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Pathogenic cellular and molecular mediators in lupus nephritis

Nature Reviews Nephrology volume 19, pages 491–508 (2023)Cite this article

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Abstract

Kidney involvement in patients with systemic lupus erythematosus — lupus nephritis (LN) — is one of the most important and common clinical manifestations of this disease and occurs in 40–60% of patients. Current treatment regimens achieve a complete kidney response in only a minority of affected individuals, and 10–15% of patients with LN develop kidney failure, with its attendant morbidity and considerable prognostic implications. Moreover, the medications most often used to treat LN — corticosteroids in combination with immunosuppressive or cytotoxic drugs — are associated with substantial side effects. Advances in proteomics, flow cytometry and RNA sequencing have led to important new insights into immune cells, molecules and mechanistic pathways that are instrumental in the pathogenesis of LN. These insights, together with a renewed focus on the study of human LN kidney tissue, suggest new therapeutic targets that are already being tested in lupus animal models and early-phase clinical trials and, as such, are hoped to eventually lead to meaningful improvements in the care of patients with systemic lupus erythematosus-associated kidney disease.

Key points

  • Understanding of the cellular and molecular mechanisms underlying lupus nephritis (LN) is progressing rapidly, facilitated by new tools for advanced ‘omic’ analyses.

  • Increasingly fine immune cell profiling based on patterns of expression of cell surface markers and genes is defining T cell and macrophage subsets that are important in disease mechanisms.

  • Chromatin release and/or its ineffective clearance stimulate adaptive and innate immunity in LN.

  • Resident kidney cells, including podocytes, mesangial cells and tubular epithelial cells, participate actively in the pathology of LN.

  • Closer attention to technical aspects in trial design is driving successes in clinical trials in systemic lupus erythematosus and stimulating much additional interest in the rational design and application of novel LN therapies.

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Fig. 1: Pathogenic consequences of immunostimulatory DNA in systemic lupus erythematosus and lupus nephritis.
Fig. 2: Sources of immunostimulatory DNA in systemic lupus erythematosus and lupus nephritis.
Fig. 3: Overview of pathogenic mechanisms in LN and potential therapeutic targets.

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Authors and Affiliations

  1. Department of Biomedical Engineering, University of Houston, Houston, TX, USA

    Chandra Mohan

  2. Division of Rheumatology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Ting Zhang

  3. Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel

    Chaim Putterman

  4. Division of Rheumatology and Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA

    Chaim Putterman

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  1. Chandra Mohan
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All authors researched data for the article, made substantial contributions to discussions of the content and wrote, reviewed or edited the manuscript before submission.

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Correspondence to Chandra Mohan or Chaim Putterman.

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Competing interests

C.P. is one of the holders of a patent describing the diagnostic use of urinary TWEAK in lupus nephritis (Method of treating lupus nephritis; Grant US-9730947-B2). C.M. and C.P. serve as scientific consultants to Equillium, which is developing anti-CD6 as a therapy for lupus nephritis. The other author declares no competing interests.

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Mohan, C., Zhang, T. & Putterman, C. Pathogenic cellular and molecular mediators in lupus nephritis. Nat Rev Nephrol 19, 491–508 (2023). https://doi.org/10.1038/s41581-023-00722-z

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