• ~50% of SLE patients develop clinically significant lupus nephritis during their disease course ^[2][3]
• In some cohorts (especially Asian and Afro-Caribbean populations), the prevalence is even higher — up to 60–80% when subclinical disease detected on protocol biopsies is included
• Lupus nephritis is more common and more severe in Orientals — this is directly relevant to Hong Kong practice ^[3]
• Juvenile-onset SLE has a particularly high incidence of renal involvement (up to 80%), and it tends to be more aggressive ^[2]

• Juvenile SLE (childhood-onset) ^[2]
• Male sex (paradoxically — while SLE is 9× commoner in females, males with SLE have a higher risk of developing renal involvement and worse renal outcomes) ^[2]
• Afro-Caribbean or Asian ethnicity
• High anti-dsDNA titres and low C3/C4 (serological markers of active disease)
• Delay in diagnosis or treatment of SLE
• Genetic factors: HLA-DR2, HLA-DR3, complement deficiencies (C1q, C2, C4)
• Socioeconomic factors: poor access to healthcare, non-adherence

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

Three layers, from capillary lumen → urinary space:

1. Fenestrated endothelium — allows passage of plasma but blocks blood cells
2. Glomerular basement membrane (GBM) — negatively charged; prevents large and anionic molecules (like albumin) from passing
3. Podocyte foot processes and slit diaphragms — the final barrier; prevent protein leakage

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

Lupus nephritis is, by definition, a manifestation of SLE. Therefore, the etiology of LN is the etiology of SLE with renal tropism:

Pathogenesis of SLE: loss of self-tolerance in immune system secondary to predisposing genetic factors and environmental triggers ^[3]

a) Genetic predisposition:

• HLA-B8, DR2, DR3 ^[2][3]
• Complement deficiencies (C1q deficiency → strongest single-gene risk; C2, C4) — impaired clearance of immune complexes and apoptotic debris
• Other susceptibility genes: IRF5, STAT4, ITGAM, BLK

b) Hormonal factors:

• Estrogen and progesterone promote B cell survival and autoantibody production ^[2]
• This explains the female predominance and flares during pregnancy/OCP use

c) Environmental triggers:

• Infections: EBV (molecular mimicry between EBNA-1 and Sm/Ro antigens), parvovirus B19, HIV-1 ^[3]
• UV light — induces apoptosis of keratinocytes, exposing nuclear antigens on cell surfaces ^[3]
• Drugs: hydralazine, procainamide, isoniazid (drug-induced lupus — though this rarely causes significant nephritis)
• Stress, chemical agents

d) Immune dysregulation:

B lymphocyte changes:

• Autoantibody production due to reaction to self-antigens (e.g. dsDNA, RNPs) — usually present on surface of cells activated or undergoing apoptosis ^[3]
• Activation by helper T cells ^[3]
• Auto-antibodies form immune complex (consists of nuclear antigens, IgG and antinuclear antibodies) → deposit in tissues and organs, especially kidney → activate complement system to cause inflammation and tissue damage ^[3]

T lymphocyte changes:

• ↓ cytotoxic and suppressor T cells ^[3]
• ↑ helper T cell population → ↑ production of autoantibodies ^[3]

Defective phagocytosis:

• Defective phagocytosis of immune complexes or apoptotic cells → persistence of self-antigen presentation and immune complexes mediates tissue damage ^[3]

• SLE is relatively common in the Chinese population (prevalence ~6 in 10,000) ^[3]
• Lupus nephritis is a recognized cause of CKD in Hong Kong — listed alongside diabetes, hypertension, IgA nephropathy, chronic pyelonephritis, etc. ^[5]
• In HK renal registries, SLE/lupus nephritis accounts for a notable proportion of glomerulonephritis-related ESRD
• Traditional Chinese Medicine (TCM) use is prevalent and can complicate management (nephrotoxic herbs, e.g. aristolochic acid causing additional tubulointerstitial injury)

Lupus nephritis results from deposition of circulating immune complexes. This activates the complement cascade leading to complement-mediated damage, leukocyte infiltration, activation of procoagulant factors, and release of cytokines ^[1][2].

Step 1: Immune Complex Formation

• Anti-dsDNA antibodies bind circulating nucleosomal DNA (released from apoptotic cells that are not properly cleared)
• These form immune complexes of variable size
• Immune complexes may also form in situ — anti-dsDNA binds to nucleosomes already "planted" in the GBM or mesangium

Step 2: Deposition in Glomeruli

• The glomerulus is particularly vulnerable because:
  • High blood flow (receives ~25% of cardiac output)
  • Fenestrated endothelium allows immune complex access to the GBM
  • The mesangium acts as a filter for circulating macromolecules
• Where immune complexes deposit determines the histological class and clinical presentation (see table in Section 3.3)

Step 3: Complement Activation

• Immune complexes activate the classical complement pathway (C1q → C4 → C2 → C3 → C5–C9)
• This generates:
  • C3a, C5a — anaphylatoxins → recruit neutrophils and monocytes
  • C5b-9 (MAC) — membrane attack complex → direct cell lysis
  • C3b — opsonization
• Complement consumption explains why C3 and C4 are low in active lupus nephritis ^[3]

Step 4: Inflammatory Response

• Recruited leukocytes release:
  • Reactive oxygen species (ROS) — direct tissue damage
  • Proteases — degrade GBM
  • Cytokines (IL-6, TNF-α, IL-1) — amplify inflammation
  • Procoagulant factors — microthrombosis in glomerular capillaries
• Endocapillary proliferation: endothelial and mesangial cell proliferation narrows capillary lumens → ↓ GFR → oliguria
• Crescent formation: severe inflammation → rupture of GBM → fibrin leak into Bowman's space → parietal epithelial cell proliferation → "crescents" (hallmark of RPGN)

Step 5: Progression to Chronic Damage

• Repeated inflammation → glomerulosclerosis, tubular atrophy, interstitial fibrosis
• Chronicity index: degree of sclerosis, fibrosis → prevent further worsening by CV risk control (ACEI, statins) ^[2]
• Eventually → advanced sclerosing (Class VI) → ESRD ^[1][2]

Not all immune complexes are preformed in the circulation. Some form in situ:

• Nucleosomal antigens bind to heparan sulfate proteoglycans in the GBM
• Circulating anti-dsDNA then binds these "planted" antigens
• This mechanism may be particularly important in Class V (membranous) LN, where subepithelial deposits are less likely to arrive as large preformed complexes

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)

• Classes are not static — patients can transition between classes over time
• Class II → Class IV (if disease flares)
• Class IV → Class VI (if inadequately treated)
• Mixed classes are common: Class III + V or Class IV + V ^[2]

• Clinical features of lupus nephritis exist on a spectrum from completely asymptomatic (Class I) to fulminant RPGN (Class IV)
• Often discovered incidentally on routine urinalysis in a known SLE patient
• Clinical features are variable: microscopic haematuria, proteinuria, AKI ^[2]
• Always look for extra-renal SLE features to help make the diagnosis

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]

• Urine multistix: RBC 3+ and protein 3+ → classic nephritic picture ^[7]
• Dysmorphic RBCs on urine microscopy → confirm glomerular origin
• RBC casts — pathognomonic of glomerulonephritis
• WBC casts — may be present (active inflammation)

This summary ties together the classification and clinical features:

APLS occurs in ~30% of SLE ^[2]. This is relevant to lupus nephritis because:

• APLS can cause renal vein thrombosis → acute flank pain, worsening proteinuria
• APLS can cause thrombotic microangiopathy in renal vessels → independent contributor to renal damage
• Presence of APLS antibodies necessitates anticoagulation

1. Duration and onset of urinary symptoms (acute vs. insidious)
2. SLE-related symptoms: rashes (malar, discoid, photosensitivity), oral ulcers, alopecia, joint pain, Raynaud's, serositis (pleurisy/pericarditis), neuropsychiatric symptoms
3. Drug history: NSAIDs (common in MSK complaints — can worsen renal function), steroids, immunosuppressants, TCM ^[7]
4. Obstetric history: recurrent miscarriages (APLS), complications of pregnancy
5. Family history: autoimmune diseases, SLE
6. Constitutional symptoms: fever, weight loss, fatigue
7. Previous investigations: ANA status, prior renal function

1. Vitals: BP (hypertension), temperature (fever → active SLE or infection)
2. Fluid status: oedema (peripheral, periorbital, sacral), JVP, lung bases
3. Skin: malar rash, discoid lesions, oral ulcers, alopecia, vasculitic rash, livedo reticularis
4. Joints: swelling, tenderness (symmetrical small joints)
5. Cardiopulmonary: pericardial rub, pleural effusion
6. Abdomen: ascites, hepatosplenomegaly (rarely)
7. Fundoscopy: if hypertensive — hypertensive retinopathy; if APLS — retinal vessel thrombosis

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]

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

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

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]

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].

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

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]

Once SLE is established (or strongly suspected), the question is: when does renal involvement warrant a biopsy?

Indications for renal biopsy in SLE ^[2][12]:

• Proteinuria > 0.5 g/day (or uPCR > 50 mg/mmol)
• Persistent haematuria (especially with dysmorphic RBCs or RBC casts)
• Raised creatinine not attributed to another mechanism

This is important because management is guided by histology ^[2]. You cannot treat lupus nephritis properly without knowing the class.

Timing: generally recommend immediately (delayed biopsy associated with ↑ risk of ESRD) ^[12].

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

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.

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

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

Aggressive BP control: indicated in all patients with CKD. More intensive BP lowering associated with ↓ mortality and ↓ risk of ESRD ^[12].

• BP target: 120–125/ < 80 for HBPM, 125–130/ < 80 for office BP ^[12]
• First-line: ACEI/ARB (dual benefit: BP + anti-proteinuric)
• Add CCB or diuretic if needed

Lipid-lowering therapy: indicated in all CKD patients as CKD is a major RF for CVD ^[12].

• Statins are first-line; weak evidence that statins may slow CKD progression ^[12]
• Chronicity index (degree of sclerosis, fibrosis) → prevent further worsening by CV risk control (ACEI, statins) ^[2]

Anti-oedema therapy: salt restriction and diuretics ^[21]:

• Dietary sodium restricted to ~2 g/day
• Loop diuretics (e.g. furosemide) usually preferred; can add thiazide or K+-sparing if inadequate ^[21]
• Monitor: fluid status (avoid hypovolaemia from underfilling) and serum K+

Anticoagulation may be considered in high-risk nephrotic syndrome patients ^[12]:

• Nephrotic syndrome is a hypercoagulable state (loss of antithrombin III, protein C/S in urine; ↑ hepatic production of fibrinogen)
• Prophylactic anticoagulation not routinely indicated unless thrombosis occurs or very high risk (e.g. serum albumin < 20 g/L + membranous pattern)
• If APLS coexists (30% of SLE) → anticoagulation may be needed independently

General care for all SLE patients: ^[2][3]

• Sun protection: avoid UV light, use umbrella, long-sleeve clothes, SPF15+ sun lotion ^[2]
• Exercise and smoking cessation (affect response to HCQ) ^[2]
• Vaccination (pneumococcal vaccination indicated for ALL as pneumococcal infection is common ^[21]; avoid live vaccines on immunosuppression)
• Screen and control CVS risk factors ^[2]
• Avoid offending drugs and OCP ^[2]
• Infection control ^[3]
• Regular monitoring: check BP and urine dipstick every visit; regular blood test on disease activity (anti-dsDNA, C3/4, ESR, CBC, L/RFT) ^[3]
• Eye check before HCQ and every year after 5 years ^[3]
• Counselling: explain disease, drug compliance, pregnancy issues and fertility issues; poor compliance is a major RF of poor prognosis ^[3]

Indications of immunosuppressants (EULAR): ^[2]

• Active Class III / IV
• Class III + V / Class IV + V
• Pure Class V + proteinuria > 1 g/day despite anti-proteinurics (e.g. ACEI)

For Class V alone with concurrent proliferative LN (i.e., Class III+V or IV+V), should be treated according to the proliferative lesion ^[12].

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

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

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

Azathioprine (AZA)

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

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

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

Class III + V / Class IV + V → should be treated according to the proliferative lesion ^[2][12].

This means: treat as Class III/IV (high-dose induction) even though there is a membranous component. The proliferative element is the more dangerous component.

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

Immunosuppressed patients are at high risk for infections:

• Screen for latent TB before starting immunosuppression (CXR, IGRA/Mantoux)
• Screen for HBV — risk of reactivation on immunosuppression; give prophylactic entecavir/tenofovir if HBsAg+
• PCP prophylaxis (co-trimoxazole) if on high-dose steroids + another immunosuppressant
• Avoid live vaccines on immunosuppression (BCG, MMR, varicella, oral polio, yellow fever)
• Pneumococcal vaccination indicated for ALL ^[21]

Cyclophosphamide gonadal toxicity: consider sperm and egg banking ^[1][20].

• GnRH agonists (e.g. leuprolide) can be co-administered with CYC to suppress ovarian function and reduce gonadal toxicity — evidence is moderate but commonly done in practice
• Young women should be counselled before CYC and offered oocyte/embryo cryopreservation

When lupus nephritis presents as RPGN (rapidly progressive, creatinine doubling in days):

• Can give empirical pulse IV methylprednisolone before renal biopsy if indicated ^[11]
• Do NOT wait for biopsy results to start treatment — delay risks irreversible damage
• After biopsy confirms Class IV with crescents → formal induction regimen
• Consider plasmapheresis if concomitant APLS with TMA or concurrent anti-GBM disease

This is the most feared complication of lupus nephritis.

• Overt renal disease occurs in ≥ 1/3 of SLE patients → 25% develop ESRD within ≤ 10 years ^[12]
• Lupus nephritis is one of the major causes of morbidity/mortality in SLE patients ^[12]
• Renal failure is one of the major causes of morbidity/mortality in SLE patients ^[12]

Why does LN progress to CKD?

• Repeated episodes of active inflammation cause irreversible glomerulosclerosis and tubulointerstitial fibrosis
• Irreversible damage to some nephrons leads to compensatory hyperfiltration in remaining nephrons → raises intraglomerular pressure → non-immunological glomerular injury → progressive glomerulosclerosis ^[8] — a vicious cycle
• This is reflected in the chronicity index on biopsy: the higher it is, the more irreversible damage has occurred ^[2]
• Ultimately, Class III/IV can progress to Class VI (advanced sclerosing) → global sclerosis of nearly all glomerular capillaries → ESRD ^[1]

Complications of CKD ^[5]:

• Fluid retention
• Metabolic acidosis
• High blood pressure
• Normochromic normocytic anaemia (loss of erythropoietin production)
• Secondary hyperparathyroidism
• Bone disease (CKD-MBD)

When ESRD is reached, the patient requires renal replacement therapy: dialysis or kidney transplantation ^[1]. Importantly, SLE can recur in a transplanted kidney, though this is relatively uncommon.

Long-term complications following kidney transplant include: ^[24]

• Infections (CMV, PJP, BK virus, MTB)
• Malignancy (PTLD — B-cell lymphoma, EBV-related)
• Cardiovascular disease
• Drug-related side effects
• Chronic allograft injury
• Recurrence of primary disease — lupus nephritis can recur in the allograft, though rates are low (~2–9%)

Class IV LN (and occasionally Class III) can present or progress to RPGN — rapidly declining renal function leading to ESRD in days to weeks ^[11].

Why does RPGN develop?

• Severe endothelial injury → GBM rupture → massive movement of plasma products into Bowman's space → massive influx of macrophages/T cells → release of proinflammatory cytokines → formation of cellular crescent ^[11]
• Followed by fibroblast proliferation and replacement by fibrous crescent (unlikely to respond to immunosuppressive treatment) ^[11] — meaning the window for treatment is narrow. Once crescents become fibrous, the damage is irreversible.

This is a nephrological emergency requiring immediate treatment with pulse IV methylprednisolone ± cyclophosphamide or rituximab ^[11].

Lupus nephritis is NOT limited to glomerular disease — it can affect glomerulus, tubules, interstitium and blood vessels at the same time ^[4][12].

• Tubulointerstitial nephritis: immune complex deposition in tubular basement membranes → tubular dysfunction (e.g. ↓ concentration ability ^[12], renal tubular acidosis — typically distal/Type 1 RTA)
• This can contribute to hypokalaemia, metabolic acidosis, and nephrocalcinosis
• TIN worsens prognosis independently of glomerular class

• Renal vascular disease due to immune complex deposits or microvascular thrombosis ^[12]
• Thrombotic microangiopathy (TMA): especially in patients with concurrent APLS (present in ~30% of SLE) ^[2] — microthrombi in glomerular capillaries and arterioles cause additional ischaemic renal damage
• Renal artery stenosis: rare; can be associated with APLS
• Renal vein thrombosis: nephrotic syndrome creates a hypercoagulable state (see below)

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

Renal vein thrombosis management: ^[26]

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

SBP (spontaneous bacterial peritonitis — especially in children with nephrotic syndrome): due to loss of immunoglobulins in urine ^[26].

• SLE itself is immunocompromising (immune dysregulation + complement deficiency from consumption)
• Immunosuppressive therapy further impairs host defence
• Fever in SLE = sepsis until proven otherwise ^[2]
• Investigation: septic workup, CRP
• Management: withhold immunosuppressants, stress-dose steroids, empirical broad-spectrum antibiotics ^[2]

Common infections in immunosuppressed SLE patients:

• Bacterial: pneumonia (pneumococcal, Pseudomonas), UTI, skin infections
• Viral: CMV, herpes zoster, BK virus
• Fungal: Pneumocystis jirovecii (PCP) — prophylaxis with co-trimoxazole if on high-dose steroids + another immunosuppressant
• Mycobacterial: TB — screen before starting immunosuppression

Resistant oedema pathophysiology: ^[26]

• Poor drug/diet compliance
• Furosemide malabsorption due to gut wall oedema

Management of resistant oedema: ^[26]

• Change to IV furosemide
• Add thiazide/potassium-sparing diuretics
• IV albumin (as adjunct to overcome underfilling and restore diuretic response)

AKI in nephrotic syndrome: ^[26]

• Hypovolaemia due to over-diuresis
• ATN (acute tubular necrosis)
• Crescentic transformation (RPGN)

Management: lower dose/withhold diuretics, rehydration ^[26].

• Nephrotic syndrome → hepatic compensation for albumin loss → ↑ lipoprotein synthesis → hypercholesterolaemia, hypertriglyceridaemia
• Increased CVS risk (accelerated coronary atherosclerosis) ^[2]:
  • Disease-related: chronic inflammation, HT due to lupus nephritis, APS ^[2]
  • Treatment-related: steroids ^[2]
• Long-term management: CV risk modifications ^[26]

Hypertension and hyperlipidaemia require monitoring, prevention and treatment as associated complications ^[1][27].

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

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].

• Diarrhoea, abdominal pain, constipation, nausea and vomiting ^[1][20]
• Anaemia, leukopenia ^[1][20]
• Teratogenic — Category D; must use effective contraception

• Hepatotoxicity, myelosuppression, pancreatitis ^[1][20]
• Interaction with allopurinol (fatal pancytopenia if co-prescribed)
• Check TPMT before starting

Cyclosporine A side effects: ^[1][20]

• Nephrotoxicity (paradoxically — the drug used to treat kidney disease can damage kidneys via afferent arteriolar vasoconstriction)
• Tremor, hirsutism/hypertrichosis, gum hyperplasia
• Hyperkalaemia
• HT/DM/hyperlipidaemia

Rituximab: ^[1][20]

• Reactivation of HBV/TB (screen before use)
• Progressive multifocal leukoencephalopathy (PML) — JC virus reactivation; rare but devastating

Belimumab: ^[1][20]

• B-cell depletion — infection risk