What is the International Society of Nephrology/Renal Pathology Society (ISN‑RPS) classification of lupus nephritis and the recommended treatment for each class?

ISN/RPS Classification of Lupus Nephritis

The International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification divides lupus nephritis into six histologic classes (I–VI) based on glomerular involvement patterns, immune deposit location, and degree of inflammation or sclerosis, with each class requiring distinct treatment approaches ranging from no immunosuppression to aggressive combination therapy. 1, 2

Classification System Overview

The ISN/RPS classification provides a standardized framework that directly guides treatment intensity based on pathologic findings. 3 The 2018 revision clarified definitions and eliminated certain subdivisions that showed poor inter-observer agreement. 4

Class I: Minimal Mesangial Lupus Nephritis

• Pathology: Mesangial immune deposits visible only on immunofluorescence or electron microscopy, without mesangial hypercellularity or leukocyte influx. 4, 1
• Treatment: No immunosuppressive therapy required; supportive care only. 1

Class II: Mesangial Proliferative Lupus Nephritis

• Pathology: Mesangial immune deposits with mesangial hypercellularity (≥4 mesangial cells fully surrounded by matrix) but no capillary involvement or leukocyte influx. 4, 2, 3
• Treatment: Generally does not require immunosuppressive treatment. 1
• Caveat: Rare cases may present with nephrotic syndrome despite mesangial-only disease, requiring individualized assessment. 5

Class III: Focal Lupus Nephritis

• Pathology: Active or inactive focal, segmental, or global endocapillary or extracapillary glomerulonephritis involving <50% of total glomeruli, with subendothelial immune deposits. 4, 3
• 2018 Revision: Eliminated segmental versus global subdivisions due to poor reproducibility; now reports active versus sclerotic lesions instead. 2
• Treatment: Aggressive immunosuppression with glucocorticoids plus either:
  • Mycophenolic acid analogs (2–3 g/day), OR
  • Low-dose intravenous cyclophosphamide, OR
  • Belimumab added to either MPAA or cyclophosphamide, OR
  • MPAA plus calcineurin inhibitor (if eGFR ≥45 ml/min/1.73 m²). 2

Class IV: Diffuse Lupus Nephritis

• Pathology: Active or inactive diffuse, segmental, or global endocapillary or extracapillary glomerulonephritis involving ≥50% of total glomeruli. 4, 1, 3
• 2018 Revision:
  • Replaced "endocapillary proliferation" with "endocapillary hypercellularity" to reflect inflammatory cell influx rather than true proliferation. 2
  • Eliminated routine IV-S (segmental) versus IV-G (global) subdivisions due to lack of reproducibility and weak clinical significance. 4, 2
  • Research suggests IV-G lesions associate with higher immune-complex burden, while IV-S shows more fibrinoid necrosis. 2
• Treatment: Same aggressive regimens as Class III (see above). 1, 2
• Prognostic Note: Presence of chronic lesions (Class IV with A/C designation) predicts worse renal outcomes and persistent proteinuria despite therapy. 6

Class V: Membranous Lupus Nephritis

• Pathology: Global or segmental subepithelial immune deposits or their sequelae, with or without mesangial alterations, visible by light microscopy and immunofluorescence. 4, 3
• Treatment Strategy:
  • When combined with Class III or IV: Treat as proliferative disease using Class III/IV regimens. 1, 2
  • Pure Class V with nephrotic-range proteinuria: Warrants immunosuppressive therapy. 1
  • Pure Class V without nephrotic syndrome: May be approached differently with less aggressive therapy. 1

Class VI: Advanced Sclerosing Lupus Nephritis

• Pathology: ≥90% of glomeruli globally sclerosed without residual activity. 1, 3
• Treatment: Preparation for renal replacement therapy rather than immunosuppression, as irreversible fibrosis predominates. 1
• Note: Rarely encountered and may require re-evaluation or removal from future classification schemes. 2

Combined Classes

Mixed proliferative and membranous disease (Class III+V or IV+V) should be reported individually in the diagnostic line and treated according to the proliferative component. 1, 3

Essential Biopsy Requirements

An adequate renal biopsy must include: 1, 2, 7

• Minimum 10 glomeruli for reliable evaluation
• Light microscopy with H&E, PAS, Masson's trichrome, and silver stains
• Immunofluorescence for IgG, C3, IgA, IgM, C1q, κ and λ light chains
• Electron microscopy for ultrastructural evaluation

Activity and Chronicity Assessment

The 2018 revision modified the National Institutes of Health (NIH) activity and chronicity indices: 4

• Fibrinoid necrosis (fibrin with GBM disruption/mesangial matrix lysis) should be specifically noted in Classes III and IV, as it may represent a pathogenetically distinct lesion. 4
• Karyorrhexis is defined as apoptotic, pyknotic, and fragmented nuclei. 4
• Activity and chronicity scoring should be applied to all classes, not restricted to III and IV. 4

Critical Clinical Pitfalls

• Never rely on clinical parameters alone: Serological and laboratory tests cannot accurately predict histological class or severity; biopsy remains mandatory. 1, 2, 7
• Do not delay biopsy for advanced GFR decline: Even with GFR <30 ml/min, perform biopsy if kidney size is normal and active disease is suspected, as superimposed active lesions may be treatable. 1
• Recognize regional presentation patterns: More than 60% of patients in some populations present at Class IV or higher, indicating need for earlier surveillance and biopsy. 8
• Assess chronicity carefully: The proportion of glomeruli with chronic lesions directly predicts treatment response and long-term renal function. 6