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Lupus nephritis: lessons from murine models

Nature Reviews Rheumatology volume 6, pages 13–20 (2010)Cite this article

Abstract

Lupus nephritis is a challenging clinical condition for which current therapies are unsatisfactory with respect to both remission induction and unwanted toxic effects. Despite intervention, the rates of end-stage renal disease seem to be increasing in the USA. Discoveries over the past decade have greatly improved our understanding of immune activation and effector inflammatory pathways in lupus nephritis; however, this increased understanding has not yet translated into the approval of an effective new therapeutic agent. An analysis of the mechanisms of action of novel immunomodulatory drugs in multiple models of murine lupus clearly shows that interacting networks of immune and effector pathways are recruited as the disease progresses. Reversing established disease by targeting a single cell population or inflammatory pathway is, therefore, difficult once long-lived autoreactive lymphocyte populations are present and peripheral organs are inflamed. Data from murine models of lupus suggest that we need to consider new paradigms for the management of systemic lupus erythematosus that include earlier immune intervention, long-term maintenance therapies and protection of target organs.

Key Points

  • The incidence of end-stage renal disease resulting from lupus nephritis is static or increasing in the USA

  • Several high-profile clinical trials of novel biologic therapies for lupus nephritis that target the immune system have failed despite convincing evidence that lupus nephritis is immune-mediated

  • Although inhibition of single cell types or inflammatory mediators can prevent disease in murine models of lupus, the efficacy of this approach is substantially lower in established disease

  • Multiple interactions between innate and adaptive immune pathways in established disease amplify inflammation and make it difficult to restore normal tolerance

  • An understanding of the pathways that mediate intrinsic renal cell activation, interstitial renal inflammation, renal hypoxia and fibrosis should yield new strategies for protection of the kidneys

  • The role of genetic polymorphisms in determining susceptibility to systemic lupus erythematosus and to renal damage might enable targeting of therapies to particular subgroups of patients

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Figure 1: Pathogenesis of lupus nephritis.
Figure 2: Dysregulated immune responses in SLE.

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  1. Center for Autoimmune and Musculoskeletal Diseases, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, 11030, NY, USA

    Anne Davidson & Cynthia Aranow

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C. Aranow declares that she has acted as a consultant for and/or received research support from the following companies: Amgen, Bristol-Myers Squibb, Genentech, Human Genome Sciences, La Jolla Pharmaceutical, Medimmune, Novo Nordisk and UCB.

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Davidson, A., Aranow, C. Lupus nephritis: lessons from murine models. Nat Rev Rheumatol 6, 13–20 (2010). https://doi.org/10.1038/nrrheum.2009.240

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