Impact of graft size and portal flow modulation in living donor liver transplantation

Abstract

The minimum graft size has been a topic of controversy in the field of living donor liver transplantation (LDLT). Sufficient graft size is crucial to sustain recipient’s immediate metabolic function and prevent small-for-size syndrome (SFSS) and early allograft dysfunction (EAD). On the other hand, donor risk also correlates directly with the graft size. Protecting donor safety is always the top priority in LDLT. Hence, it remains controversial if the minimum graft size can be lowered safely in LDLT. Graft-to-recipient weight ratio (GRWR) > 0.8% has been established as the minimal graft size criteria for decades. Our centre has showed that the minimum graft size can be safely lowered to 35% of recipient estimated standard liver volume (ESLV), which is equivalent to 0.7% of GRWR. (1-3) Recently, it has been proposed that GRWR criteria can be lowered to 0.6% in highly selected patients (4-10), yet the data is limited and only retrospective series were available. The main concern of lowering graft size lies in the occurrence of SFSS, a severe post-transplant complication associated with high morbidity and mortality rate. Inadequate graft size was thought to be the leading factor to SFSS, but recent literature suggested that suboptimal portal haemodynamic, particularly portal hypertension or hyperperfusion, can also lead to the development of SFSS. (11-15) As a result, portal flow modulation (PFM) was proposed as an important strategy to expand the use of smaller grafts while minimising the incidence of SFSS. (4, 5, 10-23) Nevertheless, the exact selection criteria, indication, timing and methods for PFM remain uncertain. The current thesis aimed to address the controversy of minimum graft size as well as the role of PFM in LDLT. Firstly, the impact of GRWR > 0.8% was analyzed based on a retrospective study of 545 patients who underwent adult LDLT in 2001-2017. Despite more patients in the small-for-size (SFS) group i.e., GRWR ≤0.8% developed SFSS, the recipient perioperative outcomes and hospital mortality (1.5% vs. 2.9%, p=0.475) were similar to the control group. Only recipient body mass index (BMI) and hepatocellular carcinoma (HCC) status were significant prognostic factors of patient and graft survival rates; whilst GRWR ≤ 0.8% and occurrence of SFSS were not. The 1-, 5- and 10-year patient survival rate (97.5%, 89.5% and 81.4%; vs. 93.9%, 85.5% and 81.6%; p=0.437) and graft survival rate (94.9%, 87.4% and 80.1%; vs. 93.1%, 84.7% and 79.6%; p=0.417) were similar between the 2 groups, respectively. In addition, one patient in the control group developed SFSS, reflecting that graft size was not the only aetiological factor of SFSS. Furthermore, donor outcomes were superior in the SFS group, reinforcing that donor safety could be protected with the use of smaller grafts. The result of this study supported lowering of GRWR criteria to below 0.8% and provided the groupwork for subsequent studies. A prospective study was carried out in 2019 to 2022 to test our hypothesis that the minimum graft size requirement can be lowered to 0.6% in adult LDLT. The primary endpoint was patient survival and secondary endpoints included perioperative mortality, risk of SFSS, need for PFM and donor outcomes. Sixty-four patients were recruited and small grafts with 0.6%≤GRWR<0.8% (SFS group) were shown to have comparable patient, graft survival rates and perioperative outcomes when compared to larger graft with GRWR ≥0.8% (control group). The 2 groups had similar incidence of SFSS (7.1% vs. 8.3%, p=0.860), hepatic artery thrombosis rate (10.7% vs. 2.8%, p=0.383) and recipient hospital mortality (14.5% vs. 8.3%, p=0.449). The results suggested that lowering of GRWR criteria to 0.6% is safe for recipients. Eleven of patients in SFS group had PFM and it was contributory to the similar incidence of SFSS when compared to the control group. Donors in the SFS group had lower postoperative complication (7.1% vs. 33.3%, p=0.012) and less severe postoperative complication defined as Clavien-Dindo grade 3a or above (0 vs. 8.3%, p=0.023). There was no donor hospital mortality. This prospective study proposed that minimal requirement of GRWR can be safely lowered to 0.6% in selected patients with early recognition of SFSS and prompt use of PFM. Finally, the role and indication of PFM in LDLT was evaluated based on a retrospective analysis of 633 patients who underwent LDLT in our centre from 2001 to 2022. The overall rate of PFM was 5.7% (36/633) and majority of patients had splenic artery ligation (16/36, 44.4%). Propensity score matching (PSM) was conducted by matching pre-transplant bilirubin, international normalised ratio (INR), platelet, graft type (right lobe or left lobe graft) and GRWR. The perioperative outcomes, patient and graft survival rates were similar between the non-PFM and PFM groups. The study demonstrated that PFM should be and only be done selectively. In conclusion, the studies in this thesis demonstrated that the minimal requirement of GRWR can be safely lowered to 0.6% to reduce donor risk and widen donor pool. Timely PFM in V selected patients can prevent SFSS and achieve excellent perioperative and long-term outcomes in LDLT with SFS grafts.