Noninvasive Optical Imaging of Glomerulonephritis
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women and is more common and severe in minority populations. The disease is characterized by the presence of antibodies (proteins that are produced by the immune system that can induce inflammation) against our own cellular components. Lupus nephritis (LN) is one of the most feared complications in SLE. LN occurs in the kidneys, an organ responsible for the filtering of blood and production of urine. LN occurs in about 50% of patients with SLE, and up to 30% of those with LN have end-stage renal disease requiring dialysis and/or kidney transplantation. The primary source of damage in LN is a process called glomerulonephritis (GN), or inflammation of the glomerulus. The glomerulus is a critical filtering structure in the kidney, and autoantibodies will bind to the glomerulus, which then drives a devastating inflammatory response. Numerous immune response pathways are activated, including a pathway known as the complement cascade. Complement activation is a central event in establishing GN, and it is considered a hallmark of LN. A major unmet need in LN is the identification of a noninvasive approach for detecting LN. Currently, there are no identified blood or urine tests that specifically reflect whether LN is present or not. Current standard parameters include assessing surrogates of complement activation, increases in autoantibody levels or markers of systemic inflammation, estimates of kidney function, and non-specific markers of glomerular injury (i.e., the presence of blood or protein in the urine). Improvement in standard parameters that are assessed happens slowly and may not be apparent for at least 6 months. Moreover, even if laboratory assessments revert to normal, repeat biopsy can reveal continued inflammation or progression of scarring in the kidney. Fluorescence molecular tomography (FMT) is an imaging approach that can monitor biologic processes in an intact, unmanipulated mouse that are detectable in the near-infrared spectrum of light. Thus, kidney imaging in mice is achievable without need for biopsy or extracting the kidney. This approach has already been applied in the experimental setting to detect cancers in humans, which represents an exciting application of this technology. Since LN is associated with numerous immunologic events and FMT provides the technical ability to noninvasively image these events within mouse kidneys, the early and late stages of experimental GN can be assessed with FMT using probes. We propose to monitor several well-established inflammatory events in GN to demonstrate proof-of-principle of this approach. Specifically, we will evaluate the sensitivity of FMT to detect complement split products (C3d), activated neutrophils (elastase) and macrophages (cathepsin B), and B cells (CD20). The impact of this proposal is significant. The identification of novel noninvasive methods to detect inflammatory changes in the kidney that can serve as a correlate for invasive renal biopsies. Additionally, this technology has the potential to monitor to therapeutic response and clinical outcome, which would be of enormous benefit to clinical trials and clinical care. Such tools would permit an earlier identification of responders and non-responders, thereby shortening the time of clinical trials. Since renal damage can progress even in individuals who are, by current definitions, classified as complete responders to therapy, recognition of ongoing renal inflammation in the absence of proteinuria or active urinary sediment would inform patient care and might prevent irreversible tissue damage.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710128
Entities
People
- Alfred Kim
Organizations
- United States Army
- Washington University in St. Louis