Small increases in physiological nitrite concentrations have now been shown to mediate a number of biological responses, including hypoxic vasodilation, cytoprotection after ischemia/ reperfusion, and regulation of gene and protein expression. Thus, while nitrite was until recently believed to be biologically inert, it is now recognized as a potentially important hypoxic signaling molecule and therapeutic agent. Nitrite mediates signaling through its reduction to nitric oxide, via reactions with several heme-containing proteins. In this report, we show for the first time that the mitochondrial electron carrier cytochrome c can also effectively reduce nitrite to NO. This nitrite reductase activity is highly regulated as it is dependent on pentacoordination of the heme iron in the protein and occurs under anoxic and acidic conditions. Further, we demonstrate that in the presence of nitrite, pentacoordinate cytochrome c generates bioavailable NO that is able to inhibit mitochondrial respiration. These data suggest an additional role for cytochrome c as a nitrite reductase that may play an important role in regulating mitochondrial function and contributing to hypoxic, redox, and apoptotic signaling within the cell.
Patients on Extra Corporeal Membrane Oxygenator (ECMO) therapy are critically ill and receive aggressive interventions including many nephrotoxic medications. In addition, they are subject to hormonal variations including renin angiotensin aldosterone dysregulation. Veno-Arterial (VA) ECMO includes a mixture of pulsatile blood flow from the heart and non-pulsatile blood flow from the ECMO circuit which changes perfusion to vital organs including kidney (ischemic reperfusion damage) when compared to Veno-Venous (VV) ECMO which maintains pulsatile blood flow from the heart. We sought to compare Acute Kidney Injury (AKI) in patients on VA and VV ECMO and renal outcomes including complete recovery, partial recovery or being dialysis dependent at the time of discharge. Methods: We conducted a retrospective observational analysis of a total of 125 adult patients who received ECMO between 2015 to 2019 at our institution. Variables including age, sex, type of ECMO, baseline creatinine, timing of AKI (both before and after ECMO initiation were included), timing of initiation of renal replacement therapy (RRT) and recovery were analyzed. Using the Acute Kidney Injury Network (AKIN) criteria, AKI was identified as well as staged between the two groups. Univariate analysis of renal outcomes between the groups at the time of discharge was compared and analyzed using R ver 3.6. P values < 0.05 were considered statistically significant. Results: Out of the 125 patients, in the analyzed cohort, 58 received VV ECMO, 64 received VA ECMO and 3 patients were not included due to history of ESRD. 51(87.9%) patients developed AKI, and 39(67.2%) patients needed RRT in the VV ECMO group whereas 58(90.6%) developed AKI, and 28(45.1%) patients needed RRT in the VA ECMO group. At the time of discharge, among the patients who developed AKI in the VV ECMO group, 22(43.1%) had complete recovery, 3(5.8%) had partial recovery, 1(1.9%) was still dependent on dialysis compared to the VA group, where 15(25.8%) had complete recovery (p=0.083), 5(7.8%) had partial recovery (p=0.557), 1(1.7%) was still dependent on dialysis (p=0.994). 25(49.01%) patients in the VV group and 37(57.8%) patients in the VA group experienced in hospital mortality (p=0.106). (Table 1) Conclusion: There was no significant difference in complete or partial renal recovery and dialysis dependency between the patients who develop AKI on VV compared with VA ECMO. This serves as preliminary data for future investigative efforts in this area.
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