Nephrosis: A long-term study of children treated with corticosteroids

THE JOURNAL OF

PEDIATRICS APRIL

1966

Volume

68

Number

4

Nepbrosis: A long-term study of children treated Mth corticosteroids When adrenocortical steroids were first used in the treatment of childhood nephrosis in the early 1950"s, the prompt and impressive diuretic response led to enthusiastic claims regarding the effects of such treatment on the morbidity and mortality o[ the disease. Toward the end o[ the decade, however, more cautious reports began to appear. In the present study a case [atality rate o[ fifteen per cent was noted at the time o[ the five year evaluation, a marked improvement over t h a t recorded in the precortico*teroid and preantibiotic eras. However, deaths [rom the disease have continued to occur in subsequent years and, at the time o[ the eight to ten year follow-up, the case [atality rate approached twenty-five per cent.

David Cornfeld, M.D., and M. William Schwartz, M.D. P FI I L A D E L P

I-I I A ,

PA.

Wt{EN ADRENOCORTIGAL steroids were first used for treatment of nephrosis in children in the early 1950's, the prompt and impressive diuretic response led some observers to make enthusiastic claims regarding the effect of such treatment on the morbidity and mortality of this disease. However, toward the end of the decade, more cautious reports began to appear. In 1955 on the basis of a 5 year follow-up in a collaborative study, the following statement was made representing the collective

experience from the nine participating clinics~ "there was no significant effect on the ratio of complete cures to deaths. On the other hand, it was the impression of all workers that the patients were doing better in general and that hormone therapy seemed to prolong life. ''1 The present study was undertaken to determine whether the effects of corticosteroid therapy in children with nephrosis were maintained beyond 5 years. One hundred and sixty-three patients with nephrosis were observed for a minimum of 5 years. Sixtytwo were followed for more than 10 years, the average for the entire group being 9.6

From the University o[ Pennsylvania School of Medicine and the Children's Hospital o[ Philadelphia.

507

508

Cornfeld and Schwartz

years. All the children received corticosteroids, although the programs of therapy varied. When these drugs were first used in this clinic they were given only to induce diuresis. After 1954, a more intensive form of treatment was employed in which the goal was complete chemical and clinical remission. The data are reviewed to compare the morbidity and mortality in the two groups of children. STUDY POPULATION An attempt was made to follow up every patient in the nephrosis clinic of the Children's Hospital of Philadelphia in whom the onset of the disease occurred between 1946 and 1959. Of the 189 children in the original group, 3 with a diagnosis of congenital nephrosis and 5 with evidence of renal failure when first seen are excluded. Eighteen patients were lost before a 5 year follow-up period had been completed. Thus data from 163 children (90 per cent of the total group with childhood nephrosis) are included. Thirty-one of the 163 children have died. Sixty children were seen in the nephrosis clinic in 1964 for an interval history and physical examination. In addition the following laboratory studies were done: hemoglobin concentration, urinalysis, urinary protein excretion during a 12 hour period, blood urea nitrogen (BUN) and serum levels of albumin and globulin. Fifty-seven of the children were examined by their own physicians, who reported their findings to the clinic. Data from the hospital records of the children who could not be located are also compiled if there was at least a 5 year follow-up. Fifteen children fell into the latter category. Sixty-seven per cent of the group were male and 33 per cent were female. Ninetyone per cent of the children were Caucasian and 2 were American-born Orientals. There were five families in which two siblings had nephrosis (a pair of brothers from another family was not included since both died of congenital neph~:osis in the neonatal period). At this time of the follow-up evaluation, 4 of the patients had had successful preg-

April 1966

nancies and had delivered normal babies. The gestational periods had been uneventful except in one woman who had minimal hypertension and slight edema. The activity of the disease was determined at 1, 2, 5, and 8 to 10 years from its onset. The disease status was classified according to the following code: I, well; II, trace of proteinuria; I I I , proteinuria with edema for more than 3 months in the preceding year; IV, active nephrosis; V, chronic nephritis with hypertension, azotemia, or advanced membranous nephritic changes on renal biopsy; VI, dead. RESULTS

The condition at 1, 2, 5, and 8 to 10 years, respectively, after the onset of nephrosis is charted in Table I. Patients who developed the disease before 1954 were evaluated at 10 years. Included in the 8 to 10 year follow-up are data on 42 children whose disease was recognized between 1954 and 1956. The proportion of children who were well or had only intermittent minimal proteinuria gradually increased during the period of observation. At the end of 1 year, 46 per cent were in this category; by 8 to 10 years, this group included approximately 59 per cent of the study population. Coincidentally, the number of children who developed evidences of chronic irreversible glomerulonephritis or who died also increased, from approximately 7 per cent at one year to 25 per cent at the 8 to 10 year follow-up. The group which demonstrated continuously active or intermittently active nephrosis gradually decreased from 46 per cent at 1 year to approximately 4 per cent at 8 to 10 years. Fifteen children were lost to follow-up after the 5 year evaluation but before the 8 to 10 year analysis. Twelve of the 15 were well when seen at 5 years, 3 still had active nephrosis (category I I I ) but showed no evidence of renal failure. A graphic description of the course of the nephrotic children followed in our clinic is presented in Fig. 1. Laboratory and clinical features present at the time of onset of the illness considered

Volume 68 Number 4

Nephrosis

509

T a b l e I. A c t i v i t y of disease in nephrotic c h i l d r e n at 1, 2, 5, a n d 8 to 10 year follow-up 1 year GrouCJ*

No,

I II III IV V VI

47 30 40 35 3 8

I

2 years % 28.2 17.8 24.9 21.4 1.9 4.8

No.

I

66 35 24 20 3 15

5 years % 39.6 21.4 14.6 12.3 1.9 9.2

No.

t

8-10 years % 54.4 11.2 14.8 1.3 3.7 15.1

89 18 24 2 6 24

No.

I

61 10 4

50.4 8.3 3.3 0.8 2.4 22.3

1

3 27

*Well: Group I, no proteinuria; II, minimal protelnuria; active: III, proteinuria and intermlnent edema; IV, active nephrosls; renal failure: V, chronic renal disease or renal failure; VI, dead. 15 (12.5 per cent) children lost to follow-up after 5 years; condition at that time: I, 11 children; II, 1 child; III, 3 children; IV, V and VI, 0 children. Follow-up less than 8 to 10 years, 42 children.

T a b l e I I . Initial l a b o r a t o r y findings in 163 n e p h r o t i c children Serum albumin (Gin. % )

% Population

BUN (rag. % )

2-3

1-2

0.15-00.5

O15

15-2525 40

5

23

29

40

33

43

20

100

~) 60 F< 80 i" 0_ 4O 11I

2

,5

8-10

YEAR OF FOLLOW-UP

WELL

ACTIVE

CHRONIC or D E A D

Fig. 1. Nephrosis: status of children treated with corticosteroids. to be either diagnostically or prognostically i m p o r t a n t are listed in T a b l e I I . M a n y of the children were started on corticosteroid t h e r a p y w i t h i n several weeks after admission to the hospital, so t h a t it is impossible to d e t e r m i n e f r o m the d a t a available w h e t h e r these signs w o u l d h a v e been persistent in the absence of t h e r a p y . A l t h o u g h one-sixth of the group h a d diastolic blood pressures above

Serum cholesterol 750 (rag. %) > 40

7

150250

2

250500

43

500- > 750

39

16

Urine (RBC/HPF) 0-3 3-5

515

> 15

53

14

16

17

80 mm. Hg, significant h y p e r t e n s i o n (levels g r e a t e r t h a n 90 mm. H g ) was n o t e d in only 2.6 p e r cent. Microscopic h e m a t u r i a ( m o r e t h a n 5 r e d blood cells p e r high p o w e r field) was present on admission in 30 p e r cent of the children. Sixty-one per cent h a d a B U N c o n c e n t r a t i o n over 15 mg. p e r cent. S e r u m cholesterol levels were elevated above 250 mg. p e r cent in all b u t 2 of the children a n d 95 p e r cent of the children h a d serum a l b u m i n concentrations below 2 Gm. p e r 100 ml. (in 43 p e r cent the level of serum a l b u m i n was below 0.5 Gm. per 100 m l . ) . N o significant correlation was f o u n d between any single presenting laboratory m e a s u r e m e n t (serum albumin, blood u r e a nitrogen, cholesterol, h e m a t u r i a ) or the presence or absence of hypertension when c o m p a r e d with the physical condition at 1, 2, 5, a n d 8 to 10 years after onset of illness. H o w e v e r , children who h a d m o r e t h a n one evidence of "nephritis" ( B U N over 25 mg. p e r cent, elevated diastolic blood pressure or h e m a t u r i a ) h a d a less favorable outcome t h a n did the group as a whole. T h e r e were 15 patients (9 p e r cent) with azotemia and h e m a t u r i a

5 10

April 1966

Corn/eld a n d S c h w a r t z

30 28.2

25

22.~ i-

20

13.1 o

5

YEAR

4"~

3l 3

io1

1.7

I-2 2-3 3-4

NUMBER

51

28 '

4'4 2.3

6-7

4

Fig. 2. Age of onset of childhood nephrosis in 181 cases.

a n d one child with hypertension a n d hem a t u r i a . A t the 5 year follow-up, 8 of these children (50 per cent) were a p p a r e n t l y cured, one h a d i n t e r m i t t e n t e d e m a , a n d 5 (31 p e r cent) were dead. I n the b a r g r a p h (Fig. 2) the age dist r i b u t i o n of children at the time of the onset of the disease is depicted. S i x t y - f o u r p e r cent of the children developed symptoms b e t w e e n the ages of 12 a n d 48 months. App r o x i m a t e l y 4 p e r cent were diagnosed before the age of 1 y e a r a n d an e q u a l n u m b e r was older t h a n 10 years. A l t h o u g h t h e r e was no statistical significance to the difference in the case f a t a l i t y rate (15.8 versus 24.4 p e r cent) between the g r o u p in which the onset of illness was b e t w e e n the ages of 1 a n d 6 years a n d the one in which the onset was after the age of 6 years ( T a b l e I I I ) , the t r e n d m a y be clinically i m p o r t a n t a n d m i g h t assume significance with a d d i t i o n a l data. A correlation b e t w e e n the outcome of nephrosis a n d the d u r a t i o n of illness p r i o r to the institution of t h e r a p y was sought ( T a b l e

T a b l e I I I . Status of child five years after onset of nephrosis in relation to age at time of onset 9 Age at onset

Groups I and I I (well) No.

6 years 6 years

]

87 23

% 66.7 63.5

Groups I I I and I V (active)

Groups V and VI (chronic or dead)

No.

No.

]

% 17.1 8.3

21 3

I

% 15.8 24.4

19 10

T a b l e IV. Status of child five years after onset of nephrosis in relation to d u r a t i o n of illness before t r e a t m e n t Duration o[ illness pre-therapy One month or less Groups Total I and II (welI) I I I and IV (active) V and VI (chronic or dead)

No.

]

80 54 12 !4

2-3 months

% 49 67 15 18

No.

I

42 29 4 9

.. 4 months or more

%

No.

26 69 10 21

41 24 10 7

t

%

25' 59 24 17

T a b l e V. D u r a t i o n of t r e a t m e n t with corticosteroids in children with nephrosis

1 Pre 1954 Post 1954

1 yr. 68% 29%

l

2 yr. 9% 18%

I

3 yr. 7% 17%

I

4 yr. 3% 7%

I

5 yr. 4% 6%

I

6 yrr. 9% 23%

Volume 68 Number 4

Nephrosis

IV). Half of the children were treated within 2 to 3 months; the rest were not treated until the disease had been clinically evident for 4 months or more. Fewer children with continuously active disease were seen in the group treated within 3 months of the onset of illness. However, there was no difference in the ultimate prognosis regardless of the duration of the disease before active treatment with corticosteroids was initiated. On the basis of the year of onset (whether pre or post 1954) the children were divided into two groups. These were similar as far as sex ratio, age of onset, and initial clinical and laboratory status. The two groups could

be distinguished by: (1) over-all duration of corticosteroid treatment (an average of 19 months for the pre 1954 series versus 38 months for the post 1954 series), (Table V), and (2) the number of cases treated with A C T H only (21 children in the pre 1954 group and none in the post 1954 group). There was no statistical significance in the case fatality rates between the two groups (Fig. 3). However, the number of intensively treated children who were maintained clinically well (i.e., without edema) was significantly greater. This advantage, seen through the 5 year follow-up, was not evident after 8 to 10 years of illness. "Late" relapses, although infrequent, did occur.

IOO

90

80 z o

70

F-

60 o. 0 0.

P'/////

50 P'////~ r/////~

I,z

Y/I/.//

40

30 lie 20

I0

:;22

0 <1954

< 1954 >1954

>1954

ONE YEAR

<1954

TWO YEAR

>1954

FIVE YEAR

<~1954 ,1954 EIGHT-TEN YEAR

(1954-CORTICOSTEROIDS

GIVEN TO

iNDUCE

DIURESIS

)'1954-CORTICOSTEROIDS

GIVEN TO

INDUCE

REMISSION

IWl WELL

GHRONIC OR DEAD

C)

SIGNIFICANT

AT

P
~)

SIGNIFICANT

AT

P < 0,05

Fig. 3. Post treatment status of nephrotic children in relation to intensity of corticosteroid

therapy.

511

5 12

Corn[eld and S c h w a r t z

April 1966

T a b l e V I . Analysis of deaths in n e p h r o t i c children

Patient Ho Mo Ch Co Fr Ha Le M Sc Sh Ha Ma Ro Wr Go Hy Sc Se Jo Rh

Year of onset

Months pre I~

Months of rt

Months survival

Cause of death

1948 1949 1950 1950 1950 1950 1950 1950 1950 1951 1951 1951 1951 1952 1952 1952 1953 1953 1953 1953

60 8 5 7 4 4 1 1 1 4 8 3 11 4 2 3 1 6 3 1

1 1 3 2 ~2 72 4 1 3 3 120 3 30 2 7 2 1 11 ~2 2

96 8 51 46 60 108 14 11 22 48 132 35 124 48 68 45 19 49 13 14

Chronic glomerulonephritis Peritonitis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Suhacute glomerulonephritis Chronic glomerulonephritis

Average Ba Ma Ro Sc Di Ch Fi Fo It McL Wh

1954 1954 1954 1954 1955 1956 1956 1956 1957 1958 1958

Average

6.6

13.5

1 2 3 2 1 1 1 3 1 1 1

4 2 3 80 5 5 4 9 7 7 18

1.5

12.9

50.6 Chronic glomerulonephritis Chronic glomerulonephritis Septicemia Viral myocarditis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Gastroenteritis Shock--post paracentesis

21 10 17 112 29 5 4 12 8 43 26 26.1

T a b l e V I I . D u r a t i o n of illness before d e a t h

Years 1 Pre 1954 Post 1954

6 7

I

2 1 1

t

3 1 1

t

4

}

6 1

F o u r t e e n patients (8.6 per cent of the total group) relapsed after clinical a n d chemical remission of f r o m 2 to 9 years. T h e s e children again responded to corticosteroid therapy. T h e r e were 31 deaths a m o n g the 163 children ( T a b l e V I ) . T h e i m m e d i a t e cause of d e a t h in 4 of the 11 children seen a f t e r 1954 was nonrenal, in contrast to only 1 of 20 a m o n g the pre-1954 cases. F o u r deaths

5 0 0

I

6

7

1 0

1 0

I

8 1 0

I

9 1 0

110111 1 1

1 0

were caused by infections, of w h i ch two were bacterial in origin; one was caused by a viral myocarditis and one by an enteritis presumably viral in etiology (each of these children h ad already shown signs of chronic renal failure p r i o r to t h e t e r m i n a l illness). T h i r t e e n of the deaths o c c u r r e d within 1 y e a r of the onset of illness ( T a b l e V I I ) . O f the 31 children who died, 9 were treated

Volume 68 Number 4

Nephrosis

5 13

T a b l e V I I I . Prognosis in c h i l d h o o d nephrosis Steroid therapy ~ No treatment Glas-] Bosgow F ton No.

Alive Symptom free Dead Total Reference No.

7 3 4 11 ~

21 17 13 34 a

28 20 17 45

%

62 44 38

Antibiotic therapy tNewl Glas- Bos- Ha-] gow ton yen No. %

50 31 28 78 2

41 27 32 73 a

19 110 3 61 10 70 29 180 ~

61 34 39

Present New study Glas- Ha- Mex- CIeve- Pre Post gow yen ico land 19541954 No.

20 14 2 22 2

61 85 55 65 10 15 71 100 ~ ~o

47 31 17 64

63 47 14 77

76 60 10 86

352 272 68 420

%

84 65 16

"XFollow-up for a m i n i m u m of two years,

within 3 m o n t h s of the onset of disease a n d one was not t r e a t e d until he h a d been ill for 5 years (he died 3 years l a t e r ) .

T a b l e I X . Nephrosis: five year foIlow-up of patients t r e a t e d with a corticosteroid Year (compiled)

1959,o ]196o' 119618 11964~

DISCUSSION T h e authors are a w a r e of a certain bias in the selection of cases in the present study; this is inevitable in a n y survey t a k e n at a medical center t h a t serves as a consultative resource for the physicians of the c o m m u nity. I n the early years, m a n y children m i g h t not have been included in the series either because t h e y h a d a p r o m p t remission or because t h e y died before referral to this hospital. M o r e recently, with the w i d e s p r e a d use of corticosteroids, the t r e a t m e n t of unc o m p l i c a t e d cases is f r e q u e n t l y u n d e r t a k e n at c o m m u n i t y hospitals and only those children who have r e f r a c t o r y nephrosis are referred to a m e d i c a l center. T h e r e is no w a y to e v a l u a t e how these factors m a y have influenced the statistics. H o w e v e r , it is possible to c o m p a r e this series with similar ones r e p o r t e d elsewhere 2-1~ a n d to analyze the effect of the t h e r a p e u t i c regimen on the ultimate outcome. O n this basis, a representative series has been collected f r o m the literature ( T a b l e V I I I ) a n d divided into the following groups: (1) those children who received no specific t h e r a p y , (2) those children who received antibacterial treatment, and (3) those children who received antibiotics a n d corticosteroids. A l t h o u g h the follow-up in these reports is variable, most of the children were seen for at least 2 years after the initiation of therapy. T h e 5 year case f a t a l i t y r a t e of a b o u t 15 p e r cent

No. of cases Per cent alive Per cent dead Per cent clinically well

100 85% 15% 48%

71 86% 14% 78%

64 73% 27% 49%

163 85% 15% 65%

~Present study.

a n d the 65 p e r cent incidence of s y m p t o m free patients represent d r a m a t i c i m p r o v e m e n t over the case f a t a l i t y rate of a p p r o x i m a t e l y 40 p e r cent in the e r a before corticosteroids a n d antibiotics were available. T h e t r e n d in nephrosis has been t o w a r d i m p r o v e m e n t in the early years. H o w e v e r , it is evident t h a t fewer children who still h a v e active illness a f t e r 5 years recover completely. D e a t h s f r o m chronic renal failure continue to occur a n d the case fatality rate increased to 22 p e r cent after 8 to 10 years. A precise c o m p a r i s o n c a n n o t be m a d e between the present study a n d other series because of the v a r i a b i l i t y in the follow-up p e r i o d a n d in the m e t h o d s of using corticosteroids. H o w ever, the over-all case f a t a l i t y rate was v e r y similar in all series in which p a t i e n t s received some form of corticosteroid t h e r a p y (Table IX). V a r i o u s features of the illness were reviewed to d e t e r m i n e h o w they m i g h t have influenced the u l t i m a t e outcome. A m o n g these were the initial clinical status of the

5 14

Corn[eld and Schwartz

patient, the duration of illness prior to institution of therapy, and the type of therapy. PRESENTING SIGNS IN RELATION TO ULTIMATE OUTCOME

T o establish criteria helpful in defining the ultimate prognosis for a child with nephrosis, Barness and associates a reviewed the records of 208 patients seen in the precorticosteroid era. They considered the presence of hypertension, acidosis, or azotemia of more than 1 month's duration a n d / o r gross hematuria at the time of onset of the illness to be the most helpful criteria for differentiating children with a poor prognosis from those with less severe disease. The present study confirmed the importance of evidence of "nephritis" at the time of diagnosis: patients who had more than one sign of diffuse glomerular injury (BUN over 25 rag. per cent, diastolic hypertension, or hematuria) had less favorable prognoses than did those without such findings. However, anasarca and marked hypoalbuminemia, cited by Grayboski and Brandt 5 as indications of a grave outcome, did not prove to be useful prog-nostically. McCrory and co-workers 9 noted that the response to corticosteroid therapy and the course in the subsequent 3 months provided useful prognostic information. A patient who did well on initial corticosteroid treatment generally continued to do so when the same drugs were used in subsequent relapses. Twenty-one patients (also included in the present study) were grouped on the basis of response to therapy. Of the 11 patients who had complete clinical and chemical remissions following the initial treatment, 9 are still well, 1 has died and 1 15-year-old boy has evidence of chronic nephritis but continues to respond to therapeutic doses of prednisone when he is edematous. A renal biopsy on this child 8 years after the onset of his illness was interpreted as normal under light microscopy, but when repeated 10 years after the onset revealed evidences of advanced glomerulonephritis. Of the 6 pagents who had diuresis with initial corticosteroid treatment but continued to have

April 1966

proteinuria, 4 are now well, 1 has chronic nephritis, and 1 has been lost to follow-up. The 4 patients refractory to treatment initiated at the time of diagnosis have died. DURATION OF ILLNESS BEFORE INSTITUTION OF THERAPY

There have been conflicting reports about the urgency of beginning corticosteroid therapy after the diagnosis of nephrosis has been established. H e y m a n n and Hunter, G from observation of 63 children, suggested that early treatment increased the chance for a favorable outcome and noted also that patients who were treated early required fewer subsequent hospitalizations for treatment of edema. Barnett, ~.1 in commenting on these findings, suggested that there might have been a bias toward favorable prognosis in the group treated early because patients who had an early and permanent remission with corticosteroids were not included. In other reviews in which a more favorable prognosis has been noted in the children treated early in the course of their illness, the duration of follow-up is relatively short. 7, 9, 12, a4 In a recent report 5 it is claimed that there is no difference in the ultimate outcome of nephrosis whether or not treatment is initiated promptly. T h e data in the present study support the latter opinion. However, the incidence of active disease is lower in the group treated within 2 to 3 months of the onset of symptoms. TREATMENT TO INDUCE DIURESIS VERSUS REMISSION

In comparing the early posttreatment course of children who received corticosteroids to induce diuresis with that of children given more intensive or prolonged therapy, it is evident that more of the latter fall into the well or mildly affected categories. This is true through the first 5 years of follow-up, suggesting an advantage for the more intensive treatment program. The difference is no longer evident at 8 to 10 years. Although there were fewer deaths in the intensively treated group, more can be anticipated among the children who now

Volume 68 Number 4

show evidences of chronic renal disease. Prolonged and intensive therapy did reduce the number of clinical relapses. There are few reports in the literature about the outcome of pregnancy in patients who have had nephrosis in childhood. K o h n and Obrinsky 15 mentioned one w o m a n with toxemia who delivered a normal b a b y and was well postpartum. I n the present study, all patients who conceived were able to carry the p r e g n a n c y to term without complications. Although there were complications from the corticosteroid therapy, including Cushingoid appearance, myopathy, pseudotumor, hemorrhagic pancreatitis, osteoporosis, serious infection, and steroid diabetes, they were not directly responsible for any deaths. SUMMARY

A study of the course of nephrosis in 163 children is reported. T h e data seem to indicate that corticosteroid therapy has significantly altered the course of the disease when contrasted with that noted in reviews from the precorticosteroid era. The 15 per cent case fatality rate at the 5 year evaluation is a marked improvement over that of approximately 40 per cent recorded before corticosteroids and antibiotics were available. However, deaths still continue to occur, and after 8 to 10 years the case fatality rate approaches 25 per cent. Intensive corticosteroid t h e r a p y has resulted in fewer relapses in the first several years of the disease, but the ultimate prognosis is no better than that obtained with less intensive therapy. The changing pattern of nephrosis adds emphasis to the need for long term followup. M a n y patients who did poorly for several years become symptom free and showed no laboratory evidence of disease thereafter, whereas others who were clinically well for as long as 9 years suffered relapses. T h e trend of the disease is toward improvement

Nephrosis

5 15

in the early years, but after 5 years fewer children with nephrosis improve and chronic renal changes and deaths continue to occur. REFERENCES

1. Riley, C. M., and Davis, R. A.: Childhood nephrosis, Pediat. Clin. North America, 893, 1955. 2. Arniel, C. G.: 164 children with nephrosis, Lancet 2: 1103, 1961. 3. Barness, L. A., Moll, G. H., and Janeway, C. A.: Nephrotic syndrome, natural history of the disease, Pediatrics 5: 486, 1950. 4. Saxena, K. M., and Crawford, J. D.: Current concepts: the treatment of nephrosis, New England J. Med. 272: 252, 1965. 5. Gryboski, J. D., and Brandt, I. K.: The nephrotic syndrome in childhood: prolonged glucocortieoid therapy, Yale J. Biol. & Med. 35: 258, 1962-63. 6. Heymann, W., and Hunter, J. L. P.: Importance of early therapy of the nephrotic syndrome, J. A. M. A. 175: 563, 1961. 7. Piel, C., Goodman, J., and Williams, G.: The nephrotic syndrome. Five years experience with steroid therapy and renal biopsy, Am. J. Dis. Child. 100: 766, 1960. 8. Barnett, H. L., Forman, C. W., and Lausan, H. D.: The nephrotic syndrome in children, in S. Z. Levine, editor: Advances in pediatrics, Chicago, 1962, Year Book Publishers, Inc., 5: 53. 9. McCrory, W. W., Rapoport, M., and Fleisher, D. S.: Estimation of severity of the nephrotic syndrome in childhood as a guide to therapy and prognosis, Pediatrics 23: 861, 1959. 10. Soto, R., CordiIlo, G., et al.: Nephrotic syndrome in children, Bol. M. Hosp. Infant. (Mex.) 16: 471, 1959. 11. Barnett, FI. L.: Comments in Yearbook of pediatrics, Chicago, 1961-62, Year Book Publishers, Inc., p. 244. 12. Lange, K.: Proceedings of the Ninth Annual Conference on the nephrotic syndrome, J. Metcoff, editor: New York, 1958, National Nephrosis Foundation, p. 234. 13. Lange, K., Strang, R., Wenk, E. J., and Slobody, L. B.: The treatment of the nephrotic syndrome with steroids in children and adults, Arch. Int. Med. 99" 760, 1957. 14. McCrory, W. W.: Proceedings of the Tenth Annual Conference on the nephrotic syndrome, J. Metcoff, editor: New York, 1958, National Nephrosis Foundation, p. 277. 15. Kohn, J. L., and Obrinsky, W.: Lipid nephrosis in children, Am. J. Dis. Child. 84: 587, 1952.