Lupus Nephritis from Pathogenesis to New Therapies: An Update

Abstract

Lupus Nephritis (LN) still represents one of the most severe complications of Systemic Lupus Erythematosus (SLE) and a major risk factor for morbidity and mortality. However, over the last few years, several studies have paved the way for a deeper understanding of its pathogenetic mechanisms and more targeted treatments. This review aims to provide a comprehensive update on progress on several key aspects in this setting: pathogenetic mechanisms of LN, including new insight into the role of autoantibodies, complement, vitamin D deficiency, and interaction between infiltrating immune cells and kidney resident ones; the evolving role of renal biopsy and biomarkers, which may integrate information from renal histology; newly approved drugs such as voclosporin (VOC) and belimumab (BEL), allowing a more articulate strategy for induction therapy, and other promising phase III-immunosuppressive (IS) agents in the pipeline. Several adjunctive treatments aimed at reducing cardiovascular risk and progression of chronic renal damage, such as antiproteinuric agents, represent an important complement to IS therapy. Furthermore, non-pharmacological measures concerning general lifestyle and diet should also be adopted when managing LN. Integrating these therapeutic areas requires an effort towards a holistic and multidisciplinary approach. At the same time, the availability of an increasingly wider armamentarium may translate into improvements in patient's renal outcomes over the next decades.

Keywords: belimumab (BEL); biomarker; chronic kidney disease (CKD); end-stage renal disease (ESRD); immunosuppressive (IS) therapy; lupus nephritis (LN); pathogenesis; renal biopsy; systemic lupus erythematosus (SLE); voclosporin (VOC).

Figure 1

Different epigenetic mechanisms mediate the impact of environmental factors in predisposing to loss of tolerance in LN (created with BioRender.com). Legend. miR—microRNA; siRNA—small interfering RNA; lncRNA—long non-coding RNA.

Figure 2

Main mechanisms of damage by nephritogenic immune complexes (IC): deposition in glomeruli and interstitium and direct activation of innate immunity cells such as plasmacytoid dendritic cells (pDC) (created with BioRender.com).

Figure 3

Activated or damaged renal tubular epithelial cells exert important immunological effects in LN (created with BioRender.com). Legend. TECs—tubular epithelial cells; BAFF—B cell activating factor; MHC—major histocompatibility complex; TLS—Tertiary lymphoid structures; TCR—T cell receptor; IFN—interferon.

Figure 4

Timeline of the development of main immunosuppressants employed in treatment of SLE and LN (created with BioRender.com). Legend. GC—glucocorticoid; CYC—cyclophosphamide; CsA—Cyclosporin A; AZA—Azathioprine; TAC—Tacrolimus; MMF—mycophenolate mofetil; RTX—Rituximab; BEL—Belimumab; VOC—voclosporin; JAK—Janus Kinase; mTOR-i—mammalian target of rapamycin inhibitor.

Figure 5

Different mechanisms of action of immunosuppressants used in SLE treatment (created with BioRender.com). Legend. CNI—calcineurin inhibitor; CYC—cyclophosphamide; MMF—mofetil mycophenolate; BAFF—B cell activating factor; APRIL—a proliferation-inducing ligand.