IgA Nephropathy

Meet the patient

A 22-year-old man walks in with cola-coloured urine he first noticed this morning, one to two days after a sore throat. He feels well, his blood pressure is 146 over 92, the dipstick shows blood and a little protein, and his C3 is normal. The lesion was always there; the mucosal infection just lit it up.^[1]

Two questions decide this stem, and they decide every glomerular haematuria stem: how many days passed between the infection and the blood — one to two days is synpharyngitic, one to three weeks is latent — and is the serum complement normal or low? Hold those two questions and the whole topic slots into place.^[1]

Berger, not Buerger — the commonest primary glomerulonephritis

IgA nephropathy is an immune-complex glomerulonephritis defined by dominant or co-dominant mesangial IgA1 deposition, first read on immunofluorescence by Jean Berger in 1968. The deposited IgA is abnormally glycosylated — galactose-deficient IgA1 (Gd-IgA1) — and the disease is now understood as autoimmune: autoantibodies against Gd-IgA1 form pathogenic circulating immune complexes that lodge in the mesangium and ignite proliferation, inflammation and scarring.^[1]

It is the commonest primary glomerulonephritis worldwide and a leading glomerular cause of end-stage kidney disease (ESKD). Approximately 20 to 40 percent of patients progress to ESKD over 20 to 30 years; because it strikes young adults, it is a major non-diabetic cause of kidney failure in the working-age population.^[1]

Berger is not Buerger. Berger disease is the kidney; Buerger disease is thromboangiitis obliterans, a smoker's peripheral vasculitis. The exam writers love this one — every cohort loses a mark to it.^[1]

And IgA nephropathy is not IgA vasculitis (Henoch-Schönlein purpura). They share the identical mesangial IgA lesion — IgA nephropathy is now regarded as the renal-limited end of the same spectrum — but IgA vasculitis adds systemic small-vessel disease: palpable purpura, abdominal pain, arthritis.^[1]

^[1]

The Oxford MEST-C score — T drives prognosis, C drives escalation

The renal biopsy is spoken in five letters, and two of them do almost all the work: T drives prognosis, C drives escalation. Before the letters, the disease sorts along three axes — clinical syndrome, primary versus secondary, and the MEST-C score.^[1]

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The Oxford classification (2009, updated since) scores the biopsy on five lesions and is the universal histological language for IgA nephropathy. Each letter predicts prognosis and informs the need for immunosuppression:^[8]

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Read MEST-C as a string — M1 E0 S1 T1 C0, for example. T means irreversible chronic damage; C means active, potentially treatable crescentic disease. The score is never read in isolation — it is interpreted with the clinical picture (proteinuria, eGFR, blood pressure), and the International IgA Nephropathy Prediction Tool folds MEST-C plus those clinical variables into a 5- and 10-year risk of ESKD that KDIGO uses to time immunosuppression.^[7]

Synpharyngitic or latent — the face-off that answers half the MCQs

One timing question and one complement question separate IgA nephropathy from post-streptococcal GN in a single line. This is the most reproduced face-off in glomerular disease, and it is worth memorising verbatim.^[1]

^[1]

The discriminator in one breath: synpharyngitic and normal C3 is IgA nephropathy; latent and low C3 is post-streptococcal GN. A low C3 in a synpharyngitic picture redirects the diagnosis away from both — to lupus nephritis (low C3 and C4, full-house immunofluorescence with C1q) or infective-endocarditis-associated GN. A normal C3 never rules out IgA nephropathy.^[1]

The faces of one lesion — from benign to explosive

The same mesangial IgA lesion wears several clinical masks: manifestations vary all the way from asymptomatic haematuria with stable kidney function to rapidly progressive glomerulonephritis, and a candidate must recognise each:^[11][12]

^{[11] [12]}

How common, who, and why it runs in families

^[1]

Biopsy prevalence is highest in East Asia — in Japan, mandatory school urinalysis screening catches large numbers of asymptomatic cases, and in China up to 45 percent of native-kidney biopsies show IgA nephropathy. It is under-represented in people of African ancestry. That geographic gradient is partly genetic.^[1]

The disease has a strong heritable component — twin concordance, familial clustering, and more than 15 GWAS loci. The headline signals sit in the HLA region (HLA-DRB1 and HLA-DQB1) and in genes governing IgA glycosylation and mucosal immunity, including C1GALT1 (the galactosyltransferase at the heart of the multi-hit hypothesis), the DEFA defensin locus, and ITGAM-ITGAX. Most loci carry small individual effects; monogenic familial IgA nephropathy is rare.^[2]

The predictors of progression examiners reward: persistent proteinuria (the strongest modifiable risk), hypertension, reduced eGFR at diagnosis, male sex, persistent microscopic haematuria, and adverse MEST-C features (especially T, S and C). Obesity and smoking accelerate CKD on top.^[1]

The four-hit hypothesis — from mucosa to mesangium

IgA nephropathy is the textbook immune-complex disease, and the modern reading is the four-hit (multi-hit) hypothesis. The four hits are sequential, and each is a therapeutic target.^[2]

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Hit 1 — over-production of Gd-IgA1. IgA1 hinge-region O-glycans are normally galactosylated. In IgA nephropathy the enzyme C1GalT1 (core-1 beta-1,3-galactosyltransferase, encoded by C1GALT1) is under-active relative to its chaperone Cosmc, leaving hinge glycans galactose-deficient. The result is Gd-IgA1 — abnormally glycosylated, poorly cleared, often polymeric, exposing neoepitopes. Production is heritable (the familial and GWAS signal) and up-regulated by mucosal infection — which is exactly why a sore throat lights up the urine.^[2]

Hit 2 — anti-Gd-IgA1 autoantibodies. The exposed hinge glycans act as neoepitopes. IgG and IgA anti-glycan autoantibodies (anti-Gd-IgA1 IgG and IgA) are produced, mostly from mucosal B-cell compartments. These autoantibodies are the second hit and are themselves measurable biomarkers of disease activity — elevated titres correlate with progression and underpin emerging serology.^[1]

Hit 3 — circulating immune complexes. Anti-Gd-IgA1 binds Gd-IgA1 (especially its polymeric forms) into large circulating immune complexes. They are too big for normal hepatic clearance (which removes properly glycosylated monomeric IgA1 via the asialoglycoprotein receptor), so they persist. In cirrhosis-associated secondary IgAN, clearance fails by a different route but produces the same net effect — complexes accumulate and deposit.^[1]

Hit 4 — mesangial deposition and injury. The complexes lodge in the glomerular mesangium, bind the transferrin receptor CD71 (over-expressed in IgA nephropathy), and activate mesangial cells. The downstream cascade is mesangial proliferation and matrix expansion (the M and E lesions), complement activation via the lectin and alternative pathways (explaining C3 co-deposition), podocyte injury driving proteinuria, and over time segmental sclerosis and tubulointerstitial fibrosis (the S and T lesions). In aggressive disease, fibrin extravasation and parietal epithelial cell activation produce crescents — the C lesion and the hallmark of rapidly progressive disease.^[1]

The mucosa-to-bone-marrow axis ties the four hits to the bedside. Mucosal B cells stimulated by respiratory or gastrointestinal infection produce polymeric IgA1, and in IgA nephropathy that output is preferentially galactose-deficient. A surge of Gd-IgA1 during a mucosal infection floods the system, forms fresh complexes, deposits in the mesangium, and produces visible haematuria within 1 to 2 days — the synpharyngitic hallmark. This is also why B-cell-directed therapies (sibeprenlimab, atacicept) and complement-directed therapies (iptacopan, ravulizumab) work — they interrupt the same cascade upstream and downstream.^[1]

The histology confirms the mechanism on three stains. Light microscopy shows mesangial hypercellularity, matrix expansion and the variable MEST-C features. Immunofluorescence is the defining modality: dominant or co-dominant mesangial IgA (IgA1, not IgA2), often with C3; IgG and IgM may co-deposit but are not dominant; and C1q is typically absent — the useful discriminator from lupus nephritis (full-house, C1q-positive). Electron microscopy shows mesangial electron-dense immune-type deposits, with diffuse foot-process effacement if an IgA-minimal-change overlap is present.^[1]

The great imitators — what else glomerular haematuria

The differential is built on three axes: timing, complement level, and the urine sediment. A low C3, a family history, or a crescentic picture each redirect the diagnosis — name them, do not round on them.^[1]

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The bedside round and the excluding bloods

Examination rarely makes the diagnosis; it stages the disease, finds complications, and catches the secondary and systemic clues. Run it in this order.^[1]

• History. Nail the timing of haematuria relative to mucosal infection — the synpharyngitic clue is the single most diagnostic historical feature. Ask about preceding sore throat or gastrointestinal illness, visible blood (cola or smoky urine), loin pain, oedema, foamy urine, and family history of renal disease, deafness or haematuria. Record NSAID use (interstitial nephritis, AKI) and systemic symptoms — rash, arthralgia, sinusitis, haemoptysis.
• Blood pressure and fluid status. Hypertension is a key prognostic marker and treatment target — measure it carefully and repeatedly. Look for oedema, basal crackles, raised JVP, and signs of advanced CKD (pallor, uraemic scratch marks).
• Secondary-IgAN clues. Stigmata of chronic liver disease (spider naevi, palmar erythema, ascites), coeliac disease (dermatitis herpetiformis, malabsorption), psoriasis, IBD, and ankylosing spondylitis (sacroiliitis).
• Systemic-disease clues. Palpable purpura (IgA vasculitis), malar rash and arthritis (lupus), sinus and lung signs (ANCA vasculitis), oral and nasal ulcers.^[1]

The bloods confirm a glomerular source, stage the disease, and exclude the mimics:^[1]

• Urinalysis and microscopy. Blood and often protein on dipstick; the spectrum runs from asymptomatic abnormalities on urinalysis to an active sediment in rapidly progressive disease.
• Proteinuria quantification. Spot PCR or ACR; the escalation trials defined their at-risk groups as proteinuria at or above 1 g/day, or PCR at or above 0.8 g/g, persisting despite optimised RAAS blockade — the thresholds that mark disease worth escalating.
• Serum creatinine and eGFR — stage and trend; most patients carry a considerable lifetime risk of kidney failure, so the trend matters as much as the number.
• Exclude-mimic serology. Complement C3 and C4, ANA and dsDNA, ANCA (MPO, PR3), anti-GBM, hepatitis B surface antigen, anti-HCV, HIV, ASO and anti-DNase B; serum electrophoresis and free light chains in older patients — the panel that separates IgA nephropathy from its mimics.^[2][3][5]

The renal biopsy — the test that names the disease

Diagnosis of IgA nephropathy requires a renal biopsy, and the defining finding is on immunofluorescence: dominant or co-dominant mesangial IgA (IgA1), often with C3, and C1q characteristically absent. Light microscopy maps the MEST-C features; electron microscopy shows mesangial electron-dense deposits, plus foot-process effacement if an IgA-minimal-change overlap is present.^[7]

When to biopsy: IgA nephropathy can only be diagnosed by kidney biopsy, so the biopsy question is really a diagnosis-and-escalation question.^[11] Biopsy to confirm the diagnosis when it is in doubt, and always when proteinuria persists at or above roughly 1 g/day (or PCR at or above 0.8 g/g) despite optimised RAAS blockade — the trial-eligible escalation zone — or when function declines or a rapidly progressive course is suspected.^[3][5] Asymptomatic microscopic haematuria with stable function sits at the benign end of the spectrum; the biopsy decision there balances diagnostic yield against bleeding risk, and persistent or rising proteinuria shifts the balance to biopsy.^[11][12]

A renal ultrasound excludes obstruction, sizes the kidneys (small scarred kidneys argue against both biopsy yield and aggressive immunosuppression), and screens for urological bleeding when the sediment is equivocal. The International IgA Nephropathy Prediction Tool then folds the MEST-C score with eGFR, mean arterial pressure, proteinuria and medication use to estimate the 5- and 10-year risk of a 50 percent eGFR decline or ESKD — quantifying who warrants immunosuppression. KDIGO endorses it.^[7]

Stable patients are monitored every 3 to 6 months — blood pressure, creatinine and eGFR, PCR or ACR, urinalysis — to catch rising proteinuria or falling eGFR early, because those are the triggers to intensify therapy. Annual cardiovascular risk assessment and vaccination review belong to long-term CKD care.^[1]

Supportive care first — the non-negotiable foundation

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There is no cure for IgA nephropathy. The foundation for every patient is optimised supportive care, and it must be in place before any immunosuppression is even considered. The STOP-IgAN trial proved the point: piling immunosuppression onto unoptimised supportive care adds nothing.^[4]

The foundation, for all patients:^[11]

• RAAS blockade first-line. An ACE inhibitor or ARB, titrated to the maximum tolerated dose, is the anchor of supportive care for proteinuric IgA nephropathy — every escalation trial demanded it first: TESTING enrolled patients only after at least 3 months of blood-pressure control with renin-angiotensin system blockade, and STOP-IgAN adjusted that blockade on the basis of proteinuria during its run-in.^[3][4]
• Blood pressure control and proteinuria reduction are the twin goals of that titration — in STOP-IgAN the run-in itself dropped proteinuria below 0.75 g/day in 94 of 309 patients, which is the point of optimising before escalating.^[4]
• Lifestyle and cardiovascular risk reduction. Smoking cessation, salt restriction, weight optimisation, exercise, avoidance of nephrotoxins, and statin and glycaemic control per CKD guidance — the "extensive, optimised supportive care" that is the documented mainstay of therapy.^[11]

The single most important modern addition to the foundation is the SGLT2 inhibitor. EMPA-KIDNEY (2023) randomly assigned patients with chronic kidney disease at risk of progression to empagliflozin 10 mg once daily or placebo and found a lower risk of kidney-disease progression or death from cardiovascular causes (hazard ratio 0.72), with results consistent among patients with or without diabetes.^[6] SGLT2 inhibitors head the list of the novel targeted therapies now reaching IgA nephropathy trials, alongside endothelin receptor blockers, targeted-release budesonide and complement blockade.^[11]

An acute gross-haematuria episode is usually self-limiting — reassure, hydrate, and monitor renal function over days. Transient AKI during severe gross haematuria (the gross-haematuria-AKI syndrome of tubular obstruction and injury by red cells) usually recovers with supportive care and rarely needs temporary dialysis; if AKI is severe or prolonged, repeat biopsy to exclude superimposed crescentic change.^[1]

The escalation ladder — when supportive care is not enough

The escalation pathway follows one logic: everyone gets optimised supportive care; patients with persistent proteinuria step up only after months of that care; rapidly progressive crescentic disease bypasses the ladder to urgent immunosuppression. The trials anchored escalation to proteinuria that persists despite optimised RAAS blockade — over at least 3 months of optimised background care in TESTING, a 6-month run-in in STOP-IgAN.^[3][4]

^{[3] [4] [5] [6] [9] [1]}

Step 3 — targeted-release budesonide (Nefecon) is an oral formulation designed to act at the gut mucosal level — the compartment where the upstream problem lives, since the galactose-deficient IgA1 of the multi-hit model is probably derived from the mucosal immune system.^[2][5] The NefIgArd trial (Lancet 2023, 2-year results) randomly assigned adults with primary IgA nephropathy and persistent proteinuria despite optimised RAAS blockade to Nefecon 16 mg once daily for 9 months followed by 15 months off drug: the time-weighted average eGFR over 2 years favoured Nefecon by 5.05 mL/min per 1.73 m2, with a durable reduction in proteinuria supporting a disease-modifying effect, and a safety profile as expected for a locally acting oral budesonide product.^[5]

Step 4 — systemic steroids are selective, and two trials set the boundary. The TESTING trial (JAMA 2017) used oral methylprednisolone 0.6 to 0.8 mg/kg/day (maximum 48 mg/day) for 2 months with weaning over 4 to 6 months; recruitment was discontinued early because of excess serious adverse events — 14.7 versus 3.2 percent, mostly serious infections (8.1 versus zero percent, including 2 deaths) — even though the renal outcome pointed to benefit (5.9 versus 15.9 percent, hazard ratio 0.37).^[3] The long-term follow-up (JAMA 2022, 503 participants) confirmed the renal benefit — primary composite outcome 28.8 versus 43.1 percent, hazard ratio 0.53 — after the excess of serious infections had led to a dose reduction to 0.4 mg/kg/day (maximum 32 mg/day) and antibiotic prophylaxis for Pneumocystis pneumonia, with adverse events increased mainly on high-dose therapy.^[9] Against that, STOP-IgAN (NEJM 2015) showed adding immunosuppression to optimised supportive care gave no significant improvement at 3 years, with more adverse effects.^[4]

Net position: systemic steroids are selective, not routine. For patients at high risk of progression, the 2021 KDIGO guideline — as summarised in the 2023 Nature Reviews Disease Primers primer — suggests considering a 6-month course of systemic corticosteroids, but the efficacy of systemic steroid treatment is under debate and serious adverse effects are common, so the decision follows an honest discussion of infection risk; the TESTING experience argues for the reduced 0.4 mg/kg/day regimen with antibiotic prophylaxis for Pneumocystis pneumonia where steroids are used.^[9][11]

Step 4 emerging — sparsentan and the complement and B-cell pipeline. Sparsentan, a dual endothelin-A and angiotensin receptor antagonist, beat irbesartan for proteinuria reduction in the PROTECT trial (Lancet 2023, 2-year results). Behind it: iptacopan (oral factor B inhibitor of the alternative pathway), ravulizumab and crovalimab (anti-C5), and B-cell depletion and BAFF-APRIL inhibition (sibeprenlimab, atacicept) targeting upstream Gd-IgA1 production.^[10]

The high-yield negative: mycophenolate mofetil is NOT effective in IgA nephropathy — the evidence base does not support it, and KDIGO recommends against it as monotherapy for proteinuria reduction. This negative is a recurring exam point.^[7]

The trials that wrote the guidelines

Six trials built the modern IgA nephropathy guideline — know each by name, intervention, and result.^[7]

Regional deltas

The diagnostic and management framework (biopsy for IgA, MEST-C, RAAS plus SGLT2, selective immunosuppression) is globally consistent, but the thresholds and the add-ons bend to resources and local practice.^[7]

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The danger — crescentic IgA nephropathy (read sober)

A crescent on the biopsy is the one finding that bypasses the supportive-care ladder. Rapidly progressive (crescentic) IgA nephropathy presents with AKI, dysmorphic red cells, red-cell casts, and C1 or C2 crescents on biopsy — and it mimics ANCA-associated vasculitis, anti-GBM disease and lupus nephritis closely enough that serology and biopsy are sent together but treatment is not delayed for either.^[1]

Treatment is urgent immunosuppression, and the pathology evidence is unusually direct: endocapillary hypercellularity and cellular crescents are the lesions shown to be responsive to immunosuppressive therapy — the one biopsy finding for which a treatment response is documented, even though confirmation in prospective randomised controlled trials is still awaited.^[1] In practice the rapidly progressive course is treated with intensive glucocorticoid-based immunosuppression as for other crescentic glomerulonephritides, while the serology that excludes the mimics — ANCA, anti-GBM, ANA — is sent in parallel without delaying treatment. Extensive crescentic change is the cue to escalate, not to observe.^[1]

^{[1] [3] [5]}

For those who reach ESKD, dialysis (haemo- or peritoneal) and transplantation follow; IgA nephropathy recurs in the graft in approximately 20 to 50 percent of recipients — usually mild subclinical mesangial IgA on protocol biopsy, occasionally aggressive and a cause of graft loss. Living-donor transplant offers the best outcomes; counsel both parties about recurrence.^[1]

The mantra, and the mnemonic

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The mantra: Synpharyngitic timing, normal complement, mesangial IgA on the biopsy — supportive care first, immunosuppression selective, and a crescent skips the queue.^[1][7]

^{[1] [3] [4] [5] [9] [11]}

Ward-round test — three stems, thirty seconds each

Stem 1 — cola urine two days after a sore throat (answer)ShowHide

A 22-year-old man has cola-coloured urine two days after a sore throat; C3 is normal. In the next bay, a 9-year-old has smoky urine and oedema three weeks after impetigo; C3 is low. Name both, and the one discriminator that settles it. Model: The first is IgA nephropathy — synpharyngitic haematuria with a normal complement, one end of a spectrum that runs from asymptomatic microscopic haematuria to rapidly progressive glomerulonephritis.^[11] The second is post-streptococcal GN — latent haematuria after impetigo with a low C3 and a raised ASO. The single discriminator is timing plus complement: haematuria with the infection versus weeks after it, normal C3 versus low C3. Biopsy the adult if the diagnosis is in doubt or proteinuria persists — at or above 1 g/day is where the escalation trials begin; the child gets supportive care.^[3]

Stem 2 — the biopsy that cannot wait (answer)ShowHide

A 30-year-old with known IgA nephropathy returns with a creatinine that has doubled in two weeks, dysmorphic red cells, red-cell casts, and crescents on biopsy (C2). What changes in the next 24 hours? Model: This is rapidly progressive (crescentic) IgA nephropathy — it bypasses the supportive-care ladder. The pathology evidence is direct: cellular crescents are the lesion shown to be responsive to immunosuppressive therapy, so the answer is urgent immunosuppression with intensive glucocorticoid-based treatment as for other crescentic glomerulonephritides, while ANCA, anti-GBM and ANA are sent in parallel to exclude the mimics — a C2 score is the cue to escalate, not to observe.^[1]

Stem 3 — the registrar who reaches for steroids first (answer)ShowHide

A 28-year-old with IgA nephropathy has proteinuria 0.8 g/day, eGFR 75, BP 128 over 78 on ramipril. The registrar wants to start systemic steroids today. What is the right next step, and why is the answer no? Model: The foundation is optimised supportive care — add an SGLT2 inhibitor (empagliflozin 10 mg once daily) to the RAAS blocker and re-treat blood pressure to target. Steroids are selective, not routine: STOP-IgAN, which used a 6-month supportive-care run-in before randomising persistent proteinuria at or above 0.75 g/day, showed no added benefit when immunosuppression is piled onto optimised supportive care, with more adverse effects; and TESTING showed real infection risk alongside its renal benefit. Only proteinuria persisting at or above roughly 1 g/day after months of optimised care, in a high-risk patient, brings targeted-release budesonide or a reduced-dose steroid course into play.^[3][4][5][6]

References12ShowHide

1. [1]Roberts IS. Pathology of IgA nephropathy. Nature Reviews Nephrology, 2014.PMID 24861083
2. [2]Cheung CK, Alexander S, Reich HN, et al. The pathogenesis of IgA nephropathy and implications for treatment. Nature Reviews Nephrology, 2025.PMID 39232245
3. [3]Lv J, Zhang H, Wong MG, et al. Effect of oral methylprednisolone on clinical outcomes in patients with IgA nephropathy: the TESTING randomized clinical trial. JAMA, 2017.PMID 28763548
4. [4]Rauen T, Eitner F, Fitzner C, et al. Intensive supportive care plus immunosuppression in IgA nephropathy. New England Journal of Medicine, 2015.PMID 26630142
5. [5]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. The Lancet, 2023.PMID 37591292
6. [6]Herrington WG, Staplin N, Wanner C, et al. Empagliflozin in patients with chronic kidney disease. New England Journal of Medicine, 2023.PMID 36331190
7. [7]Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 clinical practice guideline for the management of glomerular diseases. Kidney International, 2021.PMID 34556256
8. [8]Cattran DC, Coppo R, Cook HT, et al. The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility. Kidney International, 2009.PMID 19571790
9. [9]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.PMID 35579642
10. [10]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. The Lancet, 2023.PMID 37931634
11. [11]Stamellou E, Seikrit C, Tang SCW, et al. IgA nephropathy. Nature Reviews Disease Primers, 2023.PMID 38036542
12. [12]Pattrapornpisut P, Avila-Casado C, Reich HN. IgA Nephropathy: Core Curriculum 2021. American Journal of Kidney Diseases, 2021.PMID 34247883