Beukhof, Johan Richard

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   University of GroningenPrimary IgA-NephropathyBeukhof, Johan RichardIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1986Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Beukhof, J. R. (1986). Primary IgA-Nephropathy. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 21-06-2022SummaryI n  t he  i n t roduc t i on  o f  t h i s  t hes i s  bas i c  mo t i ves  and  assumpt ions  a restated.In chapter  I  data f rom l i terature on lGA-Nephropathy upto December 1983 arereviewed.  A heur is t ic  system of  work-hypotheses concerning mesangia l  IgA-depos i t i on  i s  deve ' l oped .  Some o f  ou r  own  c l  i n i ca l  obse rva t i ons  and  ou rresu l t s  o f  t he rap ies  a re  desc r i bed  i n  o rde r  t o  comp le te  t he  p i c tu re  o f  I gA -Nephropathy.The  re la t i on :  c i r cu l  a t i ng  I gA  _ ->  mesang ia l  I gA -depos i ! s  -2  neph r i  -t i c  symp toms  i s  d i scussed  (and  re jec ted ) .I n  chap te r  I I  da ta  on  the  75  pa t i en t s  i n  ou r  c l i n i c  w i t h  I gA -Nephropa thya re  used  to  cons t ruc t  ove ra l l  su rv i va l  cu rves  and  to  t es t  t he  "un i va r i a te "e f f ec t  o f  s ' i ng1e  r i sk fac to rs  on  the  p rognos i s  o f  g roups  o f  pa t i en t s .  Fo ri nd i v i dua l  p rognos i s  i t  i s  necessa ry  t o  de te rm ine  the  re la t i ve  we igh t  andin te rdependence  o f  r i s k fac to rs .  Fo r  non -ma themat j ca l  r eade rs  i t  i s  exp la in -ed  how th i s  can  be  done  us ing  mu l t i p l e  reg ress ion  ana l ys i s ,  f o r  i ns tance  bythe  p ropo r t i ona l  haza rds  mode l .  Us ing  s tanda rd  me thods ,  a  numer i ca l  way  toca l cu la te  po in t  es t ima tes  o f  k i dneys  su rv i va l  i s  deve loped .  A  new s imp leg raph i ca l  me thod  to  de te rm ine  j nd i v i dua l  p rognos i s  by  way  o f  a  nomogram i sdesc r i bed .  Con f i dence  l im Í t s  f o r  t hese  es t ima tes  a re  ca l cu la ted  by  a  s ta -t i s t i ca l  t heo ry ,  wh i ch  has  been  deve loped  by  one  o f  t he  coau tho rs .I n  ou r  mu l t i p l e  reg ress ion  ana l ys i s  k i dney  su rv i va l  i s  adve rse l y  i n f l uencedby  s igns  o f  ac t i ve  g lomeru loneph r i t i s  i f  pe rs i s t i ng  more  than  6  weeks  a f t e ran  a t t ack  o f  mac roscop i ca l  haematu r i a  ( i . e .  p ro te inu r i a ,  m ic roscop i ca lhaematur ia,  low GFR).  Moreover untreated hypertension turns out  to  be a badonen .  An  unexpec ted  f i nd ing  i s  t ha t  pa t i en t s  w i t hou t  g ross  haematu r i a  f a reworse  than  pa t i en t s  w i t h  e i t he r  " sys tem ic  exace rba t i ons "  o r  " sem icon t i nuousgrms haematur i  a"  .Age ,  sex ,  and  h i s to log i ca l  f ea tu res  do  no t  p rov ide  add ' i t i ona l  i n fo rma t i ono n  k i d n e y  s u r v i v a l .I n  chap te r  I I I  f o r  t he  Causas ian  subpopu la t i on  o f  ou r  pa t i en t s  i t  i s  showntha t  pa t i en t s  w i t h  and  w í thou t  mac roscop i ca l  haematu r i a  d i f f e r  i n  t he  f o l -l ow ing  aspec ts :  immunogene t i cs ,  morpho logy  o f  t he  k i dney  b iopsy ,  m ic ros -cop i ca l  haematu r i a ,  p ro te inu r i a ,  GFR,  age  and  un i va r i a te  p rognos i s .  Themost  s imple explanat ion of  these d i f ferences is  that  pr imary IgA-Nephro-pa thy  cons i s t s  o f  a t  l eas t  two  suben t i t i es .I n  chap te r  IV  i n fus ion  o f  a  l ow  dose  o f  dopamine  was  used  to  assess  thefunct ional  reserve capaci ty  of  pat ' ients wi th IgA-Nephropathy.  Heart  rateand  b loodp ressu re  rema ined  cons tan t .  0n1y  pa t i en t s  w i t h  a  base l i ne  GFR >  73ml /m in  t u rned  ou t  t o  be  ab le  t o  i nc rease  the i r  GFR.  We  specu la te  t ha t k id -neys  w i th  a  t o ta l  GFR <  73  m l /m in  canno t  i nc rease  the i r  base l i ne  GFRbecause  they  a re  a l ready  max ima l l y  hype r f i l t r a t i ng .Chapter  V shows that  a l1 pat ients wi th IgA-Nephropathy have mesangia l  depo-s i t s  by  e lec t ron  m ic roscopy  (EM) .  P resence  o r  absence  o f  p ro te inu r i a  t u rnsou t  t o  be  co r re la ted  w i th  subendo the l i a l  depos i t s  as  v i s i b l e  by  EM.  Unex -pected in  these pat ients wi th somet imes impressive haematur ia v ías thef i nd ing  tha t  p ro te inu r i a  was  " se lec t i ve "  i n  l gA -Nephropa thy  ' i f  GFR >  22  n l /ny,a tt) rnd' l-)yUol ei sl --rd-arl ll d'el sreA-urA-,:; -ret -ee3RsÊI95min  and pro te inur ia  >  0 .5  g /24  hr .l.le specuiate, that mediators of inflamtation may affect a charge barrier,which might cause select ive proteinuria,  subendothel ia l  deposits,  andperhaps also mesangial  deposit ion or nephri t ic symptoms.In chapter Vl, lymphocytes of patients with lgA-Nephropathy were shown toproduce an increased amount of the lymphokine V(aso)-P(ermabi l i ty)-F(ac-tor).  This VPF is not correlated with the amount of proteinur ia.  l , le specu-late that VPF plays some other role in IgA-Nephropathy, for instance inI  gA-deposi t i  on.Chapter VII shows the group of our patients with lgA-Nephropathy to havee leva ted  IgA 1eve1s,  a l though on ly  in  20% o f  these pa t ien ts  IgA leve ls  a rehigher than the 95% conf idence levels of a normal populat ion. The pr imaryin vivo IgA-response on the subcutaneously injected test ant igen Hel ixPomatia Haemocyanin does not differ from normal controls and appears to beswitched off  rapidly.IgA-ant i-CMV-LA levels are also normal;  however,  IgA-ant i-EBV-VCA and IgA-ant i-diphtheria-ant igen level s are elevated."spontaneous" IgA synthesis in vitro by lymphocytes of IgA-Nephropathypat ients tends to be increased, whereas PWM-st imulated IgA synthesis isnormal .These data do notthe IgA-responsegeneral  overshootserum IgA.al low one unify ing hypothesis concerning regulat ion ofin IgA-Nephropathy. Nevertheless there is nei ther aof the lgA-response, nor a gross defect in c ' learance ofPoss ib le  causes  migh t  bee.g .  due to  pers is ten t lybarr i  er.dysregulation of the secondary irmune responseact ive EBV infect ion or to a def ic ient mucosalChapter VII I  summarizes the evidence for each of the three workhypothesesconcerning the mechanism of mesangial  lgA-deposit ion:A: abnorma' l  c ircu' lat ing IgA. B: pr imari ly abnormal kidney; C: some indirectfactor causing deposit ion of normal IgA in an or iginal ly normal kidney (forinstance a mediator of inf lammation).In a longitudinal study we do not f ind evidence for hypothesis A. Also in across sect ional survey, levels of soluble i rununecomplexes (ICX) are only asma' l l  f ract ion of those in act ive SLE. No carr ier bound immunecomplexescould be detected. No indirect proof of solub1e ICX was provided by skinbiopsies, t ransfer studies and measurement of Fc receptor funct ion. In si tuICX formation could not be demonstrated. Hypothesis B can be el iminated inview of the experiences in human renal t ransp' lantat ion.Hypothes is  C is  a t t rac t i ve  because o f :1 )  "exc lus ion"  o f  the  a l te rna t ivesA and B;2)  c l in ica l  observa t ions  (h igh  preva lence o f  u r t i car ia ,  se lec t i veproteinuria,  rapidi ty of "systemic exacerbat ions",  dissociat ion of IgA-depos i ts  and nephr i t i c  symptoms) ;3 )  the  f ind ing  o f  abnoymal i t ies  in  thelynphokine VPF and in the plasmakine system.In the general discussion, the concept of primary IgA-Nephropathy as ones ing le  d isease en t i t y  i s  d iscussed.The presence of abnormal amounts of IgA in IgA-Nephropathy and severalother renal diseases and also in some normal controls cannot be denied.However,  mesangial  IgA-deposit ion is not specif ic for pr imary IgA-Nephro-pathy.96Fugl u more narrow_ly defined primary lgA-Nephropathy in caucasians is pro-bab ly ,no t  one s ing le  d isease en t i t y .Therefore we tend to see mesangial-  IgA-deposits as a useful  marker of renald isease,  bu t  no t  as  a  so l id  bas is  to  de f ine  a  d isease en t i t y ,  no"  as  ineprimum movens of such an ent i ty.  In our view an abnormal i ty- in a mediatorsystem may be the ultimate cause of IgA-Nephropathy.

Primary IgA-Nephropathy

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Primary IgA-Nephropathy

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