SGLT2 inhibition as a novel treatment for lupus nephritis

Lupus nephritis – inflammation in the kidneys caused by lupus – affects 40 to 70 percent of patients. Since current therapies target inflammation but do not stop kidney scarring or fibrosis, up to 30 percent of lupus nephritis cases develop into end-stage renal disease. Dr. Anolik believes that a class of drugs currently approved to treat type 2 diabetes – sodium-glucose cotransporter-2 (SGLT2) inhibitors – could improve lupus nephritis and reduce kidney damage. SGLT2 inhibitors have successfully prevented cardiovascular and kidney complications in patients with chronic kidney disease but have not been tested in lupus nephritis patients.

With LRA’s Lupus Mechanisms and Targets Award, Dr. Anolik will first study the effects of SGLT2 inhibitors in lupus mice.  The researchers will use state-of-the-art techniques to explore the complex interactions between nephritis disease progression, rogue immune cells stimulating lupus progression, tissue hypoxia (inadequate oxygen supply, and kidney injury. They will then test whether SGLT2 inhibitors improve kidney outcomes in patients with lupus nephritis.

What this study means for people with lupus

This research will speed up the potential clinical use of SGLT2 inhibitors in lupus nephritis patients and identify new potential treatment targets by providing novel information about how lupus nephritis disease progresses.

Despite the recent approval of new lupus therapies, there is still a significant unmet need for patients with lupus nephritis (LN). LN affects 40-70% of lupus patients, and 5-30% of them can progress to end-stage renal disease (ESRD). ESRD has a detrimental impact on the quality of life of lupus patients and represents a significant burden on the public health system. Further, available therapies target inflammatory pathways but have little impact on fibrosis or chronicity. Another critical unmet need in lupus is the lack of reliable biomarkers for predicting disease progression and response to therapy. Sodium and glucose cotransporter two inhibitors (SGLT2i) successfully prevent cardiovascular and renal adverse outcomes in patients with chronic kidney disease. However, their therapeutic potential in LN is unknown. Thus, the central objectives of this proposal are to 1) Test the therapeutic efficacy of SGLT2i in modulating hypoxia-driven tubule-interstitial fibrosis and pathogenic CD8 T cells. 2) Determine the relationship between renal hypoxia and pathogenic CD8 T cells in LN disease progression and treatment response. 3) Provide a proof of concept for the role of SGLT2i in LN patients for renal protection. Our central hypothesis is that SGLT2i will reduce renal hypoxia, decreasing proinflammatory/profibrotic HIF-1a and increasing reno-protective HIF-2a, shifting away from a pathogenic CD8 T cell effector profile, thus ameliorating renal injury and inflammation in lupus nephritis. This will be tested via the following specific Aims:
Specific Aim 1. Test the efficacy and mechanism of action of SGLT2i in LN in lupus prone mice. We will treat mice at early and more advanced stages of disease with SGLT2i and elucidate the complex interplay among SGLT2, hypoxia-induced factors and pathogenic CD8 T cells in the kidneys using a variety of experimental approaches including spatial transcriptomics.
Specific Aim 2. Examine the relationship between renal hypoxia, pathogenic CD8 T cells, and disease progression in LN patients. We will enumerate CD8 T cells in the LN kidney using the single-cell analysis from the Accelerating Medicines Partnership Phase 2 cohort. SGLT2 expression, HIF-1 expression, HIF-1–dependent gene-regulated pathways, and pro-fibrotic pathways will be evaluated and related to renal histology and longitudinal outcomes available up to 52 weeks. We will initiate a case control study of LN patients starting SGLT2i therapy as standard of care with longitudinal analysis of clinical parameters, CD8 T cells, and blood and urine biomarkers.
Completing our proposal will have significant implications for lupus patients as it will accelerate the evaluation of SGLT2i in LN clinical trials. Further, elucidating the relationship between renal hypoxia, pathogenic cell types, and fibrotic pathways in LN using state-of-the-art approaches can identify new treatment targets.