Disease overview

Barratt J et al. Nephrology (Charlton) 2007;12:275; Barratt J & Feehally J. Semin Nephrol 2011;31:349; Coppo R et al. Contrib Nephrol 1993;104:162; Gregory RL. Lab Med 1994;25:724; Harper SJ et al. Kidney Int 1994:45;836; Kokubo T et al. J Am Soc Nephrol 1998;9:2048; Lafayette RA. Transl Res 2014;163:3; Lafayette RA & Kelepouris E. Am J Nephrol 2018;47:43; Macpherson AJ et al. Mucosal Immunol 2008;1:11; Rodrigues JC et al. Clin J Am Soc Nephrol 2017;12;677; Smith AC et al. J Am Soc Nephrol 2006;17:3520; Suzuki H et al. J Am Soc Nephrol 2011;22:1795

IgA nephropathy (IgAN) – also known as Berger’s disease – is the most common form of glomerulonephritis, a chronic inflammatory condition of the kidney, in the Western world. IgAN is a serious, progressive autoimmune disease and up to 50% of patients diagnosed with IgAN will progress to end-stage renal disease (ESRD) within 20 years,1-3 a disease state requiring dialysis or kidney transplant, which represents a significant health economic burden as well as a material impact on patients’ quality of life.

To learn more about the impact of IgAN on patients and the challenges they face due to unmet treatment needs, watch this special edition video from the ‘Behind the Mystery’ segment: https://thebalancingact.com/behind-the-mystery-iga-nephropathy/

IgAN, IgA nephropathy, ESRD, end-stage renal disease, dialysis, renal failure, renal function decline

IgAN is an orphan disease, designated as an orphan indication in both the US and Europe. Calliditas’ lead product candidate, NEFECON, has been granted orphan drug designation for the treatment of IgAN in the United States and the EU, but is not yet approved for use in any country.

Burden of IgAN

IgAN, IgA nephropathy, burden of disease, glomerulonephritis

IgAN is a major cause of ESRD, causing a significant number of ESRD cases in the US each year. According to the US Renal Data System (“USRDS”) ESRD quarterly update in October 2020, the number of ESRD patients in the US amounted to 796,128 in the third quarter of 2019, with an incidence during 2018 of 130,472 patients. As a result, ESRD and CKD place a significant burden on healthcare resources.4,5 Care of patients with ERSD was estimated to cost the US$49.2 billion in 2020.4

Dialysis is estimated to cost between US$70,000 and US$200,000 per patient per year, with a total estimated annual hemodialysis cost in the United States of US$42.0 billion. The average cost of a kidney transplant is approximately US$415,000 with a total estimated annual cost in the United States of US$7.0 billion.

IgAN, IgA nephropathy, ESRD, end-stage renal disease, CKD, chronic kidney disease, healthcare burden, cost

IgAN pathophysiology: Role of the gut–kidney axis and Peyer’s patches

IgA is an antibody that plays a key role in the immune system by protecting the body from foreign substances such as bacteria and viruses. The majority of circulating IgA1 is monomeric, heavily O-galactosylated and is derived from bone-marrow-residing plasma cells.6-9 In contrast, mucosally residing plasma cells synthesize and secrete IgA1 onto mucosal surfaces that is predominately dimeric or polymeric and poorly O-galactosylated (mucosal-type IgA1).6-8

IgAN, IgA nephropathy, bone marrow, mucosal surfaces, mucosal-type IgA1, IgA1, galactose-deficient

The galactose-deficient spot at the hinge region of the IgA1 molecule is immunogenic. It therefore attracts other antibodies, forming immune complexes that become stuck in the filtration membranes of the kidney, known as the glomeruli. The trapped immune complexes initiate an inflammatory response which damages the kidney and ultimately destroys the kidney’s filtration mechanism. The accumulation and deposition of these IgA immune complexes leads to slow, progressive deterioration of renal function.10-12

IgAN, immunoglobulin A nephropathy, immunoglobulin A immune complex, IgA-IC, mesangium

According to various theories on disease origin and progression, evidence suggests that IgAN is a disease that starts in the intestine and not in the kidney itself, i.e. in the ileum where the Peyer’s patches are concentrated.13–15 Patients with IgA nephropathy have elevated levels of mucosal-type IgA1. Studies have shown that the type of IgA that deposits in the glomerular mesangium in patients with IgAN is identical to the IgA that is produced in the gut, i.e. polymeric mucosal-type IgA1.9,16 Peyer’s patches, concentrated within the gut-associated lymphoid tissue in the ileum, have been identified as a major source of mucosal-type IgA1.17,18

IgAN, IgA nephropathy, gut–kidney axis, mucosal-type IgA1, IgA1, Peyer’s patches

The kidney is a complex organ and its functions include production of hormones, absorption of minerals, filtration of the blood and removal of waste products. Creatinine levels in the blood are used to calculate the estimated glomerular filtration rate (eGFR), which is a measure of the kidney’s capacity to filter the blood. Hence, eGFR is a measure of renal function (the lower the eGFR, the less renal function remains). As the disease progresses, the eGFR deteriorates and a large proportion of patients with IgAN will eventually be afflicted by ESRD. A patient with ESRD will need dialysis or a renal transplant in order to survive.

IgAN, IgA nephropathy, kidney, renal function, CKD, chronic kidney disease, glomeruli

 

Nefecon is being studied in patients with IgAN at risk of developing end-stage renal disease, with help from some of the most prominent IgAN specialists in the world serving as external advisors and members of the company’s Scientific Study Steering Committee.

Jonathan Barratt
Professor, Department of Infection, Immunity and Inflammation, University of Leicester; Honorary Consultant Nephrologist in the John Walls Renal Unit, Leicester General Hospital, Leicester, UK
VIEW BIO
Jonathan Barratt
Professor, Department of Infection, Immunity and Inflammation, University of Leicester; Honorary Consultant Nephrologist in the John Walls Renal Unit, Leicester General Hospital, Leicester, UK

Dr. Barratt leads the Renal Research Group within the College of Life Sciences, University of Leicester and supervises a 20 strong laboratory and clinical research team focussing on basic science and translational studies in IgA nephropathy. He is the IgA nephropathy Rare Disease Group lead for the UK National Registry of Rare Kidney Diseases (RaDaR) and a member of the steering committee for the International IgA Nephropathy Network.

Dr. Barratt is the Chief Investigator and on the Advisory Boards for a number of international randomised controlled clinical trials in IgA nephropathy and a member of the FDA and American Society of Nephrology Kidney Health Initiative: Identifying Surrogate Endpoints for Clinical Trials in IgA Nephropathy Workgroup. He is an Editorial Board member for Kidney International and Clinical Journal of the American Society of Nephrology, sits on the Kidney Research UK Grants Committee and a member of the Renal GeCIP (Genomics England Clinical Interpretation Partnerships) and UK Glomerulonephritis Clinical Study Group.

Holdings in Calliditas Therapeutics AB: No holdings

Daniel C. Cattran
Professor of Medicine, University of Toronto; Senior Scientist, Toronto General Research Institute, Toronto, Ontario, Canada
VIEW BIO
Daniel C. Cattran
Professor of Medicine, University of Toronto; Senior Scientist, Toronto General Research Institute, Toronto, Ontario, Canada

Dr. Cattran is a graduate of the University of Toronto Medical School. He did his postgraduate training in both Toronto, Canada and Sydney, Australia. He is currently a Professor of Medicine at the University of Toronto and a Senior Scientist at the Toronto General Research Institute. He was the principal organizer and remains the Chair of the Toronto Glomerulonephritis Registry, which currently includes over 10,000 cases of biopsy-proven glomerulonephritis. He has published over 200 articles in peer review journals and more than 30 book chapters mostly related to the natural history, outcome and treatment studies in glomerulonephritis.

Dr. Cattran has served on the editorial board of both the American Journal of Kidney Disease and the Journal of the American Society of Nephrology and has recently completed a six-year term as an associate editor for Kidney International. He is on the editorial board of Up-to-Date and is currently the author/co-author of several of their articles in glomerular disease. He has also held a number of positions in the Canadian Society of Nephrology including a term as president. He has held a number of positions within the American Society of Nephrology including two terms on the Post Graduate Education committee and was previously a member of the ASN Glomerular Disease Advisory Group.

Holdings in Calliditas Therapeutics AB: No holdings

Jürgen Floege
Professor, head of the Department of Renal and Hypertensive Diseases, Rheumatological and Immunological Diseases (Medicine II) at the Aachen University Hospital; Director of the Department of Nephrology and Clinical Immunology at the University of Aachen, Aachen, Germany
VIEW BIO
Jürgen Floege
Professor, head of the Department of Renal and Hypertensive Diseases, Rheumatological and Immunological Diseases (Medicine II) at the Aachen University Hospital; Director of the Department of Nephrology and Clinical Immunology at the University of Aachen, Aachen, Germany

Dr. Floege is current member of the executive board of KDIGO, a society developing world-wide nephrology guidelines. He is a Distinguished Fellow of the ERA-EDTA and recipient of the 2018 ERA-EDTA Award for Outstanding Clinical Contributions to Nephrology, immediate past-president of the German Society of Nephrology as well as incoming president of the German Society of Internal Medicine, Europe’s largest professional medical society.

Together with Professors Richard Johnson, Marcello Tonelli and John Feehally he edits the best-selling textbook “Comprehensive Clinical Nephrology”. Finally, Dr. Floege is associate editor of Kidney International since Jan 2018 and currently is a member of the editorial board of Journal of the American Society of Nephrology, Nature Reviews Nephrology, Journal of Nephrology and others. His scientific work encompasses about 550 original papers, reviews and editorials, and 40 book chapters.

Holdings in Calliditas Therapeutics AB: No holdings

Richard Lafayette
Professor of Medicine (Nephrology), the Stanford University Medical Center; Director, the Stanford Glomerular Disease Center, Stanford, California, US
VIEW BIO
Richard Lafayette
Professor of Medicine (Nephrology), the Stanford University Medical Center; Director, the Stanford Glomerular Disease Center, Stanford, California, US

Dr. Lafayette is Professor of Medicine (Nephrology) at the Stanford University Medical Center. He is the founder and director of the Stanford Glomerular Disease Center and its fellowship training program. He has a longstanding interest in glomerular disease with a focus on IgA nephropathy. This interest has led to many evaluations and some elucidation of the pathogenesis of IgA nephritis and leadership in many clinical trials. He has more than 25 years of clinical experience and has more than 125 publications including 75 peer reviewed papers. He remains passionate in efforts to discover safer and more effective treatments for patients.

Holdings in Calliditas Therapeutics AB: No holdings

Brad H. Rovin
Professor, Director of the Division of Nephrology and Vice Chairman of Medicine for Research at the Ohio State University Wexner Medical Center, Columbus, Ohio, US
VIEW BIO
Brad H. Rovin
Professor, Director of the Division of Nephrology and Vice Chairman of Medicine for Research at the Ohio State University Wexner Medical Center, Columbus, Ohio, US

Dr. Rovin is the Lee A. Hebert Distinguished Professor of Nephrology. He received his Bachelor of Science in Chemical Engineering from Northwestern University in Evanston Illinois and his Doctor of Medicine from the University of Illinois Medical School in Chicago, Illinois.

He completed a residency in Internal Medicine at Barnes Hospital in St. Louis Missouri, and a Fellowship in Nephrology at Washington University School of Medicine, St. Louis. Dr. Rovin studies the pathogenesis of glomerular diseases. His research has focused on biomarker development for glomerular diseases. He also studies experimental therapeutics in an effort to find new treatments for glomerular diseases. Dr. Rovin established a multidisciplinary Lupus, Vasculitis and Glomerulonephritis clinic and directs an advanced fellowship in autoimmune diseases for nephrologists and rheumatologists.

Holdings in Calliditas Therapeutics AB: No holdings

Vladimir Tesar
Professor, Head of the Department of Nephrology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
VIEW BIO
Vladimir Tesar
Professor, Head of the Department of Nephrology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic

Dr. Tesar is currently the head of the Department of Nephrology at the General University Hospital in Prague, in the past he also served as vice-dean at the 1st School of Medicine, Charles University in Prague. He was a member of the Council of ERA-EDTA and of its Scientific Advisory Board and currently is the chair of its Immuno-nephrology Working Group. He has authored and co-authored a large number of scientific papers and presented invited lectures at many national and international conferences. Dr. Tesar’s main areas of interest are glomerular diseases, genetic diseases of the kidney and cardiovascular complications of kidney disease.

Holdings in Calliditas Therapeutics: No holdings

Hérnan Trimarchi
Professor of Medicine, Universidad Católica Argentina; Head, Nephrology Service, Hospital Británico; Head, Kidney transplant unit, Hospital Británico, Buenos Aires, Argentina
VIEW BIO
Hérnan Trimarchi
Professor of Medicine, Universidad Católica Argentina; Head, Nephrology Service, Hospital Británico; Head, Kidney transplant unit, Hospital Británico, Buenos Aires, Argentina

Dr. Trimarchi is a former council member of the Glomerular Diseases Committee of the Buenos Aires Nephrology Association and of the Argentine Society of Nephrology. He was also member of the Scientific Committees of the Argentine Congress of Nephrology for the past fifteen years. Dr. Trimarchi is currently a member of the Steering Committee of the International IgA Nephropathy Network and Editor-in-Chief of the Journal of the Argentinian Society of Nephrology “Nefrología Argentina”. He is a Fellow of the American Society of Nephrology (FASN) and of the American College of Physicians (FACP). He is an active member of the International Society of Nephrology and of the International Society of Transplantation (IST). His PhD degree in 2010 was about the endothelium in chronic hemodialysis.

Dr. Trimarchi is a member of the editorial boards of many nephrology and transplantation journals and has written several book chapters on subjects of the endothelium, hypertension, glomerulonephritis and transplantation. He is the chief editor of the recently published book, 2017, named Glomerular Diseases, the first of its kind in the Spanish language. Dr. Trimarchi is Professor of Medicine of the Universidad Católica Argentina. His scientific work encompasses more than 15 chapters in books, 110 original papers, reviews and editorials in peer-reviewed journals, of which over 70 are indexed in PubMed.

Holdings in Calliditas Therapeutics AB: No holdings

Hong Zhang
Professor of Medicine and Doctoral supervisor, Nephrology Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
VIEW BIO
Hong Zhang
Professor of Medicine and Doctoral supervisor, Nephrology Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China

Dr. Zhang received her MD from Peking University Health Science Centre in Beijing, China, and her PhD from Okayama University in Japan. She has also been a visiting researcher at the Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. Dr. Zhang is a chief physician at the Peking University First Hospital Nephrology Division, which was established in the 1950s as the first nephrology specialty division in China. She is a standing committee member of the Chinese Nephrology Association and vice-president of the Beijing Society of Nephrology. She is a committee member for various International Society of Nephrology (ISN) initiatives and programs. Dr. Zhang also sits on the International IgA Nephropathy Network (IIGANN) committee as both a member and secretary-general and is an editor for Nephrology.

Dr. Zhang’s research interests include the genetic mechanisms of glomerular disease and diagnostic and therapeutic strategies in IgA nephropathy. This interest has led to many publications in peer-reviewed journals. She is also the chief investigator for several international randomized controlled clinical trials in IgA nephropathy.

Holdings in Calliditas Therapeutics AB: No holdings

 

References

  1. Schena FP. A retrospective analysis of the natural history of primary IgA nephropathy worldwide. Am J Med 1990;89:209–215.
  2. Kiryluk K, Novak J. The genetics and immunobiology of IgA nephropathy. J Clin Invest 2014;124:2325–2332.
  3. Geddes CC, Rauta V, Gronhagen-Riska C et al. A tricontinental view of IgA nephropathy. Nephrol Dial Transplant 2003;18:1541–1548.
  4. USRDS Annual Data Report 2020. Chapter 9: healthcare expenditures for persons with ESRD. 2020. https://adr.usrds.org/2020/end-stage-renal-disease/9-healthcare-expenditures-for-persons-with-esrd [accessed Jan 2021]
  5. USRDS Annual Data Report 2020. Chapter 6: healthcare expenditures for persons with CKD. 2020. https://adr.usrds.org/2020/chronic-kidney-disease/6-healthcare-expenditures-for-persons-with-ckd [accessed Jan 2021]
  6. Boyd JK, Cheung CK, Molyneux K et al. An update on the pathogenesis and treatment of IgA nephropathy. Kidney Int 2012;81:833–843.
  7. Hwang VJ, Ulu A, van Hoorebeke J, Weiss RH. Biomarkers in IgA nephropathy. Biomark Med 2014;8:1263–1277.
  8. Boyaka PN. Inducing mucosal IgA: a challenge for vaccine adjuvants and delivery systems. J Immunol 2017;199:9–16.
  9. Yeo SC, Cheung CK, Barratt J. New insights into the pathogenesis of IgA nephropathy. Pediatr Nephrol 2018;33:763–777.
  10. Lafayette RA. Immunoglobulin A nephropathy: insights and progress. Transl Res 2014;163:3–7.
  11. Lafayette RA, Kelepouris E. Immunoglobulin A nephropathy: advances in understanding of pathogenesis and treatment. Am J Nephrol 2018;47(suppl 1):43–52.
  12. Rodrigues JC, Haas M, Reich HN. IgA nephropathy. Clin J Am Soc Nephrol 2017;12:677–686.
  13. Smith AC, Molyneux K, Feehally J, Barratt J. O-glycosylation of serum IgA1 antibodies against mucosal and systemic antigens in IgA nephropathy. J Am Soc Nephrol 2006;17:3520–3528.
  14. Floege J, Feehally J. The mucosa-kidney axis in IgA nephropathy. Nat Rev Nephrol 2016;12:147-156.
  15. Barratt J, Rovin BH, Cattran D et al. Why target the gut to treat IgA nephropathy? KI Reports 2020;5:1620–1624.
  16. Novak J, Barratt J, Julian BA, Renfrow MB. Aberrant glycosylation of the IgA1 molecule in IgA nephropathy. Semin Nephrol 2018;38:461–476.
  17. Woof JM, Kerr MA. The function of immunoglobulin A in immunity. J Pathol 2006;208:270–282.
  18. Macpherson AJ, McCoy KD, Johansen FE, Brandtzaeg P. The immune geography of IgA induction and function. Mucosal Immunol 2008;1:11–22.