor p ro gnos is o f ch ron ic nephritis.

O n e of ou r ch ie f pu rpo ses in m ak ing th is stud y has b een to p lace o ur o w n th erapeu tic

program for these pat ien ts on a soun de r fo o ting . T h e fo llow ing co m m ents rep resen t ou r

c urre n t v ie w s reg ard ing

the m anagem ent o f neph ros is based on th is study an d our p resen t

experience . It is c lea r tha t, a s in so m any chro n ic d iseases o f un know n etio logy , the

phy sic ian can d o little in th e w ay of trea tm en t w hich affec ts the rea l course of the

d isease. O n the o th er hand h is the rapeu tic p rog ram shou ld be a im ed a t p ro tec ting the

pa tien t so fa r as possib le fro m any spec ia l hazard s w h ich he ru ns an d a t m in im iz ing the

dam age caused b y th e d isease . S in ce the m ajo r cause o f d ea th in pa tien ts w ith lip o id

nephrosis is in fec tion , every effo rt shou ld be m ade to d im in ish the freq uency o f in fec tion

an d to trea t estab lish ed in fections prom ptly and tho rough ly . T he prev en tion of resp ira to ry

in fect ion s is

d ifficu lt, bu t can b e accom p lished to a cons ide rab le ex ten t by cu tting .d ow n

the con tac ts o f the p a tien t w ith p eop le ou ts ide the fam ily , p ar ticu la rly ch ild ren d uring

the w in te r m onths . T he con tin uous use o f su lfonam ides o r o f an tib io tic s in p rophy lac tic

doses d ese rves inv estiga tio n , bu t canno t be recom m end ed u n til its sa fe ty and effec tiv en ess

a re dem ons tra ted und er con tro lled cond itions . M o st im portan t is educa tio n of the paren ts

to p rom p t recogn ition of sym ptom s of in fec tion , pa rticu la rly fever, so tha t chem otherapy

m ay be ins titu ted pro m ptly , thus con tro lling bac te rem ia an d p reven tin g the d ev e lo pm ent

o f periton itis . In v iew o f the fac t tha t fa ta l in fec tions du e to E . co li have o ccurred in

severa l o f o ur pa tien ts , com b in ed pen ic illin and strep tom y cin therapy is p robab ly in d ica ted

in a ll severe in fec tions , a t leas t un til the organ ism is iden tified .

T h e secon d haza rd w hich th rea ten s th e nephro tic ch ild is the unw illing ness o f ph ysi-

c ians or p aren ts to accep t the fac t tha t the d isease is ap t to run its na tu ra l course reg ard -

l ess

of w ha t trea tm en t is adm in is te red . T he con sequen ce o f th is n atu ral reac tion to an y

ch ron ic d isease , p articu la rly one

w h ich so pro fo und ly affec ts th e ap pearance of th e pa-

tien t as nephros is, is a co n tin uous an d v alian t s tru gg le to e lim in ate th e edem a. T h is

resu lts in p ro lo nged ho sp ita liza tion , w hich subm its the p a tien t to repea ted expo sures to

in fec tiou s agen ts , and leads to cons id erab le unnecessa ry em otiona l traum a for b o th ch ild

and paren ts. In add iE in i hes# {233 } sub tle bu t im po rtan t d rfrnen ta l e ffec ts the pa tien t is

p lied w ith d iu retic s, w ith in travenous in fu sions of a ll so rts , and , if any foc i o f in fec tion

a re foun d , th ese are rem oved . T he d iu re tic s , ce r tain ly the m ercun ials , m ay in them se lv es

d a m a g e

the k id ney , in traven ous in fusion s of concen tra ted p lasm a or even serum album in

m ay b e ineffec tive or m ay prec ip ita te pu lm onary edem a if la rge doses a re g iv en to a

ch ild w ith hyp er tens ion , and th e rem ov a l o f fo c i, su ch as the tons ils an d adeno ids , m ay

be dange rous du rin g th e ed em ato us p hase . W e b elieve

inkeep ingpat ien ts

a t h o m eo r in a

she lte red en v ironm en t a s m uch as p ossib le.

T h ere is nok now n reason w h y a ch ild w ith neph rosis shou ld no t b e am b ula to ry as

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50 2 L . A . B A R N E S S , G . H . M O L L A N D C . A . JA N E W A Y

long as the edem a pe rm its activ ity . T he d iet sh ou ld be as lo w in so d ium as po ssib le ,

p rov id ed an adequa te ca lo r ic in tak e , w ith a con side rab le am oun t o f p ro te in , can b e m a in -

tam ed . P anacen te sis rem a ins th e s im ple st m e tho d o f rem ov ing ex trace llu la r flu id in th ose

ch ild ren w h o have co nsiderab le asc ite s, and in w hom the accu m ulatio rt o f flu id becom es

so g rea t a s to em barra ss ea ting , b rea th in g o r ge tting ab ou t.

Better

m eth ods o f trea tm en t w ill hav e to aw ait a c leane r u nde rstand in g o f the n atu re

o f the d isea se p ro cess. S erum a lbum in m ay b e use fu l in re liev ing edem a in som e pa tien ts ,

b u t, b ecause of its rap id ex cretion in the urine , its e ffec t is ap t to be transito ry . M oreover,

m ore da ta up on its e ffec ts on ren a l fu nc tion a re needed , be fo re on e can be ab so lu tely su re

th at it is no t in ju r ious to the neph ro tic k id ney . T he va lue o f m easle s in ocu la tion as a

the rapeu tic m easure is n o t c lea r as ye t, a lthough it p rodu ces s trik ing rem iss io ns in m any ,

bu t no t a ll pa tien ts .

F ew d iseases

tax the resources o f th e prac titio ner so ex tensive ly as th e nep hro tic syn -

; drom e. H e m ust be a co m bin atio n of in fectio us d isease ex pe rt, nu trition ist, phy sio log ist

and psych ia trist fo r th e pa tien t an d , ab ove all, gu ide , co unsello r and frien d to th e p aren ts ,

w ho h ave to live . d ay in an d d ay ou t, fo r tw o or th ree yea rs w ith a ch ild w ho ea ts poo rly

and often has periods of irritab ility o r depression , w ho frequ en tly vom its o r has d iar rhea ,

w ho se appea rance m ay beco m e gro te squ e at tim es, and w h o m ay becom e despe ra te ly sick

w ith pe riton itis and bacte rem ia a t any m o m en t. O n the o the r h an d , the sa tisfac tion of

see ing a pa tien t resto red to norm al health and activ ity a fte r severa l years o f neph ro tic

edem a is w e ll w o rth the tim e and pa tien ce req u ired .

C o N cL u s I o N s

T he reco rds o f 2 08 p a tien ts w ith the n ep hro tic sy nd rom e seen in the C h ild ren s and

In fan ts H osp ita ls o f B os ton from 192 6 to 1 948 have been rev iew ed .

T h e m a in crite ria fo und fo r d iffe ren tia ting b etw een lip o id n ep hro sis and the neph ro tic

stage o f ch ron ic g lom eru lo nephn itis have b een the p re sence o f hyp e rtensio n or azo tem ia

fo r long er than one m o nth in pa tien ts w ith the la tter d isea se , w h ich o ccurs m ore fre -

qu en tly in ch ild ren ov er fou r y ea rs o f ag e . O the r fea tu res o f the tw o d isease s m ay be in -

d is tin gu ishab le . N on ethe less ) it is d es irab le to d if fe ren tia te be tw een them , as apparen tly

few if an y pa tien ts recov er fro m the n ep hro tic sy ndrom e if the ev idences o f g lom eru lo -

neph n itis a re c lear-cu t.

L ipo id nephrosis is ch aracte r ized by the insid io us o nse t o f ed em a in you ng ch ild ren ,

usua lly b e tw een the ages of one an d four. F ind ings inc lude edem a, hy popro te inem ia ,

hy pe rch o le stero lem ia an d heavy pro te inu n ia . B loo d pre ssu re m ay be e leva ted fo r sho rt

periods , bu t ra re ly over one m on th . M icroscop ic hem atu ria does no t exc lude th e d iag nosis ,

tho ug h m acrosco p ic hem a tu ria is usu a lly ev iden ce o f g lo m enu lar in vo lv em en t.

S ym ptom s an d fin d in gs in lipo id neph ro sis m ay pe rsis t fo r from o ne to th ree years

w itho u t spec ific the rap y . E xace rba tion s w ith in fec tion , fo llo w ed b y rem iss ions shortly a fte r

the in fec tion , and rem issio n soo n a fter th e o nse t o f th e d isea se are re la tive ly com m on .

P ro gno sis is no t re lated to th e num ber o r du ra tion of ex ace rb atio ns. D eath b e fo re 1 9 4 2

w as ch ie fly du e to an in tercu rren t in fectio n . S in ce 194 2 , w ith the adven t o f su lfad iaz ine

and the n ew er an tib io tic s, dea th from in fec tion has beco m e less com m on, and has usua lly

occurred a t hom e , p re su m ab ly becau se treatm en t w as no t p rom p tly institu ted .

T he re is app aren tly no con stitu tion a l de fec t in these ch ild ren b efo re the on se t o f th e

d isease , an d gro w th and d eve lopm en t a re norm a l af te r recov e ry .

N o fo rm of treatm en t h as been fou nd w ho lly sa tisfac to ry . P aracen te sis , transfus ion and

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N E P H R O T IC S Y N D R O M E 503

low sa lt d ie t a re th e m o st com m on sup portive m easu re s used he re . A n tib io tic s a re v alu -

ab le dur in g in fec tion s an d have app aren tly low ered the m orta lity o f th e d isease in recen t

years . F oca l sources o f in fection shou ld be e lim ina ted by opera tive pro cedu re on ly w hen

surg ica l in te rven tion is defin ite ly ind ica ted . In jection s of sa lt-poor concen tra ted hu m an

serum a lbum in and the induc tion of m easles a re b e in g eva lua ted as m ethods of induc ing

a d iu re si s.

In th is se r ies app ro x im a te ly on e h alf o f th e pa tien ts w ith a c lin ical d iagno sis o f lipo id

n ep hros is have apparen tly reco vered com p le te ly w ithou t residua l d isease , w hile a sm all

n u m b er

show pers isten t alb um inun ia o r hy perten sion . It is h oped tha t w ith close r super-

v ision of

the pa tien ts and w ith ad eq ua te ch em o th erapy , th is figu re can b e s ign ifican tly

inc reased in the fu tu re .

A C K N O W L E D G M E N T

Fhe au thors w ish to thank M iss Jane W orceste r, A .B ., M .D ., S .D ., o f the D epartm en t

o f B ios ta tistic s o f the H arvard Schoo l o f Pub lic H ea lth , fo r h er gu id ance in the ana lys is

and p repara tion o f tab les .

R E F E R E N C E S

1. S ch w ar tz , H ., K o hn .,

J ., and W einer, S ., L ipo id nephro sis : O bserva tions over period o f 20 years,

A m . J. D is. C h ild . 65 :355 , 1943 .

2 . M u rph y , F . D ., W a rlie ld , L . M ., G rill, J., and A nn is, E ., L ipo id nep hros is : S tudy of 9 pa tien ts ,

w ith specia l referen ce to those observed o ver long period , A rch . In t. M ed . 62 :355 , 193 8 .

3 . H ey m a n, W ., an d S tartzm an , V ., L ipe m ic ne ph ros is, J. P ed iat. 28 : 177, 1946 .

4 . B lock , W . M ., Ja ck son , R . L ., S te arn s, G ., an d B u tsc h , M . P ., L ip o id ne phrosis: C lin ica l an d b io -

c hem ic al stud ies of 40 ch ild ren , 1 0 w ith nec rop sies , P E D ivn uc s 1 :733 , 1 94 8 .

5 . B rad ley , S . E ., and T yso n , C . J ., N eph ro tic syn drom e, N ew E ngland J. M ed . 238 :233 an d 260 ,

1948 .

6. F arr , L . E ., N eph ros is, A d va nce s in In t. M ed . 1 :22 5 , 1 94 2 .

7. W olb ach , S . B ., a nd B la ckfan , K . D ., C lin ic al a nd patho log ical stu d ie s on so-cal led tub u la r

nep hri tis (ne ph ros is), A m . J . M . S c. 1 80:453 , 1 93 0 .

8 . Janew ay , C . A ., an d o thers, D iu resis in ch ild ren w ith neph ros is : C om pariso n o f resp onse to in -

jection of norm a l hu m an seru m a lbu m in an d to in fec tion , p articu larly m ea sle s, T n . A . A m .

P h ysic ian s 61 : 10 8 , 194 8 .

9. G ala n , E ., N ep hro sis in c h ild re n , A m .

J.

D is. C hild . 77 :32 8 , 1 94 9 .

10 . R enn ie , J. B. , O ede m a tou s sy nd rom e o f n ep hnitis w ith spe cia l refere nce to p rog no sis, Q ua rt. J.

M e d . 16 :21 , 194 7 .

S P A N IS H A B S TR A C T

S mn dro ma N efr {2 43}tico

I. H istor ia N a tu ra l d e la E n ferm ed a d

S e h an rev isad o los reco rds de 20 8 pa cie n te s co n sIndrom a nefr#{ 24 3} tic o v isto s de sde 19 26 h asta 1 948 .

L o s crite rios pn in cipa les qu e se han encon trado para d ife renc ia r en tre Ia nefrosis lip o ide y la e tapa

nef r#{ 24 3} tica d e g lo m e ru lone frit is c r#{ 24 3} nica h an s ido Ia p resenc ia d e h iper ten si# {2 43} n y azo tem ia po r m #{ 22 5} se

u n m es e n p acien te s co n e sta i ltim a e nfe rm eda d .

L a n efrosis lip o ide se cara cte riza por el p r inc ip io ins id io o de e de m a en n iflo s p equ efios, gen era l-

m en te en tre las eda des d e 1 y 4 a# {2 41} os .L os d esc ubn im ien tos in clu yen ed em a, h ipo pro teinem ia, h ip er-

c o les tero le m ia y fue rte pro tein uria . L os sm ntom as y lo s de scu bn im ien tos en nef ros is lipo ide ge ne ralm en te

persis ten de 1 a 3 a #{ 241 }o s in terap ia esp ecI fic a . E l pro gn #{ 24 3} stic o no se re lac ion a co n el n C im e ro de

re m isio nes y exa cerbac ion es y ha m e jorado con e l ad ven im ien to de la su lfad iazina y an tib i# { 243 }tico s m #{ 22 5} s

n uev os, ya que Ia in fec ci# {2 43} n es responsab le po r la m ayor pas te de las m u er tes .

P or o tra p aste , en Ia eta pa ne frO tica de g lom eru lon efr itis cr#{ 24 3} nic a el pro gn #{ 243 } stic o es to dav ia pob re

y e l deso rden rena l es la causa p rinc ipa l de m uerte .

300 L ongw ood

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