Static cold storage compared with normothermic machine perfusion of the liver and effect on ischaemic-type biliary lesions after transplantation: a propensity score-matched study.

BACKGROUND: Given the susceptibility of organs to ischaemic injury, alternative preservation methods to static cold storage (SCS), such as normothermic machine perfusion (NMP) are emerging. The aim of this study was to perform a comparison between NMP and SCS in liver transplantation with particular attention to bile duct lesions. METHODS: The outcomes of 59 consecutive NMP-preserved donor livers were compared in a 1 : 1 propensity score-matched fashion to SCS control livers. Postoperative complications, patient survival, graft survival and bile duct lesions were analysed. RESULTS: While patients were matched for cold ischaemia time, the total preservation time was significantly longer in the NMP group (21 h versus 7 h, P < 0.001). Patient and graft survival rates at 1 year were 81 versus 82 per cent (P = 0.347) and 81 versus 79 per cent (P = 0.784) in the NMP and SCS groups, respectively. The postoperative complication rate was comparable (P = 0.086); 37 per cent NMP versus 34 per cent SCS patients had a Clavien-Dindo grade IIIb or above complication. There was no difference in early (30 days or less) (NMP 22 versus SCS 19 per cent, P = 0.647) and late (more than 30 days) (NMP 27 versus SCS 36 per cent, P = 0.321) biliary complications. However, NMP-preserved livers developed significantly fewer ischaemic-type bile duct lesions (NMP 3 versus SCS 14 per cent, P = 0.047). CONCLUSION: The use of NMP allowed for a significantly prolonged organ preservation with a lower rate of observed ischaemic-type bile duct lesions.

Delayed Implantation of Pumped Kidneys Decreases Renal Allograft Futility in Combined Liver-Kidney Transplantation.

BACKGROUND: Combined liver-kidney transplantation (CLKT) improves survival for liver transplant recipients with renal dysfunction; however, the tenuous perioperative hemodynamic and metabolic milieu in high-acuity CLKT recipients increases delayed graft function and kidney allograft failure. We sought to analyze whether delayed KT through pumping would improve kidney outcomes following CLKT. METHODS: A retrospective analysis (University of California Los Angeles [n = 145], Houston Methodist Hospital [n = 79]) was performed in all adults receiving CLKT at 2 high-volume transplant centers from February 2004 to January 2017, and recipients were analyzed for patient and allograft survival as well as renal outcomes following CLKT. RESULTS: A total of 63 patients (28.1%) underwent delayed implantation of pumped kidneys during CLKT (dCLKT) and 161 patients (71.9%) received early implantation of nonpumped kidneys during CLKT (eCLKT). Most recipients were high-acuity with median biologic model of end-stage liver disease (MELD) score of, 35 for dCLKT and 34 for eCLKT (P = ns). Pretransplant, dCLKT had longer intensive care unit stay, were more often intubated, and had greater vasopressor use. Despite this, dCLKT exhibited improved 1-, 3-, and 5-year patient and kidney survival (P = 0.02) and decreased length of stay (P = 0.001), kidney allograft failure (P = 0.012), and dialysis duration (P = 0.031). This reduced kidney allograft futility (death or continued need for hemodialysis within 3 mo posttransplant) for dCLKT (6.3%) compared with eCLKT (19.9%) (P = 0.013). CONCLUSIONS: Delayed implantation of pumped kidneys is associated with improved patient and renal allograft survival and decreased hospital length of stay despite longer kidney cold ischemia. These data should inform the ethical debate as to the futility of performing CLKT in high-acuity recipients.

Machine Perfusion: Cold versus Warm, versus Neither. Update on Clinical Trials.

Machine perfusion (MP) preservation is potentially one of the most significant improvements in the field of liver transplantation in the last 20 years, and it has been considered a promising strategy for improved preservation and ex situ evaluation of extended criteria donor (ECD) organs. However, MP preservation adds significant cost and logistical considerations to liver transplantation. MP protocols are mainly classified according to the perfusion temperature with hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP) being the two categories most studied so far. After extensive preclinical work, MP entered the clinical setting, and there are now several studies that demonstrated feasibility and safety. However, because of the limited quality of clinical trials, there is no compelling evidence of superiority in preservation quality, and liver MP is still considered experimental in most countries. MP preservation is moving to a more mature phase, where ongoing and future studies will bring new evidence in order to confirm their superiority in terms of clinical outcomes, organ utilization, and cost-effectiveness. Here, we present an overview of all preclinical MP studies using discarded human livers and liver MP clinical trials, and discuss their results. We describe the different perfusion protocols, pitfalls in MP study design, and provide future perspectives. Recent trials in liver MP have revealed unique challenges beyond those seen in most clinical studies. Randomized trials, correct trial design, and interpretation of data are essential to generate the data necessary to prove if MP will be the new gold standard method of liver preservation.

Bioengineering approaches to organ preservation ex vivo.

IMPACT STATEMENT: Over the past several decades, ex vivo perfusion has emerged as a promising technology for the assessment, preservation, and recovery of donor organs. Many exciting pre-clinical findings have now been translated to clinical use, and successful transplantation following ex vivo perfusion has been achieved for heart, lung, and liver. While machine perfusion provides distinct advantages over traditional cold preservation, many challenges remain, including that of long-term (multi-day) ex vivo support. Here, we provide an overview of the current status of ex vivo machine perfusion in the pre-clinical and clinical setting and share our perspective on the future direction of the field.

Ex Situ Machine Perfusion of Human Donor Livers via the Surgically Reopened Umbilical Vein: A Proof of Concept.

BACKGROUND: Machine perfusion of donor livers is typically performed via the portal vein main stem. Instead, cannulation of a reopened umbilical vein could allow machine perfusion during organ procurement and subsequent implantation in the recipient without interruption of the portal venous circulation. We aimed to assess the feasibility of portal venous machine perfusion via the umbilical vein. METHODS: During back table inspection of 5 human livers declined for transplantation, the umbilical vein was surgically reopened, dilated, and cannulated. Hypothermic and normothermic oxygenated machine perfusion (NMP) were performed using the umbilical vein for portal inflow. Three livers were perfused with hypothermic machine perfusion, 1 full liver graft underwent NMP for 4 hours, and 1 left lateral split procedure was performed under continuous NMP with portal perfusion via the umbilical vein. RESULTS: In all livers, access to the portal venous system via the umbilical vein was successfully achieved with good portal flows and macroscopically homogeneous perfusion. The full liver graft that underwent NMP via the umbilical vein for 4 hours showed good lactate clearance, normalized pH, and achieved good bile production with pH >7.55. During the split procedure under continuous NMP via the umbilical vein, the left lateral segment and extended right lobe remained equally perfused, as demonstrated by Doppler ultrasound. CONCLUSIONS: Machine perfusion with portal perfusion via the umbilical vein is feasible. Portal venous flows were similar to those obtained after cannulation of the portal vein main stem. This technique enables continuous oxygenated perfusion of liver grafts during procurement, splitting, and implantation.

Combined Hypothermic and Normothermic Machine Perfusion Improves Functional Recovery of Extended Criteria Donor Livers.

Hypothermic oxygenated perfusion (HOPE) and normothermic perfusion are seen as distinct techniques of ex situ machine perfusion of the liver. We aimed to demonstrate the feasibility of combining both techniques and whether it would improve functional parameters of donor livers into transplant standards. Ten discarded human donor livers had either 6 hours of normothermic perfusion (n = 5) or 2 hours of HOPE followed by 4 hours of normothermic perfusion (n = 5). Liver function was assessed according to our viability criteria; markers of tissue injury and hepatic metabolic activity were compared between groups. Donor characteristics were comparable. During the hypothermic perfusion phase, livers down-regulated mitochondrial respiration (oxygen uptake, P = 0.04; partial pressure of carbon dioxide perfusate, P = 0.04) and increased adenosine triphosphate levels 1.8-fold. Following normothermic perfusion, those organs achieved lower tissue expression of markers of oxidative injury (4-hydroxynonenal, P = 0.008; CD14 expression, P = 0.008) and inflammation (CD11b, P = 0.02; vascular cell adhesion molecule 1, P = 0.05) compared with livers that had normothermic perfusion alone. All livers in the combined group achieved viability criteria, whereas 40% (2/5) in the normothermic group failed (P = 0.22). In conclusion, this study suggests that a combined protocol of hypothermic oxygenated and normothermic perfusions might attenuate oxidative stress, tissue inflammation, and improve metabolic recovery of the highest-risk donor livers compared with normothermic perfusion alone.

Isquemia fría y supervivencia del injerto. Diferencias entre el primer y segundo injerto de un mismo donante / Cold ischemia and renal graft survival: A paired analysis comparing first and second grafts from the same donor

OBJETIVO: Comparar las características, evolución y supervivencia de las parejas renales procedentes de un mismo donante, con especial interés en el tiempo de isquemia fría (TIF) como factor de riesgo de supervivencia del injerto. MÉTODOS: A partir de nuestra base de datos de trasplantados renales, realizada de forma prospectiva desde 1987 hasta 2015, seleccionamos aquellos injertos emparejados procedentes de un mismo donante cadáver y los dividimos en dos grupos según correspondieran al primer o al segundo injerto. RESULTADOS: Estudiamos un total de 860 riñones emparejados. El TIF medio del primer y segundo grupo fue de 15,12 y 19,16 horas respectivamente. En el segundo grupo se observó una mayor incidencia de necrosis tubular aguda (NTA) y función inicial retrasada del injerto (FRI) (59,9% vs 69,4%; y 54,9% vs 63,5%, respectivamente p < 0,001). No se observaron diferencias significativas entre ambos grupos en las cifras de aclaramiento de creatinina o en la tasa de paso a diálisis. En términos de supervivencia del injerto, no se encontraron diferencias entre el primer y el segundo grupo (18,4 vs 18,1 años respectivamente, Log-rank p = 0,667). Adicionalmente se estudio la isquemia fría del conjunto de injertos, sin apreciar diferencias según su TIF (<14, 14-17, 17-20, >20 horas), el cual no se comportó como un factor de riesgo de supervivencia del injerto (HR=1.014 (p = 0,312)). CONCLUSIONES: La proporción de NTA y FRI es mayor en los segundos trasplantados. Sin embargo, no existen diferencias en términos de supervivencia del injerto a largo plazo. No encontramos evidencia de que un TIF por debajo de 24h se comporte como un factor de riesgo de supervivencia del injerto

OBJECTIVE: To compare the characteristics, clinical course, and survival of pairs of renal grafts from the same donor, with special interest in cold ischemia times (CIT) as a risk factor for graft survival. METHODS: We retrospectively reviewed paired grafts originating from the same cadaver donor from our prospectively recorded database of kidney transplants, from 1987 to 2015. We selected and divided them into two groups depending on whether they corresponded to the first or second graft. RESULTS: We studied a total of 860 paired kidneys. Mean CIT for the first and second groups were 15.12 and 19.16 hours, respectively. In the second group we observed higher incidences of acute tubular necrosis and initial delayed graft function (59.9% vs. 69.4% and 54.9% vs. 63.5%, respectively; p20 hours). For the set of grafts studied, CIT did not act as a risk factor for graft survival (hazard ratio [HR]=1.014; p = 0.312). CONCLUSIONS: The proportion of ATN and DGF were greater in second transplants. However, there were no differences in long-term graft survival. Furthermore, we found no evidence that a CIT for less than 24 hours acted as a risk factor to graft survival

Metabolomic analysis of perfusate during hypothermic machine perfusion of human cadaveric kidneys.

BACKGROUND: The metabolic processes occurring within the preserved kidney during hypothermic machine perfusion (HMP) are not well characterized. The aim of this study was to use nuclear magnetic resonance (NMR) spectroscopy to examine the metabolomic profile of HMP perfusate from human cadaveric kidneys awaiting transplantation and to identify possible discriminators between the profiles of kidneys with delayed graft function (DGF) and immediate graft function (IGF). METHODS: Perfusates from HMP kidneys were sampled at 45 min and 4 hr of preservation with the LifePort Kidney Transporter 1.0 (Organ Recovery Systems, Chicago, IL) using KPS-1. Prepared samples underwent 1-D Proton-NMR spectroscopy, and resultant spectra were analyzed. Clinical parameters were collected prospectively. RESULTS: Perfusate of 26 transplanted cadaveric kidneys was analyzed; 19(73%) with IGF and 7(27%) with DGF. Glucose concentrations were significantly lower in DGF kidneys compared to those with IGF at both 45 min (7.772 vs. 9.459 mM, P = 0.006) and 4 hr (8.202 vs. 10.235 mM, P = 0.003). Concentrations of inosine and leucine were significantly different between DGF and IGF kidneys at 45 min (0.002 vs. 0.013 mM, P = 0.009 and 0.011 vs. 0.006 mM, P = 0.036), and gluconate levels were also significantly different between DGF and IGF kidneys at 4 hr (49.099 vs. 59.513 mM, P = 0.009). CONCLUSION: Significant metabolic activity may be occurring in kidneys during HMP. The NMR spectroscopy of the perfusate can identify differences in the metabolomic profiles of DGF and IGF kidneys that might have a predictive role in viability assessment. Modification of harmful metabolic processes may improve outcomes for HMP kidneys.

Use of self-retaining barbed sutures decreases cold ischemia time in open nephron-sparing surgery.

PURPOSE: In the present study, we aimed to determine whether the use of self-retaining barbed sutures (SRBS) instead of conventional sutures during open partial nephrectomy leads to improved surgical outcomes. PATIENTS, MATERIALS AND METHODS: A retrospective analysis of 50 consecutive patients who underwent open partial nephrectomy for a unicentric renal tumor was performed. In 15 patients, SRBS were used for parenchymal repair during open partial nephrectomy, and in 35 patients, conventional sutures were used. The parameters related to surgical outcomes were recorded and analysis of the total patient population and subgroup analysis according to the preoperative aspects and dimensions used for an anatomical (PADUA) score classification was performed. RESULTS: The preoperative baseline values did not statistically differ between the groups. Analysis of the total patient population showed a significant difference regarding ischemia time (mean ± standard deviation) between the SRBS group (15.2 ± 6.9 min), and the conventional suture group (25.7 ± 11.8 min). There was no significant difference between the barbed and conventional sutures with regard to postoperative hemoglobin levels, decline in hemoglobin percentage, or renal function parameters. In subgroup-analysis, a significant difference in ischemia time was only found for PADUA scores 6 and 7, without any effect on the outcome parameters. CONCLUSIONS: The use of SRBS in parenchymal repair during open partial nephrectomy appears to be a safe and feasible option with decreased cold ischemia time when compared with conventional sutures. In PADUA subgroup-analysis this difference was only observed for PADUA scores 6 and 7.

A comparison of hypothermic machine perfusion versus static cold storage in an experimental model of renal ischemia reperfusion injury.

INTRODUCTION: There is increasing support for the use of hypothermic machine perfusion (HMP) in an attempt to reduce preservation injury. However, experimental evidence is needed to further examine the effects of HMP on renal ischemia reperfusion injury. METHODS: Porcine kidneys were subjected to 10 min of warm ischemia followed by 18 hr of static cold storage with hyperosomolar citrate (HOC), histidine-tryptophan-ketoglutarate (HTK), or University of Wisconsin (UW) solutions or 18 hr HMP with Kidney Perfusion Solution using the Lifeport perfusion system. Renal function, oxidative damage, and morphology were assessed during 3 hr of reperfusion with autologous blood using an isolated organ perfusion system. RESULTS: During reperfusion, intrarenal resistance was significantly lower in the HMP group compared with HOC and UW (area under the curve; HMP 3.8+/-1.7, HOC 9.1+/-4.3, UW 7.7+/-2.2, HTK 5.6+/-1.9 mm Hg/min; P=0.006), and creatinine clearance was significantly higher compared with the UW group (area under the curve creatinine clearance; HMP 9.8+/-7.3, HOC 2.2+/-1.7, UW 1.8+/-1.0, HTK 2.1+/-1.8 mL/min/100 g; P=0.004). Tubular function was significantly improved in the HMP group (P<0.05); however, levels of lipid peroxidation were significantly higher (P=0.005). CONCLUSION: HMP demonstrated a reduced level of preservation injury compared with the static techniques resulting in improved renal and tubular function and less tubular cell inflammation during reperfusion.

Evaluation of a novel system for hypothermic oxygenated pulsatile perfusion preservation.

BACKGROUND: Recently, a novel innovative machine perfusion (MP) system for hypothermic oxygenated pulsatile perfusion called the Airdrive (AD) has been developed. The aim of the study was to evaluate the biological safety of the AD system for perfusion preservation of kidney grafts in a porcine autotransplantation model using the low-viscosity perfusion solution Polysol (PS) in comparison with cold storage (CS) using PS or the University of Wisconsin solution (UW). In addition, we evaluated real-time microcirculation parameters. At sacrifice, grafts were retrieved for histological analysis and immunohistochemistry. METHODS: After assessment of the microcirculation, left kidneys were retrieved. Following the washout, kidneys were preserved for 20 hr using AD-PS, CS-PS or CS-UW. Thereafter, contralateral kidneys were removed followed by heterotopic autotransplantation of the preserved graft. Seven days after transplantation animals were sacrificed with retrieval of the grafts for histological analysis. Renal function, renal microcirculation and tissue injury including the proliferative response of tubular epithelial cells (TECs) were compared. RESULTS: Preservation using AD-PS or CS-PS resulted in higher microcirculatory flow compared with CS-UW. Improved recovery of renal function was seen in the AD-PS and CS-PS groups compared with CS-UW. Structural integrity was better preserved using AD-PS compared with both CS groups. Proliferative response of TECs was higher in CS-UW preserved grafts compared to grafts preserved using AD-PS. CONCLUSION: This study demonstrates the biological safety of the AD system in a porcine autotransplantation model. Also, the microcirculation was better preserved and less morphological injury was observed after 20 hr MP compared with CS.

[Risk factors for orthotopic liver transplantation failure in Rio Grande do Sul, Brazil]. / Fatores de risco para a falência do transplante ortotópico de fígado no Rio Grande do Sul, Brasil.

Risk factors for failure of liver transplantation from cadaveric donors were investigated in this retrospective study using data from medical records of patients in Rio Grande do Sul, Brazil, who were submitted to liver transplantation for the first time from January 1999 to July 2003 and were over 15 years of age at the time of surgery. Some 13% of failures occurred in the first month, 11% from 2 to 12 months, and 5% after 12 months; 88% of failures resulted in death and 12% in retransplantation. In the multivariate models, rate ratios for failure were higher for total family income less than 10 times the minimum wage, recipient's age > 45 years, non-whites, high clinical risk, and donor's age > or = 56 years. Female gender showed an effect in the unadjusted model only. Special attention to patients at increased risk, with income support for those with low family income, and early diagnosis of the need for transplantation may improve the success of liver transplantation.