Factors associated with low graft regeneration in the early phase after living donor liver transplantation

Takahashi, Kazuhiro; Nagai, Shunji; Collins, Kelly; Safwan, Mohamed; Rizzari, Michael; Schnickel, Gabriel T.; Yoshida, Atsushi; Abouljoud, Marwan

doi:10.1111/ctr.13690

Cited by 9 publications

(9 citation statements)

References 27 publications

(39 reference statements)

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“…After LDLT, the liver graft undergoes two different processes, namely, liver regeneration and I/R injury[ 18 ]. In liver regeneration, the remnant partial liver graft has to rapidly grow to meet the demands of the recipient’s reduced metabolic and synthetic capacities[ 19 ]. At the same time, reactive oxygen species (ROS) and inflammatory factors are generated, leading to various responses related to I/R injury[ 20 ].…”

Section: Ldltmentioning

confidence: 99%

“…It was demonstrated that an immediate posttransplant platelet count of < 68 × 10 3 /μL or a platelet count of < 30 × 10 3 /μL on POD 3 was an independent risk factor for major postoperative complications and was associated with early graft dysfunctions[ 3 , 48 ]. Takahashi et al [ 19 ] reported that a platelet count of < 60 × 10 3 /μL on POD 5 was independently associated with the incidence of postoperative morbidity in the mid-term after LDLT and was especially related to small-for-size syndrome such as ascites and infection.…”

Section: Evidence From Clinical Studiesmentioning

confidence: 99%

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Dualistic role of platelets in living donor liver transplantation: Are they harmful?

Liang¹,

Takahashi²,

Furuya³

et al. 2022

WJG

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Platelets are anucleate fragments mainly involved in hemostasis and thrombosis, and there is emerging evidence that platelets have other nonhemostatic potentials in inflammation, angiogenesis, regeneration and ischemia/reperfusion injury (I/R injury), which are involved in the physiological and pathological processes during living donor liver transplantation (LDLT). LDLT is sometimes associated with impaired regeneration and severe I/R injury, leading to postoperative complications and decreased patient survival. Recent studies have suggested that perioperative thrombocytopenia is associated with poor graft regeneration and postoperative morbidity in the short and long term after LDLT. Although it is not fully understood whether thrombocytopenia is the cause or result, increasing platelet counts are frequently suggested to improve posttransplant outcomes in clinical studies. Based on rodent experiments, previous studies have identified that platelets stimulate liver regeneration after partial hepatectomy. However, the role of platelets in LDLT is controversial, as platelets are supposed to aggravate I/R injury in the liver. Recently, a rat model of partial liver transplantation (LT) was used to demonstrate that thrombopoietin-induced thrombocytosis prior to surgery accelerated graft regeneration and improved the survival rate after transplantation. It was clarified that platelet-derived liver regeneration outweighed the associated risk of I/R injury after partial LT. Clinical strategies to increase perioperative platelet counts, such as thrombopoietin, thrombopoietin receptor agonist and platelet transfusion, may improve graft regeneration and survival after LDLT.

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Section: Ldltmentioning

confidence: 99%

Section: Evidence From Clinical Studiesmentioning

confidence: 99%

Dualistic role of platelets in living donor liver transplantation: Are they harmful?

Liang¹,

Takahashi²,

Furuya³

et al. 2022

WJG

Self Cite

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show abstract

“…40 A recent clinical study showed that kinetic growth rate of the FLR in patients after LDLTx negatively correlated with the size of FLR. 41 In addition, graft regeneration is influenced by ischemia reperfusion injury, 42 portal inflow, 43 and immune-related responses. 44 A shorter cold ischemia time, higher graft-recipient bodyweight ratio, and an immediate and remarkable increase in graft portal vein flow predicted a better prognosis after LDLTx.…”

Section: New Insights Of Postoperative Liver Regenerationmentioning

confidence: 99%

Hallmarks of postoperative liver regeneration: An updated insight on the regulatory mechanisms

Shi

Line

2019

J of Gastro and Hepatol

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Performance and advances in liver surgery makes remarkable progress of the understanding of liver regeneration. Liver regeneration after liver resection has been widely researched, and the underlying mechanism mostly concerns proliferation of hepatocytes and the influence by inflammation through activation of Kupffer cells and the other parenchymal cells, the second regenerative pathway by hepatic progenitor cells (HPCs), inducing angiogenesis, remodeling of a extracellular matrix (ECM), and termination mechanisms. New clinical surgeries and the updated multiomics analysis are exploiting the remarkable progress, especially in immune regulation and metabolic process of two emerging hallmarks. This review briefly represents a systemic outline of eight hallmarks, including hepatocyte proliferation, contribution of hepatic progenitor cells, inducing angiogenesis, reprogramming of the extracellular matrix, apoptosis and termination of proliferation, inflammation, immune and metabolic regulation, which are set as organizing characteristics of postoperative liver regeneration and future directions of refining treatment targets.

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“…(2) In liver regeneration, the remnant partial liver graft needs rapid growth to meet the demands of the recipient's reduced metabolic and synthetic capacities. (3) At the same time, reactive oxygen species (ROS) and nitric oxide are generated, leading to various inflammatory responses related to IRI. (4) In LDLT, size mismatch between the graft and recipient sometimes leads to small-for-size syndrome (SSFS).…”

mentioning

confidence: 99%

“…The clinical features of SFSS include massive ascites, hepatocyte ischemia and degeneration, enhanced cholestasis, and increased surgical complications, which are related to postoperative morbidity and mortality. (3) Therefore, effective treatments to accelerate liver regeneration under IRI in LDLT are crucial to avoid SSFS and promote graft survival.…”

mentioning

confidence: 99%

Platelets Stimulate Liver Regeneration in a Rat Model of Partial Liver Transplantation

et al. 2021

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Living donor liver transplantation (LDLT) is sometimes associated with impaired regeneration and severe ischemia/reperfusion injury (IRI) in the graft, resulting in small-for-size syndrome (SFSS). Platelets were previously reported to stimulate liver regeneration in models of hepatectomy, but the evidence in partial liver transplantation (LT) is lacking. In this study, a rat model of partial LT was used, and the impact of thrombopoietin (TPO)-induced perioperative thrombocytosis on graft regeneration, IRI, and survival was investigated. In experiment 1, a 30% partial LT was performed. Under thrombocytosis, SFSS was attenuated, as shown by decreased levels of serum aminotransferases, bilirubin, and ascites. Serum hepatocyte regeneration-related cytokines, including insulin-like growth factor-1, hepatocyte growth factor, interleukin 6 (IL6), and tumor necrosis factor α (TNF-α), were elevated. In addition, the proliferative signaling pathways, Ki-67-labeling index, proliferating cell nuclear antigen (PCNA)-labeling index, mitotic index, and liver/body weight ratio were increased under thrombocytosis. The platelet-induced regeneration was independent of TPO because increases in the Ki-67-labeling and PCNA-labeling indexes were eliminated after reducing platelet counts by antiplatelet serum in rats administered with TPO. For IRI, thrombocytosis did not aggravate oxidative stress or downstream signaling pathways, necrosis, or apoptosis in the graft. After Kupffer cell (KC) depletion, the platelet-induced attenuation of serum aminotransferases, increased serum levels of IL6 and TNF-α, and proliferation-related signaling pathways were eliminated. Moreover, platelet accumulation in the graft decreased substantially. In experiment 2, a 20% partial LT was performed, and thrombocytosis improved postoperative survival. In conclusion, our results suggested that thrombocytosis stimulated graft regeneration and prolonged survival without aggregating IRI after partial LT, and KCs vitally contributed to platelet-derived regeneration. Platelet therapies to increase perioperative platelet counts may improve the outcomes after LDLT.

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Factors associated with low graft regeneration in the early phase after living donor liver transplantation

Cited by 9 publications

References 27 publications

Dualistic role of platelets in living donor liver transplantation: Are they harmful?

Dualistic role of platelets in living donor liver transplantation: Are they harmful?

Hallmarks of postoperative liver regeneration: An updated insight on the regulatory mechanisms

Platelets Stimulate Liver Regeneration in a Rat Model of Partial Liver Transplantation

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