“Glomerular” diseases - the past 60 years:
what have we learned, and how?
J Stewart Cameron
São Paulo
Nephrology Division - University of São Paulo
22nd October 2013
Renal Unit, Guy’s Campus,
King’s College, London UK
What can we learn from the story of
glomerulonephritis about how knowledge is
acquired and applied in medicine?
Clinic
Laboratory
animals are not humans,
science can mislead,
and clinical observations often surprise,
and contain vital clues
Change or progress in Medicine
depends upon many factors:
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social milieu and beliefs
advances in other sciences
concepts and ideas
technology available
accident and luck
Change is meandering, diffuse, intermittent and crabwise,
rather than logical and linear.
Blind alleys are easily entered
and progress is NOT inevitable.
“In science the credit
goes to the man who
convinces the world,
not the man to whom
the idea first occurs”
Sir William Osler (1849-1919): Aphorisms.
Ed WB Bean, 1961
The importance of techniques:
just imagine your lab, or your clinic, without:
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Lab
Clinic
flame photometry
ultrasound
radioisotopes
CAT scans or MRI
immunoassay
effective diuretics
electrophoresis
effective BP agents
monoclonal antibodies
long-term dialysis
immunofluorescence
transplantation
electron microscopy
renal biopsy
cell culture
open-heart surgery
molecular biology intensive care
mRNA, knockouts etc. cardiac resuscitation etc.
THIS was the early 1950s, 60 years ago….
• When I was a medical student in the
1950s, I drained severelyoedematous patients’ legs using
skin punctures, just as Frederick
Dekkers had done, 3 centuries
before
- and there was an open coal fire
in the ward...
A time of rapid change
every item in these lists was introduced in a cataract of
change in the 1950s or early 1960, almost all from outside
nascent Nephrology
Jean Hamburger
Hugh de Wardener
Homer Smith
France
(1905-1989)
UK
(1916-2013)
USA
(1895-1962)
A world almost without meetings
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The world of science was very small, with few people
involved
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The first international meeting on Nephrology was held
in London in 1953
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In Evian & Geneva in 1960, at which the ISN was formed
A world almost without meetings
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The world of science was very small, with few people
involved
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The first international meeting on Nephrology was held
in London in 1953
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In Evian & Geneva in 1960, at which the ISN was formed
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the ASN was not founded until 1966, at the 3rd ISN
meeting in Washington, DC
A world without renal journals
• The first nephrological journal was Minerva Nefrologica, in
1957 - in Italian
• The first English-language journal was Nephron from the
ISN in 1963, followed by the Proceedings of the EDTA in
1964 (now NDT).
• Searching for papers was by the volumes of Index Medicus,
sitting in the library. No photocopiers, so you made notes
on cards
• Paper reprints of articles were common, and exchanged
with colleagues and friends
• Until 1963 there were just 2 books on the kidney
But people were avid to publish their work,
as always: publish or perish
“.. this Desire for Glory, and to be counted
Authors, prevails upon all.. “
1673
Thomas Sprat. The history of the Royal Society of London, 1673, p. 74
Renal biopsy- a turning point in study of
human glomerular diseases
1951
1954
Poul Iversen & Claus Brun
(1910- )
Then
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thinner (3 - 5 μm) sections
silver staining
electron microscopy
immunofluorescent staining
Robert Kark
(1911-2003)
(Pirani 1956)
(Jones 1957)
(Folli, Farquhar etc 1957)
(Kark 1959)
Renal biopsy opened up new horizons:
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post mortem changes were
avoided in tissue
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sequential observations of
renal lesions became
possible
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clinicopathological
correlations were made
more precise and
simultaneous
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thus a new nosology of
glomerulonephritis could be
put in place
The CIBA Foundation
symposium in 1961 marked
the clinical arrival of biopsy
- and glomerular diseases could be
classified by histology (1968-70)
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Minimal change disease
Focal glomerulosclerosis
(Extra) membranous nephropathy
Acute endocapillary nephritis
Mesangial proliferative GN / segmental GN
Mesangiocapillary GN types I & II
Crescentic GN
IgA nephropathy
(Cameron 1966)
Looks familiar, doesn’t it ?
Another of our failures has been to produce a more analytical and
basic classification of GN during half a century
One thing we soon had - POISONS...
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ACTH
nitrogen mustard
cortisone
prednis(ol)one
6-mercaptopurine
azathioprine
cyclophosphamide
1949
1949
1950
1955
1957
1963
1964
What made the greatest difference to patients themselves:
- effective diuretics (thiazides in 1958, furosemide in 1964) and
- hypotensive agents (1954 onwards. ACE inhibitors only 1978)
Having worked on diabetes for 3 years, I trained as a
nephrologist at Cornell (NY Hospital), on a Fulbright
scholarship and an NIH grant of $ 5 000 p.a. awarded to
physiologist Prof. Robert F Pitts. He seconded me for clinical
research studies to Dr E Lovell Becker.
Aboard US flagship “United States”
September 1962, on the way to the New
World - by boat!
At Cornell in New York, I studied
glomerular permeability in
nephrotics using multiple
endogenous protein clearances
Joachim ,Cameron & Becker
JCI 1964
Later we evolved a simple
two-protein test of
permselectivity to predict
response to steroid treatment
(in nephrotic patients). It was
popular for a while.
Cameron & Blandford
Lancet 1966
A new clinico-pathological nosology of
nephritis from biopsy
The idea of different levels of diagnosis emerged,
with poor correspondence
Cameron 1972
Cameron 1968
New descriptive and analytic technology
(1970)
peristent low complement
The Venn diagram allowed
expression of complex
relationships
nephrotic
haematuric
The life table permitted description
of timing of survival and events
- now we have relative risk, Mantel
and Cox analyses, meta-analysis
(1989) etc.etc.
Cameron 1972
By 1968, a satisfying description of
glomerulonephritis had emerged..
• a substantial minority of GN (15%) resulted from
anti-GBM antibodies
• However, most GN resulted from acute or chronic
renal deposition of circulating pre-formed
immune complexes, which could mimic most
forms of human disease
• the antigens in immune complex disease were
not related to the kidney, which was an “innocent
bystander”
Frank J.Dixon
(1968)
• C and polymorphs were the principal - perhaps
unique - modes of injury
• cell- mediated immunity played no role
How well did human nephritis compare
with the experimental models ?
The task of aligning the variety of human nephritis with
just two contrasting paradigms of experimental
nephritis was, after years of effort from 1970,
UNsuccessful…
Several forms of human nephritis did not fit in:
e.g. dense “deposit” disease, focal glomerulosclerosis,
IgA nephropathy
Many new different ways of experimental induction of
glomerulonephritis were described
1960-2010: The clinical paradigm
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Today, we still classify human glomerulonephritis
using optical microscopy appearances of
glomerular injury on renal biopsy: a major failure
to advance understanding to more fundamental
levels
although great progress has been made in
understanding anti-GBM nephritis, this forms
only 1% at most of human glomerular disease,
and details of the other 99% remain obscure
Anti-GBM disease 1960-2004
(1967) “linear” immunofluorescence described in
humans with crescentic disease & lung
haemorrhage
(1967) human serum contains anti-GBM Ab &
reproduces disease
(1970s) cytotoxic agents lower antibody and
improve prognosis
(1978) plasma exchange added to treatment
(1978) HLA linkage described (now *1501)
(1980s) molecular structure of GBM
(1994) antigen is in 3(IV)NC-1 collagen
(2001) AA sequence of antigen defined
1960-2000: mortality falls from 96% to 6%
Another success story – lupus nephritis
• In the 1950s, almost all lupus patients with III-IV
nephritis were dead by 5 years
• Corticosteroids alone in the 1950s had little impact
(Pollak, Kark et al.)
• We tried both azathioprine (1965) and
oral cyclophosphamide (1968)
+ steroids which improved results. But at a price.
• Then, we tried different “induction” and
“maintenance” therapies: cyclo + methylpred
followed by aza + low-dose oral pred
Lupus treatment 1950-1990
• The result was a dramatic improvement in results
• But still in 2000 after 10 years, of 110 class IV patients 49% had
side-effects or complications, and 30% died eventually
(Bono, Cameron et al. QJM 2001)
Lupus in the 21st century
• Half a dozen other drugs have been used to treat lupus with
some effect
• The major impact has been monoclonal antibodies acting
on aspects of the immune response
• At the moment major interest lies in rituximab, with
conflicting results.
• The latest paper, from Condon et al. in London, showed
great benefit, without the use of any maintenance steroids.
Two controlled trials, however, gave negative results, but
may have asked the “wrong” questions
“Lumpy-bumpy” immune complex disease
1960-2004
• 1973: in situ immune complex formation was described
(Mauer, McCluskey): totally ignored
• 1978: rat membranous nephropathy deposits shown to
form in situ (Couser, Hoedemaeker)
• mesangial & sub-endothelial deposits continued to be
considered from circulating immune complexes
• a tiny number (~ 50) of human cases with demonstrable
antigen and antibody in kidney were / are extrapolated to
millions of others
• VAST amounts of work on circulating complexes proved
almost completely fruitless
Immune aggregate disease:
a continuing mirage ?
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Immune aggregates are present in most forms of
nephritis in humans, both acute and progressive
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Given the possibility that in situ combination of
circulating antibody and antigen can take place within
tissue, it has been almost impossible so far to prove
that undissociated complexes may also localise into
the kidney
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The relevant antigens remain almost totally unknown
• We must ask: do circulating immune complexes play
ANY role in the pathogenesis of so-called “immune
complex” nephritis ?
At last, two new ideas in the 21st century
IgG4 disease/nephropathy
the main glomerular antigen in the majority of membranous
nephropathy patients was finally identified by Larry Beck
in David Salant’s lab in 2009: PLA2M receptor. The Ab were
Ig4 subclass - as are ADAMTS13 Ab in TTP.
C3 nephropathy
A re-examination of dense deposit disease, C3-only MCGN
etc. has led to a new classification of these entities
centering on the dysregulation of the complement
cascade, often arising from inhibitor (H or I) mutations.
Again, a link to HUS.
The mediator explosion I: cells
• in 1960-70, only leukocytes and maybe
platelets were in on the act
• by 1978, macrophages were re-identified
(EM in 1953, ignored) first in crescents
(Atkins), then in glomeruli
• THEN monoclonal antibodies arrived in
Parbtani & Cameron 1974
1981… bang!
• activated macrophages and T cells
identified in glomeruli and interstitium in
models, and in humans
• maybe mast cells involved ? (1990s)
Nolasco, Cameron et al. 1983
Mediator explosion II: soluble factors
1960 : only 2
2013: more than 100, and counting….
first the “old guard” : complement & fibrin
1978: new ideas on complement: C3NeF as an antibody and C5b-9 as
mediator in membranous
1975: angiotensin (1955)
1970: “lymphokines” - now cytokines IL1-27, TNF, interferons, etc.
1978: prostaglandins
1980: leukotrienes/lipoxins
1980: chemokines (named in 1993)
1985: PDGF, TGFβ
… PAI-1, FGF, HGF, osteopontin
1988: endothelin
1991: nitric oxide
2004: hydrogen sulphideetc.etc.
Platelets
& PF4
(1979)
New perspectives in the 1980s
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glomerular hypertension/perfusion is a
major driver of proteinuria & glomerular
damage (Brenner~1980)
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interstitial inflammation and
fibrogenesis/lysis determines prognosis
(1980), thus cell-mediated injury mainly
determines chronicity (1983)
Cameron 1981
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loss of renal “innocence”: the kidney itself plays an active
role in its immune injury (1985)
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proteinuria is not just an indicator of severity, but a
nephrotoxin (1988)
The interstitium as the field of injury?
Interstitial cells in renal injury
In the end, does it matter what the glomerular appearances may be,
if outcome is dependent on interstitial changes and
the degree of proteinuria ?
The interstitium as the field of injury?
• In GN, tubulo-interstitial events correlate better with
GFR than glomerular changes (Hutt & de Wardner 1968)
and predict outcome better
• In lupus nephritis, the number of monocytes predicts
GFR up to 5 years later (Alexoupoulos, Cameron et al
1990)
The renal parenchyma:
loss of “innocence” I: (1985-)
The reaction of the resident renal cells to injury is now seen as crucial.
Cell adhesion (1992) as well as cell attraction are important factors.
1988
The renal parenchyma:
loss of “innocence” II
• Renal tubular cells can synthesise and secrete:
- complement components
- eicosanoids
- chemokines
- growth factors, etc.
• Renal tubular cells can express MHC class II
- already known 1981 in Tx literature
• Renal tubular cells can process antigen & induce an
immune response/tolerance (1985)
protective, pathogenic, or both ?
can transform into myofibroblasts (1994)
Proteinuria emerges as a nephrotoxin
• studies of overload proteinuria & podocyte
damage were crucial but ignored (Brewer et al 19781982; Eddy 1988)
• proteinuric urine induces many mediators from
tubular cells (1990s)
• we still do not know which component(s) of
Brewer 1982
proteinuria are toxic...
“Therapies designed to reduce
proteinuria per se may have a role in
the treatment of glomerulonephritis”
Cameron 1989
Cameron 1979
Proteinuria: how does it happen ?
Electron microscopy of the
filtration barrier (1950s/60s)
Molecular anatomy of the podocyte
(1995- )
...we still don’t know
Proteinuria: how does it relate to oedema ?
1962
The overthrow of this “classical”
underfill explanation began 50
years ago and was completed in
the early 1980s (Brown, Geers &
Koomans etc. ).
This came from studies in both
animals and humans with renal
disease
2004
Proteinuria + reabsorption induces tubular sodium retention
directly, distally via NaK-ATPase (Doucet) and proximally via
activating amiloride sensitive ENaC channel
Molecular biology and glomerulonephritis
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genes of inherited glomerular disorders
genes which confer risk
sequence of relevant molecules
“knock-out” animals
mRNA analysis, RT-PCR etc.
arrays - a new nosology ?
and so on ...
Henger et al. KI 2004
New specific treatments for GN ?
• Very little of the huge accumulation of knowledge about the
immune system in the past 50 years has translated into clinical
treatments. We still promote the same tired old anti-cancer
poisons, plus:
- 1976: plasma exchange
- 1978: IV methyl prednisolone
- 1983: cyclosporine
- 1986: polyvalent IgG
- 1995: mycophenolate
- 1990: monoclonal antibodies, e.g rituximab (1999)
• But interference with antigen presentation, or the maturation of the
immune response, has been explored only in lupus and vasculitis - and
then, only to a limited extent… this needs to change
Glomerular disease:
some “last great problems” from 40 years ago
• What is the IgA doing in IgA nephropathy ?
• What are the pathogenic antigens in aggregates of
“immune complex” GN ?
• What is/are the glomerular (auto)antigen(s) in human
membranous nephropathy ? DONE 
• What triggers minimal change nephropathy ?
• What is dense deposit disease ?
• What makes proteinuria nephrotoxic ?
• What drives interstitial damage? And how can we stop it
- or promote non-scarring healing ?
Glomerular disease:
some “last great problems” from 40 years ago
• What is the IgA doing in IgA nephropathy ?
• What are the pathogenic antigens in aggregates of
“immune complex” GN ?
• What is/are the glomerular (auto)antigen(s) in human
membranous nephropathy ? DONE 
• What triggers minimal change nephropathy ?
• What is dense deposit disease ?
• What makes proteinuria nephrotoxic ?
• What drives interstitial damage? And how can we stop it
- or promote non-scarring healing ?
• Is Elvis still alive ?
“ When problems in human medicine are
being considered, the evidence from man
in entitled to at least a little consideration”
(Sir) George Pickering (1952)
Clinic
Laboratory
What will Nephrology be like in another 60 years,
in 2073?
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What is sure is that some
of the questions of today
will still be unanswered
Also that there will be new
techniques and new
questions of which we have
as yet no idea at all…
1936