2009 Biomarkers, Kidney
2014 Kidney, New Treatments, Target Identification
Novel treatments for Lupus Nephritis
The study and what it means to patients
We aim to develop new drugs that would prevent kidney disease by specifically targeting the factors that cause kidney disease in patients with lupus. These drugs would not suppress the immune system in patients whose disease is inactive, and thus will be safer than current options for long-term use.
More than 50% of patients with lupus have renal (kidney) disease, known as lupus nephritis, and there is a risk that the kidneys may stop working altogether if lupus is not well treated. The current treatments for lupus nephritis include drugs that switch off the immune system and which can themselves cause serious and unwanted effects. Therefore, the need to find new ways to treat lupus nephritis is urgent.
Recent work suggests that a protein in the kidney of some patients with lupus called annexin A2 is associated with the development of kidney disease. We have discovered that annexin A2 acts like a switch, turning on a part of the body’s immune system called the complement system. It seems that production of annexin A2 within the kidney determines whether patients with lupus develop kidney disease or not. If we can block the effect of annexin A2 we should have a new way for preventing damage to the kidney. We aim to make new drugs that do exactly this and test whether they prevent kidney disease in mice that develop lupus-like disease. These drugs should not have any effect on patients who do not have kidney disease, so they should cause fewer problems in comparison to current options.
We propose to develop novel therapeutic agents for preventing glomerular inflammation in lupus nephritis. The severity of renal involvement is variable among patients with lupus, and the detection of complement activation in a renal biopsy predicts progression of the disease. Recent work has also shown that the complement regulatory protein factor H is critical for controlling complement activation within the glomerulus in lupus. The protein annexin A2 is specifically expressed within the glomeruli of patients and mice with lupus nephritis, and we have generated preliminary data demonstrating that annexin A2 blocks factor H from regulating complement within the glomerulus. We hypothesize, therefore, that annexin A2 is a critical factor in the development of renal inflammation and injury in patients with lupus. We will develop antagonists of the annexin A2-factor H interaction in order to prevent complement activation by annexin A2, and will test these agents in a model of lupus nephritis. Because annexin A2 expression within the glomerulus is specific for active lupus nephritis, antagonists of this interaction will have minimal effect in patients with quiescent disease. These agents will have fewer side effects than standard immunosuppressive drugs and will be safe for long-term administration.
Non-Invasive Assessment of Lupus Nephritis
An invasive kidney biopsy is currently the only accurate way to determine what’s going on in the kidneys of people with lupus nephritis (inflammation). A precise diagnosis is necessary in order to distinguish those patients that need to be subjected to aggressive but potentially lifesaving treatment from those patients at less risk for serious problems. Although generally safe, a kidney biopsy usually requires an overnight stay in the hospital, and complications do occur.
With funding from LRI, Dr. Thurman and his colleagues developed a novel diagnostic tool, known as an MRI contrast agent, that makes it possible to see lupus kidney damage using MRI. The agent detects proteins deposited in the kidneys as part of the immune system’s attack, which then serves as a biomarker for disease. MRI scans of lupus mice injected with the agent showed a correlation between the amount of these proteins and the severity of kidney inflammation in early and mid-stages of disease. Using a biomarker to monitor disease may substitute for biopsy.
Results just published in the October 1 issue of Kidney International show that a novel investigational contrast agent he developed, when used with magnetic resonance imaging (MRI), can detect proteins in the kidney that indicate disease.
Dr. Thurman noted, “In addition to being potentially safer, the MRI approach should be more sensitive than biopsy by looking at the entire kidney rather than just a small sampling. MRI also could be used to track a patient’s disease over time and to measure response to treatment in a clinical trial. Based on these encouraging results, we plan to investigate the agent in lupus patients.”
“This project directly addresses the difficulties that I (and all nephrologists) face when trying to decide how much immunosuppression patients with kidney disease need. The methods we are working on, however, will also require the input of radiologists, chemists, and lots of expertise outside the research conducted in my laboratory. This funding will be invaluable in giving me the opportunity to bring this expertise together, and I think it will really permit us to develop a new and powerful diagnostic tool.”
Detection of glomerular complement C3 fragments by magnetic resonance imaging in murine lupus nephritis. Sargsyan SA, Serkova NJ, Renner B, Hasebroock KM, Larsen B, Stoldt C, McFann K, Pickering MC, Thurman JM. Kidney Int. 2012 Jan;81(2):152-9. doi: 10.1038/ki.2011.332. Epub 2011 Sep 28.