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Complement-mediated kidney diseases (CMKDs) Learning Zone
Declaration of sponsorship Novartis Pharma AG

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Declaration of sponsorship Novartis Pharma AG
Read time: 40 mins
Last updated:22nd Dec 2022
Published:22nd Dec 2022

Complement-mediated kidney diseases (CMKDs) are rare, chronic and progressive diseases1-3. Dysregulation of a component of the innate immune system – the complement cascade – causes development of these diseases, or is considered a key contributor to their pathophysiology1-3.

While C3 glomerulopathy (C3G) and atypical haemolytic uraemic syndrome (aHUS) are considered ‘prototypical’ CMKDs3,4, complement dysregulation also contributes to pathogenesis of other kidney diseases including IgA nephropathy (IgAN), membranous nephropathy (MN) and immune-complex membranoproliferative glomerulonephritis (IC-MPGN)1,3,4. Based on evidence to date, primary MN and IgAN may also be considered as CMKDs5.

CMKDs can have a devastating impact on patients4 and can progress to kidney failure1,4, requiring dialysis or transplantation3. Such adverse developments are associated with an increased risk of mortality6-8.

There are many unmet needs in the management of CMKDs, particularly for improved diagnosis9,10 and more effective treatment options10,11. As we learn more about the complex pathophysiology of each disease, more investigational treatments that target key drivers or mediators of CMKDs are progressing through clinical development4,10,12.

Complement inhibition is a key strategy showing promise for treatment of various CMKDs1,4,11. So far, two complement inhibitors have been FDA- and EMA-approved for aHUS (eculizumab13,14 and ravulizumab15,16), and numerous others are being investigated in clinical trials across other types of CMKDs4,12,17.

The growing number of complement inhibitors in clinical development4 may help to address unmet needs for more effective treatment strategies for CMKDs10,11, with potential to improve outcomes for patients with these devastating diseases4,11

Learn about recent advances in the management and treatment of CMKDs in our highlights from the American Society of Nephrology (ASN) Kidney Week 2022.

Highlights from the American Society of Nephrology (ASN) 2022

Join Dr Carla Nester as she discusses:

  • highlighting the primary drivers of disease in C3G
  • current understanding of C3
  • nephritic factors and their role in C3 glomerulopathy

Why learn about CMKDs?

An improved understanding of which rare kidney diseases can be considered as complement-mediated and considerations for diagnosis of each condition may assist healthcare professionals in recognising the signs and symptoms of these diseases. It may also assist with differential diagnosis in practice.

More details on key pathways involved in the development and progression of CMKDs, existing treatment options and investigational treatments in clinical development will assist healthcare professionals in understanding how emerging treatment options may help to address unmet needs for patients with CMKDs.

More educational content coming soon to the CMKDs Learning Zone

Interested in learning more about CMKDs, and treatments currently in clinical development? More educational content is coming soon to the CMKDs Learning Zone.

Bookmark this page to stay informed with upcoming content for CMKDs Learning Zone via the button at the bottom of this page. We will notify you when new content becomes available on Medthority.

About the CMKDs Learning Zone

The aim of this Learning Zone is to improve understanding of the role of complement in kidney disease and encourage earlier and optimal management of CMKDs.

The key objectives of the CMKDs Learning Zone are:

  • To raise awareness of the role of complement in kidney disease, resulting in the umbrella terminology ‘CMKDs’
  • To improve understanding of the role of complement in the pathophysiology of various CMKDs, starting with C3G and IgAN
  • To explore therapeutic targets within the complement system that are under investigation in CMKDs
  • To improve knowledge of C3G, including:
    • Signs and symptoms, and requirements to confirm a diagnosis
    • Current treatment strategies (as per the 2021 KDIGO glomerular disease guidelines18), and unmet needs in management
    • The role of complement in C3G pathophysiology, and investigational strategies that target complement components in C3G
  • To improve knowledge of IgAN, including:
    • Signs and symptoms
    • Considerations for diagnosis, and prognostic evaluation (using tools such as MEST-C)
    • Use of risk stratification to inform an individual’s risk of progression to end-stage renal disease and the impact of this risk on clinical decision-making

This Learning Zone is intended for nephrologists, urologists, specialists and general practitioners.

Meet the experts

The following experts provided insights on CMKDs and reviewed the CMKDs Learning Zone.

Dr Carla Nester

Dr Carla Nester is the Jean Robillard Professor of Pediatric Nephrology and the Division Director of Pediatric Nephrology, Dialysis and Transplantation at the Stead Family Children’s Hospital, University of Iowa. Dr Nester leads a translational research program focusing on the rare CMKDs. She is also the primary investigator for the C3 Glomerulopathy Natural History Study, the largest cohort of rare C3G patients in North America. She is an advisor to KidNeeds, a global C3G family community. Dr Nester is also involved in clinical trials, and her clinical practice has become a hub for bringing the new generation of anti-complement therapeutics to a rare disease population. 

Disclosures: Dr Nester has been involved in advisory boards and acted as a site investigator for Novartis, BioCryst and Apellis. She has also been a site investigator for ChemoCentryx, Alexion Pharmaceuticals and Retrophin. Dr Nester has been on a Data Safety Monitoring Board for Kira. She has also received honoraria from UpToDate, and funding from the National Institutes of Health.

Dr Edwin Wong

Dr Edwin Wong is a Consultant Nephrologist at Newcastle upon Tyne Hospitals NHS Foundation Trust and associate clinical lecturer at Newcastle University. Dr Wong’s academic renal training took place in Newcastle where he completed his Medical Research Council funded Clinical Research Training Fellowship. His research surrounded the study of complement abnormalities in aHUS, C3G and membranoproliferative glomerulonephritis (MPGN), with his work being published in top-ranking nephrology journals (J Am Soc Nephol/ Kidney Int). Dr Wong was awarded a Doctoral Thesis Prize for his PhD in 2016 and the prestigious Renal Association (Young Investigator) Raine Award in 2017.

Dr Wong’s clinical time is currently divided between the National Renal Complement Therapeutics Centre and Renal Services. His main clinical role is providing expert advice for the diagnosis and management of atypical haemolytic uraemic syndrome (aHUS) and C3 glomerulopathy (C3G) nationally. This includes implementing the NHS England Highly Specialised Services policies on the use of eculizumab in the treatment of these conditions.

Dr. Wong has been the UK chief investigator for trials of iptacopan in C3 glomerulopathy and IgA nephropathy. He is currently an investigator for both APPEAR and APPLAUSE – phase 3 studies in C3G and IgAN respectively.

Disclosures: Dr Edwin Wong has consultancy agreements for Apellis, Biocryst, Novartis, Omeros and Q32 Bio. He also has speaker’s agreements for Novartis and Alexion.

 

References

  1. Poppelaars F, Thurman JM. Complement-mediated kidney diseases. Mol Immunol. 2020;128:175-187.
  2. Heiderscheit AK, Hauer JJ, Smith RJH. C3 glomerulopathy: Understanding an ultra-rare complement-mediated renal disease. Am J Med Genet C Semin Med Genet. 2022;190(3):344-357.
  3. Willows J, Brown M, Sheerin NS. The role of complement in kidney disease. Clin Med (Lond). 2020;20(2):156-160.
  4. Fakhouri F, Schwotzer N, Golshayan D, Frémeaux-Bacchi V. The rational use of complement inhibitors in kidney diseases. Kidney International Reports. 2022.
  5. So BYF, Chan GCW, Yap DYH, Chan TM. The role of the complement system in primary membranous nephropathy: A narrative review in the era of new therapeutic targets. Front Immunol. 2022;13:1009864.
  6. Wang X, Van Lookeren Campagne M, Katschke KJ, Jr., Gullipalli D, Miwa T, Ueda Y, et al. Prevention of Fatal C3 Glomerulopathy by Recombinant Complement Receptor of the Ig Superfamily. J Am Soc Nephrol. 2018;29(8):2053-2059.
  7. Glassock RJ. Mortality Risk in IgA Nephropathy. J Am Soc Nephrol. 2019;30(5):720-722.
  8. Kościelska-Kasprzak K, Bartoszek D, Myszka M, Żabińska M, Klinger M. The complement cascade and renal disease. Archivum immunologiae et therapiae experimentalis. 2014;62(1):47-57.
  9. Feldman D, Bomback A, Nester C. National Kidney Foundation. The Voice of the Patient - C3 Glomerulopathy (C3G). 2018. Available at: https://www.kidney.org/sites/default/files/C3G_EL-PFDD_VoP-Report_3-29-18.pdf.
  10. Meuleman MS, Grunenwald A, Chauvet S. Complement C3-targeted therapy in C3 glomerulopathy, a prototype of complement-mediated kidney diseases. Semin Immunol. 2022:101634.
  11. Andrighetto S, Leventhal J, Zaza G, Cravedi P. Complement and Complement Targeting Therapies in Glomerular Diseases. Int J Mol Sci. 2019;20(24).
  12. National Institutes of Health US National Library of Medicine. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/home. Accessed 14 November 2022.
  13. Alexion Europe SAS. Eculizumab EPAR - Product Information. European Medicines Agency. Last updated 26 September 2022 2009. Available at: https://www.ema.europa.eu/en/documents/product-information/soliris-epar-product-information_en.pdf.
  14. Alexion Pharmaceuticals Inc. Eculizumab (Soliris) Full Prescribing Information (US FDA). US Food and Drug Administration. Last revised November 2020 2007. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125166s434lbl.pdf.
  15. Alexion Europe SAS. Ravulizumab EPAR - Product Information. European Medicines Agency. Last updated 29 April 2022 2019. Available at: https://www.ema.europa.eu/en/documents/product-information/ultomiris-epar-product-information_en.pdf.
  16. Alexion Pharmaceuticals Inc. Ultomiris (Ravulizumab-cwvz) - Full Prescribing Information (US FDA). US Food and Drug Administration. Last revised July 2022 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761108s021lbl.pdf.
  17. Ort M, Dingemanse J, van den Anker J, Kaufmann P. Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway. Front Immunol. 2020;11:599417.
  18. Kidney Disease: Improving Global Outcomes Diabetes Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4s):S1-s276.
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