IgA nephropathy is a glomerulonephritis characterized by predominant mesangial deposition of IgA immune complexes, typically presenting with episodic gross hematuria often concurrent with upper respiratory infections.

IgA Nephropathy (Berger's Disease)

2. Epidemiology

3. Anatomy and Relevant Functional Review

4. Aetiology

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

Category	Examples
Hepatic	Alcoholic liver disease, cirrhosis (any cause), hepatitis B/C — impaired hepatic clearance of IgA
GI / Mucosal	Coeliac disease, inflammatory bowel disease (Crohn's)
Dermatological	Dermatitis herpetiformis
Systemic vasculitis	IgA vasculitis (HSP) — same spectrum
Infections	HIV, chronic infections
Other	Ankylosing spondylitis, minimal change disease overlap

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

5. Pathophysiology — The "Multi-Hit" Hypothesis

This is the core concept. IgAN is now understood through a four-hit model ^[1]^[2]:

Mechanism	Clinical Feature
RBC leak through inflamed/damaged GBM	Haematuria
Protein leak through damaged filtration barrier (podocyte injury, GBM disruption)	Proteinuria
Reduced glomerular filtration from mesangial expansion and inflammation	Reduced GFR / elevated creatinine
Salt and water retention from reduced GFR + RAAS activation	Hypertension, oedema
Severe crescentic inflammation	Rapidly progressive glomerulonephritis (RPGN)

6. Classification

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]:

Score	Feature	Definition	Prognostic Significance
M	Mesangial hypercellularity	M0: ≤50% of glomeruli with mesangial hypercellularity; M1: > 50%	M1 → worse prognosis
E	Endocapillary hypercellularity	E0: absent; E1: present (in any glomerulus)	E1 → worse if untreated, may be responsive to immunosuppression
S	Segmental glomerulosclerosis	S0: absent; S1: present (in any glomerulus)	S1 → worse prognosis (indicates chronic damage)
T	Tubular atrophy/interstitial fibrosis	T0: 0–25%; T1: 26–50%; T2: > 50%	T1/T2 → strongly predicts progression to ESKD
C	Crescents	C0: no crescents; C1: crescents in < 25% of glomeruli; C2: ≥25%	C2 → rapidly progressive course

MEST-C — High Yield for Exams

The MEST-C score is the standard histological grading. Remember: M = Mesangial, E = Endocapillary, S = Segmental sclerosis, T = Tubular atrophy/interstitial fibrosis, C = Crescents. The "T" score is the strongest predictor of long-term renal outcome.

IgAN presents along a spectrum of clinical severity:

Phenotype	Proportion	Description
Asymptomatic microscopic haematuria ± mild proteinuria	~30–40%	Discovered incidentally or on screening; excellent short-term prognosis
Episodic macroscopic haematuria	~40–50%	Classic "synpharyngitic" episodes; usually good prognosis if proteinuria is low
Nephrotic syndrome	~5%	Heavy proteinuria (> 3.5 g/day); may overlap with minimal change disease
Acute nephritic syndrome	~5–10%	Haematuria, hypertension, oliguria, renal impairment
Rapidly progressive glomerulonephritis (RPGN)	~5%	Crescentic GN; rapid decline in renal function over weeks; medical emergency
Chronic kidney disease	Variable	Insidious progression; presents late with established CKD

7. Clinical Features

7.1 Symptoms

7.2 Signs

Sign	Pathophysiological Basis
Hypertension	Reduced GFR → sodium and water retention + RAAS activation. Present in ~30–50% at diagnosis. More common with advancing disease
Peripheral oedema	Sodium/water retention (nephritic mechanism) or hypoalbuminaemia (nephrotic mechanism)
Periorbital oedema	Hypoalbuminaemia → reduced oncotic pressure → fluid leaks into loose periorbital tissues (gravity-independent, worse in morning)
Pallor	Anaemia of CKD (if advanced) — from reduced erythropoietin production by failing kidneys

Sign	Pathophysiological Basis
Dipstick haematuria (blood ++)	RBCs leak through inflamed/damaged glomerular capillary wall into Bowman's space
Dipstick proteinuria (protein +/++)	Disruption of filtration barrier → albumin and other proteins leak through
Frothy urine	Protein acts as a surfactant → creates stable foam
Brown/smoky urine (during episodes)	Haemoglobin → methaemoglobin in acidic tubular fluid

Finding	Significance
Dysmorphic RBCs	Indicates glomerular origin of haematuria — RBCs are distorted as they squeeze through damaged GBM. Glomerular disease: dysmorphic RBC / RBC casts; Urological disease: isomorphic RBC ^[5]
Red cell casts	Pathognomonic for glomerulonephritis — formed when RBCs are trapped in Tamm-Horsfall protein casts in the tubular lumen ^[10]
Granular casts	Non-specific; indicate tubular damage

Dysmorphic RBCs and RBC Casts — High Yield

Dysmorphic RBCs and RBC casts on urine microscopy confirm a GLOMERULAR origin of haematuria. This is the single most important investigation to distinguish glomerular from urological causes of haematuria. Always request urine microscopy.

Sign	Suggests
Palpable purpura (non-blanching, lower limbs/buttocks)	IgA vasculitis (HSP)
Malar rash, discoid rash	SLE/Lupus nephritis
Joint swelling	HSP, SLE, or other autoimmune
Hepatomegaly, spider naevi, palmar erythema	Chronic liver disease (secondary IgA)
Hearing loss	Alport syndrome (differential diagnosis)

Alport syndrome → hearing deficit common → pure-tone audiometry (PTA). Mutations in the type 4 collagen genes. X-linked transmission in 80%. ^[3]

This table maps each key clinical feature back to its mechanism for exam clarity:

Clinical Feature	Underlying Mechanism
Synpharyngitic macroscopic haematuria	URTI → mucosal IgA surge → ↑Gd-IgA1 → immune complex deposition → acute mesangial inflammation → GBM disruption → RBC leak
Brown/smoky (not red) urine	RBCs undergo Hb → metHb conversion in acidic tubular fluid
No blood clots in urine	Urokinase in glomerular filtrate lyses clots
Persistent microscopic haematuria	Chronic low-grade mesangial inflammation → ongoing minor GBM damage
Proteinuria	Podocyte injury + GBM disruption → impaired size/charge selectivity
Hypertension	↓GFR → Na+/H₂O retention + RAAS activation
Oedema	Na+/H₂O retention (nephritic) or ↓albumin (nephrotic)
Progressive CKD	Chronic mesangial sclerosis + tubulo-interstitial fibrosis → irreversible nephron loss
Crescentic RPGN	Severe GBM breach → fibrin leaks into Bowman's space → macrophage/epithelial cell proliferation → crescents compressing glomerular tuft

9. Risk Factors for Disease and Progression

Risk Factor	Explanation
Asian ethnicity	Highest prevalence in East/Southeast Asians — genetic predisposition (HLA, complement gene variants)
Male sex	M:F ≈ 2–3:1
Family history	Polygenic; familial clustering observed
Mucosal immune dysregulation	Tonsillar/gut MALT overproduction of abnormally glycosylated IgA1

These are critical for clinical management and prognosis:

Risk Factor	Mechanism/Significance
Persistent proteinuria > 1 g/day	Single strongest clinical predictor of progression; reflects ongoing podocyte/GBM injury
Hypertension	Accelerates glomerular and vascular damage; target BP < 130/80 (or < 125/75 if proteinuria > 1 g/day per KDIGO 2021)
Reduced eGFR at presentation	Less renal reserve; more advanced disease at baseline
MEST-C histological score	T (tubular atrophy/interstitial fibrosis) is the strongest histological predictor; C2 (crescents ≥25%) indicates aggressive disease
Persistent haematuria	Reflects ongoing glomerular inflammation
Obesity	Glomerular hyperfiltration → accelerated injury
Smoking	Vascular injury, impaired renal blood flow
Episodes of AKI	Each episode of AKI causes further nephron loss

Proteinuria — The Key Modifiable Risk Factor

Proteinuria > 1 g/day is the single most important modifiable predictor of progression in IgAN. The entire treatment strategy revolves around reducing proteinuria. Every clinical decision point asks: "Is the proteinuria controlled?"

This comparison is commonly tested:

Feature	IgA Nephropathy	Post-Streptococcal GN	Alport Syndrome	Thin Basement Membrane Disease
Age	Young adults (15–35)	Children (5–12)	Childhood onset	Any age
Timing of haematuria	Synpharyngitic (0–2 days)	Post-infectious (1–2 weeks)	Persistent	Persistent
Gross haematuria	Common	Common	Common	Unusual (< 10%) ^[3]
Complement levels	Normal	Low C3 (consumed)	Normal	Normal
Inheritance	Polygenic, no Mendelian	None (post-infectious)	X-linked dominant (80%)	Autosomal dominant
Hearing loss	No	No	Yes (sensorineural)	No
Diagnosis	Renal biopsy (IF: IgA)	Clinical + serology (ASO, anti-DNase B)	Genetic testing / biopsy (EM)	Biopsy (EM: thin GBM)
Family Hx of CKD	Variable	No	Males → ESKD	Benign course usually
Serology	↑Serum IgA in ~50%	↓C3, ↑ASO/anti-DNase B	Normal	Normal

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

High Yield Summary

IgA Nephropathy (Berger's Disease):

Definition: Primary GN with predominant mesangial IgA1 deposition — histological diagnosis requiring renal biopsy.
Epidemiology: Most common primary GN worldwide, especially common in Hong Kong/Asia. Peak in young adults (15–35), M > F.
Pathophysiology — Four-Hit Model: ① ↑Galactose-deficient IgA1 (Gd-IgA1) → ② Autoantibodies against Gd-IgA1 → ③ Circulating immune complex formation → ④ Mesangial deposition → complement activation (alternative/lectin, NOT classical) → mesangial proliferation → glomerular injury.
Classic Presentation: Synpharyngitic macroscopic haematuria (brown/smoky urine, no clots, within 1–2 days of URTI). Between episodes: persistent microscopic haematuria ± proteinuria.
Key Distinction from PSGN: IgAN = synpharyngitic (simultaneous); PSGN = post-infectious (1–2 week latent period).
Key Signs: Dysmorphic RBCs + RBC casts on urine microscopy (glomerular origin). Normal complement. Serum IgA elevated in ~50%.
Histology: MEST-C classification — T score (tubular atrophy/interstitial fibrosis) is the strongest histological predictor of ESKD.
Prognostic Factors: Proteinuria > 1 g/day (strongest modifiable factor), hypertension, reduced eGFR, high MEST-C scores.
Complement: C3 co-deposited, C1q absent (IgA does not fix classical pathway). Serum C3/C4 are NORMAL.
Red flags for secondary causes: Purpura (HSP), liver disease (hepatic IgA clearance failure), coeliac disease.

Active Recall - IgA Nephropathy (Part 1: Definition to Clinical Features)

Differential Diagnosis of IgA Nephropathy

The differential diagnosis of IgA nephropathy is really the differential of its presenting syndromes — because IgAN doesn't announce itself with a neon sign; it presents as haematuria, proteinuria, nephritic syndrome, or progressive CKD, and you have to work through the differentials of those presentations to arrive at IgAN. Let's be systematic.

IgAN can present in several ways, and each presentation has its own differential:

Presentation	Frequency	Key DDx to Consider
Recurrent synpharyngitic macroscopic haematuria	40–50%	Alport syndrome, thin basement membrane disease (TBMD), MPGN, IgA-dominant PSGN
Incidental microscopic haematuria ± proteinuria	30–40%	TBMD, Alport syndrome, urological causes (stones, tumour, UTI)
Acute nephritic syndrome	5–10%	PSGN, lupus nephritis, MPGN, ANCA vasculitis
Nephrotic syndrome	~5%	MCD, FSGS, membranous nephropathy
Rapidly progressive GN (RPGN)	~5%	Anti-GBM disease, ANCA vasculitis, lupus nephritis, IgAN with crescents
Chronic kidney disease (insidious)	Variable	Diabetic nephropathy, hypertensive nephrosclerosis, reflux nephropathy, any chronic GN

2. Differential Diagnosis by Presentation

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]

Feature	IgA Nephropathy	Alport Syndrome	Thin Basement Membrane Disease	MPGN
Inheritance	Polygenic, no particular mode of inheritance, no one gene ^[3]	X-linked (80%), mutations in type IV collagen genes ^[3]	Autosomal dominant (heterozygous COL4A3/4 mutations — i.e., "carriers" of AR Alport) ^[14]	None (acquired)
Age/Sex	Young adults, M > F	Childhood onset, M > F (X-linked)	Any age	Children/young adults
Gross haematuria	Common	Common	Unusual ( < 10%) ^[3]	May cause episodic gross haematuria ^[14]
Timing with URTI	Synpharyngitic (0–2 days)	Not temporally linked to URTI	May be preceded by URTI (mimics IgAN/PSGN) ^[14]	Variable
Hearing loss	No	Yes — sensorineural, high-tone deafness. Hearing deficit common → pure-tone audiometry (PTA) ^[3]	No	No
FHx of CKD	Variable (no Mendelian)	Yes — renal failure / deafness primarily in males, X-linked dominant mode of inheritance ^[3]	May have FHx of haematuria (benign course usually)	No
Proteinuria	Mild to moderate (can be nephrotic rarely)	Progressive; develops over time	Usually absent; if present, consider overlap with FSGS ^[14]	Can be nephrotic
Complement	Normal C3/C4	Normal	Normal	Low C3 ± C4
Progression to ESKD	30% over 30 years	Males → ESKD by 20s–40s	Usually benign (5% progressive) ^[14]	Variable
Diagnosis	Renal biopsy (IF: mesangial IgA)	Genetic testing / biopsy EM	Electron microscopy — GBM 150–225 nm (cf 300–400 nm normal) ^[14]	Renal biopsy

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.

IgA-Dominant PSGN — A Tricky Mimic

IgA-dominant PSGN: usually presents with AKI, haematuria, proteinuria; renal biopsy also shows IgA deposition but may show diffuse proliferative GN with neutrophil infiltration and subepithelial/subendothelial electron-dense deposits ^[14]. This can be confused with IgAN on immunofluorescence because both show IgA. The distinguishing features: PSGN has low C3 (complement consumption via the classical/alternative pathway), a latent period (1–2 weeks post-pharyngitis), and subepithelial "humps" on EM, whereas IgAN has normal complement, synpharyngitic timing, and mesangial deposits only.

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]

Condition	Key Distinguishing Features	Complement	Serology
IgA nephropathy	Synpharyngitic haematuria; young Asian adult; mesangial IgA on IF	Normal C3/C4	↑Serum IgA (~50%)
Post-streptococcal GN	1–2 weeks post-pharyngitis or 3–6 weeks post-skin infection ^[6]; children 5–12 y/o; resolves spontaneously	↓C3 (returns to normal in 6–8 weeks)	↑ASO titre, ↑Anti-DNase B
Lupus nephritis	Young woman; malar rash, oral ulcers, hair loss, photosensitivity, arthralgia ^[7]; "full house" IF	↓C3, ↓C4	+ANA, +anti-dsDNA, +anti-Smith
MPGN	Can present with nephritic or nephrotic features; associated with HBV/HCV, cryoglobulinaemia, autoimmune diseases	↓C3 (persistent)	Hepatitis B/C serology, cryoglobulins
ANCA vasculitis	Older patients; epistaxis, rhinorrhoea (GPA), haemoptysis (pulmonary-renal syndrome); pauci-immune on IF	Normal	+c-ANCA (PR3) or +p-ANCA (MPO)
Anti-GBM disease (Goodpasture)	Pulmonary haemorrhage + rapidly progressive GN; linear IgG on IF; older patients	Normal	+Anti-GBM antibodies

Complement Levels — High Yield Sorting Tool

Differential diagnosis of nephritic GN by complement and IF pattern ^[13]:

Normal C3: IgA nephropathy, IgA vasculitis (HSP)
Low C3: PSGN, Lupus nephritis, Infective endocarditis-associated GN, MPGN, Essential mixed cryoglobulinaemia

This is one of the most important discriminators in the nephritic DDx. IgAN has normal complement because IgA activates the alternative/lectin pathways locally in the kidney but does not consume systemic complement to a detectable degree.

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]:

Type	IF Pattern	Cause	Key Features
Type I	Linear staining	Anti-GBM disease (Goodpasture)	Haemoptysis + RPGN; anti-GBM Ab; plasmapheresis essential
Type II	Granular staining	Immune complex RPGN	Can complicate most GN commonly a/w nephritic syndrome (e.g., SLE, IgAN, PSGN) ^[15]^[16]^[17]
Type III	Negative staining	Pauci-immune RPGN	Most are ANCA-positive; may be a/w extrarenal ANCA vasculitis ^[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].

Don't Miss RPGN

Don't miss a RPGN! ^[18] A rapidly rising creatinine (e.g., doubling within days) in the context of active urinary sediment (RBC casts) is a medical emergency. Any glomerulonephritis — including IgAN — can undergo crescentic transformation. If you suspect RPGN, urgent renal biopsy is needed, and empirical pulse IV methylprednisolone can be given before renal biopsy if indicated ^[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:

Feature	Glomerular Haematuria	Urological Haematuria
Colour	Brown / smoky / tea / cola	Bright red
Clots	Unusual (urokinase in filtrate lyses them) ^[3]^[5]	Common
Microscopy	Dysmorphic RBCs, RBC casts ^[5]	Isomorphic RBCs ^[5]
Proteinuria	Often present (concurrent glomerular injury)	Usually absent (unless massive bleeding)
Pain	Painless (or mild flank discomfort)	May have loin/suprapubic pain (stone, tumour, infection)
Frothy urine	Suggests GN ^[5]	Absent
Timing with stream	Throughout (above bladder level)	Initial (lower tract), terminal (prostate) ^[5]

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]

This deserves its own section because they are the same histological entity (mesangial IgA deposition) — the distinction is purely clinical:

IgA nephropathy and Henoch-Schönlein purpura (HSP) have IDENTICAL renal pathology. HSP has other clinical features including palpable purpura associated with leukocytoclastic vasculitis, arthritis or arthralgia, and abdominal pain which are NOT present in IgA nephropathy ^[11]^[12]

Feature	IgA Nephropathy	IgA Vasculitis (HSP)
Renal pathology	Mesangial IgA — identical	Mesangial IgA — identical
Skin	Normal	Palpable purpura (non-blanching, lower limbs/buttocks)
Joints	Normal	Arthralgia / arthritis
GI	Normal	Abdominal pain, GI bleeding, intussusception (children)
Age	Young adults	Children (peak 3–10 y/o); can occur in adults
Serum IgA	↑ in ~50%	↑ in ~50%
Complement	Normal	Normal

The current view: IgAN and HSP nephritis represent two ends of one disease spectrum — IgAN is the kidney-limited form; HSP is the systemic form with the same underlying IgA1 glycosylation defect.

Before confirming primary IgAN, always consider whether IgA deposition is secondary to another condition. This is clinically important because treating the underlying cause may improve the renal disease:

Secondary Cause	Mechanism	Key Clues
Alcoholic liver disease / Cirrhosis	Impaired hepatic clearance of IgA (liver normally clears ~60–70% of circulating IgA via the asialoglycoprotein receptor)	Stigmata of chronic liver disease (spider naevi, palmar erythema, jaundice, ascites)
Hepatitis B	Immune complex deposition + impaired hepatic IgA clearance; HBV is endemic in Hong Kong	Check HBsAg, HBV DNA
Hepatitis C	Similar mechanism; also associated with MPGN and cryoglobulinaemia	Anti-HCV, HCV RNA
Coeliac disease	Mucosal immune activation → ↑IgA production	GI symptoms, anti-tTG IgA, consider in Europeans
HIV infection	Immune dysregulation → ↑IgA	Risk factors, HIV serology
Inflammatory bowel disease (Crohn's)	Mucosal immune activation	GI symptoms, colonoscopy
Ankylosing spondylitis	HLA-B27 association; shared mucosal immune pathways	Back pain, sacroiliitis

Associated conditions: cirrhosis, coeliac disease, HIV infection ^[14]

Condition	Serum Complement	Key Serology	IF Pattern	EM
IgA nephropathy	Normal C3/C4	↑Serum IgA (~50%)	Mesangial IgA ("staghorn pattern") ^[11]^[12] ± C3; no C1q	Mesangial electron-dense deposits
PSGN	↓C3 (normalises in 6–8 wk)	↑ASO, ↑anti-DNase B	Granular IgG/C3 ("starry sky")	Subepithelial "humps"
Lupus nephritis	↓C3, ↓C4	+ANA, +anti-dsDNA	"Full house": IgG, IgA, IgM, C3, C1q	Subendothelial ± subepithelial deposits
MPGN	↓C3 (persistent)	± Hep B/C, cryoglobulins	IgG, C3	Subendothelial deposits; "tram-tracking" of GBM
Anti-GBM (Goodpasture)	Normal	+Anti-GBM Ab	Linear IgG along GBM	No immune deposits
ANCA vasculitis	Normal	+c-ANCA or +p-ANCA	Pauci-immune (negative/scanty)	No immune deposits
Alport syndrome	Normal	None	Non-specific / negative	Basket-weave GBM splitting
TBMD	Normal	None	Negative	Thin GBM (150–225 nm)
Membranous nephropathy	Normal	Anti-PLA2R (primary)	Granular IgG/C3 along GBM	Subepithelial "spike and dome"
MCD	Normal	None	Negative	Podocyte foot process effacement

The Complement Sorting Rule — Know This Cold

When you see a nephritic presentation with normal complement, your top differentials are IgA nephropathy and IgA vasculitis (HSP). When complement is low, think PSGN (transient ↓C3), lupus nephritis (↓C3 + ↓C4), MPGN (persistent ↓C3), infective endocarditis, and cryoglobulinaemia. This single lab value dramatically narrows your differential.

Don't forget the red flags that suggest the patient in front of you is NOT having a [simple] nephropathy ^[18]

Red Flag	What It Suggests Instead
Low C3/C4	PSGN, lupus nephritis, MPGN — not IgAN
Positive ANA / anti-dsDNA	Lupus nephritis
Positive ANCA	ANCA vasculitis (GPA, MPA, EGPA)
Positive anti-GBM	Anti-GBM disease / Goodpasture
Palpable purpura + abdominal pain + arthralgia	IgA vasculitis (HSP) — same spectrum but systemic
Latent period 1–2 weeks post-pharyngitis	PSGN, not IgAN
Hearing loss + FHx renal failure in males	Alport syndrome
Linear IgG on IF	Anti-GBM disease
Full house IF (IgG, IgA, IgM, C3, C1q)	Lupus nephritis
Pauci-immune IF	ANCA vasculitis
Subepithelial humps on EM	PSGN
Isomorphic RBCs + blood clots	Urological cause (stone, tumour, UTI)
Haemoptysis + RPGN	Pulmonary-renal syndrome (Goodpasture or ANCA vasculitis)
Stigmata of liver disease	Secondary IgA deposition from cirrhosis

High Yield Summary — Differential Diagnosis of IgA Nephropathy

Three glomerular causes of recurrent haematuria: IgAN (synpharyngitic, no hearing loss, polygenic), Alport syndrome (X-linked, sensorineural deafness, progressive CKD in males), TBMD (benign, thin GBM on EM, autosomal dominant carrier of COL4A3/4).
IgAN vs PSGN: IgAN = synpharyngitic (0–2 days), normal complement. PSGN = post-infectious (1–2 weeks), low C3.
IgAN vs HSP: Identical renal pathology. HSP has systemic features (purpura, arthralgia, abdominal pain). Same disease spectrum.
Complement is the key sorter: Normal C3 → IgAN, HSP. Low C3 → PSGN, lupus, MPGN, IE, cryoglobulinaemia.
RPGN classification by IF: Type I = linear (anti-GBM), Type II = granular (immune complex — IgAN can cause this), Type III = pauci-immune (ANCA).
Always exclude urological causes of haematuria: Dysmorphic RBCs/RBC casts = glomerular; isomorphic RBCs/clots = urological. Most worrying urological cause: malignancy until proven otherwise.
Always exclude secondary IgA deposition: Liver disease, HBV/HCV, coeliac, HIV, IBD.
Renal biopsy is the gold standard — IF showing predominant mesangial IgA ± C3, absent C1q confirms IgAN. Apply MEST-C score for prognosis.

Active Recall - Differential Diagnosis of IgA Nephropathy

References

^[2] Lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf ^[3] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (pp. 9–10) ^[4] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (p. 3–4, renal biopsy) ^[5] Senior notes: Maksim Surgery Notes.pdf (p. 308, haematuria DDx) ^[6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 420, PSGN) ^[7] Senior notes: Block A - Nephrology Interactive Tutorial.pdf (p. 1, lupus nephritis clues) ^[11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 995–999, GN classification, IgAN) ^[12] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp. 402–404, GN classification, IgAN, HSP) ^[13] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 421, RPGN DDx by IF and complement) ^[14] Senior notes: Ryan Ho Urogenital.pdf (pp. 59–64, IgAN clinical features, DDx, TBMD, RPGN) ^[15] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 326, RPGN classification) ^[16] Senior notes: Ryan Ho Fundamentals.pdf (p. 361, RPGN) ^[17] Senior notes: Ryan Ho Urogenital.pdf (p. 64, RPGN) ^[18] Senior notes: Block A - Nephrology Interactive Tutorial.pdf (p. 5, "Don't miss a RPGN") ^[19] Senior notes: Block A – Nephrology Data Interpretation.pdf (p. 2, renal biopsy indications)

Diagnostic Criteria, Diagnostic Algorithm, and Investigations for IgA Nephropathy

1. Diagnostic Criteria — Overview

There is no single clinical diagnostic criterion for IgA nephropathy. Unlike, say, KDIGO criteria for AKI or Jones criteria for rheumatic fever, IgAN is a histological diagnosis — you need a renal biopsy to confirm it. The clinical picture raises suspicion; the biopsy gives you the answer.

The Gold Standard — High Yield

Renal biopsy is essential for the definitive diagnosis of IgA nephropathy. The diagnosis requires demonstration of predominant mesangial IgA deposition on immunofluorescence (IF), with supportive findings on light microscopy (LM) and electron microscopy (EM). No combination of clinical features or blood tests alone can confirm IgAN. ^[4]^[19]^[20]

Modality	Diagnostic Finding in IgAN	What It Tells You
Immunofluorescence (IF)	Predominant IgA deposition in the mesangium, described as a "staghorn pattern" ± co-deposition of C3; C1q is absent or minimal ^[11]^[12]	This is THE diagnostic finding. IgA must be the dominant or co-dominant immunoglobulin. If IgG or IgM predominates, it's a different disease. Absence of C1q helps exclude lupus nephritis ("full house" includes C1q)
Light microscopy (LM)	Mild diffuse mesangial proliferation (hypercellularity) ± formation of crescents ^[11]^[12]	Confirms the glomerular pattern of injury. Severity ranges from near-normal to crescentic GN. Provides MEST-C scoring
Electron microscopy (EM)	Electron-dense deposits in the mesangium ^[11]^[12]	Confirms the location of immune complex deposition. Absence of subepithelial deposits distinguishes from membranous GN; absence of subendothelial deposits distinguishes from lupus or MPGN

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].

3. Investigation Modalities — Detailed Breakdown

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

Investigation	Expected Finding in IgAN	Interpretation / Why We Do It
Urine dipstick	Blood +/++ to +++, Protein +/++	Screening tool. Urine multistix showing RBC 3+ and protein 3+ suggests nephritic syndrome ^[7]. Dipstick detects haem — need microscopy to confirm actual RBCs (vs myoglobinuria/haemoglobinuria)
Urine microscopy	Dysmorphic RBCs, RBC casts	Confirmation by light field microscopy / visualize casts ^[7]. Dysmorphic RBCs = glomerular origin (cells distorted by passage through damaged GBM). RBC casts = pathognomonic for GN ^[5]^[20]
Urine culture and sensitivity	Sterile (negative)	Excludes UTI as cause of haematuria. Urine C/ST to rule out UTI ^[5]
Urine cytology	Negative for malignant cells	Excludes urothelial malignancy, especially in older patients. If malignant cells → cystoscopy ^[5]

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:

Method	Details	When to Use
24-hour urine protein	Gold standard but very cumbersome — patient collects all urine for 24 hours ^[10]	Research, precise quantification
Urine protein-to-creatinine ratio (uPCR)	Alternative, done on first morning void; much more convenient for patient ^[10]. In QMH, uPCR is used instead of UACR ^[10]	Routine clinical practice in HK
Urine albumin-to-creatinine ratio (UACR)	Especially for diabetic patients or CKD patients ^[10]	Diabetic nephropathy screening

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]:

Test	Expected in IgAN	Why / Interpretation
CBC	Usually normal; may show normocytic normochromic anaemia with ↓Hct if CKD advanced ^[22]^[23]	Anaemia of CKD = reduced erythropoietin. ↑WBC may suggest recent infection
RFT (Cr, Urea, eGFR)	Creatinine may be normal or elevated depending on severity. When creatinine rises, GFR has already been reduced by at least 50% ^[7]	Documents degree of renal impairment. Baseline for monitoring
Serum albumin	Normal or low (low if nephrotic)	Hypoalbuminaemia in nephrotic syndrome ^[21]
Lipid profile	Normal or elevated (elevated if nephrotic)	Hyperlipidaemia in nephrotic syndrome ^[21] — liver compensatory overproduction of lipoproteins
Fasting glucose and lipids	To identify comorbid risk factors	Important for identifying risk factors ^[10] — DM and hyperlipidaemia accelerate CKD progression
ESR	Usually increased ^[22]^[23]	Non-specific marker of inflammation

This is where you narrow the differential:

Test	Expected in IgAN	Why / What It Excludes
Serum complement C3/C4	Normal	Normal C3/C4 generally indicates non-IC-mediated GN (except IgAN — IgA-IgG immune complexes in IgAN do NOT activate complement [via classical pathway]) ^[22]^[23]^[25]. If low C3 → consider PSGN, lupus, MPGN, IE
Serum Ig pattern	↑IgA in ~50% of patients (non-specific) ^[14]^[20]	Supports suspicion but NOT diagnostic. Normal IgA does NOT exclude IgAN
ANA, anti-dsDNA	Negative	Excludes lupus nephritis ^[22]^[23]
ANCA (c-ANCA/PR3, p-ANCA/MPO)	Negative	Excludes ANCA vasculitis (GPA, MPA, EGPA) ^[22]^[23]
Anti-GBM antibodies	Negative	Excludes anti-GBM disease / Goodpasture syndrome ^[22]^[23]
ASO titre / Anti-DNase B	Negative (unless concurrent strep infection)	Confirms recent streptococcal infection for PSGN ^[22]^[23]; elevated in PSGN, not typically in IgAN
HBsAg, anti-HCV	Check to exclude secondary causes	Excludes HBV/HCV-related MPGN or secondary IgA deposition ^[22]^[23]; HBV endemic in HK
Anti-HIV	Check to exclude secondary causes	HIV can cause FSGS or secondary IgA deposition
Anti-PLA2R	Negative	Excludes primary membranous nephropathy
Cryoglobulins	Negative	Cryocrit for cryoglobulinaemia when clinically indicated (e.g., Hx of HCV infection) ^[22]^[23]
Blood cultures	If clinically indicated	Blood culture for infection when clinically indicated (e.g., persistent fever) ^[22]^[23] — excludes infective endocarditis-related GN

GC High Yield — Investigations for Haematuria

Investigations for haematuria: Renal function, Urine culture / cytology / AFB, Urinalysis, Urine microscopy, KUB, USG / Doppler ^[26]

The Complement Trick — High Yield Sorting Tool

↓C3/C4 generally indicates immune complex-mediated GN → DDx: MPGN, PSGN, lupus, cryoglobulinaemia, IE and shunt nephritis

Normal C3/C4 generally indicates non-IC-mediated GN (except IgAN) → DDx: PAN, Goodpasture, HSP/IgAN, ANCA-related renal vasculitis ^[22]^[23]^[25]

This is one of the most important sorting tools in the nephritic workup. IgAN is the exception — it is immune-complex mediated but has normal systemic complement because IgA activates complement locally (alternative/lectin pathway) rather than consuming systemic C3/C4 via the classical pathway.

Modality	Purpose in IgAN Workup	Expected Finding
USG kidneys	First-line imaging. Exclude obstruction (post-renal cause), assess kidney size, exclude PKD ^[10]^[19]^[26]	Normal-sized kidneys in early IgAN. Small kidneys → CKD (chronic scarring) ^[10]. Normal kidneys + raised Cr → consider AKI/GN → will require biopsy ^[9]
KUB (plain abdominal X-ray)	Exclude radio-opaque urinary stones	Usually normal in IgAN
Doppler USG	Assess renal vasculature if renal artery stenosis suspected	Usually normal in IgAN
CXR, CT thorax, DLCO	For pulmonary involvement if cough ± haemoptysis ^[22]^[23]	Normal in isolated IgAN; abnormal in pulmonary-renal syndromes (Goodpasture, ANCA vasculitis)

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]

3.6 Renal Biopsy — The Definitive Investigation

Renal biopsy: necessary for most cases of nephritic syndrome ^[22]^[23]

Still essential for definitive diagnosis of a number of renal diseases: glomerulonephritis (e.g., minimal change disease, FSGS, IgAN, membranous GN, membranoproliferative GN), tubulointerstitial diseases, vascular diseases ^[4]

Modality	Finding	Interpretation
LM (H&E, PAS, silver stain)	Mild diffuse mesangial proliferation (hypercellularity) ^[11]^[12]. May see segmental sclerosis, crescents, tubular atrophy/interstitial fibrosis	Apply MEST-C score for prognosis
IF	Predominant mesangial IgA deposition ("staghorn pattern") ^[11]^[12] ± C3 co-deposition; C1q absent	THE diagnostic finding. IgA must be dominant or co-dominant. C1q absence distinguishes from lupus ("full house")
EM	Electron-dense deposits in the mesangium ^[11]^[12]	Confirms mesangial immune complex location. No subepithelial humps (PSGN) or subendothelial deposits (lupus/MPGN)

Why "staghorn pattern"? On immunofluorescence microscopy, the IgA lights up the mesangial tree of the glomerulus in a branching pattern that resembles a stag's antlers — hence "staghorn." This is virtually pathognomonic for IgAN.

Condition	IF Pattern	Key Feature
IgA nephropathy	Mesangial IgA ± C3, no C1q	Staghorn mesangial pattern
PSGN	Granular IgG/C3 ("starry sky") ^[3]	Along GBM, subepithelial humps on EM
Lupus nephritis	"Full house" — IgG, IgA, IgM, C3, C1q	Subendothelial ± subepithelial deposits
Membranous GN	Granular IgG/C3 along GBM ^[20]	Subepithelial "spike and dome" on EM
Anti-GBM disease	Linear IgG along GBM	No immune deposits on EM
ANCA vasculitis	Pauci-immune (negative/scanty)	No immune deposits
MCD	Negative IF	Podocyte effacement on EM only ^[20]

Immunofluorescence pattern is the most helpful for diagnosis ^[22]^[23]

4. Risk Stratification After Biopsy

Once IgAN is confirmed, two tools are used for risk stratification:

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

Score	Feature	Grading	Prognostic Impact
M	Mesangial hypercellularity	M0 ( ≤ 50%) / M1 ( > 50%)	M1 worse
E	Endocapillary hypercellularity	E0 (absent) / E1 (present)	E1 may respond to immunosuppression
S	Segmental sclerosis	S0 (absent) / S1 (present)	S1 = chronic damage
T	Tubular atrophy / interstitial fibrosis	T0 (0–25%) / T1 (26–50%) / T2 ( > 50%)	Strongest histological predictor of ESKD
C	Crescents	C0 (none) / C1 ( < 25%) / C2 ( ≥ 25%)	C2 = RPGN phenotype

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

Category	Tests	Key Findings / Purpose
Urine	Dipstick, microscopy, C/ST, cytology, uPCR or 24h protein	Confirm glomerular haematuria; quantify proteinuria; exclude infection/malignancy
Blood — Basic	CBC, RFT, eGFR, albumin, lipids, fasting glucose	Assess renal function, complications, comorbidities
Blood — Immunology	C3/C4, Ig pattern (IgA/IgG/IgM), ANA, anti-dsDNA, ANCA, anti-GBM, ASO, anti-PLA2R	Narrow DDx; normal C3/C4 + ↑IgA supports IgAN
Blood — Infection	HBsAg, anti-HCV, anti-HIV	Exclude secondary causes
Imaging	USG kidneys, KUB	Assess kidney size; exclude obstruction/PKD
Biopsy	LM + IF + EM	Definitive diagnosis; MEST-C score for prognosis
Risk stratification	MEST-C + IgAN Prediction Tool	Guides treatment intensity

High Yield Summary — Diagnostics of IgA Nephropathy

IgAN is a histological diagnosis — renal biopsy with LM + IF + EM is required. No blood test or clinical criterion alone is diagnostic.
The diagnostic triad on biopsy: Mesangial IgA on IF ("staghorn pattern") + mesangial proliferation on LM + mesangial electron-dense deposits on EM. C1q is absent.
When to biopsy: Proteinuria > 0.5–1 g/day, declining eGFR, hypertension with active sediment, nephrotic-range proteinuria, RPGN, or diagnostic uncertainty. Isolated microscopic haematuria with normal Cr and no proteinuria → monitor.
Key blood tests: Normal C3/C4 (IgAN is the exception among immune-complex GN), ↑serum IgA in ~50% (non-specific), negative ANA/ANCA/anti-GBM. Always check HBsAg, anti-HCV, HIV.
GC slide high yield: Investigations for haematuria: Renal function, Urine culture/cytology/AFB, Urinalysis, Urine microscopy, KUB, USG/Doppler.
Urine microscopy: Dysmorphic RBCs + RBC casts = glomerular origin. This is the first and most important investigation to order.
MEST-C score: Applied on biopsy. T score (tubular atrophy/interstitial fibrosis) is the strongest histological predictor of ESKD.
Proteinuria quantification: uPCR (used at QMH) or UACR or 24h urine protein. > 1 g/day is the threshold for aggressive treatment.

Active Recall - IgAN Diagnostic Criteria, Algorithm and Investigations

References

^[3] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (pp. 9–10, 19, histology of PSGN) ^[4] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (pp. 3–4, renal biopsy essentials) ^[5] Senior notes: Maksim Surgery Notes.pdf (p. 308, haematuria workup and pearls) ^[7] Senior notes: Block A - Nephrology Interactive Tutorial.pdf (pp. 1, 3, nephritic syndrome workup) ^[9] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (p. 13, kidney size differential) ^[10] Senior notes: Block A - Introduction to Renal Investigations (RFT, urine tests and US kidneys).pdf (pp. 1, 4) ^[11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 995–999) ^[12] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp. 402–404) ^[14] Senior notes: Ryan Ho Urogenital.pdf (pp. 55, 59, 63) ^[19] Senior notes: Block A – Nephrology Data Interpretation.pdf (pp. 1–2) ^[20] Senior notes: Maksim Medicine Notes.pdf (pp. 216, 231–233) ^[21] Senior notes: Ryan Ho Urogenital.pdf (p. 55, commonly utilised investigations table) ^[22] Senior notes: Ryan Ho Urogenital.pdf (p. 63, evaluation of nephritic syndrome) ^[23] Senior notes: Ryan Ho Fundamentals.pdf (p. 360, evaluation of nephritic syndrome) ^[24] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (pp. 767–770, renal biopsy indications/contraindications, radiology) ^[25] Senior notes: Adrian Lui Pediatrics Notes.pdf (pp. 314, 325, complement sorting and evaluation) ^[26] Lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p. 21, investigations for haematuria)

Management of IgA Nephropathy

3. Tier 1: Optimised Supportive Care (ALL Patients)

This is the foundation of management for every patient with IgAN, regardless of severity. Think of it as the "non-negotiable baseline."

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]

Aspect	Detail
Drug class	ACE inhibitor (e.g., ramipril, enalapril) or ARB (e.g., losartan, valsartan, irbesartan)
Mechanism	Blocks angiotensin II → dilates the efferent arteriole → reduces intraglomerular capillary pressure → less protein forced through the damaged filtration barrier → ↓proteinuria. Also reduces TGF-β–mediated fibrosis
Indication	ALL patients with IgAN (even with modest proteinuria). First-line for both proteinuria reduction AND BP control ^[27]^[28]
Target	Proteinuria < 1 g/day (ideally < 0.5 g/day). BP < 130/80 mmHg (or < 125/75 if proteinuria > 1 g/day, per KDIGO 2021)
Dose	Titrate to maximum tolerated dose before concluding "supportive care has failed" — many patients are under-dosed
Monitoring	Recheck Cr + K+ 1–2 weeks after initiation or dose change. Expect a transient ↑Cr up to 20–30% — this is acceptable and reflects reduced intraglomerular pressure, NOT renal damage. Only stop if Cr rises > 30% or K+ > 5.5

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.

Never Combine ACEI and ARB Together

Never prescribe ACEI and ARB together ^[19]. Dual RAAS blockade was shown in the ONTARGET trial to increase risk of hyperkalaemia, hypotension, and AKI without additional benefit.

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.

Aspect	Detail
Drug class	Sodium-glucose co-transporter 2 inhibitors — "SGLT2i" (e.g., dapagliflozin, empagliflozin)
Name breakdown	"gliflozin" = glucose ("gli-") + flow ("-flozin") — these drugs make glucose "flow" out in the urine by blocking its reabsorption
Mechanism in IgAN	(1) Blocks Na+/glucose reabsorption in proximal tubule → more Na+ delivered to macula densa → tubuloglomerular feedback → afferent arteriolar constriction → ↓intraglomerular pressure → ↓proteinuria. (2) Anti-inflammatory and anti-fibrotic effects independent of glucose lowering. (3) Reduces kidney oxygen consumption (less energy spent on Na+/glucose reabsorption)
Indication	IgAN with eGFR ≥ 20 mL/min (per KDIGO 2024), regardless of diabetes status
Evidence	DAPA-CKD trial: dapagliflozin reduced risk of sustained ≥50% eGFR decline, ESKD, or renal/CV death by 39% in CKD patients (including IgAN subgroup). EMPA-KIDNEY showed similar benefits
Side effects	Genital mycotic infections (glucose in urine feeds yeast), euglycaemic DKA (rare, mostly in T1DM), volume depletion, UTI
Contraindications	eGFR < 20 (limited evidence; may still start if already on it), T1DM (high risk of euglycaemic DKA)

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.

SGLT2i — Now Standard of Care in IgAN (2024–2025 Guidelines)

SGLT2 inhibitors (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) are now recommended by KDIGO 2024 as part of first-line optimised supportive care for IgAN with eGFR ≥ 20, in addition to maximally tolerated ACEI/ARB. This is a new addition since the 2021 KDIGO guidelines.

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

Measure	Detail	Rationale
Sodium restriction	Dietary sodium restricted to ~2 g/day ^[27]^[28]	Reduces BP, enhances efficacy of RAAS blockade, reduces oedema. High salt intake directly blunts the antiproteinuric effect of ACEI/ARB
Protein intake	Protein restriction is NOT recommended due to heavy urinary protein loss — should have normal protein intake as ↑albumin excretion is associated with poorer outcomes ^[27]^[28]. However, avoid excessive protein (> 1.3 g/kg/day)	In advanced CKD (eGFR < 30), moderate protein restriction (0.6–0.8 g/kg/day) may be considered to reduce uraemic toxin load
Fluid	Generally no restriction unless nephrotic oedema	N/A
Potassium	Monitor if on ACEI/ARB or SGLT2i — may need dietary K+ restriction if hyperkalaemic	K+ retained when GFR drops and aldosterone is blocked

Control lipid and CV risk ^[9]

Measure	Detail
Statins	Lipid-lowering drugs by statins (drug of choice) — should be considered if hyperlipidaemia persists ^[27]^[28]. CKD patients are at very high CV risk
Smoking cessation	Smoking accelerates CKD progression through vascular injury
Weight management	Obesity causes glomerular hyperfiltration → accelerated damage
Glycaemic control	If concurrent DM: aim HbA1c < 7–8% ^[31]

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]

Nephrotoxin	Mechanism of Harm
NSAIDs	↓Prostaglandin → afferent arteriolar constriction → ↓GFR; also causes TIN and GN ^[19]
Aminoglycosides	Direct tubular cell toxicity (concentrated within tubular cells) [27a]
Contrast media	Direct tubular toxicity + renal vasoconstriction
Dual ACEI + ARB	Excessive ↓intraglomerular pressure → AKI ^[19]

4. Tier 2: Immunosuppressive Therapy (High-Risk Patients)

Immunosuppression is only added when optimised supportive care (maximal ACEI/ARB + SGLT2i + diet + BP control for at least 3–6 months) fails to bring proteinuria below 1 g/day AND the patient is at high risk of progression.

Immunosuppressants only if: proteinuria > 1 g/day despite ACEI, or crescentic GN ^[20]

Aspect	Detail
Drug	Prednisolone (oral) ± IV methylprednisolone pulses
Mechanism	Broad immunosuppression — suppresses T-cell activation, reduces cytokine production, reduces glomerular inflammation. "Prednisolone" = pred- (before) + nisolone (a cortisol analogue)
Evidence	TESTING trial (2022): reduced-dose steroid protocol (IV methylprednisolone 0.4 g/kg over 2 days at months 1, 3, 5 + oral prednisolone 0.4 mg/kg/day × 2 months → taper over 4–6 months) reduced the composite of 40% eGFR decline, ESKD, or renal death by ~40% in high-risk IgAN (proteinuria > 1 g/day despite ≥3 months RAAS blockade). Full-dose Pozzi regimen (6-month alternating IV MP and oral pred) had more infectious complications
Indication	Proteinuria > 1 g/day despite ≥3–6 months of optimised supportive care AND eGFR > 30 mL/min (benefit less clear at lower eGFR, and infection risk higher)
Duration	Total ~6 months (induction + taper)
Side effects	Infection (major concern — PCP prophylaxis with TMP-SMX should be considered), hyperglycaemia, osteoporosis, weight gain, peptic ulcer, adrenal suppression, avascular necrosis
Contraindications	Active infection, uncontrolled diabetes, severe osteoporosis, peptic ulcer disease, psychosis

TESTING Trial Protocol — High Yield for Exams

The TESTING trial (2022) established the current standard corticosteroid protocol for IgAN:

IV methylprednisolone 0.4 g/kg over 2 days at months 1, 3, and 5
Oral prednisolone 0.4 mg/kg/day for months 1–2, then taper by 0.05 mg/kg/day each month
Total duration ~6–9 months
PLUS TMP-SMX prophylaxis against Pneumocystis (PCP) — this was added after the initial full-dose TESTING protocol showed excess serious infections

Aspect	Detail
Drug	Budesonide 16 mg/day targeted-release formulation (Nefecon/Tarpeyo)
Mechanism	Budesonide = potent topical corticosteroid with high first-pass hepatic metabolism (90% cleared by liver). The targeted-release formulation delivers budesonide directly to the ileal Peyer's patches (gut MALT), where the aberrant IgA1-producing B cells reside. This targets the source of the problem (Hit 1 of the four-hit model) while minimising systemic steroid exposure
Evidence	NefIgArd trial (Phase 3, 2023): reduced proteinuria by ~30% and slowed eGFR decline vs placebo over 2 years in IgAN patients with proteinuria ≥ 1 g/day despite RAAS blockade
Indication	IgAN with proteinuria ≥ 1 g/day on maximised RAAS blockade, eGFR ≥ 35. FDA-approved (2021); European & Hong Kong use varies
Advantage	Lower systemic steroid side effects compared to oral prednisolone
Side effects	Fewer than systemic steroids but still possible: acne, weight gain, adrenal suppression (less), GI symptoms

Aspect	Detail
Drug	Mycophenolate mofetil (MMF) — "myco-" (fungus-derived) + "phenolate" (phenolic acid)
Mechanism	Inhibits inosine monophosphate dehydrogenase (IMPDH) → blocks de novo purine synthesis → selectively suppresses lymphocyte proliferation (lymphocytes uniquely depend on de novo pathway)
Evidence in IgAN	Mixed. Some Chinese/Asian studies showed benefit in reducing proteinuria, but Western RCTs (STOP-IgAN) did not confirm clear benefit. KDIGO 2021 suggests MMF as an alternative where corticosteroids are contraindicated or in Asian populations where evidence is more supportive
Indication	Alternative to corticosteroids if steroids contraindicated/not tolerated; sometimes used in Chinese/Asian patients based on local data
Side effects	GI upset (diarrhoea, nausea), myelosuppression (↓WCC, ↓Plt), infections, teratogenicity
Contraindications	Pregnancy (teratogenic — must use contraception), active infection, severe myelosuppression

Agent	Role in IgAN
Azathioprine	Sometimes used as maintenance after steroid induction; limited evidence in IgAN specifically
Cyclophosphamide	Reserved for crescentic/RPGN IgAN (see Tier 3); too toxic for routine use
Rituximab	Anti-CD20 monoclonal antibody. Emerging evidence in IgAN (targets B cells producing Gd-IgA1). NEFIGAN trial ongoing. Not yet standard of care
Calcineurin inhibitors (tacrolimus, ciclosporin)	Limited role; nephrotoxic themselves; occasionally used in steroid-resistant nephrotic IgAN

Steroids, cytotoxic agents and plasmapheresis if progress into RPGN ^[11]^[12]

RPGN → most require pulse IV methylprednisolone followed by daily oral prednisolone ± oral/IV cyclophosphamide or rituximab. Can give empirical pulse IV methylprednisolone before renal biopsy if indicated ^[15]^[16]^[17]

Component	Detail
IV pulse methylprednisolone	500–1000 mg daily × 3 days — rapid suppression of inflammatory cascade
Oral prednisolone	1 mg/kg/day (max 60–80 mg/day), taper over months
Cyclophosphamide	IV pulse (15 mg/kg every 2–4 weeks × 3–6 months) or oral (2 mg/kg/day × 3 months then switch to azathioprine)
Rituximab	Emerging alternative to cyclophosphamide, especially in younger patients (avoids gonadotoxicity)
Plasmapheresis	Reserved for select cases — some use in IgAN with RPGN by analogy with anti-GBM disease, but evidence is limited. More established role in anti-GBM disease and severe ANCA vasculitis ^[19]

Why is crescent formation an emergency? Crescents form when massive movement of plasma products (including fibrin) leaks into Bowman's space → macrophage/T-cell influx → cellular crescent → if untreated, fibroblast proliferation → fibrous crescent (unlikely to respond to immunosuppressive treatment) ^[15]^[16]^[17]. This means the window for treatment is narrow — once fibrous crescents form, the glomerulus is irreversibly destroyed.

Act Fast in RPGN — Don't Wait for Biopsy

Can give empirical pulse IV methylprednisolone before renal biopsy if indicated ^[15]^[16]^[17]. If a patient with known or suspected IgAN presents with rapidly rising creatinine and active urinary sediment, do NOT delay treatment while waiting for biopsy results. Give empirical IV methylprednisolone. Biopsy can follow once the patient is stabilised.

As IgAN progresses, it causes CKD with all its attendant complications. Management follows standard CKD principles:

Therapeutic objectives for CKD: Delay kidney failure, control hypertension, reduce albuminuria, treat anaemia and MBD disorder, treat acidosis and high K, control lipid and CV risk ^[9]

Complication	Management
Anaemia	Erythropoiesis-stimulating agents (ESA, e.g., epoetin) when Hb < 10 g/dL; IV iron if iron-deficient. Why anaemia? Failing kidneys produce less erythropoietin → ↓RBC production
CKD-MBD	Phosphate binders (calcium carbonate, sevelamer), active vitamin D (calcitriol/alfacalcidol). Why? ↓1α-hydroxylase in failing kidneys → ↓active vitamin D → ↓Ca²⁺ absorption → ↑PTH → secondary hyperparathyroidism → renal osteodystrophy
Metabolic acidosis	Oral sodium bicarbonate. Correction of bicarbonate through NaHCO₃ ^[33]; slows CKD progression
Hyperkalaemia	Dietary K+ restriction, potassium binders (sodium polystyrene sulfonate / patiromer), adjust ACEI/ARB dose
Fluid overload/oedema	Loop diuretics (furosemide) usually preferred; can add thiazide/K⁺-sparing if inadequate ^[27]^[28]. Salt restriction
ESKD (eGFR < 15)	Preparation for renal replacement therapy ^[34] — haemodialysis, peritoneal dialysis, or kidney transplant

Agent	Target	Status
Sparsentan	Dual endothelin receptor / angiotensin receptor antagonist	FDA-approved 2023 for IgAN (PROTECT trial); reduces proteinuria more than irbesartan alone
Iptacopan	Complement factor B inhibitor (targets alternative pathway specifically)	Phase 3 (APPLAUSE-IgAN trial); addresses Hit 4 of pathogenesis directly
Anti-APRIL/BAFF agents (e.g., sibeprenlimab, atacicept, povetacicept)	Block APRIL/BAFF → reduce B-cell survival and Gd-IgA1 production	Phase 2–3; targets Hit 1–2; very promising
Felzartamab	Anti-CD38 (targets IgA-producing plasma cells)	Phase 2

The IgAN therapeutic landscape is rapidly evolving. The key principle: newer agents aim to target specific hits in the four-hit model (reduce Gd-IgA1 production, block autoantibody formation, inhibit complement) rather than relying on broad immunosuppression.

Risk Category	Clinical Profile	Management
Low risk	Isolated microscopic haematuria, proteinuria < 0.5 g/day, normal eGFR, normal BP	Monitor only: BP + urine + Cr every 6–12 months. Lifestyle advice
Moderate risk	Proteinuria 0.5–1 g/day, or mild CKD, or controlled HTN	ACEI/ARB (max tolerated) + SGLT2i + diet + BP control. Monitor 3–6 months. Biopsy if not already done
High risk	Proteinuria > 1 g/day despite ≥3–6 months optimised supportive care, or ↓eGFR, or high MEST-C	Add corticosteroids (TESTING protocol) ± MMF or targeted budesonide. Continue ACEI/ARB + SGLT2i
Very high risk / RPGN	Crescentic IgAN, rapidly declining eGFR	IV pulse methylprednisolone + cyclophosphamide or rituximab ± plasmapheresis. URGENT
ESKD	eGFR < 15 or symptomatic uraemia	Renal replacement therapy: haemodialysis, peritoneal dialysis, or kidney transplant

High Yield Summary — Management of IgA Nephropathy

Supportive care is the foundation for ALL patients: Maximally titrated ACEI or ARB + SGLT2 inhibitor + BP < 130/80 + low-salt diet + statins + avoid nephrotoxins. Never prescribe ACEI and ARB together.
ACEI/ARB mechanism: Dilates efferent arteriole → ↓intraglomerular pressure → ↓proteinuria. Goal: proteinuria < 1 g/day.
SGLT2 inhibitors: Now standard of care (KDIGO 2024). Mechanism: ↑Na delivery to macula densa → tubuloglomerular feedback → afferent arteriolar constriction → ↓intraglomerular pressure. Complementary to ACEI/ARB.
Immunosuppression only if: Proteinuria > 1 g/day despite ≥ 3–6 months of maximal supportive care. Use TESTING protocol corticosteroids. Alternatives: targeted-release budesonide, MMF.
RPGN/Crescentic IgAN: Medical emergency. Pulse IV methylprednisolone ± cyclophosphamide/rituximab. Can treat empirically before biopsy.
IgAN recurs post-transplant (~20–35% clinically significant) because the immune defect persists.
Emerging therapies: Sparsentan (dual ETRA/ARB), complement factor B inhibitors, anti-APRIL/BAFF agents — targeting specific hits in the four-hit model.

Active Recall - Management of IgA Nephropathy

References

^[9] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (p. 17, CKD therapy aims) ^[11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 997–999, IgAN treatment) ^[12] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp. 402–404, IgAN treatment) ^[15] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 326, RPGN management) ^[16] Senior notes: Ryan Ho Fundamentals.pdf (p. 361, RPGN management) ^[17] Senior notes: Ryan Ho Urogenital.pdf (p. 64, RPGN management) ^[19] Senior notes: Block A – Nephrology Data Interpretation.pdf (pp. 2, 11, 15, dual ACEI/ARB, nephrotoxins, Goodpasture Mx) ^[20] Senior notes: Maksim Medicine Notes.pdf (pp. 231–233, IgAN management) ^[27] Senior notes: Ryan Ho Urogenital.pdf (p. 76, general approach to GN management) [27a] Senior notes: Block A - Drugs and the Kidney.pdf (pp. 8–9, nephrotoxic drugs) ^[28] Senior notes: Ryan Ho Fundamentals.pdf (p. 368, general approach to GN management) ^[29] Senior notes: Block A - WCS32 Chest pain on exertion_ ischaemic heart disease; angina pectoris.pdf (p. 39, ACEI/ARB indications, side effects, contraindications) ^[30] Senior notes: Block A - High blood pressure_ hypertension.pdf (p. 42, compelling indications for antihypertensives) ^[31] Senior notes: Endocrine Interactive Tutorial.pdf (p. 7, ARB renoprotection mechanism) ^[33] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (p. 8, NaHCO3 therapy) ^[34] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p. 28, chronic GN treatment) ^[35] Senior notes: Block A - Renal Replacement Therapies.pdf (p. 41, recurrence of IgAN post-transplant)

Complications of IgA Nephropathy

IgA nephropathy is often described as a "benign" disease — and for many patients it is. But make no mistake: 30% develop ESRD over 30 years ^[11]^[12]. The complications of IgAN can be divided into those arising from the disease process itself (progressive glomerular injury), those from the nephrotic state (if present), those from progressive CKD, and those from treatment.

1. Disease-Specific Complications

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:

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
Podocyte injury — inflammatory mediators (TGF-β, PDGF) damage podocytes → podocyte detachment → bare areas of GBM → segmental sclerosis (the "S" in MEST-C)
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)
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.

2. Complications of the Nephrotic State (If Present)

About 5% of IgAN patients develop nephrotic syndrome (proteinuria > 3.5 g/day). When this occurs, they are subject to all the classic nephrotic complications.

Complications of nephrotic syndrome: resistant oedema, AKI, renal vein thrombosis, spontaneous bacterial peritonitis (in children), CV disease ^[20]

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

Mechanism	Detail
Urinary loss of anticoagulant proteins	Antithrombin III, protein C, protein S are lost in urine (similar molecular weight to albumin) → reduced natural anticoagulant activity
Increased hepatic production of procoagulant factors	Liver compensates for urinary protein loss by ramping up protein synthesis — but this includes clotting factors (fibrinogen, factors V, VII, VIII, vWF)
Hyperviscosity	Haemoconcentration from intravascular volume depletion (oncotic pressure reduced → fluid shifts to interstitium)
Platelet hyperaggregability	Hypoalbuminaemia increases free arachidonic acid → ↑thromboxane A2 → platelet activation

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]

As IgAN progresses through CKD stages 3–5, the patient develops the full spectrum of CKD complications. These are not unique to IgAN but are the final common pathway of any chronic renal disease.

Six systemic complications of CKD: fluid retention, metabolic acidosis, high blood pressure, normochromic normocytic anaemia, secondary hyperparathyroidism, bone disease ^[9]

Complication	Pathophysiology	Clinical Manifestation
Fluid retention	↓GFR → ↓Na⁺ and water excretion → volume expansion	Peripheral oedema, pulmonary oedema, hypertension
Hypertension	Volume expansion + RAAS activation + sympathetic overactivity + ↓renal vasodilatory prostaglandins	Elevated BP → further glomerular damage (vicious cycle). Present in ~30–50% of IgAN patients at diagnosis; increases as CKD progresses
Metabolic acidosis	↓Renal ammoniagenesis → ↓H⁺ excretion (normal anion gap initially → high anion gap in advanced CKD as organic acids accumulate)	Kussmaul breathing, muscle wasting (catabolism), accelerated bone resorption. Contributes to hyperkalaemia (H⁺/K⁺ exchange)
Hyperkalaemia	↓GFR → ↓K⁺ filtration + ↓tubular K⁺ secretion (especially if on ACEI/ARB which block aldosterone)	Arrhythmias (peaked T waves → broad QRS → VF), muscle weakness. Symptoms usually only when K > 6 ^[37]
Normochromic normocytic anaemia	↓Erythropoietin (EPO) production by failing peritubular interstitial cells of the cortex + uraemic inhibition of erythropoiesis + iron deficiency (GI loss, dialysis)	Fatigue, pallor, dyspnoea on exertion. Treated with ESA (erythropoietin) + IV iron
Secondary hyperparathyroidism	↓1α-hydroxylase activity in kidney → ↓1,25-dihydroxyvitamin D₃ → ↓intestinal Ca²⁺ absorption → hypocalcaemia. Simultaneously, ↓GFR → phosphate retention → hyperphosphataemia. Both stimulate PTH release → secondary hyperparathyroidism	Renal osteodystrophy (bone pain, fractures, deformity), vascular calcification, pruritus. CKD-MBD characterised by vascular calcification ^[9]
Uraemia	Accumulation of urea, creatinine, and other uraemic toxins when GFR falls to very low levels	Nausea, vomiting, anorexia, metallic taste, uraemic pericarditis, uraemic encephalopathy, uraemic frost (rare), pruritus

CKD Complications — The Mnemonic 'ABCDEF'

A handy way to remember CKD complications:

A = Anaemia (normochromic normocytic, ↓EPO)
B = Bone disease (renal osteodystrophy, CKD-MBD, secondary hyperPTH)
C = Cardiovascular (hypertension, LVH, atherosclerosis, fluid overload)
D = Disequilibrium (electrolytes: ↑K⁺, ↑PO₄, ↓Ca²⁺, metabolic acidosis)
E = Endocrine / Uraemia (↓EPO, ↓Vit D activation, uraemic symptoms)
F = Fluid retention (oedema, pulmonary oedema)

Chronic glomerulonephritis: an important cause of CKD — mainly presents as progressive insufficiency in patients with features of glomerulonephropathy (proteinuria, haematuria), allowed to progress untreated into CKD often because there is no acute presentation ^[36]

4. Complications of Treatment

Complication	Mechanism	Management
Hyperkalaemia	↓Aldosterone → ↓K⁺ excretion in distal tubule	Monitor K⁺ 1–2 weeks after dose change. Dietary K⁺ restriction, potassium binders, dose reduction
Acute Cr rise	Efferent arteriolar dilation → ↓intraglomerular pressure → ↓GFR. A rise of up to 20–30% is acceptable and expected	Only stop if rise > 30% or persistent. ACEI and ARB are contraindicated in bilateral renal artery stenosis ^[19]
Hypotension	↓Angiotensin II → ↓systemic vascular resistance	Titrate slowly. Check volume status
Cough	ACEI only — ↑bradykinin (ACE normally degrades bradykinin)	Switch to ARB
Angioedema	ACEI > ARB — bradykinin-mediated	Stop drug. Emergency management if airway compromise

Complication	Mechanism	Prevention/Management
Infections	Broad immunosuppression → ↓T-cell, macrophage function. PCP (Pneumocystis jirovecii pneumonia) is a specific risk	TMP-SMX prophylaxis during treatment (TESTING protocol)
Hyperglycaemia / New-onset DM	↑Hepatic gluconeogenesis, ↓peripheral glucose uptake, ↑insulin resistance	Monitor fasting glucose; may need insulin
Osteoporosis	↓Osteoblast activity, ↑osteoclast activity, ↓intestinal Ca²⁺ absorption	Calcium + Vitamin D supplementation. Bisphosphonate if prolonged use
Peptic ulcer	↓Prostaglandin → ↓mucosal protection	PPI co-prescription in high-risk patients
Adrenal suppression	Exogenous corticosteroid suppresses HPA axis	Taper gradually — never stop abruptly
Weight gain / Cushingoid features	Redistributed fat deposition (central obesity, moon face, buffalo hump)	Use lowest effective dose; taper as soon as possible
Avascular necrosis	Lipid microemboli / fat cell hypertrophy compressing intraosseous blood supply	Monitor for hip/knee pain; MRI if suspected

Complication	Mechanism	Prevention
Haemorrhagic cystitis	Acrolein (metabolite) is toxic to bladder urothelium	MESNA (sodium 2-mercaptoethane sulfonate) — binds acrolein in the bladder. Adequate hydration
Myelosuppression	Alkylating agent → affects rapidly dividing bone marrow cells	Regular CBC monitoring
Gonadotoxicity	Damages germ cells (ovarian follicles, spermatogonia)	Fertility counselling. GnRH agonist for ovarian protection. Sperm banking
Malignancy	↑Risk of bladder cancer, lymphoma, leukaemia (long-term)	Limit cumulative dose; use rituximab as alternative when possible
Teratogenicity	Alkylating agent — DNA damage to embryo	Absolute contraindication in pregnancy

Complication	Mechanism
Genital mycotic infections	Glucose in urine feeds Candida species → vulvovaginal candidiasis, balanitis
UTI	Glucosuria may promote bacterial growth (though evidence is conflicting)
Volume depletion	Osmotic diuresis from glucosuria → dehydration, postural hypotension, especially in elderly or those on diuretics
Euglycaemic DKA	Rare; mostly in T1DM. ↑Glucagon + ↓insulin → lipolysis → ketogenesis, but blood glucose may be normal due to renal glucose excretion

Category	Complications	Key Points
Disease progression	CKD → ESKD (30% over 30 years)	Proteinuria is both the marker and the driver of progression
Acute disease	Crescentic RPGN (~5%); AKI during gross haematuria	RPGN = emergency — treat before biopsy. Haematuria-related AKI usually self-limited
Post-transplant	Recurrence (~20–35% clinically significant)	Immune defect persists; graft loss from recurrence ~10% at 10 years
Nephrotic complications	Thromboembolism, infection, hyperlipidaemia, resistant oedema	Only if nephrotic-range proteinuria (uncommon in IgAN ~5%)
CKD complications	Anaemia, CKD-MBD, hyperkalaemia, metabolic acidosis, fluid overload, uraemia	Standard CKD management; not unique to IgAN
Treatment complications	ACEI/ARB: hyperkalaemia, Cr rise, cough. Steroids: infection, DM, osteoporosis. Cyclophosphamide: haemorrhagic cystitis, gonadotoxicity	Risk-benefit always weighed; TMP-SMX prophylaxis with steroids

High Yield Summary — Complications of IgA Nephropathy

The most important complication is progression to ESKD — 30% over 30 years. Driven by proteinuria (tubular toxicity of filtered protein → interstitial fibrosis) and glomerulosclerosis. T score on MEST-C is the strongest histological predictor.
Crescentic transformation (RPGN) occurs in ~5% — a medical emergency. Cellular crescents are potentially reversible; fibrous crescents are not. Treat urgently with pulse methylprednisolone ± cyclophosphamide.
AKI during gross haematuria — from RBC cast tubular obstruction and haem pigment toxicity. Usually self-limited.
Recurrence post-transplant — ~20–35% clinically significant because the underlying Gd-IgA1 immune defect persists.
CKD complications (ABCDEF): Anaemia, Bone disease, Cardiovascular, Disequilibrium (electrolytes/acid-base), Endocrine/Uraemia, Fluid retention.
Nephrotic complications (if proteinuria > 3.5 g/day): thromboembolism (renal vein thrombosis, DVT, PE), infection (Ig loss), hyperlipidaemia, resistant oedema.
Treatment complications: ACEI/ARB → hyperkalaemia, Cr rise. Steroids → infection (PCP), hyperglycaemia, osteoporosis. Cyclophosphamide → haemorrhagic cystitis, gonadotoxicity.

Active Recall - Complications of IgA Nephropathy

References

^[4] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (p. 15, recurrent kidney diseases post-transplant) ^[9] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (pp. 1, 23, CKD complications) ^[10] Senior notes: Block A - Introduction to Renal Investigations (RFT, urine tests and US kidneys).pdf (p. 4, small kidneys = CKD) ^[11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 997–999, IgAN prognosis) ^[12] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp. 404, IgAN prognosis) ^[15] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 327, RPGN crescent pathogenesis) ^[16] Senior notes: Ryan Ho Fundamentals.pdf (p. 361, RPGN) ^[17] Senior notes: Ryan Ho Urogenital.pdf (p. 64, RPGN) ^[19] Senior notes: Block A – Nephrology Data Interpretation.pdf (p. 11, ACEI/ARB contraindications) ^[20] Senior notes: Maksim Medicine Notes.pdf (pp. 230–232, nephrotic syndrome complications) ^[34] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p. 28, chronic GN evaluation and treatment) ^[35] Senior notes: Block A - Renal Replacement Therapies.pdf (p. 36–41, recurrence of IgAN post-transplant) ^[36] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 327, chronic GN as cause of CKD) ^[37] Senior notes: Ryan Ho Critical Care.pdf (p. 26, hyperkalaemia management, AKI complications)

High Yield Summary

IgA Nephropathy (Berger's Disease):

Definition: Primary GN with predominant mesangial IgA1 deposition — histological diagnosis requiring renal biopsy.
Epidemiology: Most common primary GN worldwide, especially common in Hong Kong/Asia. Peak in young adults (15–35), M > F.
Pathophysiology — Four-Hit Model: ① ↑Galactose-deficient IgA1 (Gd-IgA1) → ② Autoantibodies against Gd-IgA1 → ③ Circulating immune complex formation → ④ Mesangial deposition → complement activation (alternative/lectin, NOT classical) → mesangial proliferation → glomerular injury.
Classic Presentation: Synpharyngitic macroscopic haematuria (brown/smoky urine, no clots, within 1–2 days of URTI). Between episodes: persistent microscopic haematuria ± proteinuria.
Key Distinction from PSGN: IgAN = synpharyngitic (simultaneous); PSGN = post-infectious (1–2 week latent period).
Key Signs: Dysmorphic RBCs + RBC casts on urine microscopy (glomerular origin). Normal complement. Serum IgA elevated in ~50%.
Histology: MEST-C classification — T score (tubular atrophy/interstitial fibrosis) is the strongest histological predictor of ESKD.
Prognostic Factors: Proteinuria > 1 g/day (strongest modifiable factor), hypertension, reduced eGFR, high MEST-C scores.
Complement: C3 co-deposited, C1q absent (IgA does not fix classical pathway). Serum C3/C4 are NORMAL.
Red flags for secondary causes: Purpura (HSP), liver disease (hepatic IgA clearance failure), coeliac disease.

High Yield Summary — Differential Diagnosis of IgA Nephropathy

Three glomerular causes of recurrent haematuria: IgAN (synpharyngitic, no hearing loss, polygenic), Alport syndrome (X-linked, sensorineural deafness, progressive CKD in males), TBMD (benign, thin GBM on EM, autosomal dominant carrier of COL4A3/4).
IgAN vs PSGN: IgAN = synpharyngitic (0–2 days), normal complement. PSGN = post-infectious (1–2 weeks), low C3.
IgAN vs HSP: Identical renal pathology. HSP has systemic features (purpura, arthralgia, abdominal pain). Same disease spectrum.
Complement is the key sorter: Normal C3 → IgAN, HSP. Low C3 → PSGN, lupus, MPGN, IE, cryoglobulinaemia.
RPGN classification by IF: Type I = linear (anti-GBM), Type II = granular (immune complex — IgAN can cause this), Type III = pauci-immune (ANCA).
Always exclude urological causes of haematuria: Dysmorphic RBCs/RBC casts = glomerular; isomorphic RBCs/clots = urological. Most worrying urological cause: malignancy until proven otherwise.
Always exclude secondary IgA deposition: Liver disease, HBV/HCV, coeliac, HIV, IBD.
Renal biopsy is the gold standard — IF showing predominant mesangial IgA ± C3, absent C1q confirms IgAN. Apply MEST-C score for prognosis.

High Yield Summary — Diagnostics of IgA Nephropathy

IgAN is a histological diagnosis — renal biopsy with LM + IF + EM is required. No blood test or clinical criterion alone is diagnostic.
The diagnostic triad on biopsy: Mesangial IgA on IF ("staghorn pattern") + mesangial proliferation on LM + mesangial electron-dense deposits on EM. C1q is absent.
When to biopsy: Proteinuria > 0.5–1 g/day, declining eGFR, hypertension with active sediment, nephrotic-range proteinuria, RPGN, or diagnostic uncertainty. Isolated microscopic haematuria with normal Cr and no proteinuria → monitor.
Key blood tests: Normal C3/C4 (IgAN is the exception among immune-complex GN), ↑serum IgA in ~50% (non-specific), negative ANA/ANCA/anti-GBM. Always check HBsAg, anti-HCV, HIV.
GC slide high yield: Investigations for haematuria: Renal function, Urine culture/cytology/AFB, Urinalysis, Urine microscopy, KUB, USG/Doppler.
Urine microscopy: Dysmorphic RBCs + RBC casts = glomerular origin. This is the first and most important investigation to order.
MEST-C score: Applied on biopsy. T score (tubular atrophy/interstitial fibrosis) is the strongest histological predictor of ESKD.
Proteinuria quantification: uPCR (used at QMH) or UACR or 24h urine protein. > 1 g/day is the threshold for aggressive treatment.

High Yield Summary — Management of IgA Nephropathy

Supportive care is the foundation for ALL patients: Maximally titrated ACEI or ARB + SGLT2 inhibitor + BP < 130/80 + low-salt diet + statins + avoid nephrotoxins. Never prescribe ACEI and ARB together.
ACEI/ARB mechanism: Dilates efferent arteriole → ↓intraglomerular pressure → ↓proteinuria. Goal: proteinuria < 1 g/day.
SGLT2 inhibitors: Now standard of care (KDIGO 2024). Mechanism: ↑Na delivery to macula densa → tubuloglomerular feedback → afferent arteriolar constriction → ↓intraglomerular pressure. Complementary to ACEI/ARB.
Immunosuppression only if: Proteinuria > 1 g/day despite ≥ 3–6 months of maximal supportive care. Use TESTING protocol corticosteroids. Alternatives: targeted-release budesonide, MMF.
RPGN/Crescentic IgAN: Medical emergency. Pulse IV methylprednisolone ± cyclophosphamide/rituximab. Can treat empirically before biopsy.
IgAN recurs post-transplant (~20–35% clinically significant) because the immune defect persists.
Emerging therapies: Sparsentan (dual ETRA/ARB), complement factor B inhibitors, anti-APRIL/BAFF agents — targeting specific hits in the four-hit model.

High Yield Summary — Complications of IgA Nephropathy

The most important complication is progression to ESKD — 30% over 30 years. Driven by proteinuria (tubular toxicity of filtered protein → interstitial fibrosis) and glomerulosclerosis. T score on MEST-C is the strongest histological predictor.
Crescentic transformation (RPGN) occurs in ~5% — a medical emergency. Cellular crescents are potentially reversible; fibrous crescents are not. Treat urgently with pulse methylprednisolone ± cyclophosphamide.
AKI during gross haematuria — from RBC cast tubular obstruction and haem pigment toxicity. Usually self-limited.
Recurrence post-transplant — ~20–35% clinically significant because the underlying Gd-IgA1 immune defect persists.
CKD complications (ABCDEF): Anaemia, Bone disease, Cardiovascular, Disequilibrium (electrolytes/acid-base), Endocrine/Uraemia, Fluid retention.
Nephrotic complications (if proteinuria > 3.5 g/day): thromboembolism (renal vein thrombosis, DVT, PE), infection (Ig loss), hyperlipidaemia, resistant oedema.
Treatment complications: ACEI/ARB → hyperkalaemia, Cr rise. Steroids → infection (PCP), hyperglycaemia, osteoporosis. Cyclophosphamide → haemorrhagic cystitis, gonadotoxicity.

IgA Nephropathy

1. Definition

2. Epidemiology

Global Perspective

Hong Kong / Asian Context

Demographics

Prognosis Statistics

3. Anatomy and Relevant Functional Review

The Glomerulus — A Quick Refresher

The Mesangium — Where the Action Is in IgAN

4. Aetiology

4.1 Primary (Idiopathic) IgA Nephropathy

4.2 Secondary Causes of Mesangial IgA Deposition

4.3 Genetic Susceptibility

5. Pathophysiology — The "Multi-Hit" Hypothesis

Hit 1: Increased Galactose-Deficient IgA1 (Gd-IgA1)

Hit 2: Autoantibody Formation

Hit 3: Immune Complex Formation

Hit 4: Mesangial Deposition and Glomerular Injury

Role of Complement

Summary of Pathophysiological Mechanisms Causing Clinical Features

6. Classification

6.1 Oxford Classification (MEST-C Score)

6.2 Clinical Phenotypes

6.3 International IgAN Prediction Tool

7. Clinical Features

7.1 Symptoms

A. Episodic Macroscopic Haematuria — The Classic Presentation

B. Asymptomatic Urinary Abnormalities

C. Symptoms of Nephrotic Syndrome (Uncommon)

D. Symptoms of Advanced Disease / CKD

E. Systemic Symptoms (Should Prompt Search for Secondary Causes)

7.2 Signs

A. General Examination

B. Urinary Signs

C. Urine Microscopy Findings

D. Renal Examination

E. Signs to Exclude Secondary Causes / Systemic Disease

8. Pathophysiology-Clinical Feature Mapping (Integrated Summary)

9. Risk Factors for Disease and Progression

Risk Factors for Developing IgAN

Risk Factors for Progression to ESKD

10. IgAN vs Other Glomerular Causes of Haematuria

Active Recall - IgA Nephropathy (Part 1: Definition to Clinical Features)

References

1. Framework: How IgAN Presents — And What Mimics Each Presentation

2. Differential Diagnosis by Presentation

2A. Differential Diagnosis of Recurrent Macroscopic Haematuria

2B. Differential Diagnosis of the Nephritic Syndrome Presentation

2C. Differential Diagnosis of RPGN Presentation

2D. Haematuria — Broader Differential (Urological vs Nephrological)

3. Differential Diagnosis of IgA Nephropathy vs IgA Vasculitis (HSP)

4. Secondary Causes of IgA Deposition — Always Exclude

5. Diagnostic Approach — Mermaid Flowchart

6. Summary Table: Key Serological and Histological Differentiators

7. Red Flags That the Patient in Front of You Does NOT Have IgAN

Active Recall - Differential Diagnosis of IgA Nephropathy

1. Diagnostic Criteria — Overview

1.1 The Three Pillars of Histological Diagnosis

1.2 Clinical Criteria Raising Suspicion (Triggers for Biopsy)

2. Diagnostic Algorithm

3. Investigation Modalities — Detailed Breakdown

3.1 Urinalysis — The Starting Point

3.2 Quantification of Proteinuria

3.3 Blood Tests — Basic Workup

3.4 Immunological / Serological Workup

3.5 Imaging

3.6 Renal Biopsy — The Definitive Investigation

Indications for Biopsy in Suspected IgAN

What You See on Biopsy — The "Tripod" Findings

IF Patterns in Different GN — A Comparison Table for Biopsy Interpretation

4. Risk Stratification After Biopsy

4.1 MEST-C Score (Oxford Classification)

4.2 International IgAN Prediction Tool

5. Summary: Complete Investigation Panel for Suspected IgAN

Active Recall - IgAN Diagnostic Criteria, Algorithm and Investigations

1. Overarching Principles

2. Management Algorithm — Mermaid Diagram

3. Tier 1: Optimised Supportive Care (ALL Patients)

3.1 RAAS Blockade — ACEI or ARB