Sepsis is the 8th leading cause of infant mortality in the U.S. and also is prevalent worldwide. Sepsis- induced acute kidney injury (SAKI) is a frequent complication of infant sepsis and increases the mortality rate from 25% to nearly 45%. There are no effective therapies for infant sepsis and clinicians must rely on supportive care generally begun only after the onset of symptoms. Recent findings suggest that SAKI represents a unique and poorly understood type of kidney injury in infants, which is not identical to SAKI in adults. New findings in our clinically relevant cecal ligation and puncture (CLP) model of sepsis in the rat pup indicate that renal microvascular failure, a hallmark of sepsis, is greate in the rat pup compared to the adult. Renal hemodynamics are more fragile in septic pups compared to adults and the decline in renal perfusion was associated with mitochondrial oxidant generation and oxidative stress. Consequently, I hypothesize that clinically relevant delayed therapy, which targets both the renal microcirculation and mitochondrial oxidant generation, will afford the greatest protection from SAKI in a pediatric model of sepsis by reversing capillary dysfunction and oxidative stress to break the cycle of injury and promote recovery. To test this hypothesis, Aim 1 will establish the temporal relationships between the development of microvascular failure, mitochondrial injury and oxidative stress in the kidney of rat pups made septic by CLP. These findings will be used in Aim 3 to help direct the delayed therapy protocol. Aim 2 will determine the lowest, most efficacious doses of the phosphodiesterase 4 inhibitor rolipram and the mitochondria-targeted antioxidant MitoTEMPO that improve renal capillary perfusion and reduce mitochondrial oxidants, respectively. In these acute, dose- finding studies, rolipram or MitoTEMPO will be administered at the time of CLP. Aim 3 will use the doses determined in Aim 2 to evaluate the therapeutic potential of delayed combination therapy targeting the renal microcirculation and O2?- generation. Using the most efficacious doses determined in Aim 2, rolipram and MitoTEMPO will be evaluated individually and in combination using a clinically relevant delayed dosing paradigm. The future clinical implications of the findings are strong, because I will identify pathways of injury then evaluate two new targeted therapies in a relevant model of SAKI for this understudied population.

F31DK104533

2015-01-01

2017-12-31