Sodium-glucose cotranspor ter 2 (SGLT2) inhibitors in nephrolithiasis: should we "gliflozin" patients with kidney stone disease? / Inibidores de cotransportadores sódio-glicose-2 (SGLT2) na nefrolitíase - devemos "gliflozinar" os litiásicos?

ABSTRACT 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?

RESUMO A prevalência da nefrolitíase está aumentando em todo o mundo. Apesar dos avanços na compreensão da patogênese da doença litiásica, poucos estudos demonstraram que intervenções clínicas específicas diminuem a recorrência da nefrolitíase. O objetivo desta revisão é analisar os dados atuais e efeitos potenciais dos iSGLT2 na doença litiásica e tentar responder à pergunta: devemos também "gliflozinar" os litiásicos?

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?

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.

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.

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.

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.

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 .

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.

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.

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.

Machine Perfusion for Extended Criteria Donor Livers: What Challenges Remain?

Based on the renaissance of dynamic preservation techniques, extended criteria donor (ECD) livers reclaimed a valuable eligibility in the transplantable organ pool. Being more vulnerable to ischemia, ECD livers carry an increased risk of early allograft dysfunction, primary non-function and biliary complications and, hence, unveiled the limitations of static cold storage (SCS). There is growing evidence that dynamic preservation techniques-dissimilar to SCS-mitigate reperfusion injury by reconditioning organs prior transplantation and therefore represent a useful platform to assess viability. Yet, a debate is ongoing about the advantages and disadvantages of different perfusion strategies and their best possible applications for specific categories of marginal livers, including organs from donors after circulatory death (DCD) and brain death (DBD) with extended criteria, split livers and steatotic grafts. This review critically discusses the current clinical spectrum of livers from ECD donors together with the various challenges and posttransplant outcomes in the context of standard cold storage preservation. Based on this, the potential role of machine perfusion techniques is highlighted next. Finally, future perspectives focusing on how to achieve higher utilization rates of the available donor pool are highlighted.

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.

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.

Impact of Machine Perfusion on the Immune Response After Liver Transplantation - A Primary Treatment or Just a Delivery Tool.

The frequent use of marginal livers forces transplant centres to explore novel technologies to improve organ quality and outcomes after implantation. Organ perfusion techniques are therefore frequently discussed with an ever-increasing number of experimental and clinical studies. Two main approaches, hypothermic and normothermic perfusion, are the leading strategies to be introduced in clinical practice in many western countries today. Despite this success, the number of studies, which provide robust data on the underlying mechanisms of protection conveyed through this technology remains scarce, particularly in context of different stages of ischemia-reperfusion-injury (IRI). Prior to a successful clinical implementation of machine perfusion, the concept of IRI and potential key molecules, which should be addressed to reduce IRI-associated inflammation, requires a better exploration. During ischemia, Krebs cycle metabolites, including succinate play a crucial role with their direct impact on the production of reactive oxygen species (ROS) at mitochondrial complex I upon reperfusion. Such features are even more pronounced under normothermic conditions and lead to even higher levels of downstream inflammation. The direct consequence appears with an activation of the innate immune system. The number of articles, which focus on the impact of machine perfusion with and without the use of specific perfusate additives to modulate the inflammatory cascade after transplantation is very small. This review describes first, the subcellular processes found in mitochondria, which instigate the IRI cascade together with proinflammatory downstream effects and their link to the innate immune system. Next, the impact of currently established machine perfusion strategies is described with a focus on protective mechanisms known for the different perfusion approaches. Finally, the role of such dynamic preservation techniques to deliver specific agents, which appear currently of interest to modulate this posttransplant inflammation, is discussed together with future aspects in this field.

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.

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.

Electro-Optical Biosensor Based on Embedded Double-Monolayer of Graphene Capacitor in Polymer Technology.

In this work, we present an interferometric polymer-based electro-optical device, integrated with an embedded double-monolayer graphene capacitor for biosensing applications. An external voltage across the capacitor applies an electric field to the graphene layers modifying their surface charge density and the Fermi level position in these layers. This in turn changes the electro-optic properties of the graphene layers making absorption in the waveguide tunable with external voltages. Simultaneously, it is possible to appreciate that this phenomenon contributes to the maximization of the light-graphene interaction by evanescent wave in the sensing area. As a result, it is obtained large phase changes at the output of the interferometer, as a function of small variations in the refractive index in the cladding area, which significantly increasing the sensitivity of the device. The optimum interaction length obtained was 1.24 cm considering a cladding refractive index of 1.33. An absorption change of 129 dB/mm was demonstrated. This result combined with the photonic device based on polymer technology may enable a low-cost solution for biosensing applications in Point of Care (PoC) platform.

Recommendations for Donor and Recipient Selection and Risk Prediction: Working Group Report From the ILTS Consensus Conference in DCD Liver Transplantation.

Although the utilization of donation after circulatory death donors (DCDs) for liver transplantation (LT) has increased steadily, much controversy remains, and no common acceptance criteria exist with regard to donor and recipient risk factors and prediction models. A consensus conference was organized by International Liver Transplantation Society on January 31, 2020, in Venice, Italy, to review the current clinical practice worldwide regarding DCD-LT and to develop internationally accepted guidelines. The format of the conference was based on the grade system. International experts in this field were allocated to 6 working groups and prepared evidence-based recommendations to answer-specific questions considering the currently available literature. Working group members and conference attendees served as jury to edit and confirm the final recommendations presented at the end of the conference by each working group separately. This report presents the final statements and recommendations provided by working group 2, covering the entire spectrum of donor and recipient risk factors and prediction models in DCD-LT.