Lupus Nephritis

Overview

Pathogenesis

• Genetic and epigenetic predisposition — >50 polymorphisms associated with LN susceptibility, including variants in CCR6 (Th17 pathway)
• Autoantibodies — ANA are nearly universal; anti-dsDNA (most specific), anti-Sm, anti-histone, anti-C1q, and antiphospholipid antibodies are common
• Immune complex deposition — Glomerular deposits activate complement (classical pathway via C1q), causing inflammation
• B- and T-lymphocyte dysregulation, macrophages, dendritic cells, and neutrophil extracellular traps (NETs) all contribute
• "Full house" immunofluorescence — simultaneous staining of IgG, IgM, IgA, C3, and C1q is pathognomonic

Clinical Presentation

Classification (ISN/RPS 2003, revised 2018)

• Class I (Minimal mesangial): Normal light microscopy; mesangial deposits on IF and EM only. No clinical renal disease.
• Class II (Mesangial proliferative): Mesangial hypercellularity and matrix expansion; mesangial deposits on IF/EM. Mild proteinuria/hematuria.
• Class III (Focal): Endocapillary hypercellularity in <50% of glomeruli, often segmental, ± necrosis and crescents. Focal subendothelial deposits.
• Class IV (Diffuse): Endocapillary hypercellularity in ≥50% of glomeruli. Key features:
  • Wire loops — eosinophilic thickening of peripheral capillary loops (massive subendothelial deposits)
  • "Hyaline thrombi" — intraluminal immune deposits (misnomer)
  • Karyorrhectic nuclear debris
  • Massive mesangial + subendothelial deposits on EM
  • The most severe and clinically aggressive class
• Class V (Membranous): Thickened GBM with subepithelial deposits; GBM "spikes" on silver stain; may coexist with Class III or IV ("mixed membranous-proliferative"). Presents as nephrotic syndrome.
• Class VI (Advanced sclerosing): >90% global glomerulosclerosis, no residual activity. Represents burnt-out disease.

• (A) — Active lesions (proliferative)
• (A/C) — Active + chronic
• (C) — Chronic (sclerosing)

Diagnosis

• Renal biopsy is the gold standard; required for accurate classification and treatment guidance
• Serologic markers: anti-dsDNA titres, complement (low C3/C4), ANA
• Urinalysis: active sediment (RBC casts, dysmorphic red cells), proteinuria
• SLICC criteria allow stand-alone renal criterion: biopsy-proven LN + ANA or anti-dsDNA
• Extraglomerular lesions (tubulointerstitial, vascular) add prognostic value beyond glomerular classification

Management

Induction Therapy (active proliferative LN — Class III/IV ± V)

Maintenance Therapy

• Azathioprine (1.5–2.5 mg/kg/day) or MMF (1–2 g/day)
• Hydroxychloroquine — given to all LN patients; reduces flare risk and improves long-term outcomes
• Continued for minimum 3–5 years after remission; many require indefinite treatment

Class V (Membranous LN)

• Low-level proteinuria: RAS blockade + BP control + hydroxychloroquine ± immunosuppression guided by extrarenal SLE
• Nephrotic-range proteinuria: Glucocorticoids + MMF or cyclophosphamide or calcineurin inhibitor or rituximab + hydroxychloroquine

Additional measures

• RAS blockade (ACEi/ARB) — antiproteinuric and renoprotective in all classes
• Thromboprophylaxis — antiphospholipid syndrome is common; LMWH/warfarin if APS present
• Statins — dyslipidemia management
• Rituximab — for refractory disease; not superior to standard therapy in initial trials but used in treatment-resistant cases

Plasma Exchange

Monitoring and Response

• Complete renal response: proteinuria <0.5 g/24h, stable/improved creatinine, inactive urine sediment
• Repeat biopsy may be warranted at transformation (change in clinical picture) or suspected flare
• Anti-dsDNA titres and complement levels correlate with disease activity

Pregnancy

• MMF is teratogenic — must be switched to azathioprine ≥6 weeks before conception
• Hydroxychloroquine should be maintained throughout pregnancy
• Cyclophosphamide and rituximab — contraindicated
• Tacrolimus — increasingly used as alternative
• Predictors of poor outcome: creatinine >0.9 mg/dL, proteinuria >0.5 g/24h, antiphospholipid syndrome, hypertension, active disease at conception
• Low-dose aspirin for preeclampsia prophylaxis; preeclampsia and LN flare can be clinically indistinguishable

Prognosis

• Class IV carries the worst renal prognosis without treatment
• High baseline creatinine, significant chronic damage on biopsy, crescents, and vascular lesions portend inferior outcomes
• Anti-Sm positivity and older age at presentation (>50 years) associated with worse prognosis in Korean cohorts
• With modern immunosuppression, 10-year kidney survival has improved substantially, though ESKD remains a significant risk in severe/refractory disease

An Important Clarification First

Current TB Treatment Guidelines (2024–2025)

Drug-Susceptible TB (DS-TB)

Standard 6-Month Regimen (Adults & Children ≥12 yrs)

• Cures >90% of patients
• Daily administration throughout is strongly preferred; intermittent regimens are associated with higher treatment failure, relapse, and resistance
• ATS/CDC/IDSA allow thrice-weekly supervised (DOT) regimens only in HIV-negative, non-cavitary, low-relapse-risk patients

4-Month Regimen (TBESC2/Study 31 — newer option for adults ≥12 yrs)

Children (3 months – 16 years), Non-Severe TB

Extrapulmonary TB

• Most forms: treat with the standard 6-month pulmonary regimen
• TB meningitis: extend continuation phase to 7–10 months (ATS/CDC/IDSA) or 10-month consolidation (WHO/AAP)
• Bone/joint TB, miliary TB in children: up to 12 months total

Latent TB Infection (LTBI) — Preferred Regimens

Drug-Resistant TB — The Major 2022–2024 Updates

MDR-TB / RR-TB: Four WHO-Recommended Approaches (2024 Update)

1. BPaLM — 6-Month, Fully Oral (Preferred for most MDR/RR-TB)

• Treatment success ~90%
• For: MDR/RR-TB or pre-XDR-TB, age ≥14, regardless of HIV status
• Excludes: disseminated TB, CNS TB, osteoarticular TB
• Excludes: prior exposure ≥1 month to bedaquiline, pretomanid, or linezolid
• Fluoroquinolone DST guides whether moxifloxacin is retained or dropped (→ BPaL if FQ-resistant)
• Contraindicated in pregnancy (pretomanid safety data insufficient)

2. BDLLfxCfz — 6-Month, All-Oral

• Option for those without prior exposure to bedaquiline, delamanid, and linezolid
• Either levofloxacin or clofazimine may be omitted based on DST

3. Shorter 9-Month Oral Bedaquiline-Containing Regimens

• BLMZ (bedaquiline + linezolid + moxifloxacin + pyrazinamide)
• BLLfCfZ (bedaquiline + linezolid + levofloxacin + clofazimine + pyrazinamide)
• BDLLfxZ
• For patients with no prior exposure to B, D, L, and in whom fluoroquinolone resistance is excluded

4. Individualized Longer Regimen (≥18 months)

• Optimal combination of oral drugs using WHO priority grouping
• For complex drug resistance patterns, prior treatment exposure, or contraindications to shorter regimens

Pre-XDR-TB and XDR-TB

• BPaL (without moxifloxacin) is the backbone
• Individualized regimens based on DST and exposure history

Isoniazid-Resistant TB (Hr-TB)

Special Populations

Prevention

• BCG vaccine: Given at birth in high-burden countries; 80% efficacy against severe childhood TB (meningitis, miliary); variable efficacy against adult pulmonary TB
• Infection control: Rapid diagnosis, isolation, and effective treatment render patients non-infectious within 2–4 weeks
• LTBI treatment in high-risk contacts (recent exposure, immunosuppressed, young children, HIV+)

Key Drug Abbreviations