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Iga Nephropathy-Igan PowerPoint Presentation

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Description : Check out this medical PowerPoint presentation titled "IgA Nephropathy (IgAN)” by Jai Radhakrishnan, MD and Dana Rizk, MD.

This medical PowerPoint presentation is about IgA Nephropathy (IgAN), also known as Bergers disease. IgA Nephropathy (IgAN) is a type of kidney disease that occurs when an abnormal protein called Immunoglobulin A (IgA) builds up in the small blood vessels of the kidneys. IgA is a type of antibody that helps the body fight infections, but in IgAN, it accumulates in the kidneys and causes inflammation and damage.

The exact cause of IgAN is not yet fully understood, but it is believed to be related to problems with the immune system. Some people with IgAN have a family history of the disease, which suggests that genetics may play a role.

Symptoms of IgAN can vary widely and may include blood in the urine (hematuria), protein in the urine (proteinuria), high blood pressure, and swelling in the hands, feet, or face. In some cases, there may be no symptoms at all.

Diagnosis of IgAN typically involves a kidney biopsy, which involves taking a small sample of kidney tissue to examine under a microscope. Treatment options depend on the severity of the disease and may include medications to control blood pressure and reduce inflammation, as well as lifestyle changes such as a low-salt diet and regular exercise.

In some cases, IgAN can progress to end-stage renal disease (ESRD), which requires dialysis or kidney transplantation. It is important for individuals with IgAN to work closely with their healthcare provider to manage their condition and prevent complications.

Tags : IgA Nephropathy, IgAN, Bergers disease, kidney disease, Immunoglobulin A, Nephrology, Nephrology PowerPoint presentation

Published on : Jun 07, 2023 | Views : 3343 | Downloads : 30

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Faculty
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Learning Objectives Describe the burden and the epidemiology of IgAN Perform a comprehensive diagnosis of IgAN, identifying prognostic factors that may predict the progression of the disease Explain the role and the possible consequences of proteinuria in patients with IgAN Discuss the mechanism of action, safety and efficacy of new and emerging treatments for IgAN
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Introduction to IgAN Epidemiology Pathophysiology Disease Burden
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IgA Nephropathy (IgAN) Primary defect: abnormal glycosylation of O-linked glycoproteins in the IgA1, resulting in increased galactose-deficient IgA1 (Gd-IgA1) that is bound by IgA and IgG autoantibodies Diagnosed by kidney biopsy to identify deposition of immune complexes formed by IgA antibodies in the mesangium of the glomeruli resulting in glomerular inflammation and injury Image Credit: Created with BioRender.com Lai KN et al. IgA nephropathy. Nat Rev Dis Primers. 2016;2:16001. Published 2016 Feb 11. doi:10.1038/nrdp.2016.1
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Epidemiology Lai KN et al. IgA nephropathy. Nat Rev Dis Primers. 2016;2:16001. Published 2016 Feb 11. doi:10.1038/nrdp.2016.1 Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. doi:10.1016/j.kint.2021.05.021 Neumann, ME. Clinical trials, consortiums place glomerular disease in the spotlight. Healio.com. November 12, 2020. Accessed May 18, 2021. https://www.healio.com/news/20201106/clinical-trials-consortiums-place-glomerular-disease-in-the-spotlight McGrogan A et al. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transplant. 2011;26(2):414-430. doi:10.1093/ndt/gfq665 Image Credit: Created with BioRender.com 20-25% ESRD due to glomerular disease 2.5/100,000 Global incidence 20-30% risk of IgAN disease progression to ESRD within 25 years IgAN is the most common primary glomerular disease
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Epidemiology and Socioeconomic Class Image Credit: Created with BioRender.com Lai KN et al. IgA nephropathy. Nat Rev Dis Primers. 2016;2:16001. Published 2016 Feb 11. doi:10.1038/nrdp.2016.1 McQuarrie EP et al. The incidence of biopsy-proven IgA nephropathy is associated with multiple socioeconomic deprivation. Kidney Int. 2014;85(1):198-203. doi:10.1038/ki.2013.329 Canney M et al. Socioeconomic Position and Incidence of Glomerular Diseases. Clin J Am Soc Nephrol. 2020;15(3):367-374. doi:10.2215/CJN.08060719
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IgAN & Health-Related Quality of Life Image Credit: Created with BioRender.com Libório AB et al. Proteinuria is associated with quality of life and depression in adults with primary glomerulopathy and preserved renal function. PLoS One. 2012;7(5):e37763. doi:10.1371/journal.pone.0037763 Carter SA et al. Identifying Outcomes Important to Patients with Glomerular Disease and Their Caregivers. Clin J Am Soc Nephrol. 2020;15(5):673-684. doi:10.2215/CJN.13101019 Kraus MA et al. Intensive Hemodialysis and Health-Related Quality of Life. Am J Kidney Dis. 2016;68(5S1):S33-S42. doi:10.1053/j.ajkd.2016.05.023 Mizerska-Wasiak M et al. 2020 Nov 24;17(1):84-91. doi:10.5114/aoms.2020.100367. Among dialysis patients, decreases in health related quality of life (HrQoL) are common: physical limitations, poor sleep, feelings of social isolation, and depression Higher proteinuria was associated with decreased physical well-being in adolescents Edema and kidney associated symptoms can impair physical and mental health Treatment related adverse effects of corticosteroids include weight gain, mood swings, and Cushingoid appearance are associated with a poor quality of life
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4 Hit Hypothesis Lai KN et al. IgA nephropathy. Nat Rev Dis Primers. 2016;2:16001. Published 2016 Feb 11. doi:10.1038/nrdp.2016.1 Rajasekaran A et al. IgA Nephropathy: An Interesting Autoimmune Kidney Disease. Am J Med Sci. 2021;361(2):176-194. doi:10.1016/j.amjms.2020.10.003 1. Increased circulating levels of Galactose deficient-IgA1 • Genetic predisposition • Epigenetics • Enzymatic variants • Mis-trafficking of B cells from mucosal to systemic sites 2. Production of Anti-IgA1 antibodies (IgA or IgG) • Genetic predisposition, HLA haplotype • Germline mutations • Molecular mimicry • Viral infection • Streptococcal antigens 3a. Immune complexes form in the circulation 3b. Immune complexes form 4. Immune complexes in the mesangium cause local immune activation & injury • Complement activation • Cytokine/chemokine release • Monocyte recruitment • Matrix production • Mesangial proliferation • Glomerular sclerosis • Interstitial fibrosis
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Secondary IgA Nephropathy Saha MK et al. Secondary IgA nephropathy. Kidney Int. 2018;94(4):674-681. doi:10.1016/j.kint.2018.02.030. Rajasekaran A et al. IgA Nephropathy: An Interesting Autoimmune Kidney Disease. Am J Med Sci. 2021;361(2):176-194. doi:10.1016/j.amjms.2020.10.003 Image Credit: Created with BioRender.com
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Diagnosis & Prognosis of IgAN Clinical Presentation KDIGO Diagnosis KDIGO Prognosis Initial Assessment Scoring Tools: MEST-C score, International IgAN Prediction Tool
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Clinical Presentation Common clinical presentation Hematuria Proteinuria Hypertension In 30-40% of patients, the disease is asymptomatic and is suspected after urine testing identifies proteinuria or microscopic hematuria Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. doi:10.1016/j.kint.2021.05.021 Lai KN et al. IgA nephropathy. Nat Rev Dis Primers. 2016;2:16001. Published 2016 Feb 11. doi:10.1038/nrdp.2016.1 Image Credit: Created with BioRender.com
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Diagnosis IgAN is characterized by a single histopathological feature: IgA deposits in the kidney Diagnosis occurs through kidney biopsy, with immunofluorescence for IgA deposits in the mesangium Some histopathological features (mesangial proliferation, endocapillary proliferation, segmental scarring, and tubular atrophy) have been used to predict long-term outcomes of the disease No validated biomarker available for diagnosis Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. doi:10.1016/j.kint.2021.05.021 Lai KN et al. IgA nephropathy. Nat Rev Dis Primers. 2016;2:16001. Published 2016 Feb 11. doi:10.1038/nrdp.2016.1 Penfold RS et al. Primary IgA nephropathy: current challenges and future prospects. Int J Nephrol Renovasc Dis. 2018;11:137-148. Published 2018 Apr 12. doi:10.2147/IJNRD.S129227
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Prognostic Markers Associated with Worse Outcomes Lai KN et al. IgA nephropathy. Nat Rev Dis Primers. 2016;2:16001. Published 2016 Feb 11. doi:10.1038/nrdp.2016.1
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The “MEST-C” Score Working Group of the International IgA Nephropathy Network and the Renal Pathology Society et al. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int. 2009;76(5):534-545. doi:10.1038/ki.2009.243 Oxford Classification of IgA nephropathy 2016: Update from the IgA nephropathy classification working group
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International IgAN Prediction Tool Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. doi:10.1016/j.kint.2021.05.021 Incorporates the MEST-C histologic scores and clinical features observed at the time of kidney biopsy (i.e., estimated GFR, blood pressure, proteinuria, age) KDIGO guidelines recommend not using the tool to decide the treatment but only to assist in discussions with patients regarding outcome Image Credit: https://qxmd.com/calculate/calculator_499/international-igan-prediction-tool-at-biopsy-adults. Accessed May 2022.
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Proteinuria in IgAN Severity as a negative prognostic factor for IgAN Proteinuria reduction as a treatment goal Proteinuria reduction as a meaningful secondary endpoint for improved renal outcomes Proteinuria reduction and ESRD progression
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Proteinuria as a Prognostic Factor Hypertension and proteinuria represent risk factors for the progression of IgAN (as well as all chronic kidney diseases) Kidney survival after 10 years was significantly improved in patients with proteinuria of 0.5 g/day to 1 g/day compared to patients with proteinuria >1 g/day Consistent evidence has linked sustained proteinuria in IgAN with adverse clinical outcomes including poorer kidney outcomes in proteinuria, typically > 1 g/d Cardiovascular events occur more often in patients with proteinuria Conversely, longer duration of proteinuria remission has been associated with lower risk of disease progression Thompson A et al. Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy. Clin J Am Soc Nephrol. 2019;14(3):469-481. doi:10.2215/CJN.08600718 Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. doi:10.1016/j.kint.2021.05.021 Cravedi P, Remuzzi G. Pathophysiology of proteinuria and its value as an outcome measure in chronic kidney disease. Br J Clin Pharmacol. 2013;76(4):516-523. doi:10.1111/bcp.12104. Canney M, et al. Quantifying Duration of Proteinuria Remission and Association with Clinical Outcome in IgA Nephropathy. J Am Soc Nephrol. 2021;32(2):436-447. doi:10.1681/ASN.2020030349
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Proteinuria and ERSD Progression Renal injury & reduced nephron mass Increased glomerular capillary pressure Podocyte dysfunction and loss Increased glomerular permeability to macromolecules Increased filtration of plasma proteins Excessive tubular re-absorption Release of vasoactive and inflammatory cytokines Tubular cell apoptosis, monocyte infiltration Thompson A et al. Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy. Clin J Am Soc Nephrol. 2019;14(3):469-481. doi:10.2215/CJN.08600718 Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. doi:10.1016/j.kint.2021.05.021 Cravedi P, Remuzzi G. Pathophysiology of proteinuria and its value as an outcome measure in chronic kidney disease. Br J Clin Pharmacol. 2013;76(4):516-523. doi:10.1111/bcp.12104
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Proteinuria reduction as a treatment goal U.S. Food and Drug Administration. Fda.gov. Updated March 31, 2021. Accessed May 18, 2021. https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure Canney M et al. J Am Soc Nephrol. 2021;32(2):436-447. doi:10.1681/ASN.2020030349 Webb, MJ. Healio.com. Updated January 05, 2021. Accessed May 18, 2021. https://www.healio.com/news/nephrology/20210105/length-of-proteinuria-remission-helps-predict-eskd-progression-in-iga-nephropathy The National Kidney Foundation, the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) organized a scientific workshop in 2018 FDA has supported that proteinuria (defined by urinary protein/creatinine ratio) could be a surrogate endpoint in patients with primary glomerular disease early change in albuminuria and GFR slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression
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IgAN Treatment Strategies KDIGO Recommendations Unmet Needs in Clinical Management Novel Approaches
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KDIGO Treatment Algorithm Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. doi:10.1016/j.kint.2021.05.021 Optimized Supportive Care Blood pressure management (SBP < 120 mmHg) Maximally tolerated dose of ACE Inhibitor or ARB First-line for blood pressure management Given to all patients with proteinuria > 0.5g/day regardless of hypertension diagnosis Lifestyle modifications Reduce cardiovascular risk factors If patients remain high-risk for progression, a six-month glucocorticoid trial should be considered A significant proportion of patients remain high risk following this algorithm Clinical trial enrollment
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Gaps in other management strategies Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. doi:10.1016/j.kint.2021.05.021 KDIGO recommends against the use of: Antiplatelet agents Anticoagulants Azathioprine Cyclophosphamide Calcineurin inhibitors Rituximab Fish oil Mycophenolate mofetil* Hydroxychloroquine* *not recommended in non-Chinese patients
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Unmet needs Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. doi:10.1016/j.kint.2021.05.021
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Complement Activation Inhibitors Iptacopan IONIC-FB-LRx APL-2 OMS721 Cemdisiran Ravulizumab B-cell Activation Inhibitors Atacicept Telitacicept BION-1301 Reduce Gd-IgA1 production localized Budesonide Endothelin Receptor Antagonists Sparsentan (Endothelin A, AngII) Atrasentan (Endothelin A) Novel Targets Lai KN et al. IgA nephropathy. Nat Rev Dis Primers. 2016;2:16001. Published 2016 Feb 11. doi:10.1038/nrdp.2016.1 Rajasekaran A et al. IgA Nephropathy: An Interesting Autoimmune Kidney Disease. Am J Med Sci. 2021;361(2):176-194. doi:10.1016/j.amjms.2020.10.003 Prevent Gd-IgA1 production
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Emerging Therapies: Efficacy and Safety Data from Phase 3 Trials
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Targeted-release formulation-budesonidefor the treatment of lgA nephropathy in patients at risk ofprogressing to ESKD: The NeflgArd Phase 3 trial results 1. Barratt et al. POS-830 NEFECON FOR THE TREATMENT OF IgA NEPHROPATHY IN PATIENTS AT RISK OF PROGRESSING TO END-STAGE RENAL DISEASE: THE NEFIGARD PHASE 3 TRIAL RESULTS. Kidney International Reports. 2021; 6(4): 361. https://doi.org/10.1016/j.ekir.2021.03.868.
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NEFIGARD Study: Outcomes 1. Barratt et al. POS-830 NEFECON FOR THE TREATMENT OF IgA NEPHROPATHY IN PATIENTS AT RISK OF PROGRESSING TO END-STAGE RENAL DISEASE: THE NEFIGARD PHASE 3 TRIAL RESULTS. Kidney International Reports. 2021; 6(4): 361. https://doi.org/10.1016/j.ekir.2021.03.868.
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Sparsentan Rajasekaran A et al. IgA Nephropathy: An Interesting Autoimmune Kidney Disease. Am J Med Sci. 2021;361(2):176-194. doi:10.1016/j.amjms.2020.10.003 Am J Physiol Regul Integr Comp Physiol . 2016 May 15;310(10):R877-84.
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PROTECT Study Design Clinicaltrials.gov. A Study of the Effect and Safety of Sparsentan in the Treatment of Patients With IgA Nephropathy (PROTECT). Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT03762850.
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Atrasentan Clinicaltrials.gov. Atrasentan in Patients With IgA Nephropathy (ALIGN). Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT04573478. Clinicaltrials.gov. Atrasentan in Patients With Proteinuric Glomerular Diseases (AFFINITY). Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT04573920
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ALIGN study (NCT04573478) Clinicaltrials.gov. Atrasentan in Patients With IgA Nephropathy (ALIGN). Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT04573478.
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AFFINITY study (NCT04573920) Clinicaltrials.gov. Atrasentan in Patients With Proteinuric Glomerular Diseases (AFFINITY). Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT04573920
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Iptacopan Clinicaltrials.gov. Study of Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients (APPLAUSE-IgAN). Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT04578834 https://www.novartis.com/sites/novartis_com/files/2021_iptacopan-lnp023-update-presentation.pdf
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APPLAUSE-IgAN (NCT04578834) Clinicaltrials.gov. Study of Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients (APPLAUSE-IgAN). Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT04578834
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Narsolimab - OMS721 1. Clinicaltrials.gov. Study of the Safety and Efficacy of OMS721 in Patients With Immunoglobulin A (IgA) Nephropathy. Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT03608033
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ARTEMIS – IGAN (NCT03608033) 1. Clinicaltrials.gov. Study of the Safety and Efficacy of OMS721 in Patients With Immunoglobulin A (IgA) Nephropathy. Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT03608033
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Other Emerging Therapies Rajasekaran A et al. IgA Nephropathy: An Interesting Autoimmune Kidney Disease. Am J Med Sci. 2021;361(2):176-194. doi:10.1016/j.amjms.2020.10.003 Clinicaltrials.gov. Study of Ravulizumab in Proliferative Lupus Nephritis (LN) or Immunoglobulin A Nephropathy (IgAN). Accessed 5/11/22. https://clinicaltrials.gov/ct2/show/NCT04564339. Clinicaltrials.gov. A Study of RC18 Administered Subcutaneously to Subjects With IgA(Immunoglobulin A) Nephropathy. Accessed 5/11/22. https://clinicaltrials.gov/ct2/show/NCT04291781. Clinicaltrials.gov. Safety and Tolerability of BION-1301 in Healthy Volunteers and Adults With IgA Nephropathy (IgAN). Accessed 5/11/22. https://clinicaltrials.gov/ct2/show/NCT03945318.
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Case Presentation
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Case Presentation: History 54-year-old woman referred for elevated creatinine History: 20 year history of microhematuria and episodes of gross hematuria every 2-3 years Developed hypertension 6 years earlier Developed anemia 2 years earlier Negative urology evaluation Referred to nephrology when serum creatinine reached 1.6 mg/dl Meds: amlodipine/olmesartan, clonidine, furosemide 20 mg BID, erythropoetin Exam: BP 190/90 mmHg, BMI ~35 kg/m2, 2-3+ pedal edema
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Case Presentation: Laboratory Serum Creatinine 1.9 mg/dl Urine protein 6.9 g/24hrs Urinalysis 3+ protein, 3+ heme, “RBCs but no casts” Negative/normal: ANA, complement C3/C4, ANCA, anti-GBM, cryoglobulin, HBsAg, bone marrow biopsy Renal sonogram: normal
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Case Presentation: Renal Biopsy IgA 1. Diffuse mesangial and focal segmental endocapillary and extracapillary proliferative and sclerosing glomerulonephritis, consistent with IgA nephropathy 2. Tubular atrophy, interstitial and inflammation, patchy (30%). Arterio- and arteriolosclerosis, mild. (M1, E1, S0, T1, C1).
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How would you manage this patient? Clinical Presentation Serum Creatinine 1.9 mg/dl Urine protein 6.9 g/24hrs (M1, E1, S0, T1, C1). Treatment Strategies Conservative management? Oral corticosteroids Targeted enteric corticosteroid? Mycophenolic acid analogs with corticosteroids? Cyclophosphamide? Clinical trial?
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Case Presentation: follow-up Prednisone 60mg daily with 6-month taper Clinical Presentation Serum Creatinine 1.9 mg/dl Urine protein 6.9 g/24hrs (M1, E1, S0, T1, C1).
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Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial 1, Lv J, Wong MG, Hladunewich MA, et al. Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2022;327(19):1888–1898. doi:10.1001/jama.2022.5368
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Conclusion
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Conclusion IgAN is the most common form of nephropathy and is associated with a high degree of morbidity and mortality Currently approved treatment options are largely limited to supportive care and risk factor reduction Emerging therapies that specifically target IgAN pathophysiology in Phase II and III are ongoing