Franny Jongbloed

250 CHAPTER 9 reduction in any of these markers, and the compliance of this participant could therefore be questioned. Also, the restricted diet induced a significant body weight loss compared to the control groups, what could be seen as another marker for adherence to the diet. No increase in complications or length of hospital stay occurred in the restricted diet group, indicating the safety of the diet. To conclude, in chapter 8 we were able to show the beneficial effects of a mild adaptation of this diet in living kidney donors. The diet included more protein- free snacks that patients could choose from, which might be the reason for the increased in compliance rate. The combined calorie and protein restricted (CCPR) diet induced vast improvement of kidney function in the living kidney donors, as shown by improved clearance of serum creatinine, estimated glomerular filtration rate (eGFR) and serum levels of urea in the first postoperative period. In addition, kidney transplant recipients of donors whom had received the diet showed an even more remarkable improvement of their graft function and outcome, with an average decrease in serum creatinine levels of 70% in the CCPR group compared to 40% in the control group. This improvement was accompanied by a significant lower incidence of acute rejection and slow graft function in the first postoperative period. Transcriptome profiles of kidneys subjected to the calorie and protein-restricted diet showed more heterogeneity compared to the profiles obtained in mice. Even so, the analysis of the human biopsies marked activation of the NRF2-mediated stress response and inhibition of various cytokine signaling pathways, indicative of a reduction of cellular stress and DNA damage, and therefore revealed a high overlap with our data obtained in mice 24 . Especially the activation of the NRF2-mediated stress response indicated the important role of this transcription factor. Furthermore, EIF2 signaling was significantly upregulated as well, which is a pathway strongly regulated by fasting in the irinotecan-subjected mice as well 35 . These data provide the effectiveness of a diet to activate the stress response in order to increase stress resistance against surgery-related injury. Overlaying our data with previously performed transcriptome analyses in human kidney biopsies found various genes of interest to the beneficial effect against kidney-related injury, including ASB15 , EGR2 and AXNA 53 ,54 . However, no other studies investigated gene expression changes in kidney biopsies subjected to DR up-to-date and an exact comparison of studies could therefore not be made. A recent pilot study did show signs of reduced hematological toxicity and improved DNA damage recovery in breast cancer patients whom were fasted 24 hours before undergoing chemotherapy 55 . Our study also successfully translated DR in a clinical setting, and provided the evidence that short-term DR is able to increase stress resistance in humans. Therefore, it paves the way for future implementation of DR in elective surgery patients and perhaps in cancer patients undergoing chemotherapy as well.