Lupus Research Institute Funds Innovative Studies on Kidney Disease—A Major Complication for Americans with Lupus

March 1, 2006, New York, NY – The nation observes Kidney Month in March, drawing attention to the importance of keeping these crucial fist-sized organs as healthy as possible. For the many Americans with well-established risk factors for kidney disease such as diabetes and obesity, the month will be a time to reflect on lifestyle and other health changes they can make.

But for the 1.5 million Americans with the chronic autoimmune disease, systemic lupus erythematosus (lupus), the month is a painful reminder that no matter what healthy living habits they follow, they are still at risk for developing potentially life-threatening kidney inflammation called nephritis. About a third of people with lupus suffer this complication, with some eventually requiring renal dialysis because the kidneys, which are crucial among other things for filtering wastes and balancing body fluids, essentially stop working.

The Lupus Research Institute: Pursuing a Cure

Currently, people with lupus kidney involvement have few options. "Lupus nephritis is potentially life-threatening and the medications that we use to treat it have significant and often debilitating side effects," says Lupus Research Institute President Margaret Dowd. "We need some answers, and we need them soon."

The Lupus Research Institute is working to make that happen. Over the past five years, the Institute has funded more than 55 cutting-edge, 3-year novel research projects in lupus. Much about this devastating disease, in which the body's immune system forms antibodies that attacks various tissues and organs, remains a mystery.

Nearly all of the research grants shed light on the autoimmune response that causes kidney problems in lupus, and eight currently funded studies focus directly on this topic. The grants pursue ideas that look at lupus nephritis in a new way. They represent the kind of bold, out-of-the-box thinking that characterizes the genius and promise of novel research.

"The Lupus Research Institute is willing to take a gamble on ideas which have the potential to really cut new ground," notes William E. Paul, MD, chief of the Laboratory of Immunology, NIAID-NIH.

Adds grant recipient Elahna Paul, M.D., Ph.D., at Massachusetts General Hospital in Boston, "The state of the art now is unfortunately a catch-up game. We start treating someone after they have the disease, but if we can diagnose it earlier, we can test therapeutic modalities that are less toxic and more likely to have an effect earlier in the disease process."

Hunting for New Ways to Track Kidney Problems

Three studies are looking at early markers (called "biomarkers") that signal the development or worsening of kidney disease in people with lupus. Biomarkers are urgently needed, as people with lupus often undergo grueling biopsies in which a small piece of their actual kidney is taken for analysis. Unfortunately these tests often give false or misleading results, have to be done repeatedly, and are not always safe.

Lupus Research Institute grant recipient Anne Davidson, M.D., at Columbia University in New York City, is examining whether inflammatory molecules in the urine of mice can similarly indicate nephritis onset or remission in humans. Her team has found a drug that reverses lupus nephritis in mice by blocking the activation of damage-inducing T and B cells. "We are already at the bedside," Dr. Davidson says. "If the [drug] combination works, it may be available to treat kidney involvement in lupus in three to five years."

Also at Columbia University, Robert Winchester, M.D., is using his grant to see if a particular pattern of gene activity in immune system cells he has identified as indicators of injury in kidney tissue, taken through biopsy, also appears in the blood. Hopes are high that he is on track, so that a blood test for these biomarkers can be developed to watch for kidney problems, rather than subjecting people with lupus to repeated biopsies. Grant recipient Hanno Richards, M.D., at the University of Florida in Gainesville is also testing for an "early indicator" of lupus kidney damage that can be measured through blood and urine tests. His study looks at certain molecules produced by immune system cells that lead to kidney damage.

Funding Research on How and Why Lupus Damages the Kidneys

Lupus Research Institute grant recipient Marcus Clark, M.D., at the University of Chicago has found activated immune system "B cells" in lupus kidney biopsy tissue. Dr. Clark is asking whether these B cells are promoting inflammation by secreting abnormal antibodies directly in the kidney, or possibly by helping to trigger autoreactive T cells (another type of immune system cell). Dr. Clark will piece together a potentially revealing picture-a molecular profile-of the kidney B cells in lupus.

Other researchers suspect T cells rather than B cells are to blame in lupus kidney disease. With Lupus Research Institute funding, Peter Mundel, M.D., at the Mount Sinai School of Medicine in New York City is working on an intriguing concept that the specialized kidney cells that perform blood filtering functions may be the target of autoreactive T cells that get into the organ and start reorganize the cell structure there. He is looking at the contribution of the molecule (known as B7-1) to kidney damage in lupus-prone mice.

Grant receipient Neil Greenspan, M.D., Ph.D., at Case Western Reserve University in Cleveland has bred lupus-prone mice that lack a certain type of functional antibody he suspects is involved in the kidney inflammation of lupus. If he is on track, testing for ways to block the antibody in humans is just a few steps away.

In Boston, Elahna Paul, M.D., Ph.D, at Massachusetts General Hospital is exploring the novel idea that once kidney inflammation has been triggered, kidney cells contribute to their own eventual destruction by multiplying and secreting inflammatory factors. Her findings could lead to new treatments that block kidney cell activation and prevent kidney failure in lupus—even in the presence of an ongoing autoimmune response.

And at the University of Virginia in Charlottesville, Umesh Deshmukh, Ph.D, is similarly challenging the idea that abnormal antibodies are the lone players in causing lupus kidney damage. Using lupus-prone mice, Deshmukh is investigating whether it is antibodies alone that form the basis for kidney disease in lupus, as well as where, when, and how T cells come into play.

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