Heart re-transplantation in Eurotransplant

Internationally 3% of the donor hearts are distributed to re-transplant patients. In Eurotransplant, only patients with a primary graft dysfunction (PGD) within 1 week after heart transplantation (HTX) are indicated for high urgency listing. The aim of this study is to provide evidence for the discussion on whether these patients should still be allocated with priority. All consecutive HTX performed in the period 1981-2015 were included. Multivariate Cox' model was built including: donor and recipient age and gender, ischaemia time, recipient diagnose, urgency status and era. The study population included 18 490 HTX, of these 463 (2.6%) were repeat transplants. The major indications for re-HTX were cardiac allograft vasculopathy (CAV) (50%), PGD (26%) and acute rejection (21%). In a multivariate model, compared with first HTX hazards ratio and 95% confidence interval for repeat HTX were 2.27 (1.83-2.82) for PGD, 2.24 (1.76-2.85) for acute rejection and 1.22 (1.00-1.48) for CAV (P < 0.0001). Outcome after cardiac re-HTX strongly depends on the indication for re-HTX with acceptable outcomes for CAV. In contrast, just 47.5% of all hearts transplanted in patients who were re-transplanted for PGD still functioned at 1-month post-transplant. Alternative options like VA-ECMO should be first offered before opting for acute re-transplantation

Acute vascular rejection of xenografts: roles of natural and elicited xenoreactive antibodies in activation of vascular endothelial cells and induction of procoagulant activity

Hyperacute rejection of vascularized discordant xenografts can now be effectively managed. However, acute vascular rejection (AVR) then ensues, resulting in graft destruction, coagulopathy, or both within weeks. The aim of this study was to determine associations between humoral responses to the xenograft and the induction of AVR, coagulopathy, or both

Pig kidney transplantation in baboons treated intravenously with a bovine serum albumin-Galalpha1-3Gal conjugate

The maintenance of depletion of antibody (Ab) reactive with Galalpha1-3Gal (Gal) on pig vascular endothelial cells by the intravenous (i.v.) infusion of a synthetic Gal conjugate has been proposed as a means of delaying Ab-mediated rejection of transplanted pig organs in primates. We have therefore studied the effect of the continuous i.v. infusion of bovine serum albumin conjugated to multiple synthetic Gal type 6 oligosaccharides (BSA-Gal) on anti-Gal Ab levels and on graft survival in baboons undergoing pig kidney transplantation. Group 1 baboons (n=3) underwent extracorporeal immunoadsorption of anti-Gal Ab, a cyclophosphamide (CPP)-based immunosuppressive regimen, and a non-transgenic pig kidney transplant. Group 2 (n=2) were treated identically to Group 1 but, in addition, received a continuous i.v. infusion of BSA-Gal. Group 3 (n=2) were treated identically to Group 2, but without CPP. A single baboon (Group 4) underwent extracorporeal immunoadsorption, a CPP-based regimen, and continuous i.v. BSA-Gal therapy for 28 days, but did not receive a pig kidney transplant. Two of the transplanted pig kidneys in Group 1 were excised on post transplant days 7 and 13 for a rejected ureter, and disseminated intravascular coagulation (DIC), respectively. The third baboon died of sepsis on day 6. All transplanted ureters and kidneys showed some histopathologic features of acute humoral xenograft rejection. Group 2 baboons were euthanized on days 8 and 11, respectively, for liver failure. At autopsy, there were histopathological features of widespread liver necrosis, but the pig kidneys and ureters showed no features of rejection. The pig kidneys in Group 3 baboons were excised for renal vein thrombosis (day 9) and DIC (day 12); there was no histological signs of rejection in the pig kidneys or ureter, although there were focal areas of modest liver injury in one baboon on biopsy. The single Group 4 baboon showed no biochemical or histological features of liver injury. Anti-Gal Ab levels returned in Group 1, but were maintained at negligible levels in the baboons in Groups 2 to 4 that received BSA-Gal therapy. Continuous i.v. therapy with BSA-Gal is largely successful in maintaining depletion of circulating anti-Gal antibodies and in preventing or delaying Ab deposition and acute humoral xenograft rejection in porcine grafts, but may be associated with liver injury when administered in the presence of a pig kidney transplant and CPP therapy. The mechanism of the hepatic injury remains uncertain

Acute Kidney Injury After Heart Transplantation: Risk Factors and Clinical Outcomes

Objective: Acute kidney injury (AKI) requiring renal-replacement therapy (RRT) after heart transplantation (OHT) is common and impairs outcomes. This study aimed to identify independent donor and recipient risk factors associated with RRT after OHT. Design: A retrospective data analysis. Setting: Data were collected from clinical routines in a maximum-care university hospital. Participants: Patients who underwent OHT. Interventions: The authors retrospectively analyzed data from 264 patients who underwent OHT between 2012 and 2021; 189 patients were eligible and included in the final analysis. Measurements and Main Results: The mean age was 48.0 ± 12.3 years, and 71.4% of patients were male. Ninety (47.6%) patients were on long-term mechanical circulatory support (lt-MCS). Posttransplant AKI with RRT occurred in 123 (65.1%) patients. In a multivariate analysis, preoperative body mass index >25 kg/m² (odds ratio [OR] 4.74, p < 0.001), elevated preoperative creatinine levels (OR for each mg/dL increase 3.44, p = 0.004), administration of red blood cell units during transplantation procedure (OR 2.31, p = 0.041) and ischemia time (OR for each hour increase 1.77, p = 0.004) were associated with a higher incidence of RRT. The use of renin-angiotensin-aldosterone system blockers before transplantation was associated with a reduced risk of RRT (OR 0.36, p = 0.013). The risk of mortality was 6.9-fold higher in patients who required RRT (hazard ratio 6.9, 95% CI: 2.1-22.6 p = 0.001). Previous lt-MCS, as well as donor parameters, were not associated with RRT after OHT. Conclusions: The implementation of guideline-directed medical therapy, weight reduction, minimizing ischemia time (ie, organ perfusion systems, workflow optimization), and comprehensive patient blood management potentially influences renal function and outcomes after OHT

Correlation of biochemical and hematological changes with graft failure following pig heart and kidney transplantation in baboons

We have explored biochemical and hematologic parameters that might indicate acute humoral xenograft rejection (AHXR) following pig organ transplantation in baboons. Baboons (n = 15) received an immunosuppressive regimen, and underwent a miniature swine or hDAF kidney (Group 1, n = 6) or heart (Group 2, n = 7) transplantation. Control baboons (Group 3, n = 2) received the immunosuppressive regimen without organ transplantation. Blood chemistry and hematologic parameters were measured daily. Baboon and porcine cytomegalovirus were monitored. In Groups 1 and 2, organ grafts survived for up to 29 days. A plasma fibrinogen of 600 U/L and aspartate transaminase of >300 U/L, were associated with the development of AHXR in both heart and kidney grafts. In Group 1, a decrease in platelet count of >150,000/microL within 3 days, or a count of 500 U/L was associated with graft failure. In Group 3, no abnormalities were observed. The possibility that porcine CMV may play a role in graft injury could not be excluded. Noninvasive parameters were identified that have predictive potential for AHXR. Monitoring of these might enable therapeutic intervention to reverse rejection

Depletion of anti-Gal antibodies by the intravenous infusion of Gal type 2 and 6 glycoconjugates in baboons

Natural anti-Gal antibodies (NAb) to Gal epitopes play a key role in the rejection of pig cells or organs transplanted into primates. We have investigated the effect on NAb return after extracorporeal immunoadsorption (EIA) of the continuous intravenous (i.v.) infusion of (i) bovine serum albumin conjugated to Gal type 6 oligosaccharides (BSA-Gal) or (ii) a poly l-lysine backbone conjugated to Gal type 2 or 6 oligosaccharides (PLL-Gal)

Porcine cytomegalovirus and coagulopathy in pig-to-primate xenotransplantation

A rapidly progressive disorder termed consumptive coagulopathy (CC) has been observed frequently in pig-to-baboon renal xenotransplantation. CC may be initiated by endothelial activation and induction of procoagulant factors after immunologic injury or infection, or by molecular incompatibilities between porcine coagulation proteins and primate clotting factors. The activation of porcine (P) cytomegalovirus (PCMV) and baboon (B) CMV infections has been documented in pig-to-primate xenotransplantation. The purpose of this study was to determine the contribution of PCMV and BCMV to CC

Activation of porcine cytomegalovirus, but not porcine lymphotropic herpesvirus, in pig-to-baboon xenotransplantation

Tissue-invasive disease due to porcine cytomegalovirus (PCMV) has been demonstrated after pig-to-baboon solid-organ xenotransplantation. Porcine lymphotropic herpesvirus (PLHV)-1 is associated with B cell proliferation and posttransplant lymphoproliferative disorder after allogeneic bone marrow transplantation in swine but has not been observed in pig-to-primate xenotransplantation. Activation of PCMV and PLHV-1 was investigated in 22 pig-to-baboon xenotransplants by use of quantitative polymerase chain reaction. PCMV was found in all xenografts; increased viral replication occurred in 68% of xenografts during immunosuppression. PLHV-1 was found in 12 xenografts (55%); no increases in viral replication occurred during immunosuppression. Control immunosuppressed swine coinfected with PCMV and PLHV-1 had activation of PCMV but not PLHV-1. PCMV, but not PLHV-1, is activated in solid-organ xenotransplantation