Pyruvate-enriched solution limits lactate and creatine accumulation in hypothermic machine-perfused kidney

dc.creatorMohammad, Moathen_US
dc.creatorTamayo, Jesusen_US
dc.creatorWade, Michaelen_US
dc.creatorTran, Amandaen_US
dc.creatorO'Hara, Collinen_US
dc.creatorO-Yurvati, Alberten_US
dc.creatorMallet, Robert T.en_US
dc.creator.orcid0000-0003-0311-1788 (Mohammad, Moath)
dc.creator.orcid0000-0003-4133-7884 (Tamayo, Jesus)
dc.creator.orcid0000-0002-9022-3552 (Wade, Michael)
dc.creator.orcid0000-0002-1766-5178 (Yurvati, Albert)
dc.creator.orcid0000-0001-7388-9419 (Mallet, Robert)
dc.description.abstractWith a 5% annual increase in incidence, end-stage renal disease (ESRD) is a mounting epidemic. Kidney transplantation is the only definitive treatment for ESRD, but the growing demand for transplantable kidneys greatly exceeds the supply, thus improved methods of organ preservation are urgently needed. Recently, renewed interest in hypothermic machine perfusion (HMP) has prompted refinements of perfusion solutions to improve graft performance and transplant outcomes. In previous studies, solutions containing the intermediary metabolite pyruvate prevented ATP depletion, detoxified reactive oxygen species, suppressed inflammation and optimized protection of ischemic myocardium and brain. This study aimed to examine the hypothesis that pyruvate-enriched preservation fluids provide robust preservation of histological structure and energy metabolism in porcine kidneys during 72 hours HMP. The study used 7 Yorkshire swine kidneys, which were harvested and immediately flushed with ice-cold Ringer's solution and then perfused with either control or 20 mM pyruvate-enriched Ringer's solution for 72 hours in a LifePort organ preservation system. Values for renal artery flow and resistance were recorded over time. After 72 hours HMP, the renal cortex was biopsied and analyzed for metabolite content via spectrophotometry, while the cortex and medulla were biopsied for histological evaluation. The results showed that pyruvate-enriched preservation fluids lowered creatine content by 89% (P < 0.05), and surprisingly lowered lactate content while increasing glucose-6-phosphate content, a source for maintaining antioxidant reducing power. Flow and resistance were comparable between the two groups, and histological analysis revealed interstitial and intracellular edema, varying stages of acute tubular necrosis and variable loss of overall glomerular architecture in both groups. In conclusion, pyruvate-enriched preservation fluids stabilized the cellular energy state, supplied glucose-6-phosphate for sustaining antioxidants, and shunted metabolites from the glycolytic pathway leading to lower lactate accumulation in the renal cortex. Further research is warranted to understand pyruvate's impact on oxidative stress and inflammation during HMP.en_US
dc.description.sponsorshipThis work was supported by grant #RP00027 to AHO-Y from Dallas Southwest Osteopathic Physicians Foundation. JT received stipend support from grant #5R25HL007786-29 from the National Heart, Lung and Blood Institute (Harlan P. Jones, Ph.D., PI).en_US
dc.titlePyruvate-enriched solution limits lactate and creatine accumulation in hypothermic machine-perfused kidneyen_US