Membranous Nephropathy – RDG
- Aims of the Group
1. To develop evidence based clinical care pathways. Current treatment for Membranous Nephropathy (MN) is based on knowledge and drugs available in the 1990’s. We are keen to support the development of new evidenced based therapy to improve outcomes for patients.
2. To empower and inform patients and families. We are keen to provide a resource of information for patients about MN and to encourage patients to get involved in all aspects of research into MN.
3. To audit clinical outcome. Development of a UK National Registry for Membranous Nephropathy (MN) patients will allow robust audit of outcomes. This will aim to:
- Establish a registry of biopsy proven prevalent cases and new incident cases of both primary and secondary MN starting from Jan 2013. We anticipate that there could be 1200 cases of prevalent MN (at CKD stage 2-4) in addition to 600 cases on renal replacement therapy (CKD5). We expect approx 100 incident cases per year. In total we seek to capture data on 2000 patients during the next 5 years with a minimum of one complete data return per patient per year.
- Capture and analyse clinical outcome data on patients entered into large national studies on MN since 2000 where patients consented for clinical outcome data to be collected and analysed (MRC-KRUK GN Biobank and MRC trial of immunosuppression). Our current MRC study involves identifying all prevalent cases of MN that have progressed to CKD5 and information from Renal Registry identifies approx 600 cases with half on dialysis and half transplanted. We plan to audit the clinical outcomes of those who get recurrent disease compared to those who don’t with reference to primary/secondary disease and anti-PLA2R status.
4. To promote and develop research. Specific research questions currently being investigated include:
- Why does PLA2R or THSD7A trigger autoantibody formation in MN patients?
- What is the target site on these receptors that the antibodies recognise?
- Do these autoantibodies induce proteinuria on their own or with the aid of other mediators such as complement?
- Does the level of autoantibody correlate closely with disease activity?
- How does the immune system regulate these autoantibodies when patients experience a spontaneous remission of proteinuria?
- Why do some patients experience a recurrence of MN after they have been transplanted while others don’t?
- How do existing immunosuppressive treatments affect autoantibody levels?
- How do new immunosuppressive therapies affect autoantibody levels?
- In the approximately 20% of IMN cases that don’t have either anti-PLA2R or anti-THSD7A antibodies are there autoantibodies to other podocyte cell receptors causing disease in a similar way?
- Is the mechanism of disease in secondary MN different to that in primary MN?
Our research ideas are being investigated in the three grants listed below. We will provide updates on progress during and at the completion of these studies.
- Current Activities
Current UK grants that the group are working on:
Kidney Research UK
Title: Proving the pathogenicity of anti-PLA2R antibodies in vitro and in vivo
Grant Holders: PEC Brenchley, R Lennon, E McKenzie, T Jowitt, T Coates
Period: Jan 2013 – July 2017
Kidney Research UK
Title: Blocking PLA2R receptor activation on podocytes with soluble epitope peptide can modulate the pathological effects of anti-PLA2R: a new therapy for preventing relapse in membranous nephropathy.
Grant Holders: P Brenchley, R Lennon, T Jowitt, E Mckenzie.
Period: Sept 2015- Feb 2018. £198,359
Medical Research Council
Title: Understanding the autoimmune mechanism in idiopathic membranous nephropathy.
Grant Holders: P Brenchley, E McKenzie, I Roberts, P Mathieson, S Roberts, R Kleta.
Period: Jan 2013 – Oct 2016
National Institute for Health Research i4i grant
Title: Developing PLARIA immunoadsorption therapy for patients with MN
Grant Holders: P Brenchley, S Mitra, P Slater, W Tindale, A McCarthy, S Russell, D Kanigicherla
Period: Dec 2016-Nov 2018
- International Links
EU Framework 7 Programme
Title: EURenOmics: Studing rare kidney disease across Europe
Grant Holders: Franz Schaeffer (Heidelberg, Chief Investigator), UK MN team includes P Mathieson, R Kleta, P Brenchley
Period: 2012 – 2017
- Patient Support Groups
Recent papers from the group:
Cattran D, Brenchley P. Membranous nephropathy: thinking through the therapeutic options. Nephrol Dial Transplant. 2017 Jan 1;32(suppl_1):i22-i29.doi: 10.1093/ndt/gfw404. PubMed PMID: 28391348.
Sekula P, Li Y, Stanescu HC, Wuttke M, Ekici AB, Bockenhauer D, Walz G, Powis SH, Kielstein JT, Brenchley P; GCKD Investigators., Eckardt KU, Kronenberg F,Kleta R, Köttgen A. Genetic risk variants for membranous nephropathy: extension of and association with other chronic kidney disease aetiologies. Nephrol Dial Transplant. 2017 Feb 1;32(2):325-332. doi: 10.1093/ndt/gfw001. PubMed PMID:28186573.
Cattran DC, Brenchley PE. Membranous nephropathy: integrating basic science into improved clinical management. Kidney Int. 2017 Mar ;91(3) :566-574. doi:10.1016/ j.kint.2016.09.048. Epub 2017 Jan 5. Review. PubMed PMID: 28065518.
Kanigicherla DA, Hamilton P, Czapla K, Brenchley PE. Intravenous Pulse cyclophosphamide and steroids induce immunological and clinical remission in New-incident and relapsing Primary Membranous Nephropathy. Nephrology (Carlton). 2016 Oct 24. doi: 10.1111/nep.12955. [Epub ahead of print] PubMed PMID: 27778424.
Kanigicherla DA, Short CD, Roberts SA, Hamilton P, Nikam M, Harris S,Brenchley PE, Venning MC. Long-term outcomes of persistent disease and relapse in primary membranous nephropathy. Nephrol Dial Transplant. 2016Dec;31(12):2108-2114. Epub 2016 Jan 13. PubMed PMID: 26769682.
Kanigicherla DA, Short CD, Roberts SA, Hamilton P, Nikam M, Harris S, Brenchley PE, Venning MC. Long-term outcomes of persistent disease and relapse in primary membranous nephropathy. Nephrol Dial Transplant. 2016 Jan 13. pii: gfv435. [Epub ahead of print] PubMed PMID: 26769682.
Brenchley PE. Anti-phospholipase A2 Receptor Antibody and Immunosuppression in Membranous Nephropathy: More Evidence for Pathogenicity of Anti-phospholipase A2 Receptor Autoantibodies. J Am Soc Nephrol. 2015 Oct;26(10):2308-11. doi: 10.1681/ASN.2015020181. Epub 2015 Mar 24. PubMed PMID: 25804283; PubMed Central PMCID: PMC4587708.
Fresquet M, Jowitt TA, Gummadova J, Collins R, O’Cualain R, McKenzie EA, Lennon R, Brenchley PE. Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy. J Am Soc Nephrol. 2015 Feb;26(2):302-13. doi: 10.1681/ASN.2014050502. Epub 2014 Oct 6. PubMed PMID: 25288605; PubMed Central PMCID: PMC4310666.
Bech AP, Hofstra JM, Brenchley PE, Wetzels JF. Association of anti-PLA₂R antibodies with outcomes after immunosuppressive therapy in idiopathic membranous nephropathy. Clin J Am Soc Nephrol. 2014 Aug 7;9(8):1386-92. doi: 10.2215/CJN.10471013. Epub 2014 Jul 17. PubMed PMID: 25035272; PubMed Central PMCID: PMC4123402.
Coenen MJ, Hofstra JM, Debiec H, Stanescu HC, Medlar AJ, Stengel B, Boland-Augé A, Groothuismink JM, Bockenhauer D, Powis SH, Mathieson PW, Brenchley PE, Kleta R, Wetzels JF, Ronco P. Phospholipase A2 receptor (PLA2R1) sequence variants in idiopathic membranous nephropathy. J Am Soc Nephrol. 2013 Mar;24(4):677-83. doi: 10.1681/ASN.2012070730. Epub 2013 Feb 21. PubMed PMID:23431073.
Kanigicherla D, Gummadova J, McKenzie EA, Roberts SA, Harris S, Nikam M, Poulton K, McWilliam L, Short CD, Venning M, Brenchley PE. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy. Kidney Int. 2013 May;83(5):940-8. doi: 10.1038/ki.2012.486. Epub 2013 Jan 30. PubMed PMID: 23364522.
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. Lancet. 2013 Mar 2;381(9868):744-51. doi: 10.1016/S0140-6736(12)61566-9. Epub 2013 Jan 9. PubMed PMID: 23312808; PubMed Central PMCID: PMC3590447.
Hofstra JM, Debiec H, Short CD, Pellé T, Kleta R, Mathieson PW, Ronco P, Brenchley PE, Wetzels JF. Anti-phospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy. J Am Soc Nephrol. 2012 Oct;23(10):1735-43. Epub 2012 Sep 6. PubMed PMID: 22956816; PubMed Central PMCID: PMC3458465.
Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Kottgen A, Dragomirescu L, Voinescu C, Patel N, Pearce K, Hubank M, Stephens HA, Laundy V, Padmanabhan S, Zawadzka A, Hofstra JM, Coenen MJ, den Heijer M, Kiemeney LA, Bacq-Daian D, Stengel B, Powis SH, Brenchley P, Feehally J, Rees AJ, Debiec H, Wetzels JF, Ronco P, Mathieson PW, Kleta R. Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N Engl J Med. 2011 Feb 17;364(7):616-26. doi: 10.1056/NEJMoa1009742. PubMed PMID: 21323541.
- Group Members
- Paul Brenchley, RDG Lead
- Henry Brown, Northern Ireland Lead
- Colin Geddes, Scotland Lead
- Lynne Healey, Patient Lead
- Robert Kleta, Genetics Lead
- Stephen Powis, South of England Lead
- Stephen Riley, Wales Lead
- Ian Roberts, Pathology Lead
- Caroline Savage, Industry Lead
- Durga Kanigicherla, North of England Lead
- Nicholas Webb, Clinical Lead (children)
- Disclosure of Conflicts of Interest
Written by the Membranous Nephropathy Rare Disease Group