Anti-CD47 monoclonal antibody therapy reduces ischemia-reperfusion injury of renal allografts in a porcine model of donation after cardiac death

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Abstract

We investigated whether blockade of the CD47 signaling pathway could reduce ischemia-reperfusion injury (IRI) of renal allografts donated after cardiac death (DCD) in a porcine animal model of transplantation. Renal allografts were subjected to 30 min of warm ischemia, 3.5 hours of cold ischemia and then perfused with a humanized anti-CD47 monoclonal antibody (CD47mAb) in the treatment group or HTK solution in the control group (n=4/group). The animals were euthanized 5 days after transplantation. At the time of reperfusion, indocyanine green-based in vivo imaging showed that CD47mAb-treated organs had greater and more uniform reperfusion. On post-transplant days 3–5, the treatment group had lower values compared to the control for creatinine and blood urea nitrogen. Histological examination of allograft tissues showed a significant decrease of acute tubular injury in the CD47mAb-treated group compared to control. Compared to the control group, CD47mAb treatment significantly decreased genes expression related to oxidative stress ( sod-1, gpx-1, and txn), the inflammatory response ( il-2, il-6, inf-g and tgf-b), as well as reduced protein levels of BAX, Caspase-3, MMP2, and MMP9. These data demonstrate that CD47mAb blockade decreases IRI and subsequent tissue injury in DCD renal allografts in a large animal transplant model.

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Delayed graft function in the kidney transplant.

A. Siedlecki, W Irish, D Brennan (2011)

Acute kidney injury occurs with kidney transplantation and too frequently progresses to the clinical diagnosis of delayed graft function (DGF). Poor kidney function in the first week of graft life is detrimental to the longevity of the allograft. Challenges to understand the root cause of DGF include several pathologic contributors derived from the donor (ischemic injury, inflammatory signaling) and recipient (reperfusion injury, the innate immune response and the adaptive immune response). Progressive demand for renal allografts has generated new organ categories that continue to carry high risk for DGF for deceased donor organ transplantation. New therapies seek to subdue the inflammatory response in organs with high likelihood to benefit from intervention. Future success in suppressing the development of DGF will require a concerted effort to anticipate and treat tissue injury throughout the arc of the transplantation process. ©2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

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Delayed graft function in kidney transplantation.

Norberto Perico, Dario Cattaneo, Mohamed Sayegh … (2004)

Delayed graft function is a form of acute renal failure resulting in post-transplantation oliguria, increased allograft immunogenicity and risk of acute rejection episodes, and decreased long-term survival. Factors related to the donor and prerenal, renal, or postrenal transplant factors related to the recipient can contribute to this condition. From experimental studies, we have learnt that both ischaemia and reinstitution of blood flow in ischaemically damaged kidneys after hypothermic preservation activate a complex sequence of events that sustain renal injury and play a pivotal part in the development of delayed graft function. Elucidation of the pathophysiology of renal ischaemia and reperfusion injury has contributed to the development of strategies to decrease the rate of delayed graft function, focusing on donor management, organ procurement and preservation techniques, recipient fluid management, and pharmacological agents (vasodilators, antioxidants, anti-inflammatory agents). Several new drugs show promise in animal studies in preventing or ameliorating ischaemia-reperfusion injury and possibly delayed graft function, but definitive clinical trials are lacking. The goal of monotherapy for the prevention or treatment of is perhaps unattainable, and multidrug approaches or single drug targeting multiple signals will be the next step to reduce post-transplantation injury and delayed graft function.

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Deceased-donor characteristics and the survival benefit of kidney transplantation.

Joseph Ojo, T Hulbert-Shearon, Friedrich Port … (2005)

Transplantation using kidneys from deceased donors who meet the expanded criteria donor (ECD) definition (age > or =60 years or 50 to 59 years with at least 2 of the following: history of hypertension, serum creatinine level >1.5 mg/dL [132.6 micromol/L], and cerebrovascular cause of death) is associated with 70% higher risk of graft failure compared with non-ECD transplants. However, if ECD transplants offer improved overall patient survival, inferior graft outcome may represent an acceptable trade-off. To compare mortality after ECD kidney transplantation vs that in a combined standard-therapy group of non-ECD recipients and those still receiving dialysis. Retrospective cohort study using data from a US national registry of mortality and graft outcomes among kidney transplant candidates and recipients. The cohort included 109,127 patients receiving dialysis and added to the kidney waiting list between January 1, 1995, and December 31, 2002, and followed up through July 31, 2004. Long-term (3-year) relative risk of mortality for ECD kidney recipients vs those receiving standard therapy, estimated using time-dependent Cox regression models. By end of follow-up, 7790 ECD kidney transplants were performed. Because of excess ECD recipient mortality in the perioperative period, cumulative survival did not equal that of standard-therapy patients until 3.5 years posttransplantation. Long-term relative mortality risk was 17% lower for ECD recipients (relative risk, 0.83; 95% confidence interval, 0.77-0.90; P 1350 days), ECD recipients had a 27% lower risk of death (relative risk, 0.73; 95% confidence interval, 0.64-0.83; P<.001). In areas with shorter waiting times, only recipients with diabetes demonstrated an ECD survival benefit. ECD kidney transplants should be offered principally to candidates older than 40 years in OPOs with long waiting times. In OPOs with shorter waiting times, in which non-ECD kidney transplant availability is higher, candidates should be counseled that ECD survival benefit is observed only for patients with diabetes.