SEARCH RESULTS FOR: IgA-Nephropathy

IgA Nephropathy

IgA Nephropathy: Pathogenesis & clinical findings Authors: David Campbell Matthew Hobart Reviewers: Huneza Nadeem Raafi Ali Ran Zhang Luiza Radu Julian Midgley* * MD at time of publication Galactose-deficient IgA1 (GD- IgA1) created by mucosa- bound IgA1 plasma cells is secreted into plasma instead of onto mucosal surface IgA1 plasma cells hyper- responsive to triggers (eg. URTIs, gastroenteritis) ↑ synthesis of GD-IgA1 → spill-over into plasma Immunoglobulin A1 (IgA1) plasma cells destined to reside in mucosa (eg. gut or respiratory tract) travel to and reside in inappropriate site(s) (eg. bone marrow) releasing GD-IgA1 into plasma GD-IgA1 is not cleared from plasma as quickly as IgA1 → ↑ plasma GD-IgA1 levels Hit 3: GD-IgA1-IgG complexes deposit in mesangium C3 predominant complement activation amplifies inflammatory response Renal biopsy: IgA deposits in mesangium (100% sensitive) Renal biopsy: Complement in mesangium (C3 predominant) (90-95% sensitive) A cascade of multiple immunologic hits is initiated Hit 1: ↑ Serum levels of GD-IgA1 multiple immunologic hits GD-IgA1 hinge region is structurally distinct from IgA1 that would normally circulate in plasma (lack of galactosyl groups) GD-IgA1 hinge region may mimic pathogens (ex. bacteria and viruses) or other antigens Cross reactivity of IgG against GD-IgA1, or synthesis of anti-GD-IgA1 IgG antibodies Immunoglobulin G (IgG) binds GD-IgA1 hinge region Hit 2: GD-IgA1-IgG immune complex formation Circulating GD-IgA1-IgG complexes have high affinity for glomerular endothelial cells where they damage the glycocalyx → ↑ permeability of immunoglobulins into the mesangium ↑ Production of chemokines, cytokines and complement → ↑ mesangial cell proliferation and matrix expansion Leukocyte recruitment and activation damages glomerulus and mesangium Hit 4: Inflammatory response to GD-IgA1 complexes in mesangium induce glomerular structure disruption (endothelium, basement membrane, podocytes, mesangium) and impaired glomerular function Loss of barrier functions of glomerulus allows for extravasation of blood & proteins into Bowman’s space and subsequently through tubules Renal biopsy: Glomerulosclerosis, tubulointerstitial fibrosis, glomerular vasculitis, podocyte damage Eventual end-Stage Renal Disease (ESRD) Progressive ↓ of filtration surface area within glomeruli and ↓ number of functional glomeruli Proteinuria Synpharyngitic hematuria (hematuria with dysmorphic red cells co-occurring with pharyngitis) ↓ Glomerular Filtration Rate (GFR) Nephrotic Syndrome ↑ Serum creatinine Chronic kidney disease and eventually ESRD IgAN is an autoimmune disease where IgA deposition in the glomerulus leads to an inflammatory cascade, endothelial dysfunction and mesangial expansion that damages glomeruli causing kidneys to leak blood and protein into urine and decreased kidney function. IgA nephropathy is a multifactorial disease requiring multiple immunologic hits IgA Nephropathy (IgAN) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 5, 2024 on www.thecalgaryguide.com