Mechanisms and Consequences of Injury and Repair in Older Organ Transplants

Slegtenhorst, Bendix R.; Dor, Frank J. M. F.; Elkhal, Abdala; Rodríguez, Héctor Alejandro Céspedes; Yang, Xiaoyong; Edtinger, Karoline; Quante, Markus; Chong, Anita S.; Tullius, Stefan G.

doi:10.1097/tp.0000000000000072

Cited by 35 publications

(37 citation statements)

References 158 publications

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“…The age of passenger leukocytes has previously been shown to impact allograft rejection 12-14 . However, age-related changes in parenchymal tissue may also be of relevance in allograft rejection 15-17 . Thus, to delineate whether the observed effects of donor age on allograft survival and systemic alloimmune responses were linked to age-dependent changes in parenchymal tissue or mediated by age-dependent modifications of passenger leukocytes residing within the graft, we generated chimeric C57BL/6 donor animals through lethal total body irradiation and subsequent hematopoietic reconstitution with bone marrow procured from young naïve syngeneic C57BL/6 mice.…”

Section: Resultsmentioning

confidence: 99%

CD11c ⁺ Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A

et al. 2015

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Background Organ transplantation has seen an increased utilization of organs from older donors over the past decades in an attempt to meet the globally growing shortage of donor organs. However, inferior transplant outcomes when utilizing older donor organs represent a growing challenge. Methods and Results Here, we characterize the impact of donor age on solid organ transplantation using a murine cardiac transplantation model. We found a compromised graft survival when utilizing older hearts. Shorter graft survival of older hearts was independent of organ age per se, as chimeric young or old organs repopulated with young passenger leukocytes showed comparable survival times. Transplantation of older organs triggered more potent alloimmune responses via intragraft CD11c+ dendritic cells (DCs) augmenting CD4+ and CD8+ T cell proliferation and pro-inflammatory cytokine production, particularly that of IL-17A. Of note, depletion of donor CD11c+ DCs prior to engraftment, neutralization of IL-17A or transplantation of older hearts into IL-17A-/- mice delayed rejection and reduced alloimmune responses to levels observed when transplanting young hearts. Conclusions These results demonstrate a critical role of old donor CD11c+ DCs in mounting age-dependent alloimmune responses with an augmented IL-17A response in recipient animals. Targeting IL-17A may serve as a novel therapeutic approach when transplanting older organs.

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Section: Resultsmentioning

confidence: 99%

CD11c ⁺ Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A

et al. 2015

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“…On the other hand, in the subanalysis of donors aged ≥50 years, the use of the HP did not reduce the DGF rate, but the duration of DGF was lower than in the control group, which might have a positive impact in long‐term results. The lack of benefits with related to the use of MP after a long CIT in transplants from expanded criteria donors may be due to these kidneys are more susceptible to ischemic injury in general, they have lower renal mass, more chronic histologic injuries, and lower ability for repair and regeneration . However, we must consider that these subanalysis involved a small sample of patients.…”

Section: Discussionmentioning

confidence: 99%

“…As transplantations with organs from donors aged ≥50 years and transplants from expanded criteria donors are associated with worse outcomes after transplantation, such as higher rates of DGF and lower graft survival, 23 we performed a subanalysis considering only donors aged ≥50 years and expanded criteria donors. A subanalysis including only expanded criteria donors showed that the use of HP did not improve results after the transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…The lack of benefits with related to the use of MP after a long CIT in transplants from expanded criteria donors may be due to these kidneys are more susceptible to ischemic injury in general, they have lower renal mass, more chronic histologic injuries, and lower ability for repair and regeneration. 23 However, we must consider (OR:0. 28, P = .041), as our study has also observed.…”

Section: Discussionmentioning

confidence: 99%

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Impact of machine perfusion after long static cold storage on delayed graft function incidence and duration and time to hospital discharge

Matos

Requião-Moura

Borrelli

et al. 2017

Clinical Transplantation

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Delayed graft function (DGF) is very high in our center (70%-80%), and we usually receive a kidney for transplant after more than 22 hours of static cold ischemia time (CIT). Also, there is an inadequate care of the donors, contributing to a high rate of DGF. We decided to test whether machine perfusion (MP) after a CIT improved the outcome of our transplant patients. We analyzed the incidence of DGF, its duration, and the length of hospital stay (LOS) in patients who received a kidney preserved with MP after a CIT (hybrid perfusion-HP). We included 54 deceased donors kidneys preserved with HP transplanted from Feb/13 to Jul/14, and compared them to 101 kidney transplants preserved by static cold storage (CS) from Nov/08 to May/12. The median pumping time was 11 hours. DGF incidence was 61.1% vs 79.2% (P = .02), median DGF duration was 5 vs 11 days (P < .001), and median LOS was 13 vs 18 days (P < .011), for the HP compared to CS group. The observed reduction of DGF with machine perfusion did not occur in donors over 50 years old. In the multivariate analysis, risk factors for DGF, adjusted for CIT, were donor age (OR, 1.04; P = .005) and the absence of use of MP (OR, 1.54; P = .051). In conclusion, the use of HP contributed to faster recovery of renal function and to a shorter length of hospital stay. K E Y W O R D Sdelayed graft function, kidney (allograft) function/dysfunction, organ perfusion and preservation

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“…Additionally, on unifactorial analysis, patients who were paced were significantly more likely to have had a donor‐to‐recipient weight ratio >2.0 in comparison with those who were not paced. Extreme size mismatch has been shown to increase the risk of primary graft failure, possibly due to longer operative and ischemic times associated with a difficult implant procedure …”

Section: Discussionmentioning

confidence: 99%

Permanent pacemaker implantation after pediatric heart transplantation: Risk factors, indications, and outcomes

Mahmood

Andrews

Fenton

et al. 2019

Clinical Transplantation

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Background Permanent pacemaker (PPM) placement in adults following orthotopic heart transplantation (OHT) has been well documented. However, studies concerning the need for PPM implantation in pediatric heart transplant recipients are less common. Methods Institutional transplant and pacing databases as well as patient medical records were reviewed for all pediatric patients undergoing OHT (n = 314; all with bicaval connection) at our institution between January 2000 and March 2018. Results A total of 16 patients (5.1%) were implanted with a pacemaker after transplantation. Donor age was the only significant risk factor for post‐transplant PPM implantation, with a median age of 28.5 years (7.0‐49.0) in the pacing group vs 15.5 years (0.4‐56.0) in the non‐pacing group (P = 0.009). Indication for pacemaker insertion was more often complete heart block (CHB) (12/16, 75%) than sinus node dysfunction (SND) (4/16, 25%). There was no significant difference in mortality between recipients who received a PPM and those who did not (log‐rank test; P = 0.345). Conclusions Increasing donor age is associated with increased PPM placement following pediatric heart transplantation. Interestingly, a high proportion of CHB patients recovered sinus rhythm, and long‐term outcomes for paced patients are similar to other heart transplant recipients.

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Mechanisms and Consequences of Injury and Repair in Older Organ Transplants

Cited by 35 publications

References 158 publications

CD11c ⁺ Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A

CD11c ⁺ Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A

Impact of machine perfusion after long static cold storage on delayed graft function incidence and duration and time to hospital discharge

Permanent pacemaker implantation after pediatric heart transplantation: Risk factors, indications, and outcomes

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Mechanisms and Consequences of Injury and Repair in Older Organ Transplants

Cited by 35 publications

References 158 publications

CD11c + Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A

CD11c + Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A

Impact of machine perfusion after long static cold storage on delayed graft function incidence and duration and time to hospital discharge

Permanent pacemaker implantation after pediatric heart transplantation: Risk factors, indications, and outcomes

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CD11c ⁺ Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A

CD11c ⁺ Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A