PRACTI CAL THERAPEUTICS

Drugs 42 (1): 30-51, 19910012-6667/91/0007-0030/$11.00 /0© Adis International Limited . All rights reserved.

DRU130

Management of Nephrotic Syndrome in Childhood

Tyrone Melvin and William BennettDepartments of Pediatrics and Medicine , Division of Nephrology and Hypertension,Oregon Health Sciences University, Portland, Oregon, USA

Contents303/3333353536404343444545454546

Summary

Summary1. Introduction and Early History of Nephrotic Syndrome

1.1 Relationship of Therapeutics to Rena l Histology2. Clinical Manifestations3. Pathogenesis of Proteinuria4. Natural History5. Clinical-Pathological-Therapeutic Correlations6. Outcome Defined for Each Histological Group7. Clinical Approach to Patients with Nephrotic Syndrome

7.1 Corticosteroids7.2 Cytotoxic Agents7.3 Complications of Therapy

7.3.1 Cyclophosphamide7.3.2 Chlorambucil

7.4 Complications of the Nephrotic State8. Conclusions

Nephrotic syndrome is defined as proteinuria sufficiently severe to result in hypoalbumin­aemia , oedema and hyperlipidaemia. The early modern history of this illness was characterisedby the serendipitous development of renal biopsy technique at approximately the same time asthe use of corticosteroids for nephrotic syndrome. The coincidence of these events set the stagefor evaluating therapeutic response to corticosteroids and cytotoxic agents in relation to renalhistology and ultimate clinical outcome.

The International Study of Kidney Disease in Children (ISKDC) was initiated in the 1960sas a multicentre study examining these relationships in children . Over the next decade this study,as well as contributions from other investigators, helped define optimum therapy for these child­ren. It was determined that a child with nephrotic syndrome under the age of 6 years, who didnot present with hypertension, azotaemia, hypocomplementaemia or signs of systemic illness,had an approximately 85% chance of responding to corticosteroid therapy. If only those childrenwho had minimal change histology on biopsy were considered, 94% responded. The originalregimen which is still used today , was 60 mg/m? bsa/day prednisone administered on a 3 timesper day dosage schedule for 4 weeks, followed by an additional 4 weeks of therapy at a dose of40 mg/m 2 bsa given as a single oral dose every other day.

Of those who respond roughly one-third will have no relapses, while almost half will have

Nephrotic Syndrome in Childhood 31

frequent relapses (~ 2 in 6 months) and the rest will have infrequent relapses. Patients in relapseare treated as at presentation but are usually converted to the 40 mg/m 2 bsa dose when the urinehas been free of protein for 3 days, and are then tapered off or maintained on this dose for severalweeks, depending on the individual's history of relapses and incidence of side effects from cor­ticosteroids .

For those children who are suffering frequent relapses and severe corticosteroid side effects(e.g. growth failure, morbid obesity, aseptic necrosis of bone), cytotoxic agents were identified asproviding long term remission. After inducing remission with conventional corticosteroid dos­ages, cyclophosphamide is administered at a dose of 2 rug/kg/day given as a single dose for 8weeks. This regimen was shown to lead to approximately 70% of patients being in remission 2years after completion of this course of therapy. Chlorambucil given at a dose of 0.2 rug/kg/dayas a single oral dose has been equally efficacious. A subgroup of the frequently relapsing patients,termed steroid-dependent (defined as relapsing while tapering prednisone or very shortly afterdiscontinuing prednisone) are less likely to benefit from cytotoxic therapy, with only 30% beingin remission 2 years after therapy is completed. In addition, children with histological lesionsother than minimal change (e.g. focal segmental glomerulosclerosis) are less likely to respond tocorticosteroids or cytotoxic agents.

Two other agents have been used for treatment of nephrotic syndrome. In steroid-dependentor -resistant children oral cyclosporin 7 mg/kg/day kept serum trough concentrations between100 and 200/Lg/L.Many of these patients relapsed when therapy was discontinued. Chlormethine(nitrogen mustard) has also been effective in producing long relapse-free intervals when used ata dose of 0.1 rug/kg/day, given as a single intravenous dose for 4 days.

The risks of these medications are discussed, focusing on leucopenia, infertility and risk ofsubsequent malignancy. At the dosages noted above, leucopenia is not required for the therapeuticeffect and does not usually prevent the completion of therapy, infertility is rare, and at presentthe question of increased risk of malignancy due to the use of cytotoxic agents remains unan­swered.

1. Introduction and Early History ofNephrotic Syndrome

Nephrotic syndrome in childhood is defined asproteinuria sufficiently severe to result in hypoal­buminaemia, oedema, and hyperlipidaemia. Its oc­currence does not imply a single aetiology but rathercomprises several clinical-pathological entities, eachwith a different natural history. Some of these areassociated with a systemic illness such as systemiclupus erythematosus (SLE), and are not discussedhere. Rather, the remaining idiopathic group formsthe focus of this review.

Until the late 1950s all childhood idiopathic ne­phrotic syndrome was considered as a single pro­cess (Barness et al. 1950). The advent of percuta­neous renal biopsy (Iversen & Brun 1951;Muehrckeet al. 1955) enabled the disease to be divided intorelatively distinct clinical-pathological syndromes,which was useful in predicting response to therapy

and progression to renal failure. The relative prev­alence of individual diagnostic groups was soonrecognised to be different in childhood and adultpopulations. Figure I shows the relative prevalenceof different diagnostic groups in patients with ne­phrotic syndrome seen at Guy's Hospital from 1964to 1984, as reported by Cameron (1987). It is clearthat in childhood the majority of children have anidiopathic disorder, while nephrotic syndrome inadults is frequently due to secondary causes suchas amyloidosis, diabetes mellitus, and SLE. Thesubtypes of the adult idiopathic nephrotic syn­dromes also have a completely different prevalencepattern. This review focuses on the major idio­pathic nephrotic states of childhood.

The scope of this problem is defined by an in­cidence of 2/ I00 000 (Rothenberg & Heymann1957; Schlesinger et al. 1968). No recent reportshave examined whether this estimate is changing,but the severity of illness has altered considerably.

32

%

542517

76

100

90

80

70

60

50

40

30Q)

0>

'" 20CQ)oQ;

10a.

FSGS~

Minimal changes

Drugs 42 (1) 1991

%

10.8

5.91.6

16.0}25.8

9.8

19.7

11.8

22

Allchildren

5 1015 20 30 40 50

Age at onset of NS

60 70 80 Alladults

Fig. 1. Prevalence of histological types of neph rot ic syndrome (NS) by age [reproduced with permission from Cameron (1987);deta ils of data sources can be found in this reference]. Abbreviations: HSP = Henoch-Schonle in purpura; MCGN = mes­angiocapilla ry glomerulonephritis; FSGS = focal segmental glomerulosclerosis.

Prior to the introduction of penicillin in 1944 themortality in some series was as high as 40%. Sub­sequently it. fell to 16% and with the introductionof corticosteroid therapy fell to between 3 and 7%(Barness et al. 1950; Churg et al. 1970; Habib &Kleinknecht 1971;White et al. 1970). Despite thesechanges, nephrotic syndrome remains a challengeto paediatricians, and a source of great stress to thechildren and their families. Lewis Barness' descrip­tion of the pressure felt by the practit ioner in thisillness (Barness et al. 1950) remains accurate in1991 : 'Few diseases tax the resources of the prac­tition er so extensively as the nephrotic syndrome .He must be a combination of infectious disease ex­pert , nutritionist, physiologist, and psychiatrist forthe patient and , above all, guide, counsellor andfriend to the parents.'

Before addressing the approach to diagnosis andmanagement, a review of the history of cortico-

steroid use and renal biopsy technique will serveto explain what seems to many a chaotic, frustrat ­ing and arcane synthesis of clinical characteristicsand therapeutic approaches . The problem derivesfrom 2 false assumptions: first, the novice pre­sumes that therapy derives from a systematic ap­proach based on a graded increase in understand­ing of the mechanisms of disease, incomprehensibleto all but nephrologists; and second, that the cur­rent histological classification is synonymous withknown aetiologies. As of 1950 no one could be surewhether nephrotic children had one or many path­ological processes, and therapy consisted of sod­ium reduction , high protein diet, use of sulfa andpenicillin for infection, abdominal paracentesis anda variety of other measures.

However, the early 1950s saw the first break­through in understanding and therapy for ne­phrotic syndrome . The earliest report of cortico-

Nephrotic Syndrome in Childhood

steroids can be traced to a presentation made atthe First Clinical ACTH Conference (Farnsworth1950). Why it was tried in nephrotic syndrome isunclear, although parental demands for therapy,speculation that rubeola infection (which was notedto lead to remission in some patients) might act bystimulating adrenal activity , and the observationthat normal individuals who received corticotro­phin (Acth; adrenocortico-trophic-hormone) re­tained salt and water may all have formed the im­petus [speculation of Riley (1951)]. A paucity oftherapeutic agents highlighted each new one, andcorticotrophin was exploited thoroughly.

At the conference it was reported that in some,but not all, patients a profound diuresis was ob­served with corticotrophin 40 to 50 mg/day , withdiuresis seen as early as I week into therapy(Farnsworth 1950). In rapid succession came con­

firmation of the dramatic diuresis seen in Farns­worth's patients (Lauson et al. 1952; Riley 1951;Thorn et al. 1950). Thus , the availability of a newdrug and the lack of options prompted its use asmuch as any prescient pathophysiological predic­tion of success. Thus , no one knew if or why cor­ticotrophin should really have anything to do withnephrotic syndrome and, in fact, its use was a co­incidence of need and availability.

The use of cytotoxic agents [e.g. chlormethine(mustine, nitrogen mustard)] , widely believed to bean evolutionary development from corticosteroiduse for resistant patients, actually preceded the useof corticosteroids for nephrotic syndrome. Chasiset al. (1949, 1950) used it in patients with nephritisand heavy proteinuria, and their results were con­firmed by Taylor and Corcoran (1950). The di­uresis was postulated, erroneously , to be due tosuppression of antibody synthesis.

As noted above, therefore, the early history oftherapeutics for nephrotic syndrome has not beensequential or evolutionary but was characterisedby individual trials by intrepid investigators, eachwith a unique gift for interpretation within the con­fines of a restricted base of understanding.

33

l.\ Relationship of Therapeutics toRenal Histology

It is pure coincidence that renal biopsy shouldhave become a clinical technique reported withinI year of the first report of corticosteroid use. Here,creative clinicians found they were predictive ofthe natural history of nephrotic syndrome in dif­ferent groups. As we shall see later, histological de­scription was and remains far from a statement ofcause.

Several investigators quickly adopted renal bi­opsy, buoyed up by the successofIversen and Brun(1951) and the prior experience of Alwall (1952).The first large series in which clinical manifesta­tions, histology and therapeutic outcome were syn­thesised was that of Muehrcke et al. (1955). AsMuehrcke put it, 'The therapeutic usefulness ofbi­opsy in providing data for selection of antibiotics,steroid therapy and metabolically active chemicalshas been demonstrated. Besides this it provides anunrivaled technique for studying the natural his­tory of the organ - around which rational therapymust be built.'

The use of renal biopsy in children was reported2 years later by Galan and Maso (1957), from Cuba.36 biopsies in 20 children (18 months to 10 yearsof age) with nephrotic syndrome were reported.Galan and Maso emphasised glomerular changesof thick basement membranes, cellular prolifera­tion, hyalinisation and fibrosis, and made corre­lations with the onset of nephrotic syndrome andresolution in repeat biopsies after treatment withcorticosteroids. While this did not turn out to bea representative histological description of child­hood nephrotic syndrome responsive to corticoste­roids, its approach has governed paediatric ne­phrology investigations to the present.

2. Clinical Manifestations

The description of children with nephrotic syn­drome has remained the same throughout recordedmedical experience. Barness et al. (1950) gave arepresentative and detailed description: the onsetin almost all patients was insidious , with the first

34 Drugs 42 (1) 1991

Table I. Immune function abnormalities in idiopathic nephrotic syndrome

Immune function abnormality Reference Immune function abnormality Reference

Smith et al. (1975)

Shimizu (1980)

Shakib et al. (1977)

Ballow et al. (1982); McLean

et al. (1977)

Kerpen et al. (1979), Sasdelli

et al. (1981)

Baliah et al. (1977),

Giangiacomo et al. (1975),

Sobel et al. (1976)

Heslan et al. (1982)Impaired in vitro IgG

synthesis

Decreased alternative

pathway components

(factors B and D)

Selective IgG subclass

depression

Increased immunoconglutinin Ngu et al. (1970)

levels

Increased circulating immune Levinsky et al. (1978), Poston

complexes et al. (1978)

Decreased streptococcal Baliah et al. (1977), Lange et

enzyme antibody formation al. (1981)

Immediate-type hypersensitivity

Increased serum IgE and Mansf ield et al. (1980),

antigen-specific IgE Meadow et al. (1981), Reeveset al. (1975), Schulte­Wissermann et al. (1979)

Increased incidence of atopy Mansfield et al. (1980),

Meadow et al. (1981)

Meadow et al. (1981)

Humoral immunity

Decreased EAC-rosette­

forming cells

Increased B-cell chemotactic

Iymphokine

Increased EAC-rosette­

form ing cells

Decreased serum IgG and

IgA, and increased IgM

Increased B13

Increased B8

Increased incidence of

pos itive skin tests

Remiss ion with food allergen Laurent & Lagrue (1989)

avoidance

Histocompatibility antigen relationships

Increased HLA-B12 , Alfiler et al. (1980), Thomson

decreased HLA-B7 et al. (1976), Trompeter et al.

(1980)

Alfiler et al. (1980), Mouzon­

Cambon et al. (1981), Nunez­

Roldan et al. (1982)

Mouzon-Cambon et al. (1981),

O'Regan et al. (1980)Increased B18 O'Regan et al. (1980)

Increased Al-B8 haplotype O'Regan et al. (1980),

Thomson et al. (1976)Noss et at, (1981)

Increased HLA-DRw7,

decreased DR2

Branellec et al. (1988), Nagata

et al, (1981)

Hisanaga et al. (1990)

Hinosh ita et al. (1990)

Lagrue et al. (1988)

Matsumoto (1989)

Cheng et at. (1989), Schnaper

& Aune (1985, 1987)

Posner et al. (1980

Blumberg & Cassady (1947),

Janeway et al. (1948),

Lin & Hsu (1986)

Ahuja & Wright (1989),

Kuzemko (1972)Inage et al. (1990)

Abiko et al. (1979)

Chisar i (1977), Curtiss &Edgington (1976), McLeod

et al. (1981), Menchaca &

Lefkowitz (1980), Ohta &

Matsuda (1981)

Nagata et al. (1983)

Boulton-Jones & Simpson

(1980), Lagrue et al. (1975),

Trompeter et al. (1978a)

Plager & Stutzman (1971)

Brodovsky et al. (1968), Seney

et al. (1986)

Allon et al. (1988)

Staszewski et al. (1988)

Fodor et al. (1982), litaka &West (1979), Minchin et al.

(1981), Taube et al. (1981)

Eyres et al. (1976), Ooi et al.

(1974)

Anderson et al. (1979), Mallick

et al. (1972)

Trompeter et al. (1978a)

Occurrence of MCNS after

rubeola vaccineSuppressor T-Iymphocyte

dysfunctionThymic hormone deficiency

Increased VLDL andlymphocyte blastogenesis

inhibit ion

Increased lymphocytes in

glomeruli in MCNS

Defective monocyte

phagocytosis

Cytokines

Nephrotic syndrome

associated with r1L-2 infusion

Decreased production of IL-2

Increased production of IL-2

Decreased production of IL-l

Presence of soluble immune

response suppressor

MCNS occurrence in patients

with:

Hodgkins disease

Chron ic lymphocytic

leukaemia

Mycosis fungoides

Angioimmunoblastic

lymphadenopathy

Thymoma

Remission induced by

rubeola

Cellular immunity

Decreased lymphocyte

blastogenesis in response to

antigens

Lymphocytotoxicity in

response to fetal kidney cells

Decreased leucocyte

migration

Abnormalities of T-cell

subpopulation

Presence of vascular

permeability factor

Abbreviations: MCNS = minimal change nephrotic syndrome; VLDL = very low density lipoprotein; r1L-2 = recombinant inter­

leukin-2; IL-l = interle ukin-l ; EAC = erythrocyte-antibody-complement.

Nephrotic Syndrome in Ch ildhood 35

4. Natural History

It is infrequently recalled that patients with un­treated nephrotic syndrome are not uniformly oed­ematous , but experience frequent spontaneous andoften long-lasting remissions. Barness et aL (1950),reporting on a series of patients from Boston, de­scribed the outcome of 161 cases cared for between1926 and 1946 (none treated with corticosteroids).Two-thirds of these were followed for at least 2years at the time of the report ; 41% were asymp­tomatic at follow-up. In addition, these data were

in general been focused on immunological abnor­malities. Such mechanisms are best reviewed bylimiting the discussion to those relating to minimalchange nephrotic syndrome (MCNS). Proposedmechanisms cover a broad range including allergicmanifestations, cell-mediated immune functionabnormalities, abnormalities of immunoglobulinsynthesis and unique HLA associations.

Table I has been designed to facilitate a litera­ture review of the voluminous amount of infor­mation in various areas of interest through the in­dividual cited references.

10

Dead - 40%

Symptom -free - 56%

2 4 6 8Time (years of illness)

75

25

100

3. Pathogenesis of Proteinuria

symptom noted by parents being swelling of eye­lids in 42% of cases, rapid weight gain noted in23%,and an upper respiratory tract infection in the2 or 3 days prior to the appearance of oedema in25%. They also noted that males were predomi­nant , making up 61% of their patient population.The age at onset was 3.5 years with a standard de­viation of 2.1 years.

We must keep in mind that these data weregathered and analysed prior to histological corre­lation. The discrimination between patients withlipoid (minimal change) nephrosis and those withnephrotic phases of more chronic nephritides wasbased on lack of hypertension , azotaemia and ab­sence of gross haematuria.

The laboratory features mentioned above al­lowed for a reasonable categorisation of patients.Persistent hypertension was seen in only 1% ofclinically defined lipoid nephrosis patients, azotae­mia in 8%, and microscopic haematuria was seenin 27%. These data have changed somewhat overthe years as biopsy allowed for a refinement ofgroups, but even in 1950 these features providedgood discriminating power.

Hypoalbuminaemia and hypercholesterolaemiawere also noted to be almost universal features ofthe nephrotic syndrome in addition to the heavyproteinuria. In addition, several investigators notedthat the erythrocyte sedimentation rate (ESR) wasgreatly elevated.

Diarrhoea is also highlighted as a prominentsymptom during periods of oedema, as well as skinirritation and infection. Chronic ascites was de­scribed as leading to venous dilatation of the ab­dominal wall and umbilical hernias. In addition,rectal prolapse was not uncommon. It was also re­cognised that bacterial infections were frequentduring periods of oedema, usually bacteraemia orperitonitis caused by pneumococcus, fJ haemolyticstreptococci or Escherichia coli.

Virtually every conceivable pathogenetic mech­anism has been advanced as an explanation forproteinuria in nephrotic syndrome. Research has

Fig. 2. Pattern of illness over time in 164 children with ne­phrotic syndrome (untreated) illustrating frequency of spon­taneous remissions (reproduced with permission from Arnei11961).

36 Drugs 42 (l) 1991

Response: demonstrat ion of 'prote in-free' urine «1+ on'Albustix ' or < 4 mg/h/m 2 bsa) for at least 3 days

Relapse: demonstration of proteinuria > 1+ on 'Albustix ' or> 4 mg/h/m 2 bsa) for at least 1 week

Frequent relapsing nephrotic syndrome (FRNS): initiallyresponsive with at least 2 relapses in a 6-month period

Steroid-dependent nephrotic syndrome (SDNS):occurrence ofat least 2 consecutive relapses while therapy is beingdecreased or 2 consecutive relapses each occurringwithin 2 weeks of ending a course of corticosteroid

therapy

5. Clinical-Pathological-TherapeuticCorrelations

Table II. Definitions of therapeutic responses in minimal changenephrotic syndrome (adapted from ISKDC 1977)

With a large data base detailing clinical char­acteristics and response to corticosteroids, the ad­vent of renal biopsy in the later 1950s allowed abetter understanding of the disease process. How­ever, the answers to the questions stated above re­quired many more patients than were available ina single centre. In addition, uniform histologicaldescription of biopsies and standardised treatmentprotocols were needed. It is to the credit of theearly investigators that these limitations were re­cognised and prospective controlled trials initiated.To this end, 15 centres in fact began the Interna ­tional Study of Kidney Disease in Children(ISKDC) in the 1960s. The participating centresgrew to 23 over the first 10 years of the study, dur­ing which consistent contributions to our under­standing of the natural history, pathology and ther­apeutic response of nephrotic syndrome were made.

The initial focus of the study was to relate path­ological description to clinical course and thera­peutic response. Churg et al. (1970) reported thefirst pathological findings of the ISKDC. 127 un-

features that predicted a decline in renal function?These and other questions stimulated the synthesisof clinical features, histology and therapeutic out­come; the development of this approach is re­viewed in section 5.

Abbreviation: bsa = body surface area.

10O..L---,--r---r-~F-.,.......;""t---=:;'-r---,,...--,

o

28 •"

24 f\ Infection

I'I I

20 , Itil

, IQ) I Itil

~ 16 , ,I ,

'0 I,

ci 12 I Iz I

,I I

8 I,

I,

4 :\

2 4 6 8Time (years after onset)

Fig.3. Time and cause of death in 61 children with untreatednephrotic syndrome (reproduced with permission from Ar­neil 1961).

corroborated by those of Arneil (1961) and Lawsonet al. (1960), with 49% and 48% of patients, re­spectively, being asymptomatic at 2 years. In theselast 2 series a few patients were treated with cor­ticosteroids, which may have increased the numberof asymptomatic patients, however the importantpoint is that spontaneous remission of symptomsis a common feature of untreated childhood ne­phrotic syndrome. Figure 2 illustrates the pointgraphically.

Two other important features of the illness, ashistorically described, were its tendency to waneover several years, and its association with fewdeaths in patients followed for greater than 2 years(fig. 3), suggestingthat patients spent progressivelyless and less time in the nephrotic state.

This is the background upon which all the newtherapeutic response data and histological corre­lation were added. While the clinical diagnosticskills of investigators such as Barness, Barnett, Ar­neil and the other members of these groups weregood, the cause of the disease process remained un­known and it was clear that the clinically definedgroups still did not clearly separate patients withregard to response to corticosteroids or ultimateoutcome. Were there histological features that pre­dicted steroid resistance? Were there histological

Nephrotic Syndrome in Childhood 37

Fig. 4. Exampl es of major histological types seen in childhood idiopathic neph rotic syndrome. Clockwise from top left:minimal change; mesangial proliferat ion; focal segmental sclerosis with mesangial proliferat ion; focal segmental sclerosis(reprodu ced with perm ission from Melvin et al. 1984).

treated children with idiopathic nephrotic syn­drome underwent renal biopsy; of these, 98 weredescribed as having minimal changes. In the wordsof the ISKDC there was 'absence of any conspic­uous abnormality on light microscopy. In somespecimens a slight increase of mesangial ma­trix . .. was observed, while in others there was aslight and unusuall y focal hypercellularity. How­ever, neither of these features was of sufficient de­gree to warrant the descript ion 'sclerosis' or 'pro­liferation '. An additional 12 patients were definedas having a focal sclerosing glomerular lesion. Thehallmark in these patients was the presence of glo­merular sclerosis, both focal (some glomeruli butnot all) and segmental (a portion of an individualglomeru lus but not all capillary tufts) in distribu­tion. 'The fully developed picture . . . included nor-

mal and partly and completely sclerosed glomeruliwith accompanying tubular atrophy and interstitialinflammatory changes.' In addition, it was notedthat increased mesangial cells and crescents maybe present.

Four patients had mesangial proliferation char­acterised by an increase in mcsangial cells and ma­trix. Six patients had membranoproliferative glo­merulonephritis with 'both mesangial proliferationand sclerosis with diffuse thickening of the glo­merular capillary walls' . This entity was soon ex­cluded (after 1967) as it was recognised to have ahigh rate of progression to renal failure and wasalso separated based on a low C3 initially report edby West et al. (1965) and confirmed by Ogg et al.(1968). Membranous nephropathy characterised bydiffuse thickening of glomerular walls and deposits

38 Drugs 42 (1) 1991

Table III. Distribution of renal biopsy specimens obtained from127 nephrotic children, according to glomerular changes, ster­

oid-resistance and deaths (reproduced with permission from

Churg et al. 1970)

Minimal changes 98 5 3Focal sclerotic lesions 12 10 3Proliferative glomerulonephritis

Mesangial 4 1 0With crescents 4 4 0Membranoproliferative 6 5 1

Membranous nephropathy 2 2 0

Chronic glomerulonephritis 1 1 0

Total 127 28 7

between the epithelium and basement membranewas present in 2 patients. Advanced glomerulo­nephritis was present in one - the histology notallowing for better classification. Figure 4 showsrepresentative examples of each histological type.

These patients had at the same time begun atherapeutic regimen of oral prednisone, receiving60 mg/m? body surface area (bsa) per day in 3 di­vided doses for 4 weeks, followed by intermittentprednisone 40 mg/m 2 bsa 3 consecutive days outof 7 (this was arbitrary - there was no physiologicalreason to choose this regimen other than to avoidas much corticosteroid toxicity as possible) for 4more weeks, for a total of8 weeksof therapy (Churget al. 1970).

Response was defined as 3 consecutive dayswithout significant proteinuria « 4 mg/m-' bsa/h),Patients not responding in the first 8 weeks werelabeled as nonresponders. A relapse was defined asproteinuria > 4 mg/m2 bsa/h for 3 consecutivedays, and patients in a subset having at least 2 re­lapses in a 6-month period were termed frequentrelapsers. (Table II provides a convenient glossaryof these terms , which have remained in use to thepresent.)

It was quickly realised that histology predictedresponse to therapy. Only 5/98 minimal changepatients were nonresponders, whereas 10/12patients with the focal sclerotic lesion were non-

Glomerular changes Total Steroid- Deaths

resistant

responders and 1 of 4 patients with mesangial pro­liferation was a nonresponder (table III).

As an early goal of the ISKDC was quick res­olution of the issue of whether azathioprine was ofuse in nonresponders and frequent relapsers, thesepatients were put into a placebo-controlled trial us­ing azathioprine 60 mg/m2/day (as well as inter­mittent prednisone). Ultimately , 31 nonresponderswere studied and no therapeutic advantage of aza­thioprine was detected over placebo (2 in eachgroup had reduction or cessation of proteinuria).In 36 patients with frequent relapses 5/18 on aza­thioprine and 8/18 on placebo had 1 or more re­lapses during the 180-day trial, therefore azathio­prine was abandoned as a therapeutic agent inchildhood nephrotic syndrome (lSKDC 1970).Thus, 2 major contributions of the ISKDC weremade within 3 years of its inception: the relation­ship of histology to corticosteroid response was de­fined, and use of a toxic medication with no effi­cacy was eliminated.

The prevalence of the different histological typeswas subsequently confirmed by White et al. (1970).They emphasised that a university setting may havea different prevalence pattern than an unreferredpopulation. This has been confirmed, and table IVshows both unselected and referred patient popu­lations, and prevalence of histological type in each.

The therapeutic-response relationship to histol­ogy has held up well over the years. The ISKDCdata for 219 patients with minimal change disease,published in 1981, shows 95% of patients respond­ing to a conventional prednisone course.

Two parallel concerns were also addressed. Thefirst was to define the optimum use of prednisonein frequently relapsing patients in remission. In arandomised prospective trial, involving the Ger­man multicentre study group Arbeitsgemainschaftfur Padiatrische Nephrologie (APN 1979), alter­nate-day prednisone therapy was proven more ef­ficacious than the original ISKDC protocol of 3days out of 7. Alternate-day use of corticosteroidshas. remained standard in frequently relapsingpatients in this phase of therapy.

The next issue was to resolve how best to usecytotoxic medications (cyclophosphamide, chlor-

Nephrotic Syndrome in Childhood 39

Fig. 5. Life table type analysis of remission in childhood ne­phrotic syndrome from 3 studies in which chlorambucil (Ch)or cyclophosphamide (Cy) was administered. Steroid-de­pendent (SDNS) patients are compared with frequently re­lapsing (FRNS) patients, defined as in APN (1982); time =number of years after therapy with Ch or Cy (reproducedwith permission from Melvin et al. 1984).

o Grupe (1982), Ch• APN (1982), Ch or Cyo Garinet aI. (1978), Cy

ambucil, or chlormethine) in patients with fre­quent relapses, and what effect they had in thegroup of patients resistant to prednisone. Severalgroups had independently used these agents withgratifying results, demonstrating prolonged periodsof remission (Coldbeck 1963; Etteldorf et al. 1967;Pachioli & Genova 1971 ; West et al. 1966). At thetime as the ISKDC began to investigate the issue,a controlled trial was published by Barratt andSoothill (1970) documenting the efficacy of cyclo­phosphamide. Its use was refined by differentgroups (Barratt et al. 1975; Cameron et al. 1974'~

Chiu et al. 1973) showing that 2.5 to 3.0 mg/kg/day as a single daily dose for 8 weeks was suc­cessful. Leucopenia was not required to achieve thebeneficial effect.

Similar results were seen with chlorambucil(Grupe 1973; Grupe et al. 1976; Williams et al.

100

90

80

l5 70'iii.~ 60Q)

.~ 50

rft. 40

30

20(

2 3Time (years)

SONS

4 5

Table IV. Distribution of lesions found on renal biopsy in 145

children with the nephrotic syndrome (reproducedwith permis­sion from White et al. 1970)

a 'Unselected' is defined as a patient presenting to a studyphysicianwithout referral from their primary care physician,i.e. no prior care had been given. 'Referred' is defined as apatient evaluated by a study physician only after receivingprior evaluation and therapy by a primary care physician.

Minimal changesTotal 66 (88%)

Without other 60

abnormalitiesWith focal tubular 6

atrophyWith focal glomerular 0

obsolescenceFocal glomerulosclerosis 4 (5.3%)

Proliferative glomerulonephritisDiffuse exudative 0Mesangial 4 (5.3%)

With crescents 0Focal 0Membranoproliferative 1 (1.3%)

Epimembranous 0nephropathy

Glomerular morphology Unselectedpatients''

Referredpatlentss

45 (64.3%)

39

3

3

8 (11.4%)

o4 (5.7%)

3 (4.4%)

o8 (11.4%)

2 (2.8%)

1980), documenting prolonged remission with 0.2rug/kg/day over an 8-week treatment period sim­ilar to that used with cyclophosphamide. Chior­methine was used early on but lost favour due tothe usual need to hospitalise patients for the 4 daysof consecutive intravenous dosing. There is also anunpredictable neutropenia that occurs after therapyis completed. Chlorrnethine is still used in somenoncompliant patients with excellent results. In allthese trials of cytotoxic agents, therapy was usuallybegun after induction of a corticosteroid-inducedremission; the patients were frequently maintainedon alternate-day prednisone.

The impressive results of treatment with cyto­toxic agents have made them the next therapeuticchoice after corticosteroids in frequently relapsingpatients . Figure 5 shows the data from 3 studies(APN 1982; Garin et al. 1978; Grupe 1982), dis­playing the percentage of patients in remission vstime. It also introduces a new term, steroid-de­pendent nephrotic syndrome. This subgroup of fre­quently relapsing patients consists of those whowere initially known in each centre to be the child­ren who could not remain off prednisone or whorelapsed while being tapered off prednisone. This

40

definition was refined by the APN (1982) as re­quiring 2 consecutive relapses while tapering orwithin 2 weeks of stopping prednisone. It can beseen that the frequently relapsing patients have anapproximately 70% chance of being in remission 2years after stopping therapy, while steroid-depend­ent patients have only about a 25% chance. Thispoint has been disputed by Grupe (1982); however,the definition of 'steroid-dependent' used by thisgroup was much less stringent than that of the APNand this may explain the different remission ratesseen in the 2 groups.

The difference in the long term remission ratewith cytotoxic therapy caused some investigatorsto ask whether there might be a different preva­lence of histological types in steroid-dependentpatients (many centres by this time had stoppedroutinely obtaining biopsies but rather treated first).Siegel et al. (1981) found that there was a differentprevalence pattern , with 47% having minimalchange, 29% focal segmental sclerosis and 24%mesangial proliferation. This highlighted the needfor biopsy prior to cytotoxic therapy.

The next major clinical question was how tomanage patients who were resistant to a course ofcorticosteroids. By the early 1970s this was pri­marily the group with focal sclerosing lesions. Theother histological group, mesangial proliferation,had so few patients that its therapeutic responsewas also still in question. Table V shows resultsfrom several studies, including the ISKDC, withregard to corticosteroid response and efficacy ofcytotoxic agents in focal segmental sclerosis. Theweighted mean response [defined as (number ofpatients responding to a therapeutic agent, dividedby total number of patients treated) X 100] to cor­ticosteroids and cytotoxic agents (cyclophos­phamide or chlorambucil) was 23% and 29%, re­spectively, in these 9 series, suggesting that fewpatients resistant to corticosteroids will be sensi­tive to cytotoxic agents.

Patients with mesangial proliferation appear tobe intermediate in response between corticoste­roids with a weighted mean response of 38%(Bhasin et al. 1978; Brown et al. 1979; Cohen etal. 1978; Melvin et al. 1984; Waldherr et al. 1978;

Drugs 42 (1) 1991

Table V. Therapeutic response of 283 patients with nephrotic

syndrome and focal segmental glomerular scleros is in 9 sel­

ected series of patients under the age of 20 years (adapted from

Melvin et al. 1984 with permission)

Reference No. of Steroid Cytotoxic

patients response response

White et al. (1973) 22 1{19 1{14Habib et al, (1981)a 112 27{112Hyman & Burkholder 17 0{7 1{6(1973)

Siegel et al. (1974)b 10 7{10 5{5Nash et al, (1976) 20 1{15 1/1Newman et at, (1976) 16 3{15 1{6

Schoeneman et al. 24 0/17 6/16(1978)

Mongeau et al. (1981) 25 7{25 6{17ISKDC (1981) 37 11{27

a Data also derived from personal communication.

b Defined by light microscopy. from a total of 22.

White et al. 1973). No large body of data is avail­able on cytotoxic response to patients with mes­angial proliferation.

In summary, the 1970s provided a much betterunderstanding of histology and its relation to re­sponse. A further refinement was attempted usingimmunofluorescence microscopy [which first cameinto use in the 1960s (Freedman et al. 1960; Lach­mann et al. 1962; West et al. 1965)]. A hypothesiswas advanced that the presence of IgM in theglomerulus, specifically in the mesangium (stalk re­gion of the glomerulus - see figure 4), representeda distinct pathological entity (Bhasin et al. 1978;Cohen et al. 1978; Lawler et al. 1980); however,this has been disputed by Prasad et al. (1977),Vilches et al. (1982) and Yang et al. (1984). Thisissue remains unresolved.

6. Outcome Defined for EachHistological Group

As the therapeutic response issues became clear,investigators wanted to know what the ultimateoutcome was for each histological group.

Within the minimal change group, the clinicalimpression of good outcome has been substanti-

Nephrotic Syndrome inChildhood

ated. The data from Berns et al. (1987), Fujisawiet al. (1979), the ISKDC (1981), Lewis et al. (1989)and Trompeter et al. (1985) all show that the ori­ginal notion of the disease 'burning out' in youngadulthood remains accurate. Lewis et al. (1989)provide particularly informative data on the per­centage of patients relapsing at times post-diag­nosis and the number of relapses per patient atvarious years post-diagnosis (fig. 6). These 2 graphsare particularly useful for parents and are easilyunderstood by them. Another issue on the mindsof investigators and families is: what is the likeli­hood of a relapse after prolonged remission. AgainLewis et al. (1989) provide these data, seen in fig­ure 7. Trompeter et al. (1985) provide the inter­esting addition that an onset of disease later inchildhood is associated with a shorter duration ofillness. Late relapses in adults have been high­lighted by Pru et al. (1984), showing that these re­lapses are just as likely to respond to corticoste­roids, histology remains minimal change and thata single relapse does not signal a new period offrequent relapses.

The steroid-dependent subset of the minimalchange group has until recently been more difficultto assess. The problem has been that data on thelong term outcome of steroid-dependent patients

OJ 100c:'iiic.ctl 80~(f)

E 60Ql

~C.

0 40QlOJ~

20cQlf:Qla.

2 4 6 8 10Time (yearsafter q,iagnosis)

41

was not always based on a population of patientsundergoing biopsy. A concern was that the groupmight be at risk of undergoing a histological tran­sition to focal segmental sclerosis, with a subse­quent decline in function. This seems not to be thecase. Despite the overwhelming clinical problemsin dealing with this group, the ultimate outlook isvery good. Berns et al. (1987) report on 10 patientswith steroid dependence and minimal change dis­ease. Of these, at a mean follow-up of9.9 ± 6 years,9/10 are in remission and I is still following a re­lapsing course - none is in renal failure. Kashtanet al. (1988) reported on 13 patients followed fora mean of 15.6 years. Of these, 8 are in stable re­mission (mean 5.5 years), 3 remain steroid-de­pendent (12, 18 and 22 years after onset) and 2have had single relapses after 5 and 8 years of re­mission (both corticosteroid responsive). None ofthe patients had renal insufficiency at follow-up.

In contrast, the outcome of patients with focalsegmental glomerulosclerosis (FSGS) is poor. TableVI shows the outcome of patients with FSGS in 9selected series. Roughly one-third of patients werein end-stage renal failure or dead at last follow-up,and only I in 6 was in remission.

The outcome in 58 patients with mesangial pro­liferation has shown 46% in remission, 45% with

3.0 • whole groupo age of onset < 5 years (n = 31)

2.5 • age of onset ;;, 5 years (n = 30)

~ 2.0-~c.gr 1.5(f)

~&! 1.0

0.5

O+-,....-.oy-...,..-T"""......o 2 4 6 8 10

Time(years after diagnosis)

Fig. 6. Percentage of patients relapsing and mean number of relapses per patient per year for the first 10 years after diagnosisof nephrotic syndrome (reproduced with permission from Lewis et al. 1989).

42

100

8 90sa.a.

80"~0

2 70Sen 60c:'iiia.'" 50~

'"E 40,911iia.0 30

C1lCl 20'"EC1l!:! 10C1lo,

00 1 2 3 4 5 6 7 8 9

Duration of remission (years)

Fig. 7. Percentage of patients relapsing in the 5 years of fol ­

low-up aft er I to 8 years of remission (reproduced with per­

mission from Lewis et al. 1989).

persisting proteinuria and 9% in end-stage renalfailure or dead (Bhasin et al. 1978; Brown et al.1979; Cohen et al. 1978; Melvin et al. 1984; Wald­herr et al. 1978; White et al. 1973).

Recently, cyclosporin has been used in child­hood nephrotic syndrome . This immunosuppres­sant, a cyclic undecapeptide fungal metabolite , hasbeen an extremely useful immunosuppressive agent

Drugs 42 (1) 1991

in renal, hepatic and cardiac transplantation(Keown 1990). Its biological effects are not com­pletely known but it is known to be a potent sup­pressor of T-1ymphocyte proliferation induced byantigen and mitogens (Reed et al. 1986). In addi­tion, it is known to diminish the expression of theinterleukin-2 (IL-2) receptor at a pre-transcrip­tionallevel [prevents mRNA for IL-2 receptor fromaccumulat ing (Reed et al. 1986)]. Such immuno­suppressive effects made it an attractive therapeu­tic agent for patients with frequently relapsing,steroid-dependent or steroid-resistant nephroticsyndrome .

Tejani et al. (1987) reported on 20 steroid-de­pendent and -resistant children with nephrotic syn­drome. They received oral cyclosporin at a dose of7 rug/kg/day (adjusted to maintain a trough serumconcentration of 100 to 200 ng/ml). 14 of 20 hada complete remission, including 3 of 7 who hadbeen resistant to corticosteroids and 6 of 10 withfocal segmental sclerosis. However, only 40% werein remission 20 months after therapy was discon­tinued, the majority of relapses occurring in thefirst 6 months after cessation of therapy.

Meyrier et al. (1986) had previously reporteddecreases in proteinuria in steroid-resistant patientswith nephrotic syndrome , but no complete remis­sion. Capodicasa et al. (1986) had also reported re­mission in 2 of 4 patients with steroid resistance.These successeswere followed by those reported byNiaudet et al. (1987) and Brandis et al. (1987). The

Table VI. Status of 283 patients with nephrotic syndrome and focal segmental glomerular sclerosis in 8 selected series of patients

under the age of 20 years (the studies are the same as those in table V, with the exception of the ISKDC for which no cytotoxicresponse or follow-up data are available)

Reference Status at last examination

remission proteinuria renal failure/death

White et at, (1973) 2/22 11/22 7/22Habib et al. (1981) 29/112 39/112 44/112Hyman & Burkholder (1973) 1/17 13/17 3/17Siegel et al. (1974) 6/10 2/10 2/10Nash et al. (1976) 1/20 11/20 8/20Newman et al. (1976) 3/16 10/16 2/16Schoeneman et al. (1978) 0/24 15/24 9/24Mongeau et al. (1981) 6/25 10/25 9/25

Nephrotic Syndrome in Childhood

duration of remission has varied, and when re­viewed by Ponticelli and Rivolta (1988), 53 child­ren with biopsy-proven minimal change were iden­tified in the literature with duration of therapy withcyclosporin ranging from 2 to 8 months. Of these,7 were steroid resistant and 2 of 7 had a completeremission . Overall, there was a 77% complete re­mission rate. About 50% of children relapsed offtherapy. In reviewing children with focal sclerosis,only 17% had a remission with cyclosporin.

The published data are incomplete for relapserate in this group in children, but most adults withfocal segmental sclerosis have relapsed off therapy.A controlled trial was reported in 1988 by Garinet al. Results were uniformly poor in both minimalchange and focal segmental sclerosis using a doseof 5 rug/kg/day. Overall cyclosporin is effective, es­pecially in corticosteroid-responsive patients, butas yet it is not an improvement over conventionalcytotoxic agents.

7. Clinical Approach to Patients withNephrotic Syndrome

When a child with nephrotic syndrome pre­sents, knowledge of the renal histology is helpfulas this will usually provide a good predictor of cor­ticosteroid responsiveness, likelihood of progressand of ultimate outcome . However, analysis ofclinical and laboratory data from many centres,over many decades, allows us to observe and meas­ure several parameters jhat discriminate almost aswell as the histology. Thus, the first important de­cision to be made is whether or not to perform arenal biopsy.

Briefly, if a child is 6 years of age or less, hasnormal third component of complement (C3), cre­atinine and blood pressure, and does not have hae­maturia, then there is a high likelihood of minimalchange histology and response to therapy with cor­ticosteroids (Habib & Kleinknecht 1971 ; ISKDC1978; White et al. 1970). These measurements andlaboratory studies should be completed in allpatients. In addition, the clinician should searchfor features of a nephritic presentation (oliguria,hypertension, red blood cell casts) as well as evi-

43

dence of a systemic disease, e.g. SLE. If systemicdisease and nephritis are absent, therapy may pro­ceed without biopsy. This will lead to treatment forvery few resistant patients and biopsy in very fewresponders. It should be kept in mind that not allminimal change patients will fit this mould; as Ha­bib and Kleinknecht (1971) noted in their series,36%had microscopic haematuria, 10%had a bloodurea nitrogen (BUN) >60 mg/dl (at presentation),6% had hypertension and 25% had moderately ornonselective proteinuria.

7.1 Corticosteroids

Therapy is initiated with oral prednisone at adose of 60 mg/m 2 bsa given on a 3 times dailydosage schedule. This is continued for 4 weeks andthen converted to 40 mg/m2 bsa orally in a singledose every other day for an additional 4 weeks,with a rapid taper thereafter.

It can be expected that the vast majority ofpatients will respond in the first 2 weeks and asmaller percentage will respond in the third andfourth weeks of therapy. At the end of8 weeks therewill be ,.,8% who do not respond (ISKDC 1977).In this group a few will respond if left on alternate­day prednisone for several weeks to months, butmost centres would perform a renal biopsy at thispoint to determine further therapy.

In those patients who respond several clinicalcourses usually occur (fig. 8). At best, 34%will neverhave a relapse. Of those who do relapse differentpatterns are noted, as seen in figure 8; 17%relapseinfrequently while 43% relapse frequently (2 re­lapses in 6 months) or are steroid dependent (2consecutive relapses while tapering or within 2weeks of discontinuing therapy) [ISKDC 1977].

Therapy for relapses is begun in a manner sim­ilar to initial therapy; however, a switch/IS madeto alternate-day therapy after 3 consecutive days ofprotein-free urine (as measured by dipstick). Theduration of alternate-day therapy at this point isarbitrary. Each physician must balance the possiblebenefit of prolonged alternate-day therapy (avoid­ing relapses) versus the morbidity of the cortico­steroids (obesity, hypertension and growth impair-

44

Nonrelapsers34

Infrequentrelapsers

17

New patients (n.125)

Drugs 42 (1) 1991

Nonresponders2

Fig. B. Pattern of response in 125 children with nephrotic syndrome given conventional corticostero id therapy (reproducedwith permission from ISKDC 1977).

ment). Obviously, neither situation is ideal and thelength of alternate-day prednisone should be in­dividualised.

It is worth noting that some investigators haveused pulse high-dose methylprednisone therapy forresistant patients and steroid-dependent patients(Murnaghan et al. 1984). Conversely, some centreshave shown that initial therapy in some responsivepatients may be accomplished with as little as 30mg/m2/day prednisone (Choonara et al. 1989).

7.2 Cytotoxic Agents

For patients who frequently relapse or who aresteroid dependent, cytotoxic drugs are availablewhich may provide a prolonged disease-free inter­val. It is important to perform a renal biopsy priorto cytotoxic therapy, to enable the outcome to bepredicted more accurately. Outcome is highly vari­able and prognostic data garnered from biopsy mayinfluence families' acceptance of such a regimen.It must be remembered that cytotoxic therapy isbeing used for a disease process that will most likelycease to be ' a problem by the third decade of life.

Even the most steroid-dependent patients do notprogress to renal failure and have fewer relapsesover time. Cyclophosphamide and chlorambucilshould therefore be reserved for children who havesevere steroid-induced side effects (e.g. growth fail­ure) and/or have life-threatening complications ofnephrotic syndrome (see below) .

Cyclophosphamide is used in a dose of 2 to 3rug/kg/day given as a single dose for 8 weeks. Thisis done after remission has been induced throughconventional prednisone therapy, and the patientis left on prednisone 40 mg/m2 every other day(given as a single dose) throughout the course ofcytotoxic therapy. White blood cel1 (WBC) countsare required weekly. Therapy is stopped for neu­trophil counts <1500 (resuming therapy at a lowerdosage when the WBC has recovered). Chloram­bucil is equal1y efficacious when used in a dose of0.2 rug/kg/day, Figure 5 shows the likelihood ofresponse to these regimens and how long the re­mission will last. Steroid-resistant patients are veryunlikely to respond to cytotoxic drugs, as has beendescribed earlier. Chlormethine in a dose of 0.1 mg/kg/day intravenously for 4 days is also efficacious

Nephrotic Syndrome in Childhood

but not popular due to the need for intravenousadministration (Schoeneman et al. 1983).

7.3 Complications of Therapy

In this section the complications of cytotoxictherapy are reviewed. It is assumed that the prob­lems with corticosteroid therapy are well known;these include development of centripetal obesity,acne, striae, cataracts, hypertension, pseudo-tum­our cerebri and psychological changes. Other ref­erences should be consulted for a more detaileddescription of these potentially serious problems.

7.3.1 CyclophosphamideAgreat many risks are taken when patients are

placed on cyclophosphamide. It has been reportedto be a teratogen in humans and certain other spe­cies (Gebhardt 1970; Greenberg et al. 1964) and itexerts a profound effect on gonadal tissues. If thetotal dose is kept below 200 mg/kg, toxicity to testesand ovaries is uncommon (Etteldorf et al. 1976;Lentz et al. 1977). There should be no false senseof security, however, because even at these dosagelevels oligospermia and infertility have been de­scribed (Trompeter et al. 1981).

The possibility of transitional cell neoplasia hasbeen associated with higher doses (Wall & Clausen1975) and one child has been reported to have de­veloped leukaemia after treatment for nephroticsyndrome with prednisone and cyclophosphamide(Kuis et al. 1976). Alopecia and haemorrhagic cys­titis are rare and leucopenia uncommon with theconventional dosage. The immunosuppressive ef­fect as measured by lymphocyte blastogenesis hasbeen observed to last for a mean of 4.5 years(Chapman et al. 1982).

7.3.2 ChlorambucilThe alternative cytotoxic agent to cyclophos­

phamide, chlorambucil, also has many problems.Possible teratogenic effects have been reported(Shotton & Monie 1963) and leucopenia is seen indose-dependent fashion (Kleinknecht et al. 1977).A unique complication, focal and generalised seiz­ures, has been described. Seizures appear unrelated

45

to patient age, duration of illness, patient gender,dosage or duration of therapy (Williams et al. 1978).

Gonadal toxicity is associated with cumulativedoses > 7 mg/kg (Cheviakoff et al. 1972; Richteret al. 1970). The association of chlorambucil withmalignancy is most ominous. More than 14 casesof leukaemia and solid tumours have been re­ported with its use for nonmalignant conditions inchildhood (Cameron 1977; Muller & Brandis 1981),3 of them in children with nephrotic syndrome.Despite these reports the use of chlorambucil inthousands of children worldwide suggests that theincidence of leukaemia is likely to be very low.

7.4 Complications of the Nephrotic State

Given the toxicity of the agents used to treatnephrotic syndrome it is important to review thedangers of the untreated syndrome and of itssymptomatic treatment (e.g. diuretics, albumin).

Oedema is the most frequent side effect of pro­teinuria. Oedema alone is of only cosmetic con­cern. It should initially be managed by salt restric­tion (not fluid restriction). Injudicious use ofdiuretics should be avoided as most patients havenormal to low plasma volume (Meltzer et al. 1979)and diuretics may lead to dangerous hypovolae­mia .Some patients may actually present in hy­povolaemic shock (Reimold & Marks 1966).Hydrochlorothiazide or furosemide (frusemide)may be used as long as close attention is paid tovolume status, renal function and electrolytes, asserious hypokalaemia/or hyponatraemia may re­sult.

Hyponatraemia may be seen in the absence ofdiuretic use and even after adjusting for the in­creased serum lipids. As long as the decrease ismodest (Na > 125 rnliq/L) no attempt should bemade by fluid restriction and/or increased Na in­take to increase the Na level.

Use of intravenous albumin and subsequentparenteral furosemide should be reserved for thosechildren who have ascites causing difficulty breath­ing or who require ascites reduction to allow themto lie prone for biopsy . Albumin can be dangerous.It must be administered initially in small doses of

46

0.25 to 0.5 g/kg (usinga 25%solution), given slowlyover 2 to 4 hours with close monitoring of vitalsigns, and followed by 0.25 to 0.5 mg/kg intraven­ous furosemide. Failure to provide these safe­guards may lead to rapid intravascular volume ex­pansion , congestive heart failure and pulmonaryoedema.

Infection is another major threat of the ne­phrotic state. As noted earlier in this review, in­fection claimed the lives of a great number ofchildren with nephrotic syndrome prior to antibi­otics. The use of pneumococcal vaccine and ag­gressive clinical and laboratory evaluation of signsof infection is mandatory in children with ne­phrotic syndrome due to the increased risks of en­capsulated organisms leading to spontaneous bac­terial peritonitis (Krensky et al. 1982), bacteraemiaand pneumonia.

In addition, low ionised calcium is occasionallyseen in nephrotic syndrome - a consequence of ur­inaryloss of vitamin D carrier protein and 25-hy­droxy-vitamin D3 (Goldstein et al. 1977; Kano etal. 1980). Adequate calcium intake should be as­sured and rarely vitamin D supplementation maybe required.

Certain medications may need to have theirblood concentrations adjusted, e.g. phenytoin, dueto their high degree of protein binding, since ther­apeutic concentrations while nephrotic may ac­tually be toxic.

Diarrhoea and vomiting may be complicatingfeatures, especially in the youngest children . Peri­pheral hyperalimentation or isotonic enteral for­mulas may help prevent malnutrition during theseperiods.

The last complication to be reviewed is, next toinfection, the most life threatening - thrombosis.Nephrotic patients have a clotting diathesis , due tourinary losses of antithrombin III, increased fib­rinogen, increased platelet aggregation and occa­sionally abnormalities of the naturally occurringanticoagulants, protein C and protein S (Bernard1988; Comp 1987). This hypercoagulability hasbeen associated with major venous thromboses(Lau et al. 1980).

A long list of other abnormalities has been re-

Drugs 42 (1) 1991

ported, including low levels of zinc, copper and iron(Cartwright et al. 1954), ceruloplasmin (Jensen1967), transferrin (Brown et al. 1984; Ellis 1977),and abnormal thyroid function tests.due to urinarylosses of thyroxin binding globulin (Adlkofer et al.1983). See selected references for a more detailedtreatment of these observations.

8. Conclusions

Nephrotic syndrome in childhood is an entitythat remains unexplained and a source of signifi­cant morbidity; however, many advances have beenmade over the last 45 years. Mortality has beenreduced dramatically due to the advent of antibi­otic therapy of infectious complications, and dueto corticosteroids allowing for longer disease-freeintervals . The clinical manifestations have re­mained the same, with insidious onset of oedemabeing the hallmark. Prospective clinical trials haveidentified a subgroup likely to respond to cortico­steroid therapy. Those children 6 years of age oryounger who are free of systemic illness (e.g. SLE),have no azotaemia, gross haematuria, or hyperten­sion are likely (",=,90%) to respond to prednisoneadministered orally at a dose of 60 mg/m2 bsa/daygiven on a 3 times daily dosage schedule. This isconverted to 40 mg/m2 bsa given as a single oraldose every other day at 4 weeks and continued foran additional 4 weeks. These. children do not re­quire a kidney biopsy prior to beginning therapyas they have a great likelihood of having a histo­logical appearance defined as minimal change.

The response to therapy usually occurs duringthe second week of therapy, with an ever smallernumber responding as the maximum duration of4 weeks of daily prednisone is reached. Of thosewho respond, approximately one-third will not re­lapse and the majority will have few or frequentrelapses. In the frequently relapsinggroup there willbe some who become 'dependent on corticoste­roids, relapsing soon after or during tapering of themedication . A small number ("'='5%) will not re­spond to corticosteroids (see fig. 8).

For those children who are experiencing greatmorbidity, cytotoxic agents have been very useful

Nephrotic Syndrome in Childhood

in producing a long disease-free interval in thosewho respond to corticosteroids. Cyclophosph­amide used in a dose of 2 rug/kg/day given orallyas a single dose for 8 weeks leads to approximately70% being in remission 2 years beyond the com­pletion of therapy. The subgroup that is dependenton predn isone does not fare as well, with 30% inremission 2 years post therapy (see fig. 5).

Chlorambucil has been used with similar effi­cacy at a dose of 0.2 mg/kg/day given orally as asingle dose for 8 weeks, as has chlormethine at adose of 0.1 rug/kg/day administered intravenouslyfor 4 days. Cytotoxic response in those childrenresistant to an initial course of predni sone is poor,with approximately one-quarter achieving remis­sion . Man y of the resistant and steroid-dependentpatients do not have min imal change histology onkidn ey biops ies but rath er have a much higher per­centage of focal segmental glomerulosclerosis and/or mesang ial proliferation. The focal segmentalglomerulosclerosis group has the least respondersand is most likely to progress to renal failure (seetables IV, V and VI; figs 1 and 4).

Symptomatic therapy of nephrotic syndromemay be undertaken with caution. When oedema issufficiently great to cause respirato ry probl ems orprevent the prone position for biop sy, intravenous25% hum an albumin may be administered in dosesof 0.25 to 0.5 g/kg over 2 to 4 hours, with closevital sign monitoring, and followed by intravenousfurosemide at a dose of 0.25 to 0.5 mg/kg, Thismay be don e 1 or 2 times per day. Clinical con­fidence in total body fluid status usually requiresa chest x-ray prior to initiation of this therapy andit should be accomplished during the daytime whenstaffing is at its best. Albumin should not be ad­ministered to patients with pneumonia or prior toconfirmation of good urine output, or in thosepatients with renal failure and nephrotic syn­drome. Failure to heed these warnings may lead todangerou s fluid overload man ifest as congestiveheart failure and pulmonary oedema.

The chronic use of diuretics is to be avo ided ifpossible due to complications of volume depletion,hyponatraemia and hypokalaemia . Sodium restric-

47

tion remains the foundation of therapy of oedema.Fluid intake must not be limited, however.

Insights into the pathogenesis of nephrotic syn­drome are accumulating rapidl y. Most new know­ledge highlights features of the immune response.Table I provides a convenient list of the immunefunctions that have been studied in nephrotic syn­drome. While this research has not yet led to atherapy with greater specificity and less toxicity thancorticosteroids, rapid advances in the understand­ing of immune recognition by T cells, post-receptorsignalling processes, and lymphokine action sug­gest that goal may be achieved in the not too dis­tant future .

Acknowledgements

The authors wish to thank Ms Rosemary Allen forexcellent secretarial assistance.

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Adlkofer F, Hain H, Meinhold H, Kraft D, Ramsden D, et al. Thy­roid functio n in pat ients with proteinuria and normal or in­creased serum creatini ne concentration. Acta Endocrinologica102: 367-376, 1983

Ahuja AS, Wright M. MMR and the nephrotic syndro me. BritishMedical Journal 299: 796, 1989

Alfiler CA, Roy LP, Doran T, Sheldo n A, Bashir H. HLA DRW 7and steroid responsive nephrotic syndrome of childhood. ClinicalNephrology 14: 71-74, 1980

Allon M, Campbell WG, Nasr SA, Bourke E, Stoute J, et al. Min­imal change glomerulonephropathy and interstitial infiltrationwith mycosis fungoides. American Journal of Medicine 84: 756­759, 1988

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Anderson DC, York TL, Rose G, Smith CWoAssessment of serumfactor B, serum opsonins, granulocyte chemotaxis, and infectionin nephrotic syndrome of children. Journ al of Infectious Dis­eases 140: 1-11, 1979

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APN (Arbeitsgemainschaft fur Padiatrische Nephrologie). Effect ofcytotoxic drugs in frequently relapsing nephrotic syndrome withand without steroid dependence. New England Journal of Med­icine 306: 451-454, 1982

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et al. Acute interstitial nephrit is with the nephrot ic syndro mefollowing recombinant leukocyte A interferon therapy for my­cosis fungoides. New England Journal of Medicine 310: 32-35,1984

Baliah T, Park BH, Neter E. Low ASO titers and abnormal im-

48

mu noglobulin levels in minimal lesion nephrotic syndro me inchildren . Federation Proceedings 36: 1055, 1977

Ballow M, Kennedy TL, Gaudio KM, Siegel NJ, Mclean RH. Serumhemolytic factor D values in children with steroid responsiveidiopat hic nephrotic syndrome. Journal of Pediatrics 100: 192­196, 1982

Barness LA, Moll GH, Janeway CA. Nephrotic syndrome. Pedi­atrics 5: 486-503, 1950

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Correspondence and reprints: Dr Tyrone Melvin. Department ofPediatrics, PED, Oregon Health Sciences University, 3181 SWSam Jackson Park Road , Portland, OR 97201-3042, USA.