Advisor(s)
Bradley Yoder
Committee Member(s)
Anupam Agarwal
Beatriz Leon
Brittany Lasseigne
James George
Sonya Heath
School
College of Arts and Sciences
Document Type
Dissertation
Department (new version)
Biology
Date of Award
9-9-2024
Abstract
The kidney is an intricate organ responsible for filtering our blood, maintaining bone health, regulating blood pressure, and numerous other vital functions. Acute kidney injury (AKI) is a temporary loss of kidney function, affecting up to 20% of hospitalized and 60% of critically ill patients. Despite the high mortality rate and frequency of occurrence, targeted therapies to treat AKI have not been successfully developed. Unresolved AKI confers an increased risk for the development of chronic kidney disease (CKD) and ultimately end-stage kidney disease (ESKD). Although dialysis can sustain life for individuals with ESKD, transplantation is the only definitive cure. With the drastic shortage of human kidneys, genetically modified pig kidneys may serve as a reliable resource to increase the organ supply. The immune system is a key contributor in the response to AKI and plays an important role in transplant tolerance and rejection. Kidney resident macrophages modulate the response to AKI, but the mechanism of their contribution remains unknown. We utilized single-cell, single-nucleus, and spatial transcriptomics to elucidate the cellular and molecular changes in the kidney following AKI and xenotransplantation. We first applied this to define the transcriptional and spatial heterogeneity of KRMs before and after AKI. We then used scRNAseq on cells recovered from the urine of humans with AKI to demonstrate that kidney alterations could be detected noninvasively. We then applied these technologies to characterize the human immune response in pig-to-human kidney xenotransplantation in a brain-dead human decedent. Lastly, we used the same tools we developed to assess for microchimerism and potential viral transmission after xenotransplantation. Understanding the involvement of the various KRM subpopulations will have a significant impact on our understanding of mechanisms that can be targeted for the treatment of AKI. In addition, addressing these key safety questions involved in pig-to-human xenotransplantation will propel us forward in using these genetically modified pig kidneys in living humans.
ProQuest ID
Recommended Citation
Cheung, Matthew David, "Spatiotemporal Characterization Of The Immune Response In Acute Kidney Injury And Pig-To-Human Kidney Xenotransplantation" (2024). All ETDs from UAB. 7572.
https://digitalcommons.library.uab.edu/etd-collection/7572
