Search Results (82)

Despite their reduced viability, kidneys from donors-after-circulatory-death (DCD) increase the pool of transplantable kidneys. Molecular hydrogen (H₂) is emerging as a gas with therapeutic potential against graft injury. We investigated the effect of H₂ in an ex vivo porcine model of DCD kidney transplantation. Renal arteries of male Yorkshire pigs (n = 6) were clamped in situ for 60 min to induce ischemia, and ureters and arteries were cannulated to mimic DCD kidney injury. Upon nephrectomy, kidneys were flushed with UW solution or H₂-saturated UW solution and then preserved by machine perfusion at 4 °C for 4 h followed by a 4-h reperfusion period with warm autologous blood. Urine and arterial blood samples were collected hourly. H₂ preserved renal architecture, evidenced by significantly reduced tubular necrosis and renal expression of damage markers, which corresponded with the downregulated renal expression of pro-inflammatory genes compared to the UW-only group (p < 0.05). H₂ also markedly reduced levels of serum creatinine, BUN and intrarenal resistance, while flow rate, creatinine clearance and urine output were significantly higher, which positively correlated with Trx-1 and HO-1 expression in comparison with UW only group (p < 0.05). Improvement in renal graft quality and function is associated with Trx-1/HO-1 activation, suggesting preliminary clinical trials in kidney transplantation. Full article

Donation after circulatory death (DCD) involves unavoidable ischemia–reperfusion injury (IRI). Mitochondrial permeability transition pore (MPTP) opening plays a critical role in DCD heart injury. Activation of ubiquitous calpains, including calpain-1 and calpain-2 (CPN1/2), increases MPTP opening in DCD hearts. Mitofilin, a mitochondrial inner membrane protein that regulates cristae morphology, is also involved in MPTP opening during ischemia–reperfusion. However, it remains unclear whether CPN1/2 activation contributes to mitofilin-mediated IRI in DCD hearts. We first incubated a mitofilin peptide with exogenous CPN1 in vitro to investigate the link between CPN1 activation and mitofilin degradation. Next, we tested whether CPN1/2 inhibition reduces cardiac injury in DCD hearts by preserving mitofilin and limiting MPTP opening. Sprague-Dawley (SD) rat hearts were subjected to 25 min of in vivo ischemia followed by ex vivo perfusion with or without the CPN1/2 inhibitor MDL-28170 (10 µM). In vitro incubation with CPN1 led to mitofilin degradation, confirming mitofilin as a CPN1 substrate. CPN1/2 inhibition significantly reduced infarct size compared with untreated DCD hearts, preserved mitofilin expression, and decreased MPTP opening. These findings indicate that CPN1/2 activation promotes MPTP opening in DCD hearts through mitofilin degradation. Timely inhibition of CPN1/2 represents a promising strategy to reduce cardiac injury and improve DCD heart function. Full article

During donation after circulatory death (DCD), circulating levels of mitochondrial damage-associated molecular patterns (mtDAMPs) may increase, thereby exposing donor hearts to mtDAMPs prior to procurement and during machine perfusion. Mitochondrial DNA (mtDNA) is a pro-inflammatory mtDAMP that may stimulate several intracellular cascades including that of toll-like receptor 9 (TLR9). We administered mtDNA or ODN2088 (TLR9 antagonist) to hearts at reperfusion onset using an isolated rat heart model of DCD transplantation to investigate their effects. Four experimental groups were compared: (1) no ischemia; (2) ischemia; (3) ischemia + mtDNA; (4) ischemia + ODN2088. During reperfusion, cardiac power in ischemic hearts was significantly reduced compared to non-ischemic hearts (p < 0.01), and was further decreased with mtDNA (p < 0.05), but remained unchanged with ODN2088. Reduced ventricular recovery in mtDNA-treated hearts likely resulted from lower recovery of oxidative metabolism, demonstrated by reduced oxygen efficiency (p < 0.05) and a strong tendency for increased cytochrome c release (p < 0.06),indicating mitochondrial dysfunction and disruption, respectively. ODN2088 phosphorylated IκBα (NF-κB inhibitor alpha) and appeared to decrease cardiomyocyte death compared to ischemic hearts. Given the detrimental effects of circulating mtDNA on cardiac functional and metabolic recovery, circulating mtDAMPs, and particularly mtDNA, are of clinical relevance as potential therapeutic targets for optimizing graft quality and post-transplant outcomes. Full article

Background/Objectives: Ischemia–reperfusion injury (IRI) contributes to graft dysfunction in solid organ transplantation, with the pancreas vulnerable due to its fragile vasculature. Endothelial glycocalyx (eGCX) disruption is central to this process. This study prospectively examined perioperative endothelial injury in pancreas transplantation. Methods: Fifty-two recipients were included, of whom 47 underwent simultaneous pancreas-kidney (SPK) transplantation and 5 pancreas retransplantation. Biomarkers of eGCX degradation (syndecan-1, heparan sulfate (HS) and hyaluronan) and endothelial injury (soluble thrombomodulin, VEGF and soluble VEGFR1) were measured in plasma preoperatively, 10 min after pancreas reperfusion, 24 h later, and at discharge. Associations with donor type and early post-transplant outcomes were explored. Results: A marker endothelial injury was evident within 10 min of pancreas reperfusion, before kidney implantation, characterized by increased syndecan-1, HS, and sVEGFR1, together with decreased VEGF. Hyaluronan peaked at 24 h, consistent with a broader systemic endothelial response. Controlled donation after circulatory death donors showed higher syndecan-1 levels at 10 min PR and higher VEGF at 24 h. Seven recipients developed pancreas graft loss, which was linked to lower VEGF at 10 min post-reperfusion and lower hyaluronan levels both before surgery and at discharge. Kidney acute tubular necrosis was related with higher preoperative HS and elevated 24 h sVEGFR1. Among recipients with functioning grafts, preoperative endothelial biomarkers were linked to postoperative complications. Conclusions: Pancreas transplantation triggers early endothelial injury and glycocalyx shedding, particularly in a predominant SPK setting. Perioperative endothelial biomarkers may have a value for early risk stratification after transplantation. Full article

Liver transplantation is the definitive therapy for end-stage liver disease, yet persistent organ shortages result in approximately 10% of recovered livers being discarded, with markedly higher discard rates among marginal grafts from elderly donors, donation after circulatory death (DCD), and those with macrovesicular steatosis. Machine perfusion (MP) has emerged as a paradigm-shifting preservation strategy with the potential to safely expand the usable donor pool. This narrative review examines the current evidence for three MP modalities—hypothermic machine perfusion (HMP), normothermic machine perfusion (NMP), and normothermic regional perfusion (NRP)—across various marginal donor populations, including elderly donors, steatotic grafts, donors with infectious diseases, and split liver transplantation. Current evidence demonstrates that MP significantly increases utilization of steatotic grafts with up to an eightfold rise in usage of severely steatotic organs. HMP consistently reduces non-anastomotic biliary strictures and early allograft dysfunction across donor types, while NMP enables real-time viability assessment and reduces post-reperfusion syndrome in steatotic grafts. NRP shows particular benefit in DCD organs, reducing biliary complications and improving one-year survival. Additionally, MP extends preservation times enabling next-day split liver transplantation and shows promise as a platform for ex situ antiviral therapy. Despite compelling evidence supporting MP in marginal grafts, widespread adoption remains constrained by high costs, logistical complexity, and the absence of standardized protocols. Future progress will require multicenter studies evaluating long-term outcomes alongside consensus-driven implementation frameworks. Full article

Background: Uterus transplantation (UTx) is an emerging treatment for absolute uterine factor infertility. However, the use of deceased donors is limited, and donation after circulatory death (DCD) has not yet been utilized. Ischemic injury remains a major barrier, particularly compared with living donor procedures. Hypothermic oxygenated perfusion (HOPE), which has shown protective effects in heart, liver, and kidney transplantation, may offer similar benefits for uterine grafts. Methods: We report the first series applying HOPE to human uteri to improve preservation and enable metabolic injury assessment during perfusion. Six uteri (3 DBD, 3 DCD; median donor age 53 years) underwent 8 h of HOPE following procurement, while paired tissue controls were preserved using static cold storage (SCS). Perfusion was delivered using a pressure-controlled system (15 mmHg, 10 ± 1 °C, VitaSmart^®). Perfusate and tissue samples were analyzed for mitochondrial injury, inflammation, and transcriptional responses. Results: HOPE maintained stable flows (70–150 mL/min), delivered high oxygen levels (pO₂ ≈ 1000 hPa), and increased tissue ATP levels. Stratification based on perfusate flavin mononucleotide (FMN) release identified grafts with greater Complex I/II injury. HOPE was associated with lower levels of mitochondrial injury markers and inflammatory signals, preserved tissue architecture, and promoted gene expression patterns consistent with metabolic recovery compared with paired SCS tissue controls. Conclusions: These findings suggest that HOPE may serve as a preservation approach that enables metabolic and ischemic injury assessment and may facilitate broader use of deceased donor uteri for transplantation. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with an increased risk of portal vein thrombosis (PVT), which may negatively affect post-liver transplant (LT) outcomes. We aimed to evaluate the impact of PVT on post-LT outcomes in MASLD versus non-MASLD recipients and assess outcomes in MASLD patients with PVT who received donation after circulatory death (DCD) grafts. Methods: Using the UNOS database, we analyzed adult LT recipients from 2002 to 2022. Kaplan–Meier and Cox regression models were used to assess one-year post-LT outcomes. Results: Among 46,933 LT recipients, 20% had MASLD (15% PVT prevalence) and 80% had non-MASLD etiologies (9% PVT prevalence). Overall, 3051 recipients (6.5%) received DCD grafts. PVT at the time of transplant was associated with significantly higher risks of all-cause mortality, graft failure, and death-censored graft failure (DCGF) in both MASLD and non-MASLD groups (p < 0.05), although no significant differences were observed between the two groups. In the DCD subgroup, MASLD recipients with PVT had a significantly higher risk of all-cause mortality compared to non-MASLD recipients without PVT (adjusted hazard ratio [aHR] 2.24, 95% CI 1.17–4.28, p = 0.01), but no differences were observed for graft failure or DCGF. Conclusions: PVT at the time of transplant is associated with poorer survival in MASLD and non-MASLD recipients. No difference was found between the two groups. In candidates receiving DCD grafts, the presence of PVT at time of transplant was associated with a marked increase in mortality risk, although this finding requires further validation in larger cohorts. Full article

Heart transplantation is still the definitive therapy for end-stage heart failure, yet the persistent shortage of suitable donor organs limits its application. Traditionally, static cold storage (SCS) has served as an effective standard preservation method, providing safe and adequate protection for preservation times under four hours. Yet, the need to extend this window and the specific metabolic requirements of donation after circulatory death (DCD) hearts have prompted interest in machine perfusion (MP) technologies. This literature review investigates the influence of temperature in ex situ heart perfusion, comparing normothermic (NMP), hypothermic (HMP), and subnormothermic (SNMP) strategies. Evidence from experimental models and emerging clinical studies suggests that MP can prolong preservation times, mitigate ischemic injury, and enable real-time metabolic and viability assessment of donor hearts prior to transplantation. These strategies represent a central trade-off: NMP enables real-time functional assessment of the beating heart, while HMP and SNMP approaches prioritize profound metabolic suppression to mitigate ischemic injury. Nonetheless, current data are limited by high costs, significant resource requirements, variability in perfusion protocols, and the scarcity of randomized controlled trials, particularly for HMP and SNMP. Standardization of methodologies, direct comparative studies, and the adoption of a risk-stratified preservation ecosystem are needed to clarify optimal temperature strategies. However, recent clinical successes with hypothermic strategies in traditionally normothermia-dependent donor types, such as DCD hearts, signal a potential paradigm shift, challenging established value propositions and prompting a critical re-evaluation of optimal preservation strategies. Full article

Background and Objectives: The use of controlled donation after circulatory death (cDCD) donors has significantly increased during the past decades and successfully expanded the donors’ pool. However, warm ischemia may have detrimental effects on graft function. Italian Law requires a no-touch period of at least 20 min, which is much longer compared to the 5 min accepted in most European countries. Materials and Methods This is an Italian single-centre retrospective review of all cDCD procedures performed from April 2021 to June 2025. Patients with severe brain injury undergoing withdrawal of life-sustaining therapy (WLST) were considered for cDCD. After cardiac arrest and a no-touch period of 20 min, organ reperfusion was performed using abdominal or thoraco-abdominal normothermic regional perfusion (NRP) through femoral vessels cannulation. The primary endpoint was 30-day graft survival; secondary endpoints included: incidence of primary non-function (PNF) and non-anastomotic biliary stricture (NAS) in liver transplantation, PNF and delayed graft function (DGF) in kidney transplantation, primary graft dysfunction (PGD) in heart and lung transplantation, and recipient’s survival. Results: A total of 52 patients, 33 (63%) males, median age 74 (65–79) years, underwent WLST during the study period and were included in the cDCD program. Median functional warm ischemic time (WIT), total WIT, asystolic phase, and NRP duration were 37 (34–40), 40 (37–42), 24 (23–26), and 192 (166–212) min, respectively. A total of 123 organs (46 livers, 61 kidneys, 8 hearts, and 8 lungs) were considered suitable for transplantation, procured, and successfully transplanted in 115 recipients. We report the early and mid-term outcomes of 84 recipients, including 41 liver recipients, 32 kidney recipients, and 8 heart recipients transplanted at the Azienda Ospedaliera Universitaria Integrata of Verona, and 3 lung recipients transplanted at the Azienda Ospedale Università of Padova. The 30-day graft survival was 95% in liver recipients, 97% in kidney recipients, and 100% in heart and lung recipients. PNF was observed in two liver recipients, and PGD in two lung recipients. DGF was recorded in 3 (9%) kidney recipients. Six recipients died during the follow-up, and the mean survival time was 3.9 ± 0.1 years. Conclusions: Solid organ transplantation using cDCD donors is feasible and provides excellent early and mid-term results despite longer donor asystolic times. Larger data and longer follow-up are necessary to confirm these promising results. Full article

Background: Uncontrolled donation after circulatory death (uDCD) remains underutilized globally, despite critical organ shortages. We report outcomes from Israel’s uDCD kidney transplant program compared with the matched donation after brain death (DBD) recipients. Methods: This retrospective cohort study analyzed all uDCD kidney transplants performed at the Rabin Medical Center between January 2018 and December 2024, compared with DBD transplants during the same period. Propensity score matching (1:3 ratio) was performed using recipient demographics, comorbidities, and donor characteristics. Primary outcomes included delayed graft function (DGF), graft failure, and patient survival. Results: Among 92 kidney transplants, 21 (22.8%) were from uDCD donors. After propensity-matching (21 uDCD, 63 DBD), significant baseline differences persisted: uDCD recipients were younger (47.2 ± 11.8 vs. 57.5 ± 10.9 years, p < 0.001) despite a similar dialysis vintage (7.2 ± 3.2 vs. 7.7 ± 3.7 years, p = 0.569). Warm ischemia time was 58.5 ± 12.3 vs. 3.0 ± 0.0 min (p < 0.001), and cold ischemia time was longer in uDCD (13.7 ± 5.9 vs. 8.4 ± 2.5 h, p < 0.001). DGF occurred in 90.5% of uDCD versus 54.1% of DBD recipients (p = 0.006). Graft failure was markedly higher in uDCD (28.6% vs. 1.6%, p = 0.001), yet mortality was lower (14.3% vs. 27.9%, p = 0.339). After a median follow-up of 60 months (IQR 48–72) for both groups, the death-censored 5 year graft survival rate was 71.4% for uDCD versus 98.4% for DBD (p < 0.001). Conclusions: Despite higher rates of DGF and graft failure, uDCD kidney transplantation demonstrated an acceptable 5 year patient survival rate in carefully selected younger recipients. These findings support cautious expansion of uDCD programs with rigorous recipient selection criteria and realistic outcome expectations. Full article

Background/Objectives: Rapid, objective phenotyping of donor kidneys is needed to support peri-implant decisions. Label-free Fourier-transform infrared (FTIR) spectroscopy of static cold-storage Celsior^® perfusion fluid can discriminate kidneys recovered from donation after circulatory death (DCD) versus donation after brain death (DBD). Methods: Preservation solution from isolated kidney allografts (n = 10; 5 DCD/5 DBD) matched on demographics was analyzed in the Amide I and fingerprint regions. Several spectral preprocessing steps were applied, and feature extraction was based on the Fast Correlation-Based Filter. Support vector machines and Naïve Bayes were evaluated. Unsupervised structure was assessed based on cosine distance, multidimensional scaling, and hierarchical clustering. Two-dimensional correlation spectroscopy (2D-COS) was used to examine band co-variation. Results: Donor cohorts were well balanced, except for higher terminal serum creatinine in DCD. Quality metrics were comparable, indicating no systematic technical bias. In Amide I, derivatives improved classification, but performance remained modest (e.g., second derivative with feature selection yielded an area under the curve (AUC) of 0.88 and an accuracy of 0.90 for support vector machines; Naïve Bayes reached an AUC of 0.92 with an accuracy of 0.70). The fingerprint window was most informative. Naïve Bayes with second derivative plus feature selection identified bands at ~1202, ~1203, ~1342, and ~1413 cm⁻¹ and achieved an AUC of 1.00 and an accuracy of 1.00. Unsupervised analyses showed coherent grouping in the fingerprint region, and 2D correlation maps indicated coordinated multi-band changes. Conclusions: Performance in this 10-sample pilot should be interpreted cautiously, as perfect leave-one-out cross-validation (LOOCV) estimates are vulnerable to overfitting. The findings are preliminary and hypothesis-generating, and they require confirmation in larger, multicenter cohorts with a pre-registered analysis pipeline and external validation. Full article

Heart failure represents a complex clinical syndrome characterized by progressive ventricular dysfunction, systemic congestion, and high mortality despite significant advances in pharmacological and device-based therapy. This review explores recent developments across the heart failure continuum, with a focus on therapeutic advances across the continuum of care, with emphasis on both established and emerging strategies. In patients with reduced ejection fraction, early initiation of the four pillars markedly lowers cardiovascular events, yet real-world implementation remains limited by therapeutic inertia and underdosing. Novel agents such as finerenone provide cardiorenal benefits in patients with diabetes and chronic kidney disease, while glucagon-like peptide-1 receptor agonists show promise in preserved or mildly reduced ejection fraction, particularly with obesity. Tricuspid regurgitation, once considered a secondary phenomenon, is now recognized as a modifiable contributor to disease progression, with transcatheter interventions offering new therapeutic avenues. In advanced disease, innovations including donation after circulatory death and the development of total artificial heart systems offer promising solutions to overcome organ shortages and improve access to transplantation. Together, these advances highlight a shift toward precision-guided, multidisciplinary heart failure care. Full article

Chronic kidney disease (CKD) affects over 10% of the global population, with end-stage renal disease (ESRD) necessitating renal replacement therapy. Kidney transplantation remains the optimal treatment for ESRD. However, the global donor kidney shortage crisis has led to increased reliance on deceased donor kidneys. Donors are classified as either donation after brain death (DBD) or donation after circulatory death (DCD), each associated with distinct ischemic injuries that impact graft function. Ischemia–reperfusion injury (IRI) plays a pivotal role in transplant outcomes, triggering oxidative stress, inflammation, and endothelial dysfunction. While static cold storage (SCS) remains the gold standard for organ preservation, alternative strategies such as hypothermic or normothermic machine perfusion (HMP and NMP), use of oxygen carriers during storage, and supplemental compounds to storage solutions have emerged, offering potential benefits in preserving graft viability. This review explores the cellular and molecular mechanisms of ischemic injury in deceased donor kidneys, preservation strategies tested in preclinical models, and emerging therapeutic interventions aimed at improving adverse post-transplant outcomes. Full article

Introduction: Controlled (c-) and uncontrolled (u-) DCDs are two entirely different types of donors, mainly because the duration of ischemic and reperfusion injury differs between them. We hypothesized that normothermic regional perfusion (NRP) management and performance (as indicated by the dynamic changes in blood flow and lactate) might be different in uDCDs and in cDCDs. Methods: We assessed 99 DCD donors that were consecutively evaluated by the Tuscany Regional Transplant Center from 2020 to 2024 (multi-center investigation), focusing on the comparison between NRP performance and management in uDCDs (n = 44) vs. cDCDs (n = 45). Results: NRP duration was significantly higher in uDCDs compared to cDCDs (p = 0.001). During NRP, we observed no changes in lactate values in uDCDs and cDCDs, a significant increase in transaminases, and a progressive reduction in NRP blood flow rates despite the administration of more fluids. Throughout the entire NRP duration, pH values were significantly lower and glucose levels were higher in uDCDs compared to cDCDs, even though a higher dosage of bicarbonate and insulin units were administered in uDCDs. Conclusions: In our series, we documented that NRP performance and management differed in uDCDs compared to cDCDs. This phenomenon may be mainly related to the different duration of the ischemic injury between these two types of donors. During NRP, uncontrolled DCDs showed a more severe metabolic derangement, which was only partially reversable by a more aggressive treatment (higher fluid volumes, insulin and bicarbonate dosages). Our results strongly suggest that there is likely space for optimization of NRP management in DCDs. Further research should address this issue, considering the disparity between the supply of organs and increasing transplantation needs. Full article

The clinical pathway of a patient who experiences cardiac arrest and subsequently dies (with or without organ donation) is complex. It involves uncontrolled (u-) donation after circulatory death (DCD), controlled (c-) DCD, and donor after brain death (DBD). The present paper aims to summarize existing evidence on organ donation rates among out-of-hospital cardiac arrest (OHCA) patients, with a focus on these three donor categories (uDCD, DBD, and cDCD). Furthermore, the potential to expand each donor pathway in OHCA patients will be highlighted, based on available evidence. Among non-survivor OHCA patients, the prevalence of brain death (BD) is estimated to be low, though reported data are not uniform. The diagnosis of BD is made 3 to 6 days after return of spontaneous circulation. The implementation of uDCD is known to be quite challenging due to logistical, ethical, and resource issues. Its rationale is still well grounded, mainly considering two factors: (a) the high incidence of OHCA, such that uDCD donors can be considered an existing pool of potential donors; (b) the uDCD pathway shows feasibility both under organizational (i.e., only lung uDCD program) and clinical views (normothermic regional perfusion, ex vivo machine perfusion, and an appropriate donor–recipient match). Controlled DCDs are donors who died after a planned withdrawal of life-sustaining therapy (WLST). Data on the percentage of cDCD among OHCA patients is not uniform since the percentage of utilized cDCD has been estimated at around 10%. According to available evidence, each donor pathway in OHCA has the potential to be expanded, mainly by the identification of potential donors and the implementation of DCD programs. Full article