What are the classes of lupus nephritis?

Lupus Nephritis Classification System

Lupus nephritis is classified into six distinct classes (I-VI) according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) system, which is essential for guiding treatment decisions and predicting prognosis. 1, 2

The Six Classes of Lupus Nephritis

Class I: Minimal Mesangial Lupus Nephritis

• Characterized by mesangial immune deposits detected by immunofluorescence or electron microscopy without mesangial hypercellularity on light microscopy 2
• Does not require immunosuppressive treatment; management focuses on extrarenal lupus manifestations 3
• All patients should receive hydroxychloroquine 5 mg/kg actual body weight daily unless contraindicated 3

Class II: Mesangial Proliferative Lupus Nephritis

• Defined by mesangial immune deposits with mesangial hypercellularity (four or more nuclei fully surrounded by matrix in the mesangial area) 4, 2
• When proteinuria is <1 g/day, no specific immunosuppressive therapy is needed 3
• Treatment is guided by extrarenal manifestations of lupus 3

Class III: Focal Lupus Nephritis

• Involves <50% of total glomeruli with active or inactive focal, segmental, or global endocapillary or extracapillary glomerulonephritis 2
• Requires aggressive therapy with glucocorticoids and immunosuppressive agents 1
• The 2018 ISN/RPS revision recommends subdivisions for active and sclerotic lesions rather than the previous A/C designations 4

Class IV: Diffuse Lupus Nephritis

• Involves ≥50% of total glomeruli with active or inactive diffuse, segmental, or global endocapillary or extracapillary glomerulonephritis 2
• The most severe proliferative form requiring aggressive immunosuppression with glucocorticoids and cytotoxic agents 1, 5
• The 2018 revision abandoned the segmental (IV-S) and global (IV-G) designations in favor of modified NIH activity and chronicity scoring indices 4
• The term "endocapillary proliferation" has been replaced with "endocapillary hypercellularity" to reflect that most hypercellularity is due to inflammatory cell influx rather than actual cell proliferation 4

Class V: Membranous Lupus Nephritis

• Characterized by global or segmental subepithelial immune deposits or their morphologic sequelae by light microscopy and immunofluorescence or electron microscopy 2
• When combined with Class III or IV, should be treated like proliferative disease 1
• Pure Class V with nephrotic-range proteinuria is treated with mycophenolic acid (MPA) or mycophenolate mofetil (MMF) at 2-3 g/day combined with glucocorticoids 3
• Maintenance immunosuppression should continue for at least 3 years after achieving response 3

Class VI: Advanced Sclerotic Lupus Nephritis

• Defined by ≥90% of glomeruli globally sclerosed without residual activity 2
• Generally requires preparation for renal replacement therapy rather than immunosuppression 1
• Represents irreversible end-stage kidney disease from lupus nephritis 5

Critical Diagnostic Requirements

Biopsy Processing Standards

• Renal tissue must be processed for light microscopy (LM), immunofluorescence (IF), and electron microscopy (EM) 1
• A minimum of 10 glomeruli is required for adequate evaluation 4, 1
• Light microscopy should include H&E, PAS, Masson's trichrome, and silver stains 1
• Immunofluorescence must evaluate IgG, C3, IgA, IgM, C1q, κ and λ light chains 1

Activity and Chronicity Indices

• Activity index (AI) evaluates fresh inflammatory and potentially reversible lesions, while chronicity index (CI) evaluates irreversible lesions such as sclerosis, tubular atrophy, and interstitial fibrosis 5
• High AI with low CI, particularly in Class IV, indicates need for aggressive treatment to preserve renal function 5
• High CI with low AI suggests irreversible sclerosing lesions where aggressive treatment may be unnecessary 5
• The 2018 revision proposes modified NIH activity and chronicity scoring indices to replace the previous A, C, and A/C designations for Classes III and IV 4

Important Clinical Pitfalls

Mixed Class Presentations

• Combinations of membranous and proliferative glomerulonephritis (Class III+V or Class IV+V) should be reported individually in the diagnostic line 2
• When Class V is combined with Class III or IV, treatment should follow the proliferative disease protocol 1

Clinical-Pathologic Discordance

• Similar clinical features may be observed despite very different classes of lupus nephritis 6
• In patients with nephrotic-range proteinuria, 55% had proliferative disease (Class III, IV, or mixed) while 36% had non-proliferative disease 6
• Clinical and serologic tests cannot accurately predict histological findings, making biopsy essential 1

Vascular and Tubulointerstitial Lesions

• The diagnosis should include entries for any concomitant vascular or tubulointerstitial lesions 2
• Lupus vasculopathy is defined as luminal narrowing of arterioles or terminal interlobular arteries by intramural immune deposits, typically with fibrinoid changes, without vessel wall inflammation 4
• Interstitial inflammation should be reported as occurring with or without interstitial fibrosis 4