Obstacles to implement machine perfusion technology in routine clinical practice of transplantation: Why are we not there yet?

Machine perfusion of solid human organs is an old technique, and the basic principles were presented as early as 1855 by Claude Barnard. More than 50 years ago, the first perfusion system was used in clinical kidney transplantation. Despite the well-known benefits of dynamic organ preservation and significant medical and technical development in the last decades, perfusion devices are still not in routine use. This article describes the various challenges to implement this technology in practice, critically analyzing the role of all involved stakeholders, including clinicians, hospitals, regulatory, and industry, on the background of regional differences worldwide. The clinical need for this technology is discussed first, followed by the current status of research and the impact of costs and regulations. Considering the need for strong collaborations between clinical users, regulatory bodies, and industry, integrated road maps and pathways required to achieve a wider implementation are presented. The role of research development, clear regulatory pathways, and the need for more flexible reimbursement schemes is discussed together with potential solutions to address the most relevant hurdles. This article paints an overall picture of the current liver perfusion landscape and highlights the role of clinical, regulatory, and financial stakeholders worldwide.

Eleven hours of hypothermic oxygenated machine perfusion (HOPE) for complex liver retransplantation: A case report.

This case report describes the longest reported HOPE treatment ever for an extended criteria donor organ in donation after brain death performed to enable the transplantation of a surgically complex retransplant case. Although further evidence is required, HOPE may facilitate liver retransplantation, expanding the donor organ pool and reducing time constraints on the operation.

Endothelial Cells and Mitochondria: Two Key Players in Liver Transplantation.

Building the inner layer of our blood vessels, the endothelium forms an important line communicating with deeper parenchymal cells in our organs. Previously considered passive, endothelial cells are increasingly recognized as key players in intercellular crosstalk, vascular homeostasis, and blood fluidity. Comparable to other cells, their metabolic function strongly depends on mitochondrial health, and the response to flow changes observed in endothelial cells is linked to their mitochondrial metabolism. Despite the direct impact of new dynamic preservation concepts in organ transplantation, the impact of different perfusion conditions on sinusoidal endothelial cells is not yet explored well enough. This article therefore describes the key role of liver sinusoidal endothelial cells (LSECs) together with their mitochondrial function in the context of liver transplantation. The currently available ex situ machine perfusion strategies are described with their effect on LSEC health. Specific perfusion conditions, including perfusion pressure, duration, and perfusate oxygenation are critically discussed considering the metabolic function and integrity of liver endothelial cells and their mitochondria.

A multicentre outcome analysis to define global benchmarks for donation after circulatory death liver transplantation.

BACKGROUND & AIMS: The concept of benchmarking is established in the field of transplant surgery; however, benchmark values for donation after circulatory death (DCD) liver transplantation are not available. Thus, we aimed to identify the best possible outcomes in DCD liver transplantation and to propose outcome reference values. METHODS: Based on 2,219 controlled DCD liver transplantations, collected from 17 centres in North America and Europe, we identified 1,012 low-risk, primary, adult liver transplantations with a laboratory MELD score of ≤20 points, receiving a DCD liver with a total donor warm ischemia time of ≤30 minutes and asystolic donor warm ischemia time of ≤15 minutes. Clinically relevant outcomes were selected and complications were reported according to the Clavien-Dindo-Grading and the comprehensive complication index (CCI). Corresponding benchmark cut-offs were based on median values of each centre, where the 75th-percentile was considered. RESULTS: Benchmark cases represented between 19.7% and 75% of DCD transplantations in participating centres. The 1-year retransplant and mortality rates were 4.5% and 8.4% in the benchmark group, respectively. Within the first year of follow-up, 51.1% of recipients developed at least 1 major complication (≥Clavien-Dindo-Grade III). Benchmark cut-offs were ≤3 days and ≤16 days for ICU and hospital stay, ≤66% for severe recipient complications (≥Grade III), ≤16.8% for ischemic cholangiopathy, and ≤38.9 CCI points 1 year after transplant. Comparisons with higher risk groups showed more complications and impaired graft survival outside the benchmark cut-offs. Organ perfusion techniques reduced the complications to values below benchmark cut-offs, despite higher graft risk. CONCLUSIONS: Despite excellent 1-year survival, morbidity in benchmark cases remains high. Benchmark cut-offs targeting morbidity parameters offer a valid tool to assess the protective value of new preservation technologies in higher risk groups and to provide a valid comparator cohort for future clinical trials. LAY SUMMARY: The best possible outcomes after liver transplantation of grafts donated after circulatory death (DCD) were defined using the concept of benchmarking. These were based on 2,219 liver transplantations following controlled DCD donation in 17 centres worldwide. Donor and recipient combinations with higher risk had significantly worse outcomes. However, the use of novel organ perfusion technology helped high-risk patients achieve similar outcomes as the benchmark cohort.

Mitochondria and Cancer Recurrence after Liver Transplantation-What Is the Benefit of Machine Perfusion?

Tumor recurrence after liver transplantation has been linked to multiple factors, including the recipient's tumor burden, donor factors, and ischemia-reperfusion injury (IRI). The increasing number of livers accepted from extended criteria donors has forced the transplant community to push the development of dynamic perfusion strategies. The reason behind this progress is the urgent need to reduce the clinical consequences of IRI. Two concepts appear most beneficial and include either the avoidance of ischemia, e.g., the replacement of cold storage by machine perfusion, or secondly, an endischemic organ improvement through perfusion in the recipient center prior to implantation. While several concepts, including normothermic perfusion, were found to reduce recipient transaminase levels and early allograft dysfunction, hypothermic oxygenated perfusion also reduced IRI-associated post-transplant complications and costs. With the impact on mitochondrial injury and subsequent less IRI-inflammation, this endischemic perfusion was also found to reduce the recurrence of hepatocellular carcinoma after liver transplantation. Firstly, this article highlights the contributing factors to tumor recurrence, including the surgical and medical tissue trauma and underlying mechanisms of IRI-associated inflammation. Secondly, it focuses on the role of mitochondria and associated interventions to reduce cancer recurrence. Finally, the role of machine perfusion technology as a delivery tool and as an individual treatment is discussed together with the currently available clinical studies.

Liver perfusion strategies: what is best and do ischemia times still matter?

PURPOSE OF REVIEW: This review describes recent developments in the field of liver perfusion techniques. RECENT FINDINGS: Dynamic preservation techniques are increasingly tested due to the urgent need to improve the overall poor donor utilization. With their exposure to warm ischemia, livers from donors after circulatory death (DCD) transmit additional risk for severe complications after transplantation. Although the superiority of dynamic approaches compared to static-cold-storage is widely accepted, the number of good quality studies remains limited. Most risk factors, particularly donor warm ischemia, and accepted thresholds are inconsistently reported, leading to difficulties to assess the impact of new preservation technologies. Normothermic regional perfusion (NRP) leads to good outcomes after DCD liver transplantation, with however short ischemia times. While randomized controlled trials (RCT) with NRP are lacking, results from the first RCTs with ex-situ perfusion were reported. Hypothermic oxygenated perfusion was shown to protect DCD liver recipients from ischemic cholangiopathy. In contrast, endischemic normothermic perfusion seems to not impact on the development of biliary complications, although this evidence is only available from retrospective studies. SUMMARY: Dynamic perfusion strategies impact posttransplant outcomes and are increasingly commissioned in various countries along with more evidence from RCTs. Transparent reporting of risk and utilization with uniform definitions is required to compare the role of different preservation strategies in DCD livers with prolonged ischemia times.

Mitochondria and ischemia reperfusion injury.

PURPOSE OF REVIEW: This review describes the role of mitochondria in ischemia-reperfusion-injury (IRI). RECENT FINDINGS: Mitochondria are the power-house of our cells and play a key role for the success of organ transplantation. With their respiratory chain, mitochondria are the main energy producers, to fuel metabolic processes, control cellular signalling and provide electrochemical integrity. The mitochondrial metabolism is however severely disturbed when ischemia occurs. Cellular energy depletes rapidly and various metabolites, including Succinate accumulate. At reperfusion, reactive oxygen species are immediately released from complex-I and initiate the IRI-cascade of inflammation. Prior to the development of novel therapies, the underlying mechanisms should be explored to target the best possible mitochondrial compound. A clinically relevant treatment should recharge energy and reduce Succinate accumulation before organ implantation. While many interventions focus instead on a specific molecule, which may inhibit downstream IRI-inflammation, mitochondrial protection can be directly achieved through hypothermic oxygenated perfusion (HOPE) before transplantation. SUMMARY: Mitochondria are attractive targets for novel molecules to limit IRI-associated inflammation. Although dynamic preservation techniques could serve as delivery tool for new therapeutic interventions, their own inherent mechanism should not only be studied, but considered as key treatment to reduce mitochondrial injury, as seen with the HOPE-approach.

Preventing Tumour Recurrence after Liver Transplantation: The Role of Machine Perfusion.

Tumour recurrence is currently a hot topic in liver transplantation. The basic mechanisms are increasingly discussed, and, for example, recurrence of hepatocellular carcinoma is often described in pre-injured donor livers, which frequently suffer from significant ischemia/reperfusion injury. This review article highlights the underlying mechanisms and describes the specific tissue milieu required to promote tumour recurrence after liver transplantation. We summarise the current literature in this field and show risk factors that contribute to a pro-tumour-recurrent environment. Finally, the potential role of new machine perfusion technology is discussed, including the most recent data, which demonstrate a protective effect of hypothermic oxygenated perfusion before liver transplantation.

Effects of non-pharmacological interventions on urinary citrate levels: a systematic review and meta-analysis.

BACKGROUND: Hypocitraturia is a known risk factor for nephrolithiasis, present in 20-60% of stone-forming patients. The administration of citrate or other alkali preparations has been demonstrated to benefit hypocitraturic stone formers. Dietary modifications that include citrate-containing fluids can be an alternative option to pharmacological agents. We aimed to systematically review, summarize and quantify available evidence on the effects of non-pharmacological interventions on urinary citrate and nephrolithiasis. METHODS: Manual and electronic database searches (MEDLINE/PubMed, Embase, Cochrane Library, Scopus, Scielo, LILACS) were performed for studies published up to July 2014. Two reviewers independently identified studies for inclusion and extracted data on study characteristics, outcomes and quality assessments. We included controlled studies with non-pharmacological interventions that assessed urinary citrate levels or nephrolithiasis pre- and post-intervention. Meta-analysis was performed by random effects and subgrouped by the type of intervention, and heterogeneity was analysed by I(2). RESULTS: Of the 427 studies identified, 13 studies were included (18 samples), involving 358 participants with a mean age of 43 ± 11.0 years across the studies. Interventions were grouped as commercial fruit juices, soft drinks, calcium-/magnesium-rich mineral water, high-fiber diet, low-animal-protein diet and plant extract. Almost half of the studies (6/13; 8/18 samples) reported effects in non-stone formers. Two studies included stone formers and non-stone formers. Commercial fruit juice interventions showed high I(2) (88.1%, P = 0.000) and an increase in citraturia levels ( 95% confidence interval) of 167.2 (65.4; 269) mg/day. Other types of intervention did not show important heterogeneity; however, pooled estimates were not significant. CONCLUSION: Our review indicates that further larger scale trials are required to analyze whether non-pharmacological interventions can increase urinary citrate levels and act in kidney stone prevention.

Adequate dietary intake and nutritional status in patients with nephrolithiasis: new targets and objectives.

OBJECTIVES: Modifiable risk factors for kidney stones, such as diet and nutritional status, are targets in the treatment and prevention of nephrolithiasis. The aim of the present study was to assess the nutritional state and energy and nutrient adequacy of patients with nephrolithiasis via anthropometric evaluation, dietary inquiry, and urine biochemistry. DESIGN: The present observational cross-sectional study. SETTING: An outpatient, nephrolithiasis clinic of a tertiary care, university hospital. SUBJECTS: A total of 31 patients with nephrolithiasis and 25 controls were assessed. INTERVENTIONS: All patients were subjected to nutritional evaluation, including dietary inquiry and chemical tests of blood and 24-hour urine samples. MAIN OUTCOME MEASURE: Nutritional state and nutrient ingestion adequacy. RESULTS: The group of patients with nephrolithiasis exhibited high body mass index, abdominal circumference, and body fat percentage values. The protein, sodium, calcium, potassium, and oxalate intakes differed significantly from the recommended values in both the nephrolithiasis and control groups. The nephrolithiasis and control groups differed only in terms of oxalate intake (159 ± 119.27 vs. 112 ± 47.9, respectively, P = .042). Regarding urine biochemistry, 30% of the patients with nephrolithiasis exhibited hypercalciuria, versus 12% of the control group. CONCLUSIONS: The prevalence of individuals with overweight/obesity was high in both the nephrolithiasis and control groups. This finding indicates that in addition to orientation regarding nonlithogenic dietary habits, continuous education by a multidisciplinary staff must also address the prevention and treatment of obesity.

Sodium-glucose cotranspor ter 2 (SGLT2) inhibitors in nephrolithiasis: should we "gliflozin" patients with kidney stone disease?

The prevalence of nephrolithiasis is increasing worldwide. Despite advances in understanding the pathogenesis of lithiasis, few studies have demonstrated that specific clinical interventions reduce the recurrence of nephrolithiasis. The aim of this review is to analyze the current data and potential effects of iSGLT2 in lithogenesis and try to answer the question: Should we also "gliflozin" our patients with kidney stone disease?

Effectiveness of neuromuscular electrical stimulation training combined with exercise on patient-reported outcomes measures in people with knee osteoarthritis: A systematic review and meta-analysis.

OBJECTIVE: This study examined the effectiveness of neuromuscular electrical stimulation (NMES) added to the exercise or superimposed on voluntary contractions on patient-reported outcomes measures (PROMs) in people with knee osteoarthritis (OA). METHODS: This systematic review was described according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized controlled trials (RCTs) were obtained from a systematic literature search in five electronic databases (PubMed, PEDro, LILACS, EMBASE, and SPORTDiscus) in April 2022. We described the effects of intervention according to each PROMs (scores for Pain; Self-reported functional ability; Symptoms (hear clicking, swelling, catching, restricted range of motion, and stiffness); Daily living function; Sports function; and Quality of life) and used a random-effect model to examine the impact of NMES plus exercise on pain compared with exercise in people with knee OA. RESULTS: Six RCTs (n = 367) were included. In the qualitative synthesis, the systematic literature analysis showed improvement in pain after NMES plus exercise compared with exercise alone in three studies. The other three studies revealed no difference between groups in pain, although similar improvement after treatments. In the meta-analysis, NMES at a specific joint angle combined with exercise was not superior to exercise alone in pain management (standardized mean difference = -0.33, 95% CI = -1.05 to 0.39, p = 0.37). There was no additional effect of NMES on exercise on self-reported functional ability, stiffness, and physical function compared with exercise alone. In only one study, symptoms, activities of daily living, sports function, and quality of life improved after whole-body electrostimulation combined with exercise. CONCLUSION: This review found insufficient evidence for the effectiveness of NMES combined with exercise in treating knee OA considering PROMs. While pain relief was observed in some studies, more high-quality clinical trials are needed to support the use of NMES added to the exercise in clinical practice. Electrical stimulation in a whole-body configuration combined with exercise shows promise as an alternative treatment option.

Refractory Thrombotic Thrombocytopenic Purpura in a Patient With Triple X Syndrome.

Clinical manifestations of triple X syndrome (karyotype 47, XXX) can include autoimmune diseases. We describe the occurrence of acquired thrombotic thrombocytopenic purpura (TTP), an autoimmune condition, refractory to plasmapheresis and rituximab in a patient with triple X syndrome who required vincristine administration for disease remission. To our knowledge, this rare coexistence is the first of its kind reported in Brazil.

Nephrectomy as a cause of chronic kidney disease in the treatment of urolithiasis: a case-control study.

OBJECTIVE: To analyze the clinical course of nephrectomized patients due to complications related to nephrolithiasis and ascertain the prevalence of chronic kidney disease (CKD) in this population. METHODS: From 2005 to 2010, 658 patients were treated with urolithiasis. Among these, 30 (4.6%) were nephrectomized. For each case, a control was selected and matched to the case by age, sex and disease duration. All data were collected from medical records, which contained the clinical, laboratory evaluation and diagnostic imaging. RESULTS: Age of the study group was 51.5 ± 10.4 years and the control group 47.1 ± 5.2 years. There were 17 (85%) women and three men in each group. Patients from the study group reported 3 (range, 1-5) episodes of acute renal colic before nephrectomy. Urinary tract infection and hematuria was detected in 70% of cases before surgery. In addition, half of the patients had at least one previous urological procedure. The control group showed higher urinary levels of calcium (216.1 ± 114.3 vs. 130.9 ± 72.2), uric acid (530.2 ± 197.4 vs. 424 ± 75.2) and citrate (755 ± 533 vs. 380.2 ± 260.7), p < 0.01, 0.03 and 0.01, respectively. The creatinine clearance was lower in the study group, 52.5 ± 18.8 ml/min vs. 92.9 ± 24.2 ml/min in the control group (p < 0.001). CONCLUSIONS: There was a decrease in kidney function in nephrectomized patients compared to a control group of stone-forming patients with both kidneys. Prospective studies are needed to assess the incidence of CKD in patients with nephrolithiasis submitted to nephrectomy.

Trends and Obstacles to Implement Dynamic Perfusion Concepts for Clinical Liver Transplantation: Results from a Global Web-Based Survey.

BACKGROUND: Organ perfusion technology is increasingly used in many countries, with a focus, however, on the Western world. This study investigates the current international trends and obstacles to the broader routine implementation of dynamic perfusion concepts in liver transplantation. METHODS: A web-based anonymous survey was launched in 2021. Experts of all involved specializations from 70 centers in 34 countries were contacted, based on the published literature and experience in the field of abdominal organ perfusion. RESULTS: Overall, 143 participants from 23 countries completed the survey. Most respondents were male (67.8%) and transplant surgeons (64.3%) working at university hospitals (67.9%). The majority had experience with organ perfusion (82%), applying mainly hypothermic machine perfusion (HMP; 38%) and other concepts. While most (94.4%) expect a higher utilization of marginal organs with machine perfusion, the majority considers HMP the best technique to reduce liver discard-rates. While most respondents (90%) believed machine perfusion should be fully commissioned, the lack of funding (34%) and knowledge (16%) as well as limited staff (19%) were the three main obstacles to a routine clinical implementation. CONCLUSION: Although dynamic preservation concepts are increasingly used in clinical practice, significant challenges remain. Specific financial pathways, uniform regulations, and tight collaborations among involved experts are needed to achieve wider global clinical use.

Establishing a HOPE Program in a Real-life Setting: A Brazilian Case Series.

Background: Although hypothermic oxygenated perfusion (HOPE) improves posttransplant outcomes, setting up machine perfusion programs may be subjected to specific obstacles under different conditions. This study aims to describe the establishment of HOPE in a real-life setting in Brazil. Methods: Extended criteria donors in donation after brain death organs preserved by HOPE were accepted for higher-risk candidates needing expedited transplantation, perceived as those who would benefit most from the technique because of its limited availability. Extended criteria donors was defined by the Eurotransplant criteria. High-risk transplant candidates were characterized by suboptimal surgical conditions related to the recipient or the procedure. Results: Six HOPE-preserved grafts were transplanted from February 2022 to August 2022. The mean donor risk index was 1.7 (SD 0.5). One organ was severely steatotic, and 3 had an anticipated cold ischemia time above 12 h. Recipients' mean model for end-stage liver disease was 28.67 (SD 6.79), with 1 case of retransplant, 1 of refractory ascites, and 1 of acute-on-chronic liver failure. The mean cold ischemia time was 5 h 42 min (SD 82 min), HOPE 6 h 3 min (SD 150 min), and total preservation time 11 h 46 min (SD 184 min). No case had early allograft dysfunction. The mean length of hospital stay was 10 d with 100% graft and patient survival and no ischemic cholangiopathies at a median follow-up of 15 mo (min 12, max 18). Costs and country-specific legal regulations for device utilization were the major hurdles to implementing the program. Conclusion: We presented a pathway to introduce and rationalize the use of HOPE in a scenario of challenging donor-recipient matching with good results. These findings may aid in implementing machine perfusion programs, especially in settings with limited resources or complex transplant logistics.

Cardiometabolic, functional, and psychosocial effects of a remotely supervised home-based exercise program in individuals with type 2 diabetes (RED study): study protocol for a randomized clinical trial.

BACKGROUND: Type 2 diabetes mellitus (T2D) is a serious global health problem, and exercise is considered an essential non-pharmacological tool in T2D prevention and treatment. During periods of social isolation experienced by the COVID-19 pandemic, home-based exercise programs were strongly recommended as a strategy to facilitate exercise practice and reduce the negative impacts of social isolation. Remotely supervised exercise stands out as an easily accessible strategy after the pandemic, as it is a tool that aims to facilitate access to exercise by this population. The purpose of the RED study is to verify the effects of a remotely supervised home-based exercise program compared to a control group on cardiometabolic, functional, and psychosocial outcomes in patients with T2D. METHODS: Participants are randomized into the control group (CG) and the intervention group (IG). Participants allocated to the CG receive recommendations for the practice of physical activity based on information from chapters of the Physical Activity Guide for the Brazilian Population, while the IG will perform a 12-week home-based exercise program supervised remotely by video call. The intervention has a weekly frequency of two sessions per week on non-consecutive days during the first 6 weeks and three sessions per week on non-consecutive days for the remaining 6 weeks. The RED study has HbA1c as the primary outcome, and the participants' cardiometabolic, functional, and psychosocial parameters are assessed at baseline (week 0) and post-intervention (week 13). DISCUSSION: Expected results of the proposed study will provide the knowledge base of health professionals and deliver more evidence for a growing area, i.e., home-based exercise and T2D. Additionally, this protocol aims to verify and demonstrate whether this program can be accessible and effective for different health outcomes in patients with T2D. TRIAL REGISTRATION: The RED study protocol was prospectively registered at ClinicalTrials.gov (NCT05362071). Date registered April 6, 2022. https://clinicaltrials.gov/ct2/show/NCT05362071 .

Mitochondrial injury during normothermic regional perfusion (NRP) and hypothermic oxygenated perfusion (HOPE) in a rodent model of DCD liver transplantation.

BACKGROUND: Normothermic regional perfusion (NRP) and hypothermic-oxygenated-perfusion (HOPE), were both shown to improve outcomes after liver transplantation from donors after circulatory death (DCD). Comparative clinical and mechanistical studies are however lacking. METHODS: A rodent model of NRP and HOPE, both in the donor, was developed. Following asystolic donor warm ischemia time (DWIT), the abdominal compartment was perfused either with a donor-blood-based-perfusate at 37 °C (NRP) or with oxygenated Belzer-MPS at 10 °C (donor-HOPE) for 2 h. Livers were then procured and underwent 5 h static cold storage (CS), followed by transplantation. Un-perfused and HOPE-treated DCD-livers (after CS) and healthy livers (DBD) with direct implantation after NRP served as controls. Endpoints included the entire spectrum of ischemia-reperfusion-injury. FINDINGS: Healthy control livers (DBD) showed minimal signs of inflammation during 2 h NRP and achieved 100% posttransplant recipient survival. In contrast, DCD livers with 30 and 60 min DWIT suffered from greater mitochondrial injury and inflammation as measured by increased perfusate Lactate, FMN- and HMGB-1-levels with subsequent Toll-like-receptor activation during NRP. In contrast, donor-HOPE (instead of NRP) led to significantly less mitochondrial-complex-I-injury and inflammation. Results after donor-HOPE were comparable to ex-situ HOPE after CS. Most DCD-liver recipients survived when treated with one HOPE-technique (86%), compared to only 40% after NRP (p = 0.0053). Following a reduction of DWIT (15 min), DCD liver recipients achieved comparable survivals with NRP (80%). INTERPRETATION: High-risk DCD livers benefit more from HOPE-treatment, either immediately in the donor or after cold storage. Comparative prospective clinical studies are required to translate the results. FUNDING: Funding was provided by the Swiss National Science Foundation (grant no: 32003B-140776/1, 3200B-153012/1, 320030-189055/1, and 31IC30-166909) and supported by University Careggi (grant no 32003B-140776/1) and the OTT (grant No.: DRGT641/2019, cod.prog. 19CT03) and the Max Planck Society. Work in the A.G. laboratory was partially supported by the NIH R01NS112381 and R21NS125466 grants.