Short-term fasting protects healthy kidney tissue against therapeutic damage: Towards better recovery and limiting side-effects in children with cancer

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Cancer treatments like chemotherapy have greatly improved survival rates, especially in children, but often cause serious long-term side effects that impact quality of life. This thesis explores whether short-term fasting (STF) can help protect healthy tissues and reduce these effects. We studied STF in two clinical trials: 1) in healthy adult kidney donors (FAST-study) and 2) in children with Wilms tumour undergoing nephrectomy (FIURTT-study). Preclinically, we tested STF’s protective effects against chemotherapy-induced toxicity using a paediatric mouse model and an advanced ex vivo method called organotypic tissue slices (OTS) for paediatric kidney tissue. In the FAST-study, 60 hours of STF in adult kidney donors activated a ‘survival mode’, improving the function of the donated kidney. In the FIURTT-study, children fasted for shorter periods (10, 14 or 18 hours, depending on age). Even with this brief fasting, we observed mild systemic effects in the blood and local effects in the kidney. Gene expression analysis of kidney biopsies showed no significant changes, likely due to the small number of samples and high patient variability, but gene set analysis revealed fasting-related patterns similar to those in the FAST-study. To reduce reliance on animal models and better reflect human biology, we worked on developing and improving the ex vivo organotypic tissue slice (OTS) model for paediatric kidney biopsies. This model preserves cell interactions and the tissue’s micro-environment. After optimisation, we kept OTS viable for up to a week in culture. We found that fastingmimicking conditions reduced cell proliferation, showing responses similar to other in vitro and in vivo models. Our in vivo mouse study did not show the expected chemotherapyinduced toxicities after treatment with cisplatin, doxorubicin, or irinotecan, likely due to the single-dose design. As a result, only a limited rescue effect by fasting could be observed. Future studies will explore multiple dosing regimens to better reflect clinical treatments, where combining such regimens with longer-term caloric restriction may be more feasible than short fasting periods. This thesis highlights the potential of nutritional interventions, particularly STF, in paediatric cancer treatment, which is a still largely unexplored field. More studies in adults are needed to understand the optimal type, timing, and duration of fasting and to guide its safe use before medical treatments. Evidence from adult trials shows fasting can reduce toxicity 241 & and improve quality of life, encouraging further investigation in children. Our two clinical studies, together with earlier work, show that STF is feasible and suggest it may offer protective benefits. Preclinical findings also support the idea that nutritional preconditioning could reduce treatment-related toxicities, with ex vivo models helping to accelerate testing. Ultimately, refining fas ting strategies - choosing the right type, timing, and duration - could allow integration of dietary interventions with both traditional and modern cancer therapies, potentially reducing short- and long-term side effects and, most importantly, improving quality of life.

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