Co-Investigator: Anne Davidson, MBBS
More than a third of people with lupus develop kidney disease that can lead to kidney failure. These individuals have inflammation and deposits of antibodies bound to other proteins at the glomerulus—the area of the kidney where filtration of the blood and urine formation takes place.
While treatment with drugs that suppress the immune response may reduce the inflammation and the amount of deposits, many people with lupus go on to develop scarring of the glomerulus, and kidney failure.
In his novel work, Dr. Mundel and colleagues set out to characterize the role of podocytes in lupus kidney disease, and the participation of a molecule called B7-1 in maintaining the normal structure of podocytes and their ability to carry out filtration.
Put another way, he and his team tested if B7-1 is a critical player in damaging podocytes, thereby inhibiting normal kidney function in lupus. Results may yield new methods for treating existing kidney disease in people with lupus.
Reported in New England Journal of Medicine, a new study stemming from research initiated by the LRI over a decade ago brings the promise of personalized medicine a critical step closer for those living with lupus. Researchers at Massachusetts General Hospital led by Dr. Mundel have identified the rheumatoid arthritis drug abatacept (Orencia®) as a personalized, targeted treatment for a common inflammatory kidney disease. The approach may be applicable to a range of other kidney diseases including lupus nephritis.
Targeting kidney cells with abatacept
Abatacept inhibits a protein called B7-1 that is found on immune cells and causes immune system activation. Because lupus is caused by a hyperactive immune system, researchers have zeroed in on the protein B7-1 as a potential target for treatment. Yet trials of abatacept in lupus patients, including those with lupus nephritis, have not been successful.
However, Dr. Mundel’s research suggests that it is worth looking again at abatacept to treat lupus nephritis. With his LRI Novel Research Grant, he discovered that in some patients with kidney disease, kidney cells called podocytes can also make B7-1. The protein stops the podocytes from performing their essential filtering function, leading eventually to kidney failure. So abatacept could prevent kidney damage by acting directly on kidney cells rather than on the immune system.
To test this concept, Dr. Mundel and his colleagues carried out a preliminary study in patients with a common kidney disease known as focal segmental glomerulosclerosis (FSGS).. Like lupus nephritis, FSGS is a chronic, inflammatory kidney disease with no cure or targeted treatment options. The team identified five FSGS patients who tested positive for B7-1 on their podocytes. Treatment with abatacept halted kidney damage in all five patients.
“My original hypothesis that the B7-1 produced by podocytes contributes to kidney damage was first funded by LRI, which was crucial to get me to ongoing substantial grant support from NIH”, explains Dr. Mundel.
"Thanks to that early support from LRI and subsequent support from NIH, we have identified abatacept as the first personalized, targeted treatment for kidney disease. We also identified B7-1 on podocytes as a biomarker that helps us discern which patients are most likely to benefit from therapy with abatacept."
These results need to be confirmed in a large-scale clinical trial. But they suggest that abatacept may be effective in lupus nephritis patients who have B7-1 on podocytes in their kidneys.
Abatacept in B7-1-positive proteinuric kidney disease. Yu CC, Fornoni A, Weins A, Hakroush S, Maiguel D, Sageshima J, Chen L, Ciancio G, Faridi MH, Behr D, Campbell KN, Chang JM, Chen HC, Oh J, Faul C, Arnaout MA, Fiorina P, Gupta V, Greka A, Burke GW 3rd, Mundel P. N Engl J Med. 2013 Dec 19;369(25):2416-23. doi: 10.1056/NEJMoa1304572. Epub 2013 Nov 8.
Induction of B7-1 in podocytes is associated with nephrotic syndrome. Reiser J, von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, Rastaldi MP, Calvaresi N, Watanabe H, Schwarz K, Faul C, Kretzler M, Davidson A, Sugimoto H, Kalluri R, Sharpe AH, Kreidberg JA, Mundel P. J Clin Invest. 2004 113(10):1390-7.
In 2004, Dr. Mundel won a $1.750 million grant from the National Institutes of Health funding to continue the research that he began with his LRI Novel Research Grant.