Uncovering the Molecular Signatures of Treatment Response in LN

Lupus nephritis (LN), or kidney inflammation, is one of the devastating and common complications of lupus and can worsen lupus severity and increase the risk of death. While recent FDA-approved treatments have shown promise, people with LN have a less than 50% chance of complete recovery of kidney function. Treating LN is made more challenging by an incomplete understanding of its development and progression. Surgical kidney biopsies are routinely performed to diagnose LN. However, it is less common for physicians to collect follow-up biopsies after standard treatment to assess the effectiveness of the treatment and how it impacted the kidney. Dr. Jackson will apply an innovative technique called spatial transcriptomics to previously obtained kidney biopsy samples collected before and after treatment to identify the cell types present in the kidneys associated with a response or resistance to immunosuppression.

Spatial transcriptomics is a groundbreaking tool used to measure the precise amount and location of gene activity down to the level of individual cells. It has not yet been applied to LN and, importantly, can be performed on biopsy samples already collected and stored. Dr. Jackson will apply spatial transcriptomics to kidney biopsy samples from people with LN before and after they have been treated with commonly used immunosuppressants like glucocorticoids. The dataset will include samples from people with LN who achieved remission (kidney improvement) after immunosuppression and those who did not. This will allow Dr. Jackson to assess the number and features of various immune cell types associated with response or resistance to treatment. Multiple areas of the kidneys are impacted in LN, highlighting that inflammation occurs across kidney regions. Dr. Jackson will apply this technology to these areas to identify molecular signatures, or features, associated with treatment response and uncover new cellular and molecular targets for treating LN.

What this study means for people with lupus

The application of this novel technique could transform LN treatment by allowing Dr. Jackson and his team to study cellular changes associated with remission versus persistent disease activity. Identifying features of cells able to resist immunosuppression could guide the design of improved treatments and reduce the risk of kidney failure for people with LN.

Despite recent FDA approval of new therapies to treat lupus nephritis, most patients fail to achieve clinical remission with standard-of-care treatment. This emphasizes the need for greater understanding of the pathophysiology of lupus nephritis, with the expectation that this knowledge will inform the development of effective, targeted therapies for lupus nephritis. To date, pre-clinical studies have typically used animal models to identify immune pathways driving disease, but these efforts have been plagued by limited correlation with clinical benefit in humans. For this reason, it is important to directly analyze human kidney tissue from lupus nephritis patients. However, two major limitations have plagued the field. First, although kidney biopsy is routinely used to diagnose lupus nephritis, physicians typically do not obtain repeat biopsies to assess treatment response. Thus, our understanding of the immune cells able to resist standard-of-care treatments is limited. Second, clinical biopsy tissue is not routinely processed in a manner that allows research using modern assays. To overcome these limitations, we propose leveraging a major technical advance to study lupus nephritis pathogenesis. Our approach involves a well-characterized clinical cohort, where an initial diagnostic kidney biopsy was followed by a second protocol biopsy after 6-12 months of induction immunosuppression. We will employ the innovative CosMx Spatial Molecular Imager (Nanostring, Inc.), which enables true single cell-resolution spatial transcriptomics and proteomics analysis of archived paraffin-embedded kidney biopsy tissue. By investigating the glomerular and tubulointerstitial spatial compartments and identifying immune cell and stromal signatures associated with treatment response and resistance, we expect to uncover novel cellular and molecular targets for the treatment of lupus nephritis.