Membranous nephropathy

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Membranous nephropathy

Membranous nephropathy is a type of glomerulonephritis in which autoantibodies to an antigen on the surface of the podocyte lead to severe nephrotic syndrome, and often progressive sclerosis of glomeruli.

UK centres making substantial contributions to our understanding of the pathogenesis, clinical course, and management of membranous nephropathy (MN) have included Guy’s and Bristol, but especially Manchester.

Clinical observations

From the 1970s onwards both Guy’s (Stewart Cameron) and Manchester (Netar Mallick)  realised  the value of large cohorts of patients with defined glomerular pathology, careful clinical and lab documentation, and prolonged follow up.     The MN cohorts yielded for example the first much quoted   report of an association between MN and malignancy (Guy’s) [1] and  a description  of MN with relapsing nephrotic syndrome (Manchester) [2].

Genetics

Manchester reported  the unusual phenomenon of familial membranous nephropathy  in three twin pairs, one monozygotic [3]. Mallick also built a collaboration with the  genetics group in Manchester (Rodney Harris with Peter Klouda), which had experience in immunogenetics focused on genetic variations in HLA.   This was an era when HLA typing was predominantly based on serological and cell based methodology and genetic studies  used techniques  much less specific than modern molecular approaches.    Nevertheless, Manchester’s worldwide first in reporting an association between HLA-DRW3 and membranous nephropathy in Caucasians [4] has stood the test of time, confirmed  in larger cohorts using more refined techniques.

Randomised Trials

The   UK also  completed  two  randomised controlled trials in MN  funded by MRC. Both studied subjects with MN and  heavy proteinuria and therefore at high risk of progression. An early trial  led by Stewart Cameron   provided evidence that corticosteroids alone gave no significant clinical benefit [5]. The second led by Peter Mathieson (Bristol) some twenty  years later addressed,  in MN at high risk of progression, the relative benefits and toxicity of the ‘Ponticelli regimen’ (corticosteroids with cyclophosphamide) or cyclosporin,  compared with supportive care [6]. It indicated that better outcomes were achieved with corticosteroids and cyclophosphamide, although associated with more serious adverse events compared to supportive care.

Markers of disease activity in MN

Work in Manchester   identified urinary excretion of complement activation fragments (C3dg and C5b-9) as a useful marker of active disease [7]; although this never went on to enter routine clinical practice.

Pathogenesis

In the 1980s Manchester became the leading UK centre for study of the pathogenesis of MN, and one of small number of groups around the world directing their efforts to identify the  autoantigen(s) involved in the pathogenesis of MN.   The work was started by Netar Mallick, who was soon joined by in the late 1970s by Paul Brenchley,  Colin Short, and Beatrice Coupes, who with others continued the work after Mallick’s retirement in 2000.

Read Paul Brenchley’s account of Manchester’s achievements.

The global interest in understanding MN led to Manchester hosting the 1st International Symposium on Membranous Nephropathy in 1990 at the Whitworth Art Gallery in Manchester. This was attended by the leading researchers in all aspects of MN from across Europe and USA.

Figure. 1st International Symposium on Membranous Nephropathy, Manchester 1990

Back row:          Dontscho Kerjaschki (Vienna), Phil Dyer (Manchester), Colin Short (Manchester),  Pietro Zucchelli (Bologna), Beppe d’Amico (Milan), Jim Donadio (Mayo Clinic, Rochester), Bill Couser (Seattle), Eric Honkanen (Helsinki)

Middle row:     Dan Cattran (Toronto), Paul de Jong (Groningen), Pierre Ronco (Paris) Beatrice Coupes (Manchester),  Priscilla Kincaid-Smith (Melbourne), Richard Glassock (Los Angeles), Netar Mallick (Manchester).

Front row:         ??, Paul Brenchley (Manchester), Stewart Cameron (Guy’s), Linda Hunt (Manchester), Sandy Davison (Leeds), Claudio Ponticelli (Milano), Alan Meyrier (Paris)

Authorship

John Feehally. First published July 2024.

References

  1. Row PG, Cameron JS, Turner DR, Evans DJ, White RH, Ogg CS, Chantler C, Brown CB. Membranous nephropathy. Long-term follow-up and association with neoplasia. Q J Med. 1975 Apr;44(174):207-39.
  2. Manos J, Short CD, Acheson EJ, Dyer P, Lawler W, Mallick NP, Williams G. Relapsing idiopathic membranous nephropathy. Clin Nephrol. 1982; 18:286-90.
  3. Short CD, Feehally J, Gokal R, Mallick NP Familial membranous nephropathy. Br Med J 1984;289(6457):1500.
  4. Klouda PT, Manos J, Acheson EJ, Dyer PA, Goldby FS, Harris R, Lawler W, Mallick NP, Williams G. Strong association between idiopathic membranous nephropathy and HLA-DRW3. Lancet. 1979;2(8146):770-1.
  5. Cameron JS, Healy MJ, Adu D. The Medical Research Council trial of short-term high-dose alternate day prednisolone in idiopathic membranous nephropathy with nephrotic syndrome in adults. The MRC Glomerulonephritis Working Party. Q J Med. 1990 Feb;74(274):133-56. Howman A, Chapman TL, Langdon MM, Ferguson C, Adu D, Feehally J, Gaskin GJ, Jayne DR, O’Donoghue D, Boulton-Jones M, Mathieson PW Immunosuppression for progressive membranous nephropathy: a UK randomised controlled trial.  2013 Mar 2;381(9868):744-51.
  6. Kon SP, Coupes B, Short CD, Solomon LR, Raftery MJ, Mallick NP, Brenchley PE. Urinary C5b-9 excretion and clinical course in idiopathic human membranous nephropathy. Kidney Int. 1995 Dec;48(6):1953-8.

Last Updated on September 17, 2024 by neilturn