Enhancing kidney function with thrombolytic therapy following donation after cardiac death: a multicenter quasi‐blinded prospective randomized trial

Abstract

Kidneys from donors after cardiac death (DCD) are at risk for inferior outcomes, possibly due to microthrombi and additional warm ischemia. We describe an organ procurement organization-wide trial utilizing thrombolytic tissue plasminogen activator (tPA) during machine pulsatile perfusion (MPP). A kidney from each recovered kidney pair was prospectively randomized to receive tPA (50 mg Alteplase) or no tPA (control) in the MPP perfusate. From 2011 to 2013, 24 kidneys were placed with enrolled recipients from 19 DCD kidney donors. There were no significant differences for absolute values of flow or resistance while undergoing MPP between the groups, nor rates of achieving discrete flow and resistance targets. While there was a trend toward lower creatinine and higher glomerular filtration rates in the tPA group at 3, 6, 9, and 12 months, these differences were not significant. Delayed graft function (DGF) rates were 41.7% in the tPA group vs. 58.4% in the control group (OR 0.51, 95%CI 0.10-2.59, p = 0.68). Death-censored graft survival was similar between the groups. In this pilot study, encouraging trends are seen in kidney allograft function independent of MPP parameters following DCD kidney transplantation for those kidneys receiving thrombolytic tPA and MPP, compared with standard MPP.

Lysis of cold-storage-induced microvascular obstructions for ex vivo revitalization of marginal human kidneys

“…44,45 It should be noted that pretransplant treatment of kidneys with plasmin activating enzymes (eg, tPA and streptokinase) has previously been evaluated in both preclinical and clinical studies with mixed results. [41][42][43] However, these studies delivered these enzymes in the absence of the cofactor plasminogen, which our current study demonstrates is essential for complete fibrinolytic effect. Plasminogen is currently awaiting FDA approval as a replacement therapy for patients with plasminogen deficiency but has been shown in multiple clinical trials to also be safe for use in humans.…”

“…tPA is a Food and Drug Administration (FDA)‐approved therapeutic with a long history of clinical use in humans including in the setting of transplantation 44,45 . It should be noted that pretransplant treatment of kidneys with plasmin activating enzymes (eg, tPA and streptokinase) has previously been evaluated in both preclinical and clinical studies with mixed results 41‐43 . However, these studies delivered these enzymes in the absence of the cofactor plasminogen, which our current study demonstrates is essential for complete fibrinolytic effect.…”

Infusing Mesenchymal Stromal Cells into Porcine Kidneys during Normothermic Machine Perfusion: Intact MSCs Can Be Traced and Localised to Glomeruli

“…In an attempt to decrease waiting time for a donor kidney, donation after circulatory death (DCD) is starting to play a more prominent role in many transplant centres [1]. DCD is associated with an elevated risk of inferior early transplant outcome, as a result of the inevitable detrimental effect of warm ischaemia [2,3].…”

CD47 blockade reduces ischemia/reperfusion injury in donation after cardiac death rat kidney transplantation

“…Although we demonstrate that both syngeneic and allogeneic DCD kidney transplant recipients benefited from CD47mAb therapy, no recipients survived beyond 7 days in the allogeneic model, and 30% CD47mAb treated recipients were alive at 7 days, indicating that the DCD model with 1 hr of warm ischemia after circulatory arrest resulted in severe tissue damage. This is in contrast to the human transplant setting with DCD donors, where “donor warm ischemia time” usually denotes the time after withdrawal of treatment (22, 24). Although perfusion is reduced during this period, oxygen delivery continues to occur, and the actual ischemic time after complete cessation of circulation is typically less than 10 minutes.…”

“…This is in contrast to the human transplant setting with DCD donors, where "donor warm ischemia time" usually denotes the time after withdrawal of treatment. 22,24 Although perfusion is reduced during this period, oxygen delivery continues to occur, and the actual ischemic time after complete cessation of circulation is typically less than 10 minutes. Despite the severity of our DCD model, we were able to demonstrate meaningful improvement of transplant outcomes with CD47mAb treatment of the graft.…”