• Most common primary glomerulonephritis worldwide ^[1][2]
• Accounts for ~25–50% of all primary GN in East and Southeast Asia
• In Western countries it accounts for ~10–20% of primary GN (less common but still the most frequent single entity)

• IgA nephropathy is extremely common in our locality ^[2][3]
• In Hong Kong renal biopsy registries, IgAN is consistently the number one cause of primary GN
• Higher prevalence in East Asians (Chinese, Japanese, Korean) — partly genetic, partly detection bias (many Asian countries have school/workplace urinalysis screening programmes)

• Peak incidence: 2nd–3rd decade of life (adolescents and young adults, typically 15–35 years)
• Male predominance (M:F ≈ 2–3:1 in most series)
• Rare before age 5, uncommon after age 50 (though can present at any age)

• Not a benign disease: ~30–40% of patients progress to end-stage kidney disease (ESKD) over 20–30 years ^[2]
• In Hong Kong, IgAN is one of the leading causes of ESKD requiring dialysis/transplant in young adults

Understanding IgAN requires understanding where immune complexes deposit and what that disrupts:

The nephron is the functional unit of the kidney (~1 million nephrons at birth). Each nephron includes the glomerulus and the renal tubules. Blood goes through the glomerulus and gives rise to the cell-free filtrate (urine). Normally no plasma protein or red cells are in the urine. ^[4]

The glomerular filtration barrier consists of three layers (from blood to Bowman's space):

1. Fenestrated endothelium — allows passage of plasma but not cells
2. Glomerular basement membrane (GBM) — a negatively charged mesh of type IV collagen, laminin, and proteoglycans; repels albumin (also negatively charged)
3. Podocytes (visceral epithelial cells) — interdigitating foot processes with slit diaphragms; the final size-selective barrier

The mesangium is the central supportive tissue within the glomerular tuft, consisting of:

• Mesangial cells — modified smooth muscle cells with contractile, phagocytic, and secretory functions
• Mesangial matrix — extracellular matrix between mesangial cells

The mesangium has two critical functions:

1. Structural support — provides scaffolding for glomerular capillary loops
2. Immune complex clearance — mesangial cells normally phagocytose and clear immune complexes and macromolecules filtered from the blood

In IgA nephropathy, the mesangium is overwhelmed by abnormal IgA1-containing immune complexes that it cannot clear adequately → deposition → inflammation → mesangial proliferative GN.

Why the mesangium? Because the mesangium is the "garbage disposal" of the glomerulus. When defective IgA1 circulates and forms complexes, these complexes get trapped in the mesangium — exactly where the clearance system normally operates. It's like overloading a waste-processing plant.

The vast majority of IgAN is primary/idiopathic — meaning it arises from an intrinsic immunological defect rather than from an identifiable systemic disease.

IgA can deposit in the mesangium secondarily in the context of other diseases. Always consider these before labelling a case "primary IgAN":

In Hong Kong, hepatitis B is particularly relevant as a secondary cause of IgA deposition due to its endemic prevalence. Always check HBsAg.

• GWAS studies have identified susceptibility loci on chromosomes 6p (HLA region), 1q32 (complement factor H), 22q12 (HORMAD2), 17p13, and others
• Family clustering occurs but there is no single gene or Mendelian inheritance pattern — it is polygenic ^[2][3]
• IgAN runs in families, but no particular mode of inheritance, no one gene ^[3]

• Normal IgA1 has an O-glycosylated hinge region with terminal galactose residues
• In IgAN patients, there is a deficiency of the enzyme β1,3-galactosyltransferase (C1GalT1) in IgA1-producing B cells
• This leads to under-galactosylation of the IgA1 hinge region → Gd-IgA1
• Gd-IgA1 exposes N-acetylgalactosamine (GalNAc) residues that are normally hidden

Why does this matter? Gd-IgA1 has exposed neoepitopes (sugar residues that shouldn't be visible). These become targets for autoantibody production. It's the spark that starts the fire.

Where is IgA1 produced? Predominantly in mucosal-associated lymphoid tissue (MALT) — particularly the tonsillar and gut mucosal immune system. This explains the clinical link between URTI/mucosal infection and haematuria episodes.

• The exposed GalNAc residues on Gd-IgA1 are recognized as "foreign" by the immune system
• Anti-glycan IgG and IgA autoantibodies are produced against these neoepitopes
• These autoantibodies bind to the abnormally glycosylated IgA1

• Gd-IgA1 + autoantibodies form circulating immune complexes
• These complexes are large, poorly cleared by the liver (hepatic asialoglycoprotein receptor has reduced affinity for Gd-IgA1)
• Hence they circulate in excess

• Immune complexes deposit in the mesangium (because that's where the glomerular clearance system is)
• Deposited complexes trigger:
  • Complement activation — particularly the alternative and lectin pathways (C3 is commonly co-deposited with IgA, but C1q is usually absent → classical pathway NOT activated)
  • Mesangial cell proliferation → mesangial expansion
  • Cytokine and growth factor release (TGF-β, PDGF, IL-6)
  • Extracellular matrix production → mesangial sclerosis
  • Podocyte injury → proteinuria
  • Endocapillary inflammation in more severe cases → crescent formation

C3 is commonly co-deposited but C1q is usually absent — this is because IgA does NOT fix complement via the classical pathway (IgA cannot bind C1q). Instead, it activates complement via:

• Alternative pathway (C3 directly)
• Lectin pathway (mannose-binding lectin, MBL)

This is important for differentiating IgAN from lupus nephritis (where C1q IS deposited → "full house" pattern).

The Oxford Classification (2009, updated 2016 with "C") is the internationally validated histological classification for IgA nephropathy based on renal biopsy findings. It uses the MEST-C scoring system ^[1][2]:

IgAN presents along a spectrum of clinical severity:

The International IgAN Prediction Tool (2019) integrates clinical data (age, eGFR, BP, proteinuria, race) with MEST-C biopsy score to predict individual risk of 50% eGFR decline or ESKD — used for risk stratification and treatment decisions.

These are critical for clinical management and prognosis:

This is the classic IgAN presentation. The three main glomerular causes of recurrent haematuria are commonly tested together ^[2][3]:

Within the renal causes of haematuria, three glomerular causes: (1) IgA nephropathy → common in our locality, (2) Alport's syndrome (hereditary nephritis), (3) Thin membrane disease (benign familial haematuria) ^[3]

History + urinalysis of family members helps distinguish the three glomerular causes of haematuria ^[3]

The key clinical question to separate these three at the bedside: Is there a family history of renal failure or deafness? If yes → think Alport. Is the gross haematuria temporal with URTI? If yes → think IgAN. Is it just persistent microscopic haematuria with benign course and no progression? → think TBMD.

When IgAN presents as acute nephritic syndrome (haematuria + proteinuria + hypertension + oedema + reduced GFR), the DDx includes all causes of nephritic syndrome:

Proliferative (Nephritic) GN — Primary: IgA nephropathy, Membranoproliferative GN, Rapidly progressive (Crescentic) GN. Secondary: Post-streptococcal GN, Lupus nephritis, MPGN (HBV/HCV, autoimmune, malignancy-related), RPGN ^[11][12]

When IgAN presents with rapidly declining renal function (crescent formation), it enters the RPGN differential. RPGN is a clinical syndrome, NOT a specific aetiological form of GN ^[15][16][17].

Classification of RPGN based on IF staining pattern ^[15][16][17]:

IgAN with crescentic transformation falls under Type II RPGN (granular IgA deposits). The crescent itself is a non-specific response to severe glomerular capillary wall injury — massive movement of plasma products into Bowman's space → macrophage/T-cell influx → cellular crescent → fibroblast proliferation → fibrous crescent (unlikely to respond to immunosuppression) ^[15][16][17].

Before you jump to IgAN, you must exclude non-glomerular causes of haematuria. Three large aetiological groups causing haematuria: (1) Urologic conditions (stones, tumour), (2) Renal conditions (GN, acute interstitial nephritis, polycystic kidney disease), (3) Infection (cystitis, TB, schistosomiasis) ^[3]

Most common cause of haematuria: UTI (60%). Most worrying: malignancy (until proven otherwise) ^[5]

The clinical differentiation is critical:

All Hb-positive dipstick should be accompanied by urine microscopy to differentiate haematuria vs pigmenturia ^[5]

Antiplatelet/anticoagulant use is NOT a satisfactory explanation for haematuria, except in warfarin OD ^[5]

Why do we need all three? LM tells you the pattern of injury (how bad is it?), IF tells you the causative mechanism (what is deposited and where?), and EM tells you the ultrastructural detail (exactly where are the deposits relative to the GBM?). Together, they give a complete picture. This is why kidney biopsy for definitive diagnosis of glomerular and tubulointerstitial disorder requires light microscopy (H&E, PAS, silver staining, Congo red staining), immunofluorescence, and electron microscopy ^[19].

While biopsy is definitive, you don't biopsy every patient with microscopic haematuria. Clinical criteria that raise suspicion and may trigger biopsy include:

• Recurrent synpharyngitic macroscopic haematuria in a young adult ^[14][20]
• Persistent microscopic haematuria with proteinuria > 0.5–1 g/day ^[14][20]
• Declining GFR (rising creatinine) in the context of urinary abnormalities
• Hypertension with active urinary sediment
• Clinical features consistent with glomerular disease (dysmorphic RBCs, RBC casts)

Renal biopsy is necessary for most cases of nephritic syndrome unless very small kidney on USG ^[22][23]

Renal biopsy is indicated in patients with glomerular haematuria or with risk factors for progressive diseases such as proteinuria or elevation in serum creatinine concentration ^[24]

Urinalysis: document glomerular haematuria, proteinuria and sterile pyuria ^[22][23]

Proteinuria + Haematuria + Dysmorphic RBCs + RBC casts = Proliferative glomerular disease (Nephritic pattern) ^[20]

Heavy proteinuria + NO haematuria = Non-proliferative glomerular disease (Nephrotic pattern) / DM nephropathy / Amyloidosis ^[20]

This is critical for both diagnosis and risk stratification:

Why is proteinuria quantification so important? Because proteinuria > 1 g/day is the single most important modifiable predictor of progression in IgAN. The level of proteinuria determines treatment intensity and biopsy indication.

Interpreting proteinuria levels:

• < 0.5 g/day: Mild; often observe
• 0.5–1 g/day: Moderate; consider biopsy and RAAS blockade

• 1 g/day: Significant; biopsy indicated, aggressive treatment needed

• 3.5 g/day: Nephrotic range (uncommon in IgAN, ~5%)

Commonly utilized investigations for glomerular disease ^[21][22][23]:

This is where you narrow the differential:

Someone comes in with high creatinine with a normal-sized kidney — what are you worried about? Acute kidney injury → parenchymal, vascular kidney problems → glomerulonephritis, etc. → will require a kidney biopsy ^[9]

Applied at biopsy. Already covered in Part 1, but restated for completeness:

MEST criteria used for renal biopsy grading in IgAN ^[20]

Integrates:

• Clinical variables: age, sex, race/ethnicity, eGFR at biopsy, MAP, proteinuria
• Histological variables: MEST-C scores
• Immunosuppression status

Outputs: Predicted risk of 50% eGFR decline or ESKD over 5–10 years. This guides treatment intensity (e.g., whether to add immunosuppression beyond supportive care).

BP control with ACEI/ARB ^[11][12][20]

Anti-proteinuric therapy by angiotensin inhibitor (ACEI/ARB) — Indication: in ALL glomerulonephropathy. MoA: ↓intraglomerular pressure → ↓proteinuria, which is associated with ↓rate of GFR decline. Goal: keep proteinuria < 1 g/day or uPCR < 0.5–1 g/g ^[27][28]

Why does efferent arteriolar dilation reduce proteinuria? Angiotensin II preferentially constricts the efferent arteriole (more than the afferent). This maintains high intraglomerular pressure to preserve GFR when renal perfusion drops. But in IgAN, this high pressure pushes more protein through the damaged filter. By blocking angiotensin II, the efferent arteriole dilates → pressure in the glomerular capillaries drops → less protein is forced through → proteinuria improves.

Contraindications to ACEI/ARB:

• Bilateral renal artery stenosis (removes the only mechanism maintaining GFR — efferent arteriolar constriction by angiotensin II is the sole lifeline) ^[19][29]
• Pregnancy (teratogenic — causes renal agenesis, oligohydramnios, pulmonary hypoplasia) ^[29]
• Hyperkalaemia (K+ > 5.5 mmol/L)
• Previous angioedema (especially with ACEI)
• Severe bilateral stenosis of renal arteries or single functioning kidney with stenosis

Side effects:

• Cough (ACEI) — due to accumulation of bradykinin → switch to ARB if intolerable ^[29]
• Hyperkalaemia (reduced aldosterone → reduced K+ excretion) ^[29]
• Hypotension ^[29]
• Angioedema (rare but serious) ^[29]

Chronic kidney disease → compelling indication for ACEI or ARB ^[30]

RAAS blockade has renoprotective effects — ARB-induced renal vasodilation results in an increase in renal blood flow, leading to improvement of renal ischaemia and hypoxia. ARBs are also effective in reducing urinary albumin excretion through a reduction in intraglomerular pressure and the protection of glomerular endothelium and/or podocyte injuries ^[31]

This is a major addition to IgAN management since the DAPA-CKD (2020) and EMPA-KIDNEY (2023) trials, and now directly endorsed by KDIGO 2024 guidelines for IgAN.

Why are SGLT2 inhibitors so important? They provide additional, independent nephroprotective benefit ON TOP of RAAS blockade. Their mechanism is complementary — ACEI/ARB dilates the efferent arteriole, while SGLT2i constricts the afferent arteriole. Together, they bring intraglomerular pressure down from both ends.

BP target < 130/80 mmHg (or < 125/75 if proteinuria > 1 g/day) per KDIGO 2021/2024.

• First-line: ACEI or ARB (already discussed — dual purpose)
• If BP not controlled on max ACEI/ARB: add calcium channel blocker (CCB) or thiazide diuretic
• Combination options: ACEI or ARB + CCB, or ACEI or ARB + thiazide ^[30]

Why is BP control so important? Hypertension accelerates glomerular damage through barotrauma — elevated systemic BP is transmitted to the glomerulus, especially when autoregulatory mechanisms are impaired in CKD. Every mmHg reduction in MAP translates to slower GFR decline.

Low salt and protein diet ^[11][12]

Control lipid and CV risk ^[9]

Avoid NSAIDs — they inhibit prostanoid production in the kidneys → impaired regulation of renal blood flow; can also cause acute tubulointerstitial nephritis (TIN) and direct glomerulonephritis ^[19]

Drugs can damage the kidneys in many ways [27a]

Monitor Q6-12 months ^[20]:

• Blood pressure
• Urine dipstick / uPCR (proteinuria quantification)
• Serum creatinine / eGFR
• Serum K+ (if on RAAS blockade)
• CBC (for anaemia of CKD if advanced)

This is the most important complication — and the entire management strategy exists to prevent it.

Slow and indolent yet progressive course over a period of 20–30 years. 5–30% undergo complete remission. 30% develop ESRD over 30 years ^[11][12]

Why does IgAN cause progressive CKD?

The mechanism follows a self-perpetuating cycle of glomerular injury → nephron loss → compensatory hyperfiltration → further injury:

1. Mesangial inflammation and sclerosis — chronic IgA immune complex deposition drives ongoing mesangial proliferation and extracellular matrix accumulation → mesangial expansion → gradual obliteration of glomerular capillary lumina → reduced filtration surface area
2. Podocyte injury — inflammatory mediators (TGF-β, PDGF) damage podocytes → podocyte detachment → bare areas of GBM → segmental sclerosis (the "S" in MEST-C)
3. Tubulo-interstitial fibrosis — proteinuria itself is toxic to tubular cells. Filtered proteins are reabsorbed by proximal tubular cells, triggering a pro-inflammatory and pro-fibrotic response → interstitial inflammation → fibrosis (the "T" in MEST-C — the strongest histological predictor of ESKD)
4. Compensatory hyperfiltration — as nephrons are lost, remaining nephrons increase their single-nephron GFR to compensate. This adaptive response is ultimately maladaptive — elevated intraglomerular pressure accelerates sclerosis in the surviving nephrons (the Brenner hypothesis)

Why is proteinuria both a marker AND a driver of progression? Protein in the tubular lumen is not just an indicator of glomerular damage — it causes additional tubular damage. Albumin reabsorbed by proximal tubular cells triggers NF-κB activation → chemokine release (MCP-1, RANTES) → macrophage infiltration → TGF-β → fibroblast activation → interstitial fibrosis. This is why reducing proteinuria is the single most important therapeutic goal.

Laboratory findings in chronic GN: NcNc anaemia, ↑serum urea, creatinine, PO₄, ↓Ca ± ↑K⁺ and metabolic acidosis ^[34][36]

Small kidneys → CKD ^[10] — as nephrons are progressively lost and replaced by fibrotic tissue, the kidneys physically shrink.

The most feared acute complication. Approximately 5% of IgAN patients develop crescentic GN, which can lead to ESKD in days to weeks if untreated.

Why do crescents form? A non-specific response to severe injury to the glomerular capillary wall → massive movement of plasma products (including fibrin) into Bowman's space → subsequent massive influx of macrophages/T-cells → release of proinflammatory cytokines → formation of cellular crescent → followed by fibroblast proliferation and replacement by fibrous crescent (unlikely to respond to immunosuppressive treatment) ^[15][16][17]

• Cellular crescents = early, potentially reversible with aggressive immunosuppression
• Fibrous crescents = late, irreversible — the glomerulus is destroyed

This falls under Type II RPGN (granular IF pattern — immune complex mediated) and is a medical emergency.

Serum creatinine often > 250 μmol/L at diagnosis ^[15][16][17]

During episodes of gross haematuria, patients can develop AKI — this is important and often under-recognised.

Mechanism:

• Massive RBC passage through tubules → tubular obstruction by RBC casts
• Direct tubular cell toxicity from haem pigment (iron-catalysed free radical generation → oxidative damage to tubular epithelial cells)
• Analogous to myoglobin-induced AKI in rhabdomyolysis

Clinical features:

• Rising creatinine during or shortly after a gross haematuria episode
• Usually self-limited — resolves as haematuria clears
• Management: hydration, monitoring, avoid nephrotoxins. Rarely requires dialysis

This is different from RPGN — AKI here is from the sheer volume of blood in the tubules, not from crescentic inflammation. It typically resolves when the haematuria stops.

IgA nephropathy, membranous nephropathy, and focal segmental glomerulosclerosis are known to recur in the transplanted kidney — seems to be the ones that are immune-mediated → makes sense since the antibodies are still being produced, you haven't solved that issue yet ^[35]

• Histological recurrence: IgA mesangial deposits found in ~50–60% of allografts
• Clinically significant recurrence: ~20–35% over 10 years
• Graft loss from recurrence: ~10% at 10 years

Why does it recur? The transplant replaces the damaged kidney, but the immune defect persists — the patient still has abnormal Gd-IgA1 production from mucosal B cells, autoantibodies, and circulating immune complexes. These deposit in the new kidney just as they did in the old one.

Recurrent kidney diseases are a recognised complication in post-kidney transplant patients ^[4]

Renal vein thrombosis — hypercoagulability by compensatory production of clotting factors by liver ^[20]

Manifestations:

• Deep vein thrombosis (DVT) — lower limb swelling, pain
• Renal vein thrombosis — sudden flank pain, worsening proteinuria, haematuria, acute renal impairment
• Pulmonary embolism — dyspnoea, pleuritic chest pain, tachycardia

Management: If AKI from renal vein thrombosis: thrombolysis ± embolectomy. If non-AKI: LMWH/UFH → warfarin for minimum 6–12 months while still nephrotic ^[20]

Spontaneous bacterial peritonitis — loss of Ig → antibiotics ^[20]

Why are nephrotic patients infection-prone?

• Urinary loss of immunoglobulins (particularly IgG) → ↓opsonisation capacity
• Urinary loss of complement factors (factor B, factor D of the alternative pathway)
• Oedematous tissues have impaired local immunity
• Steroid treatment (if used) further suppresses immunity

Common infections: pneumococcal infections (SBP in children, pneumonia), cellulitis, UTI.

CV disease — long-term complications → CV risk modifications ^[20]

Mechanism: The liver responds to hypoalbuminaemia by increasing protein synthesis globally. This includes increased production of lipoproteins (VLDL, LDL). Simultaneously, there is urinary loss of HDL (which is smaller and passes through the damaged filter). The result:

• ↑Total cholesterol, ↑LDL, ↑Triglycerides, ↓HDL
• Accelerated atherosclerosis → ↑cardiovascular risk

Management: Statins, lifestyle modification. Treat underlying nephrotic syndrome to resolve hyperlipidaemia.

Resistant oedema/anasarca — poor drug/diet compliance, furosemide malabsorption due to gut wall oedema → change to IV furosemide, add thiazide/potassium-sparing diuretics, IV albumin ^[20]

Why can furosemide malabsorption occur? In severe nephrotic syndrome, gut wall oedema impairs absorption of oral medications. Switching to IV administration bypasses this problem.