An in-depth analysis of the molecular changes induced by short-term calorie restriction before living kidney donation.

Aging reduces cellular resilience and increases susceptibility to organ injury, notably acute kidney injury (AKI). Ischemia-reperfusion injury (IRI) influences outcomes after kidney transplantation. In animal models, short-term calorie restriction (CR) extends lifespan and protects kidneys from IRI, but translation to patients is limited due to incomplete mechanistic insight. This study examined clinical and molecular effects of short-term CR in living kidney donors. Twelve donors were alternately assigned to CR or an ad libitum diet. CR participants consumed a formula diet providing 50% of individual caloric needs for seven days before donation. Clinical parameters and biosamples from perirenal fat, renal arteries, ureters, kidney biopsies, blood, and urine were collected. Primary outcomes were CR-induced molecular changes; clinical outcomes were secondary. CR was well tolerated and caused significant weight loss without affecting AKI incidence or increasing adverse events. Lipidomic and proteomic analyses showed enhanced lipolysis and proteostasis, reduced insulin signaling, sex-specific effects, and decreased inflammatory factors in donor arteries and ureter tissue. This hypothesis-generating study indicates that short-term CR before donation is feasible and suggests that CR promotes organ protection in humans by dampening insulin signaling and inflammation, providing a basis for future targeted interventions in clinical and transplant research moving forward.