Hepatitis-B-associated glomerular disease : a clinicopathological study of Hepatitis B virus associated Membranous Glomerulonephritis in Namibian and South African children 1974 - 2005 and a comparison with Hepatitis B associated Membranous Glomerulonephritis as well as Idiopathic Membranous Glomerulonephritis in adults

[摘要] ENGLISH ABSTRACT: Background and Objective: The most common cause of severeproteinuria/nephrotic syndrome (NS) in children worldwide is minimal change disease(MCD). This is also the pattern observed in white and Indian children in South Africa(SA). By contrast, black and mixed race/coloured children of Southern Africa in the1960s to 1990s were shown to have a different pattern of NS. One of the maindifferences was the frequency of hepatitis B virus (HBV) associatedglomerulonephritis, usually membranous glomerulonephritis (MGN). The objective ofthis project was a clinicopathological study of this subgroup of nephrotic children todocument the disease further and in particular to seek correlations betweenpathological and clinical features including prognosis. A central focus was todocument the detailed ultrastructural examination of the renal biopsies of thesechildren and to correlate the spectrum of pathological features with demographic,clinical, laboratory and prognostic features.The hypothesis was that the clinicopathological features of HBV MGN inchildren differed substantially from idiopathic MGN in general (children andadults) and also from HBV MGN in adults and that HBV MGN in children shouldbe viewed as a distinct disease.Patients and methods: The childhood (12 years and younger) patient cohort was309 children with severe proteinuria/nephrotic syndrome who presented at TygerbergHospital (TBH) over a 21 year period from 1974-1995, including 67 children fromNamibia. The study group was 71 children with HBV MGN who were followed up to2005. The comparative adult group was 45 adults with MGN of whom 12 had HBV MGN and 33 idiopathic MGN. (A comparison could not be made with idiopathic MGNin childhood as this centre only had 2 such patients during the study period.)Demographic, clinical, laboratory and renal pathology data were collected, comparedand correlated.Results: HBV associated MGN was the most frequent cause of NS in the Namibiansubgroup, 25/67 (37%) and the third most frequent, 71/309 (23%) in the childhoodcohort as a whole. The MGN group was 86% (71/83) of the total HBV childhoodnephrotic cohort, by far the dominant subgroup.The average age of the 71 children with HBV MGN was 6.0 years (range 2-12 years)at presentation and boys comprised 80% of the group. Hepatitis B envelope antigen(HBeAg) was identified in the serum of 87% of children tested. Laboratory featuresdifferent from idiopathic MGN included more prominent haematuria, mildly raisedserum transaminases and more frequently lowered serum C3 and C4 levels. Lightmicroscopic examination of renal biopsies showed mesangial proliferation in allpatients but with minimal glomerular sclerosis and interstitial disease. Onultrastructural examination mesangial and subendothelial deposits were common andprominent as was mesangial interposition. The MGN of HBV in children thereforefrequently showed mesangiocapillary glomerulonephritis (MCGN) features in additionto the subepithelial deposits of MGN. The subgroup of 23 whose renal biopsiesdisplayed severe mesangial interposition in addition to the subepithelial deposits ofMGN were termed the mixed HBV MGN-mesangiocapillary GN group. Virus likebodies and tubuloreticular inclusion bodies were both found in more than 80% ofbiopsies of childhood HBV MGN. HBeAg was identified in the subepithelial depositsin the glomeruli. This was the first time this feature was demonstrated in Africa. The 46 South African children with HBV MGN showed a cumulative remission rate of 25% at 2 years and 52% at 4 years. Seven of the children (10%) of the total cohortdeveloped chronic renal failure (CRF). Age of 6 years and above at presentation andsevere mesangial deposits on biopsy correlated with fewer remissions and pooreroutcome. In 3 patients the interval between the diagnosis of HBV MGN and the onsetof CRF was more than 19 years with the longest being 23 years. The 358 cases ofchildhood HBV MGN from Southern Africa constitute 37% of the reported childhoodpatients.Comparative dataA comparison was made between the 71 children with HBV MGN, 12 adults withHBV MGN and 33 adults with idiopathic MGN. The main differences were that bothHBV MGN groups included only coloured and black patients and were morepredominantly male while the idiopathic MGN group included all races. In the HBVpatients, haematuria was more frequent and severe, liver enzymes were frequentlyraised and C3 more frequently reduced than in the idiopathic cohort. Both groups ofadult MGN patients had normal C4 levels while the childhood HBV MGN group hadreduced C4 levels.The immune complex pattern in both of the HBV MGN adult and childhood groups onbiopsy was similar with more mesangial and subendothelial deposits as well asmesangial interposition than the idiopathic group. Despite this similarity between thetwo HBV groups, both adult groups showed more glomerular sclerosis and interstitialdisease than the childhood group. The clinical outcome of the children's cohort wasbetter than the other 2 groups with remission (52%) more frequent at 4 years (p<0.01) and better renal and patient survival.Including the 83 cases from this series, at least 1243 renal biopsy proven cases ofHBV MGN have been reported in the English literature; children (80%) and adults (20%). The male gender predominance in both age groups for HBV MGN is similar(children 79%; adults 84%) and significantly greater than for idiopathic MGN.Conclusions: The findings confirm that HBV MGN in children is a distinct form ofGN which broadens the classical morphologic description of MGN by often includinga number of mesangiocapillary GN features. The subgroup of renal biopsies with themost severe mesangiocapillary GN features was classified as the mixed HBV MGNmesangiocapillaryGN group. The MGN spectrum as a whole comprised 86% of theHBV positive childhood group. HBV MGN was the most frequent association withNS/severe proteinuria in the Namibian subgroup (37%) and the third largest group(19%) in the SA children. It showed a relatively high spontaneous remission rate butat least 10% of the children developed renal failure. Age of 6 years and above atpresentation and severe mesangial deposits on biopsy correlated with fewerremissions and poorer outcome. Extended follow up (more than 15 years) wasrequired to demonstrate renal failure in some patients in the poor outcome group.Urbanisation, associated with lower HBV carrier rates, and HBV vaccination (initiatedroutinely in 1995 in SA), have already lead to a sharply decreasing incidence of thisdisease in SA. HBV MGN has been a valuable and possibly unique model of humanGN and MGN in particular in that the HBeAg has been identified in both the serumand glomeruli enabling confirmation of the aetiological role of HBeAg.het 'n kumulatiewe remissie koers van 25% teen 2 jaar en van 52% teen 4 jaargetoon. Sewe van die kinders (10%) van die hele kohort het kroniese nierversaking(KNV) ontwikkel. Ouderdom van 6 jaar en meer by presentasie en erge mesangialeneerslae in 'n biopsie het met minder remissies en 'n swakker uitkoms gekorreleer.Drie pasiënte het meer as 19 jaar na aanvanklike voordoening ooglopende KNVontwikkel, waarvan 23 jaar die langste interval was. Die 358 gevalle van kinderjareHBV MGN van Suidelike-Afrika maak 37% uit van die gerapporteerde kinderpasiënte.Vergelykende data'n Vergelyking is getref tussen die 71 kinders met HBV MGN, 12 volwassenes metHBV MGN en 33 volwassenes met idiopatiese MGN. Die hoof verskille was dat beideHBV groepe net kleurling en swart pasiënte ingesluit het en meer oorwegend manlikwas, terwyl die idiopatiese groep alle rasse ingesluit het. In die HBV pasiënte washematurie meer algemeen en erg, lewer ensieme meer dikwels verhoog en C3 meerdikwels verlaag as in die idiopatiese kohort. Beide groepe van volwasse MGNpasiënte het normale C4 vlakke getoon terwyl die kindergroep met HBV MGNverlaagde C4 vlakke bewys het. Die immuunkompleks patroon in biopsies van dieHBV MGN volwasse en kindergroepe was soortgelyk met meer mesangiale ensubendoteliële neerslae asook meer mesangiale interposisie as in die idiopatiesegroep. Ten spyte van hierdie ooreenkoms tussen die twee HBV groepe, het die tweevolwasse groepe meer glomerulêre sklerose en interstisiële siekte as die kindergroepvertoon. Die kliniese uitkoms van die kinderkohort was beter as die ander tweegroepe met remissie (52%) wat meer algemeen was teen 4 jaar (p< 0.01) en metbeter nier- en pasïent oorlewing.Ingeslote die 83 gevalle van hierdie reeks, is ten minste 1243 nierbiopsie bewysdegevalle van HBV MGN in kinders (80%) en volwassenes (20%) in die Engelseliteratuur gerapporteer. Die manlike oorheersing in beide ouderdomsgroepe van HBVMGN is soortgelyk (kinders 79%; volwassenes 84%) en betekenisvol meer as viridiopatiese MGN.Gevolgtrekkings: Die bevindinge bevestig dat HBV MGN in kinders 'n afsonderlikevorm van GN is wat die klassieke beskrywing van MGN verbreed deur die algemeneinsluiting van 'n aantal mesangiokapillêre GN kenmerke. Die ondergroep van nierbiopsies met erge mesangiokapillêre GN kenmerke is as die gemengde HBV MGNmesangiokapillêreGN groep geklassifiseer. Die MGN spektrum in geheel het 86%van die HBV positiewe kindergroep behels. HBV MGN was die mees algemeneassosiasie met NS/erge proteïenurie in die Namibiese subgroep (37%) en die derdegrootse groep (19%) onder die SA kinders. Die siekte het 'n relatiewe hoë spontaneremissiekoers getoon, maar ten minste 10% van die kinders het nierversakingontwikkel. Ouderdom van 6 jaar en meer by presentasie en erge mesangialeneerslae in 'n nierbiopsie het met minder remissies en 'n slegter uitkoms gekorreleer.Uitgebreide opvolg (meer as 15 jaar) was nodig om nierversaking in sommige vandie swak uitkomsgroep aan te toon.Verstedeliking is geassosieerd met laer HBV draersyfers en hierdie faktor saam metalgemene HBV inenting in die kinderjare (wat in 1995 in SA begin was), het 'n skerpdaling in die voorkoms van hierdie siekte in SA teweeg gebring. HBV MGN is 'nwaardevolle en moontlik unieke model van menslike GN en MGN, veral omdat dieHBeAg in beide die serum en glomeruli identifiseer kon word om die etiologiese rolvan HBeAg te bevestig.

[发布机构] Stellenbosch University