Functional recovery after partial nephrectomy: next generation analysis.

OBJECTIVES: To provide a more rigorous assessment of factors affecting functional recovery after partial nephrectomy (PN) using novel tools that allow for analysis of more patients and improved accuracy for assessment of parenchymal volume loss, thereby revealing the potential impact of secondary factors such as ischaemia. PATIENTS AND METHODS: Of 1140 patients managed with PN (2012-2014), 670 (59%) had imaging and serum creatinine levels measured before and after PN necessary for inclusion. Recovery from ischaemia was defined as the ipsilateral glomerular filtration rate (GFR) saved normalised by parenchymal volume saved. Acute kidney injury was assessed through Spectrum Score, which quantifies the degree of acute ipsilateral renal dysfunction due to exposure to ischaemia that would otherwise be masked by the contralateral kidney. Multivariable regression was used to identify predictors of Spectrum Score and Recovery from Ischaemia. RESULTS: In all, 409/189/72 patients had warm/cold/zero ischaemia, respectively, with median (interquartile range [IQR]) ischaemia times for cold and warm ischaemia of 30 (25-42) and 22 (18-28) min, respectively. The median (IQR) global preoperative GFR and new baseline GFR (NBGFR) were 78 (63-92) and 69 (54-81) mL/min/1.73 m2 , respectively. The median (IQR) ipsilateral preoperative GFR and NBGFR were 40 (33-47) and 31 (24-38) mL/min/1.73 m2 , respectively. Functional recovery correlated strongly with parenchymal volume preserved (r = 0.83, P < 0.01). The median (IQR) decline in ipsilateral GFR associated with PN was 7.8 (4.5-12) mL/min/1.73 m2 with loss of parenchyma accounting for 81% of this loss. The median (IQR) recovery from ischaemia was similar across the cold/warm/zero ischaemia groups at 96% (90%-102%), 95% (89%-101%), and 97% (91%-102%), respectively. Independent predictors of Spectrum Score were ischaemia time, tumour complexity, and preoperative global GFR. Independent predictors of recovery from ischaemia were insulin-dependent diabetes mellitus, refractory hypertension, warm ischaemia, and Spectrum Score. CONCLUSIONS: The main determinant of functional recovery after PN is parenchymal volume preservation. A more robust and rigorous evaluation allowed us to identify secondary factors including comorbidities, increased tumour complexity, and ischaemia-related factors that are also independently associated with impaired recovery, although altogether these were much less impactful.

Addition of a liver to the normothermic perfusion circuit reduces renal pro-inflammatory factors.

BACKGROUND: Normothermic machine perfusion (NMP) provides a novel platform to preserve isolated organs in an artificial condition. Our study aimed to explore the interaction between the liver and kidney at an ex vivo organ level by adding a liver to the kidney NMP circuit. METHODS: Porcine kidney and liver obtained from abattoir were subjected to 9 h NMP after suffering 30-min warm ischemia time and 90-min cold ischemia time. The liver-kidney NMP group (n = 5) and the single-kidney NMP group (n = 5) were designed. During the NMP, perfusion parameters, blood gas analysis, and tissue samples were compared. RESULTS: The perfusate of both groups remained stable, and continuous urine production was observed during NMP. In the liver-kidney NMP group, the lactate level was low, while blood urea nitrogen increased and glucose levels decreased. After the NMP, the renal tissue in the liver-kidney group exhibited fewer histological changes such as tubular epithelium vacuolization, along with reduced expression of IL-6, IL-8, IL-1ß, NLRP3, and GSDMD. CONCLUSIONS: Our results indicated that the expression of renal pro-inflammatory factors was reduced in the liver-kidney NMP system.

Safe heart flush technique during recovery from donors after circulatory death.

BACKGROUND: Donation after circulatory death is the donation after cardiac arrest. This technique has been employed and adopted by clinicians to overcome the shortage of available hearts for transplant. Warm ischemia time plays a pivotal role in the survival outcome of the heart recipients. AIM OF THE STUDY: To assess the efficacy of using the Foley catheter to flush the heart during procurement from donation after circulatory death donors. METHODS: We utilized a 2-WAY Foley catheter to flush the heart during procurement. The catheter was prepared and modified on the back table. RESULTS: We were successfully able to flush the heart within 3 minutes from skin incision with a good recipient outcome. CONCLUSIONS: Using the Foley catheter to flush the heart during recovery from donation after circulatory death donors was both efficient and fast.

Tolerable Duration of Warm Ischaemia After Circulatory Death Is Safe For At Least One Hour in Porcine Lungs: Functional Assessment with Ex Vivo Lung Perfusion.

BACKGROUND: Lungs from donation after circulatory death (DCD) may be an underused resource for transplantation. The aim was to investigate, with a DCD pig model, if it was possible to recondition lungs exposed for up to 2 h of warm ischaemia with ex vivo lung perfusion (EVLP). METHODS: Danish domestic pigs (N = 17) were randomized into three groups. In the two study groups, lungs were exposed to either 1 or 2 h of warm ischaemia. All lungs were reconditioned and evaluated after 83 ± 38 minutes of perfusion at FiO2 1.0 and 0.21 with EVLP. Outcome measures were gas exchange, pulmonary physiology, inflammatory markers, and histopathologic assessment score. RESULTS: Lungs exposed for 2 h of warm ischaemia did not meet the criteria: PaO2 > 13 kPa required for donation compared with lungs subjected to 0 and 1 h of warm ischaemia (11.0 kPa vs. 14.2 kPa, P < 0.001). These lungs also developed an increased amount of foam and fluid in the airways. No differences in PaCO2, compliance, or pulmonary vascular resistance were observed. CONCLUSION: Results show that while lungs subjected to 0 or 1 h of warm ischaemia meet the criteria for transplantation based on EVLP evaluation, lungs subjected to 2 h of warm ischaemia did not.

[Evaluation of the results of sodium fumarate, furosemide, and mannitol on the initiation and outcome of renal warm ischemia in an experimental study].

While performing surgical treatment of the localized form of renal cell cancer by means of open or laparoscopic partial nephrectomy, renal warm ischemia is an important issue. Using renal warm ischemia allows to prevent parenchymal bleeding, to optimize conditions for resection of the tumor and to increase significantly the efficiency of hemostasis. However, an important problem is the probability of ischemic hypoxic damage of the remaining part of the kidney tissue during renal warm ischemia and renal functional impairment in the postoperative period. AIM: To compare nephroprotective activity of sodium fumarate, mannitol and furosemide using experimental model of 30- and 60-minute renal warm ischemia in rabbits. MATERIALS AND METHODS: The experiments were carried out on 360 conventional male-rabbits of the "Chinchilla" breed weighed 2,6+/-0,3 kg which were allocated into 10 groups. The control group No1 included intact animals, the control group No2 included the rabbits in which renal artery was not clamped. For the animals from the trial groups (No3-No10) the experimental model of 30- and 60-minute renal warm ischemia was used. In groups No3 and No4 no drugs were provided. Other rabbits undergone renal warm ischemia with a protection by sodium fumarate (groups No5 and No6 - 1,5 ml/kg IV), lasix (groups No7 and No8 - 3,0 mg/kg IV) and mannitol (No9 and No10 - 1,0 g/kg IV). The influence of renal warm ischemia on the renal tissue ultrastructure and the levels of NGAL, Cystatin-C and creatinine in blood and urine were studied. RESULTS: During experimental pharmacologically uncorrected 30-minute renal warm ischemia in animals, edema of the terminal part of microvilli of the proximal tubules epithelium, an increase of lysosome number in the hyaloplasm of epithelial cells, appearance of flaky content of medium electronic density in the lumens of distal tubules and collecting tubules, as well as sharp peak-like increase of NGAL and cystatin-C in blood and urine were observed. Increasing the time of ischemia up to 60 minutes was accompanied by more severe disturbances. In groups where sodium fumarate, lasix and mannitol were used the observed ultrastructural disturbances were expressed to lesser extent, whereas sodium fumarate demonstrated the best nephroprotective activity. After using mannitol the severity of disturbances was less than in the groups where mannitol, lasix or sodium fumarate were not given. Lasix and sodium salt of fumaric acid showed a higher nephroprotective activity. The best results were received in the animals received sodium fumarate. CONCLUSIONS: The studied drugs provided a nephroprotective effect regarding ischemia of rabbit kidney. The effect of sodium fumarate was the most pronounced, followed by furosemide and, to a lesser extent, mannitol. Use of sodium fumarate allows to protect and stimulate the kidney tissue effectively during oxygen deprivation under ischemic state.

Rapid postmortem ventilation improves donor lung viability by extending the tolerable warm ischemic time after cardiac death in mice.

Uncontrolled donation after cardiac death (uDCD) contributes little to ameliorating donor lung shortage due to rapidly progressive warm ischemia after circulatory arrest. Here, we demonstrated that nonhypoxia improves donor lung viability in a novel uDCD lung transplant model undergoing rapid ventilation after cardiac death and compared the evolution of ischemia-reperfusion injury to mice that underwent pulmonary artery ligation (PAL). The tolerable warm ischemia time at 37°C was initially determined in mice using a modified PAL model. The donor lung following PAL was also transplanted into syngeneic mice and compared with those that underwent rapid ventilation or no ventilation at 37°C before transplantation. Twenty-four hours following reperfusion, lung histology, [Formula: see text]/[Formula: see text] ratio, and inflammatory mediators were measured. Four hours of PAL had little impact on [Formula: see text]/[Formula: see text] ratio and acute lung injury score in contrast to significant injury induced by 5 h of PAL. Four-hour PAL lungs showed an early myeloid-dominant inflammatory signature when compared with naïve lungs and substantially injured 5 h PAL lungs. In the context of transplantation, unventilated donor lungs showed severe injury after reperfusion, whereas ventilated donor lungs showed minimal changes in [Formula: see text]/[Formula: see text] ratio, histologic score, and expression of inflammatory markers. Taken together, the tolerable warm ischemia time of murine lungs at 37°C can be extended by maintaining alveolar ventilation for up to 4 h. Nonhypoxic lung undergoing warm ischemia-reperfusion injury shows an early transcriptional signature of myeloid cell recruitment and extracellular matrix proteolysis before blood-gas barrier dysfunction and significant tissue damage.

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.

Can remote ischemic preconditioning counteract the renal functional deterioration attributable to partial nephrectomy under warm ischemia? Results of an animal study.

BACKGROUND: To investigate if remote ischemic preconditioning (RIPC) can offer any renoprotective value by counteracting the deleterious effect of partial nephrectomy (PN) under warm ischemia on renal function. METHODS: Four groups, each with 5 Wistar albino rats, were constructed; RIPC + PN, PN, RIPC and sham. Right nephrectomy was performed to constitute a solitary kidney model. RIPC denoted sequential clamping/declamping of the femoral artery/vein complex. PN was performed under warm-ischemia following RIPC. Blood samples were collected on multiple occasions until euthanasia on day 7. Immunoassays were conducted to measure the serum and tissues levels of kidney injury markers. Kidneys were examined histologically and morphometric analyzes were performed using digital scanning. RESULTS: IL-33 levels did not differ significantly between the groups. Serum levels of KIM-1, NGAL, and aldose reductase in RIPC + PN, PN and RIPC groups were significantly lower than that of sham group. Tissue biomarker levels were similar across groups. The observed trend in mean necrosis area of PN group was higher than that of RIPC + PN group (p > 0.05). The transitional zone between necrosis and healthy tissue showed a trend towards increasing width in the rats subjected to RIPC before PN vs. those who underwent PN without RIPC (p > 0.05). CONCLUSION: RIPC failed to counteract the renal functional consequences of PN under warm ischemia in a solitary kidney animal model. The supportive but marginal histological findings in favor of RIPC's renoprotective potential were not supplemented with the changes in serum and tissue biomarker levels.

Making Every Liver Count: Increased Transplant Yield of Donor Livers Through Normothermic Machine Perfusion.

OBJECTIVE: Normothermic machine perfusion (NMP) enables optimized ex-vivo preservation of a donor liver in a normal physiologic state. The impact of this emerging technology on donor liver utilization has yet to be assessed. SUMMARY BACKGROUND DATA: NMP of the donor liver and ex-vivo enhancement of its function has been envisioned for decades, however only with recent technological advances have devices been suitable for transition to clinical practice. The present study examines the effect NMP on liver utilization in the United States. METHODS: The United Network for Organ Sharing database was queried to identify deceased donor livers procured from 2016 to 2019 (n = 30596). Donor livers were divided by preservation method: standard cold-static preservation (COLD, n = 30,368) versus NMP (n = 228). Donor and recipient risk factors, liver disposition, and discard reasons were analyzed. The primary outcome was liver discard rate between 2 groups. RESULTS: A total of 4037 livers were discarded. The NMP group had a 3.5% discard rate versus 13.3% in the COLD group (P < 0.001), and this was despite NMP donors being older (47.7 vs 39.5 years, P < 0.0001), more frequently donation after cardiac death (DCD) (18% vs 7%, P < 0.001), and having a greater donor risk index (1.6 vs 1.5, P < 0.05). The most common reasons for liver discard in the COLD group were biopsy findings (38%), DCD warm ischemic time (11%), and prolonged preservation time (10%). Survival analysis, following propensity score matching, found no significant difference in 1-year overall survival between recipients of NMP versus COLD livers. CONCLUSIONS: NMP reduces the discard rate of procured livers despite its use in donors traditionally considered of more marginal quality. NMP maintains excellent graft and patient survival. Broader application of NMP technology holds the potential to generate a significant number of additional liver grafts for transplantation every year, thus greatly reducing the nationwide disparity between supply and demand.

Hypoperfusion warm ischaemia time in renal transplants from donors after circulatory death.

BACKGROUND: The donor hypoperfusion phase before asystole in renal transplants from donors after circulatory death (DCD) has been considered responsible for worse outcomes than those from donors after brain death (DBD). METHODS: We included 10 309 adult renal transplants (7128 DBD and 3181 DCD; 1 January 2010-31 December 2016) from the UK Transplant Registry. We divided DCD renal transplants into groups according to hypoperfusion warm ischaemia time (HWIT). We compared delayed graft function (DGF) rates, primary non-function (PNF) rates and graft survival among them using DBD renal transplants as a reference. RESULTS: The DGF rate was 21.7% for DBD cases, but ∼40% for DCD cases with HWIT ≤30 min (0-10 min: 42.1%, 11-20 min: 43%, 21-30 min: 38.4%) and 60% for DCD cases with HWIT >30 min (P < 0.001). All DCD groups showed higher DGF risk than DBD renal transplants in multivariable analysis {0-10 min: odds ratio [OR] 2.686 [95% confidence interval (CI) 2.352-3.068]; 11-20 min: OR 2.531 [95% CI 2.003-3.198]; 21-30 min: OR 1.764 [95% CI 1.017-3.059]; >30 min: OR 5.814 [95% CI 2.798-12.081]}. The highest risk for DGF in DCD renal transplants with HWIT >30 min was confirmed by multivariable analysis [versus DBD: OR 5.814 (95% CI 2.798-12.081) versus DCD: 0-10 min: OR 2.165 (95% CI 1.038-4.505); 11-20 min: OR 2.299 (95% CI 1.075-4.902); 21-30 min: OR 3.3 (95% CI 1.33-8.197)]. No significant differences were detected regarding PNF rates (P = 0.713) or graft survival (P = 0.757), which was confirmed by multivariable analysis. CONCLUSIONS: HWIT >30 min increases the risk for DGF greatly, but without affecting PNF or graft survival.

Adenosine A2a Receptor Stimulation Attenuates Ischemia-Reperfusion Injury and Improves Survival in A Porcine Model of DCD Liver Transplantation.

Orthotopic liver transplantation (OLT) using allografts from donation after circulatory death (DCD) is potentially associated with compromised clinical outcomes due to ischemia-reperfusion injury (IRI)-induced organ damage and graft-related complications. The aim of this study was to provide in vivo data on the effects of adenosine A2a receptor stimulation in a clinically relevant large animal model of DCD liver transplantation. Cardiac arrest was induced in German Landrace pigs (n = 10; 20-25 kg). After 30 min of warm ischemia, the donor liver was retrieved following a cold flush with 3 L of histidine-tryptophan-ketoglutarate-HTK solution. Animals of the treatment group (n = 5/group) received a standard dose of the selective adenosine receptor agonist CGS 21680 added to the cold flush. All grafts were stored for 4.5 h at 4 °C in HTK-solution before OLT. Hepatocellular injury, apoptosis, protein kinase A-PKA activity, graft microcirculation, liver function, and animal survival were assessed. Compared to untreated livers, adenosine A2a receptor stimulation resulted in improved tissue microcirculation (103% ± 5% vs. 38% ± 4% compared to baseline; p < 0.05), accelerated functional recovery of the graft (indocyanine green-plasma disappearance rate (ICG-PDR) of 75% ± 18% vs. 40% ± 30% after 3 h), increased PKA activity ratio (56% ± 3% vs. 32% ± 3%; p < 0.001 after 1 h), and consequently reduced tissue necrosis and apoptosis. The potent protective effects were clinically manifested in significantly improved survival in the treatment group after 72 h (100% vs. 40%; p = 0.04). The ex vivo administration of adenosine A2a receptor agonist during the back-table flush mitigates IRI-mediated tissue damage and improves functional graft recovery and survival in a large animal model of DCD liver transplantation.

No ischemia technique, parenchymal preservation and age are the most important determinants of renal function after partial nephrectomy.

OBJECTIVE: The aim of the present study was to compare the outcomes of Off-Clamp to On -Clamp approach during robot-assisted partial nephrectomy (RAPN). MATERIEL AND METHODS: Retrospective study of 940 patients who underwent a RAPN between 2007 and 2015 for cT1a tumors using On-Clamp or Off-Clamp approaches. Patient with solitary kidney or multifocal were excluded. Overall, 103 patients underwent Off-Clamp approach and 37 patients On-Clamp approach. We matched the patients in terms of tumor size, Charlson comorbidity index and R.E.N.A.L. score. At all, 309 patients from the On-Clamp were matched to the Off-Clamp group. We compared the clinic-pathological characteristics, perioperative morbidity and late functional outcomes between the 2 propensity score matched groups. Limitation included retrospective analysis. RESULTS: After matching, there were no difference in clinic-pathological characteristics in terms of gender, age, race, body mass index, Charlson comorbidity index, American Society of Anesthesiologists score, baseline estimated glomerular filtration rate (e-GFR), tumor size, R.E.N.A.L. score complexity, hilar (H) location between the 2 groups. Regarding perioperative outcomes; while operative time (P=0,4), estimated blood loss (P=0,28), Clavien grade III-IV complications (P=0,8) surgical reoperation (P=1), 30-day readmission (P=1), positive surgical margin (5,5% vs. 5,8%, P=0,9) were comparable between the 2 groups, there were significant difference in excisional volume loss (median, 7,08 vs. 3,51cm3, P<0,01), e-GFR decline (median, -9,7 vs. -2,2ml/min/1,73 m2, P<0,01), percent of e-GFR preservation (median, 87% vs. 97%, P<0,01), and CKD upstaging (36,5% vs. 23,3%, P=0,01), Off-Clamp approach (P=0,01), and age (P=0,02) were predictors of renal function preservation, whereas excisional volume loss (OR=1,035, CI 95% (1,015-1,06), P<0,01) predicted upstaging. CONCLUSION: RAPN for selected renal mass using Off-Clamp approach offered renal functional advantage over On-Clamp, without adding morbidities. While no ischemia technique was associated with less excisional volume loss, Off-Clamp approach, and age were independent predictors of renal function preservation. Clinical significance of these findings in various clinical settings will require further investigation.

Activation of YAP attenuates hepatic damage and fibrosis in liver ischemia-reperfusion injury.

BACKGROUND & AIMS: Hepatic ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver resection and transplantation. YAP, a key downstream effector of the Hippo pathway, is essential for determining cell fate and maintaining homeostasis in the liver. We aimed to elucidate its role in IRI. METHODS: The role of YAP/Hippo signaling was systematically studied in biopsy specimens from 60 patients after orthotopic liver transplantation (OLT), and in a mouse model of liver warm IRI. Human biopsy specimens were collected after 2-10 h of cold storage and 3 h post-reperfusion, before being screened by western blot. In the mouse model, the role of YAP was probed by activating or inhibiting YAP prior to ischemia-reperfusion. RESULTS: In human biopsies, high post-OLT YAP expression was correlated with well-preserved histology and improved hepatocellular function at postoperative day 1-7. In mice, the ischemia insult (90 min) triggered intrinsic hepatic YAP expression, which peaked at 1-6 h of reperfusion. Activation of YAP protected the liver against IR-stress, by promoting regenerative and anti-oxidative gene induction, while diminishing oxidative stress, necrosis/apoptosis and the innate inflammatory response. Inhibition of YAP aggravated hepatic IRI and suppressed repair/anti-oxidative genes. In mouse hepatocyte cultures, activating YAP prevented hypoxia-reoxygenation induced stress. Interestingly, YAP activation suppressed extracellular matrix synthesis and diminished hepatic stellate cell (HSC) activation, whereas YAP inhibition significantly delayed hepatic repair, potentiated HSC activation, and enhanced liver fibrosis at 7 days post-IRI. Notably, YAP activation failed to protect Nrf2-deficient livers against IR-mediated damage, leading to extensive fibrosis. CONCLUSION: Our novel findings document the crucial role of YAP in IR-mediated hepatocellular damage and liver fibrogenesis, providing evidence of a potential therapeutic target for the management of sterile liver inflammation in transplant recipients. LAY SUMMARY: In the clinical arm, graft YAP expression negatively correlated with liver function and tissue damage after human liver transplantation. YAP activation attenuated hepatocellular oxidative stress and diminished the innate immune response in mouse livers following ischemia-reperfusion injury. In the mouse model, YAP inhibited hepatic stellate cell activation, and abolished injury-mediated fibrogenesis up to 7 days after the ischemic insult.

Transplantation of High-risk Donor Livers After Ex Situ Resuscitation and Assessment Using Combined Hypo- and Normothermic Machine Perfusion: A Prospective Clinical Trial.

OBJECTIVE: 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. SUMMARY BACKGROUND DATA: Machine perfusion is increasingly used to resuscitate and test the function of donor livers. Although (dual) hypothermic oxygenated machine perfusion ([D]HOPE) resuscitates livers after cold storage, NMP enables assessment of hepatobiliary function. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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%. TRIAL REGISTRATION: www.trialregister.nl; NTR5972.

Hypothermic oxygenated machine perfusion alleviates liver injury in donation after circulatory death through activating autophagy in mice.

Hypothermic oxygenated machine perfusion (HOPE) is a safe and reliable method that could alleviate liver injury in donation after circulatory death (DCD). This study focuses on the role of autophagy in HOPE's protective effect on DCD liver injury. A 30-minute warm ischemic liver model was established in mice. After 4 hours of cold storage (CS), 1 hour of hypothermic machine perfusion (HMP) with 100% O2 or 100% N2 was employed. During 2 hours of reperfusion, liver tissue and perfusate were collected to evaluate liver function, oxidative stress level, apoptosis, and necrosis. Western blotting was used to explore the level of autophagy. When the liver experienced warm ischemic injury, LC3B-II expression was significantly enhanced. Compared with the CS, HOPE induced lower release of AST and ALT, as well as lower oxidative stress levels, apoptosis, and necrosis cell numbers, and led to higher tissue ATP content. Meanwhile, expression of autophagy-related proteins, such as ULK1, Atg5, and LC3B-II, increased. When oxygen was completely replaced by nitrogen, the washout effect of HMP did not activate autophagy and did not relieve DCD liver injury. When the autophagy inhibitor 3-methyladenine was used in HOPE, the protective effect of HOPE was attenuated. In conclusion, DCD liver injury activated autophagy compared with healthy liver, while HOPE alleviated DCD liver injury by increasing autophagy levels further in this mouse model. However, HMP with 100% of N2 had no beneficial effect on DCD liver injury or on autophagy levels compared with CS. The research on autophagy may provide a new strategy for alleviating DCD liver injury in clinical practice.

The application of barbed suture during the partial nephrectomy may modify perioperative results: a systematic review and meta-analysis.

BACKGROUND: Barbed sutures can avoid knot tying and speed the suture placement in the PN(partial nephrectomy). On account of the impact on clinical outcomes are ambiguous, this study is determined to identify the application of barbed suture during PN. METHODS: ClinicalTrials.gov, Cochrane Register of Clinical Studies, PubMed and EMBASE were searched for RCTs(randomized controlled trials) and cohort studies focusing on the comparison of barbed and traditional sutures in PN(last updated on Feb in 2015). According to Cochrane Library's suggestion, quality assessment was performed. Review Manager was applied to analyze all the data and sensitivity analyses were performed through omitting each study sequentially. RESULTS: Eight cohort studies and none of RCTs proved eligible (risk of bias: moderate to low,431 patients). Warm ischemia time(MD = - 6.55,95% CI -8.86 to - 4.24, P < 0.05) decreased statistically in the barbed suture group, as well as operative time(MD = - 11.29,95% CI -17.87 to-4.71, P < 0.05). Postoperative complications also reduced significantly(OR = 0.44, 95% CI 0.24 to0.80, P < 0.05). Unidirectional barbed suture resulted in fewer postoperative complications based on the subgroup analysis(OR = 0.48,95% CI 0.24 to 0.94, P < 0.05). CONCLUSIONS: The barbed suture may be a useful surgical innovation which can modify perioperative results for surgeons and patients. Randomly-designed studies with longer follow up and larger sample sizes are in the need of to explore the applicability.

Individual and Combined Impact of Oxygen and Oxygen Transporter Supplementation during Kidney Machine Preservation in a Porcine Preclinical Kidney Transplantation Model.

Marginal kidney graft preservation in machine perfusion (MP) is well-established. However, this method requires improvement in order to mitigate oxidative stress during ischemia-reperfusion, by using oxygenation or an O2 carrier with anti-oxidant capacities (hemoglobin of the marine worm; M101). In our preclinical porcine (pig related) model, kidneys were submitted to 1h-warm ischemia, followed by 23 h hypothermic preservation in Waves® MP before auto-transplantation. Four groups were studied: W (MP without 100%-O2), W-O2 (MP with 100%-O2; also called hyperoxia), W-M101 (MP without 100%-O2 + M101 2 g/L), W-O2 + M101 (MP with 100%-O2 + M101 2 g/L) (n = 6/group). Results: Kidneys preserved in the W-M101 group showed lower resistance, compared to our W group. During the first week post-transplantation, W-O2 and W-M101 groups showed a lower blood creatinine and better glomerular filtration rate. KIM-1 and IL-18 blood levels were lower in the W-M101 group, while blood levels of AST and NGAL were lower in groups with 100% O2. Three months after transplantation, fractional excretion of sodium and the proteinuria/creatinuria ratio remained higher in the W group, creatininemia was lower in the W-M101 group, and kidney fibrosis was lower in M101 groups. We concluded that supplementation with M101 associated with or without 100% O2 improved the Waves® MP effect upon kidney recovery and late graft outcome.

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.

Impact of warm ischaemia time on postoperative renal function after partial nephrectomy for clinical T1 renal cell carcinoma: a propensity score-matched study.

OBJECTIVES: To analyse the effect of prolonged warm ischaemia time (WIT) on long-term renal function after partial nephrectomy (PN), as controversy still exists as to whether prolonged WIT adversely affects the incidence of chronic kidney disease (CKD) after PN. PATIENTS AND METHODS: We reviewed data from 1816 patients who underwent PN for a clinical T1 renal tumour. The propensity scores for prolonged WIT were calculated with the shorter WIT group (<30 min) matched to the longer WIT group (≥30 min) in a 2:1 ratio. Multivariate analysis was used to determine independent predictors for occurrence of postoperative CKD [defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 ] and major renal function deterioration (MRFD; defined as an eGFR decrease of ≥25% postoperatively). RESULTS: After propensity score matching, there was no significant difference in CKD-free survival between the two WIT groups (P = 0.787). Furthermore, longer WIT did not show any significant associations with postoperative CKD-free survival [hazard ratio (HR) 1.002, 95% confidence interval (CI) 0.989-1.015; P = 0.765) and MRFD-free survival (HR 1.014, 95% CI 1.000-1.028; P = 0.055). From further subgroup analyses using more specific WIT thresholds (≤20, 21-30, 31-40, 41-50, ≥50 min) and status of preoperative CKD, no significant differences were noted in CKD and MRFD-free survival amongst the subgroups (all P > 0.05). CONCLUSIONS: Prolonged WIT was not associated with increased incidence of CKD or MRFD after PN.

Transplantation of Cold Stored Porcine Kidneys After Controlled Oxygenated Rewarming.

The concept of "controlled oxygenated rewarming" (COR) using ex vivo machine perfusion after cold storage was evaluated as tool to improve renal graft function after transplantation. Renal function after 20 min warm ischemia and 21 h cold storage was studied in an auto-transplant model in pigs (25-30 kg, n = 6 per group). In the study group, preimplant ex vivo machine perfusion for 90 min was added after cold storage, including gentle warming up of the graft to 20°C (COR). Kidneys that were only cold stored for 21 h served as controls. In vivo follow up was one week; the remaining native kidney was removed during transplantation. COR significantly improved cortical microcirculation upon early reperfusion and reduced free radical mediated injury and cellular apoptosis. Post-transplant kidney function (peak levels in serum) was also largely and significantly improved in comparison to the control group. A weak inverse correlation was found between renal flow during COR and later peak creatinine after transplantation (r2 = 0.5), better values were seen for oxygen consumption, measured during machine perfusion at 20°C (r2 = 0.81). Gentle graft rewarming prior to transplantation by COR improves post-transplant graft outcome and may also be a valuable adjunct in pretransplant graft assessment.