IgA Nephropathy

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide^[1] — dominant IgA deposition, usually accompanied by C3 and sometimes IgG or IgM, in the glomerular mesangium on immunofluorescence, driving mesangial cell proliferation, complement activation (largely via the alternative and lectin pathways, since IgA does not activate the classical pathway), and progressive glomerular injury.^[2] The dominant current pathogenic model is a multi-hit process: (1) increased circulating galactose-deficient IgA1 (Gd-IgA1), an aberrantly glycosylated form of IgA1; (2) production of autoantibodies directed against this Gd-IgA1; (3) formation of pathogenic Gd-IgA1-containing immune complexes; and (4) mesangial deposition of these complexes, triggering the cytokine release, complement activation, and cell proliferation that drive glomerular and, over time, tubulointerstitial injury.^[1]

This chapter is a dedicated, disease-specific companion to this platform's general Glomerulonephritis chapter, which covers the shared nephritic/nephrotic syndromic framework, the initial urinalysis-and-serology triage across all major GN etiologies, and IgA nephropathy's place among them at a survey level. This chapter instead details what is specific and modern about IgA nephropathy itself: biopsy-based histologic staging and risk stratification, and a pharmacotherapy landscape that has changed substantially in recent years — from a foundation of maximized renin-angiotensin system (RAS) blockade, through an SGLT2 inhibitor and a genuinely novel gut-targeted corticosteroid formulation, to a narrower and more selective role for conventional systemic immunosuppression than in older practice, and newer complement- and endothelin-pathway-targeted agents at the frontier. Cross-references to the general chapter are used throughout rather than duplicating its content.

IgA vasculitis (formerly Henoch-Schönlein purpura) is the systemic form of the same underlying immunopathology — the identical Gd-IgA1-driven glomerular lesion occurring alongside palpable purpura, arthralgia, and abdominal pain, most classically in children — and is covered by the same current international guideline as IgA nephropathy.^[2] This chapter focuses on isolated (renal-limited) IgA nephropathy, predominantly an adult presentation; a patient with the systemic vasculitic syndrome should be managed under pediatric or adult rheumatology/nephrology co-direction for its extra-renal features.

Epidemiology

IgA nephropathy is the most common primary glomerulonephritis identified on biopsy worldwide, though reported incidence varies substantially by region and by how liberally biopsy is pursued for isolated hematuria and/or proteinuria — a factor the current KDIGO guideline specifically flags as inconsistent across health systems, including within Canada.^[2][3] Incidence is highest in East Asian populations (particularly China, Japan, and Korea, where routine urinalysis screening programs detect more asymptomatic cases), intermediate in White populations, and lower in Black populations, though the degree to which this reflects true biologic variation versus differences in screening and biopsy practice remains an active question.^[1] Onset is most common in the second and third decades of life, with a male-to-female ratio of roughly 2 to 1 in most reported cohorts.^[1]

• East Asian ethnicity carries the highest reported incidence; White ethnicity is intermediate; Black ethnicity has the lowest reported incidence — though detection and biopsy-practice differences across regions likely contribute to some of this variation.^[1]
• A family history of IgA nephropathy or of unexplained kidney failure — genome-wide association studies have identified numerous susceptibility loci, several overlapping with mucosal immunity and inflammatory bowel disease genes, consistent with the disease's mucosal-immune origin, though clinical genetic testing is not part of routine practice.^[1]
• Male sex — most cohorts report a male-to-female ratio of roughly 2 to 1.^[1]
• Celiac disease — a recognized association, again consistent with a mucosal-immune driver; screen for celiac disease in an atypical or treatment-resistant presentation. See this platform's Celiac Disease chapter for the complete workup.
• Chronic liver disease, particularly cirrhosis — reduced hepatic clearance of circulating IgA1 immune complexes can produce a secondary IgA nephropathy; the distinction from primary IgA nephropathy matters less for pharmacologic management than for identifying and addressing the underlying liver disease.^[1]
• HIV infection and, less commonly, other chronic mucosal or systemic inflammatory conditions (for example, ankylosing spondylitis and other seronegative spondyloarthropathies) — recognized secondary associations worth considering, particularly in an atypical presentation.^[1]
• Recurrent tonsillitis or recurrent upper respiratory infections — a recognized trigger for episodic synpharyngitic gross hematuria in a patient who already has IgA nephropathy, rather than an independent cause of the underlying disease.^[2]

Complications

Left untreated or inadequately treated, IgA nephropathy is a genuine, common cause of progressive chronic kidney disease — cohort data report roughly 20% to 40% of patients progressing to kidney failure within 10 to 20 years of diagnosis, with some cohorts reporting still higher rates over longer follow-up, and the individual trajectory driven largely by the modifiable and histologic risk factors detailed in Assessment & Diagnosis.^[1] Sustained proteinuria and hypertension additionally carry the same elevated long-term cardiovascular risk seen across proteinuric chronic kidney disease generally — see this platform's Chronic Kidney Disease chapter for the complete cardiovascular risk-reduction framework, which applies identically here.

Renal biopsy — the diagnostic gold standard

Renal biopsy remains required for a definitive diagnosis of IgA nephropathy: light microscopy, immunofluorescence, and electron microscopy together, since the defining finding — dominant or co-dominant IgA deposition in the glomerular mesangium, typically accompanied by C3 and often by IgG or IgM, with mesangial electron-dense deposits on electron microscopy — cannot be inferred from clinical or serologic findings alone.^[2] The current KDIGO guideline specifically encourages a more liberal biopsy threshold than older guidance, given how much biopsy-confirmed histology (see MEST-C below) now informs both prognosis and treatment selection.^[2]

Differential diagnosis

Consider specifically before attributing isolated glomerular hematuria to IgA nephropathy: thin basement membrane nephropathy (a benign, often familial cause of persistent microscopic hematuria with a normal or near-normal long-term prognosis); Alport syndrome (a genetic type IV collagen disorder — suspect with a family history of hematuria, sensorineural hearing loss, or kidney failure, and confirm with GBM immunostaining or genetic testing where suspected); and post-infectious glomerulonephritis (distinguished chiefly by the 1- to 3-week latency after infection and low complement — see the general Glomerulonephritis chapter). This platform's separate Hematuria chapter should be used for the complete triage framework when a glomerular source is not yet established.^[1]

Serologies and other testing

Serum IgA is elevated in only about half of patients with biopsy-proven IgA nephropathy and is neither sensitive nor specific enough to establish or exclude the diagnosis — a normal serum IgA does not rule out IgA nephropathy, and biopsy remains necessary.^[1] Serum galactose-deficient IgA1 (Gd-IgA1) levels and anti-Gd-IgA1 autoantibody assays are active areas of biomarker research but remain investigational rather than routine diagnostic tools at this time.^[2] Complement levels are typically normal in IgA nephropathy (see the general Glomerulonephritis chapter's serology-based triage table) — a low complement should instead prompt reconsideration of the diagnosis.

Oxford Classification (MEST-C) — histologic risk stratification

Every IgA nephropathy biopsy should be scored using the Oxford Classification (MEST-C), the internationally standardized histologic risk-stratification system, since several of its components carry independent prognostic weight and inform treatment intensity.^[4]

Risk stratification for progression to kidney failure

Treatment intensity in IgA nephropathy should be individualized to a patient's actual risk of progression, not applied uniformly to every biopsy-confirmed diagnosis — the single most useful framework combines the modifiable and non-modifiable factors below.

• Proteinuria level is the single most important, and most modifiable, prognostic marker — patients who achieve and maintain proteinuria at or below the treatment target (see Goals of Therapy) have substantially better long-term kidney survival than those with persistent higher-level proteinuria, and the trend in proteinuria over time is a more useful treatment-response marker than any single value.^[2]
• Hypertension, both at diagnosis and if inadequately controlled over follow-up, independently predicts faster progression.^[1]
• Reduced eGFR at diagnosis — a lower starting eGFR is an independent predictor of progression to kidney failure.^[1]
• Oxford MEST-C histologic features — particularly the T (tubular atrophy/interstitial fibrosis) and C (crescents) scores — add independent prognostic information beyond the clinical variables alone.^[4]
• The International IgA Nephropathy Prediction Tool (IIgANPT) combines age, blood pressure, eGFR, proteinuria, the MEST score, and RAS-inhibitor/immunosuppression use at the time of biopsy into an individualized estimate of the 5-year risk of a 50% eGFR decline or kidney failure. It was developed and externally validated across large multi-ethnic cohorts, led by a University of British Columbia nephrologist, and is the current recommended method for personalized risk communication and for guiding how aggressively to treat a given patient.^[5]

• Reduce proteinuria to below 0.5 g/day, and ideally below 0.3 g/day where achievable — the current KDIGO 2025 guideline's stricter target, replacing the previous generation's under-1-g/day goal, reflecting evidence that even proteinuria in the 0.5-1 g/day range carries a meaningfully elevated risk of progression compared with lower levels.^[2]
• Preserve kidney function and slow the rate of eGFR decline, recognizing that in IgA nephropathy this depends first on maximized supportive care and, for higher-risk patients, on disease-specific pharmacotherapy layered on top of it — not on RAS blockade alone.
• Control blood pressure to the same target used in this platform's Chronic Kidney Disease chapter, since hypertension is itself an independent driver of progression.
• Risk-stratify treatment intensity rather than applying it uniformly. Many patients — particularly those with normal or near-normal proteinuria and eGFR at diagnosis and favourable Oxford MEST-C features — need only conservative supportive management (RAS blockade, blood pressure control, and monitoring) and will do well without ever requiring an SGLT2 inhibitor, targeted-release budesonide, or systemic immunosuppression. Reserve escalation for patients whose risk stratification (see Assessment & Diagnosis) genuinely supports it.^[2][3]

• Sodium restriction (roughly under 2 g/day) to support blood pressure control and enhance the proteinuria-lowering effect of RAS blockade.
• Weight management and regular physical activity as part of overall blood pressure and cardiovascular risk control.
• Smoking cessation.
• Nephrotoxin avoidance (regular NSAID use, unnecessary contrast exposure) — see the Chronic Kidney Disease chapter's nephrotoxin stewardship table, which applies identically here.
• Omega-3 fatty acid (fish oil) supplementation has historically been used adjunctively in IgA nephropathy; trial evidence for a meaningful effect on hard kidney outcomes is modest and inconsistent, so it should be treated as a low-risk adjunct rather than a substitute for the pharmacotherapy above.^[1]
• Vaccination review and completion before starting significant immunosuppression wherever the clinical timeline allows, consistent with the general Glomerulonephritis chapter's approach.

Patient education

Reassure patients that an episode of synpharyngitic gross hematuria occurring alongside a cold or sore throat is a recognized feature of the disease itself, not necessarily a sign of an acute complication — but teach them to report a new episode, or one that does not resolve as previous episodes did, to their care team rather than assuming it is routine every time.^[2] Reinforce that RAS blockade and, where used, an SGLT2 inhibitor are working even when the patient feels entirely well and should not be stopped without discussion, since benefit is measured in the proteinuria trend and long-term kidney survival, not day-to-day symptoms. For a patient prescribed targeted-release budesonide, explicitly teach that the capsule must be swallowed whole and never crushed, chewed, or opened — its enteric and ileal-release coating is what targets the drug to the distal small bowel, and defeating that coating both destroys the intended local mechanism and risks converting the dose into a much larger systemic corticosteroid exposure. Teach the same infection-prevention behaviours as the general Glomerulonephritis chapter for any patient on significant immunosuppression, and confirm effective contraception is in place before mycophenolate mofetil is started in anyone who could become pregnant.

Pregnancy

ACE inhibitors and ARBs are contraindicated in pregnancy and should be stopped before conception is attempted where feasible, or immediately once pregnancy is confirmed; SGLT2 inhibitors, targeted-release budesonide, mycophenolate mofetil, cyclophosphamide, iptacopan, and sparsentan are also not recommended in pregnancy given insufficient safety data or known teratogenicity, and should be reviewed and generally stopped before conception is attempted.^[2] Active IgA nephropathy — particularly with hypertension or significant proteinuria — meaningfully raises the risk of preeclampsia and fetal growth restriction and needs joint nephrology and maternal-fetal medicine (obstetric) co-management from the outset, not management from this chapter's framework alone; this mirrors the general Glomerulonephritis chapter's identical pregnancy-co-management principle.

Breastfeeding

Prednisone is generally considered compatible with breastfeeding at usual doses. Confirm the compatibility of any other agent in this chapter against current lactation references before assuming it is safe, rather than extrapolating from the pregnancy contraindication alone — several of the newer agents in this chapter (SGLT2 inhibitors, targeted-release budesonide, iptacopan, sparsentan) have limited or no lactation safety data.

Pediatrics

IgA nephropathy does occur in children, generally with a more favourable prognosis than the equivalent presentation in an adult, and IgA vasculitis (the systemic form of the same disease) is predominantly a pediatric presentation — dosing and regimen specifics should follow pediatric nephrology direction rather than the adult framework in this chapter.

Older adults

A new IgA nephropathy diagnosis in an older adult should specifically prompt consideration of secondary causes — chronic liver disease and HIV among them — rather than assuming primary disease by default; see Risk Factors.

Renal impairment

SGLT2 inhibitor initiation requires an adequate eGFR per current product labelling; several agents in this chapter require dose adjustment as eGFR declines through disease progression — see the Chronic Kidney Disease chapter's general renal-dosing principles, which apply throughout this chapter as well.

Monitor the urine protein-to-creatinine ratio, blood pressure, and eGFR at a frequency individualized to disease activity and treatment phase — roughly every 3 to 6 months once stable on supportive care alone, more frequently during any dose titration or after starting disease-specific pharmacotherapy.

RAS blockade and SGLT2 inhibitor

Serum creatinine and potassium 2 to 4 weeks after starting or up-titrating an ACE inhibitor or ARB, and periodically thereafter — identical to the general Glomerulonephritis and Chronic Kidney Disease chapters' approach. Reassess proteinuria only after a minimum of roughly 90 days of maximized, stable therapy before judging response.

Targeted-release budesonide

Blood pressure and blood glucose periodically through the 9-month course, and monitor for infection and mood/sleep disturbance as with any corticosteroid exposure, though generally less pronounced than with a conventional systemic regimen.^[7]

Systemic immunosuppression

Follow the same agent-specific monitoring detailed in the general Glomerulonephritis chapter's Monitoring & Follow-Up section (CBC and cumulative-dose tracking for cyclophosphamide, CBC/liver enzymes for mycophenolate mofetil, Pneumocystis jirovecii prophylaxis during sustained high-dose immunosuppression) — not duplicated here.

Iptacopan and sparsentan

Confirm meningococcal and other relevant vaccinations are up to date before starting iptacopan, given the infection risk of alternative-complement-pathway inhibition, and monitor liver function periodically while on sparsentan given its hepatotoxicity signal.^[9][10]

Repeat biopsy

Not routine — reserve for genuine diagnostic uncertainty or unexplained treatment failure rather than as a standard follow-up test.

1. Persistent proteinuria above target despite maximized RAS blockade and an SGLT2 inhibitor for at least 90 days: reassess adherence and blood pressure control first, then consider targeted-release budesonide if not already used and the patient's risk profile supports it.^[2]
2. Inadequate response to, or relapse after, a completed targeted-release budesonide course: reassess adherence (including correct, whole-capsule administration) and the diagnosis, then discuss systemic immunosuppression or referral for a newer complement- or endothelin-pathway-targeted agent with nephrology.^[2]
3. Rapidly progressive or crescentic presentation not responding to initial immunosuppression: urgent nephrology reassessment following the general Glomerulonephritis chapter's RPGN algorithm, including consideration of plasma exchange in severe cases.
4. eGFR declining despite an apparently adequate regimen: reconfirm the diagnosis is correct and consider a secondary cause (see Risk Factors) or a repeat biopsy before assuming simple treatment failure, and reassess whether an emerging agent (iptacopan, sparsentan) is now appropriate and accessible.^[3]

• Attributing gross hematuria occurring alongside an upper respiratory infection to post-streptococcal glomerulonephritis rather than recognizing the synpharyngitic pattern distinctive of IgA nephropathy — the timing (concurrent versus a 1- to 3-week delay) is the key distinguishing clue.^[2]
• Assuming a normal serum IgA excludes the diagnosis — it is elevated in only about half of biopsy-confirmed cases and is not a diagnostic test on its own.^[1]
• Starting an SGLT2 inhibitor, targeted-release budesonide, or systemic immunosuppression before RAS blockade has actually been maximized and given an adequate trial (roughly 90 days) — escalating around an under-optimized foundation rather than completing it first.^[2]
• Treating every biopsy-confirmed diagnosis with the same treatment intensity rather than risk-stratifying using proteinuria trend, eGFR, and Oxford MEST-C features — over-treating a genuinely low-risk patient exposes them to real drug toxicity for no proven benefit.^[2]
• Instructing a patient to crush, chew, or open a targeted-release budesonide capsule — this defeats the ileal-targeted delivery mechanism entirely.^[7]
• Starting an SGLT2 inhibitor concurrently with induction immunosuppression rather than waiting for stable therapy.^[3]
• Using rituximab for the usual proteinuric/progressive pattern of IgA nephropathy — randomized trial evidence has not shown benefit in this setting.^[2]
• Missing a rapidly progressive (crescentic) presentation because a rising creatinine is attributed to routine disease fluctuation rather than triggering urgent referral.^[2]
• Assuming a newer agent (iptacopan, sparsentan, or targeted-release budesonide) is automatically funded and accessible without confirming current Canadian coverage.^[3]

How to use this table: Doses require patient-specific confirmation, including renal/hepatic adjustment where relevant, and follow the risk-stratified pathway in Choose Initial Treatment above rather than a single fixed protocol. Select any drug name to open its complete Pharmasist Drug Database page. Confirm current Canadian funding/access status for the newer agents (targeted-release budesonide, iptacopan, sparsentan) before assuming availability.

Renin-Angiotensin System Blockade — The Essential Foundation

Start in essentially every patient with proteinuria of 0.5 g/day or more, before any disease-specific pharmacotherapy. Titrate to the highest approved/tolerated dose for the proteinuria-lowering effect, not just to a blood pressure target.

SGLT2 Inhibitor — Add-On Renoprotection

Add on top of maximized, stable RAS blockade for patients with an adequate eGFR and persistent proteinuria. Avoid starting concurrently with induction immunosuppression.

Targeted-Release Budesonide — Disease-Specific, Gut-Targeted Corticosteroid

For patients at meaningful risk of progression despite at least 90 days of optimized supportive care. Enteric- and ileal-release coating targets the Peyer's patches of the distal ileum; substantially reduced systemic exposure compared with conventional oral corticosteroids, though not eliminated.

Conventional Systemic Immunosuppression — A Narrower, Selective Role

Reserved for patients at high risk of progression despite maximized supportive care and, typically, after targeted-release budesonide has been considered — not a default therapy. Crescentic/rapidly progressive disease is the clearest indication for cyclophosphamide-based therapy.

Emerging Complement- and Endothelin-Pathway-Targeted Agents

Mechanistically new agents with positive phase 3 data, targeting IgA nephropathy's specific pathophysiology. A genuinely expanding frontier, not yet first-line.