There is a consensus that portal venous pressure (PVP) modulation prevents portal hypertension (PHT) and consequent complications after adult‐to‐adult living donor liver transplantation (ALDLT). However, PVP‐modulation strategies need to be updated based on the most recent findings. We examined our 10‐year experience of PVP modulation and reevaluated whether it was necessary for all recipients or for selected recipients in ALDLT. In this retrospective study, 319 patients who underwent ALDLT from 2007 to 2016 were divided into 3 groups according to the necessity and results of PVP modulation: not indicated (n = 189), indicated and succeeded (n = 92), and indicated but failed (n = 38). Graft survival and associations with various clinical factors were investigated. PVP modulation was performed mainly by splenectomy to lower final PVP to ≤15 mm Hg. Successful PVP modulation improved prognosis to be equivalent to that of patients who did not need modulation, whereas failed modulation was associated with increased incidence of small‐for‐size syndrome (SFSS;P= 0.003) and early graft loss (EGL;P= 0.006). Among patients with failed modulation, donor age ≥ 45 years (hazard ratio [HR], 3.67;P= 0.02) and ABO incompatibility (HR, 3.90;P= 0.01) were independent risk factors for graft loss. Survival analysis showed that PVP > 15 mm Hg was related to poor prognosis in grafts from either ABO‐incompatible or older donor age ≥ 45 years (P< 0.001), but it did not negatively affect grafts from ABO‐compatible/identical and young donor age < 45 years (P= 0.27). In conclusion, intentional PVP modulation is not necessarily required in all recipients. Although grafts from both ABO‐compatible/identical and young donors can tolerate PHT, lowering PVP to ≤15 mm Hg is a key to preventing SFSS and consequent EGL with grafts from either ABO‐incompatible or older donors.

The impact of an imbalanced graft‐to‐spleen volume ratio (GSVR) on posttransplant outcomes other than postreperfusion portal hypertension remains unknown. The importance of GSVR might vary according to whether simultaneous splenectomy (SPX) is performed. This retrospective study divided 349 living donor liver transplantation (LDLT) recipients from 2006 to 2017 into two groups: low GSVR (≤0.70 g/mL) and normal GSVR (>0.70 g/mL). The cutoff value of GSVR was set based on the 1^st quartile of the distributed data. Graft survival and associations with various clinical factors were investigated between the groups according to whether SPX was performed. Low GSVR did not affect outcomes when SPX was performed. In contrast, it was associated with an increased incidence of early graft loss (EGL) and poor graft survival by presenting posttransplant thrombocytopenia, cholestasis, coagulopathy, and ascites when the spleen was preserved. Among patients with a preserved spleen, the multivariable analysis results revealed that donor age and low GSVR were independent risk factors for graft loss. In conclusion, low GSVR was an independent predictor of graft loss after LDLT when the spleen was preserved. Preserved spleen with extremely low GSVR may be related to persistent hypersplenism, impaired graft function, and consequent EGL.

Although cold preservation remains the gold standard in organ transplantation, cold stress–induced cellular injury is a significant problem in clinical orthotopic liver transplantation (OLT). Because a recent study showed that cold stress activates ferroptosis, a form of regulated cell death, we investigated whether and how ferroptosis determines OLT outcomes in mice and humans. Treatment with ferroptosis inhibitor (ferrostatin-1) during cold preservation reduced lipid peroxidation (malondialdehyde; MDA), primarily in liver sinusoidal endothelial cells (LSECs), and alleviated ischemia/reperfusion injury in mouse OLT. Similarly, ferrostatin-1 reduced cell death in cold-stressed LSEC cultures. LSECs deficient in nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of ferroptosis, were susceptible to cold stress–induced cell death, concomitant with enhanced endoplasmic reticulum (ER) stress and expression of mitochondrial Ca ²⁺ uptake regulator (MICU1). Indeed, supplementing MICU1 inhibitor reduced ER stress, MDA expression, and cell death in NRF2-deficient but not WT LSECs, suggesting NRF2 is a critical regulator of MICU1-mediated ferroptosis. Consistent with murine data, enhanced liver NRF2 expression reduced MDA levels, hepatocellular damage, and incidence of early allograft dysfunction in human OLT recipients. This translational study provides a clinically applicable strategy in which inhibition of ferroptosis during liver cold preservation mitigates OLT injury by protecting LSECs from peritransplant stress via an NRF2-regulatory mechanism.