Arch. Dis. Childh., 1965, 40, 659.

NEPHROSIS: A CLINICAL AND HISTOLOGICAL STUDYOF 38 CHILDREN

BY

R. McLAREN TODD and M. J. BOUTONFrom the Department of Child Health, Liverpool University, and Alder Hey Children's Hospital, Liverpool

(RECEIVED FOR PUBLICATION MARCH 29, 1965)

Many attempts have been made to classify renaldiseases in general and glomerulonephritis inparticular since Richard Bright (1836) reported hisclassical researches into the clinical and pathologicalchanges in his patients suffering from kidney disease.The word nephrosis was coined by Muller (1905) todefine a clinical condition characterized by oedema,albuminuria, and hypoproteinaemia. Volhard andFahr (1914) classified Bright's disease into threegroups, (A) nephrosis, (B) nephritis, and (C) arterio-sclerosis. The best known classification in thiscountry is that of Ellis (1942) who divided nephritisinto types 1 and 2: its great merit was that it attempt-ed to correlate clinical features with histologicalchanges. In our experience, however, it is oftenimpossible to divide renal lesions into these twotypes, for there are often transitions from one type toanother, and even the correlation between histologi-cal features and clinical findings is poor. Theattempts by Dodge, Daeschner, Rosenberg, Brennan,Travis, and Hopps (1962) to introduce modificationsof the Ellis system only lead to further confusion,especially when comparing their results with those ofother workers. We have, therefore, come to theconclusion that the only helpful classification ofnephritis is one based on descriptive morphology; inour experience this classification is of considerablehelp in prognosis, though it might not be of as muchassistance in unravelling the aetiology of this groupof diseases. It is likely that the kidney responds inmuch the same way to a variety of insults, but someof the changes may be permanent, some may developslowly over a period of years, some may be progres-sive, and yet others may resolve completely. Webelieve that renal biopsy may be of considerable helpin prognosis by providing evidence of the types ofchanges occurring in the kidney.The patients we have studied have all shown

clinical evidence of nephrosis. We apply this termto patients presenting a characteristic group of

symptoms, signs, and biochemical features, i.e.oedema, albuminuria, hypoproteinaemia, and hyper-cholesterolaemia; all are often of insidious onset andvary in degree over a period of years. This clinicalview of nephrosis is well described by Kramer,Goldman, and Cason (1952), who add that nephrosisoccupies a position shared by few diseases inmedicine: its aetiology is unknown, its courseunpredictable, its prognosis uncertain, and itstreatment unsatisfactory.Over the past decade knowledge of the natural

history of nephrosis has increased, due in no smallmeasure to the improved biochemical and histologicaltechniques which have been employed, and treatmenthas been more satisfactory since corticosteroidsbecame available. It is our purpose in presentingthe clinical, biochemical, and histological features of38 children suffering from nephrosis to suggest that amore accurate diagnosis is possible, a more valid'prognosis can be made, and the response to corti-costeroids can be predicted.

Clinical FeaturesThe patients were all seen at Alder Hey Children's

Hospital, Liverpool; 25 were boys and 13 were girls.The age at onset of the illness varied from 14 monthsto 131 years, but as is shown in Fig. 1, 25 of thechildren were below the age of 6 years when firstadmitted to hospital; they have been followed up inthe out-patient department for periods up to 10years. The illness did not have a seasonal incidenceand was not more common in the winter monthswhen respiratory infections were prevalent, the onsetof symptoms in half the patients being in the monthsof October to March and in the other half from Aprilto September. There was, however, a history ofpyrexial illness within 1 month of the onset ofnephrosis in 27 of the 38 patients; 24 of them gave ahistory of a cold, tonsillitis, or otitis, 2 of them had

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TODD AND BOUTON

cells in excess of 10 per 1/6 field were present in 6patients (Table 1).

Investigations

5 6 7 8 9 10 11 12 13 14

FIG. 1.-Age distribution of 38 children suffering from nephrosis.

recently recovered from gastro-enteritis, and 1 hadsuffered from boils.The presenting symptoms were oedema in 36

patients, pallor in 17, abdominal pain in 1 1, vomitingin 7, and a rash in 3.At the initial clinical examination all patients

except 2 had oedema of variable degree: in 3 patientsit was minimal, i.e. slight puffiness of the eyelids; in13 it was moderate, i.e. pitting oedema of shins or

feet; and in 20 it was severe, i.e. there were localizedcollections of fluid either in the peritoneal cavity,pleural cavity, or scrotum. Blood pressure was

normal in 21 and raised in 17 patients. Albuminuriawas present in all 38 patients: it was recorded as +in 5, + + in 4, and + + + in 29 patients; red blood

Throat swabs were taken from 32 patients: in 27 nopathogenic organisms were grown, in 4 haemolyticstreptococci were isolated, and in 1 Haemophilusparainfluenzae was isolated.

Blood urea was below 40 mg./100 ml. in allpatients except 7, in whom it was between 40 and 50mg./100 ml.

Total serum protein estimations and electrophoreticfractionations were carried out in all 38 patients andserum cholesterol values were measured in 34patients. The total serum protein levels weresubnormal in all except 2 patients; there was markedreduction in the levels of albumin, some reduction iny-globulins, and an increase in oct-globulins. Thesechanges are recorded in Fig. 2 and are related to thehistological features obtained at renal biopsy. Itwill be seen that in the membranous type of nephrosisthe total serum protein levels were not as low as inthe other types, and the y-globulin levels were normalor above normal in 4 of the 6 patients with membran-ous nephrosis.Renal biopsy was performed in all 38 patients.

Jungmann in 1924 was the first person to report hisresults of renal biopsies which were obtained duringthe course of abdominal operations. Percutaneousneedle biopsy was first used by Nils Alwall of theUniversity of Lund in 1944, but publication of hisresults was delayed until 1952. A relatively smallamount of renal tissue is obtained by percutaneousbiopsy, and the specimen may be torn or fragmented.

TABLE 1DETAILS OF 38 CASES OF NEPHROSIS GROUPED ACCORDING TO RENAL HISTOLOGY

Proliferative Membranous Minimal Mixed Total

Number of patients 20 6 8 4 38History of recent infection 11 4 6 3 24Haem. strep. in throat .2 1 1 - 4Oedema-minimal. .. 1 2 - - 3

moderate. 4 2 5 2 13severe .14 1 3 2 20

Albuminuria + .2 1 2 - 5++ .2 1 _ 1 4+ + + .. .. .. .. .. .. 16 4 6 3 29

Urine-RBC over 10 per 1/6 field - 2 - 4 6Blood pressure-normal .8 4 6 3 21

raised .12 2 2 1 17Blood urea < 40 mg./100 ml. 15 6 6 4 31

40-50 mg./100 ml. 5 - 2 - 7Blood cholesterol-normal 5 2 - - 7

240-350 mg./l00 ml. 7 2 2 2 13over 350 mg./100 ml. 7 2 4 1 14not done .1 - 2 1 4

Deaths 1 2 - 1 4Still active clinically .2 2 - - 4In remission-clinical.1 - 1 2 4

clinical and urine .2 1 - 3clinical, urine, and biochemistry.. 14* 2t 6 1 23

* Four off treatment. t One off treatment.

660

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CLINICAL AND HISTOLOGICAL STUD Y OF NEPHROSIS2 3 4 2 3 4

TOTAL PROTEIN ALBUMIN

2 3 4 2 3 4 2 3

y cx2GLOBULIN GLOBULIN

FIG. 2.-Serum proteins-total and fractional, and cholesterol levels in 38 cases of nephrosis grouped according to renal histology.(1) Proliferative. (2) Membranous. (3) Minimal. (4) Mixed. Broken lines indicate normal ranges.

It has been our practice to enlist the help of our

surgical colleague, Mr. Herbert Johnston, to obtaina specimen of renal tissue by open biopsy. Thisentails a small incision in the loin not more than 1 in.(2 5 cm.) long, exposure of the kidney, and removalof 0 25 in. (0 6 cm.) cube of renal cortex underdirect vision. The renal tissue contains 25 to 30glomeruli per section, the specimen is not fragmented,and no serious complications have been observed.There was some delay in wound healing in a fewpatients who at the time of biopsy had massiveoedema and who were already on treatment withcorticosteroids. The histological features enabledus to divide the material into 4 types.

Minimal proliferative. This is probably identicalwith 'lipoid nephrosis'. The glomeruli show verylittle histological abnormality, but careful analysiswill often show that there may be proliferation ofnuclei in some of the glomeruli, or some reduction inthe number of open capillary loops. They are filledby an eosinophilic material which probably representsa swelling of the mesangium.

Proliferative. All the changes described aboveare present but are more marked. The number ofnuclei in the glomerular tuft is increased, but we havenot found it possible to differentiate those of endo-thelial from those of epithelial origin. There isincreased staining of the mesangium and the capillarylumen no longer appears patent. There is some

rigidity of the basement membrane, which may beslightly thickened focally. There is diminution ofthe capsular space and synechiae are quite frequent.In a minority of cases there is proliferation of thecells lining Bowman's capsule, and crescents can beseen. We do not consider their presence to haveany sinister significance, as implied by Ellis, but onlythat they indicate a more severe reaction. Norcould their frequency be correlated with the length ofthe disease process.

Periodic acid-Schiff staining reveals an increasein PAS-positive material in the tuft, which is mainlydeposited like fibrils throughout the mesangium.They are probably the early stages of fibrillary scars.

This group is very heterogeneous and probablycontains aetiologically different diseases. It is not

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TODD AND BOUTONsurprising, therefore, that it is this group that hasgiven rise to most controversy, and has a less clearprognosis. But if it is remembered that the diseaseis in a state of 'flux' and can resolve or progress, muchof the controversy is easily explained. In our

experience with children the prognosis, as will beseen later, is good; but in adults the prognosis may bedifferent (Kark, Pirani, Pollak, Muehrcke, andBlainey, 1958; Blainey, Brewer, Hardwicke, andSoothill, 1960).

Proliferative changes are sometimes focal, that isto say they are confined to one or two lobules of theglomerulus and often to only a few glomeruli.Although we have found these changes more often inpatients who present with haematuria (Bouton andTodd-to be published), they also occur in some

patients with the clinical and biochemical features ofnephrosis.

This focal lesion is basically the same as thatwhich occurs in Schonlein-Henoch purpura (Heptin-stall, 1960), but when nephrotic features arise theglomerular lesion may become more generalized andepithelial crescents may be seen; it is still possible,however, to recognize focal scars in areas of focallobular accentuation of proliferation, and differencesbetween the glomeruli in the degree of involvement.Membranous. This group is the easiest to

recognize. Our criteria have been diffuse thickeningof the basement membrane without any accompany-ing proliferation of nuclei. The thickening isusually marked and must not be confused with therigidity which is often present in mainly proliferativecases. This thickening stains positively with PAS,but not infrequently the original basement membranestains distinctly and the 'thickening' appears toconsist of a material that has been deposited againstthe basement membrane, rather than a thickening ofthe original membrane. This type of lesion ispermanent and can be progressive.

Mixed. It is not surprising that a number of casesshow changes that are mainly proliferative in someglomeruli but mainly membranous in others. Twopatients with clinical features of nephrosis also hadevidence of Schonlein-Henoch purpura, and histo-logical examination showed that mixed changes were

present. They showed clinical improvement afterprolonged steroid therapy, the serum proteinsbecame normal, but a small amount of albuminpersisted in the urine. It is pertinent here to pointout that the proliferative changes in these patientsand in other patients who did not have nephrosiswere very marked, and included proliferation ofextracapillary Bowman's membrane epithelium andnumerous crescents. These changes were indis-tinguishable from those described in the so-called

progressive form of Ellis type I subacute nephritis,and are further evidence that this classification isunworkable, as most ofthem have recovered clinicallyand have not yet developed chronic nephritis.

TreatmentThe main objectives in the treatment of our

patients have been (i) to increase the level of serumproteins; (ii) to eliminate oedema; (iii) to preventinfections, especially those caused by pneumococciand streptococci; and (iv) to sustain the morale ofpatients and their parents in what is a long-termillness, often punctuated by exacerbations andremissions. We have attempted to achieve theseobjectives by the following four methods: (a) theprovision of a high-protein, low-salt diet, supple-mented in 3 patients by intravenous infusions of salt-free plasma; (b) the prophylactic use of penicillingiven orally, in a dosage of 200,000 units twice daily,for a period of years; (c) the use of diuretics:hydrochlorothiazide was given to 9 patients,chlorothiazide to 6, spironolactone to 8, andfrusemide to 1; and (d) the use of corticosteroids.

Prednisolone was the only corticosteroid given to 23patients; in a further 9 patients it was given initiallybut changed to a water-soluble corticosteroid, e.g.prednisol, triamcinolone, because of lack of clinicalresponse; in a further 3 patients prednisolone wasgiven after a short course of ACTH, and in 3patients corticosteroids other than prednisolone weregiven. The corticosteroid used reflected the prefer-ence of the paediatrician in charge of the patient, butprednisolone was usually preferred.The initial dosage of prednisolone was 50 to 75

mg. daily and it was continued as a rule for 2 weeksuntil clinical response was obtained, and then gradu-ally reduced over a period of 4 to 6 weeks to amaintenance dose of 71 to 10 mg.; the maintenancedose was continued usually for years until the resultsof urine and blood analysis showed normality; in onepatient prednisolone was discontinued after 10 weeksand during the subsequent 4 years he has not had arelapse either clinical or biochemical.

Response to TreatmentInitial clinical response to steroid therapy occurred

within a month in all patients except two, one withmembranous changes and one with proliferativechanges and necrotizing glomerulitis, and both thesepatients died. Relapse, indicated by recurrence ofoedema and increase of albuminuria, was a commonfeature in all 4 groups. Relapse occurred on 58occasions in 20 survivors in the proliferative groupover an aggregate period of 91 patient years, i.e. an

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CLIANICAL AND HISTOLOGICAL STUDY OF NEPHROSIS

average of 1 relapse per patient every 18 months; inthe membranous group of 6 patients, there were 2deaths, 2 patients remained active clinically, 2responded initially but 1 of them relapsed; in theminimal group there were 17 relapses in 8 patients in31 years, i.e. 1 relapse per patient every 23 months;in the 4 patients showing mixed changes there was 1

death and relapse occurred in 2 of the survivorswithin 1 year of initial diagnosis.

Complications were observed in 3 patients; one

patient developed osteoporosis of the spine after hehad been on prednisolone for 4 years, and 2patients developed pneumococcal peritonitis inspite of prophylactic penicillin therapy.

Recovery was judged by three criteria, namelyclinical disappearance of oedema, cessation ofalbuminuria, and return to biochemical normality.Complete clinical, urinary, and biochemical recovery

occurred in 14 patients in the proliferative group and4 of these patients have stopped steroids; in a further2 patients, clinical and urinary examination was

negative but serum protein levels were not completelynormal, and in 2 patients there was no oedema butalbuminuria persisted and serum proteins were

abnormal; 2 patients continued to have activeclinical disease.

Complete recovery occurred in 2 of the 6 patientswith membranous changes, 6 of 8 patients withminimal changes, and 1 of 3 patients with mixedchanges. Death occurred in 4 of the 38 patients.One patient, a-girl of2 years, had proliferative changeswith necrotizing glomerulitis: she was unresponsiveto steroids and died in cardiac failure 5j monthsafter the onset of symptoms. The second death wasin a girl aged 131 years with membranous changeswhich failed to respond to steroids: she becamehypertensive and died 18 months after the onset of theillness. The third death occurred in a boy aged 5 yearswith mixed changes, who was treated with steroidsbut who died 3 months after onset of symptoms.The fourth death occurred in a boy with membranouschanges with a clinical history of 6 months' duration,who was unresponsive to steroids.

DiscussionThe main problems encountered in patients

suffering from nephrosis are those concerned with(a) diagnosis, (b) treatment, and (c) prognosis.

(a) Diagnosis. Oedema, albuminuria, hypopro-teinaemia, and hypercholesterolaemia are the clinicalfeatures of nephrosis, but these four abnormalities donot give any indication of the underlying cause.

Kark et al. (1958) state that in adults there are 40disease states which can produce nephrosis: in 46 of

their 98 patients nephrosis was due to intrinsic renaldisease, i.e. glomerulo-nephritis, but in others it wasdue to systemic diseases such as lupus erythematosus,amyloidosis, diabetes mellitus, Schonlein-Henochpurpura, drugs, e.g. mercury, gold, tridione, in whichthe renal involvement was but one element. Thusrenal biopsy enables a more accurate diagnosis to bemade.

Estimation of the levels of y- and X2-globulins to-gether with level of blood cholesterol may indicatewhether membranous changes are present; in themembranous type y-globulin may be above normal,oc2-level may not be raised excessively, and cholesterolmay be normal. In contrast, in patients showingproliferative changes at biopsy, the o2-level is raisedoften in excess of 1 g./100 ml., y-globulin level isreduced and serum cholesterol level is often raisedto 300 mg./100 ml. or more.

(b) Treatment. Many forms of therapy have beenadvocated for nephrosis; in their review of treatmentused at the Children's Medical Center, Boston, Mass.during the years 1926 to 1948, Barness, Moll, andJaneway (1950) list 64 forms of treatment. There isgeneral agreement that steroids have proved ofconsiderable value in the treatment of nephrosis inchildhood, and in most patients oedema disappears,and other clinical and biochemical changes indicatea favourable response to steroids. In adults,however, the outlook is not so favourable. Rossand Smith (1963) followed for a period of 5 years theprogress of 26 adults treated with steroids; 4 respond-ed by complete loss of proteinuria, in 7 proteinuriawas reduced to less than 1 g. per litre, but in 15patients failure to respond to steroids was reported.There are certain disadvantages in the prolonged useof steroids, such as stunting of growth, moon face,striae, osteoporosis, hypocalcaemia, and eye changes.Renal biopsy may be of help in deciding whetherresponse to steroids is likely to occur; when prolifera-tive changes are present, response to steroids usuallyoccurs, but when membranous changes are alreadypresent it is unlikely that they will be influenced bysteroids.

Relapses are frequently encountered in patientssuffering with nephrosis and they are often provokedby certain infections. Respiratory tract infectionswill often be followed by reappearance of oedemaand other signs of activity; when these infections arebacterial in origin, e.g. streptococcal, penicillin maybe helpful in prophylaxis, but when epidemic viralinfections are prevalent no form ofchemoprophylaxisis of avail.

(c) Prognosis. It is extremely difficult in childrensuffering from nephrosis to give a direct answer to

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TODD AND BOUTONTABLE 2

OUTCOME OF 590 CASES OF NEPHROSIS ACCORDING TO VARIOUS TYPES OF TREATMENT

Date

1926 to 1938 (pre-chemotherapy)1939 to 1942 (sulphonamides)1943 to 1948 (penicillin)

1922 to 1942

1917 to 1938 (pre chemotherapy)1945 to 1957: no steroids

steroids

1929 to 1936 (low sodium diet, pre-sulphonamide)1937 to 1945 (sulphonamides)1946 to 1950 (penicillin, etc.)1951 to 1955 (cortisone, ACTH)1955 to 1957 (prednisolone)

1948 to 1955 (50% given steroids)

1956 to 1964 (steroids)

the parents' request to indicate the probable course

of the illness or its length, but certain factors are ofconsiderable help in forming a prognostic judgement.A severe degree of oedema by no means indicates a

bad prognosis, neither is prognosis worse if albumin-uria is marked. In 6 patients red blood cells were

present in the urine in excess of 10 per 1/6 field, andin many of these red cells exceeded 100 per 1/6field, in 4 of these 6 patients there was either no

response or a poor response to steroids; thus in our

experience haematuria is a poor prognostic sign.Serum cholesterol levels were usually raised, but in 8patients levels were normal; the response of all but1 of these 8 patients to treatment was poor andsuggests that estimation of the cholesterol level is ofprognostic value. Blainey et al. (1960) in their studyof nephrotic syndrome in adults found that thehighest values for serum cholesterol were obtained inthose patients who responded best to treatment.

Long-term follow up of patients suffering fromnephrosis indicates the improved prognosis, as

judged by mortality, resulting from the introductionfirst of sulphonamides and later of antibiotics;further improvement in prognosis has resulted fromthe introduction of steroids. Table 2 lists the resultsof treatment of 590 children suffering from nephrosis,and relates the results to the form of therapy used.The over-all mortality rate is 38% and the 'cure' rate444, using the term 'cure' for absence of clinicalevidence of disease when assessed at least 3 yearsafter the onset of the illness. Following theintroduction of chemotherapeutic agents there was a

slight improvement in prognosis, while with theintroduction of steroids the mortality rate has beenreduced by half and the 'cure' rate has increased.

No.of -

Patients

403264

40

786240

1141375322

32

38

590

Well

No. 0

17 42-59 2818 28

12 30

?41 5333 5316 40

3 2813 3218 4826 4214 64

14 44

30 78

264 44

Active

No. %'

6 152 717 27

6 15

9 156 15

4 3614 345 14

18 396 27

7 22

4 11

104 118

Deaths

No. 0O17 42-521 6529 45

22 55

?37 4720 3218 45

4 3614 3414 389 192 9

11 34

4 11

222 38

The percentage of deaths in the series of patientsrecorded in Table 2 was 45% before chemotherapy,43% with chemotherapy but without steroids, and21 % with chemotherapy and steroids. The 'cure'rates in the three corresponding groups were 38 %,40 %, and 54 %. The only anomalous report is thatfrom Great Ormond Street Children's Hospital(Lawson, Moncrieff, and Payne, 1960) in which the'cure' rate without steroids was 53% and withsteroids 40 %, and the death rate 32% withoutsteroids and 45% with steroids. In Alder HeyChildren's Hospital, comparison of experience for1948 to 1955 (Todd, 1957) with the present series(1956 to 1964) shows a reduction in mortality from34% to 11 % and an increase of 'cure' from 44% to78 %. There may well be an increase in the mortalityrate and a decrease in the 'cure' rate as the follow-upperiod lengthens, but judging from our furtherobservation of patients reported in 1957 (Todd) thecure rate should approach 700% after a minimumobservation period of 3 years.

Conclusions and SummaryThe clinical and biochemical features and the

histological appearances of the biopsied kidney havebeen studied in 38 children, varying in age from 14months to 13- years, who were suffering fromnephrosis.

Renal biopsy has contributed to our knowledge ofthis illness in three main ways. First, it has led to a

more accurate diagnosis, not only by excluding suchdiseases as lupus erythematosus, Schonlein-Henochpurpura, amyloidosis etc., but also by demonstratingthe nature of the renal changes, whether proliferative

664

Author

Barness et al. (1950) ..

Schwarz, Kohn, andWeiner (1943)

Lawson et al. (1960) .

Arneil (1961) ..

Todd (1957) . .

Todd and Bouton (thisinvestigation)

Area

Boston, Mass.

New York

London

Glasgow

Liverpool

Liverpool

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CLINICAL AND HISTOLOGICAL STUD Y OF NEPHROSIS 665

or membranous, and their extent. Secondly, it hasinfluenced treatment, steroid therapy being likely tobe successful in patients showing proliferativechanges, whereas the value of steroids is doubtfulwhen membranous changes are already present.Thirdly, prognosis can be more accurate; in general,patients showing proliferative changes have a betterprognosis, largely because of the value of steroids ina lesion which is potentially reversible, whereas theprognosis is poor in patients already showingmembranous changes.

Alterations in the levels of serum proteins can berelated to some extent to the histological picture.In the proliferative group, the total serum proteinlevels are often very reduced, and y-globulin is low,whereas in the membranous group, the total serumproteins are not reduced so much, and y-globulinlevel is often normal or even raised.The long-term prognosis for nephrosis is discussed

in the light of the published reports; it has improvedconsiderably over the past 4 decades and the three-year 'cure' rate in children treated with antibioticsand steroids now approaches 7000.

We wish to thank all our colleagues for their help inthis study, especially the Consultant Paediatricians forallowing us access to their patients, Mr. Herbert Johnstonwho performed the renal biopsies, and Mr. J. T. Irelandfor the biochemical investigations.

REFERENCES

Alwall, N. (1952). Aspiration biopsy of the kidney. Acta med.scand., 143, 430.

Arneil, G. C. (1961). 164 children with nephrosis. Lancet, 2, 1103.Barness, L. A., Moll, G. H., and Janeway, C. A. (1950). Nephrotic

syndrome. I. Natural history of the disease. Pediatrics, 5,486.

Blainey, J. D., Brewer, D. B., Hardwicke, J., and Soothill, J. F. (1960).The nephrotic syndrome. Quart. J. Med., 29, 235.

Bright, R. (1836). Cases and observations, illustrative of renaldisease accompanied with the secretion of albuminous urine.Guy's Hosp. Rep., 1, 3838.

Dodge, W. F., Daeschner, C. W., Jr., Rosenberg, H. S., Brennan, J.C., Travis, L. B., and Hopps, H. C. (1962). Percutaneous renalbiopsy in children. III. The nephrotic syndrome. Pediatrics,30, 459.

Ellis, A. (1942). Natural history of Bright's disease. Lancet, 1, 1.Heptinstall, R. H. (1960). Chapter 4. In Recent Advances inPathology,

7th ed., ed. C. V. Harrison, p. 89. Churchill, London.Jungmann, P. (1924). Ober chronische Streptokokkeninfektionen.

Dtsch. med. Wschr., 50, 71.Kark, R. M., Pirani, C. L., Pollak, V. E., Muehrcke, R. C., and

Blainey, J. D. (1958). The nephrotic syndrome in adults: acommon disorder with many causes. Ann. intern. Med., 49, 751.

Kramer, B., Goldman, H., and Cason, L. (1952). The treatment ofthe nonedematous nephrotic child with ACTH. J. Pediat., 41,792.

Lawson, D., Moncrieff, A., and Payne, W. W. (1960). Forty years ofnephrosis in childhood. Arch. Dis. Childh., 35, 115.

Miuller, F. (1905). Morbus Brightii. Verh. dtsch. path. Ges., 9, 64.Ross, E. J., and Smith, J. F. (1963). The use of steroids in the treat-

ment of the nephrotic syndrome in adults. Quart. J. Med., 32,65.

Schwarz, H., Kohn, J. L., and Weiner, S. B. (1943). Lipid nephrosis.Amer. J. Dis. Child., 65, 355.

Todd, R. McL. (1957). The natural history of nephrosis. Arch. Dis.Childh., 32, 99.

Volhard, F., and Fahr, T. (1914). Die Brightsche Nierenkrankheit.Springer, Berlin.

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