There is a long history of substantial UK contributions to our knowledge of the   description, causes and treatment of glomerular disease. This page describes these achievements up to the beginning  of the 21^st  century.

The 19th Century

Richard Bright, a physician at Guy’s Hospital London, described the association of proteinuria with renal disease. We now know that proteinuria is the hallmark of glomerular disease, and for a hundred years after his death, the group of conditions we now collect under the umbrella name,  glomerulonephritis, were widely known as Bright’s disease.

At the core of Bright’s work  was the personal observation of cases with clinicopathological correlation, pathological material at that time being of course limited to macroscopic review of autopsy specimens.

His magisterial Reports of Medical Cases (1827), is notable not only for the lucid case descriptions, but also for the beautiful illustrations of autopsy kidneys from people with a range of kidney disorders. (was Bright, a gifted artist,  responsible for the colour, or are the names on the bottom of the illustrations,  W Sway and E Sway, the artists as well as the engravers.)

Bright’s most important insight was to recognise a link between ‘the dropsy’ (i.e. widespread oedema), albuminous urine (i.e.proteinuria) and kidney disease. An observation now so axiomatic it is hard for us to appreciate there was a time when this was not at all understood.

He also recognised an association between kidney disease and left ventricular hypertrophy and thus indirectly to hypertension – remember this was fifty years before Frederick Mohamed (also a Guy’s physician) became the first person to measure blood pressure in humans in a clinical setting.

Bright dominates this era, but there are some other less known names  from the 19^th century who did important work. They include William Wells (1757-1817) of St. Thomas’s Hospital, the first person to study coaguable urine ( i.e. containing albumin) in people with and without dropsy; and Robert Christison ( 1797-1882) ), the Edinburgh physician who published, in the same decade as Bright, his observations on acute nephritis during a scarlatina epidemic.

1940s and 50s

Following Bright’s work, there was little further change in the next one hundred years. Then Arthur Ellis (1883-1966), a physician at the London Hospital,   following in the tradition of Bright, published in 1942 a series of articles reporting a 20 year experience of  some 600 patients with Bright’s Disease, who he followed up regularly, including the study of autopsy material [1]).  The work was to be presented by Ellis in the Croonian Lecture The natural history of Bright’s disease  at the Royal College of Physicians in 1941, but the event was cancelled because the Luftwaffe dropped a bomb on the lecture theatre due to be used. Ellis had no additional techniques to those available to Bright other than the measurement of blood pressure and of blood urea. Ellis, working with younger colleagues Clifford Wilson (1906-1967) and Horace Evans (1903-1963), had simplified (most would now say ‘oversimplified’) cases into  a new  classification – Ellis Type 1 nephritis (acute nephritic syndrome)  and    Ellis Type 2 nephritis, in which he  bundled up all chronic patients with progressive proteinuric kidney impairment, regardless of whether they were clinically nephrotic, and regardless of any pathological findings. This simple approach had appeal, came into wide usage, and could still be found in medical textbooks into the 1960s. It disappeared when renal biopsy began to identify  multiple different morphological patterns within the  broad group of ‘Type 2’.

Study of glomerular disease made little or no progress (in the UK or beyond) after Ellis until two major changes in the 1950s – the appreciation that corticosteroids (a newly available therapeutic) had a major impact on some patterns of glomerular disease, and soon after the introduction of renal biopsy.

Corticosteroids

The advent of corticosteroids as a medical therapy excited physicians with many interests. One of the most dramatic benefits was shown in children with nephrotic syndrome, in the majority of whom it provoked prompt resolution of nephrotic syndrome. This was first published in 1952  by Gavin Arneil from the Royal Hospital for Sick Children, Glasgow [2] .

Renal biopsy transforms the field

The advent of renal biopsy transformed the study of glomerulonephritis (GN) allowing a classification to emerge based mostly on morphology. First described in 1951 using an aspiration technique by Brun & Iversen in Denmark, this  was soon superceded by the needle technique first described by Kark & Muehrcke in Chicago. Its uptake was rapid, and the first renal biopsies were performed in the UK at St. Mary’s Hospital, London by Mark ‘Jo’ Joekes  in adults, and by Richard White at Great Ormond Street Hospital in children.

At first biopsies were assessed by light microscopy only, but immunofluorescence on frozen tissue  was added from 1956 and electron microscopy by 1957.  Immunofluorescence in the early years was limited by the available reagents so that looking for deposition of IgG, IgM and complement components became routine, but reliable reagents for IgA were not available until the late1960s.

An early  paper by Joekes and Robert Heptinstall reporting findings in 134 renal biopsies was highly influential in opening a new framework for the analysis of the then problematic grouping known as ‘focal’ GN [4] .

1960s onwards

An important international symposium was held at the CIBA Foundation in London in 1961 entitled ‘Renal Biopsy’ [5]. Developed by the CIBA Foundation’s energetic secretary Gordon Wolstenholme   it brought together pathologists and nephrologists from the UK, Europe and USA, and was chaired by Arnold Rich (pathologist, Johns Hopkins, Baltimore, USA). UK representatives included only three pathologists – Robert Heptinstall , John Hardwicke (Birmingham) and Michael Hutt (St. Thomas’s). UK nephrologists present were Douglas Black (Manchester), John Blainey (Birmingham), Stewart Cameron (Guy’s), Michael Darmady (Portsmouth), John Hardwicke (Birmingham),  Mark ‘Jo’ Joekes (St. Mary’s) , Malcolm Milne (Westminster), Max Rosenheim (UCH), Hugh de Wardener (Charing Cross), and Clifford Wilson (London Hospital). [6].

Although the findings reported at that CIBA Symposium were largely descriptive, they established the value of both precise morphological description and careful clinicopathological correlations. And helped to ensure that collaborative partnership between pathologists and nephrologists became the norm. (Link soon to page on development of UK renal pathology).

For the three decades following the CIBA Symposium, UK work on glomerular disease was based predominantly in three  centres treating adults – Guy’s Hospital, the Royal Postgraduate Medical School at Hammersmith Hospital, and  Manchester. And in three paediatric centres – Guy’s Hospital,  Great Ormond Street Hospital, Birmingham Children’s Hospital.

From the 1990s onwards migration of nephrologists who had trained in these centres led also  to foci of work on glomerular disease notably in Bristol, Birmingham, Leicester and Edinburgh.

1970-2000s

Birmingham

 

Bristol

 

Guy’s

The Guy’s group was led by Stewart Cameron who from the late 1960s became part of an  international group, which was never formally constituted but proved to be the driving force for progress in the understanding and treatment of glomerular disease. Among others with Cameron were Renée Habib (pathologist from Paris), Richard Glassock (USA), and Priscilla Kincaid-Smith (Melbourne).

Stewart Cameron outside Richard Bright’s house in Bristol    Cameron trod in the footsteps of his predecessor at Guy’s, Richard Bright, in using sequential study of personally observed cases as the basis for understanding better the causes, classification, course and treatment of GN. These clinical observations being linked to the best available  laboratory information, which for Cameron included renal biopsy and soluble immunological blood markers. He was the first investigator to use actuarial survival graphics to report outcomes in glomerular disease and led a series of RCTs investigating corticosteroids and other immunosuppressive agents in glomerular disease. Studies were run at Guy’s,  then collaboratively across London, and then nationally. Cameron’s main focus was on clinical studies, although he also ran laboratory studies, notably on the role of platelets in glomerular injury. Cameron was joined in the 1980s by Gwyn Williams from Hammersmith Hospital.

Manchester

The Manchester group led by Netar Mallick also emphasised natural history studies in glomerular disease, expanding lab work on disease mechanisms following the appointment of Paul Brenchley in 1978. The group published on minimal change nephrotic syndrome, IgA nephropathy, and particularly on membranous nephropathy in which Brenchley developed an international profile from 2010 onwards for his work on the role of M-type PLA2receptor as the autoantigen in membranous nephropathy.

Hammersmith

Hammersmith Hospital became a leader in glomerular disease through the research group bult up by Keith Peters, appointed Professor of Medicine in 1974. Hammersmith became particularly associated with anti-GBM disease; both laboratory  study of the Goodpasture antigen, and the introduction of the first successful treatment for this condition using plasma exchange and immunosuppression. Hammersmith also had  a strong experimental emphasis on the role of complement in glomerular injury, and later in the role of autoantigens and other disease mechanisms in renal vasculitis (link to follow).

The   large Hammersmith group was redeployed when Peters moved to be Regius Professor of Physic in Cambridge in 1987. And the subsequent impact of this group in a number of centres is impressive.

Among those who moved with Peters to  Cambridge were Martin Lockwood, Peter Mathieson and David Jayne. Lockwood continued work on vasculitis until his untimely early death. Mathieson soon moved to a new chair of nephrology in Bristol where he developed, with the paediatric nephrologist Moin Saleem, a high profile focus on podocyte biology, and later on in glomerular endothelial cell biology (with Simon Satchell). David Jayne moved to St George’s before returning to Cambridge and became  a  leader in clinical trials in vasculitis through the EUVAS (European Vasculitis Study) group.

John Savill left Hammersmith for the chair of medicine in Nottingham, and soon to the chair of medicine in Edinburgh. He studied inflammation and apoptosis but before long a became a national medical leader, including directing the MRC.

Andy Rees soon left Hammersmith for the Regius Chair of medicine in Aberdeen continuing a laboratory focus  on inflammation. He was accompanied by Neil Turner who  moved on to the chair of nephrology in Edinburgh continuing his studies on the Goodpasture antigen, taking him into the study of Alport disease.

Charles Pusey and Liz Lightstone remained at Hammersmith. Pusey focusing on anti-GBM disease and experimental work through  small animal studies of glomerular injury. Lightstone becoming an authoritative voice on lupus nephritis, as well as pregnancy in women with kidney disease.

Caroline Savage moved from Hammersmith to Birmingham where she continued work on vasculitis with Lorraine Harper.

Leicester

Leicester developed from the 1990s a reputation for its work on IgA nephropathy, led by John Feehally, who had trained in Manchester, and later by Jonathan Barratt. The Leicester group was the first to report altered glycosylation of the IgA1 molecule in IgA nephropathy, now appreciated as a pivotal abnormality in its pathogenesis.

Treatment of glomerular diseases

The UK played an important role in improving the treatment of glomerular disease.

From the 1960s to the turn of the century, treatment of GN was still be based on immunomodulation, using agents had almost all been introduced in other clinical settings and were repurposed for GN. Corticosteroids – undoubtedly beneficial in childhood nephrosis and for extrarenal manifestation of lupus became widely used.

Cyclophosphamide (first used in cancer chemotherapy), azathioprine and calcineurin inhibitors (introduced to suppress allo-immunity in transplantation) were all still being used for GN.

The broad premise that GN had an immune basis opened the door to empirical treatment. Opinion was often  valued over evidence, indeed there was a dearth of high-quality trial evidence to support their use (a worldwide not a UK problem right up to the 1990s). Two exceptions were RCTs undertaken in the UK  funded by the MRC. The first, published in 1970, was a trial of corticosteroids  in adult nephrotics conducted by Douglas Black (Manchester) with the statistician  Geoffrey Rose (London) and renal pathologist Douglas Brewer (Birmingham)¹ .  This was a seminal trial,  not least because it was  probably the  first RCT ever conducted in renal disease. It provided convincing evidence that corticosteroids are effective in nephrotics with minimal change, but not (in the doses used) in membranous nephropathy or a miscellaneous group with  ‘proliferative nephritis’.

Also funded by MRC was a later RCT of higher dose corticosteroids in membranous nephropathy led by Stewart Cameron, published in 1990 [7], which showed no convincing benefit.

In a few cases empirical use was justified – the best example being the regimen for anti-GBM Goodpasture) disease introduced by Hammersmith Hospital in the 1970s – plasma exchange with corticosteroids and cyclophosphamide to remove and prevent resynthesis of pathogenic antibodies. The evidence was very strong for benefit when the regimen was correctly applied (i.e. when the glomerular lesions were potentially reversible); and the rarity of the condition made it virtually impossible to mount an RCT.

But in many areas rather toxic immunomodulation was offered for GN on the basis of expert opinion.

Randomised clinical trials (RCTs)

By the 1990s a culture change was emerging: more UK nephrologists began to take leading roles in developing RCTs for GN. The EUVAS study group, in which David Jayne (Cambridge) played a leading role, developed a series of RCTs in systemic vasculitis with glomerular involvement. Peter Mathieson (Bristol) led an RCT funded by MRC in membranous nephropathy at high risk of progression [8].

Despite these efforts, some UK  nephrologists were at first reluctant  to recruit their patients into these RCTs, apparently because some felt they already knew the correct treatment, and so recruiting into a trial might mean randomisation to a suboptimal treatment.  This was exemplified in the Mathieson trial of membranous nephropathy which because of slow recruitment was not published until 2013, more than a decade after the study was launched.

Since the turn of the century a more realistic acceptance of uncertainty as a justification for RCTs has spread among younger nephrologists, and the UK has become a more effective leader and contributor in RCTs in GN.

References

1. Ellis A Lancet 1942; i: 1-7; i: 34-36, I 72-76.
2. Arneil G. Arch Dis Child 1952; 27: 322-328. There had been an earlier preliminary one-page report in 1950 by Henry Barnett & colleagues from New York, but Arneil’s was the first definitive publication.
3. Heptinstall RH, Joekes AM. Focal glomerulonephritis. A study based on renal biopsies. Q J Med. 1959 Jul;28:329-46.
4. A previous CIBA Symposium on ‘The Kidney’ in partnership with the Renal Association had been held in London in 1953[5]. (The Kidney, eds. AAG Lewis, GEW Wolstenholme, Little Brown & CO Boston, 1954). At that meeting there was a preliminary report of Danish experience with aspiration biopsy of the kidney, but the remainder of the symposium was exclusively concerned with tubular physiology and pathophysiology; reflecting the focus of nephrology in the 1950s before biopsy opened up the study of glomerular disease.
5. Heptinstall had by then emigrated permanently to the USA, but had done his influential work to that point in London)
6. Ciba Foundation Symposium on Renal Biopsy – Clinical & Pathological Significance, eds Wolstenholme GEW, Cameron MP. J&A Churchill Ltd, London 1961.
7. Cameron JS et al. Q J Med. 1990 Feb;74(274):133-5
8. Lancet. 2013 Mar 2;381(9868):744-51

Authorship

John Feehally. First published 5 Aug 2024

 

Last Updated on September 13, 2024 by neilturn