Should advanced perfusion be the standard of care for donation after circulatory death liver transplant?

As an alternative to static cold storage (SCS), advanced perfusion techniques such as normothermic regional perfusion and ex-situ perfusion (normothermic or hypothermic) have emerged as a way to improve the ischemic injury suffered by donation after circulatory death (DCD) livers. Multiple studies have been published that have demonstrated superior post-DCD liver transplant outcomes when using advanced perfusion compared with SCS. In particular, these studies have shown lower rates of ischemic cholangiopathy with advanced perfusion. In addition to the improved post-liver transplant outcomes, studies have also demonstrated higher rates of liver utilization from DCD donors when advanced perfusion is used compared with SCS. Given the high rates of graft loss in patients who develop ischemic cholangiopathy, the significant reduction seen in DCD donor livers that have undergone advanced perfusion represents a key step in more broad utilization of these livers. With such compelling evidence from multiple trials, it seems reasonable to ask the question: should advanced perfusion be the standard of care for DCD liver transplant?

Extended Right Hepatectomy to Inferior Vena Cava Under Total Vascular Exclusion, Veno-Venous Bypass and In Situ Hypothermic Perfusion of the Future Liver Remnant.

BACKGROUND: Venous obstruction at the hepatic veins-inferior vena cava confluence can be particularly challenging to manage if an associated liver resection is needed. Total vascular exclusion (TVE) with veno-venous bypass (VVB) and hypothermic in situ perfusion (HP) of the future liver remnant can be used in these conditions.1,2 METHODS: The patient was a 58-year-old with a voluminous adrenal cancer invading the kidney, the right liver and the retrohepatic inferior vena cava with intraluminal thrombus extending up to the hepatic veins confluence. A right hepatectomy, extended to segment 1, the right kidney, and the retrohepatic inferior vena cava was planned. RESULTS: The parenchymal liver transection was performed under a TVE, VVB, and HP of the left liver to decrease blood losses and risk of postoperative liver failure. Vena cava reconstruction was achieved by a ringed Gore-Tex prosthesis with reimplantation of the left renal vein. Total duration of veno-venous bypass and liver vascular exclusion were 2 h 40 min and 2 h 10 min, respectively. The patient was discharged on postoperative day 17. CONCLUSIONS: Total vascular exclusion with veno-venous bypass and in-situ liver hypothermic perfusion increases the safety of major liver resection requiring complex vascular reconstruction.1,2 TVE under VVB and HP of the future liver remnant is used at our institution when: (1) TVE will last more than 30 min; (2) vascular reconstruction is needed; (3) in the presence of venous obstruction; (4) in the presence of injured liver parenchyma; and (5) in the presence of cardiovascular comorbidities.

Graft preservation in heart transplantation: current approaches.

Heart transplantation (HTx) represents the current best surgical treatment for patients affected by end-stage heart failure. However, with the improvement of medical and interventional therapies, the population of HTx candidates is increasingly old and at high-risk for mortality and complications. Moreover, the use of "extended donor criteria" to deal with the shortage of donors could increase the risk of worse outcomes after HTx. In this setting, the strategy of donor organ preservation could significantly affect HTx results. The most widely used technique for donor organ preservation is static cold storage in ice. New techniques that are clinically being used for donor heart preservation include static controlled hypothermia and machine perfusion (MP) systems. Controlled hypothermia allows for a monitored cold storage between 4°C and 8°C. This simple technique seems to better preserve the donor heart when compared to ice, probably avoiding tissue injury due to sub-zero °C temperatures. MP platforms are divided in normothermic and hypothermic, and continuously perfuse the donor heart, reducing ischemic time, a well-known independent risk factor for mortality after HTx. Also, normothermic MP permits to evaluate marginal donor grafts, and could represent a safe and effective technique to expand the available donor pool. However, despite the increasing number of donor hearts preserved with these new approaches, whether these techniques could be considered superior to traditional CS still represents a matter of debate. The aim of this review is to summarize and critically assess the available clinical data on donor heart preservation strategies employed for HTx.

Hypothermic Perfusion Modifies the Association Between Anti-LG3 Antibodies and Delayed Graft Function in Kidney Recipients.

We previously reported associations between autoantibodies to the LG3 fragment of perlecan, anti-LG3, and a higher risk of delayed graft function (DGF) in kidney transplant recipients. Here, we aimed to determine whether some factors that modulate ischemia-reperfusion injury (IRI) can modify this association. We performed a retrospective cohort study in kidney transplant recipients in 2 university-affiliated centers. In 687 patients, we show that high pre-transplant anti-LG3 are associated with DGF when the kidney is transported on ice (odds ratio (OR): 1.75, 95% confidence interval 1.02-3.00), but not when placed on hypothermic perfusion pump (OR: 0.78, 95% CI 0.43-1.37). In patients with DGF, high pre-transplant anti-LG3 are associated with a higher risk of graft failure (subdistribution hazard ratio (SHR): 4.07, 95% CI: 1.80, 9.22), while this was not the case in patients with immediate graft function (SHR: 0.50, 95% CI 0.19, 1.29). High anti-LG3 levels are associated with a higher risk of DGF in kidneys exposed to cold storage, but not when hypothermic pump perfusion is used. High anti-LG3 are also associated with a higher risk of graft failure in patients who experience DGF, a clinical manifestation of severe IRI.

Ex-Vivo Preservation of Heart Allografts-An Overview of the Current State.

As heart transplantation continues to be the gold-standard therapy for end-stage heart failure, the supply-demand imbalance of available organs worsens. Until recently, there have been no advances in increasing the donor pool, as prolonged cold ischemic time excludes the use of certain donors. The TransMedics Organ Care System (OCS) allows for ex-vivo normothermic perfusion, which allows for a reduction of cold ischemic time and allows for long-distance procurements. Furthermore, the OCS allows for real-time monitoring and assessment of allograft quality, which can be crucial for extended-criteria donors or donation after cardiac death (DCD) donors. Conversely, the XVIVO device allows for hypothermic perfusion to preserve allografts. Despite their limitations, these devices have the potential to alleviate the supply-demand imbalance in donor availability.

Clinical outcomes of robotic-assisted laparoscopic partial nephrectomy with renal hypothermia perfusion by renal artery balloon catheter in treating patients with complex renal tumors.

Objective: This study aimed to investigate the safety and efficacy of renal hypothermic perfusion by renal artery balloon catheter during robot-assisted laparoscopic partial nephrectomy (P-RALPN) for patients with complex renal tumors. Materials and methods: We retrospectively identified 45 patients with complex renal tumors who received standard robot-assisted laparoscopic partial nephrectomy (S-RALPN) and 11 patients treated with P-RALPN from September 2017 to October 2021. Preoperative patients' characteristics and intraoperative surgical parameters including operating time, blood loss, hospitalization, pre- and post-surgical glomerular filtration rate (GFR), and postoperative survival time were collected and compared between the two groups. The patients' body temperature, real-time kidney temperature, and short-term renal function were analyzed in the P-RALPN group. Results: There was no statistically significant difference on median intraoperative estimated blood loss and postoperative hospitalization between the two groups. Patients who received P-RALPN had a slightly longer operative time than those who received S-RALPN (103.1 versus 125.9; p = 0.09). In the P-RALPN group, the volume of perfusion solution was 533.2 ml (range, 255.0-750.0 ml), the median temperature of kidney was 22.6°C (range, 21.7-24.1°C) after the kidney cools down, and the median minimum intraoperative temperature of patients was 36.1°C (range 35.2-36.7°C). The ischemia time in the S-RALPN group was markedly lower than that in the P-RALPN group (21.5 versus 34.8; p < 0.01). However, the loss of GFR was much higher for the S-RALPN group after the surgery. (28.9 versus 18.4; p < 0.01). Importantly, patients had similar postoperative survival time between the two groups (p = 0.42; HR = 0.27). Conclusion: P-RALPN is a safe and feasible surgery in the treatment of patients with complex renal tumors, which provides a new operative approach for clinicians to treat these patients.

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 Delivery of Pharmacologic Agents During Machine Perfusion to Prevent Ischaemia-Reperfusion Injury: From Murine Model to Clinical Trials.

Donor organ shortage still remains a serious obstacle for the access of wait-list patients to kidney transplantation, the best treatment for End-Stage Kidney Disease (ESKD). To expand the number of transplants, the use of lower quality organs from older ECD or DCD donors has become an established routine but at the price of increased incidence of Primary Non-Function, Delay Graft Function and lower-long term graft survival. In the last years, several improvements have been made in the field of renal transplantation from surgical procedure to preservation strategies. To improve renal outcomes, research has focused on development of innovative and dynamic preservation techniques, in order to assess graft function and promote regeneration by pharmacological intervention before transplantation. This review provides an overview of the current knowledge of these new preservation strategies by machine perfusions and pharmacological interventions at different timing possibilities: in the organ donor, ex-vivo during perfusion machine reconditioning or after implementation in the recipient. We will report therapies as anti-oxidant and anti-inflammatory agents, senolytics agents, complement inhibitors, HDL, siRNA and H2S supplementation. Renal delivery of pharmacologic agents during preservation state provides a window of opportunity to treat the organ in an isolated manner and a crucial route of administration. Even if few studies have been reported of transplantation after ex-vivo drugs administration, targeting the biological pathway associated to kidney failure (i.e. oxidative stress, complement system, fibrosis) might be a promising therapeutic strategy to improve the quality of various donor organs and expand organ availability.

Ischemia-Reperfusion Injuries Assessment during Pancreas Preservation.

Maintaining organ viability between donation and transplantation is of critical importance for optimal graft function and survival. To date in pancreas transplantation, static cold storage (SCS) is the most widely practiced method of organ preservation. The first experiments in ex vivo perfusion of the pancreas were performed at the beginning of the 20th century. These perfusions led to organ oedema, hemorrhage, and venous congestion after revascularization. Despite these early hurdles, a number of factors now favor the use of perfusion during preservation: the encouraging results of HMP in kidney transplantation, the development of new perfusion solutions, and the development of organ perfusion machines for the lung, heart, kidneys and liver. This has led to a resurgence of research in machine perfusion for whole organ pancreas preservation. This review highlights the ischemia-reperfusion injuries assessment during ex vivo pancreas perfusion, both for assessment in pre-clinical experimental models as well for future use in the clinic. We evaluated perfusion dynamics, oedema assessment, especially by impedance analysis and MRI, whole organ oxygen consumption, tissue oxygen tension, metabolite concentrations in tissue and perfusate, mitochondrial respiration, cell death, especially by histology, total cell free DNA, caspase activation, and exocrine and endocrine assessment.

Kidney Transplants From Donors on Extracorporeal Membrane Oxygenation Prior to Death Are Associated With Better Long-Term Renal Function Compared to Donors After Circulatory Death.

Donation after circulatory death (DCD) allows expansion of the donor pool. We report on 11 years of Italian experience by comparing the outcome of grafts from DCD and extracorporeal membrane oxygenation (ECMO) prior to death donation (EPD), a new donor category. We studied 58 kidney recipients from DCD or EPD and collected donor/recipient clinical characteristics. Primary non function (PNF) and delayed graft function (DGF) rates, dialysis need, hospitalization duration, and patient and graft survival rates were compared. The estimated glomerular filtration rate (eGFR) was measured throughout the follow-up. Better clinical outcomes were achieved with EPD than with DCD despite similar graft and patient survival rates The total warm ischemia time (WIT) was longer in the DCD group than in the EPD group. Pure WIT was the highest in the class II group. The DGF rate was higher in the DCD group than in the EPD group. PNF rate was similar in the groups. Dialysis need was the greatest and hospitalization the longest in the class II DCD group. eGFR was lower in the class II DCD group than in the EPD group. Our results indicate good clinical outcomes of kidney transplants from DCD despite the long "no-touch period" and show that ECMO in the procurement phase improves graft outcome, suggesting EPD as a source for pool expansion.

Successful pancreas allotransplantations after hypothermic machine perfusion in a novel diabetic porcine model: a controlled study.

The standard technique for pancreas preservation for transplantation is static cold storage (SCS). In this experimental study, we compare SCS to hypothermic machine perfusion (HMP) of the pancreas to assess if the latter could safely prolong the ischaemia period prior to transplantation. We worked in two phases, first with organ preservation for 24 h and second, preservation for either 2 or 6 h before allotransplantation. In phase 1, exocrine injury markers were found to be nonsignificantly lower, in the HMP group (n = 3) vs. SCS (n = 3) after 24 h of preservation; amylase (P = 0.2), lipase (P = 0.3) and lactate dehydrogenase (P = 0.1). In phase 2, 14 recipient diabetic pigs (after total pancreatectomy) received allotransplantations with n = 4 and n = 4 pancreases after HMP for 2 and 6 h vs. n = 3 and n = 3 pancreases after SCS for 2 and 6 h, respectively. There were no differences in recipient survival (P = 0.7), and mean survival was 14 days (0-53 days). All recipients had allograft function defined as detectable C-peptide and independent normoglycemia. We have not highlighted vascular thrombosis in all allotransplantations. This study reports the first successful pancreas allotransplantation after HMP preservation for up to 6 h with no evidence of graft thrombosis.

Outcome after ex situ or ante situm liver resection with hypothermic perfusion and auto-transplantation: A single-centre experience in adult and paediatric patients.

BACKGROUND: Evolving surgical technology and medical treatment have led to an expansion of indications to enable resection of large hepatic tumours with involvement of other abdominal structures. METHODS: Twelve extended liver and abdominal resections, either ex situ with auto-transplantation of the liver remnant or ante situm with veno-venous bypass (VVBP) were performed between 2016 and 2018. We describe our preoperative assessment, compare surgical strategies and assess outcomes. RESULTS: The median age of the 10 adult patients was 50.5 years with a majority suffering from sarcoma-like tumours. The two paediatric patients were 3 and 8 years of age, both with hepatoblastoma. Two patients underwent ex situ resections with auto-transplantation of the liver remnant, and nine patients had ante situm tumour removal with the use of VVBP in four. All patients achieved a good immediate liver function. Local infection and acute kidney injury were found in two patients. One patient underwent biliary reconstruction for bile leak. Tumour recurrence was seen in seven patients (58.3%), with four lung metastases. Five patients died from tumour recurrence (41.7%) during the follow-up. CONCLUSION: Extreme liver resections should be performed in experienced centres, where surgical subspecialties are available with access to cardiovascular support. Additionally, experience in split and living-donor liver transplantation is beneficial.

Ex situ hypothermic perfusion of nonhuman primate pancreas: A feasibility study.

Pancreatic static cold storage (SCS) is the gold-standard method for pancreas preservation. Our main objective was to evaluate feasibility of hypothermic perfusion (HP) of nonhuman primates' pancreases for potential organ transplantation. Seven baboon pancreases were tested. Animals were included in a study approved by the French Research Ministry of Health. Two groups were compared: the control group (n = 2) was preserved using conventional SCS for 24-h and the perfusion group (n = 5) used HP for 24-h, with three different perfusion pressures (PP): 15 (n = 3), 20 (n = 1), and 25 mm Hg (n = 1). In the control group, focal congestion of islets was observed after 6-h. At 24-h, ischemic necrosis and multifocal congestion also occurred. In the HP group, at 15 mm Hg PP, multifocal congestion of islets was present at 24-h. At 20 mm Hg PP, no ischemic necrosis was found after 6-h. At 12-h and 24-h, focal congestion of islets was seen. At 25 mm Hg PP, focal congestion of islets appeared after 12-h. Immunostaining for insulin, glucagon, and somatostatin was normal and similar in controls and perfused pancreas transplants even after 24-h. Apoptosis index represented by cleaved caspase 3 activity, was less than 1% in perfusion and control groups, even after 24-h. HP of nonhuman primate pancreas is feasible and not deleterious as far as 24-h compared to SCS. SCS for more than 12-h was harmful for the transplants. Systolic perfusion pressure between 15-20 mm Hg did not cause any pathological injury of the tested organs.

Hypothermic perfusion hepatectomy for unresectable liver cancer: A single-center experience.

BACKGROUND: The resection of liver tumors that involve the hepatic veins adjacent to the vena cava or hepatic hilum is technically challenging. We present our surgical techniques and the long-term outcome of five patients with conventionally unresectable tumors. METHODS: Five patients with conventionally unresectable tumors were successfully treated by "ex-situ liver resection" and "in-situ and ante-situm hypothermic liver perfusion" under total vascular exclusion and venovenous bypass. RESULTS: These approaches allowed complete tumor removal with vascular reconstruction under a bloodless surgical field, while minimizing hepatic ischemic injury and preserving liver function. No perioperative mortalities occurred, and postoperative complications were minimal. The postoperative survival periods were limited due to the advanced malignancies in our patients, but the survival benefit was encouraging. The median postoperative survival time was 29.1 months, with the longest survival period being nearly 10 years. These approaches improved the quality of life and provided an opportunity for additional treatment. CONCLUSIONS: Hypothermic perfusion hepatectomy is a realistic option for achieving surgical cure or significantly improved survival and quality of life in patients with tumors deemed unresectable using conventional normothermic hepatectomy. These approaches can overcome the limitations of the liver's restricted normothermic ischemia tolerance or inaccessible tumor locations.

Application of Hypothermic Perfusion via a Renal Artery Balloon Catheter During Robot-assisted Partial Nephrectomy and Effect on Renal Function.

RATIONALE OBJECTIVES: To assess the feasibility, safety, and effect of hypothermic perfusion on postoperative renal function employing a renal artery balloon catheter inserted via robot-assisted partial nephrectomy (h-RAPN) to treat renal tumors. MATERIALS AND METHODS: Forty-three patients with renal tumors were studied between March 2013 and August 2017. Renal artery balloon catheters were placed under angiographic guidance, and the balloon was fully inflated to occlude the renal artery during surgery. After establishing venous outflow, a robot-assisted partial nephrectomy was performed following perfusion with sodium lactate Ringer's solution at 4°C through the balloon catheter. Renal dynamic imaging was used to assess renal function, with calculation units consisting of glomerular filtration rate per unit volume of the kidney (GFR-UV). RESULTS: Six patients were converted to radical nephrectomy intraoperatively, and the remaining 37 patients successfully underwent the h-RAPN procedure. Two patients had incomplete occlusion of the renal artery and received supplementary arterial clamp occlusion intraoperatively. One patient's balloon catheter slipped out of position preoperatively, and the patient was returned to the interventional radiology suite for balloon reinsertion, after which the patient underwent surgery successfully. No patients had severe complications. The average cold ischemia time was 39.5 ± 9.7 min (range, 22-123 min), the average temperature of the affected kidney during surgery was 19.3 ± 3.5°C (17.2-26.7°C), the average postoperative GFR-UV of the affected kidney was 0.42 ± 0.09 ml/min/ml (0.21-1.24 ml/min), and the average postoperative GFR-UV of the healthy kidney was 0.30 ± 0.04 ml/min/ml (P > 0.05). Multiple regression analysis indicated that cold ischemia time was an independent risk factor affecting the postoperative GFR of the affected kidney. CONCLUSION: The advantages of h-RAPN include a clear surgical field enabling precise resection. When hypothermic perfusion via a renal artery balloon catheter is performed in conjunction with h-RAPN, the surgical time can be lengthened without increasing impairment of the affected kidney function, making this a safe and effective method of treating kidney tumors.

Differential selective hypothermic intercostal artery perfusion: a new method to probe spinal cord perfusion during thoracoabdominal aortic aneurysm repair.

OBJECTIVE: To prevent paraplegia in patients undergoing thoracoabdominal aortic aneurysm repair, the importance of preoperative identification of the Adamkiewicz artery and reconstruction of critical intercostal artery have been advocated. Conversely, significance of collateral network for spinal cord perfusion has been recognized. We invented a new system consisting of a direct monitoring of cerebrospinal fluid temperature (CSFT) and differential selective hypothermic intercostal artery perfusion (D-HIAP). METHODS: After exposing a critical intercostal artery, a 10-mm prosthetic graft was anastomosed in an end to side fashion. A balloon-tipped catheter was inserted into the graft to perfuse with 15 °C blood. Neighboring intercostal arteries were also perfused in the same fashion. Serial monitoring of CSFT was performed. Between January 2011 and January 2015, D-HIAP was employed in 50 patients with Adamkiewicz artery that located within a reconstructed area. RESULTS: Significant CSFT drop was recorded after initiation of D-HIAP in 42 (84%) patients. Of those, 34 (68%) patients showed significantly lowered CSFT with D-HIAP into a single critical intercostal artery. Perfusion into plural intercostal arteries was necessary for CSFT drop in 2 cases (4%), and plural intercostal artery perfusion further enhanced CSFT drop that had been modestly achieved by single intercostal artery perfusion in 6 cases (12%). Eight (16%) patients did not exhibit a significant drop in CSFT even when D-HIAP was employed for the critical and neighboring intercostal arteries. CONCLUSIONS: The detection of a disparity in temperature between the intrathecal space and blood generated by D-HIAP revealed individual variability in CSFT changes, which may imply a complexity in spinal cord perfusion. Intraoperative D-HIAP may help to identify a major blood supply for spinal cord perfusion and underlying collateral network.

Role of perfusion machines in the setting of clinical liver transplantation: A qualitative systematic review.

Growing enthusiasm around machine perfusion (MP) in clinical liver transplantation (LT) may be the preamble for standardized practice to expand the donors' pool. The present systematic review investigated all the liver transplantations performed using grafts treated with MP. A systematic review of 309 papers was performed. Eventually, 27 articles were enrolled for the study. A total number of 173 cases were reported. Only 12 cohort studies were identified: the remaining ones were case reports or case series. Hypothermic machine perfusion was performed in 102 (59.0%), normothermic machine perfusion in 65 (37.6%), and controlled oxygenated rewarming in the remaining 6 (3.4%) cases. Donor characteristics, evaluation of graft quality, and endpoints were not homogeneous among the studies. Overall, post-LT results were excellent, with 1.2 and 4.0% of patients experienced primary non-function and ischemic-type biliary lesions, respectively. CONCLUSION: Until now, no study exists that addresses the role of MP in selecting liver grafts available for LT. All the published studies mainly focused on the feasibility and safety of this new technology. Further research investigating the selection process of marginal donors is required.