THE OFFICIAL NEWS SOURCE OF ACR CONVERGENCE 2022 • NOVEMBER 10-14



Lupus nephritis research may find approaches that limit renal damage

Marcus Clark, MD

Kidney inflammation and fibrosis so often seen in patients with lupus is associated with adaptive immune responses in the tissue of the kidney. New data on the pathways leading to kidney injury in lupus nephritis suggest new therapeutic targeting approaches that may limit renal damage.

“Most people focus on glomerulonephritis when the glomeruli make up maybe 10 percent of the kidney,” said Marcus Clark, MD, Chief of Rheumatology at the Gwen Knapp Center for Lupus and Immunology Research at the University of Chicago. “We’re focusing on the tubulointerstitium, which makes up about 85 percent of the kidney, because that’s where most of the prognostically meaningful disease activity occurs. This growing focus on the tubulointerstitium is a shift from the past 40 to 50 years of work on the glomeruli.”

Dr. Clark will kick off the ACR symposium Lupus Nephritis: Immune Cell Networks and Pathogenesis, which takes place from 8:30 – 10:00 am Monday in Room W375a. The symposium will present state-of-the-art data on a variety of cellular and molecular interactions in the kidney and preview mechanistic insights from both animal models and human tissue that may inform translational research leading to potential therapeutic targets.

He noted that up to half of lupus nephritis patients with severe tubulointerstitial inflammation currently progress to renal failure within three to four years of diagnosis.

A clear need in lupus nephritis is effective treatment for tubulointerstitial inflammation that prevents progression to renal failure. A limitation in developing effective treatment modalities has been the continuing dependence on kidney biopsies qualitatively read by pathologists. Quantitative and independent methods for reading renal biopsies that capture prognostically meaningful histological features are needed. No matter how experienced the pathologist, current readings are more qualitative and can vary from pathologist to pathologist.

“We have developed tools that make the assessment of renal biopsies highly quantitative and unbiased,” Dr. Clark said. “We are using machine learning to usher in an era of quantitative pathology to identify the cells and processes that actually cause the tubulointerstitial damage that may be resistant to current therapies. Our goal is to understand that process so we can better develop targets.”

Dr. Clark’s lab has identified at least one previously unknown target, a major antigen presenting for T cells. Current results suggest that specific antigens could drive activation of T cells in the tubulointerstitium that results in inflammation, fibrosis, and renal failure.

Macrophages in the kidney also play a role in the pathogenesis of lupus nephritis.

Anne Davidson, MBBS
Anne Davidson, MBBS

“It has been known for quite a long time that if you biopsy the kidneys of lupus patients and they have a lot of macrophages, that tends to be associated with a poorer prognosis,” said Anne Davidson, MBBS, Professor, Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases at The Feinstein Institute for Medical Research and Professor of Molecular Medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.

“We’ve been asking what kind of macrophages are in the kidney, what is their function, and is there something we could do to alter their function that might be helpful to patients?”

Macrophages in the kidneys of both humans and mice with lupus tend to be more of the anti-inflammatory or reparative type that could foster fibrosis, Dr. Davidson said, but with additional proinflammatory characteristics. Her lab is accumulating evidence that may link specific types of macrophages with specific outcomes in both human and mouse models.

Janos Peti-Peterdi, MD, PHD, Professor of Physiology and Neurosciences and of Medicine and Director of the Multi-Photon Microscopy Core at the University of Southern California Keck School of Medicine, Los Angeles, CA, will explore the latest clues to the pathomechanisms of lupus nephritis using intravital multi-photon microscopy to visualize kidney tissues in action.

“We have seen some pretty novel data coming out of samples from humans with lupus nephritis,” Dr. Davidson said. “At the same time, we still do not have good treatments for this disease. This symposium will provide a solid review of what’s new in lupus nephritis and a look at what’s coming.”