Steroid-responsive nephrotic syndrome and allergy ... · sensitivity nephrotic syndrome was found,...

Archives of Disease in Childhood, 1981, 56, 509-516

Steroid-responsive nephrotic syndrome and allergy:clinical studiesS R MEADOW AND J K SARSFIELD

Department ofPaediatrics and Child Health, University ofLeeds and St James's University Hospital, Leeds

MMARY Eighty-four children with steroid-responsive nephrotic syndrome who had been shownto have, or were believed to have, minimal change histology were investigated to study the relation-ship between steroid-responsive nephrotic syndrome and allergy. They were found to have a greater

incidence of the standard atopic disorders-asthma, eczema, recurrent urticaria, and hay fever.Their 1st-degree relatives had an increased incidence of these atopic disorders too. A nasal dischargewas a frequent precursor or an accompaniment of nephrotic syndrome, but an overt atopic disorderat the same time was rare. Such disorders, related to relapse, occurred in only 5 children; in none wasit a consistent or recurrent happening at the time of each relapse. No example of pollen hyper-sensitivity nephrotic syndrome was found, and no particular allergen could be identified withcertainty as responsible for a child's nephrotic syndrome. No association was found between thetime of relapse and the season of the year, or the season in which the child was born. Children withnephrotic syndrome had a greater incidence of positive skin tests to common antigens, the com-

parative frequency of positive reactions to different antigens being similar to that found in childrenwith asthma, although the total frequency was about half that of children with asthma. Despite theincreased incidence of clinical features of atopy, measures to reduce the frequency of relapse ofnephrotic syndrome by allergen avoidance, the use of disodium cromoglycate, and the use of a neworal antiallergic drug were unsuccessful.

Children with steroid-responsive nephrotic syndromeform a well-defined group. The renal biopsy shows anearly normal appearance on light microscopicalexamination (minimal changes), and the syndromeresponds to treatment with corticosteroid drugs;subsequent relapse is usual. This type of nephroticsyndrome is more common in early childhood thanat any other time in life. The origin and cause remaina mystery, and effective management is limited.There have been isolated case reports of the

syndrome occurring in response to exposure to grasspollens. There have also been reports ofthe syndromeoccurring at the same time as other allergic symptomsin atopic persons.1-4The aim of this study was to define the relationship

between steroid-responsive nephrotic syndrome ofchildhood and allergy. Eighty-four children withnephrotic syndrome form the basis of the study.Clinical and laboratory evidence of atopy in thechildren and their relatives are presented.Management trials were designed to see if inter-

ruption of an allergic cause or mechanism couldprevent relapse or reduce the need for corticosteroids.

Methods

Children. Three groups were studied.

Nephrotic syndromeSixty-two boys and 22 girls had nephrotic syndrome(heavy proteinuria >0 05 g/kg per day, serumalbumin <25 g/l, and variable oedema). Thediagnosis of steroid-responsive nephrotic syndromewas made on the basis of a characteristic clinicalhistory, confirmatory laboratory evidence, responseto treatment with corticosteroids, and the absence ofcontradictory features (for example hypocomple-mentaemia, hypertension, persistent azotaemia, orhaematuria). In 41 the renal biopsy showed 'minimalchanges'. (It is unlikely that the 43 children who didnot have biopsies would have shown histologicalappearances other than minimal changes becausetheir clinical course and findings were even moretypical of minimal change nephrotic syndrome thanthe 41 in whom the renal biopsy showed minimalchanges only.)

Children with equivocal renal histology and other509

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510 Meadow and Sarsfield

forms of nephrotic syndrome were excluded from thestudy. Two-thirds of the children had been referredby paediatricians outside Leeds. They had beenreferred because of problems with their management,and therefore many of them had had frequentrelapses or needed unacceptably large doses ofcorticosteroids to stay in remission. It was notpossible to include all 84 in each study, therefore thenumber of children included in each study wasgenerally smaller than the total number of 84. Unlessotherwise stated, the children were not specificallyselected for each study, and the different groups of70 or so children reported were found to becomparable in terms of age, sex, pattern of illness,and amount of previous treatment.Twelve had each had a single bout of nephrotic

syndrome with no recurrence in the first 2 yearsafter onset (single nephrotic syndrome). Seventy-twohad had subsequent relapses, and most of theserelapses had been frequent (relapsing nephroticsyndrome). Age at onset of nephrotic syndromeranged from 1 * 2 to 13 * 1 (mean 5* 4) years.

Control group AThis group comprised 80 children from a generalpaediatric outpatient clinic. Most had urineinfections, respiratory tract infections, haematuria,or pains of unknown causes. Children whose primecomplaint was asthma, eczema, or hay fever wereexcluded (although an atopic child presenting foranother reason might be included). The children werechosen because they were about the same age andof the same sex as the children with nephroticsyndrome. Necessary limitation in the performanceof certain tests resulted in further selection. Bloodsamples were obtained only if venepuncture wasotherwise necessary for the child. Skin tests weredone only after informed parental consent had beengiven, and if we thought the procedure would notupset the child.

Control group BThis group comprised 60 healthy children from avillage near Leeds. The children were chosen toprovide an approximate sex and age match to thechildren with nephrotic syndrome.The study was approved by the hospital ethical

committee.

Clinical studies. The history was taken at a series ofspecially arranged clinics. At the time of the visit allthe children had been in remission for at least 2weeks, and most of them had been in remission formany months.A questionnaire about allergy in the child and

family was completed separately by the two of us. We

saw the parents separately, some parents seeingSRM first, others JKS. The information wasrecorded separately, but at the end of each sessionthis information was compared to provide an agreedallergy status sheet for each patient. We did this toavoid bias in the collection and interpretation ofpossible allergy but in practice there was agreementbetween us on nearly all the children.The following allergic illnesses were sought by

direct questioning: asthma (recurrent wheezing),eczema (infantile or flexural), allergic rhinitis (hayfever), urticaria recurring at least twice, or occurringtwice in response to a known provoking agent. Atthe start of the study questions were asked also aboutfood allergy.A history of the same disorders was sought in the

child's siblings and parents (that is the 1st-degreerelatives). The parents of the nephrotic childrenwere asked to think back carefully to the time ofonset or relapse of nephrotic syndrome to identifyany preceding or accompanying incidents. Particularattention was paid to the time of year, associatedsymptoms, treatments, activities, diet, and domicileat the time of onset or relapse of the nephroticsyndrome. Each child had a physical examinationand his urine was examined.

Clinical observations were compared using x2analysis.

Skin testing. Skin prick tests5 were performed on theventral surface of the forearm using disposableNo 25 gauge hypodermic needles. All patients weretested against solutions of house-dust, house-dustmite (Dermatophagoides pteronyssinus), grass pollenmix, mould mix, milk, egg, fish, and cereal. If thechild had regular contact with a pet at home or atschool, skin tests were performed with the relevantextract-for example cat fur or dog hair. Any childwith a suspicious history for any food or allergenwas tested against that allergen if available. Bencardallergen extracts were used.

Eosinophil count. The blood was placed in asequestrene bottle and subsequently stained with 2%eosin in aqueous acetone. The eosinophils werecounted in a Fuchs-Rosenthal counting chamber.

Results

History of allergic disorder. A positive history of anallergic disorder was present in 26 (34%) of 77children with nephrotic syndrome. A positivehistory was present in 6 (55%) of 11 children with asingle nephrotic syndrome, and in 20 (31 %) of 65children with relapsing nephrotic syndrome. The


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Steroid-responsive nephrotic syndrome and allergy: clinical studies 511

disorders noted were: asthma (in 12), eczema (in 9),recurrent urticaria (in 8), and hay fever (in 4); 4children had at least 2 ofthese disorders.

Evidence of food allergy was weak, and no clearcase of food allergy was apparent.The incidence of the 4 main allergic disorders in

the control groups was significantly lower (Table 1).

Family history of allergic disorder. A history of atleast one of the 4 main allergic disorders waspresent in at least one lst-degree relative of 37 of the75 children for whom parents could provide reliabledetails. The proportion was similar for childrenwith relap3ing or single nephrotic syndrome. It was asignificantly higher proportion than the incidence ofallergic disorders in the 1st-degree relatives ofthe control group B (Table 2).

Search for seasonal or other provocative factors.

Upper respiratory tract infectionThe only fact consistently given by many parents wasthat onset of the syndrome and of the relapse hadfollowed a 'cold' or, less often, a 'cough' and 'sorethroat'. Thirty-five of 71 children with relapsingnephrotic syndrome had a history of at least 2episodes of the syndrome within 3 days of suchupper respiratory tract symptoms. In about halfof these 35 children the relapses 'always' wereassociated with a 'cold'. Although the parentsreported upper respiratory tract symptoms, there isno certainty that such respiratory symptoms were theresult of infection and not due to allergic, physical,or emotional factors. However, in some cases othermembers of the family had had similar symptomswhich suggested a communicable viral cause.

Table 1 Incidence ofallergy (asthma, eczema,urticaria, or hayfever)Group Allergy P

No %

Nephrotic syndrome (n = 77) 26 34Controls A (n = 80) 15 19 <0*01Controls B (n = 45) 6 13 <0.01

Table 2 Incidence ofasthma, eczema, urticaria, or hayfever in the Ist-degree relatives

Group Affected 1st-degree Prelative

No %

Nephrotic children (n = 75) 37 50ControlA(n = 79) 29 37 <0-2Control B (n = 44) 14 32 <0-01

Of the 12 children who had only a single bout ofnephrotic syndrome there was associated 'cold' inonly 3, but the parents of 2 others remembered thatacute wheezing had been the main precedingcomplaint (see below).

Allergic disorder in relation to onsetThree of 12 children who had each had a singlenephrotic syndrome had had an allergic disorder inthe 3 days preceding onset of oedema (asthma in 2,and eczema in 1). Two of 72 children with relapsingnephrotic syndrome had each had an allergicdisorder (urticaria) within 3 days of onset of oedema.

SeasonalfactorsDespite careful questioning and research none of72 children with relapsing nephrotic syndromecould show a pattern of seasonal relapse followed byremission until the same season the following year.The month of first onset is shown in Fig. 1 for

children with either relapsing or single nephroticsyndrome. The onset was distributed throughoutthe year, being in the 6 winter months (October toMarch) for 38 children with relapsing nephroticsyndrome, and in the 6 summer months for theother 30 children with relapsing nephrotic syndrome.Onset was less common in April, May, and June.To test the hypothesis that exposure to particular

allergens in infancy, before maturation of theimmunological process, was relevant, the month ofbirth of each child was noted. Of the 72 children withrelapsing nephrotic syndrome the birth months wereequally divided between the 6 winter months andthe 6 summer ones, with a peak in July (Fig. 2).Although 6 of the children born in July had theironsets of nephrotic syndrome in the peak month ofSeptember, no consistent relationship could be foundbetween the month of birth, month of onset ofnephrotic syndrome, the pattern of the illness, or theassociated or preceding illnesses.

Children with hayfeverOf the 4 children with a clear history of hay fever innone had the initial onset of nephrotic syndromebeen at the time of hay fever, nor, indeed, had itbeen in the summer. One had had a recurrence(that is a relapse) at the time of hay fever symptoms.She presented with nephrotic syndrome in January,went into remission, and had no further trouble until17 months later after she had spent an afternoonwalking through hay fields. She developed severeallergic rhinitis that afternoon and within 3 dayshad generalised oedema of nephrotic syndrome.After this experience she avoided grass fields as muchas possible. She had no further relapses in the hayfever season.


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Table 3 Frequency ofpositive skinprick tests

Grade Nephrotic syndrome Controls(n = 77) (n = 50)

No % No %

A 14 18 5 10B 12 16 4 8C 14 18 4 8Total A B C 40 52 13 26 (P<0.01)Negative 37 48 37 74

14 Fig10012

3

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0-.

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4 ~~~~~~~~40

2 c~~~~~~~~~~ 20

Jm Fleb McirAor Mov Jun uiv Aun &--n Oet Nov Do

JwU rc HPA #AF uy JLN July muy 1ip 1& 1-4u Li

Month of birth

Fig. 1 Month offirst onset of nephrotic syndrome.Single means that the child had no subsequent relapse.Fig. 2 Month ofbirth ofchildren with nephroticsyndrome. Dotted line shows the national distributionofbirths during theperiod that most ofthe childrenwere born.

Skin prick testsThe response to skin prick tests was graded accordingto the number of positive reactions obtained. Aweal of at least 2 mm diameter was consideredpositive. The following grades were used: gradeA = 1 positive test, grade B = 2-4 positive tests, andgrade C = at least 5 positive tests.For each grade there was a higher proportion of

nephrotic children than children of control group A,and the total proportion of nephrotic children withany positive test (52 %) was significantly higher thanthe proportion of controls with a positive test (26 %)(Table 3).No late skin reactions of the type III hypersen-

sitivity response were observed or reported in anychild.

Fig. 3 shows the allergens that most often produceda positive response in the nephrotic children com-pared with the allergens that most often produced a

Incidence of positive skin tests(Weal diameter!2mm)

C

10

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lIUr

801-

60[

"'I4btcd^§sR+S O

Fig. 3 Incidence ofpositive skin prick tests to commonallergens in children with nephrotic syndrome comparedwith children with asthma.

positive response in 133 asthmatic children in theLeeds area. The pattern was similar in both groupsbut far more children with asthma had positiveresponses to skin tests.

Blood eosinophil countIt is usual to consider levels above 0 4 x 109/l as

abnormal. Thirteen (21 %) of 62 nephrotic childrenhad peripheral blood eosinophil counts of >0 4x 109/l. Two (7%) of 30 control children fromgroup A had similar eosinophilia.

Management trials

Three separate trials were carried out on (1) allergenavoidance, (2) disodium cromoglycate, (3) BRL10833.


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The procedure used for testing urine samples andidentifying relapse was similar in each of these trials.Second morning urine specimens were tested dailyusing chemically impregnated plastic test strips(Albustix by Ames Company). The results wererecorded daily on a recording form. If 3 consecutivedaily specimens showed an Albustix reading of 2+or more, a timed collection of urine was madefor accurate quantitative determination. Relapsewas defined as a protein excretion of >50 mg/kgper day.

Allergen avoidance. Any child who had at least onepositive radioallergosorbent test for specific IgE to afood, or a pet, was told to avoid that particular foodor animal; there were 8 such children. At the time ofthe trial 5 children (group C) were dependent on corti-costeroids in order to stay in remission. The other3 children (group D) had required at least 2 coursesof corticosteroids during the previous year becauseof relapse of nephrotic syndrome. All were inremission. A special diet was constructed which wasnot only free of suspected allergens but wasalso low in other foods that have a reputation forcausing allergic symptoms in the UK. The diet wasbegun in hospital and the parents were instructed inits preparation and use before the child was allowedhome.For a child suspected of being allergic to an

animal extensive discussion took place with theparents in order to reduce to a minimum the chanceof the child coming into contact with the animaleither directly or indirectly.

This avoidance regimen was begun in hospital,and once it was fully understood and was likely tobe complied with satisfactorily, the child wasallowed home to continue with the same regimen.The prednisolone was continued in the initial dosefor the first 2 weeks and then was gradually reduceduntil at 4 weeks it was stopped.

ResultsAll 5 children in group C relapsed within 4 weeks ofstopping prednisolone. All the parents stated thatthe allergen avoidance regimen had been maintained.The children in group D persisted with allergen

avoidance for 6 months but this still did not preventrelapse of nephrotic syndrome and did not appear tomake any appreciable difference to the frequency ofrelapse.

Disodium cromoglycate. Ten children with frequentlyrelapsing nephrotic syndrome were receiving regulartreatment with corticosteroids (mean dose 29mg/M2 every other day) at the time the trial began.

Each was placed in a treatment group or a controlgroup, ensuring that the children in each were ofcomparable age and taking a comparable predni-solone dose, and that atopic features (incidence ofsymptoms, positive skin prick test, and raised IgElevels) were also similar.The treatment group received disodium cromo-

glycate in each of the following three forms for42 days: (1) 20 mg spincap (Intal plain) inhaledfrom spinhaler twice daily. (2) 20 mg spincap (Intalplain) contents ingested orally twice daily. (3) 10 mginsufflation capsule (Rynacrom) taken as 2 sprays toeach nostril 3 times daily.Doses of prednisolone began to be reduced 2 days

after starting disodium cromoglycate, and continuedto be so until all corticosteroids had been stopped at28 days. Prednisolone was reduced and then stoppedin a similar manner for children in the control group.

ResultsAll the children relapsed within 11 weeks of stoppingprednisolone. Three of the 5 children who werehaving disodium cromoglycate relapsed while stillreceiving the drug. The other 2 relapsed, 1 of themone week after, and the other 7 weeks after stoppingdisodium cromoglycate. The treatment group had acombined total of 33 weeks in remission, whereas thecontrol group had 40 weeks in remission.

BRL 10833. This drug is a new nitroindanedionederivative and has antiallergic activity when takenorally. Treatment with BRL 10833 did not preventrelapse in 6 children with steroid-dependent nephroticsyndrome who had required >10 mg/M2 alternate-day prednisolone. For 4 children who had required<10 mg/M2 alternate-day prednisolone the 56 daysof BRL 10833 may have prevented relapse duringtreatment but it did not induce a long remission.Further details of this trial have been described.6

Discussion

This enquiry into atopic disorders in the nephroticchildren and their relatives was confined to asthma,eczema, allergic rhinitis, and recurrent urticaria.Some studies have been carried out on at least 50symptoms-such as sweating, erratic appetite,flatus, and urgency of micturition.7 The limited andclearly-defined atopic disorders sought by usproved to be easily identifiable in the children andin the lst-degree relatives. Moreover our methodminimised observer bias.There was a significant increase of atopic disorder

in the nephrotic children compared with the hospitalcontrol group A. The difference is even more


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pronounced if the nephrotic children are comparedwith the healthy schoolchildren (control group B).The 13% incidence of atopic disease in controlgroup B is close to the incidence of 15% found in alarge Swedish survey8 and comes within the 12-20%range which is often quoted as being the incidence ofatopic disease in Europe and North America.9 The1st-degree relatives of the nephrotic children alsohad an appreciably higher incidence of atopic dis-orders than the healthy controls. This was expectedin view of the likely genetic influences on atopicdisease and its expression.An increased incidence ofatopic disease in children

with nephrotic syndrome has been suggested by thework of Ohnishi in Japan'0 and Thomson et al. inLondon." Our survey which was larger, moredetailed, and used stricter diagnostic criteria confirmsthat there is an increased incidence.

Despite the fact that 26 nephrotic children gave aclear history of atopic disorders, only 5 of them hadhad an episode of that disorder immediately before,or at the time of onset of nephrotic syndrome. Noneof them could produce a convincing history of anassociation between atopic symptoms and nephroticsyndrome; the exacerbations of, for instance,asthma were unrelated in time to the relapses ofnephrotic syndrome.An important symptom volunteered by parents of

half the nephrotic children was that onset of thesyndrome or relapse was often linked with 'a cold' or'a runny nose'. In a few cases this was clearly a viralinfection affecting others in the family, but for manychildren the parents maintained 'it was not a cold,just a runny nose'. If such cases had been included asexamples of allergic rhinitis (which they may be), theincidence of atopy in the nephrotic children wouldhave been very high. The difficulty was that despitecareful questioning no provocative factor could befound to account for the runny nose. It is interestingthat a runny nose was not common in the 12 childrenwho each had only had a single bout of nephroticsyndrome.

Seasonal factors were not found to be important inrelation to the onset of nephrotic syndrome or tosubsequent relapses. In our region the pollen seasonis mainly in May, June, and July, whereas house-dustmite, another common allergen, is more prevalent inSeptember and October. There was nothing in thetiming of the nephrotic syndrome to suggest acommon relationship to these seasons. In view of thewell-documented cases of nephrotic syndromeassociated with hay fever it was notable that only4 out of 77 children had a history of hay fever andthat only one had had a relapse at the time ofallergic rhinitis in the pollen season. Seasonal

nephrotic syndrome does occur4 but this surveysuggests that it is a rare accompaniment of trouble-some nephrotic syndrome, since the nephroticchildren in this survey represent the more difficultcases from a catchment area of 5 million populationduring a 6-year period.The absence of a consistent relationship between

month of birth, month of onset of nephroticsyndrome, and the pattern of the illness did notsupport the type of sensitisation phenomenon whichmay be relevant to the acquisition of sensitivity inearly life for children with asthma and eczema.12-4

Nearly half (40%) of the nephrotic children hadat least one positive skin response. This was signi-ficantly greater than the control group. It is alsohigher than the 20% which is quoted as being themaximum frequency of abnormal skin tests inhealthy'non-allergic' people.15The increase in positive skin tests fits in with the

earlier finding of an increased incidence of atopicdisorder in nephrotic children. An increasedincidence of positive skin tests to grass pollencompared with controls was found in nephroticchildren by Thomson and colleagues." Althougheach child was tested with at least 8 differentallergens, positive responses were mainly confinedto house-dust, house-dust mite, grass pollens, andmoulds. This was similar to the findings on asthmaticchildren in the Leeds area.The results of the management trials were dis-

appointing. For allergen avoidance to be successfulone needs to be sure that one particular allergen aloneis responsible for the symptoms and that it ispossible to avoid it. Allergen avoidance wasunsuccessful in the 8 children on whom it wasinflicted. The evidence that an allergen might beresponsible came partly from the history and partlyfrom the fact that each child had a positive responseto the radioallergosorbent test for that particularallergen. But in no case was the history as convincingas one would have liked, and the results confirmedthat avoiding the suspected allergen did not help inthe short term.During the preparation for this trial it became

clear how extremely difficult it is to define theallergens in various environments. Although parentssuggested factors-such as the water at Scarborough,the school hamster, or a change in the weather-aspreceding each relapse, further questioning led tomany other variable factors. One Asian child whorelapses regularly in Yorkshire had spent two longperiods with relatives in Pakistan where she isrelapse-free and no longer needs corticosteroids tostay in remission. It seems logical to implicateadverse environmental factors in Yorkshire (or


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protective ones in Pakistan), but the list is very long;different foods, water, climate, clothing, housing,micro-organisms, etc. So far we have failed toidentify which factor, or combination of factors,causes her to be healthy in Pakistan and ill inYorkshire.There has been a report of diminished proteinuria

in 6 American children who were put on an 'elementalfluid diet'.16 It was claimed that milk hypersensitivitywas the cause of the nephrotic syndrome. However,to be certain that a food is responsible for anintermittent disorder there must be remissionwhen the child stops eating it, relapse when it isreintroduced, and continued remission with con-tinued avoidance.Disodium cromoglycate was tried because of its

proved efficacy for extrinsic asthma. At the time ofthe trial its efficacy by powder inhalation for asthmaand by nasal insufflation for hay fever had beenestablished17 and there were preliminary reports thatoral cromoglycate might be effective for variousgastrointestinal disorders.18 We decided to give it bythree different routes because of the possibility thatit might be effective either because of its activity atmucus membranes, or by virtue of the 4% of itthat is absorbed after inhalation, or even by virtueof the proportion of the absorbed drug that isexcreted in the urine.19Disodium cromoglycate did not appear to prevent

or delay relapse in the children to whom it was given.All relapsed during or shortly after they had stoppedtaking prednisolone. Concurrently a similar trial ofcromoglycate was taking place in London.20 Thattrial too failed to demonstrate benefit to the childrenreceiving the drug, although one child had previouslybeen encountered with hay fever and summertimerelapses of nephrotic syndrome who might have beenhelped by intranasal cromoglycate.The pattern of absorption and excretion of

disodium cromoglycate means that it has littlechance of systemic effect, apart from that resultingfrom its activity at surfaces-nasal, pulmonary, andalimentary mucus membranes. It had been hopedthat if a drug of similar action and which, too, wasabsorbed could be developed, further benefit mightbe achieved. This is an arguable hypothesis, sincecromoglycate itself acts on mast cells which areparticularly numerous in those areas to which currentforms of cromoglycate administration deliver it.However, there was the possibility that an orallyabsorbed drug which stablised mast cells might bebeneficial to some children with nephrotic syndrome.Our carefully controlled trial of BRL 10833 did notbenefit many of the nephrotic children. It is possiblethat it was helpful to a few children who had

formerly taken low doses of maintenance pred-nisolone, but such children do not present difficultclinical problems and few would be consideredsuitable for the drug. A trial of another new mast cellstabilising drug doxantrazole has been disappointingtoo.2'

Pollen hypersensitivity is a rare cause of nephroticsyndrome. It is logical to expect other allergens tocause nephrotic syndrome, particularly as we haveshown such children to have an increased incidenceof atopy. However, our own work, and that ofothers, suggests that at present various antiallergicmanoeuvres fail to help children with steroid-responsive nephrotic syndrome. This may bebecause hypersensitivity plays no causal role. Itequally well could result from our failure to identifythe provoking allergen.

We thank the paediatricians who referred thechildren, the staff in Leeds who helped in their careand investigation, the Medical Illustration Depart-ment, St James's University Hospital, our assistantMrs Wendy Pearson, Dr G Wainscott and Dr J TBrocklebank who assisted with the BRL 10833treatment trial, and Beecham Research Laboratoriesfor supplying the trial drug.

The Children's Kidney Fund, University of Leeds,provided financial support.

References

Hardwicke J, Soothill J F, Squire J R, Holti G. Nephroticsyndrome with pollen hypersensitivity. Lancet 1959; i:500-2.

2 Wittig H J, Goldman A S. Nephrotic syndrome associatedwith inhaled allergens. Lancet 1970; i: 542-3.

3 Williamson D A J. Letter: Nephrotic syndrome associatedwith inhaled allergens. Lancet 1970; i: 778.

4 Reeves W G, Cameron J S, Johansson S G 0, Ogg C S,Peters D K, Weller R 0. Seasonal nephrotic syndrome.Clin Allergy 1975; 5: 121-37.Squire J R. The relationship between horse dandruffand horse serum antigens in asthma. Clin Sci 1950; 9:127-50.

6 Meadow S R, Brocklebank J T, Wainscott G. Letter:Anti-allergic drugs in idiopathic nephrotic syndrome ofchildhood. Lancet 1978; : 1200.Fontana V J, Spain W C, Desanctis A G. The role ofallergy in nephrosis. NY State J Med 1956; 56: 3907-10.

8 Kjellman N I M. Atopic disease in seven-year-oldchildren. Acta Paediatr Scand 1977; 66: 465-71.

9 Rapaport H G, Appel S J, Szanton V L. Incidence ofallergy in a pediatric population. Ann Allergy 1960; 18:45-9.

10 Ohnishi M, Kimura K, Matsumoto T, Sakamoto F,Yamaguchi M, Kadowaki J. Idiopathic nephroticsyndrome and atopic features. In the proceedings of theFourteenth Annual Meeting of the Japanese Society ofPaediatric Nephrology 1978. Abstract 97.


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Thomson P D, Stokes C R, Barratt T M, Turner M W,Soothill J F. HLA antigens and atopic features in steroid-responsive nephrotic syndrome ofchildhood. Lancet 1976;ii: 765-8.

12 Taylor B, Norman A P, Orgel H A, Stokes C R, TurnerM W, Soothill J F. Transient IgA deficiency and patho-genesis of infantile atopy. Lancet 1973; ii: 111-3.

13 Soothill J F, Stokes C R, Turner M W, Norman A P,Taylor B. Predisposing factors and the development ofreaginic allergy in infancy. Clin Allergy 1976; 6: 305-19.

14 Warner J 0, Price J F. House dust mite sensitivity inchildhood asthma. Arch Dis Child 1978; 53: 710-3.

15 Hagy G W, Settipane G A. The frequency of allergens andpositive skin tests among college students (abstract).J Allergy 1966; 37: 107-8.

18 Sandberg D H, Mcintosh R M, Bernstein C W, Carr R,Strauss J. Severe steroid-responsive nephrosis associatedwith hypersensitivity. Lancet 1977; i: 388-91.

17 Bierman C W, Soyka L F. The use of cromolyn sodium inthe treatment of asthma in children. Pediatrics 1975; 55:586-8.

18 Freier S, Berger H. Disodium cromoglycate in gastro-intestinal protein intolerance. Lancet 1973; i: 913-5.

19 Walker S R, Richards A J, Paterson J W. The absorption,excretion, and metabolism of disodium (14C) cromo-glycate in man (abstract). Biochem J 1971; 125: 27P.

20 Trompeter R S, Thomson P D, Barratt T M, Soothill J F.Controlled trial of disodium cromoglycate in preventionof relapse of steroid responsive nephrotic syndrome ofchildhood. Arch Dis Child 1978; 53: 430-2.

21 Bluett N H, Chantler C, Hughes D T. Letter: Failure ofdoxantrazole in steroid-sensitive nephrotic syndrome.Lancet 1977; i: 809.

Correspondence to Professor S R Meadow, Depart-ment of Paediatrics and Child Health, St James'sUniversity Hospital, Beckett Street, Leeds LS9 7TF.

Received 25 May 1980


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