Uncovering the Circulating Factor in FSGS
Abstract
Focal segmental glomerulosclerosis (FSGS), a specific area of encouragement within the Fiscal Year 2017 Peer Reviewed Medical Research Program Topic Areas, is one of the most common causes of kidney failure in early adulthood that results in debilitating protein loss in the urine and buildup of toxins from the blood due to abnormal filtration kidney filtration. When severe, FSGS may impair kidney function to the point of requiring dialysis or a transplant. FSGS may occur naturally, which is called primary FSGS, or may be a secondary result of other medical abnormalities such as autoimmune diseases like lupus, infectious diseases like HIV, or exposure to chemicals or toxins. FSGS typically occurs without symptoms and many affected patients are unaware of the progressive renal injury resulting from the disease that leads to damage of specialized cells, called podocytes, which reside at the blood-urine interface and cause this interface to become malformed and function inappropriately. As a result of this damage to the cells and membranes separating the blood-urine interface, the junction becomes leaky and protein is lost in the urine. FSGS is prevalent in adults and especially patients of Asian or African American descent. FSGS may be indicated by the presence of protein on a routine urine test, but an invasive kidney biopsy is necessary for confirmation of the disease. Because of the silent nature of renal dysfunction that results from FSGS, military recruits may be diagnosed with FSGS during the initial physical exam for basic training that typically requires a urine test. The critical problem in primary FSGS is that the cause is unknown. End-stage renal disease (ESRD) resulting from FSGS may require dialysis or kidney transplantation. Primary FSGS often recurs in the transplanted kidney (called recurrent FSGS). Primary FSGS and recurrence after transplant are thought to be due to a conserved, circulating factor in blood; however, progress in developing new diagnostic tests for FSGS or finding new cures for the disease is severely hampered by the heretofore inability to identify this unknown causative factor within the blood. This project aims to address this major bottleneck to progress in FSGS research and treatment of patients, military Service members, and Veterans afflicted with the disease. To uncover the circulating factor in FSGS, we have assembled a multidisciplinary and multi-institutional team with expertise in nephrology, kidney transplantation, protein chemistry, stem cell biology, and regenerative medicine. The investigative team will leverage exclusive access to an available biobank of plasma from nearly 60 patients with FSGS who have received a kidney transplant at the primary applicant institution. Of these patients, over one-third developed recurrent FSGS — a rare scientific and investigative resource consisting of the precise cohort of patients who are most at risk for carrying the unknown causative factor for FSGS. The team will also utilize a novel chromatography and gel electrophoresis strategy to fractionated plasma with the goal of progressively isolating and enriching for the presence of the unknown factor (Aim 1). As a novel, laboratory-based test-bed to assess for the presence of the kidney-damaging factor, we developed the ability to grow early kidney tissue — called kidney organoids — which will be used as a state-of-the-art model to test the ability of each serum fraction to disrupt the cells and membranes separating the blood-urine interface within kidney organoids (Aim 2). This cutting-edge, laboratory-based assay, based upon new breakthroughs in stem cell biology, will enable us to uniquely determine which fractions lead to regression of kidney organoids and damage to the cells and membrane that would normally form the blood-urine barrier in an actual organ. Abnormally formed organoids will indicate which fraction of patient plasma may contain the unknown blood-borne fact
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810748
Entities
People
- Jason A Wertheim
Organizations
- Northwestern University
- United States Army