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Dissecting the histological features of lupus nephritis highlights new common patterns of injury in class III/IV
  1. Maddalena Maria Bolognesi1,
  2. Giulia Capitoli2,
  3. Stefania Galimberti2,
  4. Giorgio Cattoretti1,3,
  5. Ingeborg Bajema4,
  6. Jan A Bruijn4,
  7. H Terence Cook5,
  8. Laure-Helene Noel6,
  9. Fabio Pagni1,3,
  10. Franco Ferrario3,
  11. Maria Wester Trejo4,
  12. Vincenzo L'Imperio1,3
  1. 1 Pathology, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
  2. 2 Bicocca Bioinformatics Biostatistics and Bioimaging B4 Center, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
  3. 3 Pathology Department, ASST Monza - San Gerardo Hospital, Monza, Italy
  4. 4 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
  5. 5 Department for Immunology and Inflammation, Centre for Inflammatory Disease, Imperial College London, London, UK
  6. 6 Department of Pathology, Necker Hospital, Paris, France
  1. Correspondence to Dr Maddalena Maria Bolognesi, Pathology, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, 20900, Italy; maddalena.bolognesi{at}


Objective The International Society of Nephrology/Renal Pathology Society classification is the gold standard for the characterisation of lupus nephritis (LN) on renal biopsy, with therapeutic repercussions. Its recent revision simplified the current class subdivisions, eliminating the S/G forms of class IV, although data on a possible pathogenetic/clinical value of this subdivision are still contradictory.

Methods 353 renal biopsies from Belimumab International Study in LN were assessed through central pathology review. Univariate logistic models and a decision tree were performed on 314 adequate biopsies to evaluate the impact of histological features on focal/diffuse classes. Removing class I/II (n=6) and ‘pure’ class V (n=34), principal component analysis (PCA) and heatmap were used to explore similarities among III, IVS and IVG biopsies either incorporating or not the mixed classes (+V, n=274). Finally, a method aimed at partitioning the cases into k clusters based on their similarity (KMeans), was used to study features from the cohort of ‘pure’ class III/IVS/IVG cases (n=214) to determine alternative subdivisions based on phenotypic data.

Results Segmental endocapillary hypercellularity (EH) was prevalent in class III, global EH, wire loops, hyaline thrombi and double contours were hallmarks of class IVG, with IVS cases showing intermediate characteristics. Heatmap and PCA confirmed the segregation of these features among classes, showing better segregation for focal/diffuse LN as compared with the mixed classes (+V). KMeans revealed the presence of two main clusters, membranoproliferative-like (n=83) or vasculitis-like (n=131).

Conclusions This study reveals new phenotypic forms of LN surpassing the traditional classes as determined by the current classification. Future validation and confirmation are required to confirm these findings.

  • Lupus Nephritis
  • Autoimmune Diseases
  • Lupus Erythematosus, Systemic

Data availability statement

Data are available on reasonable request.

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Data availability statement

Data are available on reasonable request.

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  • Handling editor Josef S Smolen

  • Twitter @FabioPagni1, @VLimperioMD

  • Contributors MMB and VL'I conceptualised the manuscript, writing a first draft, and coordinated the data collection during the renal biopsy scoring process. GCap and SG performed the statistical analysis. GCat and FP organised the local biopsy images acquisition and scoring activities and provided their support during the project. IB, JAB, HTC, FF and L-HN performed the renal biopsy scoring in the context of BLISS-LN trial. MWT critically revised the manuscript and provided English grammar revision. VL'I is the guarantor, coordinated the project and revised the final version of the manuscript. All the authors revised and approved the present form of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests IB, JAB, HTC, FF, L-HN received honoraria from GlaxoSmithKline (London, Great Britain) for their participation in the BLISS-LN trial as central review board.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.