Ex situ dual hypothermic oxygenated machine perfusion (DHOPE) and normothermic machine perfusion (NMP) of donor livers may have a complementary effect when applied sequentially. While DHOPE ...resuscitates the mitochondria and increases hepatic adenosine triphosphate (ATP) content, NMP enables hepatobiliary viability assessment prior to transplantation. In contrast to DHOPE, NMP requires a perfusion solution with an oxygen carrier, for which red blood cells (RBC) have been used in most series. RBC, however, have limitations and cannot be used cold. We, therefore, established a protocol of sequential DHOPE, controlled oxygenated rewarming (COR), and NMP using a new hemoglobin‐based oxygen carrier (HBOC)‐based perfusion fluid (DHOPE‐COR‐NMP trial, NTR5972). Seven livers from donation after circulatory death (DCD) donors, which were initially declined for transplantation nationwide, underwent DHOPE‐COR‐NMP. Livers were considered transplantable if perfusate pH and lactate normalized, bile production was ≥10 mL and biliary pH > 7.45 within 150 minutes of NMP. Based on these criteria five livers were transplanted. The primary endpoint, 3‐month graft survival, was a 100%. In conclusion, sequential DHOPE‐COR‐NMP using an HBOC‐based perfusion fluid offers a novel method of liver machine perfusion for combined resuscitation and viability testing of suboptimal livers prior to transplantation.
This clinical cohort study indicates that a combination of hypo‐ and normothermic machine perfusion, using a preservation fluid containing an hemoglobin‐based oxygen carrier, is feasible and provides a tool to resuscitate and select initially declined high‐risk donor livers that can be transplanted successfully.
Transplantation of livers obtained from donors after circulatory death is associated with an increased risk of nonanastomotic biliary strictures. Hypothermic oxygenated machine perfusion of livers ...may reduce the incidence of biliary complications, but data from prospective, controlled studies are limited.
In this multicenter, controlled trial, we randomly assigned patients who were undergoing transplantation of a liver obtained from a donor after circulatory death to receive that liver either after hypothermic oxygenated machine perfusion (machine-perfusion group) or after conventional static cold storage alone (control group). The primary end point was the incidence of nonanastomotic biliary strictures within 6 months after transplantation. Secondary end points included other graft-related and general complications.
A total of 160 patients were enrolled, of whom 78 received a machine-perfused liver and 78 received a liver after static cold storage only (4 patients did not receive a liver in this trial). Nonanastomotic biliary strictures occurred in 6% of the patients in the machine-perfusion group and in 18% of those in the control group (risk ratio, 0.36; 95% confidence interval CI, 0.14 to 0.94; P = 0.03). Postreperfusion syndrome occurred in 12% of the recipients of a machine-perfused liver and in 27% of those in the control group (risk ratio, 0.43; 95% CI, 0.20 to 0.91). Early allograft dysfunction occurred in 26% of the machine-perfused livers, as compared with 40% of control livers (risk ratio, 0.61; 95% CI, 0.39 to 0.96). The cumulative number of treatments for nonanastomotic biliary strictures was lower by a factor of almost 4 after machine perfusion, as compared with control. The incidence of adverse events was similar in the two groups.
Hypothermic oxygenated machine perfusion led to a lower risk of nonanastomotic biliary strictures following the transplantation of livers obtained from donors after circulatory death than conventional static cold storage. (Funded by Fonds NutsOhra; DHOPE-DCD ClinicalTrials.gov number, NCT02584283.).
Ex situ normothermic machine perfusion (NMP) is increasingly used for viability assessment of high‐risk donor livers, whereas dual hypothermic oxygenated machine perfusion (DHOPE) reduces ...ischemia‐reperfusion injury. We aimed to resuscitate and test the viability of initially‐discarded, high‐risk donor livers using sequential DHOPE and NMP with two different oxygen carriers: an artificial hemoglobin‐based oxygen carrier (HBOC) or red blood cells (RBC). In a prospective observational cohort study of 54 livers that underwent DHOPE‐NMP, the first 18 procedures were performed with a HBOC‐based perfusion solution and the subsequent 36 procedures were performed with an RBC‐based perfusion solution for the NMP phase. All but one livers were derived from extended criteria donation after circulatory death donors, with a median donor risk index of 2.84 (IQR 2.52–3.11). After functional assessment during NMP, 34 livers (63% utilization), met the viability criteria and were transplanted. One‐year graft and patient survival were 94% and 100%, respectively. Post‐transplant cholangiopathy occurred in 1 patient (3%). There were no significant differences in utilization rate and post‐transplant outcomes between the HBOC and RBC group. Ex situ machine perfusion using sequential DHOPE‐NMP for resuscitation and viability assessment of high‐risk donor livers results in excellent transplant outcomes, irrespective of the oxygen carrier used.
Sequential end‐ischemic hypothermic and normothermic machine perfusion results in safe transplantation of previously discarded, high‐risk, human donor livers, irrespective of the oxygen carrier used for normothermic perfusion.
Liver retransplantation (re-LT) accounts for up to 22% after primary liver transplantation (LT), and using donor livers for retransplantation can only be justified by successful outcomes.
A total of ...2,387 adult recipients with 2,778 LT, between 1979 and 2017, were analyzed to determine risk factors and outcome of re-LT in the Netherlands.
Of 2,778 LT, 336 (12.1%) were first, 43 (1.5%) were second, and 12 (0.5%) were third or fourth re-LT. The 5-year patient survival for primary LT, and first, second, and third or fourth re-LT were 74.0%, 70.8%, 63.3%, and 57.1%, respectively (P = 0.10). Recipient age (≤60 years) (OR 1.96, P < 0.001), era (1979-2006) (OR 1.56, P = 0.003), donor after circulatory death (DCD) (OR 1.96, P < 0.001), and cold ischemia time (CIT) (>9 h) (OR 1.42, P = 0.007) were significant risk factors for retransplantation after primary LT.
Recipient age, era, DCD, and prolonged CIT were identified as parameters for retransplantation. The outcome after the first re-LT was good, and comparable to those of primary transplants. Survival after multiple re-LT was not significantly different from the first retransplant group, legitimizing third and fourth re-LT to well-selected patients.
Congenital disorders of glycosylation (CDG) are a rapidly expanding group of rare genetic defects in glycosylation. In a novel CDG subgroup of vacuolar‐ATPase (V‐ATPase) assembly defects, various ...degrees of hepatic injury have been described, including end‐stage liver disease. However, the CDG diagnostic workflow can be complex as liver disease per se may be associated with abnormal glycosylation. Therefore, we collected serum samples of patients with a wide range of liver pathology to study the performance and yield of two CDG screening methods. Our aim was to identify glycosylation patterns that could help to differentiate between primary and secondary glycosylation defects in liver disease. To this end, we analyzed serum samples of 1042 adult liver disease patients. This cohort consisted of 567 liver transplant candidates and 475 chronic liver disease patients. Our workflow consisted of screening for abnormal glycosylation by transferrin isoelectric focusing (tIEF), followed by in‐depth analysis of the abnormal samples with quadruple time‐of‐flight mass spectrometry (QTOF‐MS). Screening with tIEF resulted in identification of 247 (26%) abnormal samples. QTOF‐MS analysis of 110 of those did not reveal glycosylation abnormalities comparable with those seen in V‐ATPase assembly factor defects. However, two patients presented with isolated sialylation deficiency. Fucosylation was significantly increased in liver transplant candidates compared to healthy controls and patients with chronic liver disease. In conclusion, a significant percentage of patients with liver disease presented with abnormal CDG screening results. However, the glycosylation pattern was not indicative for a V‐ATPase assembly factor defect. Advanced glycoanalytical techniques assist in the dissection of secondary and primary glycosylation defects.
The aim of this study was to evaluate sequential hypothermic and normothermic machine perfusion (NMP) as a tool to resuscitate and assess viability of initially declined donor livers to enable safe ...transplantation.
Machine perfusion is increasingly used to resuscitate and test the function of donor livers. Although (dual) hypothermic oxygenated machine perfusion (DHOPE) resuscitates livers after cold storage, NMP enables assessment of hepatobiliary function.
In a prospective clinical trial, nationwide declined livers were subjected to ex situ NMP (viability assessment phase), preceded by 1-hour DHOPE (resuscitation phase) and 1 hour of controlled oxygenated rewarming (COR), using a perfusion fluid containing an hemoglobin-based oxygen carrier. During the first 2.5 hours of NMP, hepatobiliary viability was assessed, using predefined criteria: perfusate lactate <1.7 mmol/L, pH 7.35 to 7.45, bile production >10 mL, and bile pH >7.45. Livers meeting all criteria were accepted for transplantation. Primary endpoint was 3-month graft survival.
Sixteen livers underwent DHOPE-COR-NMP. All livers were from donors after circulatory death, with median age of 63 (range 42-82) years and median Eurotransplant donor risk index of 2.82. During NMP, all livers cleared lactate and produced sufficient bile volume, but in 5 livers bile pH remained <7.45. The 11 (69%) livers that met all viability criteria were successfully transplanted, with 100% patient and graft survival at 3 and 6 months. Introduction of DHOPE-COR-NMP increased the number of deceased donor liver transplants by 20%.
Sequential DHOPE-COR-NMP enabled resuscitation and safe selection of initially declined high-risk donor livers, thereby increasing the number of transplantable livers by 20%.
www.trialregister.nl; NTR5972.
Liver transplantation is frequently associated with hyperkalemia, especially after graft reperfusion. Dual hypothermic oxygenated machine perfusion (DHOPE) reduces ischemia/reperfusion injury and ...improves graft function, compared to conventional static cold storage (SCS). We examined the effect of DHOPE on ex situ and in vivo shifts of potassium and sodium. Potassium and sodium shifts were derived from balance measurements in a preclinical study of livers that underwent DHOPE (n = 6) or SCS alone (n = 9), followed by ex situ normothermic reperfusion. Similar measurements were performed in a clinical study of DHOPE‐preserved livers (n = 10) and control livers that were transplanted after SCS only (n = 9). During DHOPE, preclinical and clinical livers released a mean of 17 ± 2 and 34 ± 6 mmol potassium and took up 25 ± 9 and 24 ± 14 mmol sodium, respectively. After subsequent normothermic reperfusion, DHOPE‐preserved livers took up a mean of 19 ± 3 mmol potassium, while controls released 8 ± 5 mmol potassium. During liver transplantation, blood potassium levels decreased upon reperfusion of DHOPE‐preserved livers while levels increased after reperfusion of SCS‐preserved liver, delta potassium levels were ‐0.77 ± 0.20 vs. +0.64 ± 0.37 mmol/L, respectively (P = .002). While hyperkalemia is generally anticipated during transplantation of SCS‐preserved livers, reperfusion of hypothermic machine perfused livers can lead to decreased blood potassium or even hypokalemia in the recipient.
The authors examine the effect of hypothermic oxygenated machine perfusion of donor livers on ex situ and in vivo potassium and sodium shifts and find that although hyperkalemia frequently occurs after reperfusion of a conventionally preserved liver, reperfusion of a hypothermic machine‐perfused liver leads to a decrease in blood potassium or even hypokalemia in the recipient.
The major concern in liver transplantation of grafts from donation after circulatory death (DCD) donors remains the high incidence of non-anastomotic biliary strictures (NAS). Machine perfusion has ...been proposed as an alternative strategy for organ preservation which reduces ischemia-reperfusion injury (IRI). Experimental studies have shown that dual hypothermic oxygenated machine perfusion (DHOPE) is associated with less IRI, improved hepatocellular function, and better preserved mitochondrial and endothelial function compared to conventional static cold storage (SCS). Moreover, DHOPE was safely applied with promising results in a recently performed phase-1 study. The aim of the current study is to determine the efficacy of DHOPE in reducing the incidence of NAS after DCD liver transplantation.
This is an international multicenter randomized controlled trial. Adult patients (≥18 yrs. old) undergoing transplantation of a DCD donor liver (Maastricht category III) will be randomized between the intervention and control group. In the intervention group, livers will be subjected to two hours of end-ischemic DHOPE after SCS and before implantation. In the control group, livers will be subjected to care as usual with conventional SCS only. Primary outcome is the incidence of symptomatic NAS diagnosed by a blinded adjudication committee. In all patients, magnetic resonance cholangiography will be obtained at six months after transplantation.
DHOPE is associated with reduced IRI of the bile ducts. Whether reduced IRI of the bile ducts leads to lower incidence of NAS after DCD liver transplantation can only be examined in a randomized controlled trial.
The trial was registered in Clinicaltrials.gov in September 2015 with the identifier NCT02584283 .
Long‐term survival in orthotopic liver transplant (OLT) recipients remains impaired because of many contributing factors, including a low pretransplant muscle mass (or sarcopenia). However, influence ...of posttransplant muscle mass on survival is currently unknown. We hypothesized that posttransplant urinary creatinine excretion rate (CER), an established noninvasive marker of total body muscle mass, is associated with long‐term survival after OLT. In a single‐center cohort study of 382 adult OLT recipients, mean ± standard deviation CER at 1 year posttransplantation was 13.3 ± 3.7 mmol/24 h in men and 9.4 ± 2.6 mmol/24 h in women. During median follow‐up for 9.8 y (interquartile range 6.4‐15.0 y), 104 (27.2%) OLT recipients died and 44 (11.5%) developed graft failure. In Cox regression analyses, as continuous variable, low CER was associated with increased risk for mortality (HR = 0.43, 95% CI: 0.26‐0.71, P = .001) and graft failure (HR = 0.42, 95% CI: 0.20‐0.90, P = .03), independent of age, sex, and body surface area. Similarly, OLT recipients in the lowest tertile had an increased risk for mortality (HR = 2.69; 95% CI: 1.47‐4.91, P = .001) and graft failure (HR = 2.77, 95% CI: 1.04‐7.39, P = .04), compared to OLT recipients in the highest tertile. We conclude that 1 year posttransplant low total body muscle mass is associated with long‐term risk of mortality and graft failure in OLT recipients.
Twenty‐four hour urinary creatinine excretion, reflecting total body muscle mass, is inversely associated with long‐term outcome after liver transplantation.
Short-term survival after orthotopic liver transplantation (OLT) has improved over the past decades, but long-term survival remains impaired. The effects of obesity on long-term survival after OLT ...are controversial. Because pre-transplant body mass index (BMI) can be confounded by ascites, we hypothesized that post-transplant BMI at 1 year could predict long-term survival.
A post-hoc analysis was performed of an observational cohort study consisting of adult recipients of a first OLT between 1993 and 2010. Baseline BMI was measured at 1-year post-transplantation to represent a stable condition. Recipients were stratified into normal weight (BMI < 25 kg/m2), overweight (25 ≤ BMI ≤ 30 kg/m2), and obese (BMI > 30 kg/m2). Kaplan-Meier survival analyses were performed with log-rank testing, followed by multivariable Cox proportional hazards regression analysis.
Out of 370 included recipients, 184 had normal weight, 136 were overweight, and 50 were obese at 1-year post-transplantation. After median follow-up for 12.3 years, 107 recipients had died, of whom 46 (25%) had normal weight, 39 (29%) were overweight, and 22 (44%) were obese (log-rank P = 0.020). Obese recipients had a significantly increased mortality risk compared to normal weight recipients (HR 2.00, 95% CI 1.08–3.68, P = 0.027). BMI was inversely associated with 15 years patient survival (HR 1.08, 95% CI 1.03–1.14, P = 0.001 per kg/m2), independent of age, gender, muscle mass, transplant characteristics, cardiovascular risk factors, kidney- and liver function.
Obesity at 1-year post-transplantation conveys a 2-fold increased mortality risk, which may offer potential for interventional strategies (i.e. dietary advice, lifestyle modification, or bariatric surgery) to improve long-term survival after OLT.
•Long-term survival after liver transplantation is impaired.•Post-transplant body mass index at 1 year was used to predict long-term survival.•Obesity at 1 year post-transplantation conveys a 2-fold increased mortality risk.•Body mass index was inversely associated with 15 years patient survival.
PDF
