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.
Chronic kidney disease is a complication for at least 20% of children receiving a bone marrow transplant and we do not fully understand why this risk is so high. The proposed research project will define how imbalances in the immune system and BK virus infection, known causes of kidney injury after kidney transplant, similarly contribute to kidney disease in children undergoing a bone marrow transplant. Stronger evidence for an association between immune mediated kidney injury, viral infection, and chronic kidney disease in this patient population would support future research studies designed to prevent, treat, or slow the progression of chronic kidney disease in children who are immunosuppressed, including recipients of a solid organ or bone marrow transplant.
