Pretransplant Organ Research Articles

Ex vivo heart perfusion: an updated systematic review.

Due to the discrepancy between patients awaiting a heart transplant and the availability of donor hearts, strategies to expand the donor pool and improve the transplant's success are crucial. This review aims to summarize current knowledge on the ex vivo heart preservation (EVHP) experience as an alternative to standard cold static storage (CSS). EVHP techniques can improve the preservation of the donor's heart before transplantation and allow for pre-transplant organ evaluation.

Intensive care risk and long-term outcomes in pediatric allogeneic hematopoietic cell transplant recipients

AbstractAllogeneic hematopoietic cell transplantation (HCT) can be complicated by life-threatening organ toxicity and infection necessitating intensive care. Epidemiologic data have been limited by single-center studies, poor database granularity, and a lack of long-term survivors. To identify contemporary trends in intensive care unit (ICU) use and long-term outcomes, we merged data from the Center for International Blood and Marrow Transplant Research and the Virtual Pediatric Systems databases. We identified 6995 pediatric patients with HCT aged ≤21 years who underwent first allogeneic HCT between 2008 and 2014 across 69 centers in the United States or Canada and followed patients until the year 2020. ICU admission was required for 1067 patients (8.3% by day +100, 12.8% by 1 year, and 15.3% by 5 years after HCT), and was linked to demographic background, pretransplant organ toxicity, allograft type and HLA-match, and the development of graft-versus-host disease or malignancy relapse. Survival to ICU discharge was 85.7%, but more than half of ICU survivors required ICU readmission, leading to 52.5% and 42.6% survival at 1- and 5-years post-ICU transfer, respectively. ICU survival was worse among patients with malignant disease, poor pretransplant organ function, and alloreactivity risk factors. Among 1-year HCT survivors, those who required ICU in the first year had 10% lower survival at 5 years and developed new dialysis-dependent renal failure at a greater rate (P<.001). Thus, although ICU management is common and survival to ICU discharge is high, ongoing complications necessitate recurrent ICU admission and lead to a poor 1-year outcome in select patients who are at high risk.

Nanotherapeutics for solid organ transplantation: new kid onthe block.

Nanotherapeutics for solid organ transplantation: new kid onthe block.

Magnetic resonance imaging during warm ex vivo kidney perfusion.

The shortage of donor organs for transplantation remains a worldwide problem. The utilization of suboptimal deceased donors enlarges the pool of potential organs, yet consequently, clinicians face the difficult decision of whether these sub-optimal organs are of sufficient quality for transplantation. Novel technologies could play a pivotal role in making pre-transplant organ assessment more objective and reliable. Ex vivo normothermic machine perfusion (NMP) at temperatures around 35-37°C allows organ quality assessment in a near-physiological environment. Advanced magnetic resonance imaging (MRI) techniques convey unique information about an organ's structural and functional integrity. The concept of applying magnetic resonance imaging during renal normothermic machine perfusion is novel in both renal and radiological research and we have developed the first MRI-compatible NMP setup for human-sized kidneys. We were able to obtain a detailed and real-time view of ongoing processes inside renal grafts during ex vivo perfusion. This new technique can visualize structural abnormalities, quantify regional flow distribution, renal metabolism, and local oxygen availability, and track the distribution of ex vivo administered cellular therapy. This platform allows for advanced pre-transplant organ assessment, provides a new realistic tool for studies into renal physiology and metabolism, and may facilitate therapeutic tracing of pharmacological and cellular interventions to an isolated kidney.

Sense and Sensibilities of Organ Perfusion as a Kidney and Liver Viability Assessment Platform.

Predicting organ viability before transplantation remains one of the most challenging and ambitious objectives in transplant surgery. Waitlist mortality is high while transplantable organs are discarded. Currently, around 20% of deceased donor kidneys and livers are discarded because of “poor organ quality”, Decisions to discard are still mainly a subjective judgement since there are only limited reliable tools predictive of outcome available. Organ perfusion technology has been posed as a platform for pre-transplant organ viability assessment. Markers of graft injury and function as well as perfusion parameters have been investigated as possible viability markers during ex-situ hypothermic and normothermic perfusion. We provide an overview of the available evidence for the use of kidney and liver perfusion as a tool to predict posttransplant outcomes. Although evidence shows post-transplant outcomes can be predicted by both injury markers and perfusion parameters during hypothermic kidney perfusion, the predictive accuracy is too low to warrant clinical decision making based upon these parameters alone. In liver, further evidence on the usefulness of hypothermic perfusion as a predictive tool is needed. Normothermic perfusion, during which the organ remains fully metabolically active, seems a more promising platform for true viability assessment. Although we do not yet fully understand “on-pump” organ behaviour at normothermia, initial data in kidney and liver are promising. Besides the need for well-designed (registry) studies to advance the field, the catch-22 of selection bias in clinical studies needs addressing.

Renal Normothermic Machine Perfusion: The Road Toward Clinical Implementation of a Promising Pretransplant Organ Assessment Tool.

The increased utilization of high-risk renal grafts for transplantation requires optimization of pretransplant organ assessment strategies. Current decision-making methods to accept an organ for transplantation lack overall predictive power and always contain an element of subjectivity. Normothermic machine perfusion (NMP) creates near-physiological conditions, which might facilitate a more objective assessment of organ quality before transplantation. NMP is rapidly gaining popularity, with various transplant centers developing their own NMP protocols and renal viability criteria. However, to date, no validated sets of on-pump viability markers exist nor are there unified NMP protocols. This review provides a critical overview of the fundamentals of current renal NMP protocols and proposes a framework to approach further development of ex vivo organ evaluation. We also comment on the potential logistical implications of routine clinical use of NMP, which is a more complex procedure compared with static cold storage or even hypothermic machine perfusion.

Magnetic resonance imaging assessment of renal flow distribution patterns during exvivo normothermic machine perfusion in porcine and human kidneys.

SummaryAcceptance criteria of deceased donor organs have gradually been extended toward suboptimal quality, posing an urgent need for more objective pre‐transplant organ assessment. Ex vivo normothermic machine perfusion (NMP) combined with magnetic resonance imaging (MRI) could assist clinicians in deciding whether a donor kidney is suitable for transplantation. Aim of this study was to characterize the regional distribution of perfusate flow during NMP, to better understand how ex vivo kidney assessment protocols should eventually be designed. Nine porcine and 4 human discarded kidneys underwent 3 h of NMP in an MRI‐compatible perfusion setup. Arterial spin labeling scans were performed every 15 min, resulting in perfusion‐weighted images that visualize intrarenal flow distribution. At the start of NMP, all kidneys were mainly centrally perfused and it took time for the outer cortex to reach its physiological dominant perfusion state. Calculated corticomedullary ratios based on the perfusion maps reached a physiological range comparable to in vivo observations, but only after 1 to 2 h after the start of NMP. Before that, the functionally important renal cortex appeared severely underperfused. Our findings suggest that early functional NMP quality assessment markers may not reflect actual physiology and should therefore be interpreted with caution.

Photoacoustic imaging of kidney fibrosis for assessing pretransplant organ quality.

Roughly 10% of the world's population has chronic kidney disease (CKD). In its advanced stages, CKD greatly increases the risk of hospitalization and death. Although kidney transplantation has revolutionized the care of advanced CKD, clinicians have limited ways of assessing donor kidney quality. Thus, optimal donor kidney-recipient matching cannot be performed, meaning that some patients receive damaged kidneys that function poorly. Fibrosis is a form of chronic damage often present in donor kidneys, and it is an important predictor of future renal function. Currently, no safe, easy-to-perform technique exists that accurately quantifies renal fibrosis. We describe a potentially novel photoacoustic (PA) imaging technique that directly images collagen, the principal component of fibrotic tissue. PA imaging noninvasively quantifies whole kidney fibrotic burden in mice, and cortical fibrosis in pig and human kidneys, with outstanding accuracy and speed. Remarkably, 3-dimensional PA imaging exhibited sufficiently high resolution to capture intrarenal variations in collagen content. We further show that PA imaging can be performed in a setting that mimics human kidney transplantation, suggesting the potential for rapid clinical translation. Taken together, our data suggest that PA collagen imaging is a major advance in fibrosis quantification that could have widespread preclinical and clinical impact.

Outcome of treosulfan-based reduced-toxicity conditioning regimens for HSCT in high-risk patients with primary immune deficiencies.

HSCT is the curative therapeutic option in PIDs. Due to the increase in survival rates, reduced-toxicity conditioning regimens with treosulfan have become another alternative. The purpose of this retrospective study was to analyze the outcome of treosulfan-based conditioning before HSCT for patients with PID. A total of 15 patients that received a treosulfan-based conditioning regimen for HSCT were recruited. Type of diagnosis, donor and stem cell source, pretransplant organ damage, infections, engraftment, chimerism, and transplant-related toxicities were analyzed. At a median follow-up time of 32months, the overall survival was 86.7%. Following HSCT, 14 of 15 patients had engraftment, with 86.7% of the cohort having full-donor chimerism. The most common toxicity was seen on the skin (53.3%). Acute GVHD and chronic GVHD were documented in 53% and 20% of the study population, respectively. Although the cohort consisted of patients with pretransplant liver damage, SOS manifestations were documented in 20%. Treosulfan-based conditioning regimens before HSCT are associated with lower toxicity compared to myeloablative regimens, are safe, and have high engraftment rates with full-donor chimerism in patients having PID, regardless of the specified genetic diagnosis and donor type.

Outcome of BONE Marrow Transplantation in Congenital Diskeratosis: Preliminary DATA from the European Group for BONE Marrow Transplantation (EBMT)

▪Hematopoietic Stem cell Transplantation (HSCT) is the definitive treatment for bone marrow failure in diskeratosis congenita (DC). Organ dysfunction (mainly lung and gastrointestinal tract) are often part of the disease and may be a limiting factor for or may affect the final outcome of HSCT. Scarce data or relatively small cohort studies are available in current literature on outcome of HSCT in this disease. We analyzed the outcome of 87 patients diagnosed with DC reported in the data base of the European Society for Blood an Bone Marrow Transplantation (EBMT) who underwent HSCT from 1979 to 2014. In particular we analyzed data on type of HSCT, characteristic of donors, source of cells, incidence of acute and chronic GvHD. Males were 76%. Median age at diagnosis of DC was 5.7 years (0-33 yrs), median age at HSCT was 11.2 years (range 0.56-41 yrs). Median time from diagnosis to HSCT was 19 months (0.62-304 mo). The cell source was bone marrow (BM) in 67%, peripheral blood (PB) in 22% and cord blood (CB) 11%. Twenty six percent of patients were engrafted from a matched related and 53% from a matched unrelated donor. Twenty one percent of subjects were engrafted from a mismatched (both related and unrelated) HSCT. Engraftment was documented in 95% of subjects: 4 % had primary graft failure and 10% lost the graft. Overall 35 patients (40%) died, and 52 were alive (60%) at last follow-up. Causes of death were: infections (43%), multi-organ failure (26%), rejection/oss of graft (14%), GvDH (8.5%) undefined (8.5%). In 32% of cases death was related to transplant. Lung injury was present in 17% of subjects who died. Acute GVDH (mainly grade 2-4) and chronic GvHD occurred in 39% and 30% of cases. Five year OS was 60 %. OS was not significantly different by calendar period (before and after year 2000: 50% vs 67% respectively, p=0.424), by age at transplant (below and above age of 12 years: 64% vs 55% respectively ; p= 0.564) and by source of cells (marrow 60%, cord blood 68%, and peripheral cells 46%; p= 0.687). Conversely, OS in HSCT from mismatched donor was inferior to that of transplants from matched donor (38% vs 65% respectively; p= 0.045). The use of radiotherapy or busulfan (any dose) in the conditioning vs other regimens did not impact on 5 y-OS ( 58% vs 62% respectively; p=0.898). HSCT from HLA matched donor can be considered a treatment option in DC. Transplant related mortality looks rater high. Multi organ failure and lung injury are amongst the main causes of death thus pointing to pre-transplant organ status as important determinant of HSCT outcome. DisclosuresDufour:Pfizer: Consultancy.

Clinical Significance of Risk Stratification Based on Disease Risk Index and Hematopoietic Cell Transplantation-Comorbidity Index

Introduction: Allogeneic hematopoietic cell transplantation (HCT) has curative potential for a variety of hematologic malignancies. However, the success of HCT is heavily dependent on the disease and remission status. Armand et al. recently proposed a disease risk index (DRI) to assess the risk for allogeneic HCT based on the disease and remission status, and could be used to risk stratification on survival (Armand et al Blood 2012), but evaluation of its clinical significance is limited. HCT-comorbidity index (HCT-CI) was developed as a measure of pretransplant organ dysfunctions (Sorror et al Blood 2005), which has been shown to be associated with nonrelapse mortality (NRM). In order to clarify any association between pretransplant factors including DRI and HCT-CI, and respective overall survival (OS), NRM and relapse rate, we retrospectively reviewed the data of patients who underwent allogeneic HCT at our department.Patients and Methods: A total of 305 patients with hematologic malignancies who underwent initial allogeneic HCT at our department between January 2000 and April 2013 were included. After excluding patients with insufficient HCT data, we included a total of 244 patients (138 male, 106 female) with a median age of 49.5 (range 15-69) years. A total of 133 patients received myeloablative conditioning and 111 received reduced-intensity regimens. Stem cell sources were bone marrow (n=177), peripheral blood (n=32), combined peripheral blood and bone marrow (n=1), and cord blood (n=34). A total of 146 patients received tacrolimus-based regimens and 98 patients received cyclosporine-based regimens for GVHD prophylaxis. The DRI has four risk-based categories (low, intermediate, high, and very high) and the HCT-CI has three categories in order of ascending risk (0, 1-2 and ≥3). OS was calculated with the Kaplan-Meier method, compared among groups with the log-rank test, and multivariable Cox regression analyses were used to evaluate factors associated with OS. The cumulative incidence of NRM and relapse were calculated while treating relapse and death without relapse, respectively, as competing events, and competing risk regression analyses were used to evaluate risk factors associated with NRM and relapse.Results: The median follow-up for survivors was 4.7 years (range 0.1-14.2 years). Pretransplant disease risks in the DRI low, intermediate, high, and very high risk groups were 8%, 60%, 25%, and 7%, and 4-year OS in the same groups were 74%, 64%, 35%, and 12%, respectively (Figure 1, p<0.001). Four-year OS among patients with a HCT-CI of 0, 1-2, and ≥3 were 63%, 52%, and 41%, respectively. Multivariable analysis showed a significant association with OS for DRI (high risk hazard ratio [HR] 2.62, p<0.001; very high risk HR 5.26, p<0.001 versus intermediate risk), HCT-CI (HCT-CI ≥3 HR 1.64, p=0.022 versus HCT-CI 0-2), 2-4 performance status (HR 3.10, p<0.001), and donor-recipient ABO minor-mismatch (HR 2.00, p=0.005 versus ABO match). The cumulative incidence of 4-year NRM was 25%, and NRM was significantly associated with HCT-CI (HCT-CI ≥3 HR 2.27, p=0.003 versus HCT-CI 0-2) and 2-4 performance status (HR 3.89, p<0.001). The cumulative incidence of 4-year relapse was 25%, and relapse was significantly associated with DRI (high risk HR 2.26, p=0.012; very high risk HR 8.11, p<0.001 versus intermediate risk). Finally, we reclassified all patients into four risk groups incorporating DRI and HCT-CI: DRI low-intermediate plus HCT-CI 0-2 (group I), DRI low-intermediate plus HCT-CI ≥3, or DRI high plus HCT-CI 0-2 (group II), DRI high plus HCT-CI ≥3 (group III), and DRI very high (group IV). Four-year OS among patients with group I, II, III, and IV were 68%, 47%, 25%, and 12%, respectively (Figure 2, p<0.001).Conclusions: Our results suggest that risk stratification with DRI and HCT-CI for the prognosis of relapse and NRM may be useful for patients undergoing allogeneic HCT. Larger and prospective studies are warranted to more precisely validate these findings. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Donation After Circulatory Death

Organ donation after circulatory death (DCD) has been endorsed by the World Health Organization and is practiced worldwide. This overview examines current DCD practices, identifies problems and challenges, and suggests clinical strategies for possible improvement. Although there is uniform agreement on DCD donor candidacy (ventilator-dependent individuals with nonrecoverable or irreversible neurologic injury not meeting brain death criteria), there are variations in all aspects of DCD practice. Utilization of DCD organs is limited by hypoxia, hypotension, reduced--then absent--organ perfusion, and ischemia/reperfusion syndrome. Nevertheless, DCD kidneys exhibit comparable function and survival to donors with brain death kidneys, although they have higher rates of primary graft nonfunction, delayed graft function, discard, and retrieval associated injury. Concern over ischemic organ injury underscores the reluctance to recover extrarenal DCD organs since lack of medical therapy to support inadequate allograft function limits their acceptability. Nevertheless, limited results with DCD pancreas, liver, and lung allografts (but not heart) are now approaching that of donors with brain death organs. Pretransplant machine perfusion of DCD kidneys (vs. static storage) may reduce delayed graft function but has no effect on long-term organ function and survival. Normothermic regional perfusion used during DCD abdominal organ retrieval may reduce ischemic organ injury and increase the number of usable organs, although critical confirmative studies have yet to be done. Minor increases in usable DCD kidneys could accrue from increased use of pediatric DCD kidneys and from selective use of DCD/ECD kidneys, whereas a modest increase could result through utilization of donors declared dead beyond 1 hr from withdrawal of life support therapy. A significant increase in transplantable kidneys could be achieved by extension of the concept of living kidney donation in relation to imminent death of potential DCD donors. Progress in research to identify, prevent, and repair DCD-associated organ retrieval injury should improve utilization of DCD organs. Recent results using ex situ pretransplant organ perfusion of DCD organs has been encouraging in this regard.

Autologous Hemopoietic Stem-Cell Transplantation in Patients with Preexisting Cardiac Abnormalities.

INTRODUCTION: High dose chemotherapy and autologous hemopoietic stem cells transplantation (AHSCT) represents an useful treatment for patients undergoing hematological diseases. Relapsed lymphomas, acute leukemias and multiple myeloma achieve a better outcome with a low incidence of complications and mortality related to the procedure. Assessment of pre-transplant organ function (including cardiopulmonary, kidney and liver) is a routine part of eligibility criteria for AHSCT protocols. Left ventricle (LV) function has been considered one of the most important risk factor in predicting complications or mortality related to transplantation, although, previous studies have not confirmed these issues. The purpose of our retrospective study was to investigate differences among clinical outcome, therapeutic requirements and Transplant Related Mortality (TRM) in patients (pts) undergoing AHSCT with and without cardiac pathology.METHODS: We retrospectively reviewed data from 290 pts undergoing AHSCT between September 1991 to June 2006. Routine pretransplant evaluation included ECG and Bidimensional Echocardiography (BE). We compared Group A including pts with any of the following: Impairment of Left Ventricle systolic function (ILVF) (Ejection fraction <50%), Ischaemic cardiac disease (ICD), Dilated myocardiopathy (DM), Valvulopathy (VP), Chronic arrythmia (CA), Wall motion abnormalities (WMA), and Restrictive myocardiopathy (RM); and Group B pts with no cardiac abnormalities. Clinical course, infectious, cardiopulmonary or other complications, hematological recovery time and TRM were reviewed for each enrolled pts. Statistical analysis was performed using chi square tests.RESULTS: Group B (control) included 269 of 290 evaluated pts without cardiac abnormalities and group A included 21 pts with the following criteria: 5 pts: DM, 5 pts: ICD, 6 pts: VP, 2 pts: CA, 2 pts: RM and 1 pts: ILVF. Mean age in Group A was higher than control group (49,1 ±13 vs 36,1 ±16) p<0,001. No differences was found between both groups about: Gender (male 58% vs female 51%), Diagnosis (Group A: Non-Hodgkin's Lymphoma 38,1%, Hodgkin's Disease 14,3%, Acute Leukemia 9,5%, Multiple Myeloma 38,1% vs Group B: Non-Hodgkin's Lymphoma 24,5%, Hodgkin's Disease 26,7%, Acute Leukemia 17,4%, Multiple Myeloma 19,3%), Stem cell source (Group A: Peripheral Blood Stem cells 90,5% vs 72% in group B) or Mean number of administered CD 34 positive cells (4,2 × 106 ±2,5/kg in group A vs 7,066 ±3,4/kg in control group). Comparative Results between Groups are shown in the table:CONCLUSIONS: No significant differences were observed among hospitalization time, infectious episodes, extracardiac toxicities and transplant related mortality. The incidence of cardiac complications was higher but this did not increase the number of TRM. These results prevent us about rigid eligibility criteria that potentially denie patients the benefit of AHSCT.Group AGroup BHospitalization days*23±524±10,3Neutrophil Engrafment (days)*11,3±3,712,05±4,3Days on antibiotics*11±4,111,6±5,5Positive Blood Cultures(%)*23,827,1Platelet engrafment (days)*13,5915,66Packed red cell transfused (n)*4,23,22Platelet transfused (n)*5,95,64Acute Renal dysfunction(%)*9,54Congestive Heart Failure(%)**14,32,8Hepatotoxicity(%)*14,38,3Pulmonary Injury(%)*4,73,8Arrythmias(%)**14,32,9Grade III–IV Mucositis(%)*42,951TRM(%)*4,83,42* p NS **p<0,05

The sentinel chicken revisited: the impact of West Nile virus infection on transplant patients.

The sentinel chicken revisited: the impact of West Nile virus infection on transplant patients.

Nonfreezing cryopreservation--a possible means of improving long-term transplant function?

Improving organ preservation techniques for transplantation is one of the most important goals of transplantation research. We have established a new, nonfreezing cryopreservation method to optimize the viability of rat kidneys for transplantation with up to 4 M dimethylsulphoxide (DMSO) in EuroCollins solution (EC) at -5 degrees C to -15 degrees C. We have confirmed the occurrence of a tubular and glomerular defect pattern that mediates acute tubular necrosis (ATN) and that may be a cause of major histocompatibility complex (MHC) independent immunological components of chronic transplant rejection. The extent of this defect [transplant survival and function, 31P-NMR spectroscopy, histological defect index] in the nonfreezing cryopreserved groups (n = 22) is significantly (P = 0.017) lower than in the simple cold storage group (n = 12). Quality and localization of the lesions in kidney transplants can elucidate the context of organ preservation, progressive hyperfiltration defects, and the occurrence of graft failure without elevated frequency of acute rejection episodes. These results indicate that further efforts to provide higher pretransplant organ viability without using it to prolong cold storage intervals may provide better insight into MHC-independent factors of chronic transplant failure and may result in improved long-term transplant outcome.

Nonfreezing cryopreservation – a possible means of improving long-term transplant function?

Abstract Improving organ preservation techniques for transplantation is one of the most important goals of transplantation research. We have established a new, non-freezing cryopreservation method to optimize the viability of rat kidneys for transplantation with up to 4 M dimethylsulphoxide (DMSO) in EuroCollins solution (EC) at -5 °C to -15 °C. We have confirmed the occurrence of a tubular and glomerular defect pattern that mediates acute tubular necrosis (ATN) and that may be a cause of major histocompatibility complex (MHC) independent immunological components of chronic transplant rejection. The extent of this defect [transplant survival and function, 31P-NMR spectroscopy, histological defect index] in the nonfreezing cryopreserved groups (n= 22) is significantly (P= 0.017) lower than in the simple cold storage group (n= 12). Quality and localization of the lesions in kidney transplants can elucidate the context of organ preservation, progressive hyperfiltration defects, and the occurrence of graft failure without elevated frequency of acute rejection episodes. These results indicate that further efforts to provide higher pretransplant organ viability without using it to prolong cold storage intervals may provide better insight into MHC-independent factors of chronic transplant failure and may result in improved long-term transplant outcome.