The gut microbiome has emerged as a critical determinant of health and disease across virtually all organ systems. In the context of chronic kidney disease (CKD) and renal transplantation, mounting evidence reveals a complex bidirectional relationship between the intestinal microbiota and kidney function-commonly referred to as the gut-kidney axis. Patients with CKD harbor a profoundly altered gut microbial ecosystem characterized by reduced diversity, depletion of beneficial commensal organisms, and expansion of pathobiont taxa capable of generating uremic toxins and pro-inflammatory mediators. These perturbations are further compounded by the uremic milieu itself, dietary restrictions, frequent antibiotic exposure, and the use of immunosuppressive agents following transplantation. The gut-liver-kidney axis adds an additional layer of complexity, linking hepatic metabolism, bile acid signaling, endotoxemia, and systemic immune activation to the progression of renal disease. Gut-derived metabolites-including short-chain fatty acids (SCFAs), bile acids, trimethylamine N-oxide (TMAO), and tryptophan-derived uremic solutes such as indoxyl sulfate and p-cresyl sulfate-serve as molecular mediators of inter-organ crosstalk and have been identified as both biomarkers and therapeutic targets. A growing body of literature supports the diagnostic and prognostic utility of microbiome composition and its metabolic signatures in patients with CKD and those undergoing renal replacement therapy. Therapeutic strategies aimed at restoring microbial homeostasis-encompassing dietary interventions, prebiotics, probiotics, synbiotics, fecal microbiota transplantation (FMT), bile acid-based therapies, and novel pharmacological approaches-hold considerable promise for improving outcomes in CKD and transplant recipients. Importantly, the bidirectional relationship between immunosuppressive drugs and the gut microbiota has emerged as a clinically significant determinant of both microbial ecology and drug pharmacokinetics: each major immunosuppressive agent class-corticosteroids, calcineurin inhibitors, mycophenolate mofetil, and mTOR inhibitors-induces characteristic dysbiotic patterns, while in turn, the microbiota modulates drug bioavailability through enzymatic biotransformation (notably bacterial beta-glucuronidase activity affecting mycophenolic acid enterohepatic recirculation) and modulation of host drug-metabolizing enzymes. This narrative review provides a comprehensive overview of the current understanding of microbiome dysbiosis in the setting of renal disease and transplantation, examines the mechanistic underpinnings of the gut-liver-kidney axis, details the multifaceted impact of dysbiosis on transplant outcomes-including allograft function and rejection, infection, post-transplant diabetes, and cardiovascular complications-and critically appraises the translational potential of microbiome-targeted interventions. We conclude by highlighting ongoing challenges and future directions toward personalized, microbiome-informed clinical care.

BACKGROUND: Glucose is an important fuel in cancer cells, however, its availability may be limited in solid tumors. Cell-autonomous, metabolic adaptations of cancer cells and non-malignant cells to glucose deprivation are still incompletely understood. METHODS: Here, we addressed the changes in central carbon metabolism in lung cancer cells and normal lung cells facing glucose limitation using stable isotopic labeling followed by nuclear magnetic resonance spectroscopy and mass spectrometry. RESULTS: Elevated levels and the release of newly synthesized aspartate were among the most prominent changes in low compared to high glucose conditions. The low glucose-induced export of aspartate occurred in different lung cancer cell lines, but also bronchial epithelial cells and cancer-associated fibroblasts. It was accompanied by a reduced use of aspartate in purine synthesis and suppressed by hypoxia. A knockout of the malate-aspartate shuttle (MAS) enzyme mitochondrial aspartate aminotransferase (GOT2) decreased aspartate release. Low glucose conditions diminished reduced nicotinamide adenine dinucleotide (NADH) and restoring NADH reversed aspartate synthesis, suggesting that the distal, NADH-dependent arm of the MAS is compromised under glucose deprivation. CONCLUSIONS: Cells accumulate and release aspartate, a biosynthetic precursor and signaling molecule, under low glucose conditions, largely due to a truncated MAS, as part of their adaptive metabolic response.

BACKGROUND Liver transplantation is the only treatment for acute and chronic liver failure, but the global organ shortage has increased reliance on extended criteria donor livers, which are more susceptible to ischemia-reperfusion injury. While static cold storage is standard, these grafts often require improved preservation strategies. AIM To summarize the current state of small animal liver machine perfusion (MP), highlight variability in protocols, and emphasize the need for standardization to guide future research. METHODS A comprehensive literature search of PubMed was conducted to identify studies on small animal (rat and mouse) ex vivo liver MP. Only English-language animal studies were included, with no restrictions on publication date. Relevant full-text articles were reviewed, and reference lists were screened to ensure completeness. RESULTS Small animal liver MP provides a cost-effective model to explore dynamic preservation strategies. Rat perfusion studies face challenges including dual-vessel perfusion, maintaining physiological perfusate volumes, and lack of standardized protocols. Open- and closed-circuit setups have distinct advantages and limitations, and experimental designs vary widely across studies. CONCLUSION This review illustrates the wide variability in small animal liver MP protocols and underscores the urgent need for standardization. Addressing these inconsistencies will enhance reproducibility, facilitate comparison across studies, and support the development of optimized liver preservation strategies.

Objectives The impact of climate change on health is well recognised, yet its influence on postoperative complications remains underexplored. This systematic review examines how climatic factors—particularly temperature, humidity and seasonal variations—affect surgical outcomes.Design Systematic review with narrative synthesis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines.Data sources A comprehensive search of PubMed, Web of Science and the Cochrane Library from June 2015 to June 2025 was conducted. An additional supplementary PubMed search was performed to identify further relevant studies.Eligibility criteria for selecting studies Included were studies published in English or German that examined associations between climatic factors, including temperature, humidity, precipitation or seasonality and postoperative outcomes in surgical patients. Studies without a surgical or climatic focus, animal studies, reviews and commentaries were excluded.Data extraction and synthesis Two reviewers independently screened studies and extracted data using predefined criteria. Risk of bias was assessed using the Newcastle-Ottawa Scale. Due to methodological heterogeneity, findings were synthesised narratively.Results Fifteen studies were included. High ambient temperatures were frequently associated with increased risks of surgical site infections (SSIs). Some large studies reported that even a one-degree rise significantly elevated infection rates. Humidity was also linked to higher infection rates, with evidence suggesting an independent effect in some cases. Seasonal changes influenced complication rates across regions and surgical disciplines, with infection and pneumonia peaks in summer or winter months. A few studies reported increased risks during heavy rainfall or institutional transitions such as the ‘July effect’.Conclusion Overall, elevated temperature and humidity appear to be associated with increased postoperative risks, especially SSIs. Seasonal patterns may further influence outcomes depending on geography and procedure type. While the available evidence supports a link between climate and surgical complications, methodological differences and limited adjustment for confounders highlight the need for more rigorous studies.

This study aimed to evaluate whether continuous axillary temperature monitoring using a wearable patch enables earlier detection of postoperative infections compared to conventional intermittent infrared thermometry. 103 surgical patients were included in this prospective, single-center study and monitored over an 11-month period. Continuous axillary temperature monitoring using the SteadyTemp ® patch was compared to routine infrared measurements performed as part of clinical routine. The primary outcome was fever detection rate (≥ 38.0 °C). Secondary outcomes included the correlation between fever detection and laboratory values as well as the frequency of clinical interventions. Out of 103 included patients, fever was detected in 33 cases. Continuous monitoring identified fever in 31 of these 33 patients (93.9%), whereas infrared thermometry detected fever in only 12 cases (36.4%). In 16 cases where antibiotic therapy was initiated or adjusted due to newly detected fever, the patch detected fever in 15 patients, compared to only 7 detections by infrared thermometry. Surgical interventions due to suspected infections were performed in 5 patients, and fever was detected by the patch in all cases, while infrared thermometry detected fever in only 2 of these patients. Due to the frequent failure of infrared thermometry to detect fever, a scoring system was developed to assess the clinical relevance of fever detection. Continuous temperature monitoring with the SteadyTemp ® patch demonstrated superior fever detection compared to infrared thermometry, leading to earlier identification of febrile events. This study suggests that continuous temperature monitoring may enhance infection surveillance in surgical patients, allowing for more timely clinical interventions.

Proteinuria is an established biomarker in native kidney disease, there is, however, a lack of data on its significance for assessing organ quality in the setting of deceased kidney donors. Donor urinary protein-to-creatinine ratio (UPCR) has been associated with the extent of chronic lesions in pre-transplant kidney graft biopsies in a prospective single center study. Validating this association in a larger multicenter cohort and assessing its value in addition to known clinical predictors might help to improve evaluation of organ quality and organ utilization. We are currently conducting a prospective observational multi-center study recruiting 300 consecutive adult deceased kidney donor and kidney graft recipient pairs procured and transplanted in all four Austrian transplant centers. The primary aim is to validate donor UPCR for assessing graft quality of kidney grafts from deceased donors by examining the association of donor UPCR with the extent of chronic lesions in pre-implant kidney grafts (glomerulosclerosis, arteriosclerosis/arteriolosclerosis, interstitial fibrosis and tubular atrophy = total chronic lesion score). The secondary objective is the evaluation of donor UPCR for the prediction of graft function after one year, and building of a donor urine biobank. The study in currently ongoing; the expected end of study is by the last quarter of 2027. The trial centers at Vienna, Linz, Graz and Innsbruck have started including patients and samples in January 2023, March 2024, April 2024 and June 2024, respectively. To date, 125 donor-recipient pairs have been included, with an estimated inclusion of the last patient by July 2026. While proteinuria in donor reports is often noted semi-quantitatively and not linked to graft quality, a preliminary study has shown that a quantitative and qualitative assessment of donor proteinuria can predict chronic graft damage. Confirming these findings through a large multicenter study, alongside known graft quality predictors, could help develop better prediction models for graft quality. These models have the potential to enhance pre-implant risk assessment and organ utilization. Establishing a large comprehensive donor urine bio-database will enable further research.

Prostaglandin E1 (PGE1), also known as Alprostadil, has been widely studied for its positive effects in solid organ transplantation. This pharmacological agent offers notable benefits in heart, lung, and particularly liver and kidney transplants, leading to improved outcomes such as reduced ischaemia-reperfusion injury (IRI), better graft viability, and increased patient survival.Evidence suggests that PGE1 is effective in organ preservation, reducing IRI, preventing primary graft dysfunction, improving both short- and long-term survival, shortening stays in the intensive care unit (ICU), and decreasing the risk of acute kidney failure, especially after liver transplantation.The principal biological actions of PGE1, which make the compound a valuable tool in organ transplantation are the following: it acts as a vasodilator, improving organ perfusion by reducing peripheral vascular resistance in the kidney and liver. Furthermore, it provides cytoprotection and has anti-inflammatory effects, shielding cells and tissues from IRI, lowering oxidative stress, and moderating immune responses. Finally, PGE1 has established anti-platelet and fibrinolytic properties: it inhibits platelet aggregation and promotes fibrinolysis, further protecting the graft, impacting the platelet activation, and especially their release of potassium ions during activation. These combined effects—vasodilation, cytoprotection, anti-inflammation, and anti-platelet activity—lead to better clinical outcomes, including faster organ function recovery, improved graft and patient survival, and a reduced risk of acute rejection.In kidney transplantation, PGE1 has been shown to protect organs when administered during machine perfusion (but not during cold storage). It enhances renal function during reperfusion, lowers vascular resistance, and limits IRI, when given immediately after reperfusion. By reducing oxidative stress and inflammation, PGE1 supports quicker graft recovery and better overall results.PGE1’s rapid metabolism and widespread distribution of its receptors, along with well-understood receptor-mediated effects, make it a promising option for perioperative management in solid organ transplantation. Its capacity to reduce IRI, suppress inflammation, and support vascular function is supported by strong pre-clinical and clinical evidence.In the present review, we summarize available evidence that position PGE1 as a valuable therapeutic adjunct for improving transplantation outcomes.

Machine perfusion (MP) is gaining importance in liver transplantation, the only cure for many end-stage liver diseases. Varieties of different MP protocols are available. Currently, various MP protocols are available, differing not only in perfusion temperature but also in the specific perfusion solution required. We aimed to investigate the performance of an HTK-based perfusate during sub-normothermic MP (SNMP) of discarded human liver grafts compared to that of a UW-based solution. Twenty discarded livers (rejected for transplantation by all centers) were subjected to ex-vivo SNMP at 21°C with either HTK- or UW-based solution for 12 h. Perfusate and tissue samples collected before the start, after 6 h, and at the end of SNMP were analyzed for liver enzymes, along with mRNA expression of perfusate and tissue markers associated with organ damage. Hepatocellular viability was assessed by measuring bile production, monitoring pH stability, and analyzing histological changes in HE stained tissue sections. After propensity score matching 16 livers were analyzed. Overall, no differences between HTK- and UW-based solution were detected, except for an increased MLKL mRNA expression and impaired pH stability during SNMP with HTK-based perfusate. No other investigated parameters of cell injury, inflammation or hepatocellular viability supported this finding. Bile production was higher in the 6 HTK-perfused livers compared to the three UW-perfused livers that produced bile. Overall, these findings suggest that HTK performs comparably to a UW-based solution during 12 h of liver SNMP.

Serine and glycine give rise to important building blocks in proliferating cells. Both amino acids are either synthesized de novo or taken up from the extracellular space. In lung cancer, serine synthesis gene expression is variable, yet, expression of the initial enzyme, phosphoglycerate dehydrogenase (PHGDH), was found to be associated with poor prognosis. While the contribution of de novo synthesis to serine pools has been shown to be enhanced by serine starvation, the impact of glucose deprivation, a commonly found condition in solid cancers is poorly understood. Here, we utilized a stable isotopic tracing approach to assess serine and glycine de novo synthesis and uptake in different lung cancer cell lines and normal bronchial epithelial cells in variable serine, glycine, and glucose conditions. Under low glucose supplementation (0.2 mM, 3–5% of normal plasma levels), serine de novo synthesis was maintained or even activated. As previously reported, also gluconeogenesis supplied carbons from glutamine to serine and glycine under these conditions. Unexpectedly, low glucose treatment consistently enhanced serine to glycine conversion, along with an up-regulation of the mitochondrial one-carbon metabolism enzymes, serine hydroxymethyltransferase (SHMT2) and methylenetetrahydrofolate dehydrogenase (MTHFD2). The relative contribution of de novo synthesis greatly increased in low serine/glycine conditions. In bronchial epithelial cells, adaptations occurred in a similar fashion as in cancer cells, but serine synthesis and serine to glycine conversion, as assessed by label enrichments and gene expression levels, were generally lower than in (PHGDH positive) cancer cells. In summary, we found a variable contribution of glucose or non-glucose carbon sources to serine and glycine and a high adaptability of the downstream one-carbon metabolism pathway to variable glucose supply.

Cytomegalovirus (CMV) infection detrimentally influences graft survival in kidney transplant recipients, with the risk primarily determined by recipient and donor serostatus. However, recipient CD8+ T cells play a crucial role in CMV control. The optimal preventive strategy (prophylaxis vs. pre-emptive treatment), particularly for seropositive (intermediate risk) recipients, remains uncertain. We investigated CD8+ T cell subpopulation dynamics and CMV occurrence (DNAemia ≥ 100 IU/mL) in 65 kidney transplant recipients, collecting peripheral blood mononuclear cells before (T1) and 1 year after transplantation (T2). Comparing the two timepoints, we found an increase in granulocyte, monocyte and CD3+CD8+ T cells numbers, while FoxP3+CD25+, LAG-3+ and PD-1+ frequencies were reduced at T2. CMV DNAemia occurred in 33 recipients (55.8%) during the first year. Intermediate risk patients were disproportionally affected by posttransplant CMV (N = 29/45, 64.4%). Intermediate risk recipients developing CMV after transplantation exhibited lower leukocyte, monocyte, and granulocyte counts and higher FoxP3+CD25+ frequencies in CD3+CD8+ T cells pre-transplantation compared to patients staying CMV negative. Pre-transplant FoxP3+CD25+ in CD3+CD8+ T cells had the best discriminatory potential for CMV infection prediction within the first year after transplantation (AUC: 0.746). The FoxP3+CD25+ CD3+CD8+ T cell subset may aid in selecting intermediate risk kidney transplant recipients for CMV prophylaxis.

Abstract Solid organ transplantation continues to be the only or most efficient therapeutic solution for several end-stage diseases. The success of such transplantation is largely dependent on the swift transportation of organs from donors to recipients, as Cold Ischemia Time (CIT) plays a critical role in determining the recipient’s medical outcome. This study explores the potential of Advanced Air Mobility (AAM) in the context of organ transplantation in Austria and Germany. AAM, in the healthcare sector, is associated with potential overall process time savings via air transportation, thereby reducing CIT. However, the application of AAM for organ transplantation has not yet been implemented in Europe. This study employs a Monte Carlo simulation to derive the trip length distributions for organ transplantation in Austria and Germany. By utilizing data from Eurotransplant (2018–2021) and ÖBIG (2017–2021), it was found that 48% of organ transports within Germany, and 80% of organ transports within Austria, fall within a trip length of less than 150 km. This distance is within the capabilities of today’s AAM technology. Anticipated time benefits of up to 30 min compared to ground-based transport can be expected. Furthermore, the optimization of the organ transport process, facilitated by AAM, promises greater potential for CIT reduction.

N-acetyl-selenomethionine (NASeLM), a representative of the selenium compounds, failed to convince in clinical studies and cell cultures that it neither inhibits cancer growth nor has a chemoprotective effect. This study aims to find out whether NASeLM shows a growth-inhibiting property compared to the carrier substance N-Acetyl-L-methionine (NALM) on two different cancer cells, namely Jurkat cells and MTC-SK cells. Methods: Jurkat and MTC-SK cells were cultured in the absence or presence of varying concentrations (0–500 µg/mL) of NASeLM and NALM solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of Jurkat and MTC-SK cells. Results: Both substances, NASeLM and NALM, were similarly able to inhibit cell growth and mitochondrial activity of Jurkat cells in a concentration-dependent and time-dependent manner up to 70%. Only the determination of caspase activity showed that only NASeLM was able to increase this to almost 40% compared to the control as well as the same lack of NALM. However, the experiments on MTC-SK cells showed a clear difference in favor of NASeLM compared to NALM. While NASeLM was able to reduce cell growth to up to 55%, the same amount of NALM was only at around 15%, which turned out to be highly significant (p < 0.001). The same could also be measured for the reduction in MTC-SK mitochondrial activity. Time dependence could also be recognized: the longer both substances, NASeLM and NALM, were incubated, the higher the effect on cell growth and mitochondrial activity, in favour of NASeLM. Only NASeLM was able to increase caspase-3 activity in MTC-SK cells: at 250 µg/mL NASeLM, caspase-3 activity increased significantly to 28% after 24 and 48 h compared to the control (14%) or the same NALM concentration (14%). After 72 h, this could still increase to 37%. A further increase in the NASeLM concentration did not result in higher caspase-3 activity. Conclusion: NASeLM could clearly increase caspase-3 activity in both cell types, Jurkat or MTC-SK cells, and thus induce cell death. NALM and NASeLM showed a reduction in cell growth and mitochondrial activity in both cell lines: While NALM and NASeLM showed almost identical measurements on Jurkat cells, NASeLM was much more effective on MTC-SK than the non-selenium-containing carrier, indicating that it has additional anti-chemoprotective effects.

Dynamic preservation methods such as normothermic, subnormothermic, and hypothermic machine perfusion circuits have emerged as viable alternatives to conventional static cold storage. These organ perfusion technologies serve as preservation methods and enable organ assessment, reconditioning, and repair before transplantation. Gene therapy is a novel strategy with the potential to transform the field of graft optimization and treatment. Thereby specific pathways involved in the transplantation process can be targeted and modified. This review aims to provide an overview of gene delivery methods during ex vivo machine perfusion of kidney and liver grafts. Recent literature on state-of-the-art gene therapy approaches during ex situ organ preservation, especially with respect to ischemia-reperfusion injury, as well as acute and chronic graft rejection have been analyzed. Additionally, potential challenges that could affect further refinement of this therapeutic modality are outlined.