IgA Nephropathy (N02.B)

Causes

The etiology of IgA nephropathy is multifactorial and involves a complex interaction between genetic susceptibility, dysregulated mucosal immunity, and abnormal immunoglobulin production. The disease is driven by increased production of galactose-deficient IgA1 molecules, primarily originating from mucosal immune tissues of the respiratory and gastrointestinal tracts. These structurally abnormal IgA1 molecules are recognized as antigenic, leading to formation of autoantibodies and circulating immune complexes that subsequently deposit within the renal mesangium. Genetic factors affecting immune regulation, complement activation, and glycosylation pathways contribute to disease susceptibility, while environmental triggers such as respiratory infections, gastrointestinal inflammation, and alterations in the gut microbiome may provoke immune activation and disease flares. The strong association between episodes of hematuria and mucosal infections highlights the central role of abnormal mucosal immune signaling in the development of the disease. Over time, persistent immune complex deposition and inflammatory activation promote progressive glomerular injury and renal dysfunction.

Pathophysiology

The pathophysiology of IgA nephropathy centers on abnormal mucosal immune regulation and the formation of pathogenic IgA-containing immune complexes that deposit within the renal glomeruli. The disease is driven by overproduction of galactose-deficient IgA1 (Gd-IgA1), an abnormally glycosylated form of immunoglobulin A that is recognized as antigenic by the immune system. Autoantibodies directed against these altered IgA1 molecules form circulating immune complexes that accumulate within the mesangium of the glomeruli. Mesangial deposition activates inflammatory pathways, including complement activation—particularly the alternative and lectin pathways—leading to mesangial cell proliferation, cytokine release, oxidative stress, and extracellular matrix expansion. These inflammatory processes progressively damage the glomerular filtration barrier, resulting in hematuria, proteinuria, and declining renal function. Over time, chronic immune-mediated injury promotes glomerulosclerosis, tubulointerstitial fibrosis, and irreversible nephron loss, which may ultimately progress to chronic kidney disease or end-stage renal failure.

Clinical features

The clinical features of IgA nephropathy are highly variable and may range from asymptomatic microscopic hematuria to progressive chronic kidney disease. The classic presentation is recurrent episodes of gross hematuria that occur shortly after upper respiratory or gastrointestinal infections, reflecting abnormal mucosal immune activation. Many patients also develop persistent microscopic hematuria and varying degrees of proteinuria, which may be detected incidentally on routine urinalysis. Hypertension, edema, and declining renal function can emerge as the disease progresses. In more severe cases, nephrotic-range proteinuria or rapidly progressive glomerulonephritis with acute kidney injury may occur. Some patients remain clinically stable for decades, while others gradually develop glomerulosclerosis, chronic kidney disease, and eventual end-stage renal failure. Because symptoms may initially be subtle or intermittent, diagnosis is often delayed until renal abnormalities become more apparent through laboratory evaluation.

Diagnosis

The diagnosis of IgA nephropathy is established through a combination of clinical evaluation, laboratory findings, and definitive renal biopsy. Patients commonly present with recurrent hematuria, proteinuria, hypertension, or declining renal function, often following upper respiratory or gastrointestinal infections. Urinalysis typically demonstrates microscopic or gross hematuria with variable proteinuria, while blood testing may reveal impaired kidney function depending on disease severity. Although elevated serum IgA levels may be present in some patients, they are neither sensitive nor specific for diagnosis. The gold standard for diagnosis is kidney biopsy, which demonstrates dominant or codominant mesangial deposition of IgA on immunofluorescence microscopy, often accompanied by mesangial proliferation and varying degrees of glomerular scarring. Additional histopathologic assessment using the Oxford Classification helps characterize disease severity and predict prognosis by evaluating mesangial hypercellularity, endocapillary proliferation, segmental sclerosis, tubular atrophy, and interstitial fibrosis.

Mechanism of action videos

• Atacicept FDA-approved July 7, 2026 for IgA Nephropathy
• IgA Nephropathy- An Overview of the Therapeutic Market
• Sparsentan- Non-Immunosuppressive Treatment for Focal Segmental Glomerulosclerosis

Biological pathways

• VEGF binds to VEGFR leading to receptor dimerization
• SUMOylation of intracellular receptors
• CDC42 GTPase cycle
• Nuclear Receptor transcription pathway
• TNFs bind their physiological receptors
• TNFR2 non-canonical NF-kB pathway
• Generic Transcription Pathway
• Interleukin-4 and Interleukin-13 signaling
• RNA Polymerase II Transcription
• Activation of C3 and C5
• VEGF ligand-receptor interactions
• Complement cascade
• GPVI-mediated activation cascade

Clinical trials

• A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Sefaxersen, an Antisense Inhibitor of Complement Factor B, in Patients With Primary IgA Nephropathy at High Risk of Progression
• A Multicenter Rollover Extension Program (REP) to Evaluate the Long-term Safety and Tolerability of Open Label Iptacopan in Adult Participants With Primary IgA Nephropathy Who Have Completed Study CLNP023X2203 or CLNP023A2301
• An Exploratory Clinical Study Evaluate the Safety and Efficacy of Universal Universal Allogeneic CAR-T Cells Targeting CD19 and BCMA in the Treatment of B Cell-Related Autoimmune Disease
• A Phase 3 Multicenter, Randomized, Double-Blind, Placebo Controlled Trial to Evaluate Efficacy and Safety of Mezagitamab (TAK-079) in Study Participants With Primary IgA Nephropathy in Combination With Stable Background Therapy
• A Randomized, Double-Blind, Placebo-Controlled Phase II Clinical Study to Evaluate the Efficacy and Safety of SHR-2173 Injection in Patients With Primary IgA Nephropathy
• A Multicenter, Open-label Trial to Evaluate the Long-term Safety and Tolerability of HRS-5965 Capsules in Patients With Primary IgA Nephropathy
• A Phase 2, Open-Label, Single-Arm, Cohort Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Sparsentan Treatment in Pediatric Subjects With Selected Proteinuric Glomerular Diseases
• A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of YKST02 in Participants With Primary IgA Nephropathy
• A Multicenter Open-label Extension Study to Evaluate the Long-term Safety and Tolerability of Zigakibart in Adults With Primary IgA Nephropathy.
• A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Felzartamab in Adults With IgA Nephropathy (PREVAIL)
• A Phase 2/3, Multicenter, Open-label Trial to Evaluate the Long-term Safety, Tolerability, and Efficacy of Sibeprenlimab Administered Subcutaneously in Subjects With Immunoglobulin A Nephropathy.
• A Phase 2 Study to Assess ADX-038 in Chinese Adults With Complement-Mediated Kidney Disease
• A Phase 1, Randomized, Placebo-Controlled, Single Ascending Dose First-in-Human Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of VIS649 Administered Intravenously in Healthy Subjects
• A Phase 1/2a Dose-Escalating Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and/or Pharmacodynamics of ARO-C3 in Adult Healthy Volunteers and in Adult Patients With Complement-Mediated Renal Disease
• A Double Blind, Randomized, Placebo-Controlled, Multicenter Phase IIa, Clinical Trial to Assess Efficacy and Safety of the Human Anti-CD38 Antibody Felzartamab in IgA Nephropathy
• A Randomized, Double-blind, Placebo-controlled Phase II Clinical Study to Evaluate the Efficacy and Safety of SLN12140 in Adult Patients With Primary IgA Nephropathy
• A Multicenter, Single Arm, Open Label Biopsy Study to Evaluate Structural and Functional Changes in Kidneys of Adult Patients With IgA Nephropathy Receiving Iptacopan on Top of Supportive Care
• A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study to Evaluate the Efficacy and Safety of VIS649 in Participants With Immunoglobulin A (IgA) Nephropathy
• A Clinical Study Evaluating the Safety and Efficacy of GT719 Universal Cell Injection in the Treatment of Immune-mediated Kidney Diseases
• A Phase 2 Study to Assess ADX-038 in Participants With Complement-Mediated Kidney Disease
• A Phase 2, Multicenter, Open-label Study to Evaluate the Safety and Efficacy of JADE101 in Participants With Immunoglobulin A Nephropathy (JUNIPER)
• A Randomized, Multicenter, Double-blind, Parallel-group, Active-control Study of the Efficacy and Safety of Sparsentan for the Treatment of Immunoglobulin A Nephropathy
• A Phase 1/2, Multicenter Trial to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BION-1301 in Healthy Volunteers and Adults With IgA Nephropathy
• A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Ravulizumab in Adult Participants With Immunoglobulin A Nephropathy (IgAN)
• A Single-arm, Multicenter, Phase III Study to Assess Efficacy, Pharmacokinetics, Safety and Tolerability of Iptacopan in Pediatric Patients of 2 to <18 Years of Age With Primary Immunoglobulin A Nephropathy (IgAN)
• A Clinical Study on the Safety and Efficacy of CD19-Targeted Universal CAR-γδ T Cells in Relapsed/Refractory Autoimmune Nephropathy
• A Phase II, Open-Label Study of NM8074 in Patients With Immunoglobulin A Nephropathy (IgAN)
• A Phase I/II, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of MIL116 in Healthy Participants and Patients With IgA Nephropathy
• A Study Evaluating Monthly (Every 4 Weeks) Dosing of Atacicept in Patients With IgAN
• Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of WAL0921 in Patients With Glomerular Kidney Diseases and Proteinuria
• An Exploratory Clinical Study Evaluate the Safety and Efficacy of Universal Universal Allogeneic CAR-T Cells Targeting CD19 and BCMA in the Treatment of B Cell-Related Autoimmune Disease
• An Open-label, Multicenter Study to Assess the Effect of Zigakibart Treatment on Histologic, Circulating, and Excreted Markers of Kidney Disease and Dysfunction in Adult Patients With IgA Nephropathy.
• A Phase 3, Randomized, Double-blind, Placebo-controlled Study of BION-1301 in Adults With IgA Nephropathy (The BEYOND Study)
• A Single-arm, Multicenter, Phase III Study to Assess Efficacy, Pharmacokinetics, Safety and Tolerability of Atrasentan in Pediatric Patients of 2 to <18 Years of Age With Primary Immunoglobulin A Nephropathy (IgAN)
• A Phase 1/2a Dose-Escalating Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of ARO-CFB in Adult Healthy Volunteers and Adult Patients With Complement-Mediated Kidney Disease
• A Phase 3, Open-Label, Multicenter Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of Ravulizumab in Pediatric Participants (2 to < 18 Years of Age) With Primary Immunoglobulin A Nephropathy (IgAN)
• A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose-Ranging Study to Evaluate the Efficacy and Safety of HS-10542 Capsules in Primary Immunoglobulin A (IgA) Nephropathy
• A Randomized, Double-blind, Multicenter, Placebo-controlled, Parallel Groups, Phase II Clinical Trial to Evaluate the Efficacy and Safety of HR19042 Capsules in the Treatment of Primary IgA Nephropathy.
• An Open-Label Biomarker Study of BHV-1400 in IgA Nephropathy
• A Phase I Clinical Study to Evaluate the Safety, Tolerability, PK and PD of RG002C0106 Injection in Adult Participants With Normal Renal Function and Mild-to-Moderate Renal Impairment