Immune dysregulation and kidney disease after hematopoietic cell transplant

Children'S Hosp Of Philadelphia, Philadelphia PA

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): I am a junior investigator in pediatric nephrology with a strong record of studying kidney disease in hematopoietic cell transplant (HCT) recipients and other immunosuppressed patients. I am committed to an academic career in patient-oriented research with the long-term career goal of leading independent, translational investigations focused on reducing chronic kidney disease (CKD) in HCT and solid organ transplant recipients. My short-term career goal is to hone my skills and training in clinical and translational research by receiving more specialized, formal instruction at the Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania (Penn). Specifically, the objectives of this career development award are: 1) To develop an understanding of immune responses and kidney injury in immunosuppressed children in order to design future interventional studies, 2) To develop the skills necessary to analyze complex longitudinal data by learning advanced statistical methods, and 3) To develop a multi-disciplinary collaboration across two large children's hospitals enabling future translational studies in children post-HCT or solid organ transplant. This training plan will take advantage of an outstanding research environment (CHOP and Penn) and mentorship from senior faculty with expertise in cohort studies, pediatric CKD, kidney transplant, HCT, immunology, and infectious diseases. CKD after pediatric HCT is a significant problem to investigate because 7,000 patients receive an allogeneic HCT each year in the United States, >15% of whom are children. Overall mortality after HCT is unacceptably high-7 years after transplant only about half of patients are alive. CKD, which is a complication in at least 20% of children receiving an HCT, contributes to the high risk of morbidity and mortality after HCT. However, most cases of CKD after HCT are currently considered idiopathic. Identifying novel, modifiable targets for the prevention and treatment of CKD could improve the health and survival of this patient population. We hypothesize that immune dysregulation involving the kidney contributes to CKD after HCT. We will test this hypothesis with two Aims, the first to define the association between BK viral infection, under activation of the immune system, and CKD, and the second to define the association between over activation of the immune system (immune mediated kidney injury) and CKD. These Aims are based on a conceptual model similar to complications of kidney transplant, where impaired immunity leads to BK virus nephropathy and activated immunity causes allograft rejection. To test our hypothesis, we will develop a prospective observational cohort of 150 children undergoing allogeneic HCT at CHOP and CCHMC to systematically measure BK viremia and novel urine markers (CXCL9 and 10) of immune mediated kidney disease during the first year after HCT. This research strategy will provide the evidence for future independent funding proposals designed to decrease morbidity and mortality by preventing, treating, or slowing the progression of CKD in children who are immunosuppressed, including those receiving an HCT or solid organ transplant.