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Ma ł gorzata W ą growska-Danilewicz 1 , Marian Danilewicz 2

Clinicopathological  characteristics of segmental (IV-S) and global ( IV-G ) active subclasses of class IV lupus nephritis. Ma ł gorzata W ą growska-Danilewicz 1 , Marian Danilewicz 2 1 Department of Nephropathology , Medical University of Łódź , Poland

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Ma ł gorzata W ą growska-Danilewicz 1 , Marian Danilewicz 2

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  1. Clinicopathological characteristics of segmental (IV-S)and global (IV-G) active subclasses of class IV lupus nephritis • Małgorzata Wągrowska-Danilewicz1, Marian Danilewicz2 • 1 Department of Nephropathology, Medical University of Łódź, Poland • 2 Department of Pathomorphology, Medical University of Łódź, Poland Disclosurestatement: no conflict of interest

  2. Lupusnephritisoccursinup to 50%- 80% of SLE patients,usuallywithinthe first year of diseaseonset • Theclinicalmanifestation of SLE-associatedrenaldiseaseareextremelydiverse, rangingfromasymptomatic hematuria and proteinuria to fullnephroticsyndrome and rapidly progressive renalfailure • A kidneybiopsyisessentialinestablishingdiagnosis and prognosis, and guidingtreatment • Thepathologicmanifestations of renaldiseasein SLE patientsareheterogeneous, however most patientshaveimmune-mediatedglomerulardisease, withvariabletubulointerstitial and vascularlesions

  3. Class IV isthe most common form of activelupusnephritis • This class is divided into diffuse segmental (IV-S) lupus nephritis when ≥50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) lupus nephritis when ≥50% of the involved glomeruli have global lesions. • Segmental is defined as a glomerular lesion that involves less than half of the glomerular tuft • This definitions might cause misclassifications of the two subclasses because they are sensitive to sampling error: sample sizes are often small • Itissuggestedthat IV-S/A and IV-G/A lupusnephritishavedifferentpathogenesis • The data concerningoutcomeinpatientswith IV-S/A and IV-G/A arecontroversial, howeverinthemajority of studiesno significantdifferencesinoutcomesweredetected(Mittal et al. Am J Kidney Dis, 2004, Yokoyama et al. KidneyInt 2004, Catharina M et al. J AmSocNephrol, 2012, Grootscholten et al., NephrolDialTransplant, 2007).

  4. Activediffuseproliferativelupusnephritismaydemonstrate: • LM: • Wireloops • Hyalinethrombi • Endocapillaryhypercellularity • Mesangialhypercellurality • Necrotizinglesions • Cellularcrescents • IF : revealsdeposition of immunoglobulin and complementcomponentsinbothmesangium and intheperipheralcapillarywalls („full-housepattern”- staining of IgG, IgA, IgM and complementcomponents C1q, C3) • EM: revealsthepresence of subendothelialdepositisincapillaryloops, inmesangium, and occasionallyaccompanied by subepithelialdeposits.

  5. The purpose of the study was to compareinclassIVA/S LN and IVA/G LN • The clinical & laboratory data • Immunofluorescencefindings • Morphologicalglomerularactivefeatures

  6. Material - consisted of34 renalbiopsiesfromadultpatientswith IV ClasslupusnephritiswhounderwentrenalbiopsyinDepartment of NephropathologyinMedicalUniversity of Lodz. Patients 18 years of age and olderwho met four American College of Rheumatologycriteria for systemiclupuserythematosus (SLE) Renalbiopsyspecimenswereroutinelyprocessed by lightmicroscopy, immunofluorescence, and insomecases by electronmicroscopy. Criteria applied to thebiopsyspecimens: mnimalnumber of 10 glomeruli for LM analysis, and 5 glomeruli for IF analysis Thediffuseglomerularlesionsin IV Class LN werereclassifiedusingclassification ISN/RPS system (Weening et al. KidneyInt, 2004).

  7. Clinical & laboratory data We compared:

  8. Microscopicglomerularactivefeatures we compared

  9. Segmentalendocapillaryhypercellularity Segmentalnecrosis of glomerulartuft

  10. Cellularcrescent Segmentalactivefeatures

  11. Global features: wireloops, hyalinethrombi, hypercellularity Global activefeatures

  12. Immunofluorescencestudy

  13. Mesangial and paramesangialdeposits

  14. Subepithelialdeposits

  15. Statisticalanalysis • Thedifferencesbetweengroupswereassessedusingchi² test. • Results were considered statistically significant if P < 0.05. • Laboratory&clinical data: • Thepresence of hypertension • Nephroticsyndrome • Acuterenalfailure • Chronicrenalfailure • Proteinuria <2g/24h • Hematuria • Immunofluorescencefindings: • Strongmesangialstaining/orstrongperipheralwallstaining • Immunoglobulin: (IgG, IgA, IgM) and component of complement (C3, C1q) • Theintensity of immunoglobulin and complementcomponentstaining (0, +1, +2, +3) • Lightmicroscopy: • Endocapillaryhypercellularity • Cellularcrescents • Necrosis of glomerulartuft (disruption of capillarywall, fibrinoidnecrosis, karyorrhexis) • Hyalinethrombi • Wireloops

  16. RESULTS: Clinicalmanifestation of thedisease - thepercentage of patientspresentedwithchronicrenalfailure, acuterenalfailure, nephroticsyndrome, hematuria, proteinuria <0.2g/24h, and hypertensionin IV-S/A and IV-G/A group

  17. P<0.0001 Thepercentage of biopsieswiththedominance of mesangialorperipheralcapillarywallstainingin IV-S/A and IV-G/A group

  18. Thepercentage of biopsieswithIgG (0), IgG(+1), IgG(+2), and IgG(+3) stainingin IV-S/A and IV-G/A group

  19. Thepercentage of biopsieswithIgA (0), IgA(+1), IgA(+2), and IgA(+3) stainingin IV-S/A and IV-G/A group

  20. Thepercentage of biopsieswithIgM (0), IgM(+1), IgM(+2), and IgM(+3) stainingin IV-S/A and IV-G/A group

  21. Thepercentage of biopsieswith C3 (0), C3(+1), C3(+2), and C3(+3) stainingin IV-S/A and IV-G/A group

  22. Thepercentage of biopsieswith C1q(0), C1q(+1), C1q(+2), and C1q(+3) stainingin IV-S/A and IV-G/A group

  23. Thepercentage of biopsieswithfibrinoidnecrosis, hyalinethrombi, wireloops, cellularcrescents, capillarywalldisruption, karyorrhexis and endocapillaryhypercellularityin IV-S/A and IV-G/A group

  24. Summary: thecomparison – subclass IV-S/A LN vs. subclassIV-G/A LN • In IV–S/A LN: • More oftenhematuria and proteinuria <2g/24h • Thedominance of mesangialdeposits • Theintensity of Immunoglobulin staining was lowerin IV-S/A thaninIV-G/A group • High rate of fibrinoidnecrosis • Endocapillaryhypercellularity was less frequentlyfoundthaninIV-G/A group • In IV-G/A LN: • More oftennephroticsyndrome and hypertension • Thedominance of peripheralwallstaining • Theintensity of immunoglobulin staining was strongerinIV-G/A thanin IV-S/A group • Hyalinethrombi was detectedonlyinIV-G/A • WireloopsweremoreoftenfoundinIV-G/A thanin IV-S/A • Endocapillaryhypercellularity was moreoftenfoundinIV-G/A thanin IV-S/A

  25. Gao JJ et al. RheumatolInt 2012.Class IV-G had higher score of immunofluorescence index.Class IV-S had a higher percentage of glomerularfibrinoid necrosis • Monova D et al. ISRN Immunology 2011. The serum creatine levels, proteinuria. and diastolic blood pressure were significantly greater in the class IV-G. Histologically combined lesions with segmental endocapillary proliferation and fibrinoid necrosis were more frequent in the class IV-S. • Grootscholten C et al. Nephrol Dial Transplant 2008. More endocapillary proliferation and higher scores for wire loops were present in the biopsies categorized as class IV-G. • Hill GS et al. Kidney Int, 2005. Patients with IV-G lesions had worse proteinuria. Patients with class IV-G lesions had greater overall immune deposits and subendothelial deposits on IF and greater hyaline deposits on LM. By contrast, class IV-S showed predominant mesangial deposits and a much higher rate of glomerularfibrinoid necroses • Jourde-Chiche N et al. ClinNephrol 2011. Class IV-S and Class IV-G display very distinct histologic patterns, and may also have distinct pathogenic mechanisms. Class IV-S is associated with more frequent tuft necrosis, whereas Class IV-G may exhibit larger amounts of IgG deposition in the capillary wall, forming wire loops and hyaline thrombi. • Mittal B et al. Am J Kidney Dis 2004.The percentage of glomeruli with cellular crescents also was greater in the IV-S group, but the difference was not significant.

  26. Conclusions: • theclinicopathologicdifferencesin IV-S/A and IV-G/A LN, mayconfirmthesuggestion that these lesions have a different pathogenesis, • howeverourstudyhadseverallimitationincluding a smallnumber of patients. • Further studies should be conducted to clarify whether morphological and clinical differences between IV-S/A and IV-G/A lupus nephritis are important for predicting the course of disease and response to therapy

  27. Thanks for yoursattention

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