Taner, Timuçin

Outcomes of kidney-alone transplantation (KAT) in former simultaneous liver-kidney (SLK) transplant candidates after liver waitlist delisting are not well defined. Using Scientific Registry of Transplant Recipients (SRTR) data, we identified adult recipients who underwent KAT between 2005 and 2025 after prior SLK listing (RLD-KAT), which was matched 1:5 to primary KAT recipients without liver disease by age, transplant year, and diabetes status. Patient and graft survival were evaluated using the Kaplan-Meier method and multivariable Cox proportional hazards models. We identified 163 RLD-KAT recipients matched to 815 controls. Unadjusted Kaplan-Meier analyses demonstrated lower patient survival in RLD-KAT (p = 0.020), whereas death-censored and overall graft survival were similar (p > 0.05). In multivariable models, death-censored graft survival (HR 0.89; 95% CI 0.51–1.53), overall graft survival (HR 1.00; 95% CI 0.73–1.36), and patient survival (HR 1.07; 95% CI 0.76–1.5) did not differ significantly. Six RLD-KAT recipients (3.7%) subsequently underwent liver transplantation. Kidney-alone transplantation in prior SLK candidates was associated with acceptable patient and graft outcomes and a low incidence of subsequent liver transplantation.

Background and Aims: Liver fibrosis and cirrhosis are major global health burdens with limited treatments. Activated HSCs drive fibrosis through increased proliferation, migration, collagen deposition and glycolysis. The aim of this study is to elucidate the signaling events that lead to enhanced glycolysis, subsequent HSC activation, and liver fibrosis. Approach and Results: Utilizing a phospho-kinase array, we identified with no lysine kinase 1 (WNK1) as a new kinase in primary human HSCs activated by the profibrotic PDGF-B. PDGF-mediated glycolysis in HSCs was attenuated by the WNK1 selective inhibitor, WNK-IN-11, as measured by live-cell metabolic assay, Glifon-300 fluorescence, Glucose-Glo assay, and glucose transporter 1 immunofluorescence. To understand how WNK1 promotes glycolysis, we employed chemical genetics where an engineered WNK1 carrying threonine 301 to glycine mutation (WNK1 T301G ) mutant with a modified ATP pocket accommodated a specific ATP-γ-S analogue to thio-phosphorylate its substrates. Thio-phosphorylated proteins were analyzed by mass spectrometry, which identified the glycolytic protein, triosephosphate isomerase 1 (TPI1), as a novel WNK1 direct substrate. TPI1 interacted with WNK1 in condensates, membrane-less phase separation structures. Condensate disruption and knockdown of TPI1 or WNK1 reduced HSC proliferation and migration in vitro. In vivo, pharmacological or genetic WNK1 inhibition significantly attenuated liver fibrosis in carbon tetrachloride and high-fat, choline-deficient, L -amino acid diet mouse models. Finally, WNK1 inhibition reduced fibrogenesis ex vivo in human precision-cut liver slices. Conclusions: These findings identify WNK1 as a previously unrecognized kinase that promotes HSC activation and liver fibrosis via TPI1-mediated glycolysis, highlighting the WNK1-TPI1 axis as a potential therapeutic target.

TRAIL is a TNF family ligand that trimerizes TRAIL-R1 (DR4) or TRAIL-R2 (DR5) to induce apoptosis, necroptosis, and/or NF-κB activation in receptor-bearing cells. We previously identified TRAILshort as a splice variant of TRAIL that lacks cysteine 230, cannot trimerize, and acts as a dominant-negative ligand that blocks TRAIL-mediated apoptosis. TRAILshort is expressed on cell surfaces and within extracellular vesicles, enabling it to confer TRAIL resistance to both producing and bystander cells. In this study, we showed that elevated TRAILshort levels were associated with chronic viral infections, cancer, and autoimmune diseases, suggesting a link to impaired immune regulation. Using unbiased phosphoproteomics and mechanistic studies, we demonstrated that TRAILshort binding to DR5 recruited and activated the phosphatase Src homology region 2 domain–containing phosphatase 1 (SHP-1), leading to zeta-chain-associated protein kinase 70 (ZAP-70) dephosphorylation, disruption of ZAP-70–CD3ζ interactions, and impaired T cell receptor signaling, thereby reducing T cell activation, proliferation, and cytokine production in response to antigen or CD3/CD28 ligation. Genetic or pharmacologic SHP-1 inhibition reverses these effects. In humanized mouse models, TRAILshort promoted the persistence of transformed mouse embryonic fibroblasts (MEFs) and L428 and antagonized CD19-directed CAR T cell activity, revealing TRAILshort as an immunomodulator of T cell function with therapeutic implications, including blocking TRAILshort to restore T cell immunity or delivering TRAILshort to enforce tolerance. TRAILshort, a variant of TRAIL, suppresses T cell function and immune responses in cancer and infectious diseases, highlighting its potential as a therapeutic target.

Early allograft failure (EAF) after living donor liver transplantation (LDLT) remains a clinical challenge. Existing prediction models developed for deceased donor transplantation poorly apply to LDLT due to distinct surgical and physiological factors. This study identifies clinical determinants of EAF and develops an LDLT-specific prediction model. We conducted a multicenter retrospective cohort study from 17 high-volume LDLT centers (January 2016–December 2020) with external validation at a tertiary center in Saudi Arabia (January 2015–December 2022). The primary outcome was EAF (graft loss or patient death ≤90 d). Multivariable mixed-effects logistic regression identified preoperative/intraoperative risk factors. The EAGLE-LDLT model was constructed using postoperative laboratory values. Performance was compared against established models (EAD, MEAF, A2ALL) using ROC analysis and decision curve analysis. The development cohort included 2944 adult LDLT recipients (67.7% male; median age 55 y; median MELD 14) with a 5.5% EAF rate. External validation included 1020 recipients (median MELD 21, 6.7% EAF). Independent risk factors for EAF were MELD (OR 1.06, 95% CI 1.04–1.08), donor BMI (OR 1.05, 95% CI 1.00–1.10), portal vein thrombosis (OR 1.73, 95% CI 1.13–2.63), and hepaticojejunostomy (OR 1.58, 95% CI 1.06–2.36). The EAGLE-LDLT model incorporating peak ALT (>468 U/L), peak INR (>1.9), and bilirubin (>3.5 mg/dL) and INR (>1.3) at POD7, demonstrated superior discrimination (AUC=0.81) compared with MEAF (AUC=0.77, p =0.004), EAD (AUC=0.67, p <0.001), and A2ALL (AUC=0.65, p <0.001). EAGLE-LDLT achieved balanced sensitivity (75.0%) and specificity (73.7%), effectively stratifying patients into high-risk (15% of patients; 40.4% EAF incidence) and low-risk groups. Preoperative and intraoperative clinical factors predict EAF in LDLT. The EAGLE-LDLT model accurately identifies LDLT recipients at the highest risk for EAF postoperatively.

Living donor liver transplantation (LDLT) is an established therapy with curative intent for pediatric and adult patients with acute liver failure and end-stage liver disease. Donor safety remains paramount and commences during preoperative evaluation and assessment. Given the importance of the topic, the International Liver Transplantation Society and International Living Donor Liver Transplantation Group consensus conference on Living Liver Donor Safety was convened in March 2025 (Toronto, Canada). Recommendations were based on the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for assessment of recommendations, and the Danish model of consensus was followed. This report presents 28 recommendations from the working group focused on addressing clinically relevant questions related to the preoperative aspects of living donor safety including assessment of donor acceptability (age, body mass index and hepatic steatosis; medical conditions and contraindications), medical and surgical workup (liver function and procoagulant workup; anatomical considerations and safe remnant), and psychosocial evaluation (timing and team; underlying conditions; non-directed, paired, and anonymous directed donors; urgent living donor workups for acute liver failure).

The success of living donor liver transplantation (LDLT) has bridged the growing gap between organ demand and availability in patients with liver failure or liver cancer. Safety of the living liver donor (LLD) is paramount, and astute intraoperative management plays a critical role in ensuring optimal outcomes for them. Given that intraoperative surgical and anesthesia practices vary widely across centers, the International Liver Transplantation Society (ILTS) and the International Living Donor Liver Transplantation Group (iLDLT Group) convened a global consensus conference in Toronto in March 2025 to develop guidelines for intraoperative management of the LLD. This manuscript details the recommendations on intraoperative considerations for the safety of LLD developed by Working Group II of the Consensus Scientific Committee, using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for assessment of recommendations, and the Danish model of consensus. Working Group II focused on intraoperative monitoring, fluid and ventilation strategies, surgical techniques for vascular and biliary division, surgeon and center-specific experience, and intraoperative crises planning. These guidelines aim to support both established and emerging LDLT teams to ensure high-quality and safe intraoperative care for the LLD.

Background: Splanchnic venous thrombosis (SVT) is a potentially severe and frequently underdiagnosed complication following splenectomy in patients with hematologic diseases. Despite its clinical importance, no standardized, evidence-based guidelines currently exist to inform perioperative prevention, diagnosis, or treatment in this population. Materials and Methods: A systematic review and meta-analysis were conducted following PRISMA guidelines to estimate the incidence and risk factors for SVT after splenectomy in patients with hematologic diseases. Twenty-eight observational studies comprising 5025 patients were included. Risk factor data were analyzed using random-effects models. In parallel, an international Delphi consensus process was performed involving 35 experts (hematologists and surgeons) from 14 countries. Experts were assigned to five domain-specific groups and developed clinical statements on prophylaxis, diagnosis, and management of SVT. Consensus was defined as ≥80% agreement, and recommendations were graded using the GRADE framework. Results: The pooled incidence of SVT after splenectomy was 11.4%, with higher rates in studies using routine imaging (20.7%) and those conducted at single centers (15.1%). Splenic size and weight were significant risk factors, while age, BMI, and platelet count were not. Disease-specific risk was highest in patients with myeloproliferative neoplasms, lymphoma, and thalassemia. The Delphi process generated 25 consensus statements, 14 of which were classified as strong recommendations. Key guidance included perioperative vaccination, individualized thromboprophylaxis with BMI-adjusted low molecular weight heparin, selective Doppler-based screening in high-risk patients, and stepwise anticoagulation regimens based on thrombus burden and clinical evolution. Conclusion: This study presents the first international consensus-based guidelines for managing SVT after splenectomy in patients with hematologic disease. Developed through systematic evidence synthesis and expert consensus, these recommendations provide a practical framework rather than definitive standards of care and support individualized prevention, detection, and treatment strategies in this high-risk population.

Living donor liver transplantation (LDLT) is a life-saving procedure for patients with end-stage liver disease. As its use expands worldwide, ensuring the safety and well-being of live liver donors (LLD) is of paramount importance. Published evidence on early postoperative complications after living donor hepatectomy—those occurring within 90 days of surgery—is limited, and standardized postoperative care protocols are lacking. The International Liver Transplantation Society (ILTS) and the International Living Donor Liver Transplantation Group (iLDLT Group) convened a consensus conference in Toronto in March 2025 to develop guidelines for the safe care of the LLDs. This manuscript details the recommendations on early postoperative considerations for the safety of LLDs developed by Working Group III (WGIII) of the Consensus Scientific Committee, using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for assessment of recommendations, and the Danish model of consensus. WGIII addressed four key areas: (1) standardized postoperative care, (2) early biliary complications, (3) early postoperative liver dysfunction, and (4) early postdischarge follow-up. This report emphasizes the need for vigilant postoperative monitoring in specialized units, with access to experienced providers and defined clinical pathways. Structured clinical and psychosocial follow-up protocols, perioperative prophylaxis for surgical site infections and venous thromboembolism, and management of early biliary and vascular complications are discussed. These may help standardize care, reduce complications and improve short-term outcomes in LLDs.

Living liver donation is a critical component for addressing organ shortage and improving outcomes for patients with end-stage liver disease. As the prevalence of living donor liver transplantation (LDLT) increases worldwide, understanding and optimizing long-term donor health is paramount. The 2025 International Liver Transplantation Society and International Living Donor Liver Transplantation Society (ILTS-iLDLT) Consensus Conference convened experts in the field of liver transplantation to establish evidence-based guidelines focused on the long-term medical, psychological, and social considerations following living liver donation. The aim of this working group was to integrate current evidence and expert consensus on donor follow-up protocols, risk assessment, and management strategies to promote long-term donor health, quality of life, and living liver donor programs globally to safeguard the welfare of this unique population.