Prevent acute kidney injury in sepsis by mimicking hibernation

Hibernators are able to withstand periods of profoundly reduced metabolism and body temperature (“torpor”), interspersed by brief periods of rewarming (“arousal”) without signs of organ injury. Specific adaptations allow maintenance of mitochondrial homeostasis, limit oxidative stress and protect against cell death. Unraveling the precise molecular mechanisms that allow hibernators to cycle through torpor and arousal without precipitating organ injury may translate into novel pharmacological approaches to limit kidney injury in patients with sepsis.

Renal energy crisis in sepsis-associated kidney injury: relevance and therapeutic opportunities of sustaining renal mitochondrial function


Acute kidney injury (AKI) is most frequently caused by sepsis, which is the leading cause of death among patients on the intensive care unit (ICU). The occurrence of renal dysfunction is a very strong risk factor for mortality and is associated with a threefold higher mortality rate during sepsis. Moreover, AKI leads to a 9-fold increased risk for developing chronic kidney disease (CKD), a 3-fold high risk for developing end-stage renal disease (ESRD) and doubles long-term mortality rate. Despite intensive research, the pathogenesis of sepsis-associated AKI and its effects on survival remain poorly understood. Therefore, current therapy is limited to antibiotics and supportive care. Mitochondrial dysfunction, which mainly results from damage induced by free radicals, is emerging as a key event in the induction of AKI during sepsis. Dysfunctional mitochondria produce less ATP, while the generation of free radicals is augmented. The current therapy to supply high levels of oxygen may accelerate renal mitochondrial damage by stimulating free radical formation. Depletion of ATP and damage induced by free radicals can progress into renal cell death. Moreover, damaged renal mitochondria may induce remote organ injury by releasing free radicals and damage-associated molecular patterns (DAMPs), which amplifies the septic response. Therefore, preserving renal mitochondria may limit organ injury and increase survival. A potential solution to preserve renal mitochondrial health may be found in nature, as hibernators have a superior resistance to free radicals, which is, at least in part, mediated by endogenous production of hydrogen sulfide (H2S): a potent scavenger of free radicals and a substitute mitochondrial electron donor. In accord, H2S protects against AKI, inflammation and mortality induced by renal ischemia/reperfusion in non-hibernators. However, studies on the effects of exogenous administered H2S on inflammation in sepsis show contradicting results, which may be explained by a narrow therapeutic window of H2S. To overcome the cytotoxic effects of H2S, we have developed ‘chromanol-derived compounds’ in our laboratory that mimic the cytoprotective effects of H2S, stimulate mitochondrial ATP production and reduce free radical formation.


Financial support: Dutch Kidney Foundation and Junior Scientific Masterclass (UMCG)