Classification of Lupus Glomerulonephritis: Five Years Later

Classification of Lupus Glomerulonephritis: Five Years LaterJ. Charles Jennette, MDClass I Class II Class IIIClass IV-GClass IV-SClass V

Who Classified Lupus Nephritis?“Original WHO Classification”Buffalo, NY, 1974; or Geneva, 1975“Modified WHO Classification”ISKDC, Paris, 1980 (Churg and Sobin, 1982)“Modified WHO Classification”Churg 1995

Appel, Silva, Pirani, et al,Medicine 57:371-410, 1978(“according to a classificaation proposed by the WHO”)Class I. NormalNormal by LM, EM and IFClass II. Mesangial ChangesA. Minimal alterations(normal by LM, mesangial deposits by IF and EM)B. Mesangial Glomerulitis(mesangial hypercellularity)Class III. Focal and Segmental Prroliferative Glomerulonephritisl (50% glomeruli involved)Class V. Membranous GlomerulonephritisPureMixed Patterns (such as Class III associated with Class V)

Post card sent from Ed Lewis to Mel Schwrtz while Ed Lewiswas at the 1980 ISKDC Meeting

Jacob Churg, 1982 (based on modifications at the ISKDC):“WHO Morphologic Classification of Lupus Nephritis”I. Normala. Nil (by all techniques)b. Normal by LM, but deposits by EM or IFII. Pure Mesangial Alterations (Mesangiopathy)a. Mesangial widening/mild hypercellularityb. Moderate hyperrcellularityIII. Focal Segmental Glomerulonephritisa. Active necrotizing lesionsb. Active and sclerosing lesionsc. Sclerosing lesioonsIV. Diffuse Glomerulonephritisa. Without segmental lesionsb., c., and d. like a., b. and c. aboveV. Diffuse Membranous Glomerulonephritisa. Pureb. Associated withcategory IIc. Associated withcategory IIId. Associated withcategory IVVI. Advanced Sclerosing Glomerulonephritis

Jacob Churg, 1995:WHO Morphologic Classification of Lupus Nephritis (modified)I. NormalA. Nil (by all techniques)B. Normal by LM, but deposits by EM or IFII. Pure Mesangial Alterations (Mesangiopathy)A. Mesangial widening/mild hypercellularityB. Moderate hypercellularitylIII. Focal Segmental GlomerulonephritisA. Active necrotizing lesionsB. Active and scleerosing lesionsC. Sclerosing lesionsIV. Diffuse GlomerulonephritisA. Without segmeental lesionsB., C., and D. like A., B. and C. aboveV. Diffuse Membranous GlomerulonephritisA. PureB. Associated with category IIVI. Advanced Sclerosing Glomerulonephritis50% cutoff betweenIII and IVV-C and V-Ddeleted.

Problems with the WHO Lupus Nephritis Classification•Different versions with no official peer-reviewed version•Lack of precise definitions of terms and criteria for different classes•Never validated for reproducibility•Unnecessary subcategorization based on mesangial hypercellularity•No guidance for classifying borderline lesions•Confusion about class III and claass IV•Uncertainty about how to classifysegmental necrotizing lesions•Different approaches to classifying mixed proliferative andmembranous lesions•Cumbersome designations for activity it and chronicityit

100Outcome of Lupus Nephritislity of Survivaal, %806040n=35WHO Class IV“WHO Class III (>50%)”Probabi202436WHOClass” Vc (>50%)” & Vd02 4 6 8 10 12 14 16 YearsKorbet, Lewis, Schwartz, et al., Am J Kidney Dis 35:904-914, 2000

urvival , %Pr robabili ity of S10080604020n=352436Outcome of Lupus NephritisMost renal pathologists t would classifyall of these as class IVWHOWHO Class IV“WHO Class III (>50%)”Class” Vc (>50%)” & Vd02 4 6 8 10 121416YearsKorbet, Lewis, Schwartz, et al., Am J Kidney Dis 35:904-914, 2000

ISN/RPS Working Group on the Classification of LupusGlomerulonephritisPATHOLOGISTS:Charles Alpers, U.S.A.Jan Bruijn, NetherlandsTerrence Cook, EnglandVivette D'Agati Agati, U.S.A.Franco Ferrario, ItalyAgnes Fogo, U.S.A.Gary Hill, ParisPrue Hill, AustraliaCharles Jennette, U.S.A.Lai-Ming Looi, MalaysiaLuiz Moura, BrazilMichio Nagata, JapanMelvin Schwartz, U.S.A.Surya Seshan, U.S.A.Jan J. Weening, NetherlandsCLINICIANS:Gerald Appel, U.S.A.James Balow, U.S.A.Ellen Ginzler, U.S.A.Lee Hebert, U.S.A.Norella Kong, MalaysiaPhillipe Lesavre, FranceMichael Lockshin, U.S.A.Hirofumi Makino, Japan

The Classification of Glomerulonephritis inSystemic Lupus Erythematosus RevisitedJan J. Weening, Vivette D. D’Agati, Melvin M. Schwartz, Surya V.Seshan, Charles E. Alpers, Gerald B. Appel, James E. Balow, Jan A.Bruijn, Terence Cook, Franco Ferrario, Agnes B. Fogo, Ellen M.Ginzler, Lee Hebert, Gary Hill, PrueHill, J. Charles Jennette, NorellaC. Kong, Philippe Lesavre, MichaelLockshin, Lai-Meng Looi, HirofumiMakino21, Luiz A. Moura, Michio Nagata, on behalf of theInternational Society of Nephrologyand Renal Pathology SocietyWorking Group on the classificationof lupus nephritisKidney Int 2004;65:521-530 and J Am Soc Nephrol, 2004;15:241-250

2004 ISN/RPS Consensus Conference on the Classification ofLupus GlomerulonephritisClass IMinimal mesangiallupus glomerulonephritis (LGN)Class IIClass IIIClass IVMesangial proliferative LGNFocal LGN (involvinng < 50% of glomeruli)Diffuse LGN (involving 50% or > glomeruli)Class IVSClass IVGPredominantly segmentalPredoominantly globalClass VClass VIMembranous LGNAdvanced scleroticLGN (> 90% sclerotic glomeruli)

ISN/RPS Classification ofLupus GlomerulonephritisClass I Class II Class IIIClass IV-GClass IV-SClass V

ISN/RPS Classification ofLupus GlomerulonephritisClass I Minimal mesangial lupus glomeruloonephritis. Normal glomeruli by lightmicroscopy, but mesangial immune deposits by immunofluorescence.Normal histologyMesangial stainingfor IgGMesangial electrondense immunecomplex deposits

ISN/RPS Classification ofLupus GlomerulonephritisClass II Mesangial proliferative lupus glomerulonephritis. Purely mesangialhypercellularity of any degree or mesangial matrix expansion by light microscopy, withmesangial immune deposits.There may be a few isolated subepithelial or subendothelial deposits visible byimmunofluorescence or electron microscopy,but not by light microscopy.SegmentalmesangialhypercellularityMesangial stainingfor IgGMesangial electrondense immunecomplex deposits

ISN/RPS Classification ofLupus GlomerulonephritisClass III Focal lupus glomerulonephritis. Active or inactive focal, segmental orglobal endo- or extracapillary glomerulonephrritis involving

Class IV Diffuse lupus glomerulonephritis. Active or inactive diffuse, segmental or globalendo- or extracapillary glomerulonephritis involving 50% or more of all glomeruli, typically withdiffuse subendothelial immune deposits, with orwithout mesangial alterations. This class isdivided into diffuse segmental (IV-S) lupus nephritis when 50% of the involved glomeruli havesegmental lesions, and diffuse global (IV-G) lupus nephritis when 50% of the involvedglomeruli have global lesions. IV-S and IV-G aredivided into (A): active lesions, (A/C): activeand chronic lesions, and (C): chronic inactive lesions with scars.Global injury (IV-G)Extensivesubendothelialelectron denseimmune complexdepositsSegmental injury (IV-S)Less immunoglobulinMinor electronsubendothelialdense immunecomplexdeposits

ISN/RPS Classification of Lupus GlomerulonephritisClass V Membranous lupus glomerulonephritis. Global or segmental subepithelialimmune deposits or their morphologic sequelaae by light microscopy and byimmunofluorescence or electron microscopy, with or without mesangial alterations.A diagnosis of both Class III & Class V or Class IV & Class V is given when there arecombined lesions.Thick capillary wallSegmentalmesangialhypercellularityGlobal granularcapillary wallstaining for IgGSubepithelialimmune complexdeposits

ISN/RPS Classification ofLupus GlomerulonephritisClass VI Advanced sclerosis lupus glomerulonephritis. 90% or more of glomeruliglobally sclerosed without residual activity. (ISN/RPS 2004)

Appel et al.78Churg82ISN/RPS04No lesion by LM,Class IClass IA No lupus GNIF or EMMesangial Class II A Class I Bdeposits but nohypercellularityMesangial Class II B Class II A,BhypercellularityFocal (50%) GNDiffuse (>50%)Proliferative GNClass IIIClass IVClass IVClass III A,B,CClass IV B,C,DMembranous Class V Class VMembranousplus ProliferativeClass V&IIIClass V&IVClass IV A,B,C,DClass VCClass VDClass IClass IIClass III A,A/C,CClass IVS A,A/C,CClass IVG A,A/C,CClass VClass III&VClass IV&V

Presenting clinical Manifestationss of Different ISN/RPS ClassesClinical I II IIIFeatureAsymptomatichematuriaAsymptomaticproteinurian=5 n=54 n=107 n=111 n=87 n=159 n=1840 19 222 4 6 5 040 42 257 6 13 0Nephrotic20 15 1740 38 65 11syndromeNephriticsyndromeAcute renalfailure0 20 3427 26 7 00 4 2Chronic renal0 0 0failureIV-G IV-S V VI18 16 2 04 8 8 89100 100 1000 100 100 100 100% % %% % % %Seshan S, Jennette JC. Renal disease in systemic lupus erythematosus with emphasis on classificationof lupus glomerulonephritis: advances and implications. Arch Pathol Lab Med 2009;133:233-48.

Comparison of ISN/RPS Class IV Segmental (S) and Global (G) VariantsNajafiMittal (2004)Yokoyama(2001)(2004)# of patients 24 S 35 G 11 S 22G 6 S 17 GSC Cr S>G G>S G = SProteinuria G > S G > S G = SHTN G>S G>S NRWireloops G > S G > S NRFocal necrosis S>G S>G NRCellularity G > S G > S NRAc index G = S G = S G > SChr index S > G G = S G > SWorse outcome S > G G = S S > GTrendFollow-up 10yrs 55-38mth 95-214 mthHillSchwartzKimHiramatsu(2005) (2007) (2008) (2008)15 S 31G 22 S 22 Q39 G12 S 30G 14 S 41GG> S G=Q=S G = S G = SG > S G=Q=S G > S G > SG>S G=Q=S G=S G=SG > S G>Q>S NRS>G G>Q>S NRG > S NR G > SG > S G=Q>S G = S G = SG > S Q>S>G G = S G = SG > S Q>S>G G > S G > STrend10yrs 10yrs 10yrs 10yrs

Lupus Sever Segmental Glomerulonephritis (SSGN, similar but not identical to IV-S)veersusLupus Diffuse Proliferatic Glomerulonephritis (DPGN, similar but not identical to IV-G)Number (%) of renal biopsy specimmens with the histologic finding:Behara VY, Whittier WL, Korbet SM, Schwartz MM, Martens M, Lewis EJ. Pathogenetic featuresof severe segmental lupus nephritis. Nephrol Dial Transplant. 2010;25:153-9.

Lupus Sever Segmental Glomerulonephritis (SSGN, similar but not identical to IV-S)veersusLupus Diffuse Proliferatic Glomerulonephritis (DPGN, similar but not identical to IV-G)Percent of glomeruli per of renal biiopsy with the histologic finding:Behara VY, Whittier WL, Korbet SM, Schwartz MM, Martens M, Lewis EJ. Pathogenetic featuresof severe segmental lupus nephritis. Nephrol Dial Transplant. 2010;25:153-9.

Lupus Sever Segmental Glomerulonephritis (SSGN, similar but not identical to IV-S)veersusLupus Diffuse Proliferatic Glomerulonephritis (DPGN, similar but not identical to IV-G)Peripheral IgG Staining by IFMSubendothelial Deposits by EMBehara VY, Whittier WL, Korbet SM, Schwartz MM, Martens M, Lewis EJ. Pathogenetic featuresof severe segmental lupus nephritis. Nephrol Dial Transplant. 2010;25:153-9.

ISN/RPS IV-S and IV-Gdoes not result in thesame classification asLewis-WHO III ≥ 50%and Lewis-WHO IVSchwartz MM, Korbet SM, Lewis EJ; Collaborative Study Group. The prognosis andpathogenesis of severe lupus glomerulonephritis. Nephrol Dial Transplant. 2008;23:1298-306.

ISN/RPS IV-S and IV-Gdoes not result in the same classification asLewis-WHO III ≥ 50%and Lewis-WHO IVRenal SurvivalISN/RPS IV-G (n=39)ISN/RPS IV-S (n=22)Lewis-WHO IIILewis “IV-Q” (n=22)≥ 50%(n=44)Schwartz MM, Korbet SM, Lewis EJ; Collaborative Study Group. The prognosis andpathogenesis of severe lupus glomerulonephritis. Nephrol Dial Transplant. 2008;23:1298-306.

Crescents are a marker of an aggressive variant of lupus GNincluding the Lewis-WHO III ≥ 50%Schwartz MM, Korbet SM, Katz RS, Lewis EJ. Evidence of concurrent immunopathologicalmechanisms determining the pathology of severe lupus nephritis. Lupus 2009;18:149-58.

Crescents are a marker of an aggressive variant of lupus GNincluding but not limited to the Lewis-WHO III ≥ 50%Schwartz et al “propose that diffuse global lupus GN with crescents is best describedas WHO class IV + WHO class III.”Schwartz MM, Korbet SM, Katz RS, Lewis EJ. Evidence of concurrent immunopathologicalmechanisms determining the pathology of severe lupus nephritis. Lupus 2009;18:149-58.

•The ISN/RPS Classificationwidespread acceptance andFive Years Later:System has garnereduse.•The ISN/RPS Classification System has resulted in ahigher level of interobserver reproducibility.•Multiple studies have found that lupus nephritis ISN/RPSClass IV-S has similar or better outcomes than lupusnephritis ISN/RPS Class IV-G.•Schwartz et al conclude thatt ISN/RPS class IV-S versusIV-G does not capture the major differences in prognosisand pathogenesis of severe lupus GN, and thus anotherround of classification adjustments is likely.

Anyone WHO ISN’t confusedreally doesn’t understand d thesituation.Edward R. Murrow