17:I[462708,["/_next/static/chunks/3yo3kiro3bmlp.js","/_next/static/chunks/3vr2wvd8f2efb.js","/_next/static/chunks/2vtmb68_vu-9t.js","/_next/static/chunks/2s8mt6_8wrpfo.js","/_next/static/chunks/3vkulz2i3l61y.js","/_next/static/chunks/1cqw2i1silz0i.js","/_next/static/chunks/14dbm3lm_t629.js","/_next/static/chunks/335_v2mb569ld.js","/_next/static/chunks/3ykn5ops9bft5.js","/_next/static/chunks/3cmavum774kjt.js","/_next/static/chunks/3th-0-a2xf9qs.js","/_next/static/chunks/0p0xpwde6kzmv.js","/_next/static/chunks/401-sxxnzbtf_.js","/_next/static/chunks/0wywtv698a1v0.js","/_next/static/chunks/2botzqwpnrzyj.js"],"ArticleReader"] 18:T5858,## Summary IgA nephropathy (IgAN) is an immune-complex glomerular disease defined by dominant or codominant IgA deposition in the glomerular mesangium on kidney biopsy. Presentation ranges from episodic visible hematuria during mucosal infection to persistent microscopic hematuria, proteinuria, hypertension, chronic kidney disease (CKD), nephrotic syndrome, acute kidney injury, or rapidly progressive glomerulonephritis. Clinical features can suggest IgAN, but **kidney biopsy establishes the diagnosis** and should also assess chronicity and the Oxford MEST-C lesions.[1] KDIGO 2025 recommends considering biopsy when IgAN is plausible and proteinuria is **≥0.5 g/day or equivalent**, unless biopsy risk outweighs benefit. Long-term risk is driven most consistently by eGFR and persistent proteinuria. Proteinuria **≥0.5 g/day is clinically important**; the treatment goal is **<0.5 g/day, ideally <0.3 g/day**, while preserving eGFR and controlling blood pressure.[1] Supportive kidney protection is the foundation of treatment: sodium restriction, smoking cessation, individualized blood-pressure control, maximally tolerated renin-angiotensin system (RAS) blockade when appropriate, and an SGLT2 inhibitor for many adults at meaningful risk of progression.[1,2] Disease-specific therapy is added according to lifetime kidney risk, residual proteinuria, eGFR, comorbidity, toxicity, reproductive considerations, and local regulatory access. Options include targeted-release budesonide, sparsentan, and selected systemic glucocorticoid regimens; U.S. practice now also includes recently approved endothelin-, complement-, APRIL-, and BAFF/APRIL-directed therapies for defined high-risk populations.[1,3-9] Rapidly progressive IgAN is uncommon. KDIGO defines it as a **≥50% decline in eGFR over ≤3 months** after excluding alternative causes. Crescents on biopsy alone do not define rapidly progressive disease. Active necrotizing/crescentic IgAN causing rapid loss of kidney function requires urgent nephrology care and may be treated with glucocorticoids plus cyclophosphamide using principles applied to rapidly progressive immune glomerulonephritis.[1] > **Clinical pearl:** Treatment intensity should follow the patient’s kidney-risk trajectory—especially eGFR slope and persistent proteinuria—not the MEST-C score or one urine result in isolation. ## Disease spectrum IgAN is characterized by mesangial deposition of IgA-containing immune complexes, usually involving galactose-deficient IgA1. Clinical phenotypes include: - recurrent visible hematuria, often concurrent with an upper-respiratory or gastrointestinal infection; - persistent microscopic hematuria with proteinuria; - proteinuric CKD with hypertension; - nephrotic-range proteinuria, with or without true nephrotic syndrome; - acute kidney injury associated with heavy visible hematuria; - rapidly progressive glomerulonephritis; - secondary IgA-dominant disease associated with liver disease, infection, inflammatory bowel disease, autoimmune disease, or other systemic conditions. IgA vasculitis shares related biology but has systemic small-vessel involvement and requires a distinct clinical assessment. ## Pathophysiology A widely accepted model links several processes:[1] 1. increased production of galactose-deficient IgA1; 2. autoantibodies directed against altered IgA1 hinge-region glycans; 3. formation of circulating immune complexes; 4. mesangial trapping and activation; 5. complement and inflammatory signaling, particularly alternative and lectin pathway activity; 6. glomerular injury, proteinuria, fibrosis, and progressive nephron loss. Immune activity and irreversible scarring coexist to varying degrees. In later disease, fibrosis and nephron loss may dominate even when active inflammation is limited, which is why indiscriminate immunosuppression can add toxicity without meaningful kidney benefit. ## Clinical presentation | Presentation | Main implication | Immediate priorities | |---|---|---| | Visible hematuria during/soon after mucosal infection | Classic mucosal-triggered phenotype | Confirm glomerular source; quantify protein; check creatinine/eGFR and blood pressure | | Persistent microscopic hematuria + proteinuria | Common chronic phenotype | Quantify UACR/UPCR; establish eGFR trajectory; consider biopsy at the guideline threshold | | Hypertension + declining eGFR | Higher-risk progressive disease or another kidney process | Review trajectory, drugs, volume status, obstruction, secondary disease; nephrology review | | Nephrotic syndrome | Possible IgAN with podocytopathy/minimal-change pattern or severe glomerular injury | Urgent biopsy/pathology review; assess edema, albumin, thrombosis risk | | AKI with gross hematuria | Tubular obstruction/injury from glomerular bleeding may occur | Supportive care; exclude obstruction, infection, nephrotoxins; follow recovery | | Rapid eGFR decline | Crescentic/necrotizing IgAN or unrelated AKI | Urgent nephrology care and biopsy-based classification | Many patients are asymptomatic apart from abnormal urinalysis. Others report cola-colored urine, edema, headache related to hypertension, or symptoms of advanced CKD. ## Diagnostic approach ### Initial testing Obtain: - serum creatinine and eGFR; - urinalysis with microscopy; - urine albumin-to-creatinine ratio (UACR) and/or protein-to-creatinine ratio (UPCR); - blood pressure; - serum albumin when proteinuria is substantial; - CBC and metabolic profile when systemic illness or advanced CKD is plausible. Confirm persistent proteinuria with repeat quantitative testing when clinically stable. Fever, strenuous exercise, urinary infection, and acute illness can transiently increase protein excretion. ### When to perform kidney biopsy KDIGO 2025 advises considering biopsy in adults with suspected IgAN and **proteinuria ≥0.5 g/day or equivalent** when biopsy is not contraindicated.[1] Biopsy should also be strongly considered when there is: - unexplained reduction in eGFR; - rapidly progressive kidney dysfunction; - nephrotic syndrome; - substantial proteinuria with atypical features; - concern for another glomerular disease; - systemic findings suggesting a secondary process. The biopsy should confirm IgA-dominant or codominant mesangial deposits, define active lesions, and quantify chronic damage. ### Oxford MEST-C score | Component | Lesion | |---|---| | M | Mesangial hypercellularity | | E | Endocapillary hypercellularity | | S | Segmental glomerulosclerosis/adhesion | | T | Tubular atrophy/interstitial fibrosis | | C | Cellular/fibrocellular crescents | MEST-C adds prognostic information but **does not independently dictate immunosuppressive treatment**.[1] Persistent proteinuria, eGFR trajectory, age, blood pressure, treatment toxicity, and overall lifetime risk remain central. ### International IgAN Prediction Tool The International IgAN Prediction Tool uses clinical and biopsy variables to estimate kidney-risk trajectories after biopsy. It is useful for prognosis and shared decision-making but should not be used as a stand-alone trigger for one specific drug.[1] ## Secondary causes and mimics Use targeted assessment for: - chronic liver disease or portal hypertension; - chronic infection; - inflammatory bowel disease; - celiac disease; - autoimmune disease; - monoclonal gammopathy; - infection-related IgA-dominant glomerulonephritis; - hereditary basement-membrane disorders when hematuria is familial or hearing/ocular findings coexist. Broad serologic panels without clinical direction have low yield. ## Treatment goals Management has two parallel aims: 1. reduce nonspecific nephron stress and cardiovascular risk; 2. reduce IgAN-specific immune or vasoactive injury in patients whose expected benefit justifies added risk. Practical goals are: - stable or slowly declining eGFR; - proteinuria **<0.5 g/day, ideally <0.3 g/day**; - individualized blood-pressure control; - prevention of avoidable AKI and treatment toxicity.[1] ## Supportive kidney-protective care ### Lifestyle and cardiovascular risk Address: - dietary sodium intake, generally aiming for <2 g sodium/day when feasible; - regular physical activity; - healthy body weight; - smoking cessation; - moderation of alcohol; - avoidance of unnecessary nephrotoxins; - vaccination appropriate to CKD and planned immunomodulatory therapy. ### RAS blockade Use an **ACE inhibitor or ARB at the maximally tolerated dose** for adults with clinically important proteinuria when not contraindicated.[1] Monitor: - blood pressure; - creatinine/eGFR after initiation and titration; - potassium; - orthostatic symptoms. Do not combine an ACE inhibitor with an ARB. A larger-than-expected creatinine rise should prompt review for volume depletion, NSAID exposure, renovascular disease, severe hypotension, or another acute process. ### SGLT2 inhibitors KDIGO 2025 suggests an SGLT2 inhibitor for adults with IgAN at risk of progressive kidney-function loss.[1] The prespecified IgAN subgroup of DAPA-CKD supported kidney benefit beyond diabetes.[2] Practical safety points: - expect a small early eGFR dip; - review volume status and diuretic dose; - counsel about genital mycotic infection; - withhold during prolonged fasting, major surgery, or severe acute illness when ketoacidosis risk rises; - follow current local labeling for eGFR thresholds and dosing. ## Disease-specific therapy ### Targeted-release budesonide KDIGO 2025 suggests a **9-month course** of targeted-release budesonide for appropriate patients with primary IgAN at risk of progression.[1] NefIgArd used **16 mg orally once daily for 9 months** and demonstrated proteinuria reduction with a favorable subsequent eGFR effect.[3] Monitor for: - glucocorticoid adverse effects despite targeted intestinal delivery; - blood pressure and glucose changes; - infection; - edema/weight change; - adrenal suppression; - hepatic disease and drug interactions. Availability and approved populations differ by jurisdiction. ### Sparsentan Sparsentan combines endothelin type-A and angiotensin II type-1 receptor antagonism. PROTECT used **400 mg orally once daily** and showed greater proteinuria reduction than irbesartan with a favorable chronic eGFR slope.[4] > **Caution:** **Do not combine sparsentan with an ACE inhibitor or ARB.** Sparsentan already provides angiotensin-receptor blockade. Monitor blood pressure, potassium, kidney function, edema/fluid retention, liver safety, and reproductive precautions according to current labeling.[1,4] ### Systemic glucocorticoids Systemic glucocorticoids can reduce kidney events in selected higher-risk patients but carry important infectious and metabolic toxicity. TESTING demonstrated kidney benefit with methylprednisolone but also serious adverse events, especially with the original higher-dose regimen.[5] A reduced-dose regimen described by KDIGO is: - methylprednisolone **0.4 mg/kg/day, maximum 32 mg/day, for 2 months**; - then reduce by **4 mg/day each month**; - total treatment duration **6–9 months**; - provide Pneumocystis prophylaxis during higher-risk systemic therapy when indicated.[1,5] Avoid or use extreme caution when toxicity risk is high, including: - eGFR <30 mL/min/1.73 m²; - diabetes or major prediabetes; - obesity; - active/latent infection without appropriate management; - peptic ulcer disease; - severe psychiatric disease; - osteoporosis; - cataract/glaucoma risk; - frailty or major infection susceptibility. ### U.S. therapies approved after the KDIGO evidence review The U.S. therapeutic landscape changed rapidly in 2025–2026. Several agents received FDA approval for reduction of proteinuria in adults with primary IgAN at risk of progression. Eligibility, concomitant therapy, dosing, safety requirements, and reimbursement differ, so current prescribing information and nephrology input are essential.[6-9] | Therapy / mechanism | Current U.S. role | Important clinical point | |---|---|---| | **Atrasentan**, endothelin-A antagonist | FDA accelerated approval in April 2025 for adults at risk of rapid progression, generally UPCR ≥1.5 g/g | Proteinuria-based approval; monitor fluid retention and other label-specific risks[6] | | **Iptacopan**, complement factor-B inhibitor | FDA accelerated approval to reduce proteinuria in adults at risk of rapid progression | Complement inhibition requires infection-prevention measures and current label review[7] | | **Sibeprenlimab-szsi**, APRIL blocker | FDA accelerated approval November 2025; **400 mg SC every 4 weeks** | Month-9 proteinuria reduction supported approval; infection and vaccine precautions apply[8] | | **Atacicept-vymj**, BAFF/APRIL pathway inhibitor | FDA accelerated approval in 2026; **150 mg SC weekly** | Proteinuria endpoint supported approval; infection and vaccine precautions apply[9] | For sibeprenlimab, FDA reported approximately **50% proteinuria reduction at month 9** versus a 2% increase with placebo in the approval population; for atacicept, FDA reported an average **46% reduction at month 9** in the interim efficacy cohort.[8,9] > **Evidence note:** These accelerated approvals rely on proteinuria as a surrogate endpoint. For the newer agents, definitive long-term preservation of kidney function had not yet been established at approval; confirmatory trials are required. Do not assume equivalence or superiority across agents from cross-trial proteinuria percentages.[6-9] The 2026 KDOQI U.S. commentary emphasizes earlier biopsy-based diagnosis, risk stratification, and integration of emerging disease-modifying therapies into individualized U.S. care.[10] ## Special clinical scenarios ### AKI with visible hematuria Heavy glomerular bleeding can cause tubular obstruction and tubular injury. Management is usually supportive: - correct volume depletion; - avoid nephrotoxins; - monitor creatinine and urine output; - investigate alternative acute causes. If kidney function fails to recover after hematuria settles, reassess promptly; repeat biopsy may be needed when the clinical course is not consistent with expected recovery.[1] ### Nephrotic syndrome True nephrotic syndrome is unusual in classic IgAN. Re-review pathology for minimal-change-pattern podocytopathy or another process. When biopsy supports IgAN with minimal-change disease, treatment generally follows minimal-change disease principles rather than escalating IgAN-specific therapy solely because proteinuria is heavy.[1] Nephrotic-range proteinuria without hypoalbuminemia/edema can instead reflect advanced glomerular scarring or secondary focal segmental glomerulosclerosis. ### Rapidly progressive IgAN Suspect rapidly progressive IgAN when eGFR falls by **≥50% within ≤3 months** after excluding reversible causes.[1] Urgent pathway: 1. verify the creatinine trajectory; 2. exclude volume depletion, obstruction, drug toxicity, infection, and thrombotic microangiopathy; 3. obtain urgent nephrology input; 4. obtain kidney biopsy or urgent pathology review; 5. if active crescentic/necrotizing IgAN is responsible, consider cyclophosphamide plus systemic glucocorticoids using rapidly progressive glomerulonephritis principles; 6. provide infection prophylaxis and toxicity monitoring appropriate to the regimen. Crescents in a patient with stable kidney function are **not** equivalent to rapidly progressive IgAN. ### Pregnancy Preconception planning is important. ACE inhibitors, ARBs, sparsentan, SGLT2 inhibitors, and several newer disease-specific drugs are not suitable during pregnancy or require strict reproductive precautions. Switch blood-pressure therapy to pregnancy-compatible agents and review every disease-modifying drug before conception. Patients with reduced eGFR, significant proteinuria, or hypertension need coordinated nephrology and maternal-fetal care because maternal and fetal risks rise with baseline kidney disease severity. ## Monitoring | Clinical state | Monitoring focus | |---|---| | Stable, low proteinuria, preserved eGFR | BP, creatinine/eGFR, quantitative protein every 3–6 months initially, then individualized | | Persistent proteinuria or active titration | BP, eGFR, potassium, proteinuria every 4–12 weeks until stable | | RAS blocker or SGLT2 inhibitor initiation | Early renal function/electrolyte assessment, volume review, then routine CKD follow-up | | Endothelin-pathway therapy | BP, edema/weight, kidney function, potassium, liver/reproductive monitoring as required by the specific label | | Immune-targeted biologic therapy | Infection screening/monitoring, immunization review, label-specific laboratory surveillance | | Systemic glucocorticoids | Infection, glucose, BP, weight, bone protection, psychiatric and ocular toxicity; prophylaxis as indicated | | Falling eGFR | Shorten interval; reassess adherence, volume status, secondary causes, and treatment strategy | Track **trends and slope**, not a single creatinine or UPCR value. ## Referral and escalation Urgent nephrology assessment is appropriate for: - rapidly rising creatinine or oliguria; - rapidly progressive eGFR loss; - nephrotic syndrome; - severe or resistant hypertension; - hyperkalemia limiting kidney-protective therapy; - suspected systemic vasculitis or infection-related glomerulonephritis; - pregnancy with significant kidney disease. Biopsy-proven IgAN warrants ongoing specialist follow-up because eligibility for disease-specific therapy and kidney-risk estimates can change over time. ## Complications and prognosis Potential complications include: - progressive CKD and kidney failure; - hypertension; - cardiovascular disease; - nephrotic complications in selected phenotypes; - treatment-related infection, metabolic toxicity, edema, liver injury, or reproductive risk depending on therapy. Long-term course is heterogeneous. Persistent proteinuria, lower eGFR, hypertension, and adverse chronic biopsy lesions increase lifetime risk. Modern treatment aims for sustained proteinuria reduction and preservation of eGFR over years to decades rather than temporary normalization of urinary findings. ## Practical decision pathway 1. Hematuria/proteinuria compatible with IgAN → quantify protein, establish eGFR trend, assess blood pressure. 2. Proteinuria ≥0.5 g/day equivalent or atypical/high-risk features → consider kidney biopsy. 3. Biopsy-proven IgAN → document MEST-C and calculate/consider validated risk prediction, but prioritize clinical trajectory. 4. Optimize sodium intake, BP, maximally tolerated RAS blockade, and SGLT2 therapy where appropriate. 5. Reassess proteinuria and eGFR trajectory after supportive optimization. 6. Persistent meaningful risk → choose disease-specific therapy according to eGFR, proteinuria, prior therapy, toxicity, pregnancy plans, regulatory indication, and access. 7. Rapid eGFR loss ≥50% within ≤3 months → urgent exclusion of reversible causes and biopsy-based rapidly progressive pathway. 8. Continue serial proteinuria and eGFR monitoring; escalate treatment based on residual risk and objective trajectory rather than fixed treatment calendars alone. ## Related library topics - [Chronic Kidney Disease](chronic-kidney-disease.md) - [Hyperkalemia](hyperkalemia.md) - [Nephrotic Syndrome in Adults](nephrotic-syndrome-in-adults.md) - [Minimal Change Disease in Adults](minimal-change-disease-in-adults.md) ## References 1. Kidney Disease: Improving Global Outcomes (KDIGO) IgA Nephropathy Guideline Work Group. KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy and Immunoglobulin A Vasculitis. *Kidney International*. 2025;108(4S):S1-S71. doi:10.1016/j.kint.2025.04.004. PMID:40975564. https://kdigo.org/guidelines/iga-nephropathy/ 2. Wheeler DC, Toto RD, Stefánsson BV, et al. A prespecified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. *Kidney International*. 2021;100(1):215-224. doi:10.1016/j.kint.2021.03.033. PMID:33878338. https://pubmed.ncbi.nlm.nih.gov/33878338/ 3. Lafayette R, Kristensen J, Stone A, et al. Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial. *Lancet*. 2023;402:859-870. doi:10.1016/S0140-6736(23)01554-4. https://doi.org/10.1016/S0140-6736(23)01554-4 4. Rovin BH, Barratt J, Heerspink HJL, et al. Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial. *Lancet*. 2023;402(10417):2077-2090. doi:10.1016/S0140-6736(23)02302-4. PMID:37931634. https://pubmed.ncbi.nlm.nih.gov/37931634/ 5. 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. PMID:35579642. https://pubmed.ncbi.nlm.nih.gov/35579642/ 6. U.S. Food and Drug Administration. Drug Trials Snapshot: Vanrafia (atrasentan). Original approval April 2, 2025. https://www.fda.gov/drugs/drug-trials-snapshots/drug-trials-snapshot-vanrafia 7. U.S. Food and Drug Administration. Fabhalta (iptacopan): approved indications include accelerated approval for reduction of proteinuria in adults with primary IgA nephropathy at risk of rapid progression. FDA. 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-adults-complement-3-glomerulopathy-rare-kidney-disease-reduce 8. U.S. Food and Drug Administration. FDA approves a new treatment for primary immunoglobulin A nephropathy: Voyxact (sibeprenlimab-szsi). November 25, 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-new-treatment-primary-immunoglobulin-nephropathy 9. U.S. Food and Drug Administration. FDA Approves New Treatment to Reduce Proteinuria in Adults with Primary Immunoglobulin A Nephropathy: Trutakna (atacicept-vymj). 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-new-treatment-reduce-proteinuria-adults-primary-immunoglobulin-nephropathy 10. Ayoub I, Coppock G, Wadhwani S, Yau T. KDOQI US Commentary on the 2025 KDIGO Clinical Practice Guideline for the Management of IgA Nephropathy and IgA Vasculitis. *American Journal of Kidney Diseases*. 2026;88(1):18-35. doi:10.1053/j.ajkd.2026.02.639. PMID:42095796. https://pubmed.ncbi.nlm.nih.gov/42095796/19:T5878,## Summary IgA nephropathy (IgAN) is an immune-complex glomerular disease defined by dominant or codominant IgA deposition in the glomerular mesangium on kidney biopsy. Presentation ranges from episodic visible hematuria during mucosal infection to persistent microscopic hematuria, proteinuria, hypertension, chronic kidney disease (CKD), nephrotic syndrome, [acute kidney injury](/library/acute-kidney-injury), or rapidly progressive glomerulonephritis. Clinical features can suggest IgAN, but **kidney biopsy establishes the diagnosis** and should also assess chronicity and the Oxford MEST-C lesions.[1] KDIGO 2025 recommends considering biopsy when IgAN is plausible and proteinuria is **≥0.5 g/day or equivalent**, unless biopsy risk outweighs benefit. Long-term risk is driven most consistently by eGFR and persistent proteinuria. Proteinuria **≥0.5 g/day is clinically important**; the treatment goal is **<0.5 g/day, ideally <0.3 g/day**, while preserving eGFR and controlling blood pressure.[1] Supportive kidney protection is the foundation of treatment: sodium restriction, smoking cessation, individualized blood-pressure control, maximally tolerated renin-angiotensin system (RAS) blockade when appropriate, and an SGLT2 inhibitor for many adults at meaningful risk of progression.[1,2] Disease-specific therapy is added according to lifetime kidney risk, residual proteinuria, eGFR, comorbidity, toxicity, reproductive considerations, and local regulatory access. Options include targeted-release budesonide, sparsentan, and selected systemic glucocorticoid regimens; U.S. practice now also includes recently approved endothelin-, complement-, APRIL-, and BAFF/APRIL-directed therapies for defined high-risk populations.[1,3-9] Rapidly progressive IgAN is uncommon. KDIGO defines it as a **≥50% decline in eGFR over ≤3 months** after excluding alternative causes. Crescents on biopsy alone do not define rapidly progressive disease. Active necrotizing/crescentic IgAN causing rapid loss of kidney function requires urgent nephrology care and may be treated with glucocorticoids plus cyclophosphamide using principles applied to rapidly progressive immune glomerulonephritis.[1] > **Clinical pearl:** Treatment intensity should follow the patient’s kidney-risk trajectory—especially eGFR slope and persistent proteinuria—not the MEST-C score or one urine result in isolation. ## Disease spectrum IgAN is characterized by mesangial deposition of IgA-containing immune complexes, usually involving galactose-deficient IgA1. Clinical phenotypes include: - recurrent visible hematuria, often concurrent with an upper-respiratory or gastrointestinal infection; - persistent microscopic hematuria with proteinuria; - proteinuric CKD with hypertension; - nephrotic-range proteinuria, with or without true nephrotic syndrome; - acute kidney injury associated with heavy visible hematuria; - rapidly progressive glomerulonephritis; - secondary IgA-dominant disease associated with liver disease, infection, inflammatory bowel disease, autoimmune disease, or other systemic conditions. IgA vasculitis shares related biology but has systemic small-vessel involvement and requires a distinct clinical assessment. ## Pathophysiology A widely accepted model links several processes:[1] 1. increased production of galactose-deficient IgA1; 2. autoantibodies directed against altered IgA1 hinge-region glycans; 3. formation of circulating immune complexes; 4. mesangial trapping and activation; 5. complement and inflammatory signaling, particularly alternative and lectin pathway activity; 6. glomerular injury, proteinuria, fibrosis, and progressive nephron loss. Immune activity and irreversible scarring coexist to varying degrees. In later disease, fibrosis and nephron loss may dominate even when active inflammation is limited, which is why indiscriminate immunosuppression can add toxicity without meaningful kidney benefit. ## Clinical presentation | Presentation | Main implication | Immediate priorities | |---|---|---| | Visible hematuria during/soon after mucosal infection | Classic mucosal-triggered phenotype | Confirm glomerular source; quantify protein; check creatinine/eGFR and blood pressure | | Persistent microscopic hematuria + proteinuria | Common chronic phenotype | Quantify UACR/UPCR; establish eGFR trajectory; consider biopsy at the guideline threshold | | Hypertension + declining eGFR | Higher-risk progressive disease or another kidney process | Review trajectory, drugs, volume status, obstruction, secondary disease; nephrology review | | Nephrotic syndrome | Possible IgAN with podocytopathy/minimal-change pattern or severe glomerular injury | Urgent biopsy/pathology review; assess edema, albumin, thrombosis risk | | AKI with gross hematuria | Tubular obstruction/injury from glomerular bleeding may occur | Supportive care; exclude obstruction, infection, nephrotoxins; follow recovery | | Rapid eGFR decline | Crescentic/necrotizing IgAN or unrelated AKI | Urgent nephrology care and biopsy-based classification | Many patients are asymptomatic apart from abnormal urinalysis. Others report cola-colored urine, edema, headache related to hypertension, or symptoms of advanced CKD. ## Diagnostic approach ### Initial testing Obtain: - serum creatinine and eGFR; - urinalysis with microscopy; - urine albumin-to-creatinine ratio (UACR) and/or protein-to-creatinine ratio (UPCR); - blood pressure; - serum albumin when proteinuria is substantial; - CBC and metabolic profile when systemic illness or advanced CKD is plausible. Confirm persistent proteinuria with repeat quantitative testing when clinically stable. Fever, strenuous exercise, urinary infection, and acute illness can transiently increase protein excretion. ### When to perform kidney biopsy KDIGO 2025 advises considering biopsy in adults with suspected IgAN and **proteinuria ≥0.5 g/day or equivalent** when biopsy is not contraindicated.[1] Biopsy should also be strongly considered when there is: - unexplained reduction in eGFR; - rapidly progressive kidney dysfunction; - nephrotic syndrome; - substantial proteinuria with atypical features; - concern for another glomerular disease; - systemic findings suggesting a secondary process. The biopsy should confirm IgA-dominant or codominant mesangial deposits, define active lesions, and quantify chronic damage. ### Oxford MEST-C score | Component | Lesion | |---|---| | M | Mesangial hypercellularity | | E | Endocapillary hypercellularity | | S | Segmental glomerulosclerosis/adhesion | | T | Tubular atrophy/interstitial fibrosis | | C | Cellular/fibrocellular crescents | MEST-C adds prognostic information but **does not independently dictate immunosuppressive treatment**.[1] Persistent proteinuria, eGFR trajectory, age, blood pressure, treatment toxicity, and overall lifetime risk remain central. ### International IgAN Prediction Tool The International IgAN Prediction Tool uses clinical and biopsy variables to estimate kidney-risk trajectories after biopsy. It is useful for prognosis and shared decision-making but should not be used as a stand-alone trigger for one specific drug.[1] ## Secondary causes and mimics Use targeted assessment for: - chronic liver disease or portal hypertension; - chronic infection; - inflammatory bowel disease; - celiac disease; - autoimmune disease; - monoclonal gammopathy; - infection-related IgA-dominant glomerulonephritis; - hereditary basement-membrane disorders when hematuria is familial or hearing/ocular findings coexist. Broad serologic panels without clinical direction have low yield. ## Treatment goals Management has two parallel aims: 1. reduce nonspecific nephron stress and cardiovascular risk; 2. reduce IgAN-specific immune or vasoactive injury in patients whose expected benefit justifies added risk. Practical goals are: - stable or slowly declining eGFR; - proteinuria **<0.5 g/day, ideally <0.3 g/day**; - individualized blood-pressure control; - prevention of avoidable AKI and treatment toxicity.[1] ## Supportive kidney-protective care ### Lifestyle and cardiovascular risk Address: - dietary sodium intake, generally aiming for <2 g sodium/day when feasible; - regular physical activity; - healthy body weight; - smoking cessation; - moderation of alcohol; - avoidance of unnecessary nephrotoxins; - vaccination appropriate to CKD and planned immunomodulatory therapy. ### RAS blockade Use an **ACE inhibitor or ARB at the maximally tolerated dose** for adults with clinically important proteinuria when not contraindicated.[1] Monitor: - blood pressure; - creatinine/eGFR after initiation and titration; - potassium; - orthostatic symptoms. Do not combine an ACE inhibitor with an ARB. A larger-than-expected creatinine rise should prompt review for volume depletion, NSAID exposure, renovascular disease, severe hypotension, or another acute process. ### SGLT2 inhibitors KDIGO 2025 suggests an SGLT2 inhibitor for adults with IgAN at risk of progressive kidney-function loss.[1] The prespecified IgAN subgroup of DAPA-CKD supported kidney benefit beyond diabetes.[2] Practical safety points: - expect a small early eGFR dip; - review volume status and diuretic dose; - counsel about genital mycotic infection; - withhold during prolonged fasting, major surgery, or severe acute illness when ketoacidosis risk rises; - follow current local labeling for eGFR thresholds and dosing. ## Disease-specific therapy ### Targeted-release budesonide KDIGO 2025 suggests a **9-month course** of targeted-release budesonide for appropriate patients with primary IgAN at risk of progression.[1] NefIgArd used **16 mg orally once daily for 9 months** and demonstrated proteinuria reduction with a favorable subsequent eGFR effect.[3] Monitor for: - glucocorticoid adverse effects despite targeted intestinal delivery; - blood pressure and glucose changes; - infection; - edema/weight change; - adrenal suppression; - hepatic disease and drug interactions. Availability and approved populations differ by jurisdiction. ### Sparsentan Sparsentan combines endothelin type-A and angiotensin II type-1 receptor antagonism. PROTECT used **400 mg orally once daily** and showed greater proteinuria reduction than irbesartan with a favorable chronic eGFR slope.[4] > **Caution:** **Do not combine sparsentan with an ACE inhibitor or ARB.** Sparsentan already provides angiotensin-receptor blockade. Monitor blood pressure, potassium, kidney function, edema/fluid retention, liver safety, and reproductive precautions according to current labeling.[1,4] ### Systemic glucocorticoids Systemic glucocorticoids can reduce kidney events in selected higher-risk patients but carry important infectious and metabolic toxicity. TESTING demonstrated kidney benefit with methylprednisolone but also serious adverse events, especially with the original higher-dose regimen.[5] A reduced-dose regimen described by KDIGO is: - methylprednisolone **0.4 mg/kg/day, maximum 32 mg/day, for 2 months**; - then reduce by **4 mg/day each month**; - total treatment duration **6–9 months**; - provide Pneumocystis prophylaxis during higher-risk systemic therapy when indicated.[1,5] Avoid or use extreme caution when toxicity risk is high, including: - eGFR <30 mL/min/1.73 m²; - diabetes or major prediabetes; - obesity; - active/latent infection without appropriate management; - peptic ulcer disease; - severe psychiatric disease; - osteoporosis; - cataract/glaucoma risk; - frailty or major infection susceptibility. ### U.S. therapies approved after the KDIGO evidence review The U.S. therapeutic landscape changed rapidly in 2025–2026. Several agents received FDA approval for reduction of proteinuria in adults with primary IgAN at risk of progression. Eligibility, concomitant therapy, dosing, safety requirements, and reimbursement differ, so current prescribing information and nephrology input are essential.[6-9] | Therapy / mechanism | Current U.S. role | Important clinical point | |---|---|---| | **Atrasentan**, endothelin-A antagonist | FDA accelerated approval in April 2025 for adults at risk of rapid progression, generally UPCR ≥1.5 g/g | Proteinuria-based approval; monitor fluid retention and other label-specific risks[6] | | **Iptacopan**, complement factor-B inhibitor | FDA accelerated approval to reduce proteinuria in adults at risk of rapid progression | Complement inhibition requires infection-prevention measures and current label review[7] | | **Sibeprenlimab-szsi**, APRIL blocker | FDA accelerated approval November 2025; **400 mg SC every 4 weeks** | Month-9 proteinuria reduction supported approval; infection and vaccine precautions apply[8] | | **Atacicept-vymj**, BAFF/APRIL pathway inhibitor | FDA accelerated approval in 2026; **150 mg SC weekly** | Proteinuria endpoint supported approval; infection and vaccine precautions apply[9] | For sibeprenlimab, FDA reported approximately **50% proteinuria reduction at month 9** versus a 2% increase with placebo in the approval population; for atacicept, FDA reported an average **46% reduction at month 9** in the interim efficacy cohort.[8,9] > **Evidence note:** These accelerated approvals rely on proteinuria as a surrogate endpoint. For the newer agents, definitive long-term preservation of kidney function had not yet been established at approval; confirmatory trials are required. Do not assume equivalence or superiority across agents from cross-trial proteinuria percentages.[6-9] The 2026 KDOQI U.S. commentary emphasizes earlier biopsy-based diagnosis, risk stratification, and integration of emerging disease-modifying therapies into individualized U.S. care.[10] ## Special clinical scenarios ### AKI with visible hematuria Heavy glomerular bleeding can cause tubular obstruction and tubular injury. Management is usually supportive: - correct volume depletion; - avoid nephrotoxins; - monitor creatinine and urine output; - investigate alternative acute causes. If kidney function fails to recover after hematuria settles, reassess promptly; repeat biopsy may be needed when the clinical course is not consistent with expected recovery.[1] ### Nephrotic syndrome True nephrotic syndrome is unusual in classic IgAN. Re-review pathology for minimal-change-pattern podocytopathy or another process. When biopsy supports IgAN with minimal-change disease, treatment generally follows minimal-change disease principles rather than escalating IgAN-specific therapy solely because proteinuria is heavy.[1] Nephrotic-range proteinuria without hypoalbuminemia/edema can instead reflect advanced glomerular scarring or secondary focal segmental glomerulosclerosis. ### Rapidly progressive IgAN Suspect rapidly progressive IgAN when eGFR falls by **≥50% within ≤3 months** after excluding reversible causes.[1] Urgent pathway: 1. verify the creatinine trajectory; 2. exclude volume depletion, obstruction, drug toxicity, infection, and thrombotic microangiopathy; 3. obtain urgent nephrology input; 4. obtain kidney biopsy or urgent pathology review; 5. if active crescentic/necrotizing IgAN is responsible, consider cyclophosphamide plus systemic glucocorticoids using rapidly progressive glomerulonephritis principles; 6. provide infection prophylaxis and toxicity monitoring appropriate to the regimen. Crescents in a patient with stable kidney function are **not** equivalent to rapidly progressive IgAN. ### Pregnancy Preconception planning is important. ACE inhibitors, ARBs, sparsentan, SGLT2 inhibitors, and several newer disease-specific drugs are not suitable during pregnancy or require strict reproductive precautions. Switch blood-pressure therapy to pregnancy-compatible agents and review every disease-modifying drug before conception. Patients with reduced eGFR, significant proteinuria, or hypertension need coordinated nephrology and maternal-fetal care because maternal and fetal risks rise with baseline kidney disease severity. ## Monitoring | Clinical state | Monitoring focus | |---|---| | Stable, low proteinuria, preserved eGFR | BP, creatinine/eGFR, quantitative protein every 3–6 months initially, then individualized | | Persistent proteinuria or active titration | BP, eGFR, potassium, proteinuria every 4–12 weeks until stable | | RAS blocker or SGLT2 inhibitor initiation | Early renal function/electrolyte assessment, volume review, then routine CKD follow-up | | Endothelin-pathway therapy | BP, edema/weight, kidney function, potassium, liver/reproductive monitoring as required by the specific label | | Immune-targeted biologic therapy | Infection screening/monitoring, immunization review, label-specific laboratory surveillance | | Systemic glucocorticoids | Infection, glucose, BP, weight, bone protection, psychiatric and ocular toxicity; prophylaxis as indicated | | Falling eGFR | Shorten interval; reassess adherence, volume status, secondary causes, and treatment strategy | Track **trends and slope**, not a single creatinine or UPCR value. ## Referral and escalation Urgent nephrology assessment is appropriate for: - rapidly rising creatinine or oliguria; - rapidly progressive eGFR loss; - nephrotic syndrome; - severe or resistant hypertension; - hyperkalemia limiting kidney-protective therapy; - suspected systemic vasculitis or infection-related glomerulonephritis; - pregnancy with significant kidney disease. Biopsy-proven IgAN warrants ongoing specialist follow-up because eligibility for disease-specific therapy and kidney-risk estimates can change over time. ## Complications and prognosis Potential complications include: - progressive CKD and kidney failure; - hypertension; - cardiovascular disease; - nephrotic complications in selected phenotypes; - treatment-related infection, metabolic toxicity, edema, liver injury, or reproductive risk depending on therapy. Long-term course is heterogeneous. Persistent proteinuria, lower eGFR, hypertension, and adverse chronic biopsy lesions increase lifetime risk. Modern treatment aims for sustained proteinuria reduction and preservation of eGFR over years to decades rather than temporary normalization of urinary findings. ## Practical decision pathway 1. Hematuria/proteinuria compatible with IgAN → quantify protein, establish eGFR trend, assess blood pressure. 2. Proteinuria ≥0.5 g/day equivalent or atypical/high-risk features → consider kidney biopsy. 3. Biopsy-proven IgAN → document MEST-C and calculate/consider validated risk prediction, but prioritize clinical trajectory. 4. Optimize sodium intake, BP, maximally tolerated RAS blockade, and SGLT2 therapy where appropriate. 5. Reassess proteinuria and eGFR trajectory after supportive optimization. 6. Persistent meaningful risk → choose disease-specific therapy according to eGFR, proteinuria, prior therapy, toxicity, pregnancy plans, regulatory indication, and access. 7. Rapid eGFR loss ≥50% within ≤3 months → urgent exclusion of reversible causes and biopsy-based rapidly progressive pathway. 8. Continue serial proteinuria and eGFR monitoring; escalate treatment based on residual risk and objective trajectory rather than fixed treatment calendars alone. ## Related library topics - [Chronic Kidney Disease](chronic-kidney-disease.md) - [Hyperkalemia](hyperkalemia.md) - [Nephrotic Syndrome in Adults](nephrotic-syndrome-in-adults.md) - [Minimal Change Disease in Adults](minimal-change-disease-in-adults.md) ## References 1. Kidney Disease: Improving Global Outcomes (KDIGO) IgA Nephropathy Guideline Work Group. KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy and Immunoglobulin A Vasculitis. *Kidney International*. 2025;108(4S):S1-S71. doi:10.1016/j.kint.2025.04.004. PMID:40975564. https://kdigo.org/guidelines/iga-nephropathy/ 2. Wheeler DC, Toto RD, Stefánsson BV, et al. A prespecified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. *Kidney International*. 2021;100(1):215-224. doi:10.1016/j.kint.2021.03.033. PMID:33878338. https://pubmed.ncbi.nlm.nih.gov/33878338/ 3. Lafayette R, Kristensen J, Stone A, et al. Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial. *Lancet*. 2023;402:859-870. doi:10.1016/S0140-6736(23)01554-4. https://doi.org/10.1016/S0140-6736(23)01554-4 4. Rovin BH, Barratt J, Heerspink HJL, et al. Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial. *Lancet*. 2023;402(10417):2077-2090. doi:10.1016/S0140-6736(23)02302-4. PMID:37931634. https://pubmed.ncbi.nlm.nih.gov/37931634/ 5. 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. PMID:35579642. https://pubmed.ncbi.nlm.nih.gov/35579642/ 6. U.S. Food and Drug Administration. Drug Trials Snapshot: Vanrafia (atrasentan). Original approval April 2, 2025. https://www.fda.gov/drugs/drug-trials-snapshots/drug-trials-snapshot-vanrafia 7. U.S. Food and Drug Administration. Fabhalta (iptacopan): approved indications include accelerated approval for reduction of proteinuria in adults with primary IgA nephropathy at risk of rapid progression. FDA. 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-adults-complement-3-glomerulopathy-rare-kidney-disease-reduce 8. U.S. Food and Drug Administration. FDA approves a new treatment for primary immunoglobulin A nephropathy: Voyxact (sibeprenlimab-szsi). November 25, 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-new-treatment-primary-immunoglobulin-nephropathy 9. U.S. Food and Drug Administration. FDA Approves New Treatment to Reduce Proteinuria in Adults with Primary Immunoglobulin A Nephropathy: Trutakna (atacicept-vymj). 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-new-treatment-reduce-proteinuria-adults-primary-immunoglobulin-nephropathy 10. Ayoub I, Coppock G, Wadhwani S, Yau T. KDOQI US Commentary on the 2025 KDIGO Clinical Practice Guideline for the Management of IgA Nephropathy and IgA Vasculitis. *American Journal of Kidney Diseases*. 2026;88(1):18-35. doi:10.1053/j.ajkd.2026.02.639. 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