Transcript
Announcer:
Welcome to ReachMD. This medical industry feature, titled “The Four-Hit Model of IgA Nephropathy Pathogenesis,” is sponsored by Novartis Pharmaceuticals Corporation. Here’s Dr Jai Radhakrishnan.
Dr Radhakrishnan:
Hello, my name is Dr Jai Radhakrishnan and I am a nephrologist at Columbia University Medical Center in New York. In this video, we will discuss the four-hit model of immunoglobulin A (or IgA) nephropathy pathogenesis.
IgA nephropathy is the most common primary glomerulonephritis globally.4,10,13,14 About 25 adults per million are affected each year worldwide.4,14 IgA nephropathy affects younger adults (aged 20-30 years) more than older adults and distribution by sex varies geographically.8,15 IgA nephropathy is a highly heterogeneous disease; the presentation varies from asymptomatic microscopic hematuria to a more severe course characterized by sustained proteinuria, hypertension, and, in some patients, rapid deterioration of kidney function.4,14
Based on data from a recent large cohort study of 2,299 adults and 140 children with IgA nephropathy conducted in the UK, 50% of patients with IgA nephropathy progressed to kidney failure within 10 to 15 years of diagnosis.8 The most widely accepted mechanism for the pathogenesis of IgA nephropathy is referred to as the “four-hit model,” which is a sequence of four events that can occur in the pathogenesis of IgA nephropathy.15-17
Hit 1 involves increased production of galactose-deficient IgA1 (or Gd-IgA1), which is the predominant subclass of IgA found in serum.10,11,15 Patients with IgA nephropathy demonstrate increased circulating levels of IgA1,17,18 which is polymeric and lacks terminal galactose moieties, or GalNAc, and galactose in its hinge region.9 This form of IgA1 is referred to as “poorly galactosylated IgA1” or galactose-deficient IgA1. Galactose-deficient IgA1 originates in the mucosa and is produced at the mucosa-associated lymphoid tissue by antibody-secreting B cells.9,10 The changes in O-galactosylation of the IgA1 hinge region could trigger conformational changes to the molecule and a subsequent immune response.9
Hit 2 involves increased production of antiglycan autoantibodies directed against galactose-deficient IgA1.10 Autoantibodies in IgA nephropathy recognize GalNAc residues in the hinge region of galactose-deficient IgA1.15 These specific autoantibodies can include IgG or IgA, but IgG is the predominant isotype.15
The increased production of autoantibodies directed against galactose-deficient IgA1 results in Hit 3, which is the formation of immune complexes.10 Patients with IgA nephropathy have higher circulating levels of immune complexes compared with healthy individuals.14 These immune complexes are pathogenic and composed of galactose-deficient IgA1 and anti-galactose-deficient IgA1 autoantibodies.14,15 These immune complexes are inefficiently cleared from circulation, so they tend to deposit in the renal mesangium.14
Hit 4 involves immune complex deposition and activation of inflammatory pathways,10 including the complement system.16 Deposition and recognition of immune complexes by mesangial IgA receptors trigger mesangial cell proliferation, release of proinflammatory and profibrotic mediators, and podocyte damage.9 Continued immune complex deposition and mesangial cell activation can lead to progressive glomerular injury and, potentially, kidney failure.9 Consequently, hits 1, 2, 3, and 4 are involved in the pathogenesis of IgA nephropathy.
In summary, the pathogenesis of IgA nephropathy is complex and involves four stages or “hits”.15-17 Thank you for your time and interest in this video.
Announcer:
This program was sponsored by Novartis Pharmaceuticals Corporation. If you missed any part of this discussion, visit ReachMD.com/IndustryFeature. This is ReachMD. Be Part of the Knowledge.
References:
- Lai KN et al. Nat Rev Dis Primers. 2016;2:16001.
- Rizk DV et al. Front Immunol. 2019;10:504.
- McGrogan A et al. Nephrol Dial Transplant. 2011;26(2):414-430.
- Penfold RS et al. Int J Nephrol Renovasc Dis. 2018;11:137-148.
- Sim JJ et al. Am J Kidney Dis. 2016;68(4):533-544.
- Swaminathan S et al. Clin J Am Soc Nephrol. 2006;1(3):483-487.
- Magistroni R et al. Kidney Int. 2015;88(5):974-989.
- Pitcher D et al. Clin J Am Soc Nephrol. 2023;18(6):727-738. doi:10.2215/CJN.0000000000000135
- Boyd JK et al. Kidney Int. 2012;81(9):833-843.
- Gesualdo L et al. Semin Immunopathol. 2021;43(5):657-668.
- Schroeder HW Jr, Cavacini L. J Allergy Clin Immunol. 2010;125(2 supply 2):S41-S52.
- Tecklenborg J et al. Clin Exp Immunol. 2018;192(2):142-150.
- Moldoveanu Z, Wyatt RJ, Lee JY et al. Kidney Int. 2007;71(11):1148-1154. doi:10.1038/sj.ki.5002185
- Pattrapornpisut P, Avila-Cascado C, Reich HN. AM J Kidney Dis. 2021;78(3):429-441. doi:10.1053/j.ajkd.2021.01.024
- Knoppova B, Reily C, King RG et al. J Clin Med. 2021;10(19):4501. doi:10.3390/jcm10194501
- Maillard N, Wyatt RJ, Julian BA et al. J Am Soc Nephrol. 2015;26(7):1503-1512. doi:10.1681/ASN.2014101000
- Chang S, Li X-K. Front Med (Lausanne). 2020;7:92. doi:10.3389/fmed.2020.00092
- Elíasdóttir S, Khramova A, Saeed A et al. BMC Nephrol. 2023;24(1):160. doi:10.1186/s12882-023-03198-y
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