NEPHROTIC SYNDROME: FROM TODDLERS TO TWENTIES

255 a study design based on a there should be a followdefined population geographically in such a design of at least The rate 80%.20 advantages up have been shown previously.22122 We were able to achieve a follow-up rate of 97-5% and therefore a comparison with other such study populations was feasible. The follow-up study could have been designed either in a centralised or in a decentralised manner; because all infants were enrolled anonymously and financial resources were limited, the decentralised design was maintained. Because of the biases possibly introduced by non-participants and of the need to achieve an acceptable follow-up rate, frequent consultations between the study centre and the participating paediatricians took place. By such close cooperation the high follow-up rate was attained. Because of the decentralised organisation of the follow-up programme inter-observer variability was likely to occur, lowering the reliability of the collected data. However, the precoded questionnaires were designed to minimise the risk of ambiguous answers. One year after the last child reached the corrected age of 2 years, data on 85 children were still missing at the study centre. Data on 13 of them remained incomplete and were lost to follow up. Because the proportion of major and minor handicaps in the remaining 72 children was similar to that found in the other 859 survivors, these 72 children could have been excluded from the study, saving time and effort. However, previous investigators have claimed, that to avoid bias, such data must be included1-25 The fact that in our study there was no difference in handicap rates, could be attributed to the decentralised study design: when children were lost to follow-up the reason was likely to be organisational rather than related to their impairment. Therefore, in a design such as ours, a follow-up rate of 90%

Bax has stated that in

may be

acceptable. Although handicaps in the surviving infants did not appear to be related to gestational age or birthweight, other risk factors, such as socioeconomic status, obstetrical history, fetal presentation, gender, mode of delivery, and the occurrence of idiopathic respiratory distress syndrome, and intracranial haemorrhage during the neonatal period have not been taken into account. Multivariate analysis will be required to establish the importance of each of these factors separately. We thank the paediatricians in the 101 paediatnc departments who participated in this study, and the general practitioners and child health centre personnel involved in the follow-up study for providing the data. The Project On Preterm and Small for gestational age infants is financially supported by the Praeventiefonds, The Hague (grant 28-766).

Correspondence should be addressed to T.

M.

v

Z-vd A.

REFERENCES

SP, Verwey RA, Brand R, Bennebroek Gravenhorst J, Keirse MJNC, Ruys JH. Neonatal mortality risk in relation to gestational age and birthweignt. Lancet 1986; i 55-57 2. Verloove-Vanhorick SP, Verwey RA Project On Preterm and Small for gestational age infants in the Netherlands 1983. Thesis. State Univesity Leiden, 1987. p 377. 3. van de Bor M, Verloove-Vanhorick SP, Brand R, Kense MJNC, Ruys JH Incidence and prediction of periventricular-intraventricular hemorrhage in very preterm infants J Perinat Med 1987; 15: 333-39 4 Verloove-Vanhorick SP, Verwey RA, Ebeling MCA, Brand R, Ruys JH. Mortality in very preterm and very low birth weight infants according to place of birth and level 1. Verloove-Vanhorick

of care. Pediatrics

1988; 81: 404-11. 5. Beganovic N, Verloove-Vanhorick SP, Brand

R, Ruys JH. Total parenteral nutrition and sepsis. Arch Dis Child 1988, 63: 66-67. 6. Kollée LAA, Verloove-Vanhorick SP, Verwey RA, Brand R, Ruys JH Maternal and neonatal transport Results of a national collaborative survey of preterm and very low birthweight infants in the Netherlands Obstet Gynecol (m press). 7. van de Bor M, Verloove-Vanhorick SP, Brand R, Ruys JH. Patent ductus artenosus in a cohort of 1338 preterm infants a collaborative study. Paediatr Perinat Epidemiol 1988; 2: 328-36

Hospital Practice NEPHROTIC SYNDROME: FROM TODDLERS TO TWENTIES MALCOLM A. LEWIS EILEEN M. BAILDOM NEVILLE DAVIS IAN B. HOUSTON ROBERT J. POSTLETHWAITE

Royal Manchester Children’s Hospital, Pendlebury, Manchester M27 1HA

Summary

63

patients with steroid-sensitive, biopsynephrotic minimal-change

proven

syndrome were followed for between 10 and 21 years. 2 died. All the survivors had normal renal function and blood pressure, and only 2 had a single attack. Frequent relapse was more common with young age of onset and in boys. The frequency of relapse fell rapidly over the first 4 years after diagnosis and then plateaued. Relapses continued into adult life. No definite endpoint to the disease could be defined although there was a linear relation between length of remission and risk of subsequent relapse. INTRODUCTION

EARLY reports of the International Study of Kidney Disease in Childhood (ISKDC),12 showed that 77% of cases of childhood nephrotic syndrome had minimal-change histology. The short-term prognosis seemed good for most children, both for those with minimal-change disease and for a large proportion of those with other histological variants such as mesangial proliferative glomerulonephritis. Since then there have been several reports with long-term

8.

Schlesinger-Was EA. Longitudinal study of a psychomotor development of a group of

infants in child health clinics T Soc Geneesk 1982; 60: 602-05. AL, Turcan DM, Rawlings G, Reynolds EOR. Prognosis for infants weighing 1000 g or less at birth. Arch Dis Child 1977; 52: 97-104. 10. Lloyd BW. Outcome of very-low-birthweight babies from Wolverhampton. Lancet 1984; ii: 739-41 11. Yu VYH, Watkins A, Bajuk B Neonatal and postneonatal mortality in very low birthweight infants. Arch Dis Child 1984; 59: 987-99 12. Saigal S, Rosenbaum P, Stoskopf B, Milner R Follow-up of infants 501 to 1,500 gm birth weight delivered to residents of a geographically defined region with perinatal intensive care facilities J Pediatr 1982; 100: 606-13 13. Johnson MA, Cox M, McKim E. Outcome of infants of very low birth weight. a geographically based study. Can Med Assoc J 1987, 136: 1157-65. 14 Hack M, Blanche C, Rivers A, Fanaroff AA. The very low birth weight infant: the broader spectrum of morbidity during infancy and early childhood. J Dev Behav Pediatr 1983; 4: 243-49. 15. Fetter WPF, Baerts W, Borst LE. Late morbiditeit bij kinderen met een geboortegewicht van minder dan 1500 gram, geboren in de periode 1979-1983. Ned Tijdschr Geneeskd 1986; 130: 1143-46 16. Hunt CE, Brouillette RT. Sudden infant death syndrome: 1987 perspective J Pediatr 9. Stewart

1987; 110: 669-78. M, Merkatz IR, Jones PK, Fanaroff AA Changing trends of neonatal and postneonatal deaths in very-low-birth-weight infants Am J Obstet Gynecol 1980;

17. Hack

137: 797-800. 18 Editorial. The fate of the baby under 1501 g at birth Lancet 1980; i 461-63. 19 Koppe JG, Treffers PE. Intensive care and the very low birth weight infant. Lancet

1981; ii: 527-28. 20. Bax M. Following up the small baby Dev Med Child Neurol 1983; 25: 415-16. 21 Kiely JL, Paneth N. Follow-up studies of low-birthweight infants: suggestions for

22.

design, analysis and reporting. Dev Med Child Neurol 1981; 23: 96-100. Johnson MA, Macfarlane AJ. Neonatal intensive care: trends in morbidity. Lancet

1988; ii. 168 23. Bernuth H v, Harnack G-A v, Vogelsang U. Organisatorische Probleme bei der Betreuung von Risikokindern Mschr Kinderheilk 1970; 118: 570-71. 24. Morley R, Mutch L Follow up studies-their design, organisation and analysis. Report of a meeting held in Cambridge on 21 Oct 1987, Cambridge, Great Britain; 1-14. 25. Tyson JE, Lasky RE, Rosenfeld CR, Dowling S, Gant N Jr. An analysis of potential biases in the loss of indigent infants to follow-up Early Hum Dev 1988; 16: 13-25.

256

Fig 1-Percentage of patients relapsing (left) and mean number of relapses per patient per year (right) for the first 10 years after diagnosis. x=whole group,

0 = age of onset

<

5 years (n = 31), .

follow-up showing a varied outlook.3-9 Most of this variability can be explained by the heterogeneous patient groups studied; the majority of reports came from tertiary referral centres and histological diagnoses were often not available. However, Tejani9 has suggested that even in steroid-responsive, minimal-change disease the prognosis can be uncertain since morphological transition (to focal segmental glomerulosclerosis) on repeat biopsy and subsequent renal impairment develop in a significant proportion (62-5%) of patients who frequently relapse. Tejani showed that during follow-up ranging from 5 to 18 years renal death occurred in 25%; an actuarial survival curve showed that at a mean of 20 years’ disease duration all those with morphological transition would probably reach end-stage renal status. Tejani’s findings are very different from those in two other reports. Trompeter et al8 found no renal impairment during follow-up of 15-20-5 years amongst a cohort of 152 children with biopsy-proven, minimal-change disease; nor did Koskimies et aF amongst 94 children with steroid-sensitive nephrotic syndrome during follow-up of 5-14 years. In view of these conflicting reports we have examined the clinical course and long-term prognosis of a well defined group of children with steroid-sensitive, biopsy-proven,

minimal-change nephrotic syndrome. PATIENTS AND METHODS

Patients We have included all 68 patients with nephrotic syndrome referred to the Royal Manchester Children’s Hospital between 1963 and 1976 who showed complete steroid responsiveness and who had minimal-change histology. Thus a minimum 10-year follow-up (mean 14 years, range 10-21 years) was possible. All patients had had a histological diagnosis of minimal-change disease made by one histopathologist, with biopsy specimens taken either at presentation (in accord with the ISKDC study which was operative at the time) or before a course of cyclophosphamide. Information was obtained from the patients’ records at the children’s hospital and later at adult nephrology clinics.

Definitions The following detinitions were used, according to ISKDC criteria: proteinuria, ’Albustix’2 + or more on a first morning urine

=

age of onset:? 5 years

(n

=

30).

overnight urine protein excretion of over or more consecutive days of

specimen,

or a

measured

40

per

m2; relapse, three

mg/h

proteinuria. Treatment Protocols Standard steroid therapy was prednisolone 60 mg/m2 per day in divided doses until albustix testing of the first morning urine was trace or negative for three consecutive days. Prednisolone 40 mg/m2 per day was then given as a single dose on alternate days for four weeks. Long-term steroid therapy was rarely used. Relapses were treated as they occurred, although in most cases therapy was withheld until the fifth to seventh day of heavy proteinuria (albustix 3 + or 4 +) in case spontaneous remission occurred. Cytotoxic drug therapy was used when relapses occurred frequently, such that steroid toxicity was present or anticipated, and after appropriate discussion with parents. In the period up to 1974 most of these patients received cyclophosphamide, as described in the ISKDC trial. In this trial the dosage of cyclophosphamide was 5 mg/kg per day until leucopenia was induced, when smaller doses were given to maintain modest leucopenia for a further six weeks. During 1974 a standard regimen of 2-5 mg/kg daily for 56 days was adopted and maintained thereafter. Of the 61 patients included in the final analysis, 17 received steroid therapy only during follow-up. 44 received steroids and cytotoxic drugs. 34 of these 44 received a single course of cyclophosphamide and 3 had two courses, 1 patient received azathioprine only, and the remaining 6 received more than one cytotoxic agent at different times. All patients were asked to test their first morning urine sample daily and to ’phone the hospital when relapse occurred. Treatment was then begun as outlined.

Statistical Analysis Statistical

analysis was done with the Wilcoxon paired-sample the significance of frequencies of relapse in different groups. The chi-squared test and the calculation of correlation coefficients between variables were also used as appropriate. test to assess

RESULTS

Group

Characteristics

Of the 68 patients 5 were lost to follow-up. Of the remaining 63 patients, 2 died-I from peritonitis and septicaemia in the first attack and 1 from sagittal sinus thrombosis in the first relapse. The case fatality was thus

257

dependent separately.

upon another and

they have been considered

Age effect.-There was a significant inverse correlation between age of onset and the total number of relapses during the first 10 years after diagnosis (r = 0-51, p < 0-001). When the children were considered by age of onset before or after the fifth birthday (fig 1) the increased frequency of relapse amongst the younger patients is clearly seen (p < 0-01). Sex effect.-Female sex conferred an advantage (fig 2), with a smaller proportion of girls than boys relapsing in each

year (p <

0-01).

Treatment effect.-The rapid fall in the rate of relapse first few years of follow-up was most pronounced in group S + C (fig 3). Overall, the proportion of patients relapsing per year was significantly greater in group S + C than in group S (p < 005). This difference was most pronounced during the first 3 years. In the final 7 years of follow-up the proportions of patients relapsing in the two groups did not differ significantly. 38 of the patients in group S + C received cytotoxic therapy in the first 3 years after diagnosis; a further 3 received this treatment in the fourth year, and 3 received their first cytotoxic drugs after the fourth year. over the

Fig 2-Percentage of boys ( 0 ) and girls ( )relapsing in each year of follow-up for the first 10 years after diagnosis.

3%. At the end of follow-up no patient was hypertensive (blood pressure over the 97th percentile for age) and all had a serum creatinine of under 100 jmol/1. The modal age of onset was 2 years, mean and median age of onset was 5 years, and the male to female ratio was 35/1.

Relapses One

relapses occurred in 59 (97%) of the 61 surviving patients. The rate of relapse, in respect of the number of patients relapsing each year and the number of relapses per patient per year, fell rapidly over the first 3-4 years of follow-up but thereafter changed little (fig 1). Three variables that might influence this picture were considered-age of onset, gender, and treatment. Treatment was separated into two broad groups, those who received only steroids (group S) and those who received steroids and cytotoxics (group S + C). The age distributions in the sexes, the proportion of males to females, and the age or more

distribution in the

significantly.

Thus

Remissions

Various periods of remission were studied to establish whether there was a point after which relapses were unlikely to recur. Remissions of 1-8 years were considered, and only the patients with a full 5-year follow-up after remission were included (fig 4). There was an inverse linear relation between the length of remission and the proportion of patients relapsing in the subsequent 5 years (r=0-94, p < 0001). Thus, for example, after 5 years of remission the risk of relapse in the subsequent 5 years is 22-6% (95%

did not differ of these variables was totally

two treatment groups none

Fig 3-Pereentage of patients relapsing in groups S + C (0) and group S () in each year of follow-up for the first 10 years after diagnosis.

of patients relapsing in the 5 years of follow-up after 1-8 years of remission.

Fig 4-Percentage y = 52 1 - 5

9x, shaded area = 95% confidence interval.

258

confidence interval [CI] 17-6% to 27-5%); after 8 years of remission this risk falls to 4-9% (95% CI 0% to 13-7%). The longest individual periods of remission followed by relapse were 11 and 14 years. Adulthood In some patients relapses continued into adult life. At the time of the study 45 patients were over 16 years of age and 12 of these (26-7%) had had relapses after their sixteenth birthday. 5 (31 %) of 16 who were under 5 years old and 7 (24%) of 29 who were aged 5 or more at presentation relapsed after their sixteenth birthday; the difference was not significant. 26 patients were over 20 years old at the time of the study and 5 (19-2%) of these relapsed after this age. There was no relation between early age of onset and risk of relapse over the ages of 16 or 20 years. 2 patients were over 25 years old when studied and 1 of these had relapsed after this age. DISCUSSION

Hypertension, renal failure, or clinically important renal impairment did not develop in any of our patients. This finding accords with those of Trompeter et al8 and Koskimies et al. In these and our series 291 patients with biopsy-proven, minimal-change disease were followed up for between 5 and 21 years, and none had progressed to renal failure; 213 patients had a mean follow-up of 17-1years (range 10-21 years), and at least 99 patients had a frequently relapsing course. Trompeter et al8 did not record the number of frequently relapsing patients in his series, but about

50%

of

his

cohort

received

a

course

of

cyclophosphamide, suggesting that the total number of such patients was about 175. Thus the predictions of Tejani9 from his small series of 48 patients have not been confirmed. 97% of our cohort relapsed during follow-up. It is generally accepted that about a third of children have a single attack of nephrotic syndrome; this figure seems to originate from an early ISKDC report’° in which the follow-up was only 6 months. Trompeter et al8 could not establish the frequency of relapse in many patients but estimated that 30% of their cohort had a single attack. In Koskimies and colleagues’7 series 24% of children with steroid-sensitive disease had a single episode in 5-14 years of follow-up. There are several reasons why we observed fewer patients with a single attack. First, as a tertiary referral centre we could have been seeing a highly selected population. However, since many patients were referred for renal biopsy in their first attack (in accord with the ISKDC trial) this is unlikely to be the sole explanation. Second, our close monitoring of proteinuria detected relapses early. A proportion of patients who relapse undergo spontaneous remission (2-5% for every day a relapse is left untreated, unpublished data), and so if daily urinalyses were not done routinely the true incidence of relapse would be underestimated. Other workers have not reported how patients were monitored after initial presentation and treatment. Third, relapses may occur after long remission intervals. Even after 5 years’ remission, almost a quarter of patients will relapse over the next 5 years. If follow-up is less than 10-15 years, therefore, the proportion that never relapse will be greatly overestimated. Although our figure of 3% may well be an underestimate of the proportion of children having a single attack, we feel that figures of between 20% and 30% are an overestimate, attributable to inadequate or incomplete follow-up.

Trompeter et al8 suggested that early age of onset predisposed to a lengthy relapsing course and was inversely related to duration of disease. Our more detailed study is the first to show clearly the natural history of the treated disease. Frequency of relapse is related to age of onset, sex, and time since diagnosis. Age of onset under 5 years and male sex are independently associated with a higher rate of relapse throughout the 10 years after diagnosis. Frequency of relapse falls rapidly over the first 4 years in all groups. This decrease is most pronounced in those treated with cytotoxic drugs and steroids (compared with those treated with steroids alone) and so is likely to be the result of cytotoxic therapy," particularly since the plateau reached is the same in the two groups. The plateau seen in the proportion of patients relapsing about 4 years after the onset of disease makes it impossible to predict the total disease duration for any group we studied. Thus the finding that relapses continued into adult life and that patients whose disease begins later in childhood may relapse as adults is not surprising. Clearly these findings have implications for patients with steroid-sensitive nephrotic syndrome, and for their parents. After the difficulties of the initial illness have been overcome parents should be prepared for the likelihood of relapses but reassured that the frequency of relapse will lessen with time. In patients with a frequently relapsing course the combination of steroid and cytotoxic therapy is likely to reduce the relapse rate. Of those with frequent relapses initially, as seen in fig 3, only 34% will relapse in the fifth year after diagnosis and 20% in the tenth. We have shown an inverse relation between duration of remission and risk of relapse in the following 5 years. After 1 year of remission about 46% of patients will subsequently relapse, and even after 5 years about 22% of patients will relapse. Although the risk seems to be negligible after 9 years of remission, the curve of the upper confidence limit remains well above zero. Thus even 9 years of remission cannot define the disease endpoint-as indicated by our 2 patients who relapsed after 11 and 14 years of remission,

respectively. These data are important for the counselling of older children and adults. Clearly, while the risk of relapse is high, daily home urinalysis is essential. With lengthening remission periods patients often test their urine less often, partly as a show of adolescent rebellion. However, testing less than twice weekly places the patient at risk of apparently unheralded oedema and other complications of relapse, since several days of heavy proteinuria may have gone undetected. Together with results from other studies, we have shown a 3% case fatality from potentially avoidable complications of the nephrotic state. We recommend that urine should be tested at least twice weekly until a minimum of 5 years of continuous remission have been accomplished and the risk of subsequent relapse falls to below 25%. We encourage patients to continue regular testing until 9 or more years of continuous remission have been achieved and the risk of subsequent relapse is negligible. Many patients, however, will not be willing to continue for this long, and so the best compromise is to recommend urine testing at the time of any minor infections when there is probably an increased risk of relapse. We thank Dr N. Mahk for assistance with the data collection from his adult Mrs K. Cordwell for typing the script.

nephrology clinic and

259

Organisation have reported on the status of allergen immunotherapy with recommendations about use. World Health

Therapeutics

MECHANISMS OF IMMUNOTHERAPY

CURRENT STATUS OF ALLERGEN IMMUNOTHERAPY

Shortened Version of a World Health Organisation/ International Union of Immunological Societies

Working Group Report* ALLERGEN

immunotherapy (hyposensitisation) initiated

by Noon in 1911.1 is the administration of gradually

increasing quantities of allergen extract to ameliorate the effects of subsequent exposure to the allergen. The procedure has been widely used to treat immediate hypersensitivity type reactions (now known to be primarily mediated by allergen-specific IgE antibodies) such as rhinoconjunctivitis, asthma, or severe reactions to insect stings. Immunotherapy in food-related disorders is not indicated at present. The availability of potent drugs for the management of these conditions has caused a change in the use of immunotherapy. There has also been doubt about efficacy and the most appropriate immunotherapy regimens. In addition some patients’ symptoms deteriorate despite immunotherapy and several adverse reactions, including deaths, have occurred. Immunotherapy is easy to administer and in most patients is well tolerated. With inappropriate selection of patients, allergen extracts, or regimens, however, poor results can be expected, and most of the deaths associated with this therapy occur in inexperienced hands. This has led to public concern and a report by the UK Committee on Safety of Medicines which placed restrictions on this practice.2 The clinical immunology committee of the International Union of Immunological Societies (IUIS) and the microbiology and immunology support services of the *The members of the

working group were: R. A. Thompson (Chairman), Regional Immunology Department, East Birmingham Hospital, UK; J. Bousquet, Respiratory Diseases Service, Hôpital Aiguelongue, Montpelier, France; S. Cohen, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA; P. C. Frei, Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; L. Jager, Institute for Clinical Immunology, Jena, East Germany; P. H. Lambert, Microbiology and Immunology Support Services, WHO, Geneva; M. H. Lessof, Department of Medicine, Guy’s Hospital, London, UK; R. H. Loblay, Clinical Immunology Research Centre, University of Sydney, Australia; H. J. Mailing, Allergy Unit, Rigshospitalet, Copenhagen, Denmark; P. S. Norman, Clinical Immunology Division, Good Samaritan Hospital, Baltimore, Maryland, USA; A. L. de Weck, Institute for Clinical Immunology, Berne, Switzerland; and B. Weeke, Allergy Unit, Rigshospitalet, Copenhagen, Denmark. The full report will appear in Bull WHO, July, 1989.

1.

Churg J,

Habib R, White RHR. Pathology of the nephrotic syndrome in children Lancet 1970; ii: 1299-1302. 2. A report of the International Study of Kidney Disease in Childhood. Pnmary nephrotic syndrome in children: clinical significance of histological variants of minimal change and of diffuse mesangial hypercellularity. Kidney Int 1981, 20: 765-71. 3 Cornfeld D, Schwartz MW Nephrosis a long term study of children treated with corticosteroids J Pediatr 1966; 68: 507-15. 4 Siegel NJ, Goldberg B, Krassner LS, Hayslett JP. Long term follow up of children with steroid responsive nephrotic syndrome. Pediatrics 1972; 81: 251-58 5. Makker SP, Heymann W. The idiopathic nephrotic syndrome of childhood: a clinical re-evaluation of 148 cases. Am J Dis Child 1974, 127: 830-37. 6 Schwartz MW, Schwartz GJ, Cornfeld D. A 16 year follow up study of 163 children with nephrotic syndrome. Pediatrics 1974, 54: 547-52

immunological changes occur in patients undergoing but the precise mechanism by which immunotherapy allergen Various

are alleviated is unknown. Several possibilities, which mutually exclusive, have been proposed, including altered regulation of IgE synthesis, production of blocking antibodies of other isotypes, and decreased reactivity of effector mechanisms. The treatment of IgE-mediated drug reactions, especially reactions to antibiotics, by the frequent injection of incremental doses of the drug over a short period until the therapeutic level is achieved produces clinical tolerance, which is lost on cessation of therapy. The mechanism probably involves hapten inhibition.3

symptoms are not

CLINICAL STUDIES

Since the introduction of immunotherapy evaluation of efficacy has been hampered by lack of standardised allergen preparations, poor definitions of benefit, variation in patients’ perception of symptoms, differences between actual and presumed allergen exposure, and other concurrent allergies and non-specific triggers.4 Nevertheless, controlled studies of a few allergens have shown that specific immunotherapy is effective in IgE-mediated anaphylactic reactions, especially bee and wasp venom sensitivity’ and in rhinoconjunctivitis and asthma due to pollens.6-10 Although extracts of house dust have been used for years in house dust sensitivity, such extracts should be replaced by extracts of the allergens commonly found in dust, such as mites1U2 and animal danders.13 Studies in mould sensitivity cases are encouraging,14,15 but most mould-sensitive patients are allergic to several species and commercial extracts have yet to be characterised and standardised adequately. Bacterial vaccines were consistently ineffective in several controlled studies of asthma4 and should not be used for allergen-specific immunotherapy. Proof of the efficacy of candida extract is also lacking. Commercial catalogues of allergen extracts usually contain lists of hundreds of other inhaled materials available for diagnostic testing and immunotherapy. Although such preparations may be useful for diagnosis, support for their use for immunotherapy depends on uncontrolled observation without evidence of immunological response and is a matter for individual clinical judgement. STANDARDISATION

Allergen extracts are heterogeneous mixtures of specific allergenic determinants and inert materials. Furthermore the IgE responses to the allergenic determinants vary from patient to patient. Although extracts are commonly labelled for potency in terms of dry weight of starting material per volume of extracting fluid or in protein nitrogen units (1PNU 10 ng protein nitrogen), neither system is necessarily related to allergenic or immunising activity. Biological activity units16-18 are more appropriate. Several other immunological techniques measure specific allergenic components directly with monoclonal or specific polyclonal =

7. Koskimies O, Vilska J,

Rapola J, Hallman N Long term outcome of primary nephrotic syndrome Arch Dis Child 1982; 57: 544-48 8 Trompeter RS, Lloyd BW, White RHR, Hicks J, Cameron JS Long-term outcome for children with minimal change nephrotic syndrome. Lancet 1985; i: 368-70. 9. Tejani A. Morphological transition in minimal change nephrotic syndrome. Nephron 1985, 39: 157-59. 10 Bamett HL. The natural and treatment history of glomerular diseases in children. what can we learn from international co-operative studies? In Giovannetti S, Bonomini V, D’Amico G, eds. Proceedings of the sixth international conference of nephrology, Florence, 1975. Basel Karger, 1976 470-85. 11. International

Study of Kidney Disease in Children. Prospective, controlled trial of cyclophosphamide therapy in children with nephrotic syndrome Lancet 1974, ii:

423-27.