Renal disease, epidermal necrosis, and epithelial cell antibodies

J E Deal, RW Groves, A W Harmer, K I Welsh, D M MacDonald, S P A Rigden

AbstractObjective-To describe the association between

epithelial cell IgM, which has previously been asso-ciated with an increased incidence of loss of renalgraft in children, with a novel cutaneous eruptionand unexplained native renal disease.Design-Observational study on children with

epithelial cell antibody presenting with unexplainedrenal or skin disease.Setting-General paediatric department and

regional paediatric nephrology unit.Patients-Six children (five girls, one boy), who

presented to the unit in 1989-90.Results-Three children, two of whom had a

history of a hyperpigmented rash, presented withhypertension, proteinuria, and impaired renalfunction. Renal biopsy specimens from two of thesechildren showed severe arteriolar endothelial cellswelling with arteriolar occlusion. These childrenfully recovered after treatment with antihypertensivedrugs. The third child developed end stage renalfailure and required dialysis. Three other childrenpresented with an unusual cutaneous eruption butno evidence of renal disease. Histology of theskin lesions showed acute epidermal necrosis andfeatures consistent with a viral infection.Conclusions-The aetiology and pathogenesis of

the epithelial cell antibody are unknown. Thesecases indicate that it may have a role in native kidneydisease and focal epidermal necrosis. Clinical andhistological features suggest that the antibody maybe associated with a viral infection.

Departments of PaediatricNephrology andDermatology and TissueTyping Laboratory, Guy'sHospital, London SEI 9RTJ E Deal, MRCP, lecturer inpaediatric nephrologyRW Groves, MRCP, registrarin dermatologyAW Harmer, BSC, researchfellowK I Welsh, PHD, seniorlecturer in immunogeneticsDM MacDonald, FRCP,consultant dermnatologistS P A Rigden, FRcp,consultant paediatricnephrologist

Correspondence to:Dr J E Deal, Department ofPaediatric Nephrology,Guy's Hospital, LondonSE1 9RT.

BMJ 1991;303:161-3

IntroductionAn IgM antibody directed against an epithelial cell

line, A549, has been detected by flow cytometry' inchildren undergoing renal transplantation, and itspresence strongly correlates with an increased inci-dence of graft loss.2 In most children with this antibodygraft loss was early and histological changes were foundthat were consistent with antibody mediated rejection:interstitial haemorrhage and swelling and vacuolationof arteriolar and capillary endothelial cells. We do notknow whether the association between the presence ofthe antibody in renal graft recipien-ts and graft loss is'causal or coincidental. The aetiology and pathogenicityof the antibody are unknown, but preliminary findingsshow that in normal renal tissue it binds to distaltubular epithelial cells and vascular endothelium (BHartley, personal communication)..-The antibody has also been-. detected in people

who have not received transplants, including healthy

Clinical details ofsix children

Case AgeNo (years) Sex Rash Proteinuria Hypertension Renal function

1 7-5 F + ++ +++ Acuterenalfailure2 9 F + ++ `++ Chronic renal failure3 7 F ++ Normal4 10-3 F ++ Normad5 12-3 F ++ Normal6 15S8 M + +++ Acuterenalfailure

FIG 1-Renal biopsy specimen showing vascular endothelial cellswelling and vacuolation (arrows). Silver methanamine stain counter-stained with haematoxylin and eosin. (Magnification x 400)

members of staff and parents of children undergoingtransplantation. In these subjects it does not seem to beassociated with any specific clinical signs or symptoms.However, we also detected the antibody in six childrenwho had not received transplants but who presented toour unit in 1989-90 with systemic disease. We describethe clinical features of these children and speculate ontheir association with the antibody.

Case historiesThe table shows the clinical details of the six patients

(five Afro-Caribbean girls, one white boy). All thechildren had a prodromal flu-like illness with fever,non-specific aches and pains, lethargy, and headaches.There was no history of contact with recognisedinfectious diseases. The children in cases 4 and 5 weresisters, and their mother also had the antibody detectedin her serum, though she had no symptoms. Theparents and three siblings of the child in case 6 had alsohad symptoms of a viral-like illness and all werepositive for the antibody, although no other member ofthe family had cutaneous or renal disease.

CASE 1This child presented with accelerated hypertension,

proteinuria, and acute renal failure. She had had ahyperpigmented rash on her arms and legs three to fourmonths before presentation, which had consisted ofnumerous 0-5-2-0 cm circular lesions. The lesionshad faded leaving hyperpigmented macules. Renalxiltrasonograpbii showed normal size kidneys withincreased- echog ficity, and computed tomographyshowed bilateral areas of low attenuation in structur-ally normal kidneys, which suggested ischaemia.Renography with technetium-99m labelled dimer-captosuccin.i acid (DMSA) showed bilateral patchyuptake;- intriaven,ous urography and micturating cysto-urethrography gave nortual results; and renal arterio-grapbhyshowed normal main vessels but small irregularrenal arteries with distal pruning. Segmental occlusionof glomerular tufts by eosinophilic material, mildpatchy interstitial oedema, and swelling and vacuo-

BMJ VOLUME 303 20 JULY 1991 161

lation of vascular endothelial cells were found on renalbiopsy (fig 1). There was no deposition of complementor immunoglobulins.

She had neutrophil leucocytosis and thrombocytosis.She was weakly positive for nuclear and parietal cellantibodies and positive for neutrophil cytosolicIgM. Her complement levels were normal except for araised C3 titre. Her titres for antistreptolysin 0and antiDNAse B were raised, suggesting recentstreptococcal infection.

She was treated with antihypertensive drugs andsix months later was normotensive without any treat-ment. Her renal function and renal biopsy specimenappeared normal and less uptake of 'Tc-DMSA wasseen on renography.

CASE 2

This girl had a hyperpigmented rash similar to thatdescribed in case 1 three to four months beforepresenting with hypertension, proteinuria, and chronicrenal failure. The rash had faded leaving hyper-pigmented macules. There was no evidence of vesico-ureteric reflux or renal scarring and she had normalsized kidneys. Renal biopsy showed severe irreversiblechronic renal damage of unknown cause with normalblood vessels. Immunoperoxidase studies showeddeposition of IgM, C3, and Clq.

She was weakly positive for nuclear and smoothmuscle antibodies, but her complement concentrationswere normal. She was treated with antihypertensivedrugs and her renal function was managed medically,but her condition deteriorated and she becamedependent on dialysis.

CASES 3-5

All these children presented with a short history of afew hyperpigmented lesions (up to three) that werepredominantly distally sited on the arms and legs. Thelesions were oval or round, 2-3 cm in diameter, tender,hyperpigmented, and had an erythematous basewith incipient bullous change suggestive of epidermalnecrosis (fig 2). One week after development thenecrotic epidermis, which became dry, sloughed offleaving a hypopigmented macule. These areas subse-quently repigmented, producing a peripheral hyper-pigmented halo. None ofthe girls had evidence ofrenaldisease at presentation.

Skin biopsy specimens from two of the girls (cases3 and 4) showed acute epidermal necrosis with amoderate perivascular infiltrate comprising lympho-cytes, macrophages, and eosinophils. Multinucleatekeratinocytes were seen at the edge of the lesions,and some epidermal cells contained nuclear inclusionbodies (fig 3). Haematological investigations gavenormal results. The girl in case 4 was weakly positive

FIG 2-Typical lesion from case 4 showing hyperpigmnented centre andinflammato,y rim

FIG 3-Skin biopsy specimen from case 2. Note epidermal giant cellsand multiple intranuclear inclusion bodies (arrows). Haematoxylinand eosin stain. (Magnification x 125)

for smooth muscle antibodies and for neutrophilcytosolic IgM and IgG. Her sister (case 5) also wasweakly positive for neutrophil cytosolic IgM. None ofthese children received any treatment.

CASE 6

This boy presented with accelerated hypertension,proteinuria, and acute renal failure. He had no historyof hyperpigmented rash. Renal ultrasonographyshowed normal sized kidneys and increased echo-genicity. Scanning with *-Tc-DMSA gave abnormalresults, but the results of arteriography were normal.The appearance of his renal biopsy specimen wassimilar to that in case 1 with segmental occlusionof glomerular tufts, patchy interstitial oedema, andswelling and vacuolation of vascular endothelial cells.There was no deposition of complement or immuno-globulins. Haematological investigations showed aslightly raised erythrocyte sedimentation rate (31 mmin first hour). The results of screening for autoanti-bodies and neutrophil cytosolic immunoglobulin werenegative. He was treated with antihypertensive drugsand three months later he had stopped all treatmentand had normal renal function and normal results onscanning with 99mTc-DMSA.

All six children had epithelial cell IgM antibody atfollow up 9-12 months after presentation.

DiscussionThese children are clinically heterogeneous but have

in common the presence of an epithelial cell antibodyin their serum. Investigations did not find any of thepreviously recognised causes of glomerulonephritis,vasculitis, systemic disease, renal failare, or epidermalnecrosis. In patients with renal transplants thepresence of epithelial cell antibody is associated withantibody mediated vascular rejection. The appear-ances of biopsy specimens in two of the three childrenwith native renal disease were similar and have notbeen described before in native kidneys, suggestingthat the renal disease may have been linked to thepresence of this antibody.The skin lesions in cases 3-5 were unusual both

clinically and histologically. All these girls were ofAfro-Caribbean descent. None of the children whohave received transplants, including those of Afro-Caribbean descent, and in whom the epithelial cellantibody has been detected have had a history ofrashes. Histological examination showed keratinocyte,giant cell formation and intranuclear inclusions, whichare typical of virus infection. There was no ballooningdegeneration or other signs typical of herpes infection.Some features of the histology in these children

BMJ VOLUME 303 20 JULY 1991162

resembled those seen in skin biopsy specimens andoral mucous membrane lesions (Koplick spots) fromchildren with measles.3An alternative explanation of the skin lesions would

be erythema multiforme or a fixed drug eruption.Although some of the histopathological results mightbe compatible with these diagnoses,45 the presenceof multinucleate keratinocytes and inclusion bodieswould be unusual. No history was obtained, on closequestioning, of taking any drug, including proprietaryand traditional remedies.

Although the cause of the signs and symptoms seenin these children is unknown there were variousclinical aspects that suggest a viral aetiology and, byextrapolation, a viral association with epithelial cellantibody. All our patients had symptoms suggestive ofa preceding viral illness; evidence of streptococcalinfection was found in only one. None of the childrenhad parvovirus antibodies. Two of the patients livedtogether, and their mother and the parents and siblingsof the boy in case 6 all tested positive for the antibody,which is compatible with an infectious aetiology. Thepatients all came from south east London but apartfrom the two sisters had not been in contact with eachother.

Systemic and renal disease associated with circulat-ing antibodies and immune complexes is well recog-nised in systemic lupus erythematosus, Goodpasture'ssyndrome, Wegener's granulomatosis, and small vesselpolyarteritis.6 The presence of antibodies in these

disorders does not necessarily, however, correlate withthe severity and spectrum of disease. In Goodpasture'ssyndrome the antibody is known to be pathogenic butin other disorders the role of circulating antibodies andimmune complexes is less clear. Antibodies have alsobeen implicated in certain skin disorders. Antibodiesto intercellular components of the stratum spinosumhave been found in 90% of cases of pemphigusvulgaris, and in 70% of cases of bullous pemphigoidantibodies to basement membrane zone antigens of thestratified epithelium have been found.7

JD was supported by Action Research for the CrippledChild.

1 Harmer AW, Haskard D, Koffman CG, Welsh KI. Novel antibodies associatedwith unexplained loss of renal allografts. Transpl Int 1990;3:66-9.

2 Harmer AW, Rigsden SPA, Koffman CG, Welsh KI. Preliminary report:dramatic rise in renal allograft failure rate. Lancet 1990;335:1184-5.

3 Ackerman AB, Suringa DWR. Multinucleate epidermal cells in measles.Arch Dennatol 1971;103:180-4.

4 Bedi TR, Pinkus H. Histopathological spectrum of erythema multiforme.Br7 Dermatol 1976;95:243-50.

5 Lever WF, Schaumberg-Lever G, eds. Histopathology of the skin. Philadelphia:J B Lippincott, 1983:259-70.

6 Pusey CD, Venning MC, Peters DK. Immunopathology of glomerular andinterstitial disease. In: Schrier RW, Gottschalk CW, eds. Diseases of thekidney. 4th ed. Boston: Little Brown, 1988:1827-83.

7 Beutner EH, Chorzelski TP, Jablonska S. Clinical significance of immuno-fluorescence tests of sera and skin in bullous diseases. In: Beutner EH,Chorzelski TP, Kumar V, eds. Imnnunopathology of the skin. 3rd ed. NewYork: John Wiley, 1987:177-205.

(Accepted 14 May 1991)

Growth of asthmatic children during treatment with budesonide: adouble blind trial

Ole D Wolthers, S0ren Pedersen

Department of Paediatrics,Kolding Hospital,DenmarkOle D Wolthers, MD,research fellowS0ren Pedersen, MD,consultant paediatrician

Correspondence to:Dr 0 D Wolthers, Siriusvej9, DK-8270 H0jbjerg,Denmark.

BMJ 1991;303:163-5

AbstractObjective-To determine whether the inhaled

glucocorticosteroid budesonide has any adverseeffect on short term linear growth in children withmild asthma.

Setting-Outpatient clinic in secondary referralcentre.Patients- 15 children aged 6-13 years with normal

statural growth velocity during the previous year, nosigns of puberty, and no use of systemic or topicalsteroids in the two months before the study.Design of interventions-Double blind, random-

ised crossover trial with two active periods in whichbudesonide was given in divided daily doses of 200,ug and 800 Fg. During run in and two washoutperiods placebo was given. After the second washoutperiod the children received open treatment with 400[ig budesonide daily. All periods were of 18 days'duration.Main outcome measure-Growth of the lower leg

as measured twice a week by knemometry.Results-Mean growth velocity of the lower leg

was 0-63 mm/week during run in and during washout0-64mm/week. Budesonide treatmentwas associatedwith a significant dose related reduction of growthvelocity: the mean reduction in growth velocityduring treatment was 0*11 (95% confidence interval-0' 15 to 0 37) mm/week with 200 Fg budesonide and0*36 (0-13 to 0.59) mm/week with 800 [ig budesonide(p<005; Page's test). During treatment with400 pg budesonide a reduction of 0*17 (-0-10 to0-45) mm/week was found.Conclusions-Treatment with inhaled budesonide

is associated with a dose related suppression of shortterm linear growth in children with mild asthma.

IntroductionThe risk of systemic side effects of inhaled gluco-

corticosteroids in children with asthma has been muchdebated.'7 Special attention has been paid to the risk ofgrowth suppression,-'- but studies on this issue havebeen associated with methodological problems andconflicting results have been reported.7' 19 Recently,however, knemometry has been established as apowerful tool for monitoring short term linear growthin children, measuring changes in lower leg length withan accuracy of 0-09-0-16 mm.21022 It has been suggestedthat this method may be a useful physiologicalalternative or adjunct to the biochemical measures ofsystemic effects of topical steroids in children.23 24 Theaim of the present study was to investigate by means ofknemometry whether the inhaled glucocorticosteroidbudesonide has any adverse effect on short term lineargrowth in children with mild asthma.

Patients and methodsWhen planning the study we estimated the standard

deviation of the mean growth rate of the lower leg to be0-20 num/week.2526 On this assumption we calculatedthat 12 patients would be sufficient for a power of 0 90to detect a 50% reduction in growth rate, which wasconsidered a clinically relevant difference.27 A 20% rateof withdrawals was estimated, thus increasing thestudy population by three patients.

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