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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

Thesis (DMed)--Stellenbosch University, 2011. / ENGLISH ABSTRACT: Background and Objective: The most common cause of severe
proteinuria/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 the
1960s to 1990s were shown to have a different pattern of NS. One of the main
differences was the frequency of hepatitis B virus (HBV) associated
glomerulonephritis, usually membranous glomerulonephritis (MGN). The objective of
this project was a clinicopathological study of this subgroup of nephrotic children to
document the disease further and in particular to seek correlations between
pathological and clinical features including prognosis. A central focus was to
document the detailed ultrastructural examination of the renal biopsies of these
children 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 in
children differed substantially from idiopathic MGN in general (children and
adults) and also from HBV MGN in adults and that HBV MGN in children should
be viewed as a distinct disease.
Patients and methods: The childhood (12 years and younger) patient cohort was
309 children with severe proteinuria/nephrotic syndrome who presented at Tygerberg
Hospital (TBH) over a 21 year period from 1974-1995, including 67 children from
Namibia. The study group was 71 children with HBV MGN who were followed up to
2005. 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 MGN
in childhood as this centre only had 2 such patients during the study period.)
Demographic, clinical, laboratory and renal pathology data were collected, compared
and correlated.
Results: HBV associated MGN was the most frequent cause of NS in the Namibian
subgroup, 25/67 (37%) and the third most frequent, 71/309 (23%) in the childhood
cohort as a whole. The MGN group was 86% (71/83) of the total HBV childhood
nephrotic 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 features
different from idiopathic MGN included more prominent haematuria, mildly raised
serum transaminases and more frequently lowered serum C3 and C4 levels. Light
microscopic examination of renal biopsies showed mesangial proliferation in all
patients but with minimal glomerular sclerosis and interstitial disease. On
ultrastructural examination mesangial and subendothelial deposits were common and
prominent as was mesangial interposition. The MGN of HBV in children therefore
frequently showed mesangiocapillary glomerulonephritis (MCGN) features in addition
to the subepithelial deposits of MGN. The subgroup of 23 whose renal biopsies
displayed severe mesangial interposition in addition to the subepithelial deposits of
MGN were termed the mixed HBV MGN-mesangiocapillary GN group. Virus like
bodies and tubuloreticular inclusion bodies were both found in more than 80% of
biopsies of childhood HBV MGN. HBeAg was identified in the subepithelial deposits
in 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 cohort
developed chronic renal failure (CRF). Age of 6 years and above at presentation and
severe mesangial deposits on biopsy correlated with fewer remissions and poorer
outcome. In 3 patients the interval between the diagnosis of HBV MGN and the onset
of CRF was more than 19 years with the longest being 23 years. The 358 cases of
childhood HBV MGN from Southern Africa constitute 37% of the reported childhood
patients.
Comparative data
A comparison was made between the 71 children with HBV MGN, 12 adults with
HBV MGN and 33 adults with idiopathic MGN. The main differences were that both
HBV MGN groups included only coloured and black patients and were more
predominantly male while the idiopathic MGN group included all races. In the HBV
patients, haematuria was more frequent and severe, liver enzymes were frequently
raised and C3 more frequently reduced than in the idiopathic cohort. Both groups of
adult MGN patients had normal C4 levels while the childhood HBV MGN group had
reduced C4 levels.
The immune complex pattern in both of the HBV MGN adult and childhood groups on
biopsy was similar with more mesangial and subendothelial deposits as well as
mesangial interposition than the idiopathic group. Despite this similarity between the
two HBV groups, both adult groups showed more glomerular sclerosis and interstitial
disease than the childhood group. The clinical outcome of the children’s cohort was
better 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 of
HBV 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 of
GN which broadens the classical morphologic description of MGN by often including
a number of mesangiocapillary GN features. The subgroup of renal biopsies with the
most severe mesangiocapillary GN features was classified as the mixed HBV MGNmesangiocapillary
GN group. The MGN spectrum as a whole comprised 86% of the
HBV positive childhood group. HBV MGN was the most frequent association with
NS/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 but
at least 10% of the children developed renal failure. Age of 6 years and above at
presentation and severe mesangial deposits on biopsy correlated with fewer
remissions and poorer outcome. Extended follow up (more than 15 years) was
required to demonstrate renal failure in some patients in the poor outcome group.
Urbanisation, associated with lower HBV carrier rates, and HBV vaccination (initiated
routinely in 1995 in SA), have already lead to a sharply decreasing incidence of this
disease in SA. HBV MGN has been a valuable and possibly unique model of human
GN and MGN in particular in that the HBeAg has been identified in both the serum
and glomeruli enabling confirmation of the aetiological role of HBeAg. het ’n kumulatiewe remissie koers van 25% teen 2 jaar en van 52% teen 4 jaar
getoon. Sewe van die kinders (10%) van die hele kohort het kroniese nierversaking
(KNV) ontwikkel. Ouderdom van 6 jaar en meer by presentasie en erge mesangiale
neerslae in ‘n biopsie het met minder remissies en ’n swakker uitkoms gekorreleer.
Drie pasiënte het meer as 19 jaar na aanvanklike voordoening ooglopende KNV
ontwikkel, waarvan 23 jaar die langste interval was. Die 358 gevalle van kinderjare
HBV MGN van Suidelike-Afrika maak 37% uit van die gerapporteerde kinder
pasiënte.
Vergelykende data
’n Vergelyking is getref tussen die 71 kinders met HBV MGN, 12 volwassenes met
HBV MGN en 33 volwassenes met idiopatiese MGN. Die hoof verskille was dat beide
HBV groepe net kleurling en swart pasiënte ingesluit het en meer oorwegend manlik
was, terwyl die idiopatiese groep alle rasse ingesluit het. In die HBV pasiënte was
hematurie meer algemeen en erg, lewer ensieme meer dikwels verhoog en C3 meer
dikwels verlaag as in die idiopatiese kohort. Beide groepe van volwasse MGN
pasiënte het normale C4 vlakke getoon terwyl die kindergroep met HBV MGN
verlaagde C4 vlakke bewys het. Die immuunkompleks patroon in biopsies van die
HBV MGN volwasse en kindergroepe was soortgelyk met meer mesangiale en
subendoteliële neerslae asook meer mesangiale interposisie as in die idiopatiese
groep. Ten spyte van hierdie ooreenkoms tussen die twee HBV groepe, het die twee
volwasse groepe meer glomerulêre sklerose en interstisiële siekte as die kindergroep
vertoon. Die kliniese uitkoms van die kinderkohort was beter as die ander twee
groepe met remissie (52%) wat meer algemeen was teen 4 jaar (p< 0.01) en met
beter nier- en pasïent oorlewing. Ingeslote die 83 gevalle van hierdie reeks, is ten minste 1243 nierbiopsie bewysde
gevalle van HBV MGN in kinders (80%) en volwassenes (20%) in die Engelse
literatuur gerapporteer. Die manlike oorheersing in beide ouderdomsgroepe van HBV
MGN is soortgelyk (kinders 79%; volwassenes 84%) en betekenisvol meer as vir
idiopatiese MGN.
Gevolgtrekkings: Die bevindinge bevestig dat HBV MGN in kinders ’n afsonderlike
vorm van GN is wat die klassieke beskrywing van MGN verbreed deur die algemene
insluiting van ’n aantal mesangiokapillêre GN kenmerke. Die ondergroep van nier
biopsies met erge mesangiokapillêre GN kenmerke is as die gemengde HBV MGNmesangiokapillêre
GN groep geklassifiseer. Die MGN spektrum in geheel het 86%
van die HBV positiewe kindergroep behels. HBV MGN was die mees algemene
assosiasie met NS/erge proteïenurie in die Namibiese subgroep (37%) en die derde
grootse groep (19%) onder die SA kinders. Die siekte het ’n relatiewe hoë spontane
remissiekoers getoon, maar ten minste 10% van die kinders het nierversaking
ontwikkel. Ouderdom van 6 jaar en meer by presentasie en erge mesangiale
neerslae in ‘n nierbiopsie het met minder remissies en ’n slegter uitkoms gekorreleer.
Uitgebreide opvolg (meer as 15 jaar) was nodig om nierversaking in sommige van
die swak uitkomsgroep aan te toon.
Verstedeliking is geassosieerd met laer HBV draersyfers en hierdie faktor saam met
algemene HBV inenting in die kinderjare (wat in 1995 in SA begin was), het ’n skerp
daling in die voorkoms van hierdie siekte in SA teweeg gebring. HBV MGN is ’n
waardevolle en moontlik unieke model van menslike GN en MGN, veral omdat die
HBeAg in beide die serum en glomeruli identifiseer kon word om die etiologiese rol
van HBeAg te bevestig. / AFRIKAANSE OPSOMMING: Agtergrond en Doelwit: Die algemeenste oorsaak van erge proteïenurie/nefrotiese
sindroom (NS) in kinders wêreldwyd is minimale veranderingsiekte. Hierdie patroon
kom ook voor in blanke- en Indiër kinders in Suid-Afrika. In teenstelling hiermee is
aangetoon dat swart en kleurling/gemengde ras kinders in Suider Afrika tussen die
jare 1960s tot 1990s ’n ander patroon van nefrotiese sindroom gehad het. Een van
die hoof verskille was die algemene voorkoms van hepatitis B virus (HBV)
geassosieerde glomerulonefritis, gewoonlik membraneuse glomerulonefritis (MGN).
Die doelwit van hierdie projek was ’n klinies-patologiese studie van hierdie subgroep
van nefrotiese kinders ten einde die siekte verder te beskryf en veral om korrelasies
te tref tussen patologiese en kliniese kenmerke insluitende prognose. Die
gedetaileerde ultrastrukturele ondersoek van die kinders se nierbiopsies en die
korrelasie van die spektrum patologiese kenmerke met demografiese, kliniese,
laboratorium en prognostiese kenmerke was ‘n sentrale fokusarea.
Die hipotese was dat die klinies-patologiese kenmerke van HBV MGN in
kinders wesenlik van idiopatiese MGN in die algemeen verskil (in kinders en
volwassenes) en ook van HBV MGN in volwassenes, en dat die beeld in kinders
as ’n afsonderlike siekte beskou behoort te word.
Pasiënte en metodes: Die kinder kohort (12 jaar en jonger) was 309 kinders met
erge proteïenurie/nefrotiese sindroom wie in Tygerberg Hospitaal (TBH) behandel
was oor ‘n 21 jarige periode vanaf 1974 tot 1995, insluitende 67 kinders van Namibië.
Die studiegroep was 71 kinders met HBV MGN wie waar moontlik tot 2005 opgevolg was. Die vergelykende volwasse groep was 45 volwassenes met MGN van wie 12
HBV MGN gehad het en 33 idiopatiese MGN. (’n Vergelyking met idiopatiese MGN
in kinders kon nie gedoen word nie omdat hierdie sentrum net twee sulke pasiënte
tydens die studietyd behandel het.) Demografiese, kliniese, laboratorium en
nierpatologie inligting is versamel, vergelyk en gekorreleer.
Resultate: HBV geassosieerde MGN was die algemeenste oorsaak van NS in die
Namibiese subgroep, 25/67 (37%) en die derde mees algemeen, 71/309 (23%) in die
kinder kohort as geheel. Die MGN groep was 86% (71/83) van die totale HBV kinder
nefrotiese kohort en verreweg die oorheersende subgroep.
Die gemiddelde ouderdom van die 71 kinders met HBV MGN by presentering was
6.0 jaar (reikwydte 2-12 jaar) en seuns het 80% van die groep behels. Hepatitis B
omhullingsantigeen (envelope antigen- HBeAg) is aangetoon in die serum van 87%
van die kinders wie daarvoor getoets is. Laboratoriumkenmerke wat van idiopatiese
MGN verskil het, het ingesluit meer prominente hematurie, gering verhoogde serum
transaminases en meer dikwels verlaagde serum C3 en C4 vlakke. Ligmikroskopiese
ondersoek van die nierbiopsies het mesangiale proliferasie in elke pasiënt getoon,
maar met minimale glomerulêre sklerose en interstisiële siekte. Met ultrastrukturele
ondersoek was mesangiale en subendoteliële neerslae asook mesangiale
interposisie algemeen. Die MGN van HBV in kinders het dus dikwels kenmerke van
mesangiokapillêre glomerulonefritis getoon bo en behalwe die subepiteliële neerslae
van MGN. Die ondergroep van 23 van wie die nierbiopsies erge mesangiale
interposisie aangetoon het asook die subepiteliale neerslae van MGN is die
gemengde HBV MGN-mesangiokapillêre GN groep genoem. Virustipe liggaampies
en tubuloretikulêre insluitingsliggaampies is in meer as 80% van die biopsies
bevestig. HBeAg was in die subepiteliële neerslae identifiseer. Dit was die eerste
keer dat hierdie kenmerk in Afrika identifiseer is. Die 46 Suid-Afrikaanse kinders

Identiferoai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/38011
Date12 1900
CreatorsBates, William D.
ContributorsMoosa, M. R., Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. General Internal medicine.
PublisherStellenbosch : Stellenbosch University
Source SetsSouth African National ETD Portal
Languageen_ZA
Detected LanguageEnglish
TypeThesis
Format347 p. : ill.
RightsStellenbosch University

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