Lupus Nephritis

Epidemiology & Risk Factors

• More prevalent and more severe in Asian and Black populations compared to Caucasians; in China, Korea, and Japan, LN accounts for >50% of all secondary glomerular diseases
• Higher genetic risk burden in East Asian populations (more risk variant alleles from GWAS data)

• 50 genetic polymorphisms linked to LN susceptibility, including variants in CCR6 (a Th17 surface marker)

• Disease onset after age 50 is associated with more chronic damage and inferior outcomes

Pathogenesis

• Circulating autoantibodies to nuclear antigens (ANAs) - most specific are anti-dsDNA antibodies; others include anti-histone, anti-RNP, anti-Sm, anti-C1q, and anti-endothelial antibodies
• Glomerular immune complex deposition with complement activation (classical pathway via C1q)
• B- and T-lymphocyte dysregulation; macrophage and dendritic cell involvement
• Neutrophil extracellular traps (NETs) and apoptotic pathway involvement
• Infiltration of kidneys by neutrophils, T cells, B cells, macrophages, and dendritic cells
• Key mediators: chemokines, interferons (especially type I), and interferon regulatory factors

• Disruption of cell-cell interactions
• Vascular injury and hypoxia
• Glomerulosclerosis and interstitial fibrosis

ISN/RPS Classification (2003, revised 2018)

Histological Images

Fig. 55.57 - Class I LN: Mesangial IgG staining (IF, x400). - Henry's Clinical Diagnosis

Fig. 55.65 - Class IV LN: Endocapillary hypercellularity and diffuse glomerular involvement (H&E, x400). - Henry's Clinical Diagnosis

Fig. 55.71 - Class IV LN: Strong IgG staining in glomerular mesangium and peripheral capillary loops (IF, x400). - Henry's Clinical Diagnosis

Fig. 55.76 - Class V LN: GBM spiking on silver stain (x630). - Henry's Clinical Diagnosis

Clinical Features

• Hematuria (usually microscopic)
• Proteinuria - ranges from subnephrotic to nephrotic-range
• Nephrotic syndrome - especially in class V
• Urinary red cell casts - suggest active proliferative disease
• Renal insufficiency - more common in class III/IV
• Tubular defects

Diagnosis

ACR criteria (1997) - 4 of 11 required (96% sensitivity and specificity for SLE):

SLICC classification (2012) - more sensitive, especially in early SLE:

Treatment

General Principles

• All patients with LN should receive hydroxychloroquine (reduces flares, improves renal outcomes, safe long-term)
• Treatment is in two phases: induction (rapid disease control) followed by long-term maintenance
• ACE inhibitors or ARBs for proteinuria reduction (hold before conception)

Induction (Classes III/IV, and V with proteinuria):

1. Corticosteroids + IV cyclophosphamide (CYC) - NIH protocol or Euro-Lupus low-dose protocol
2. Corticosteroids + mycophenolate mofetil (MMF) - preferred in many centers due to comparable efficacy with better tolerability; treatment evolved from cyclophosphamide-dominant to MMF-dominant regimens since 1980s

• Belimumab (anti-BLYS) and voclosporin (calcineurin inhibitor) - approved as add-on to MMF + corticosteroids for active LN
• Rituximab (anti-CD20) - evidence suggests it offers no additional benefit over conventional therapy in standard cases; used in refractory disease

Maintenance:

• MMF or azathioprine with low-dose corticosteroids
• Hydroxychloroquine continued long-term
• Duration typically ≥3 years

Therapeutic Plasma Exchange (TPE):

• Large RCT (Lupus Nephritis Collaborative Study Group) showed TPE does not improve clinical outcomes in LN despite more rapid reduction of anti-dsDNA antibodies
• TPE may be considered in select patients with LN + severe thrombotic microangiopathy or refractory antiphospholipid syndrome (American Society for Apheresis: Category III indication)

Pregnancy and Lupus Nephritis

• LN flares occur in ~30% of pregnancies and ~15% postpartum
• Prophylactic postpartum corticosteroid dose increase is not indicated
• All pregnant SLE women should continue hydroxychloroquine (reduces flares and fetal growth restriction)
• Safe in pregnancy: corticosteroids, azathioprine, tacrolimus, hydroxychloroquine, low-dose aspirin, LMWH, IVIG, plasma exchange
• Contraindicated in pregnancy: MMF (teratogenic - microtia, cleft palate, auditory canal atresia, micrognathia), cyclophosphamide (teratogenic), rituximab (B-cell depletion in fetus)
• Ideal: disease remission for ≥6 months before conception; MMF switched to azathioprine before conception
• Distinguishing LN flare from preeclampsia is a major challenge (both cause hypertension, proteinuria, AKI, thrombocytopenia); complement levels and anti-dsDNA titers can help

Prognosis

• High baseline serum creatinine and significant chronic damage on biopsy indicate unfavorable long-term renal prognosis
• Vascular/endothelial abnormalities and crescents on biopsy = aggressive disease
• Anti-Sm antibody (detected in ~49% of biopsy-proven LN in Korea) associated with worse renal prognosis
• ESKD is a major long-term risk, especially in Asian populations

Recent Evidence (PubMed 2024-2026)

Systemic Lupus Erythematosus (SLE)

Epidemiology

• Predominantly affects women of childbearing age (F:M ratio ~9:1)
• Prevalence is highest in Black, Hispanic, and Asian women compared to White women
• Onset typically between ages 15-45; can occur at any age
• Low socioeconomic status, environmental toxins (mercury, pesticides), certain viral infections, and UV light exposure are associated with disease development

Pathogenesis

Fig. 6.25 - Pathogenesis of SLE: susceptibility genes + external triggers → defective clearance of apoptotic debris → TLR stimulation of B cells and dendritic cells → type 1 interferon production → persistent high-level antinuclear IgG antibody production. (Robbins Pathologic Basis of Disease)

Genetic Factors

• ~25% concordance in monozygotic twins (implying strong environmental contribution too)
• Susceptibility genes impair maintenance of self-tolerance

Environmental Triggers

• UV radiation - alters DNA methylation, generates self-stimulatory nucleic acids, activates keratinocyte immune responses
• EBV infection - induces interferon response, activates SLE susceptibility genes
• Gut microbiome - increased gut permeability promotes translocation of gut microbes and development of lupus-specific autoantibodies

Innate Immunity Defects

• Neutrophils have higher turnover in SLE, delivering a large load of stimulatory nucleic acids
• Defective phagocyte clearance of apoptotic debris and immune complexes
• Toll-like receptors (TLRs) in plasmacytoid dendritic cells are triggered by nucleic acid debris → produce type 1 interferons (IFN-α)
• Type 1 IFN amplifies the autoimmune response by priming neutrophils and sensitizing the adaptive immune system

Adaptive Immunity Defects

• B cells lose tolerance and differentiate (via age-associated B cells, or ABCs) into autoantibody-secreting plasma cells
• T follicular and T peripheral helper cells promote B-cell differentiation into high-affinity autoantibody-secreting plasma cells
• T regulatory cells are defective - fail to maintain tolerance in T and B cells
• Autoantibodies complexed with nucleic acids induce more type 1 IFN in a feed-forward loop

Autoantibody Profile

Diagnostic Criteria

ACR Criteria (1997) - 4 of 11 required (96% sensitivity and specificity):

1. Malar (butterfly) rash
2. Discoid rash
3. Photosensitivity
4. Oral ulcers
5. Non-erosive arthritis
6. Serositis (pleuritis or pericarditis)
7. Renal disorder (proteinuria >0.5 g/day or casts)
8. Neurologic disorder (seizures or psychosis)
9. Hematologic disorder (hemolytic anemia, leukopenia, thrombocytopenia)
10. Immunologic disorder (anti-dsDNA, anti-Sm, antiphospholipid antibodies)
11. Positive ANA

SLICC Criteria (2012) - more sensitive, especially in early SLE:

• Requires ≥4 criteria (≥1 clinical + ≥1 immunologic), OR biopsy-proven lupus nephritis + ANA or anti-dsDNA
• More sensitive than ACR but slightly less specific

Clinical Manifestations

Systemic / Constitutional

• Fatigue (80-100%), fever (55-85%), weight loss (60%), anorexia
• ~15% have relatively mild disease with fatigue and arthralgia only

Musculoskeletal (80-90%)

• Non-erosive polyarthritis or arthralgia - most common presenting symptom
• Jaccoud's arthropathy (reducible deformities from joint laxity, not erosion)
• Myalgia, myositis

Cutaneous (85%) - 4 of 11 ACR criteria are mucocutaneous

• Classic butterfly (malar) rash - erythema on cheeks and bridge of nose, nasolabial fold typically spared (unlike dermatomyositis); resolves without scarring
• Widespread photosensitive erythema
• Interface dermatitis on biopsy

• Annular or psoriasiform plaques, photosensitive; no scarring
• Strongly associated with anti-Ro/SS-A antibodies (70-90%)

• Coin-shaped plaques with dyspigmentation and scarring
• "Carpet-tack" adherent scale in conchal bowl of ear is characteristic
• <5% of DLE patients have the high-titer ANA levels of SLE

• Bullous LE (HLA-DR2+; responds dramatically to dapsone; anti-type VII collagen antibodies)
• "Lupus hairs" - short frontal hairs from telogen effluvium and increased fragility
• Diffuse non-scarring alopecia
• Vascular lesions (fingertip/toe edema, nailfold telangiectasia, Raynaud's) in 50%
• Oral/mucosal ulcers (20-30%)
• Livedo reticularis, leg ulcers (suggest antiphospholipid syndrome)
• Lupus panniculitis/profundus - firm nodules with overlying saucer-shaped depressions

Diagnostic approach flowchart for cutaneous LE:

Fig. 61-12 - Approach to skin lesions suspicious for CLE. (Fitzpatrick's Dermatology)

Renal (50-70%)

• Lupus nephritis is the most serious complication (see [prior detailed LN summary])
• Hematuria, proteinuria, casts, renal insufficiency
• Up to 40% have clinically significant renal involvement (glomerulonephritis, tubulointerstitial nephritis)
• ISN/RPS Classification Classes I-VI

Neuropsychiatric SLE (NPSLE) - up to 90% have CNS involvement at some point

• Depression and anxiety each in ~25%
• Cognitive impairment (subclinical) in 11-54%; features include slowed processing, attention deficits, memory impairment
• Seizures - prevalence 3-51%
• Psychosis - 5-8% (but ~30% on prednisone 60-100 mg/day develop psychotic symptoms)
• Cerebrovascular disease - 5-18%; multi-infarct dementia possible
• ANA titer ≥1:40 in up to 99% of SLE patients at some point
• Mechanisms: antineuronal antibodies crossing BBB, antiphospholipid antibodies, inflammatory cytokines

Cardiovascular

• Pericarditis (most common cardiac manifestation) - symptomatic or asymptomatic in up to 50%
• Libman-Sacks endocarditis - nonbacterial verrucous vegetations on either surface of valve leaflets (unlike rheumatic fever which affects lines of closure only); mitral and aortic valves most common
• Accelerated coronary atherosclerosis (especially with long-standing disease and corticosteroid use)
• Myocarditis (less common)

Pulmonary

• Pleuritis/pleural effusions (~50%)
• Lupus pneumonitis, diffuse alveolar hemorrhage (rare but severe)
• Chronic interstitial fibrosis and secondary pulmonary hypertension

Hematologic (100%)

• Anemia (~50%) - normochromic normocytic (chronic disease), autoimmune hemolytic anemia, iron deficiency
• Leukopenia (<4000/μL) in ~50% - usually lymphopenia (<1500/μL) rather than neutropenia
• Thrombocytopenia (<150,000/μL) - usually mild, but can be severe
• Splenomegaly, "onion-skin" penicillary arteries (concentric intimal hyperplasia) in spleen
• Rarely atypical hemolytic-uremic syndrome (schistocytes, low ADAMTS13, elevated LDH)

Gastrointestinal

• Nausea, vomiting, diarrhea during flares
• Mesenteric vasculitis - can cause intestinal perforation, bleeding, ischemia; requires high-dose glucocorticoids
• Elevated liver enzymes (flare, medications, or co-existing autoimmune hepatitis)
• Protein-losing enteropathy

Ocular

• Keratoconjunctivitis sicca (even without secondary Sjögren's)
• Retinal vasculitis (rare; requires aggressive immunosuppression to prevent blindness)
• Episcleritis, scleritis, uveitis, optic neuritis

Antiphospholipid Syndrome (secondary APS)

• Venous and arterial thromboses
• Recurrent spontaneous miscarriages
• Focal cerebral or ocular ischemia
• Associated with IgG/IgM anticardiolipin antibodies and lupus anticoagulant

Morphology (Robbins Pathologic Basis of Disease)

Treatment

All patients - Background therapy:

• Hydroxychloroquine (HCQ) - backbone of all SLE treatment; reduces flare frequency, improves survival, safe long-term including in pregnancy; max 5 mg/kg/day (retinal toxicity monitoring required)
• Sun protection
• ACE inhibitors/ARBs for renal protection

Mild disease (SLEDAI ≤6, BILAG C):

• NSAIDs (short-term for arthritis/serositis)
• Low-dose corticosteroids
• Antimalarials (HCQ)
• Methotrexate (skin, joints)

Moderate disease (SLEDAI 7-12, ≥2 BILAG B):

• Moderate-dose corticosteroids
• Methotrexate or azathioprine (joints, skin)
• Mycophenolate mofetil (MMF) (serositis, skin, joints)
• Belimumab (anti-BLyS/BAFF) or anifrolumab (anti-IFN-α receptor) as first-line additions in some moderate/severe extrarenal disease

Severe disease (SLEDAI >12, BILAG A, or major organ-threatening):

• IV methylprednisolone pulses then oral prednisone
• IV cyclophosphamide (CYC) - for severe neuropsychiatric SLE, diffuse alveolar hemorrhage, severe vasculitis
• Belimumab and anifrolumab as add-on for severe extrarenal skin/joint disease (NOT recommended for severe neuropsychiatric SLE)
• Rituximab (anti-CD20) - for refractory cytopenias
• IVIG, plasmapheresis - for severe NPSLE, TTP-like disease
• Anticoagulation (VKA) for APS-related thrombosis

Biological agents (summary):

Recent Evidence (PubMed 2025-2026)

• 2025 EULAR Guidelines (PMID 41107121) - updated recommendations for SLE with kidney involvement, endorsing belimumab and voclosporin as add-on therapies for LN
• Telitacicept Phase 3 RCT (PMID 41092329, NEJM Oct 2025) - telitacicept (dual BLyS + APRIL inhibitor) showed significant benefit in SLE; a new emerging biologic option
• Cutaneous LE review (PMID 41204012, Nat Rev Rheumatol Dec 2025) - updated pathogenesis-to-targeted-therapy review

Prognosis & Monitoring

• Goals: low disease activity or remission on ongoing therapy
• Majority of patients have active disease despite therapy or frequent flares
• Major causes of morbidity: renal failure (LN), cardiovascular disease (accelerated atherosclerosis), infections (from immunosuppression)
• Monitoring: Anti-dsDNA titers, complement (C3, C4), CBC, urinalysis with microscopy, creatinine, BP
• HCQ retinal toxicity screen annually after 5 years of use
• Anti-Ro/SS-A screening in all pregnant women (neonatal heart block risk)

IgA Nephropathy (Berger Disease)

Epidemiology

• Most common primary glomerulonephritis globally - accounts for 40-50% of primary GN in Asia (>45% of primary GN in China) and 10-20% in the USA
• Peak incidence: 2nd and 3rd decades of life
• Male predominance in White populations (M:F ratio 2:1 to 3:1); approaches 1:1 in Asian populations
• Very uncommon in Black populations
• Rare familial clustering; predominantly sporadic
• Geographic variation in prevalence likely reflects both true differences and differences in detection (biopsy thresholds)

Pathogenesis - The Four-Hit Model

Diseases Associated with Secondary IgAN

Biopsy - Histological Findings

Immunofluorescence (diagnostic hallmark)

• Dominant or codominant mesangial IgA deposition (must exceed any other immunoglobulin)
• Typically polymeric IgA1 with J-chain
• C3 co-deposits in up to 90%
• IgG in ~40%, IgM in ~40%
• C1q absent (distinguishes from lupus nephritis which shows "full house")
• Properdin (alternative pathway) + factor H commonly co-deposit

Light Microscopy

• Mesangial widening and hypercellularity (most common)
• Endocapillary hypercellularity
• Focal segmental sclerosis (indicates chronicity)
• Crescents (aggressive disease; RPGN presentation)
• Rarely, nearly normal glomeruli (mild disease)

Electron Microscopy

• Mesangial and paramesangial electron-dense deposits (confirming the IF pattern)
• Subepithelial/subendothelial deposits also possible
• Capillary loop deposits indicate worse prognosis

Key Histological Images

Fig. 12.12 - IgA nephropathy. (A) LM: mesangial proliferation and matrix increase. (B) IF: characteristic mesangial IgA deposition. (Robbins & Kumar Basic Pathology)

Fig. 55.26 - IgA nephropathy with crescent formation. Cellular crescent in Bowman space (Jones silver, x400). (Henry's Clinical Diagnosis)

Glomerular schematic - IgA nephropathy: mesangial deposits plus mesangial cell proliferation. (Harrison's 22E)

Fig. 55.24 - IgA nephropathy: mesangial hypercellularity and matrix increase (PAS, x400). (Henry's Clinical Diagnosis)

Oxford (MEST-C) Classification

Clinical Presentations

Diagnosis

• Kidney biopsy is required - no blood or urine biomarker is diagnostic
• Serum IgA levels are elevated in 20-50% of patients, but are not diagnostic
• Serum IgA deposits found in skin biopsies in 15-55% of patients
• Biopsy confirms dominant mesangial IgA1 on IF

Prognosis

• 20-40% of patients reach ESKD over 20-30 years (varies considerably by population and risk factors)
• Median life expectancy reduced by ~10 years in some populations (USA southeastern cohort)
• Episodes of macroscopic hematuria alone do NOT confer worse prognosis
• Older age at diagnosis is associated with worse prognosis (likely reflects later stage disease)

Poor prognostic factors (Box 24.2 - IgAN Risk Prediction):

• Persistent proteinuria (time-averaged proteinuria is the strongest modifiable predictor; risk is low when <0.2 g/24h)
• Hypertension at presentation
• Reduced eGFR at biopsy
• Higher MEST-C scores (especially T1/T2 and C2)
• Capillary loop IgA deposits on IF
• Hyperuricemia, smoking, high BMI
• Persistent hematuria (hematuria remission associated with better outcomes)

Treatment

Supportive / Baseline Therapy (all patients):

• ACE inhibitors or ARBs - cornerstone for all patients with proteinuria >0.5-1 g/day; reduce proteinuria and slow progression; target BP <130/80 mmHg
• SGLT2 inhibitors (e.g., dapagliflozin) - now shown to reduce adverse kidney outcomes in IgAN; recommended as add-on in patients at risk of progression
• Lifestyle: BP control, smoking cessation, weight management, treatment of hyperuricemia
• Management of underlying conditions (e.g., celiac disease, tonsillitis)
• Tonsillectomy - suggested benefit in select Asian patients with recurrent tonsillitis-triggered hematuria; evidence limited

Immunosuppression (selected patients at high risk of progression):

• Targeted-release budesonide (Nefecon) - oral formulation delivering budesonide to the ileum/Peyer's patches; shown to reduce proteinuria and preserve eGFR in patients at risk of rapid progression (Phase 3 NefIgArd trial); approved by FDA 2023 for IgAN with urine protein-creatinine ratio ≥1.5 g/g
• Systemic corticosteroids - conflicting evidence; the STOP-IgAN and TESTING trials showed benefit in reducing proteinuria but increased serious adverse events; use with caution; some guidelines recommend a 6-month course in high-risk patients
• Fish oil (omega-3 fatty acids) - modest benefit in some small studies; generally safe
• Cytotoxic agents (cyclophosphamide, azathioprine) - reserved for crescentic/RPGN presentation
• Plasmapheresis - considered for RPGN presentation with crescents

RPGN presentation:

• Systemic corticosteroids + cyclophosphamide or rituximab
• Plasmapheresis considered

Recent Evidence - Landmark 2025 NEJM Trials

1. Iptacopan (Alternative Complement Pathway Inhibitor)

• PMID 39453772 - APPLAUSE-IgAN trial
• Iptacopan is an oral factor B inhibitor (blocks the alternative complement pathway amplification loop)
• Significantly reduced proteinuria vs. placebo in patients with IgAN
• First complement inhibitor approved/in late-stage development specifically targeting the alternative pathway in IgAN

2. Atrasentan (Endothelin-1 Receptor Antagonist)

• PMID 39460694 - ALIGN trial
• Atrasentan is a selective endothelin-A receptor antagonist
• Phase 3 trial showed significant reduction in proteinuria and kidney function preservation in IgAN patients
• Builds on its earlier use in diabetic nephropathy

Additional Recent Evidence:

• Nat Rev Nephrol 2025 (PMID 39232245) - comprehensive pathogenesis-to-treatment review highlighting the multi-hit model and new therapeutic targets
• Kidney Int 2025 (PMID 39894081) - "call for a new paradigm" review supporting combination therapy targeting multiple pathways simultaneously
• IPNA Guidelines 2025 (PMID 39331079) - pediatric IgAN and IgA vasculitis nephritis recommendations

Emerging Therapeutic Targets