Dissertation
Disease or development: oxidative stress in the pediatric kidney-brain axis
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2022
DOI: 10.25820/etd.006636
Abstract
Chronic kidney disease (CKD) affects millions of people worldwide- not just adults, but children as well. The causes of CKD are many, ranging from congenital kidney anomalies to immune induced to sequelae of other diseases processes such as malignancy. The kidneys, typically two fist-shaped organs located retroperitoneal, are responsible for the ultrafiltration of blood, reabsorption of ions and small molecules, and maintenance of homeostasis. Long-term kidney dysfunction in children has been associated with a variety of comorbidities including disrupted physical growth, increased psychosocial issues, and lower academic achievement.While dialysis and kidney transplant can treat CKD, this disease remains incurable and
therefore, the need for discovering therapeutic targets for mitigating disease progression is critical.Cisplatin is a commonly used chemotherapeutic with a major nephrotoxicity remaining a major complication of treatment. This thesis will describe a translational approach to mitigating kidney injury associated with cisplatin, starting with an in vitro model of cisplatin-induced reactive oxygen species (ROS) production linked to kidney cell death and clinical kidney dysfunction. Use of a novel therapeutic, GC4419 (avasopasem manganese), dismuted superoxide (O2•_) after cisplatin to increase cell survival. In a randomized phase 2b trial of avasopasem manganese, those who received 90 mg had significantly higher estimated glomerular filtration rate (eGFR) up to two years after cisplatin chemotherapy compared to those in the placebo and comparator group. Adults who did not receive GC4419 had significant CKD development measuring in ≥ stage 3 CKD two years after cisplatin chemotherapy.
Children who also receive cisplatin chemotherapy are not only at risk for CKD, but also the developmental disruptions associated with kidney dysfunction. Children, adolescents, and young adults (AYA) treated with cisplatin show a continual decline of kidney function throughout early adulthood. By the average age of 30, this population has lost an average of 48.5% of their total eGFR, measuring in stage 2 CKD after cisplatin chemotherapy. The children and AYA population treated with cisplatin in this cohort demonstrated a risk for loss of function at a rate of three-times faster than their age-matched peers.
The risk for CKD in children is not insignificant. This population is at risk for cognitive deficit, school difficulties, lower employment rates in adulthood and comparatively lower quality of life. Furthermore, there is evidence to support the presence of neurodevelopmental differences among children with CKD that can be noted even before the need for dialysis or transplantation. Through magnetic resonance imaging (MRI), we show that the previously reported structural brain differences in pediatric CKD are associated with evidence for aberrant redox metabolism within the brain using a T2* relaxation time sequence. Brain T2* relaxation time was correlated with abnormally high markers of neuroinflammation and oxidative stress. Furthermore, these findings predict performance on neurocognitive testing. These findings support a role for abnormal redox metabolism in the propagation of CKD-associated brain differences. This is critical to inform our understanding of the “kidney-brain axis” and provide future directions to evaluate novel therapeutic targets that leverage novel antioxidant scavengers to mitigate changes in the pediatric CKD brain.
Details
- Title: Subtitle
- Disease or development: oxidative stress in the pediatric kidney-brain axis
- Creators
- Emily J. Steinbach-Swehla
- Contributors
- Lyndsay A. Harshman (Advisor)Douglas R. Spitz (Advisor)Joseph J. Cullen (Committee Member)Vincent A. Magnotta (Committee Member)Dao-Fu Dai (Committee Member)Jennifer G. Jetton (Committee Member)Timothy R. Koscik (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Free Radical and Radiation Biology)
- Date degree season
- Summer 2022
- DOI
- 10.25820/etd.006636
- Publisher
- University of Iowa
- Number of pages
- xxii, 146 pages
- Copyright
- Copyright 2022 Emily J. Steinbach-Swehla
- Language
- English
- Description illustrations
- illustrations
- Description bibliographic
- Includes bibliographical references (pages 129-146).
- Public Abstract (ETD)
Chronic kidney disease (CKD) affects millions of people worldwide- not just adults, but children as well. Long-term kidney disease in children has been associated with a variety of health concerns including disrupted physical growth, increased psychosocial issues, and lower academic achievement. While dialysis and kidney transplant can treat CKD, this disease remains incurable and the need for discovering preventative treatments of disease progression, such as chemotherapy (cisplatin) CKD is critical.
This thesis will describe a kidney cell model of cisplatin-induced oxidative stress linked to cell death and clinical kidney dysfunction. Use of a novel therapeutic, GC4419 (avasopasem manganese), eliminated kidney injury due to oxidative stress after cisplatin and increased kidney cell survival. In a phase 2b trial of GC4419, those who received 90 mg had significantly better kidney function two years after cisplatin chemotherapy compared to those who did not receive GC4419 and had kidney functions measuring in ≥ stage 3 CKD.
Children who also receive cisplatin chemotherapy are not only at risk for CKD, but also the developmental disruptions associated with kidney dysfunction. Children, adolescents, and young adults treated with cisplatin show a continual decline of kidney function. By the average age of 30, this population has lost an average of 48.5% of their total kidney function measuring in stage 2 CKD. Lifelong battles with CKD, such as this, were also shown to pose a significant risk to the developing brain. Through MRI, we show that CKD associated brain deviances are suggestive of aberrant oxidative stress within the kidney. These findings not only provide a link to the “kidney-brain axis” but also provide a possible therapeutic target for mitigating changes in the pediatric CKD brain.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984285345902771
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