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]

[1]

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]

[8]

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 five faces of one lesion

The same mesangial IgA lesion wears five clinical masks, and a candidate must recognise each:[1]

[1]

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]

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]

[1] [1]

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. Dysmorphic RBCs (acanthocytes) and red-cell casts confirm a glomerular source and separate IgA nephropathy from urological bleeding.
• Proteinuria quantification. Spot PCR or ACR on a first-morning sample; PCR over 0.5 to 1 g/day (ACR over 30 mg/mmol) is the biopsy trigger and nephrology-referral threshold.
• Serum creatinine and eGFR — stage and trend. Serum IgA is raised in up to half but is non-specific and non-diagnostic; a normal level does not exclude the disease.
• Complement C3 and C4 — typically NORMAL; a frankly low C3 redirects to post-strep GN (low C3, normal C4), lupus (low C3 and C4) or endocarditis-associated GN.
• Exclude-mimic serology. 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.[1]

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: suspected IgA nephropathy plus any of — proteinuria over 0.5 to 1 g/day, rising or elevated creatinine, hypertension, or atypical features (active sediment suggesting RPGN, nephrotic syndrome, suspected systemic disease). Isolated microscopic haematuria with normal renal function and minimal proteinuria (under 0.5 g/day) may be monitored without biopsy — but persistent or rising proteinuria shifts the balance to biopsy.[1]

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

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:[1]

• RAAS blockade first-line. An ACE inhibitor or ARB for every patient with proteinuria over 0.5 to 1 g/day — for example ramipril 2.5 mg orally once daily, titrated to 10 mg/day, or losartan 50 mg orally once daily, titrated to 100 mg/day. It lowers intraglomerular pressure and reduces proteinuria independent of systemic blood pressure. Check creatinine and potassium within 1 to 2 weeks of starting or dose change; accept a creatinine rise up to 30 percent; do not stop for asymptomatic potassium under 6.0 mmol/L. Avoid in bilateral renal artery stenosis and pregnancy.
• Blood pressure target under 130/80 mmHg — under 125/75 mmHg if proteinuric. Add a dihydropyridine calcium-channel blocker (amlodipine 5 to 10 mg/day) or a diuretic as needed.
• Proteinuria reduction is the central goal — sustained proteinuria reduction is the strongest modifiable predictor of a good outcome.
• Lifestyle. Smoking cessation, salt restriction (under 5 to 6 g sodium per day), weight optimisation, exercise, avoidance of nephrotoxins (NSAIDs, herbal remedies, iodinated contrast without cover).
• Cardiovascular risk reduction. IgA nephropathy is a cardiovascular-risk equivalent in CKD — statin per CKD guidance, glycaemic control if diabetic, antiplatelet for established vascular disease.[1]

The single most important modern addition to the foundation is the SGLT2 inhibitor — dapagliflozin 10 mg/day or empagliflozin 10 mg/day — for proteinuric CKD regardless of diabetes. EMPA-KIDNEY (2023) showed empagliflozin slowed CKD progression across primary kidney diseases including glomerular disease, with consistent benefit in IgA nephropathy. Watch volume status, genital mycotic infection, and euglycaemic ketoacidosis in diabetics; stop in pregnancy and around acute illness or surgery.[6]

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 supportive care; high-risk patients with persistent proteinuria step up after 90 days; crescentic disease bypasses the ladder to urgent immunosuppression. The decision is anchored on the Prediction Tool and the proteinuria response to optimised supportive care over at least 90 days.[7]

[7]

Step 3 — targeted-release budesonide (Nefecon) delivers budesonide to the distal ileum — the Peyer's-patch-rich region where Gd-IgA1-producing mucosal B cells live — to down-regulate the upstream autoimmune process. The NefIgArd trial (Lancet 2023, 2-year results) showed proteinuria reduction and slowed eGFR decline in high-risk IgA nephropathy. The regimen is 16 mg orally once daily for 9 months, then taper to 12 mg then 8 mg. Expect glucocorticoid effects (blood pressure, glucose, bone) despite gut targeting; it does not replace supportive care.[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 tapering over 6 to 8 months and reduced kidney failure — but with a significant increase in serious infections, including a high-dose arm (0.8 to 1 mg/kg/day) stopped early. The long-term follow-up (JAMA 2022) confirmed durable renal benefit at the modified lower dose of 0.4 to 0.6 mg/kg/day with Pneumocystis prophylaxis and bone and GI protection — the regimen now used in practice. Against that, STOP-IgAN (NEJM 2015) showed adding immunosuppression to optimised supportive care gave no added renal benefit at 3 years.[3][4][9]

Net position (KDIGO 2021): a short course of systemic steroids may be considered in selected high-risk patients with preserved GFR (usually over 30 to 50 mL/min) after an honest discussion of infection risk — they are NOT routine. Add Pneumocystis prophylaxis (co-trimoxazole 480 mg once daily or three times weekly) for prolonged courses, with glucose, blood pressure and bone-density surveillance.[7]

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]

[7]

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]

Induce urgently, as for ANCA-associated vasculitis: pulse methylprednisolone 0.5 to 1 g IV daily for 3 days, then oral prednisolone 1 mg/kg/day (max 60 to 80 mg/day) tapering, plus cyclophosphamide 2 mg/kg/day orally (or IV pulse 15 mg/kg every 2 weeks, age- and GFR-adjusted) for 3 to 6 months; then maintain with azathioprine or mycophenolate plus low-dose prednisolone. Plasma exchange has a limited role in selected severe cases. A C1 or C2 score is the trigger to escalate — not to observe.[1]

[1]

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

[8]

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

[7]

Ward-round test — three stems, thirty seconds each

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

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 (1 to 2 days) with a normal complement. The second is post-streptococcal GN — latent haematuria (1 to 3 weeks) with a low C3 and a raised ASO. The single discriminator is timing plus complement: synpharyngitic and normal C3 versus latent and low C3. Biopsy the adult only if proteinuria is over 0.5 to 1 g/day or function falls; the child gets supportive care and usually resolves.[1]

Stem 2 — the biopsy that cannot wait (answer)

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. Induce urgently as for ANCA-associated vasculitis: pulse methylprednisolone 0.5 to 1 g IV daily for 3 days, then oral prednisolone 1 mg/kg/day plus cyclophosphamide 2 mg/kg/day for 3 to 6 months, then maintenance with azathioprine or mycophenolate plus low-dose prednisolone. Send ANCA, anti-GBM and ANA to exclude the mimics, but do not wait for them — a C2 score is the trigger to escalate, not to observe.[1]

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

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/day) to the RAAS blocker, confirm BP is under 130 over 80, and reassess proteinuria at 90 days. Steroids are selective, not routine: STOP-IgAN showed no added benefit when immunosuppression is piled on without optimised supportive care, and TESTING showed real infection risk. Only persistent proteinuria over 0.75 to 1 g/day at 90 days, in a high-risk patient with preserved GFR, brings targeted-release budesonide or a modified low-dose steroid course into play.[4][6][7]

References

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