Role of coagulation in persistent renal ischemia following reperfusion in an animal model

Abstract

Ischemic acute kidney injury (AKI) is common, deadly, and accelerates progression of chronic kidney disease (CKD), yet has not specific therapy. After ischemia, reperfusion is patchy with early and persistent impairment in regional renal blood flow and cellular injury. We tested the hypothesis that intrarenal coagulation results in sustained renal ischemia following reperfusion, using a well-characterized model. Markedly decreased, but heterogeneous, microvascular plasma flow with microthrombi was found postischemia by intravital microscopy. Widespread tissue factor expression and fibrin deposition were also apparent. Clotting was accompanied by complement activation and inflammation. Treatment with exosomes derived from renal tubular cells or with the fibrinolytic urokinase, given 24 hours postischemia after renal failure was established, improved microvascular flow, coagulation, serum creatinine and histological evidence of injury. These data support the hypothesis that intrarenal clotting occurs early and the resultant sustained ischemia is a critical determinant of renal failure following ischemia; they demonstrate that the coagulation abnormalities are amenable to therapy and that therapy results in improvement in both function and postischemic inflammation.

Novel Ps-Ome Mirna130b-3p Reduces Inflammation and Injury and Improves Survival After Renal Ischemia-Reperfusion Injury

“…In addition, because of the controlled ischemic time used for the biochemical analysis, there could be significant differences in the availability of PS-OME miR130 at the site of injury relating to the physiologic changes that would be proportional to the ischemic time. An example could be changes in delivery secondary to clot burden and the time required for recovery of tissue debris (51). Likewise, the differences in perfusion, drug delivery, and serum and tissue eCIRP concentrations after treatment may have important implications that have not been fully investigated in our study.…”

Impaired microvascular circulation in distant organs following renal ischemia

“…Intravital multi-photon fluorescence microscopy [30,32,34]. Microvascular flow was quantified 24 and 48 hours post-ischemia by intravital imaging using an Olympus Fluoview 1000 confocal/multiphoton microscope, Olympus Corporation, Center Valley PA.…”

“…Microvascular plasma flow was visualized after infusion of fluorescein conjugated albumin (Molecular Probes, 2mg in 0.5ml physiological saline) and serial images acquired approximately every 0.5 second. Plasma flow was quantified as movement of dye-excluding erythrocytes in line scans (with correction for microvascular angle) [30]. We focused on the longer (48 hour) time point when serum creatinine had improved to near baseline levels, but preliminary studies (S1 Fig in S1 File) did show similar results at the 24 hour time point.…”

“…All quantification was performed without knowledge of experimental group. Additional measures of inflammation included myeloperoxidase activity [38,41] and polymerase chain reaction for complement component C3 and intercellular adhesion molecule-1 (ICAM) [30] measured in tissue.…”

“…The purpose of the present study was an investigation of microvascular abnormalities in extra-renal organs after renal ischemia and reperfusion. We hypothesized that the microvascular coagulation and impaired perfusion seen in the kidney postischemia [30] would also impact remote organs.…”