January 28, 2021
Developing safe and effective treatments for lupus nephritis has been an urgent and long-standing goal in the lupus community. As the leading private funding agency for lupus research, the LRA and its legacy organizations have dedicated significant focus and resources towards addressing this continued challenge, awarding over 40 grants to address this unmet area of study.
Lupus Nephritis, a Serious and Common Complication
Lupus is a chronic, complex autoimmune disease that affects hundreds of thousands of people worldwide. In lupus, the immune system, which is designed to protect against infection, creates antibodies that can attack any part of the body including the kidneys, brain, heart, lungs, blood, skin, and joints. Kidney damage due to attacks by immune cells (lupus nephritis) is one of the most common complications of lupus, affecting as many as half of adults with lupus[i]. When the kidneys become inflamed, they can’t effectively get rid of waste products and other toxins from the body.
LRA Funding Contributes to Lupus Nephritis Breakthroughs
Over the past 20 years, the LRA has funded more than 40 research projects focused specifically on lupus nephritis, and their results have led to critical advances in understanding of lupus nephritis and therapeutic development for this condition. Following are highlights of key discoveries supported by the LRA:
- Dr. Chandra Mohan, at The University of Texas Southwestern Medical Center identified a molecule in the urine of lupus patients known as ALCAM (activated leukocyte cell adhesion molecule) that helps both activate disease-causing T cells and traffic to the kidney where they can unleash their destructive potential . He demonstrated that higher than normal levels of ALCAM could be detected in the urine of lupus patients compared to healthy controls and thus serve as a useful and non-invasive biomarker to track disease progression. This work is now partially aiding the repurposing of Equillium’s drug called itolizumab, for lupus nephritis. Itolizumab blocks ALCAM from binding with another molecule on T cells thus inhibiting activation and trafficking of disease-causing T cells and preventing damage to the kidney.
- Dr. Janos Peti-Petardi at the University of Southern California has utilized an innovative technology called intravital multifocal microscopy that allows scientists to view cells inside tissue and better understand the specific types of immune cells that cause damage in the kidney. Overcoming the common technical limitations of studying the kidney architecture has remained a major barrier to pushing the needle in lupus nephritis research. Dr. Peti-Petardi and his team demonstrated that resident kidney cells interacted with incoming immune cells and incited inflammation. His novel finding was that this interaction occurred because the kidney cells had a sticky layer, known as the glycocalyx. His work showed that targeting the glycocalyx would prevent the immune cells from interacting with the kidney cells thus preventing inflammation. Therefore, the glycocalx layer may be a viable candidate for therapeutic intervention.
- Dr. Joseph Craft at Yale University revealed significant insight into how nephritis develops when his team showed that the T cells that cause damage in the kidney have high levels of a protein on its surface known as HIF-1. HIF-1 allows those T cells to extend their survival, thus prolonging inflammation that damages the fragile vessels in the kidney. He found that repurposing an investigational cancer therapy called PX-478 lessened the symptoms of lupus nephritis in mice. This exciting finding suggests the potential for a multi-purpose drug that could treat lupus nephritis as well as certain types of cancer.
Looking Ahead to Future Discovery
The work in lupus nephritis must continue until enough treatment options are available to make personalized medicine a reality. Currently, the LRA is funding additional studies that will provide important insights in diagnosing, monitoring and treating lupus nephritis. Highlights underway include:
- Dr. Vicki Kelley at Harvard Medical School is studying how a protein expressed on some immune cells called Ptprz, contributes to kidney inflammation in nephritis patients. She and her team are determining if targeting this protein may protect the kidney from damage caused by inflammation.
- Dr. Erika Boesen at University of Nebraska is studying if a newly discovered type of cell death called ferroptosis contributes to kidney damage by promoting the inflammation that characterizes lupus nephritis.
- Dr. Jason Knight at the University of Michigan, is mapping out how turning off a protein called elastase could prevent kidney damage and other dangerous complications.
- Dr. Laurence Morel at University of Florida is testing combinations of sugar-reducing drugs like metformin, a drug widely used in diabetes, with the three approved lupus treatments to see whether they can slow down or reverse kidney damage in lupus models.
- Dr. Vipin Kumar at University of California San Diego is testing a novel hypothesis backed by his own preliminary data to explore a drug already used to fight tropical parasites as a potential oral medication to prevent and treat kidney damage in lupus.
- Dr. Jeremy Tilstra at University of Pittsburgh is figuring out how to exhaust T cells that typically cause damage in nephritis patients so they are too tired to attack the kidneys and other organs.
- Dr. Elena Wen-Yuan Hsieh at University of Colorado is using state-of-the-art technology to map, on a single cell level, the unique aspects of how lupus nephritis develops in pediatric patients
- Dr. Marcus Clark at the University of Chicago is using cutting-edge computer programs to analyze images from the kidneys of lupus patients to see which immune cells in each patient are interacting to cause inflammation. These different interactions might show how each patient will progress, and could be used to tailor more individualized therapies.
- Nir Hacohen at Harvard University has made significant headway in identifying the many cell types that play a role in the development of lupus nephritis. His team has identified what the cells look like as well as where and how they travel to the kidney to cause damage. This mapping system also allows scientists to better identify the shared immune responses between mice and humans, which will help scientists know which mouse models mimic the human response as closely as possible.
- Major advances in lupus nephritis research have been made through the collaborative efforts fostered through the Accelerating Medicines Partnership (AMP) for RA and SLE, a federal program the LRA supports as a key partner. The AMP SLE program is designed to provide a deep molecular characterization of kidney tissue, blood and urine samples from patients with lupus nephritis. Over 350 lupus patients have contributed to this program. Additionally, physicians are following these patients to see how their lupus nephritis responds to therapy. These studies are also designed to measure how well patients with lupus nephritis respond to their current medications, and if there are molecular pathways that can be linked with disease progression and response to therapy. This information may allow physicians to better treat their patients with current medications and enable discovery of new medicines.[ii]
- The LRA is also collaborating with the National Kidney Foundation on education programs for healthcare professionals to improve how lupus nephritis is diagnosed, monitored and treated lupus nephritis.[iv]
- In addition, Lupus Therapeutics, an affiliate of LRA, is conducting clinical trials to test the effectiveness of two potential lupus nephritis treatments — BMS-986165 from Bristol Myers Squibb and guselkumab from Janssen — through its Lupus Clinical Investigators Network, LuCIN. Another study, Dynamic Imaging of Variation in Lupus Nephritis (DIVINE) is comparing the effectiveness of non-invasive imaging to surgical biopsy of kidney tissue for monitoring the progression of lupus nephritis and its treatment.[iii]
This is a historic moment in lupus with two new drug approvals — Benlysta® and LupkynisTM for lupus nephritis in just over a month. Previously, there were no drugs specifically indicated for this common and serious complication of lupus. However, the LRA is committed to advancing research further to improve how lupus nephritis is diagnosed and monitored, as well as personalize treatment with additional treatment options to meet individual patients’ needs.
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[i] Lupus and Kidney Disease. (Lupus Nephritis). National Institute of Diabetes and Digestive and Kidney Diseases. Available at: https://www.niddk.nih.gov/health-information/kidney-disease/lupus-nephritis. Accessed June 3, 2019.
[ii] Good News on Lupus Nephritis Discoveries from ACR Convergence 2020. Lupus Research Alliance. Available at: https://www.lupusresearch.org/good-news-on-lupus-nephritis-discoveries-from-acr-convergence-2020/
[iii] Dynamic Imaging of Variation in Lupus Nephritis. Available at: https://clinicaltrials.gov/ct2/show/NCT03180021?term=DIVINE&draw=1
[iv] Lupus Research Alliance and National Kidney Foundation. New Survey Shows Education and Communication Gaps in Lupus Nephritis Care. Available at: https://www.lupusresearch.org/new-survey-shows-education-and-communication-gaps-in-lupus-nephritis-care/.