IgA Nephropathy & IgA Vasculitis

The contract between this chapter and the reader.

1. 1. Define IgA nephropathy as the commonest GN and its lesion.
2. 2. Explain the multi-hit pathogenesis (galactose-deficient IgA1).
3. 3. Recognise IgA vasculitis as the systemic form.
4. 4. Recognise the clinical presentations.
5. 5. Diagnose with biopsy (mesangial IgA, MEST-C).
6. 6. Apply supportive therapy (RAAS, SGLT2) as the foundation.
7. 7. Use immunosuppression and newer agents appropriately.
8. 8. Manage crescentic IgA and IgA vasculitis.
9. 9. Understand the prognosis and the evolving evidence.

A sixty-second reading. Each bullet stands alone.

• IgA nephropathy is the commonest glomerulonephritis worldwide.
• It is caused by mesangial deposition of galactose-deficient IgA1 immune complexes.
• The “multi-hit” pathogenesis: galactose-deficient IgA1, anti-glycan antibodies, immune complexes, and mesangial deposition.
• IgA vasculitis (Henoch-Schönlein purpura) is the systemic form, with purpura, arthritis, abdominal pain, and nephritis.
• It presents with synpharyngitic gross hematuria, or with asymptomatic hematuria and proteinuria.
• Biopsy shows mesangial IgA-dominant deposits; the MEST-C score is prognostic.
• There is no reliable serum diagnostic test.
• Supportive therapy — RAAS blockade and SGLT2 inhibition — is the foundation for all with proteinuria.
• Corticosteroids are used cautiously for high-risk disease, balancing benefit against infection.
• Newer agents include targeted-release budesonide and a dual endothelin/angiotensin antagonist.
• Crescentic IgA nephropathy is treated like other crescentic GN with immunosuppression.
• IgA vasculitis is often self-limiting, with immunosuppression for significant nephritis.
• Proteinuria is the key modifiable predictor and the therapeutic target.

The medical core. An expert should agree IgA nephropathy and IgA vasculitis are fully covered here.

Why it matters at the bedside

IgA nephropathy is the commonest glomerulonephritis on Earth, and for decades it offered little to do beyond blood-pressure control and watching. That has changed fast: a clear pathogenic story, a supportive foundation that now includes SGLT2 inhibitors, and a wave of new targeted drugs have made it one of the most actively evolving areas in nephrology — with proteinuria as the number to chase.

What it is: the commonest GN

• IgA nephropathy is defined by mesangial deposition of IgA1 — specifically galactose-deficient IgA1 — in immune complexes. On the biopsy it is the mesangial-IgA-dominant disease of the first chapter; clinically it is extraordinarily common and ranges from a benign, incidental microscopic haematuria to a relentlessly progressive nephritis. Its sheer frequency makes it a disease every clinician meets.

The multi-hit pathogenesis

• The mechanism is a four-step ‘multi-hit’ cascade: first, galactose-deficient IgA1 is produced; second, anti-glycan autoantibodies recognise it; third, the two form circulating immune complexes; and fourth, those complexes deposit in the mesangium, triggering proliferation, complement activation, and inflammatory injury. Each hit is a potential drug target, which is exactly what the new therapies exploit.

IgA vasculitis: the systemic form

• IgA vasculitis (formerly Henoch-Schönlein purpura) is the systemic expression of the same IgA deposition, depositing not only in the kidney but in the skin (palpable purpura, classically on the lower limbs), the joints (arthritis), and the gut (abdominal pain, gastrointestinal bleeding). It is commoner in children and usually self-limiting, but the renal involvement can be significant and occasionally severe.

Clinical presentations

• IgA nephropathy presents in two classic ways: synpharyngitic gross haematuria — visible haematuria during or just after an upper respiratory infection — or, more often, asymptomatic microscopic haematuria with proteinuria found incidentally. The course is highly variable, from indolent and stable to progressive, and occasionally crescentic and rapidly progressive. IgA vasculitis presents with its tetrad of purpura, arthritis, abdominal pain, and nephritis.

Diagnosis: biopsy and MEST-C

• The diagnosis is histologic — there is no reliable serum test (a raised serum IgA is neither sensitive nor specific). The biopsy shows mesangial IgA-dominant deposits on immunofluorescence (the defining finding) with mesangial proliferation on light microscopy, and is graded by the Oxford MEST-C score — Mesangial hypercellularity, Endocapillary hypercellularity, Segmental sclerosis, Tubular atrophy, and Crescents — which carries prognostic weight. IgA vasculitis is often diagnosed clinically from the purpura, with biopsy when the nephritis needs characterising.

Supportive therapy: the foundation

• For everyone with proteinuria, the foundation is supportive and must be optimised before anything else: RAAS blockade to reduce proteinuria and control blood pressure, an SGLT2 inhibitor (now established in proteinuric chronic kidney disease including IgA), and lifestyle measures. Many patients are well controlled on this alone, and optimising it is the precondition for considering immunosuppression.

Immunosuppression and the steroid controversy

• Whether to add corticosteroids for high-risk disease — persistent significant proteinuria despite optimised supportive care — is genuinely contested. The TESTING trial showed that steroids reduce progression but at the cost of significant infection and other toxicity, so they are used cautiously, in selected high-risk patients, with the risks weighed and mitigated. The era of reflexive steroids for IgA has passed.

Newer agents

• A wave of targeted therapies now extends the options: targeted-release budesonide, a gut-directed corticosteroid that reduces the production of galactose-deficient IgA1 at its mucosal source (with proteinuria benefit in trials); a dual endothelin-and-angiotensin receptor antagonist that reduces proteinuria; and complement-pathway inhibitors in development. These map directly onto the multi-hit mechanism, attacking it at different points.

Crescentic IgA and IgA vasculitis

• Two situations call for more. Crescentic IgA nephropathy presenting as rapidly progressive glomerulonephritis is treated like other crescentic disease, with immunosuppression (corticosteroids, sometimes with cyclophosphamide) — a renal emergency. And IgA vasculitis, though usually self-limiting and managed supportively, warrants immunosuppression when the nephritis is significant or progressive.

Prognosis and the evolving evidence

• Prognosis is variable but matters: although many patients are indolent, a substantial fraction progress to kidney failure over years to decades. The predictors — proteinuria (the key modifiable one), hypertension, reduced GFR, and the MEST-C score (crescents and sclerosis worst) — guide risk, and proteinuria reduction is the therapeutic target and the surrogate on which the new trials rest. The evidence is changing rapidly, and IgA nephropathy is now a disease in therapeutic motion.

Five fully-built tables.

Table A — The disease at a glance

Table B — The multi-hit pathogenesis

Table C — Presentations

Table D — Treatment

Table E — Prognostic predictors (MEST-C)

Visualise & Map

Causal chains, each ending in a named action.

Chain 1 — The multi-hit

Galactose-deficient IgA1 + anti-glycan antibody → immune complexes → mesangial deposition and inflammation → nephritis → ACTION: reduce proteinuria (RAAS, SGLT2) and target the mechanism.

Chain 2 — The fingerprint

IgA1 complexes deposit in the mesangium → dominant mesangial IgA on immunofluorescence → the diagnostic finding → ACTION: biopsy and score MEST-C.

Chain 3 — The driver of progression

Persistent proteinuria → ongoing nephron injury → progression to kidney failure → ACTION: target proteinuria as the key modifiable predictor.

Chain 4 — The high-risk patient

Proteinuria persists despite optimised supportive therapy → high progression risk → a case for escalation → ACTION: consider corticosteroids (weighing infection) or a newer agent.

Chain 5 — The crescentic turn

Severe IgA injury → crescents → rapidly progressive glomerulonephritis → ACTION: immunosuppress urgently as for other crescentic GN.

Numbered rules. These numbers are the cross-reference handle for the cases and flowcharts.

Clinical Reasoning

Five cases. Each stops you at a decision before it answers it.

Every mechanism from Level 3 earns a bedside consequence and an action.

Exhaustive. Every rule in the chapter is here.

Safety & Evidence

Panel A — Red flags

Panel B — NEVER DO

Anti-patterns clinicians fall into. Each becomes a Level 22 distractor.

The grade reflects strength of evidence, not importance.

Patient Decisions

Outcomes as natural frequencies. Figures are representative; the direction of effect is given where precise numbers are uncertain.

Apply & Test

Copy-paste chart notes that map to the real decisions in this chapter.

Template 1 — IgA diagnosis / risk note

• Presentation: synpharyngitic haematuria / microscopic haematuria + proteinuria; vasculitis features ___.
• Biopsy: mesangial IgA-dominant; MEST-C score ___.
• Risk: proteinuria level; BP; GFR; crescents/sclerosis ___.
• Systemic (IgA vasculitis) features: purpura, arthritis, abdominal pain ___.
• Risk category: low / high / crescentic ___.

Template 2 — Treatment-escalation note

• Foundation: RAAS blockade; SGLT2 inhibitor; BP; lifestyle ___.
• Proteinuria response to optimised support: ___.
• Escalation (high-risk): corticosteroids (infection risk weighed) / targeted-release budesonide / endothelin-angiotensin antagonist ___.
• Crescentic / RPGN: immunosuppression ___.
• IgA vasculitis: supportive / immunosuppression for nephritis ___.

Pre-rounds compression. Rules only.

Active recall. At least one card per objective.

Micro-teaching for rounds. Two scenarios, five steps each.

Metacognition anchored to this chapter's tensions. No answers provided.

1. 1. Steroids reduce progression but cause serious infection; how do you decide for whom the trade is worth it, knowing the future risk is only a probability?
2. 2. The new trials use proteinuria as a surrogate for hard outcomes; how much should a proteinuria response, short of proven kidney survival, drive your prescribing?
3. 3. The evidence is changing yearly; how do you adopt promising new agents without abandoning the discipline of optimising the cheap, proven foundation first?
4. 4. Much IgA is indolent and much progresses; how do you communicate a prognosis that is genuinely uncertain for the individual in front of you?
5. 5. Each hit of the multi-hit cascade is now a drug target; how do you choose among mechanisms when several agents each lower proteinuria?

Nine items, each anchored in this chapter. At least one per objective.