Key Points:

1. Histopathologic lesions that are highly characteristic of LN:

• IgG dominant “full house” glomerular deposits: IgG, IgA, IgM, C1q, and C3

• Glomerular deposits at multiple sites: subendothelial, intramembranous, trans membranous, subendothelial, and mesangial
• Extraglomerular deposits: tubular basement membranes, interstitium, blood vessels
• Prominent tubulo-reticular inclusions/structures
• Mesangial deposits are a prerequisite for the diagnosis of lupus nephritis.

2. The original ISN/RPS Classification of Lupus Nephritis (2004) was reviewed and key elements are included here (for the recently revised ISN/RPS classification from February 2018, see a summary at the end)

• Active sediment, proteinuria, nephrotic syndrome, impaired renal function, HTN, anti-dsDNA do not reliably predict lupus class and therefore require a biopsy.

3. Class I- Minimal mesangial LN

• normal glomeruli by LM but deposits in the mesangium by IF/EM
• Full house pattern on IF (characteristic in all LN classes)
• minimal clinical renal disease, therefore, these patients rarely undergo biopsy

4. Class II- Mesangial Proliferative LN

• Mesangial hypercellularity in association with mesangial immune deposits on IF/EM
• Any subendothelial deposits by LM or capillary wall immune deposits on IF exclude Class II and warrants Class III or IV designation.
• There should be no glomerulosclerosis as a result of pure mesangial deposition. If glomerulosclerosis is seen, then findings are no longer classified as a Class II-&gt. Distinguishing if the glomerulosclerosis is due to LN vs another unrelated issue (aging, hypertension, obesity, etc.) is based on the judgment of the pathologist.
• Clinical correlates: HTN uncommon, < 50% have microscopic hematuria and/or proteinuria (<1 g); Nephrotic syndrome and significant renal insufficiency are very rare and should prompt a search for another cause (eg. Podocytopathy).

5. Class III- Focal proliferative LN

• <50% of glomeruli have evidence of glomerular lesion (proliferation, necrosis, “wire loops”, Karyorrhexis, crescents) involvement by LM, although other glomeruli might have Class II mesangial lesions
• If the proliferation is very focal or the sample size is small, it may be misleading and lead to under calling the biopsy findings as a Class II LN.
• Combined Class III (or IV) and Class V requires extensive sub-epithelial deposits (in addition to the subendothelial deposits that characterize Class III/IV LN), defined as at least 50% of the glomerular capillary surface of at least 50% of glomeruli by LM or IF.
• Clinical correlates: variable, 1/3rd with HTN, hematuria/proteinuria in about 50%, decreased GFR in 25%, and nephrotic syndrome in about one 3rd

6. Class IV- Diffuse Proliferative LN

• >50% of glomeruli by LM
• Most common class seen (likely result of who clinicians decide to biopsy)
• Previously classified into segmental, IV-S or global, IV-G
  • IV-S: >50% of involved gloms have segmental lesions; IV-G: >50% of the involved gloms have global lesions
  • Controversy about whether the subdivision of class IV into segmental and global should continue exists [This is suggested to be eliminated in the new ISN/RPS classification from February 2018, see below]- historically evidence suggested that IV-S did worse clinically than IV-G
  • Clinical correlates: hematuria and proteinuria are present in virtually all patients, frequent nephrotic range proteinuria (~50%), HTN, reduced eGFR, hypocomplementemia (esp C3), elevated anti dsDNA levels

7. Class V- Membranous LN

• Global or segmental continuous granular subepithelial immune deposits, often with concomitant mesangial deposits/hypercellularity
• Scattered subendothelial deposits may be identified by IF or EM; if visible by LM, warrant a combined Class III or IV depending on the distribution.
• Clinical correlates: nephrotic syndrome, similar to idiopathic membranous nephropathy; microscopic hematuria and HTN may also be seen; sCr usually only slightly elevated or normal; up to one 3rd may present without extra-renal disease; may precede the diagnosis of SLE by months or years; may present with no other clinical or serologic manifestations of SLE (serologic markers may be negative)

8. Class VI- Advanced sclerosis LN

• At least 90% global glomerulosclerosis with clinical or pathologic evidence that the sclerosis is attributable to LN (can be challenging to determine)
• No evidence of ongoing active glomerular disease; usually marked IFTA

9. NIH Activity vs. Chronicity Index

• Can be more helpful with regards to treatment decisions; debate about reproducibility; present in new 2018 classification (see below).
• Activity index parameters (graded 0-3, total score 0-24): endocapillary hypercellularity, glomerular neutrophils, karyorrhexis/fibrinoid necrosis (x2), cellular crescents (x2), hyaline deposits (thrombi/wire loops), interstitial inflammation
• Chronicity index parameters (graded 0-3, total score 0-12): glomerular sclerosis, fibrous crescents, tubular atrophy, interstitial fibrosis
• Activity index >11 or Chronicity index >3 -> high risk of ESRD

10. Nonimmune complex Injury in SLE

• ANCA
  • Consider if scant immune complex deposits but fibrinoid necrosis and crescents.
  • Always check an ANCA when the necrotizing, crescentic disease is noted on biopsy.
• Podocytopathies
  • Can see Class II lesions on LM and on EM, but with massive podocyte effacement.
  • MCD or FSGS patterns of injury
  • Very difficult to diagnose MCD in addition to Class III, IV, V, as these can already be associated with podocyte effacement and proteinuria (esp. Class V)
• Antiphospholipid or cryoglobulin autoantibodies may promote thrombotic and inflammatory vascular lesions

11. Lupus vasculopathy- characterized by necrosis and IC that occlude the lumen of arterioles and small arteries, bad prognostic sign (seen esp in Class III and IV) (Gonzalez-Suarez ML, Lupus 2014)

It is important to note that the classification of the pathology of lupus nephritis has been subject to major modification as outlined by the ISN/RPS Working Group for lupus nephritis in their Phase 1 report in February 2018 (https://www.kidney-international.org/article/S0085-2538(17)30859-1/pdf 6). Key highlights from this report include:

• Reassessment of the threshold for what would be considered mesangial hypercellularity in class II lupus nephritis
• Elimination of the term “endocapillary proliferation” in favor of “endocapillary hypercellularity” to better reflect the nature of underlying pathology.
• A lower threshold to what degree of extracapillary proliferation would be considered “crescents” and the explicit inclusion of fibrin and fibrous matrix as components of the crescents.
• Detailed definition of cellular versus fibrous versus fibrocellular crescents
• A formal definition for what defines fibrinoid necrosis: “fibrin associated with glomerular basement membrane disruption and/or lysis of the mesangial matrix; this lesion does not require the presence of karyorrhexis”
• Elimination of segmental and global subdivision of class IV due to the lack of interobserver agreement and unclear clinical significance
• Elimination of the current dichotomous activity/chronicity designation (A, C, A/C) in favor of a more nuanced and quantitative grading through a modified NIH lupus nephritis activity/chronicity scoring system
• Inclusion of the tubulointerstitium as a compartment for assessment of inflammation and fibrosis