Lupus nephritis is a serious complication of systemic lupus erythematosus in which immune complex deposition in the kidneys causes glomerular inflammation, potentially leading to renal failure.

Lupus Nephritis

2. Epidemiology

Factor	Detail
Sex	Female predominance (9:1) reflecting SLE demographics ^[2]^[3]
Age	Peak onset 20–40 years; juvenile SLE has higher renal involvement
Ethnicity	Afro-Caribbean > Asian/Oriental > Caucasian (both incidence and severity)
Hong Kong context	SLE is relatively common in Chinese populations; LN is a major cause of secondary glomerulonephritis

3. Anatomy and Function — Relevance to Lupus Nephritis

Understanding where immune complexes deposit — and why different deposit locations produce different clinical syndromes — is absolutely fundamental to understanding lupus nephritis classification.

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

The glomerulus consists of:

Bowman's capsule (parietal epithelial cells)
  └── Urinary/Bowman's space
       └── Glomerular capillary tuft
            ├── Endothelial cells (fenestrated — allow filtration)
            ├── Glomerular basement membrane (GBM) — the main filtration barrier
            ├── Podocytes (visceral epithelial cells) — with foot processes and slit diaphragms
            └── Mesangium (mesangial cells + matrix) — structural support & phagocytic function

This is the key to understanding the ISN/RPS classification:

Deposit Location	Mechanism	Clinical Consequence
Mesangial	Mesangial cells phagocytose and process immune complexes → mild inflammation	Mild disease (Class I–II): microscopic haematuria, mild proteinuria
Subendothelial (between endothelium and GBM)	Deposits are in direct contact with circulating blood → robust inflammatory response → complement activation, neutrophil/monocyte recruitment	Nephritic picture: haematuria, RBC casts, hypertension, AKI → Class III/IV
Subepithelial (between GBM and podocytes)	Deposits damage podocyte foot processes → disruption of slit diaphragm → massive protein leak; but deposits are "hidden" from circulating blood so less inflammatory cell recruitment	Nephrotic picture: heavy proteinuria, nephrotic syndrome → Class V

Deposit Location → Clinical Syndrome

Mesangial deposits → activate complement → nephritic-like; subepithelial deposit → nephrotic-like ^[2]. This is the single most important concept for understanding why different LN classes present differently. Subendothelial deposits cause the most inflammation because they are directly accessible to circulating immune cells.

4. Etiology (Focus on Hong Kong)

5. Pathophysiology of Lupus Nephritis

Marker	Pathophysiological Role	Clinical Utility
Anti-dsDNA	Major component of pathogenic immune complexes	High specificity for SLE (~60%); use for diagnosis AND monitoring of disease progression, esp. for lupus nephritis ^[3]
C3, C4	Consumed by classical pathway activation during IC-mediated inflammation	Low in active disease; use for diagnosis AND monitoring ^[3]
C1q antibodies	May impair C1q-mediated clearance of IC	Associated with proliferative LN; some centers use for monitoring

Anti-dsDNA and Complement — Monitoring Tip

Anti-dsDNA for diagnosis and monitoring; C3/C4 for diagnosis and monitoring. Rising anti-dsDNA + falling C3/C4 = impending lupus nephritis flare. ^[3] ANA and anti-ENA have NO role in monitoring disease activity ^[3].

6. Classification — ISN/RPS Classification (2003, Revised 2018)

This is the WHO/ISN/RPS classification used universally. Overlapping of classes is common ^[1].

One etiology (SLE) may produce a variety of histologic patterns — this is why renal biopsy is essential ^[6].

Class	Name	Light Microscopy (LM)	IF / EM	Clinical Presentation	Notes
I	Minimal mesangial	Normal (LM)	Mesangial immune deposits (EM/IF)	Normal / minimal urinary abnormalities	Rarely biopsied
II	Mesangial proliferative	Mesangial hypercellularity with expansion of mesangial matrix	Mesangial immune deposits	Microscopic haematuria / proteinuria	Generally good prognosis
III	Focal nephritis	< 50% glomeruli affected	Subendothelial and mesangial immune deposits	Haematuria / proteinuria / ↓GFR / hypertension / ± nephrotic	Active (A), chronic (C), or A/C
IV	Diffuse nephritis	≥ 50% glomeruli affected with crescent formation	Subendothelial and mesangial deposits; Full-house staining (ALL IgG, IgA, IgM, C3 and C1q)	Haematuria / proteinuria / ↓GFR / hypertension / ± nephrotic	MOST common and MOST severe form; presents as RPGN (crescentic GN) ^[1]
	IV-G: Global	IV-S: Segmental			Sub-classified by extent
V	Membranous nephritis	Thickened glomerular capillary wall	Subepithelial and mesangial immune deposits	Proteinuria / nephrotic syndrome	Presents as membranous GN ^[1]
VI	Advanced sclerosing	Global sclerosis of nearly all glomerular capillaries	—	ESRD	Irreversible damage

Full-House Staining — Pathognomonic

Full-house staining on IF (ALL IgG, IgA, IgM, C3 and C1q) is virtually pathognomonic for lupus nephritis (especially Class IV) ^[1]. No other glomerulonephritis reliably shows deposition of all five immunoreactants. If you see full-house staining on a histology question — think lupus.

Renal biopsy reports include: ^[2]

Histology (class)
Activity index: proliferation & inflammation → determines intensity of treatment
Chronicity index: degree of sclerosis, fibrosis → prevents further worsening by CV risk control (ACEI, statins)

Index	Components	Clinical Significance
Activity Index (0–24)	Endocapillary proliferation, cellular crescents, karyorrhexis/fibrinoid necrosis, glomerular leukocyte infiltration, wire loop deposits, interstitial inflammation	High AI → aggressive immunosuppression needed
Chronicity Index (0–12)	Glomerulosclerosis, fibrous crescents, tubular atrophy, interstitial fibrosis	High CI → less likely to respond to immunosuppression; focus on renoprotection

High Yield — Activity vs. Chronicity

A high activity index means the disease is "hot" and treatable with immunosuppression. A high chronicity index means the horse has already bolted — scarring is irreversible, and you focus on slowing further decline (RAAS blockade, BP control, lipid control). Repeat biopsy if disease progresses ^[2].

7. Clinical Features

Symptom	Pathophysiological Basis	LN Class Association
Asymptomatic	Minimal immune complex deposition with preserved GFR	Class I, II
Frothy/foamy urine	Heavy proteinuria (> 3.5 g/day) → excess protein lowers urine surface tension	Class III (partial), IV, V
Tea/cola-coloured urine (macroscopic haematuria)	GBM disruption → RBCs leak into Bowman's space and urine; dysmorphic RBCs/casts give dark colour	Class III, IV
Reduced urine output (oliguria)	Endocapillary proliferation and crescent formation narrow/obliterate capillary lumens → ↓ GFR → ↓ urine production	Class III, IV (especially RPGN)
Periorbital and leg swelling (oedema)	Two mechanisms: (1) nephrotic: hypoalbuminaemia → ↓ oncotic pressure → fluid leaks to interstitium; (2) nephritic: salt and water retention due to ↓ GFR	Class III, IV (nephritic); V (nephrotic)
Weight gain	Fluid retention from salt/water retention and/or hypoalbuminaemia	III, IV, V
Fatigue / malaise	Uraemia (in AKI/CKD); anaemia (chronic disease, haemolytic); general SLE constitutional symptoms	Any class with renal impairment
Nausea, poor appetite	Uraemia → stimulates chemoreceptor trigger zone	Class IV (if AKI severe), VI
Headache	Hypertension from fluid overload and RAAS activation	III, IV
Dyspnoea	Fluid overload → pulmonary oedema; or concomitant SLE pleuritis/shrinking lung	Advanced III, IV
Flank/loin pain	Renal capsular distension (if kidneys acutely swollen); renal vein thrombosis (if nephrotic + APLS)	Uncommon; consider thrombosis

Associated SLE symptoms (often coexist and help clinch the diagnosis):

Hair loss, oral ulcers, rashes (photosensitivity) → lupus nephritis ^[7]
Joint pain (bilateral small hand joints) — arthralgia/arthritis ^[7]
Constitutional: fever, weight loss, poor appetite ^[2]^[3]

Sign	Pathophysiological Basis	Clinical Note
Hypertension (BP > 140/90)	↓ GFR → Na+/water retention → volume expansion; RAAS activation from renal ischaemia	A 34-year-old with SLE features and BP 152/92 should raise alarm for lupus nephritis ^[7]
Peripheral oedema (pitting, bilateral lower limbs)	Hypoalbuminaemia (nephrotic) or Na+/water retention (nephritic)	Sacral oedema if bedridden
Periorbital oedema	Low oncotic pressure → fluid accumulates in loose periorbital tissue; classically worse in the morning	More suggestive of nephrotic syndrome
Ascites	Severe hypoalbuminaemia → transudative ascites	In severe nephrotic syndrome
Pleural effusion / pulmonary oedema	Fluid overload ± low oncotic pressure	Bilateral basal crackles, ↓ air entry
Pallor	Anaemia of chronic disease; haemolytic anaemia (AIHA in SLE); erythropoietin deficiency (CKD)	Check reticulocyte count, Coombs test
Malar (butterfly) rash	Acute cutaneous lupus — immune complex deposition in dermal-epidermal junction, UV-triggered	Erythematous maculopapular rash in butterfly distribution over cheeks and bridge of nose, sparing nasolabial fold ^[2]
Oral ulcers	Mucosal vasculitis	Usually painless ^[2]
Alopecia	Non-scarring (active SLE); scarring (discoid lupus)
Arthritis	Symmetrical non-erosive small joint polyarthritis resembling RA ^[3]	Morning stiffness typically in minutes (cf. > 1 hr in RA)
Livedo reticularis	Vasospasm / microthrombosis — especially if APLS coexists	Purple reticular pattern on skin
Raynaud's phenomenon	Vasospasm of digital arteries → white → blue → red	Present in ~20% of SLE

This summary ties together the classification and clinical features:

Class	Clinical Syndrome	Key Features
I	Normal / subclinical	No symptoms; normal urinalysis or minimal changes detectable only on biopsy
II	Asymptomatic urinary abnormalities	Microscopic haematuria / proteinuria ^[1]
III	Acute nephritic syndrome ± nephrotic features	Haematuria / proteinuria / ↓GFR / hypertension / ± nephrotic ^[1]
IV	Acute nephritic syndrome / RPGN	MOST common and MOST severe; presents as RPGN (crescentic GN) ^[1]; rapid ↓GFR over days–weeks
V	Nephrotic syndrome	Proteinuria / nephrotic syndrome; presents as membranous GN ^[1]; insidious onset, often without haematuria
VI	Chronic kidney disease / ESRD	Irreversible; shrunken kidneys; symptoms of uraemia

The Classic Exam Vignette

A 34-year-old Chinese lady with good past health presented with generalised malaise, pain over bilateral small hand joints and lower limb swelling. BP 152/92 mmHg. Urine multistix: RBC 3+ and protein 3+. ^[7]

This is lupus nephritis until proven otherwise. The triad of: (1) young female, (2) joint pain + constitutional symptoms, (3) nephritic urine + hypertension = classic presentation. Next steps: autoimmune serologies (ANA, anti-dsDNA, C3/C4) and renal biopsy.

8. Approach to a Patient Suspected of Lupus Nephritis

This is critically important because management is guided by histology ^[2]:

Indications for renal biopsy: ^[2]

Proteinuria > 0.5 g/day
Persistent haematuria
Raised creatinine not attributed to another mechanism

When to Biopsy — The 0.5g Rule

Many students forget that the threshold for biopsy in SLE is proteinuria > 0.5 g/day (not the 3.5 g nephrotic range). This is because even "moderate" proteinuria in SLE may indicate Class III/IV disease requiring aggressive immunosuppression. Don't wait for nephrotic-range proteinuria!

High Yield Summary

Definition: Lupus nephritis = renal inflammation in SLE caused by immune complex deposition in glomeruli → complement activation → tissue damage.

Epidemiology: ~50% of SLE patients; more common and severe in Asians and Afro-Caribbeans; risk factors include juvenile SLE, male sex, high anti-dsDNA, low complement.

Pathophysiology: Anti-dsDNA + nuclear antigens → immune complexes → deposit in mesangium (Class I/II), subendothelium (Class III/IV), subepithelium (Class V) → complement activation → inflammation ± podocyte injury.

Classification: ISN/RPS 6 classes:

Class I (minimal mesangial) → normal
Class II (mesangial proliferative) → microscopic haematuria/proteinuria
Class III (focal, < 50%) → nephritic ± nephrotic
Class IV (diffuse, ≥ 50%) → MOST common and MOST severe; RPGN
Class V (membranous) → nephrotic
Class VI (advanced sclerosing) → ESRD

Full-house staining (IgG, IgA, IgM, C3, C1q) is pathognomonic for LN (esp. Class IV).

Activity index → guides immunosuppression intensity. Chronicity index → guides renoprotective strategy.

Biopsy indications: proteinuria > 0.5 g/day, persistent haematuria, unexplained ↑Cr.

Monitoring: Anti-dsDNA (↑ = active) + C3/C4 (↓ = active). ANA/anti-ENA NOT for monitoring.

Active Recall - Lupus Nephritis (Definition to Clinical Features)

Differential Diagnosis of Lupus Nephritis

When you are faced with a patient who has features suspicious for lupus nephritis — say, a young woman with haematuria, proteinuria, hypertension, oedema, and perhaps some extra-renal clues — you need a systematic framework. The differential diagnosis operates at two levels:

Level 1 — What is causing this glomerulonephritis? (i.e., DDx of the presenting clinical syndrome — nephritic, nephrotic, RPGN, or asymptomatic urinary abnormalities)
Level 2 — Is it really lupus nephritis, or is this a different renal pathology in an SLE patient? (i.e., non-LN causes of renal dysfunction in SLE)

We will work through both levels systematically.

1. Level 1 — Differential Diagnosis by Clinical Syndrome

Lupus nephritis can present as virtually any glomerular syndrome. The DDx therefore depends on how the patient presents.

Nephritic syndrome is a common presentation of most proliferative glomerulonephritides (GN) ^[7].

The key diagnostic question: What is causing haematuria + proteinuria + hypertension + oedema + impaired renal function?

Differential diagnosis of acute nephritic syndrome: ^[7]^[8]^[9]

Diagnosis	Key Distinguishing Features	Complement	Serology
Lupus nephritis	Young female, SLE features (rash, arthritis, oral ulcers, alopecia, serositis), characteristic rash and arthritis suggest SLE ^[8]^[9]	↓ C3/C4	ANA +, anti-dsDNA +, anti-Sm +
Post-streptococcal GN (PSGN)	URTI 7–10 days before ^[8]^[9]; children 2–10 yr; self-limiting	↓ C3 (normalises by 4 weeks; if persists → consider lupus nephritis / MPGN) ^[2]	ASOT ↑, anti-DNase B ↑
IgA nephropathy	Synpharyngitic haematuria (gross haematuria within 1–2 days of URTI — i.e., concurrent not delayed) ^[8]^[9]; commonest primary GN	Normal C3/C4 (IgA-IgG IC does NOT activate complement) ^[8]	↑ Serum IgA (50%)
ANCA-associated vasculitis (GPA, MPA, EGPA)	Palpable purpura/petechial rash suggest vasculitis; triad of sinusitis, pulmonary infiltrates and nephritis suggest Wegener's ^[8]^[9]; older patients	Normal C3/C4	ANCA + (c-ANCA/PR3 for GPA; p-ANCA/MPO for MPA)
Anti-GBM disease / Goodpasture syndrome	Haemoptysis suggests pulmonary haemorrhage ^[8]^[9]; older patients (bimodal: young males, elderly)	Normal C3/C4	Anti-GBM +
Membranoproliferative GN (MPGN)	Chronic; a/w HCV, cryoglobulinaemia, malignancy	↓ C3/C4	HCV Ab, cryocrit
Infective endocarditis-associated GN	Persistent fever + new murmur; embolic phenomena	↓ C3/C4	Blood cultures +; echocardiogram
Cryoglobulinaemic GN	Purpura, arthralgia, neuropathy; a/w HCV	↓ C3/C4	Cryocrit +
HSP / IgA vasculitis	Children; palpable purpura (lower limbs), abdominal pain, arthralgia	Normal C3/C4	Clinical diagnosis

High Yield — Complement Levels as the Great Discriminator

Serum complement level is important in helping narrow the differential diagnosis: ^[8]^[9]

↓ C3/C4 generally indicates IC-mediated GN → DDx: MPGN, PSGN, lupus, cryoglobulinaemia, IE and shunt nephritis ^[8]^[9]
Normal C3/C4 generally indicates non-IC-mediated GN (except IgAN) → DDx: PAN, Goodpasture, HSP/IgAN, ANCA-related renal vasculitis ^[8]^[9]

This single test dramatically narrows your differential. Lupus nephritis causes low C3 AND C4 (classical pathway consumption). PSGN typically only drops C3 (alternative pathway).

When lupus nephritis presents as nephrotic syndrome (heavy proteinuria, hypoalbuminaemia, oedema, hyperlipidaemia), the DDx shifts:

Diagnosis	Age Group	Distinguishing Features
Minimal change disease (MCD)	Children (most common cause); adults too	Selective proteinuria, normal complement, responds to steroids
Focal segmental glomerulosclerosis (FSGS)	Any age	Non-selective proteinuria, may have haematuria; HIV-associated (collapsing variant) ^[10]
Membranous nephropathy (primary)	Adults > 40	Anti-PLA2R antibody positive (~70%); a/w malignancy in elderly
Lupus nephritis Class V	Young females	SLE features, anti-dsDNA +, ↓ C3/C4, full-house staining on biopsy
Diabetic nephropathy	Diabetic patients	Long-standing DM, progressive proteinuria, retinopathy coexists
Amyloidosis	Older adults	Congo red +, apple-green birefringence; a/w myeloma, chronic inflammation
Membranous nephropathy (secondary)	Any age	HBV most often induces membranous nephropathy; HCV most often induces MPGN ^[10]; malignancy; drugs (gold, penicillamine)

Age-based DDx for nephrotic and nephritic syndromes: ^[2]

Age	Nephrotic	Nephritic
< 15y	MCD, FSGS	PSGN, IgAN/HSP
15–40y	MCD, FSGS, Membranous	IgAN, PSGN, Lupus nephritis, RPGN
> 40y	MCD, Membranous, DM, Amyloidosis	PSGN, IgAN, RPGN

RPGN is a clinical syndrome but NOT a specific etiology of GN ^[2]^[11]. When LN presents as RPGN (creatinine doubling over days to weeks), the DDx is classified by IF staining pattern: ^[8]^[11]

Type	IF Pattern	Cause	Complement	Key Serology
Type I	Linear	Anti-GBM disease	Normal	Anti-GBM +
Type II	Granular	Immune complex-mediated: SLE (LN), IgAN, PSGN, cryoglobulinaemia	↓ (in LN, PSGN, MPGN)	ANA, anti-dsDNA, ASOT, cryocrit
Type III	Negative (pauci-immune)	ANCA-associated vasculitis (GPA, MPA, EGPA)	Normal	ANCA +

Lupus nephritis causing RPGN falls under Type II (granular IF) — it can complicate most GN commonly associated with nephritic syndrome (e.g. SLE, IgAN, PSGN) as an extreme form due to extensive endothelial injury ^[11].

High Yield — RPGN Classification by IF

Classification of RPGN is based on IF staining pattern: ^[8]^[11]

Type I (linear staining) = anti-GBM disease
Type II (granular staining) = immune complex RPGN — this is where lupus nephritis falls
Type III (negative staining) = pauci-immune RPGN, usually ANCA-positive

This classification directly determines management. Lupus nephritis RPGN = high-dose steroids + cyclophosphamide/MMF. Anti-GBM = plasmapheresis. ANCA-vasculitis = rituximab/cyclophosphamide.

Not every renal problem in an SLE patient is lupus nephritis. Renal involvement in SLE is NOT limited to glomerular disease — may have tubulointerstitial (tubulointerstitial nephritis) or vascular (RVT, RAS due to antiphospholipid syndrome) involvement ^[12].

Diagnosis	Mechanism	Clue
Lupus nephritis (Class I–VI)	IC deposition in glomeruli	Active sediment (dysmorphic RBCs, casts), proteinuria, ↑anti-dsDNA, ↓C3/C4
Drug-induced AKI (NSAIDs)	NSAIDs inhibit prostanoid production → impaired regulation of renal blood flow ^[13]; also cause TIN and GN	Ask for drug history — NSAIDs possible given MSK complaints ^[7]; bland sediment; eosinophiluria if TIN
Drug-induced TIN	Hypersensitivity reaction to drugs (NSAIDs, antibiotics, PPIs)	Fever, rash, eosinophilia, eosinophiluria, WBC casts; may mimic LN flare
Thrombotic microangiopathy (TMA)	APLS-associated or TTP-like; microthrombi in renal vessels	Schistocytes on blood film, ↓ platelets, ↑ LDH, ↓ haptoglobin
Antiphospholipid nephropathy	Microvascular thrombosis in renal arteries/arterioles	Hypertension, bland sediment, APLS antibodies +; biopsy shows thrombotic lesions
Renal vein thrombosis	Nephrotic syndrome → hypercoagulable state; or APLS	Acute flank pain, haematuria, sudden ↑ proteinuria; CT venography diagnostic
Lupus tubulointerstitial nephritis	IC deposition in tubular basement membranes	Tubular dysfunction (↓ concentration ability) ^[12]; distal RTA (Type 1)
Hypertensive nephrosclerosis	Chronic hypertension → afferent arteriolar sclerosis	Long-standing HTN, proteinuria < 1 g/day, bland sediment
Infection	Immunosuppressed patients → UTI, sepsis	Fever, pyuria, positive urine culture, ↑ CRP (active SLE doesn't usually evoke ↑CRP — CRP elevation likely due to infection ^[3])
TCM nephrotoxicity	Aristolochic acid, heavy metals	History of TCM use; tubular injury pattern

CRP — The Infection Discriminator

Active SLE does not usually evoke ↑ CRP. If CRP is elevated, think infection ^[3]. This is a very useful clinical pearl — most autoimmune diseases raise ESR but SLE characteristically keeps CRP normal unless there is concomitant infection, serositis, or active arthritis.

3. Approach to Narrowing the Differential

The workup for glomerulonephritis includes: ^[14]

Autoimmune markers: ANA, Anti-dsDNA, C3/4, ANCA, Anti-GBM, CRP, cryoglobulins
Exclude infective causes (e.g. HBV/HCV/HIV/VDRL/malaria)
Malignancy screen (e.g. tumour markers, SIEP) especially in elderly
Renal biopsy: LM/IF/EM findings → Diagnosis, guide treatment decisions and prognosis

Suggestive clinical findings to ask about: ^[8]^[9]

Clue	Points Towards
Relationship with URTI: URTI 7–10 days before = PSGN; concurrent = IgAN ^[8]^[9]	PSGN vs. IgA nephropathy
Palpable purpura / petechial rash → vasculitis ^[8]^[9]	ANCA vasculitis, HSP, cryoglobulinaemia
Haemoptysis → pulmonary haemorrhage ^[8]^[9]	Goodpasture, GPA, MPA
Triad of sinusitis, pulmonary infiltrates and nephritis → Wegener's (GPA) ^[8]^[9]	GPA
Characteristic rash and arthritis → SLE ^[8]^[9]	Lupus nephritis
Hair loss, oral ulcers, rashes, photosensitivity ^[7]	Lupus nephritis
Drug history — NSAIDs ^[7]	Drug-induced AKI / TIN

Renal biopsy is necessary for most cases of nephritic syndrome ^[8]^[9] unless kidneys are very small on ultrasound (suggesting chronic irreversible disease).

Immunofluorescence pattern is the most helpful for diagnosis: ^[8]^[9]

IF Pattern	Diagnosis
Full-house (IgG, IgA, IgM, C3, C1q)	Lupus nephritis (virtually pathognomonic) ^[1]
Dominant IgA	IgA nephropathy / HSP nephritis
Linear IgG along GBM	Anti-GBM disease
Granular IgG + C3	Immune complex GN (PSGN, MPGN, cryoglobulinaemia)
Pauci-immune (negative/minimal)	ANCA-associated vasculitis

The differential diagnosis of lupus nephritis is best understood as three concentric circles:

Innermost circle: Confirming it is lupus nephritis → SLE features + active sediment + anti-dsDNA ↑ + C3/C4 ↓ + full-house IF on biopsy
Middle circle: Other glomerulonephritides that mimic the same clinical syndrome → use complement, serology, and IF pattern to differentiate
Outermost circle: Non-GN renal pathologies in SLE patients → drug-induced (NSAIDs), TMA/APLS nephropathy, TIN, infection, hypertensive nephrosclerosis

High Yield Summary

DDx of Lupus Nephritis — Key Framework:

By complement level:
- Low C3/C4 (IC-mediated): Lupus nephritis, PSGN, MPGN, cryoglobulinaemia, IE
- Normal C3/C4 (non-IC): ANCA vasculitis, anti-GBM disease, IgA nephropathy, HSP
By RPGN IF pattern:
- Type I (linear) = Anti-GBM
- Type II (granular) = Lupus nephritis, PSGN, IgAN, cryoglobulinaemia
- Type III (pauci-immune) = ANCA vasculitis
Non-LN renal disease in SLE:
- Drug-induced (NSAIDs), APLS nephropathy/TMA, TIN, infection, hypertensive nephrosclerosis
Key discriminators:
- Full-house IF staining = lupus nephritis
- CRP ↑ in SLE = think infection, not flare
- URTI 7–10 days before = PSGN; concurrent = IgAN
- Characteristic rash + arthritis = SLE
Renal biopsy is the definitive investigation — needed for most cases of nephritic syndrome.

Active Recall - Differential Diagnosis of Lupus Nephritis

References

^[1] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai) — Lupus nephritis section (p1000, p1728) ^[2] Senior notes: Maksim Medicine Notes — Nephrology, GN section (p229–233) and Lupus nephritis (p315–317) ^[3] Senior notes: Ryan Ho Rheumatology — SLE section (p70, p73, p75) ^[7] Senior notes: Block A - Nephrology Interactive Tutorial — Case 1 (p1) ^[8] Senior notes: Adrian Lui Pediatrics Notes — Nephritic syndrome evaluation (p325–326) ^[9] Senior notes: Ryan Ho Urogenital — GN evaluation (p63); Ryan Ho Fundamentals — GN evaluation (p360–361) ^[10] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai) — GN diagnosis (p995, p1008); MBBS Final MB (Pediatrics) — GN diagnosis (p402, p415, p421) ^[11] Senior notes: Ryan Ho Fundamentals — RPGN (p361); Adrian Lui Pediatrics Notes — RPGN (p326) ^[12] Senior notes: Ryan Ho Urogenital — Lupus nephritis (p87) ^[13] Senior notes: Block A – Nephrology Data Interpretation — Drug-induced AKI (p11) ^[14] Lecture slides: Introduction-kidney-Ix (p23) ^[15] Lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury (p16) ^[16] Lecture slides: GC_Interactive tutorial (Nephr case 1) student copy (p1)

Diagnostic Criteria, Diagnostic Algorithm, and Investigations for Lupus Nephritis

1. Diagnostic Criteria

The diagnosis of lupus nephritis requires two things: (A) establishing that the patient has SLE, and (B) confirming that the kidney is involved and determining the histological class. Let's work through both.

1.1 Establishing the Diagnosis of SLE

Before you can diagnose lupus nephritis, you need to confirm the patient has lupus. Two major classification systems are used:

Classification criteria: EULAR/ACR criteria 2019 — 7 clinical domains + 3 immunological domains. SLE if ANA positive + total score of ≥ 10 ^[2].

Entry criterion: ANA positive (≥ 1:80 on HEp-2 cells or equivalent)
If ANA is negative, you cannot classify the patient as SLE under this system
Then, additive weighted scoring across 10 domains; each domain counts its highest-weighted criterion only
Total score ≥ 10 → classified as SLE

Key renal domain scoring in 2019 EULAR/ACR:

Finding	Score
Proteinuria > 0.5 g/24h	+4
Class II or V LN on biopsy	+8
Class III or IV LN on biopsy	+10 (highest single-criterion score)

This tells you how heavily renal involvement weighs in the classification — a patient with biopsy-proven Class III/IV LN and positive ANA already scores ≥ 10 on that criterion alone.

SLICC criteria: 4 out of 17 criteria including at least 1 clinical criterion and 1 immunological criterion (OR) biopsy-proven lupus nephritis with +ve ANA or anti-dsDNA ^[1]^[3]^[17].

This is a critical point:

High Yield — SLICC Shortcut

Under SLICC criteria, biopsy-proven lupus nephritis with positive ANA or anti-dsDNA is sufficient to diagnose SLE — even if the patient does not meet 4 out of 17 criteria ^[1]^[3]^[17]. This reflects the clinical reality that some patients present first with isolated nephritis before developing other SLE manifestations.

Advantages of SLICC over ACR: allows diagnosis solely based on biopsy-proven lupus nephritis; avoids duplication of correlated cutaneous features; includes more cutaneous, neurologic and immunologic criteria; greater sensitivity (97% vs 83%) but lower specificity (84% vs 96%) ^[3].

SLICC Renal criterion ^[1]^[17]:

Urine protein-to-creatinine ratio or 24-hour urine protein representing 500 mg protein/24 hours
Red blood cell casts

SLICC Immunological criteria (at least 1 needed) ^[1]^[17]:

Criterion	Notes
ANA	Above lab reference range
Anti-dsDNA	Above lab reference range (except ELISA: 2× above)
Anti-Sm	Positive
Antiphospholipid Ab	Lupus anticoagulant, anti-cardiolipin, anti-β2-GPI, or false-positive VDRL
Low complement	Low C3, low C4, or low CH50
Direct Coombs test	Positive (in absence of haemolytic anaemia)

3. Investigation Modalities — Systematic Approach

Investigation	What to Look For	Interpretation
Urine dipstick	Blood, protein	RBC 3+ and protein 3+ = nephritic picture ^[7]; protein alone = nephrotic
Urine microscopy	Dysmorphic RBCs, RBC casts → glomerular haematuria ^[8]^[9]	RBC casts are pathognomonic of glomerulonephritis; WBC casts suggest interstitial nephritis or pyelonephritis
BP measurement	Hypertension	BP 152/92 in a young woman → consider nephritis ^[7]
Fluid status	Oedema, JVP, lung bases	Nephritic (volume overload) vs. nephrotic (oncotic) oedema

3.2 Blood Investigations

Investigation	Expected Finding in LN	Why
CBC with differential ^[8]	NcNc anaemia with ↓ Hct (anaemia of chronic disease or AIHA); leukopenia (< 4000); lymphopenia (< 1000); thrombocytopenia (< 100,000)	SLE causes pancytopenia via autoantibodies (Type II HSR) and bone marrow suppression; haemolytic anaemia via anti-RBC antibodies
RFT (Cr, urea, eGFR) ^[8]^[4]	Raised creatinine, raised urea, ↓ eGFR	Document degree of renal impairment ^[8]; Cr > 250 μmol/L at diagnosis in RPGN
Serum albumin	Low (< 30 g/L if nephrotic)	Heavy proteinuria → urinary albumin loss → hypoalbuminaemia
LFT	↓ Albumin; check to rule out ↓ production from liver disease ^[3]	Check LFT to rule out decreased production in liver disease when interpreting low complement ^[3]
Lipid profile	Hyperlipidaemia (if nephrotic)	Liver compensates for albumin loss by ↑ lipoprotein synthesis
ESR	Usually increased ^[8]	Non-specific marker of inflammation; elevated by ↑ immunoglobulins
CRP	Usually normal or mildly elevated	Active SLE doesn't evoke ↑ CRP → if elevated, likely infection ^[3]; may be elevated in serositis, arthritis, or vasculitis
DAT (Direct Coombs)	May be positive	Autoimmune haemolytic anaemia in SLE
Clotting profile	↑ APTT (if lupus anticoagulant present)	APLS coexists in ~30% of SLE; paradoxically, ↑ APTT = thrombotic risk
FBG/lipids	Screen CV risk	Screen and control CVS risk factors ^[2]

ESR vs CRP in SLE — A Critical Distinction

In most inflammatory diseases, ESR and CRP rise together. In SLE, ESR rises but CRP stays normal during flares. This is because CRP is an acute-phase reactant driven by IL-6, and SLE flares produce relatively little IL-6 compared to infections.

If CRP is elevated in SLE → think infection, not flare ^[3]. This principle helps you distinguish a lupus flare from infection in a febrile immunosuppressed patient — a life-or-death distinction on the ward.

Work up for glomerulonephritis includes autoimmune markers: ANA, Anti-dsDNA, C3/4, ANCA, Anti-GBM, CRP, cryoglobulins ^[14].

Marker	Result in LN	Sensitivity/Specificity	Role	Clinical Notes
ANA	Positive (usually ≥ 1:160)	Most sensitive (> 95% in SLE) but non-specific ^[2]^[3]	Entry criterion for diagnosis; NOT for monitoring ^[3]	+ve in 5–15% of normal population; also +ve in other CTDs
Anti-dsDNA	Positive (elevated titre)	Highly specific (~60% sensitivity) ^[3]^[18]	For diagnosis AND monitoring (esp. lupus nephritis) ^[2]^[3]^[18]	Titre correlates with overall disease activity ^[18]
Anti-Sm	Positive in 10–30%	Most specific for SLE ^[2]	Diagnosis; associated with neurological involvement
C3/C4	Low (both, due to classical pathway)	N/A	For diagnosis AND monitoring ^[2]^[3]	Low in active disease → consumption of C' for opsonization of IC ^[2]
Anti-ENA panel (Ro, La, RNP)	Variable	Not specific/sensitive for SLE individually	Diagnosis and prognosis on complications	If negative, repeat regularly; if positive, no need to repeat (no correlation with disease activity) ^[3]
Antiphospholipid Ab	Positive in ~40% of SLE	N/A	Screen for APLS	Lupus anticoagulant (most thrombogenic), anti-cardiolipin, anti-β2-GPI

Monitoring of disease activity: NO role for ANA and anti-ENA ^[3].

Anti-dsDNA: occurs in ~60% of patients with SLE. Highly specific for SLE. Is one of the classification criteria for SLE. Titre correlates with overall disease activity. May be associated with lupus nephritis. ^[18]

Exclude infective causes (e.g. HBV/HCV/HIV/VDRL/malaria) ^[14]:

Test	Purpose
HBV serology (HBsAg, HBeAg)	HBV → membranous nephropathy; also important before starting immunosuppression (risk of reactivation)
HCV serology (anti-HCV)	HCV → MPGN / cryoglobulinaemia
HIV serology	HIV → collapsing FSGS
VDRL	Syphilis → membranous nephropathy; also false-positive VDRL is a criterion for APLS

Malignancy screen (e.g. tumour markers, SIEP) especially in elderly ^[14]:

Serum/urine immunofixation electrophoresis (SIEP) and serum free light chains → amyloidosis, myeloma

Other serologies to distinguish from DDx:

Test	Purpose
ANCA (and subtypes) ^[8]^[9]	Screen for ANCA vasculitis (GPA, MPA, EGPA)
Anti-GBM ^[8]^[9]	Screen for anti-GBM disease / Goodpasture
ASOT (anti-streptolysin O) ^[8]^[9]	Confirm recent streptococcal infection (PSGN)
Cryocrit ^[8]^[9]	Cryoglobulinaemia
Blood culture ^[8]^[9]	Infective endocarditis

Investigation	Expected Finding	Interpretation
Urine dipstick	Blood +++, Protein +++	Screening; not quantitative
Urine microscopy	Dysmorphic RBCs, RBC casts ^[8]^[9]	RBC casts = diagnostic of intrarenal/glomerular origin ^[15]; proteinuria + haematuria + dysmorphic RBC + RBC casts = proliferative glomerular disease (nephritic pattern) ^[15]
24-hour urine protein	> 0.5 g/day (biopsy threshold); may be nephrotic (> 3.5 g/day)	Likely to show heavy proteinuria in nephrotic range in active LN ^[1]
Spot uPCR (urine protein:creatinine ratio)	> 50 mg/mmol (≈ 0.5 g/day)	Convenient alternative to 24h collection
Creatinine clearance (24h urine)	Reduced	Likely to show impaired renal function ^[1]
Urine culture	Negative (sterile pyuria)	Rule out UTI; pyuria + negative culture = "sterile pyuria" (consider interstitial nephritis or GN)

Interpreting Urinalysis Findings

Urinalysis interpretation: ^[15]

Proteinuria + Haematuria + Dysmorphic RBC + RBC casts → Proliferative glomerular disease (nephritic pattern)
Heavy proteinuria + NO haematuria → Non-proliferative glomerular disease (nephrotic pattern) / DM nephropathy / Amyloidosis
Granular or epithelial cell casts + Renal tubular epithelial cells → Tubulointerstitial nephritis / ATN
Pyuria → UTI / Interstitial nephritis / Nephrolithiasis

Investigation	Purpose	Expected Finding
USG kidneys	Exclude concomitant abnormalities such as renal stones; confirm kidneys are not shrunken before proceeding to renal biopsy ^[1]	Normal-sized kidneys in active LN; shrunken kidneys = chronic damage (Class VI / CKD — biopsy less useful)
CXR	Screen for pulmonary involvement (pleural effusion, pulmonary oedema, pulmonary haemorrhage if Goodpasture/vasculitis in DDx)	Pleural effusion (SLE serositis or fluid overload); bilateral infiltrates if pulmonary haemorrhage
CT thorax / DLCO	For pulmonary involvement if cough ± haemoptysis ^[8]^[9]	Pulmonary haemorrhage → ↑ DLCO (counter-intuitively, because blood in alveoli absorbs CO)
Echocardiogram	SLE cardiac involvement; for IE if persistent fever + murmur ^[8]^[9]	Pericardial effusion, Libman-Sacks endocarditis (sterile vegetations), valvular dysfunction

3.5 Renal Biopsy — The Gold Standard

Renal biopsy: LM/IF/EM findings → Diagnosis, guide treatment decisions and prognosis ^[14].

Renal biopsy is necessary for most cases of nephritic syndrome unless very small kidney on USG ^[8]^[9].

Item	Rationale
Normal clotting and haemostatic parameters including platelet count ^[1]	Biopsy involves puncturing a highly vascularised organ; SLE patients may have thrombocytopenia or APLS
USG kidneys: confirm not shrunken ^[1]	Shrunken kidneys = chronic irreversible disease; biopsy unlikely to change management
BP controlled	↓ Risk of post-biopsy haemorrhage
Stop anticoagulants/antiplatelets	↓ Bleeding risk

Modality	What It Shows	Key LN Findings
Light Microscopy (LM)	Overall architecture, cellularity, sclerosis, crescents	Mesangial expansion (Class II); endocapillary proliferation (III/IV); crescents (IV); thickened capillary walls / "wire loops" (IV); global sclerosis (VI)
Immunofluorescence (IF)	Pattern and type of immune deposits	Full-house staining: ALL IgG, IgA, IgM, C3 and C1q (pathognomonic of LN, esp. Class IV) ^[1]; mesangial deposits (I/II); subendothelial (III/IV); subepithelial (V)
Electron Microscopy (EM)	Precise location of deposits; foot process effacement	Electron-dense deposits in mesangium, subendothelium, or subepithelium; reticular aggregates (tubuloreticular inclusions) — virtually pathognomonic of LN (interferon footprint)

Immunofluorescence pattern is most helpful for diagnosis ^[8]^[9].

Class	LM	IF	EM	Activity/Chronicity
I	Normal	Mesangial immune deposits	Mesangial dense deposits	—
II	Mesangial hypercellularity + matrix expansion	Mesangial immune deposits	Mesangial ± rare subepithelial/subendothelial	Low AI, low CI
III	< 50% glomeruli: segmental/global endocapillary proliferation, fibrinoid necrosis	Subendothelial + mesangial deposits	Subendothelial + mesangial	Active (A), Chronic (C), or A/C
IV	≥ 50% glomeruli: diffuse endocapillary proliferation, crescents, wire loops	Full-house staining	Subendothelial (massive) + mesangial	Highest AI; variable CI
V	Thickened glomerular capillary wall	Subepithelial + mesangial deposits	Subepithelial "spike and dome"	Low AI unless combined with III/IV
VI	Global sclerosis of nearly all (≥ 90%) glomerular capillaries	Variable, often attenuated	Scarred	Very high CI

Wire Loops and Tubuloreticular Inclusions

"Wire loop" lesions on LM = thickened capillary walls due to massive subendothelial immune complex deposits (Class IV). They look like loops of wire under the microscope because the GBM is so thickened.

Tubuloreticular inclusions (TRIs) on EM = organised structures within endothelial cell endoplasmic reticulum, thought to be an "interferon footprint." While not exclusive to LN, they are very suggestive and support the diagnosis.

Investigation	When to Order	Expected Finding If Positive
ASOT / anti-DNase B	Recent URTI 7–10 days prior	Confirms recent strep infection → PSGN
Throat swab	Acute pharyngitis	Group A Streptococcus
ANCA + subtypes	Suspected vasculitis	c-ANCA/PR3 → GPA; p-ANCA/MPO → MPA
Anti-GBM Ab	Haemoptysis + nephritis	Linear IgG on IF → Goodpasture
Cryocrit	Purpura + HCV + nephritis	Cryoglobulins → cryoglobulinaemic GN
Blood culture	Persistent fever + murmur	IE-associated GN

Persistently low C3 > 8 weeks raises the possibility of lupus nephritis or membranoproliferative glomerulonephritis ^[19].

Disease	C3	C4	Explanation
Lupus nephritis	↓	↓	Classical pathway activation (C1q → C4 → C2 → C3) consumes both
PSGN	↓	Normal	Predominantly alternative pathway activation; C3 normalises by 4–8 weeks
MPGN (Type I)	↓	↓	Classical pathway
MPGN (C3 glomerulopathy)	↓↓	Normal	Alternative pathway dysregulation
Cryoglobulinaemia	↓	↓↓	Classical pathway; C4 characteristically very low
Anti-GBM	Normal	Normal	Not complement-mediated
ANCA vasculitis	Normal	Normal	Pauci-immune
IgA nephropathy	Normal	Normal	IgA does not efficiently activate complement

Investigation Category	Tests	Key Findings in LN
Bedside	Urine dipstick, BP, fluid assessment	Blood +++, Protein +++, HTN, oedema
Urine	Microscopy, 24h protein/uPCR, CrCl	Dysmorphic RBCs, RBC casts, proteinuria > 0.5 g/d
Basic bloods	CBC, RFT, albumin, ESR/CRP, LFT	Pancytopenia, ↑ Cr, ↓ albumin, ↑ ESR with normal CRP
Autoimmune	ANA, anti-dsDNA, C3/C4, anti-Sm, anti-ENA, APLS Ab	ANA+, anti-dsDNA+, ↓ C3/C4
Exclude other causes	HBV/HCV/HIV, VDRL, ANCA, anti-GBM, ASOT, cryocrit	Negative (if LN); positive → alternative DDx
Imaging	USG kidneys, CXR	Normal-sized kidneys, ± pleural effusion/pulmonary oedema
Biopsy	LM, IF, EM	Class-specific findings; full-house IF; activity + chronicity indices

High Yield Summary

Diagnostic Criteria:

EULAR/ACR 2019: ANA+ entry criterion + total score ≥ 10 (Class III/IV LN scores 10 alone)
SLICC 2012: 4/17 criteria (≥ 1 clinical + ≥ 1 immunological) OR biopsy-proven LN with ANA/anti-dsDNA+

Biopsy Indications:

Proteinuria > 0.5 g/day, persistent haematuria, raised Cr not otherwise explained
Pre-biopsy: USG (confirm normal size), clotting, platelet count

Key Serological Workup:

ANA (screening), anti-dsDNA (diagnosis + monitoring), C3/C4 (diagnosis + monitoring)
ANA/anti-ENA NOT for monitoring; anti-dsDNA + C3/C4 ARE for monitoring
CRP ↑ → think infection, not SLE flare

Biopsy Interpretation:

Full-house staining (IgG, IgA, IgM, C3, C1q) is pathognomonic of LN
Activity Index → determines immunosuppression intensity
Chronicity Index → determines renoprotective strategy
Repeat biopsy if disease progresses

Complement Interpretation:

Low C3 + C4 → lupus nephritis, MPGN, cryoglobulinaemia
Low C3 only → PSGN (normalises by 4–8 weeks; if persists → consider LN/MPGN)
Normal C3/C4 → ANCA vasculitis, anti-GBM, IgAN

Active Recall - Diagnostic Criteria, Algorithm and Investigations for Lupus Nephritis

References

^[1] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai) — Case study (p1734); MBBS Final MB (Pediatrics) (Felix PY Lai) — Case study (p728) ^[2] Senior notes: Maksim Medicine Notes — Rheumatology, SLE investigations and Lupus nephritis (p315, p317) ^[3] Senior notes: Ryan Ho Rheumatology — SLE diagnostic workup, SLICC criteria, ANA/anti-dsDNA/complement interpretation (p73–75) ^[4] Senior notes: Block A - Nephrotology Teaching Clinic RTD — Diagnosis of renal diseases (p3) ^[7] Senior notes: Block A - Nephrology Interactive Tutorial — Case 1 (p1) ^[8] Senior notes: Adrian Lui Pediatrics Notes — Nephritic syndrome evaluation (p325) ^[9] Senior notes: Ryan Ho Fundamentals — GN evaluation (p360); Ryan Ho Urogenital — GN evaluation (p63) ^[12] Senior notes: Ryan Ho Urogenital — Lupus nephritis diagnostic evaluation and repeat biopsy indications (p88) ^[14] Lecture slides: Introduction-kidney-Ix (p23); Lecture slides: Nephrology - ntroduction to Renal Investigation (p23) ^[15] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai) — Urinalysis interpretation (p928) ^[17] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai) — SLICC criteria (p1723); MBBS Final MB (Pediatrics) (Felix PY Lai) — SLICC criteria (p717) ^[18] Lecture slides: GC 046. Facial rash and painful fingers_SLE (p53) ^[19] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury — PSGN complement (p19)

Management Algorithm and Treatment Modalities for Lupus Nephritis

Management of lupus nephritis is one of the most commonly tested SAQ topics in HKUMed summatives. The overarching principle is straightforward: management is guided by histology ^[2]. You cannot properly treat lupus nephritis without a renal biopsy telling you the ISN/RPS class, the activity index, and the chronicity index. Treatment then follows a two-phase strategy — induction (hit hard, induce remission) followed by maintenance (keep remission, minimise drug toxicity).

2. Non-Immunosuppressive Therapy — For ALL Classes

Non-immunosuppressive therapy in ALL instances of CKD ^[12]. These measures apply to every lupus nephritis patient regardless of class. Think of them as the "foundation" upon which immunosuppression is built.

HCQ: indicated for ALL SLE patients unless contraindicated ^[1]^[3]^[20].

Name breakdown: Hydroxychloroquine — "hydroxy" = hydroxylated derivative of "chloroquine" (originally an anti-malarial). It is an immunomodulator, NOT an immunosuppressant.

Feature	Detail
Indication	ALL patients ^[1]^[20]
Benefits	Reduces flare rate, organ damage and mortality; VERY effective in relieving constitutional symptoms, MSS and skin manifestations ^[1]^[20]
Mechanism	Inhibits TLR7/9 signalling in plasmacytoid dendritic cells → ↓ interferon-α production → ↓ B cell activation and autoantibody production; also stabilises lysosomes, inhibits antigen presentation
Dosage	< 5 mg/kg/day (2020 updated ophthalmology guideline lowered from previous 6.5 mg/kg limit to reduce retinal toxicity risk)
Key side effects	GI disturbances (MOST common side effect necessitating discontinuation — nausea, vomiting, diarrhoea) ^[1]^[20]
	Retinopathy (Bull's eye maculopathy) — baseline ophthalmological examination required; annual screening required after 5 years of usage ^[1]^[20]
	Hyperpigmentation; myopathy and neuropathy; corneal deposition ^[1]^[20]
Special note	HCQ is NOT immunosuppressive ^[1]^[20]; smoking associated with poor response to HCQ ^[2]^[3]

High Yield — HCQ for ALL SLE Patients

HCQ is the backbone of SLE management. It should be given to ALL patients with SLE unless contraindicated. It reduces flares, prevents organ damage, improves survival, has anti-thrombotic properties, and improves lipid profiles. In lupus nephritis specifically, HCQ has been shown to reduce the risk of renal flares and improve renal survival. Never forget to prescribe it.

Anti-proteinuric therapy by ACEI/ARB: indicated in ALL glomerulopathy ^[21].

Feature	Detail
Mechanism	↓ intraglomerular pressure → ↓ proteinuria, which is associated with ↓ rate of GFR decline ^[21]
Proteinuria goal	UACR < 500–1000 mg/g or 24h protein < 1 g/day; if cannot be achieved, aim ≥ 50–60% ↓ urine protein to non-nephrotic range ^[12]
Additional benefits	ACEI/ARB ↓ efferent arteriolar tone → ↓ glomerular hypertension → renoprotection; also may ↓ hepatic lipoprotein production by reducing albumin loss ^[21]
Monitoring	Check K+ and Cr 1–2 weeks after initiation — expect small Cr rise (up to 30% acceptable); hyperkalaemia risk
Contraindications	Bilateral renal artery stenosis; pregnancy; severe hyperkalaemia

Chronic kidney disease → ACEI or ARB is a compelling indication for these drugs in hypertension management ^[22].

3. Immunosuppressive Therapy — Class-Specific

This is the table you need to know cold for exams:

Class	Management	Details
I — Minimal mesangial	Conservative Tx (BP control, RAAS inhibitor, HCQ) ^[2]	No treatment (probably will not have a biopsy done due to minimal proteinuria) ^[1]
II — Mesangial proliferative	Conservative Tx (BP control, RAAS inhibitor, HCQ) ^[2]	Consider low-dose steroids if proteinuria > 1 g/day, ↑ anti-dsDNA or ↓ C3 ^[2]
III — Focal (< 50%)	Induction + Maintenance immunosuppression	See below
IV — Diffuse (≥ 50%)	Induction + Maintenance immunosuppression	MOST common and MOST severe form ^[1]
V — Membranous	Immunosuppression if proteinuria > 1 g/day despite ACEI	Medium-dose steroids + steroid-sparing
VI — Advanced sclerosing	ESRD planning ^[2]	Dialysis or transplantation (patient already in ESRD) ^[1]; immunosuppression NOT helpful ^[12]

3.3 Induction Therapy — Class III/IV (The Most Important Regimen)

Induction (6 months): high-dose steroid + IV MMF / cyclophosphamide ^[2].

Goal: Rapidly suppress active inflammation to prevent irreversible glomerular damage.

High-dose: 1 mg/kg/day (oral prednisolone) ± Pulse: IV methylprednisolone 1 g/day for 3 days ^[1]^[3]^[12].

Route	Dose	When
IV pulse methylprednisolone	0.5–1 g/day for 3 days ^[3]	Severe/life-threatening major organ involvement; RPGN presentation
Oral prednisolone	1 mg/kg/day (high-dose) ^[1]	After IV pulse, then taper gradually
Taper	Usually reduce by 5–10 mg every 1–2 weeks	Aim ≤ 7.5 mg/day by 3–6 months

Why high-dose steroids? Glucocorticoids are the most rapidly acting immunosuppressants available. They:

Suppress NF-κB → ↓ cytokine production (IL-1, IL-6, TNF-α)
↓ T and B cell activation
↓ Neutrophil migration and adhesion
↓ Complement-mediated damage

But they have devastating long-term side effects (osteoporosis, diabetes, cataracts, AVN, infection, Cushingoid features), hence the need for a steroid-sparing agent.

MMF: lupus nephritis (preferred over CYC) ^[1]^[20].

Name breakdown: Mycophenolate = "myco" (from fungus, as it was originally isolated from Penicillium) + "phenolate" (chemical structure). Mofetil = morpholinoethyl ester prodrug.

Feature	Detail
Mechanism	Inhibits inosine monophosphate dehydrogenase (IMPDH) → blocks de novo purine synthesis → selectively inhibits T and B lymphocyte proliferation (lymphocytes uniquely depend on the de novo pathway, unlike other cells which can use the salvage pathway)
Dose	Induction: 2–3 g/day (divided BD)
Pregnancy	Category D — teratogenic; must use contraception ^[1]^[20]
Side effects	Diarrhoea, abdominal pain, constipation, nausea and vomiting, anaemia, leukopenia ^[1]^[20]
Advantages over CYC	Similar efficacy for induction; better tolerated; no gonadal toxicity; preferred in young women
Monitoring	CBC (leucopenia), LFT

CYC: lupus nephritis, CNS diseases ^[1]^[20].

Name breakdown: Cyclo- (ring structure) + phosph- (phosphorus) + amide (nitrogen-containing). It is an alkylating agent — it cross-links DNA strands, preventing cell division.

Feature	Detail
Mechanism	Alkylates DNA → cross-links prevent replication → cytotoxic to rapidly dividing cells (especially lymphocytes)
Route	IV pulse (preferred — less cumulative toxicity) or oral
Regimen	Euro-Lupus protocol: IV 500 mg Q2W × 6 doses (lower dose, similar efficacy, fewer side effects) OR NIH protocol: IV 0.5–1 g/m² monthly × 6 months
Pregnancy	Category X — absolute contraindication in pregnancy ^[1]^[20]
Side effects	Gonadal toxicity (consider sperm and egg banking): male oligospermia, female infertility/premature ovarian failure (premature menopause) ^[1]^[20]
	Teratogenicity ^[1]^[20]
	Bladder toxicity: haemorrhagic cystitis, bladder cancer ^[1]^[20] — give MESNA (2-mercaptoethane sulfonate) with IV CYC to bind acrolein and prevent urothelial damage
	Secondary malignancy: leukaemia, lymphoma ^[1]^[20]
	Myelosuppression: neutropenia, leucopenia, thrombocytopenia ^[1]^[20]
	Alopecia ^[1]^[20]
Monitoring	CBC (nadir WBC at 10–14 days post dose); urinalysis (haemorrhagic cystitis); fertility counselling

MMF vs CYC — Which to Choose?

Current KDIGO 2024 and EULAR/ERA-EDTA guidelines consider MMF and CYC as equivalent first-line options for induction in Class III/IV LN. In practice:

MMF is preferred in young women of childbearing age (no gonadal toxicity, no Category X)
CYC is preferred in severe/rapidly progressive disease (especially RPGN), high chronicity index, or non-adherent patients (IV dosing ensures compliance)
If resistant to induction therapy: use MMF if fail CYC; use CYC if fail MMF; use rituximab if failed both ^[12]

Maintenance (≥ 2 years): low-dose steroid + MMF / azathioprine ^[2].

Goal: Prevent relapse while minimising long-term drug toxicity.

Agent	Details
Prednisolone	Taper to ≤ 5–7.5 mg/day; ideally withdraw completely if remission sustained
MMF (preferred)	1–2 g/day; superior to AZA in preventing relapse in most trials
Azathioprine (AZA)	2 mg/kg/day; alternative to MMF; safer in pregnancy (Category D but acceptable in pregnancy with monitoring, unlike CYC Category X)

Azathioprine (AZA)

AZA: lupus nephritis, diseases refractory to HCQ ^[1]^[20].

Name breakdown: Aza- (nitrogen) + thio- (sulphur) + purine (the target metabolic pathway).

Feature	Detail
Mechanism	Prodrug → converted to 6-mercaptopurine (6-MP) → inhibits purine synthesis → ↓ lymphocyte proliferation
Important pharmacogenomics	Check TPMT (thiopurine methyltransferase) genotype/activity before starting — deficiency → accumulation of toxic metabolites → severe myelosuppression
Side effects	Hepatotoxicity, myelosuppression, pancreatitis ^[1]^[20]
Drug interaction	NEVER co-prescribe with allopurinol (inhibits xanthine oxidase → ↑ 6-MP levels → fatal pancytopenia). If allopurinol needed, switch to febuxostat or reduce AZA dose by 75%.
Pregnancy	Category D but widely used in pregnancy when benefits outweigh risks

Class V induction: medium-dose steroids + steroid-sparing agents (azathioprine) ^[1].

Feature	Detail
Steroid dose	Medium dose = 0.5–0.75 mg/kg/day ^[1] (lower than Class III/IV)
Steroid-sparing	MMF or AZA; some centres use calcineurin inhibitors (CNI — tacrolimus/ciclosporin) for pure membranous LN
Maintenance	Low-dose steroid + MMF/AZA ^[1]

Why lower-dose steroids for Class V? Class V is a non-proliferative, predominantly nephrotic picture. The inflammatory component is less severe than Class III/IV (subepithelial deposits are "hidden" from circulating blood). You still need immunosuppression for heavy proteinuria, but the intensity can be lower.

Calcineurin inhibitors (CNI) in Class V: CNI have modulatory effects on podocytes ^[23] — tacrolimus stabilises podocyte cytoskeleton independently of its immunosuppressive action, which is particularly relevant in membranous disease where podocyte injury is the primary pathology. Used as add-on or alternative in refractory Class V.

3.7 Refractory / Resistant Disease

If resistant to induction therapy: ^[12]

Use MMF if fail cyclophosphamide
Use cyclophosphamide if fail MMF
Use rituximab if failed both

Name breakdown: Ri-tuxi-mab → "rituxi" from chimeric anti-CD20 + "-mab" (monoclonal antibody).

Feature	Detail
Mechanism	Anti-CD20 monoclonal antibody → depletes B lymphocytes (CD20 is expressed on mature B cells but not plasma cells or stem cells) → ↓ autoantibody production, ↓ B cell antigen presentation
Indication	Refractory LN (failed both MMF and CYC); also used in ANCA vasculitis
Dose	375 mg/m² weekly × 4 or 1000 mg × 2 doses (2 weeks apart)
Side effects	Infusion reactions; progressive multifocal leukoencephalopathy (PML — rare but fatal); hepatitis B reactivation (screen before use); infection
Monitoring	Immunoglobulin levels; HBV status; CBC

Anti-BAFF (belimumab) ^[3] — newer biologic approved for active SLE including lupus nephritis:

Feature	Detail
Mechanism	Monoclonal antibody against BAFF (B-cell activating factor, also called BLyS) → inhibits B cell survival and differentiation → ↓ autoantibody production
Indication	Add-on to standard therapy (steroids + MMF or CYC) in active LN; BLISS-LN trial showed improved renal response when added to standard induction
Significance	First biologic specifically approved for lupus nephritis (2020); represents a major advance

A newer calcineurin inhibitor specifically studied in lupus nephritis (AURORA trial):

Feature	Detail
Mechanism	CNI — inhibits calcineurin → ↓ T cell activation; also direct podocyte-stabilising effect
Indication	Active Class III, IV, or V LN, added to standard MMF + steroids
Advantage	Does not require drug level monitoring (unlike tacrolimus/ciclosporin); fixed dosing
Side effects	Nephrotoxicity (vasoconstriction of afferent arteriole); hypertension; GI symptoms; tremor

2024–2026 KDIGO Update — Multi-Target Therapy

Current best practice for Class III/IV (and V) lupus nephritis increasingly favours multi-target therapy: steroids + MMF + either belimumab or voclosporin (or both in severe cases). The BLISS-LN and AURORA trials demonstrated superior complete renal response rates when these agents are added to standard induction. This is the direction of the field, though exam questions may still test the "classic" regimen (steroids + MMF/CYC).

4. Special Treatment Considerations

Pregnancy issues and fertility issues must be discussed ^[3].

Drug	Pregnancy Safety	Notes
HCQ	Safe — continue throughout pregnancy	Reduces flares during pregnancy; ↓ risk of neonatal lupus
Prednisolone	Acceptable with caution	Metabolised by placental 11β-HSD2; minimal fetal exposure; but ↑ risk of GDM, PROM
AZA	Acceptable (Category D but used)	Fetal liver lacks enzyme to convert to active metabolite → relatively protected
MMF	Category D — TERATOGENIC — STOP before conception	Switch to AZA at least 3 months before planned pregnancy
CYC	Category X — ABSOLUTE CONTRAINDICATION ^[1]^[20]	Gonadal toxicity: consider sperm and egg banking before starting ^[1]^[20]
Voclosporin/tacrolimus	Limited data; generally avoided	Tacrolimus has been used in pregnancy for transplant patients
Rituximab/belimumab	Avoid in pregnancy	Insufficient safety data; risk of neonatal B cell depletion
ACEI/ARB	CONTRAINDICATED in pregnancy	Fetotoxic — oligohydramnios, renal dysgenesis, pulmonary hypoplasia

Responsiveness to treatment is usually indicated by: ^[12]

Substantial ↓ urine protein excretion (e.g. ≤ 0.33 g/day, ≤ 0.5 g/day or < 1 g/day)
Improvement or stabilisation of serum creatinine
Improvement of urinary sediment (e.g. ≤ 5 or 10 RBCs/HPF, no casts)

Response	Definition
Complete renal response	Proteinuria < 0.5 g/day (or uPCR < 50 mg/mmol) + normal or near-normal GFR + inactive sediment
Partial renal response	≥ 50% ↓ proteinuria to sub-nephrotic levels + stable/improved GFR
No response	Failure to achieve partial response by 6–12 months

Regular monitoring: check BP and urine dipstick every visit; regular blood test on disease activity (anti-dsDNA, C3/4, ESR, CBC, L/RFT) ^[3].

Parameter	Frequency	Purpose
Anti-dsDNA + C3/C4	Every 1–3 months	Disease activity; rising anti-dsDNA + falling C3/C4 = impending flare
Urine dipstick + uPCR	Every visit	Monitor proteinuria response
Serum Cr + eGFR	Every 1–3 months	Monitor renal function
CBC	Every 2–4 weeks (during induction); Q1–3 months (maintenance)	Drug toxicity (myelosuppression from AZA/MMF/CYC)
LFT	Q3–6 months	AZA hepatotoxicity
Eye examination	Before HCQ and every year after 5 years ^[3]	HCQ retinopathy (bull's eye maculopathy)
BP	Every visit	Renoprotection
Lipids, HbA1c	Annually	CVS risk; steroid-induced diabetes

Class	Induction	Maintenance	Key Points
I	None	HCQ + RAAS inhibitor	Rarely biopsied
II	Conservative ± low-dose steroids	HCQ + RAAS inhibitor	Steroids if proteinuria > 1g/day, ↑ anti-dsDNA, ↓ C3 ^[2]
III/IV	High-dose steroids (1 mg/kg/day ± IV pulse) + MMF or CYC × 6 months	Low-dose steroids + MMF or AZA for ≥ 2 years	± Belimumab or voclosporin (multi-target)
V (pure)	Medium-dose steroids (0.5–0.75 mg/kg/day) + MMF or AZA	Low-dose steroids + MMF or AZA	Only if proteinuria > 1g/day despite ACEI ^[2]
III+V / IV+V	Treat as Class III/IV	Treat as Class III/IV	Proliferative component dictates treatment ^[2]^[12]
VI	None (immunosuppression not helpful)	ESRD planning	Dialysis / transplant ^[1]

High Yield Summary

Management Principles:

Management is guided by histology — you need a renal biopsy ^[2]
HCQ for ALL SLE patients ^[1]^[20]
RAAS blockade (ACEI/ARB) for ALL proteinuric CKD ^[12]^[21]
Aggressive BP control, lipid control, CVS risk management for ALL ^[12]

Class III/IV (Active Proliferative) — The Big One:

Induction (6 months): high-dose steroids + MMF or CYC ^[2]
Maintenance (≥ 2 years): low-dose steroids + MMF or AZA ^[2]
Refractory: switch MMF ↔ CYC; then rituximab ^[12]

Class V (Pure Membranous):

Only treat if proteinuria > 1g/day despite ACEI
Medium-dose steroids + MMF/AZA ^[1]

Class VI (Advanced Sclerosing):

ESRD planning — immunosuppression NOT helpful ^[1]^[12]

Key Drug Points:

MMF: preferred over CYC (especially in young women); Category D
CYC: Category X; gonadal toxicity — offer fertility preservation
AZA: check TPMT; NEVER co-prescribe with allopurinol
Belimumab and voclosporin: newer add-on agents improving outcomes

Active Recall - Management of Lupus Nephritis

References

^[1] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai) — LN classification and treatment (p1000, p1732, p1734); MBBS Final MB (Pediatrics) (Felix PY Lai) — LN treatment (p722, p726, p728) ^[2] Senior notes: Maksim Medicine Notes — Lupus nephritis management, WHO classification (p315, p317) ^[3] Senior notes: Ryan Ho Rheumatology — SLE management, monitoring, general care (p76) ^[7] Senior notes: Block A - Nephrology Interactive Tutorial — Case 1 (p1) ^[11] Senior notes: Ryan Ho Fundamentals — RPGN management (p361) ^[12] Senior notes: Ryan Ho Urogenital — Lupus nephritis management, non-IS and IS therapy (p88–89) ^[20] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai) — HCQ, immunosuppressants table (p1732); MBBS Final MB (Pediatrics) (Felix PY Lai) — same table (p726) ^[21] Senior notes: Ryan Ho Fundamentals — General approach to GN management (p368) ^[22] Senior notes: Block A - High blood pressure: hypertension — Compelling indications for ACEI/ARB (p42) ^[23] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and AKI — CNI and podocytes (p24)

Complications of Lupus Nephritis

Complications of lupus nephritis can be organised into three categories: (A) complications of the disease itself (renal and extra-renal), (B) complications of the nephrotic/nephritic syndrome, and (C) complications of treatment. In practice, many patients suffer from a mixture of all three simultaneously, making this one of the most complex conditions to manage long-term.

1. Complications of the Disease — Renal

2. Complications of the Nephrotic/Nephritic Syndrome

These are not unique to lupus nephritis — they complicate any glomerular disease presenting with nephrotic or nephritic features — but they are particularly important in LN because of the overlap with SLE-related prothrombotic and immunocompromised states.

Pulmonary embolism — especially in lupus membranous nephropathy or antiphospholipid syndrome ^[25].

Complication	Mechanism	Clinical Note
DVT / PE	Nephrotic syndrome → loss of antithrombin III, protein C, protein S in urine + ↑ hepatic production of fibrinogen and clotting factors → hypercoagulable state	Risk compounded by APLS (present in ~30% SLE)
Renal vein thrombosis	Hypercoagulability by compensatory production of clotting factors by liver ^[26]	Sudden ↑ proteinuria, flank pain, AKI; diagnose with Doppler USG or CT angiography

Renal vein thrombosis management: ^[26]

If AKI: thrombolysis ± embolectomy
If non-AKI: LMWH/UFH → warfarin for minimum 6–12 months while still nephrotic

3. Complications of Treatment

This is a high-yield exam topic. The case vignette typically presents a lupus nephritis patient on treatment who develops a new problem — and you must determine whether it is a disease flare, an infection, or a drug side effect.

Complication	Mechanism	Clinical Relevance to LN
Cushingoid features	Exogenous cortisol → fat redistribution (moon face, buffalo hump, central obesity)	Physical exam: Cushingoid ^[27]
Osteoporosis	↓ Osteoblast activity + ↑ osteoclast activity + ↓ Ca²⁺ absorption	Osteoporosis: treatment-related (steroids) ^[2]; give calcium, vitamin D, bisphosphonate
AVN (avascular necrosis)	Steroid-induced fat embolism or lipocyte hypertrophy in subchondral bone → ↓ blood supply	AVN hip: active disease or steroid-induced ^[2]; right hip particularly painful on climbing stairs ^[27] — MRI is diagnostic
Diabetes mellitus	↑ Hepatic gluconeogenesis + ↓ peripheral insulin sensitivity	Monitor HbA1c; SGLT2i may have dual benefit (glycaemic + renoprotective)
Infections	Impaired neutrophil, lymphocyte, and monocyte function	Patient is immunocompromised — SLE itself + corticosteroids + azathioprine ^[27]
Cataracts	Posterior subcapsular — mechanism not fully understood (? oxidative damage to lens proteins)	Annual eye screening
Peptic ulcer / GI bleed	↓ Prostaglandin-mediated gastric mucosal protection	Anaemia: micro (GI bleed due to steroid use) ^[2]; co-prescribe PPI
Hypertension	Mineralocorticoid effect → Na⁺/H₂O retention	Compounds LN-related HTN
Psychosis	Direct CNS effects of glucocorticoids	DDx of psychosis in SLE: disease (neuropsychiatric lupus) vs. steroid-induced ^[2]

Complications of treatment: leukopenia, infection, alopecia (cyclophosphamide), amenorrhoea (cyclophosphamide) ^[1]^[27].

Complication	Mechanism	Prevention
Gonadal toxicity: oligospermia (male), premature ovarian failure (female) ^[1]^[20]	Alkylating agent destroys rapidly dividing germ cells	Consider sperm and egg banking; GnRH agonists may reduce ovarian damage
Haemorrhagic cystitis	Acrolein (CYC metabolite) is directly toxic to urothelium	MESNA (binds acrolein); adequate hydration; monitor urinalysis
Bladder cancer	Chronic acrolein exposure → urothelial carcinogenesis	Long-term urinalysis surveillance
Secondary malignancy (leukaemia, lymphoma) ^[1]^[20]	Alkylation of haematopoietic stem cell DNA → mutagenesis	Minimise cumulative dose; use Euro-Lupus protocol
Myelosuppression (neutropenia, leucopenia, thrombocytopenia) ^[1]^[20]	Non-selective cytotoxicity to bone marrow	Monitor CBC; nadir WBC 10–14 days post dose
Alopecia ^[1]^[20]^[27]	Destruction of rapidly dividing hair follicle cells	Usually reversible
Teratogenicity (Category X) ^[1]^[20]	DNA alkylation in developing fetus	Absolute contraindication in pregnancy

MMF is used as first-line treatment for proliferative lupus nephritis because of lower frequency of adverse effects compared to cyclophosphamide, e.g. premature ovarian failure and haemorrhagic cystitis ^[28].

While not "complications of lupus nephritis" per se, these coexisting SLE manifestations significantly worsen the overall prognosis and must be actively monitored:

Complication	Relevance
Antiphospholipid syndrome (APLS)	Present in ~30%; causes thrombosis (DVT/PE, stroke), recurrent miscarriage; worsens renal prognosis via TMA
Neuropsychiatric lupus	Seizures, psychosis, myelitis, neuropathy — DDx: active disease vs. steroid-induced vs. infection vs. metabolic ^[2]^[28]
Libman-Sacks endocarditis	Pathognomonic: atypical sterile valvular vegetations ^[2]; risk of embolic stroke
Serositis	Pleurisy, pericarditis — pleuritic chest pain exacerbated by deep breathing ^[27]; DDx: lupus flare vs. infection vs. PE
Pulmonary complications	Pleurisy (up to 93%); acute pneumonitis (1–2%); ILD (3–9%); PE (especially in membranous LN or APLS); pulmonary arterial hypertension ^[25]
Haematological	Anaemia: micro (GI bleed from steroids) vs. normo (ACD) vs. macro (AIHA); neutropenia; thrombocytopenia ^[2]

This is the most commonly examined complication scenario:

Case: A 35-year-old lady diagnosed with SLE 3 years ago (polyarthritis, malar rash, lupus nephritis), treated with prednisolone + azathioprine, now presents with fever, chills, chest pain worse on deep breathing, and hip pain ^[27].

Q: What are the possible causes of fever? ^[27]

Relapse of underlying SLE
Infection due to immunocompromised state
- SLE itself is immunocompromising
- Patient is taking corticosteroids and azathioprine

Q: What are the possible causes of chest pain? ^[27]

Serositis (manifestation of lupus or secondary to chest infection)
Pulmonary embolism ± infarction

Q: What about the hip pain? ^[2]

AVN hip: active disease or steroid-induced — investigate with MRI
DDx: septic arthritis (immunosuppressed patient)

Q: What complications require attention? ^[1]^[27]

Hypertension
Hyperlipidaemia
Complications of treatment: leukopenia, infection, alopecia (CYC), amenorrhoea (CYC)

High Yield Summary

Complications of Lupus Nephritis — Three Categories:

1. Disease complications:

Progression to CKD/ESRD (25% within 10 years) — via glomerulosclerosis, hyperfiltration injury
RPGN — crescentic transformation; nephrological emergency
TIN — tubular dysfunction, RTA
Renal vascular disease — TMA (especially with APLS), renal vein thrombosis

2. Nephrotic/nephritic syndrome complications:

Thromboembolic events (DVT/PE, renal vein thrombosis) — hypercoagulable state ± APLS
Infection — loss of immunoglobulins + immunosuppression
Resistant oedema, AKI from over-diuresis, hyperlipidaemia/accelerated CVD

3. Treatment complications:

Steroids: Cushingoid, osteoporosis, AVN, DM, infection, cataracts, psychosis
CYC: gonadal toxicity, haemorrhagic cystitis, secondary malignancy, myelosuppression, alopecia
MMF: GI side effects, myelosuppression, teratogenicity
AZA: hepatotoxicity, myelosuppression, pancreatitis; NEVER with allopurinol
CNI: nephrotoxicity, tremor, gum hyperplasia, HT/DM
Rituximab: HBV/TB reactivation, PML

Key Exam Scenarios:

Fever in treated LN = infection until proven otherwise
Hip pain in LN = steroid-induced AVN vs. septic arthritis vs. active disease
Poor prognostic factors: male sex, young age, Class IV disease, APLS, high disease activity

Active Recall - Complications of Lupus Nephritis

References

^[1] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai) — LN classification, treatment, prognosis, case studies (p1733–1735); MBBS Final MB (Pediatrics) (Felix PY Lai) — same sections (p727–729) ^[2] Senior notes: Maksim Medicine Notes — SLE clinical features, disease monitoring, poor prognostic factors, special considerations (p314–317) ^[4] Senior notes: Block A - Nephrotology Teaching Clinic RTD — Lupus nephritis affecting multiple compartments (p5) ^[5] Senior notes: Block A - Chronic Kidney Disease and its Complications — CKD complications and causes (p8, p23) ^[8] Senior notes: Adrian Lui Pediatrics Notes — Glomerulosclerosis mechanism (p328) ^[11] Senior notes: Ryan Ho Fundamentals — RPGN pathogenesis and crescent formation (p361) ^[12] Senior notes: Ryan Ho Urogenital — Lupus nephritis renal involvement, management (p87–89) ^[20] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai) — Drug side effects table (p1732–1733); MBBS Final MB (Pediatrics) (Felix PY Lai) — same (p726–727) ^[24] Senior notes: Block A - Renal Replacement Therapies — Long-term transplant complications (p36) ^[25] Senior notes: Ryan Ho Respiratory — Respiratory manifestations of SLE (p128) ^[26] Senior notes: Maksim Medicine Notes — Nephrotic syndrome complications and management (p230–232) ^[27] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai) — Case 2 (p1735); MBBS Final MB (Pediatrics) (Felix PY Lai) — Case 2 (p729) ^[28] Lecture slides: Handbook of Internal Medicine 2024 — Lupus nephritis and NPSLE (p441–442)

High Yield Summary

Definition: Lupus nephritis = renal inflammation in SLE caused by immune complex deposition in glomeruli → complement activation → tissue damage.

Epidemiology: ~50% of SLE patients; more common and severe in Asians and Afro-Caribbeans; risk factors include juvenile SLE, male sex, high anti-dsDNA, low complement.

Classification: ISN/RPS 6 classes:

Class I (minimal mesangial) → normal
Class II (mesangial proliferative) → microscopic haematuria/proteinuria
Class III (focal, < 50%) → nephritic ± nephrotic
Class IV (diffuse, ≥ 50%) → MOST common and MOST severe; RPGN
Class V (membranous) → nephrotic
Class VI (advanced sclerosing) → ESRD

Full-house staining (IgG, IgA, IgM, C3, C1q) is pathognomonic for LN (esp. Class IV).

Activity index → guides immunosuppression intensity. Chronicity index → guides renoprotective strategy.

Biopsy indications: proteinuria > 0.5 g/day, persistent haematuria, unexplained ↑Cr.

Monitoring: Anti-dsDNA (↑ = active) + C3/C4 (↓ = active). ANA/anti-ENA NOT for monitoring.

High Yield Summary

DDx of Lupus Nephritis — Key Framework:

By complement level:
- Low C3/C4 (IC-mediated): Lupus nephritis, PSGN, MPGN, cryoglobulinaemia, IE
- Normal C3/C4 (non-IC): ANCA vasculitis, anti-GBM disease, IgA nephropathy, HSP
By RPGN IF pattern:
- Type I (linear) = Anti-GBM
- Type II (granular) = Lupus nephritis, PSGN, IgAN, cryoglobulinaemia
- Type III (pauci-immune) = ANCA vasculitis
Non-LN renal disease in SLE:
- Drug-induced (NSAIDs), APLS nephropathy/TMA, TIN, infection, hypertensive nephrosclerosis
Key discriminators:
- Full-house IF staining = lupus nephritis
- CRP ↑ in SLE = think infection, not flare
- URTI 7–10 days before = PSGN; concurrent = IgAN
- Characteristic rash + arthritis = SLE
Renal biopsy is the definitive investigation — needed for most cases of nephritic syndrome.

High Yield Summary

Diagnostic Criteria:

EULAR/ACR 2019: ANA+ entry criterion + total score ≥ 10 (Class III/IV LN scores 10 alone)
SLICC 2012: 4/17 criteria (≥ 1 clinical + ≥ 1 immunological) OR biopsy-proven LN with ANA/anti-dsDNA+

Biopsy Indications:

Proteinuria > 0.5 g/day, persistent haematuria, raised Cr not otherwise explained
Pre-biopsy: USG (confirm normal size), clotting, platelet count

Key Serological Workup:

ANA (screening), anti-dsDNA (diagnosis + monitoring), C3/C4 (diagnosis + monitoring)
ANA/anti-ENA NOT for monitoring; anti-dsDNA + C3/C4 ARE for monitoring
CRP ↑ → think infection, not SLE flare

Biopsy Interpretation:

Full-house staining (IgG, IgA, IgM, C3, C1q) is pathognomonic of LN
Activity Index → determines immunosuppression intensity
Chronicity Index → determines renoprotective strategy
Repeat biopsy if disease progresses

Complement Interpretation:

Low C3 + C4 → lupus nephritis, MPGN, cryoglobulinaemia
Low C3 only → PSGN (normalises by 4–8 weeks; if persists → consider LN/MPGN)
Normal C3/C4 → ANCA vasculitis, anti-GBM, IgAN

High Yield Summary

Management Principles:

Management is guided by histology — you need a renal biopsy ^[2]
HCQ for ALL SLE patients ^[1]^[20]
RAAS blockade (ACEI/ARB) for ALL proteinuric CKD ^[12]^[21]
Aggressive BP control, lipid control, CVS risk management for ALL ^[12]

Class III/IV (Active Proliferative) — The Big One:

Induction (6 months): high-dose steroids + MMF or CYC ^[2]
Maintenance (≥ 2 years): low-dose steroids + MMF or AZA ^[2]
Refractory: switch MMF ↔ CYC; then rituximab ^[12]

Class V (Pure Membranous):

Only treat if proteinuria > 1g/day despite ACEI
Medium-dose steroids + MMF/AZA ^[1]

Class VI (Advanced Sclerosing):

ESRD planning — immunosuppression NOT helpful ^[1]^[12]

Key Drug Points:

MMF: preferred over CYC (especially in young women); Category D
CYC: Category X; gonadal toxicity — offer fertility preservation
AZA: check TPMT; NEVER co-prescribe with allopurinol
Belimumab and voclosporin: newer add-on agents improving outcomes

High Yield Summary

Complications of Lupus Nephritis — Three Categories:

1. Disease complications:

Progression to CKD/ESRD (25% within 10 years) — via glomerulosclerosis, hyperfiltration injury
RPGN — crescentic transformation; nephrological emergency
TIN — tubular dysfunction, RTA
Renal vascular disease — TMA (especially with APLS), renal vein thrombosis

2. Nephrotic/nephritic syndrome complications:

Thromboembolic events (DVT/PE, renal vein thrombosis) — hypercoagulable state ± APLS
Infection — loss of immunoglobulins + immunosuppression
Resistant oedema, AKI from over-diuresis, hyperlipidaemia/accelerated CVD

3. Treatment complications:

Steroids: Cushingoid, osteoporosis, AVN, DM, infection, cataracts, psychosis
CYC: gonadal toxicity, haemorrhagic cystitis, secondary malignancy, myelosuppression, alopecia
MMF: GI side effects, myelosuppression, teratogenicity
AZA: hepatotoxicity, myelosuppression, pancreatitis; NEVER with allopurinol
CNI: nephrotoxicity, tremor, gum hyperplasia, HT/DM
Rituximab: HBV/TB reactivation, PML

Key Exam Scenarios:

Fever in treated LN = infection until proven otherwise
Hip pain in LN = steroid-induced AVN vs. septic arthritis vs. active disease
Poor prognostic factors: male sex, young age, Class IV disease, APLS, high disease activity

Lupus Nephritis

Lupus Nephritis

2. Epidemiology

3. Anatomy and Function — Relevance to Lupus Nephritis

4. Etiology (Focus on Hong Kong)

5. Pathophysiology of Lupus Nephritis

6. Classification — ISN/RPS Classification (2003, Revised 2018)

7. Clinical Features

8. Approach to a Patient Suspected of Lupus Nephritis

Active Recall - Lupus Nephritis (Definition to Clinical Features)

Differential Diagnosis of Lupus Nephritis

1. Level 1 — Differential Diagnosis by Clinical Syndrome

3. Approach to Narrowing the Differential

Active Recall - Differential Diagnosis of Lupus Nephritis

References

Diagnostic Criteria, Diagnostic Algorithm, and Investigations for Lupus Nephritis

1. Diagnostic Criteria

1.1 Establishing the Diagnosis of SLE

2.1 Step-by-Step Walkthrough

3. Investigation Modalities — Systematic Approach

3.2 Blood Investigations

3.5 Renal Biopsy — The Gold Standard

Active Recall - Diagnostic Criteria, Algorithm and Investigations for Lupus Nephritis

References

Management Algorithm and Treatment Modalities for Lupus Nephritis

2. Non-Immunosuppressive Therapy — For ALL Classes

3. Immunosuppressive Therapy — Class-Specific

3.3 Induction Therapy — Class III/IV (The Most Important Regimen)

Azathioprine (AZA)

3.7 Refractory / Resistant Disease

4. Special Treatment Considerations

Active Recall - Management of Lupus Nephritis

References

Complications of Lupus Nephritis

1. Complications of the Disease — Renal

2. Complications of the Nephrotic/Nephritic Syndrome

3. Complications of Treatment

Active Recall - Complications of Lupus Nephritis

References

On this page

Lupus Nephritis

1. Definition

2. Epidemiology

2.1 Prevalence and Incidence

2.2 Demographics

2.3 Risk Factors for Developing Lupus Nephritis

3. Anatomy and Function — Relevance to Lupus Nephritis

3.1 Normal Glomerular Anatomy

3.2 The Glomerular Filtration Barrier

3.3 Why the Location of Immune Complex Deposits Matters

4. Etiology (Focus on Hong Kong)

4.1 SLE as the Primary Etiology

4.2 Pathogenesis of SLE (Brief — as Foundation for LN)

4.3 Hong Kong Context

5. Pathophysiology of Lupus Nephritis

5.1 Overview — The Immune Complex Disease Model

5.2 Step-by-Step Pathophysiology

5.3 Detailed Mechanisms

5.4 Role of Anti-dsDNA and Complement in Pathophysiology

5.5 In Situ Immune Complex Formation

6. Classification — ISN/RPS Classification (2003, Revised 2018)

6.1 Activity Index vs. Chronicity Index

6.2 Transformation Between Classes

7. Clinical Features

7.1 General Principles

7.2 Symptoms

7.3 Signs

7.4 Urinalysis Findings (Not Yet "Investigations" — These Are Clinical Bedside Signs)

7.5 Clinical Syndromes by Class

7.6 Associated Features — Antiphospholipid Syndrome

8. Approach to a Patient Suspected of Lupus Nephritis

8.1 Key History Points

8.2 Key Examination Points

9. Indications for Renal Biopsy in Lupus Nephritis

Active Recall - Lupus Nephritis (Definition to Clinical Features)

References

1. Level 1 — Differential Diagnosis by Clinical Syndrome

1.1 Acute Nephritic Syndrome (the commonest LN presentation — Class III/IV)

1.2 Nephrotic Syndrome (Class V — Membranous LN)

1.3 RPGN (Rapidly Progressive Glomerulonephritis — Severe Class III/IV)

2. Level 2 — Renal Disease in a Known SLE Patient (Is It Really LN?)

3. Approach to Narrowing the Differential

3.1 Systematic Serological Approach

3.2 Key History Clues That Shift the DDx

3.3 Renal Biopsy — The Definitive Discriminator

4. Summary — How to Think About the DDx

Active Recall - Differential Diagnosis of Lupus Nephritis

1. Diagnostic Criteria

1.1 Establishing the Diagnosis of SLE

A. 2019 EULAR/ACR Classification Criteria (Current Standard)

B. 2012 SLICC Diagnostic Criteria

1.2 Confirming Lupus Nephritis — The Biopsy Threshold

2. Diagnostic Algorithm

3. Investigation Modalities — Systematic Approach

3.1 Bedside Investigations

3.2 Blood Investigations

A. Basic Bloods

B. Autoimmune Serology

C. Exclude Other Causes

3.3 Urine Investigations

3.4 Imaging

3.5 Renal Biopsy — The Gold Standard

A. Pre-Biopsy Checklist

B. Biopsy Processing — Three Modalities

C. Key Histopathological Features by Class (Detailed)

D. When to Repeat Biopsy

3.6 Special Investigations for Differential Diagnosis

3.7 Interpretation of Complement — Key Diagnostic Table

4. Summary Table — Putting It All Together

Active Recall - Diagnostic Criteria, Algorithm and Investigations for Lupus Nephritis

1. Management Algorithm — Overview

2. Non-Immunosuppressive Therapy — For ALL Classes

2.1 Hydroxychloroquine (HCQ) — The Universal Drug

2.2 RAAS Blockade (ACEI/ARB) — Anti-Proteinuric Therapy

2.3 Blood Pressure Control

2.4 Lipid-Lowering Therapy

2.5 Anti-Oedema Therapy

2.6 Anticoagulation

2.7 Other General Measures

3. Immunosuppressive Therapy — Class-Specific