The aim of this work was to assess the association between graft-to-recipient weight ratio (GRWR) in adult-to-adult living donor liver transplantation (LDLT) and hepatocellular carcinoma (HCC) recurrence. A search of the MEDLINE and EMBASE databases was performed until December 2022 for studies comparing different GRWRs in the prognosis of HCC recipients in LDLT. Data were pooled to evaluate 1- and 3-year survival rates. We identified three studies, including a total of 782 patients (168 GRWR < 0.8 vs. 614 GRWR ≥ 0.8%). The pooled overall survival was 85% and 77% at one year and 90% and 83% at three years for GRWR < 0.8 and GRWR ≥ 0.8, respectively. The largest series found that, in patients within Milan criteria, the GRWR was not associated with lower oncological outcomes. However, patients with HCC outside the Milan criteria with a GRWR < 0.8% had lower survival and higher tumor recurrence rates. The GRWR < 0.8% appears to be associated with lower survival rates in HCC recipients, particularly for candidates with tumors outside established HCC criteria. Although the data are scarce, the results of this study suggest that considering the individual GRWR not only as risk factor for small-for-size-syndrome but also as contributor to HCC recurrence in patients undergoing LDLT would be beneficial. Novel perfusion technologies and pharmacological interventions may contribute to improving outcomes.

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Association between Hepatocellular Carcinoma Recurrence and Graft Size in Living Donor Liver Transplantation: A Systematic Review

We would like to congratulate the authors for publishing this important article on the outcome of utilizing left lobe grafts in their series of living donor liver transplantation (LDLT).1 Their study represents one of the largest series of utilizing left lobe grafts in the West and showed favorable 1-, 3-, and 5-year graft survival of 97%, 94%, and 89% comparable to the right lobe graft survival of 99%, 96%, and 93% (P = 0.97). This contrasts sharply from the European experience of 46 left lobe LDLTs from 4 centers showing a relatively poor 1-year graft survival of 59.4% due to a high rate of small for size syndrome (SFSS) and hepatic artery thrombosis.2 The key to their excellent outcomes was achieved by the use of venous outflow augmentation and liberal use of splenectomy to modulate portal inflow. From their series, 61 of 130 (47%) recipients received left lobe graft. Donor/recipient selection likely played a huge role to their highly favorable outcomes. The Kyoto group previously showed that the overall survival was significantly worse when using left lobe graft compared with right lobe graft in recipients who were considered high risk (at least 2 risk factors of: model for end-stage liver disease [MELD] score > 20; preoperative hospitalization; recent preoperative bacterial infection).3 In contrast, no difference in survival were found between left lobe or right lobe recipient if only 1 risk factor was present. The Kyushu group reported donor age ≥ 48 years, MELD score ≥ 19, and end portal venous pressure ≥ 19 mm Hg as the important factors for the development of SFSS.4 These factors reflect on the poor graft quality from higher donor age, poor clinical status of the recipient and excessive portal flow after reperfusion of the partial graft. To highlight the important of graft selection, the Kyushu group has also devised a scoring system that incorporates factors such as graft size, donor age, MELD score, and the presence of portosystemic shunts, which correlate well with graft survival and can be employed for graft selection.5 Although there is currently no consensus on the selection criteria when comes to choosing left lobe graft, most groups have demonstrated that donor age, and MELD score as crucial deciding factors as mentioned. In fact, the European cohort with poor outcome with left lobe grafts reported MELD score >14 as the most significant factor for the development of SFSS.2 Looking at the Cleveland cohort, it is very clear that this is a highly selected group of donors and recipients when considering for left lobe graft with a donor median age of 36 years (interquartile range, 31–41 years), low median MELD score of 12 (interquartile range, 10, 16), and less severe portal hypertension as evident by the low median splenic volume (611 mL for left lobe graft compared with 918 for right lobe graft). Their left lobe graft experience has been accumulated over 8 years from 2013 to 2020 sharing between the 2 centers ranging from 5 to 17 left lobe grafts per year (mean 7 to 8 per year). This likely represents only a fraction of their overall liver transplant activity and further suggests that the recipients chosen for left lobe graft were highly selected. As regards to the use of inflow modulation such as splenectomy in this series, a group from Tokyo has described in their series of 42 LDLTs using exclusively left lobe graft without the use of any inflow modulation technique with a very good 1-, 3-, and 5-year graft survival rate of 100%, 97%, and 91%, despite 38% of their recipients had graft-to-recipient weight ratio (GRWR) of less than 0.8%.6 Therefore, it is unclear how much contribution to current reported outcomes were related to patient selection or the use of splenectomy, the use of which has been shown to be a protective for graft dysfunction here. Although the reported morbidities with splenectomy were acceptable in this series, with sicker recipients, the added morbidity of splenectomy may become problematic and could lead to worse outcomes. It has been well established that the grafts are considered small for size when the GRWR is less than 0.8% or the standard liver volume is less than 35%.7 This article has also reported the graft outcome when actual size of the graft was smaller than the expected minimum GRWR of 0.6%. While the 5-year graft survival of 88% and only 1 mortality amongst the 9 left lobe recipients is impressive, this is still small numbers, from selected donors and recipients. Until there are more data and replication of this practice in other centers, we feel that the usage of small left lobe grafts remains an option for very few and not a promised land for the many. 

Comment on “Living Donor Liver Transplantation With Augmented Venous Outflow and Splenectomy: A Promised Land for Small Left Lobe Grafts”

We appreciate the comments of Ng et al.1 with regard to our recent study. The authors concluded that our series of living donor liver transplantation (LDLT), especially left lobe graft (LLG)-LDLT was highly selective based on recipient demographics including a low median model for end-stage liver disease (MELD) score. There is no doubt that careful selection is important to achieve favorable outcomes to allow for proof of concept in any innovative surgical endeavor, especially in LDLT. Nevertheless, we believe that the LLG-LDLTs in our series were not overly selective. Importantly, our LLG rate was 47% of adult LDLT performed in our program, which is one of the highest LLG utilization rates in Western countries. Our goal is to maximize overall donor safety by preferential use of LLG when a high rate of recipient survival can be reasonably assured. It is universally recognized that in Western countries with high penetrance of deceased donor grafts, a program’s median MELD score for LDLT is lower than that for deceased donor liver transplantation (DDLT).3 Therefore, a lower median MELD score in LDLT is not indicative of being highly overly selective regarding recipients. Although we do not have a firm institutional MELD score threshold that excludes LDLT evaluation, when a candidate’s MELD score is high enough to receive DDLT in a timely manner, the LDLT option may not be the best path forward. Nevertheless, we still preserve the LDLT option for certain high MELD patients when timely LDLT is preferred. In this setting, the 1-year graft survival following LDLT for patients with MELD greater than 25 remains favorable and comparable to that for MELD less than 25 in our series. It should be emphasized that we rarely exclude the LDLT option because of recipient-donor selection mismatch as Ng et al. suspected. Our LDLT accounts for 14% to 16 % of our annual transplant volume. The reason is simply the lack of willing live donors, rather than declining the donor candidates. To increase LDLT volume, more education of the public to facilitate donor recruitment is an imperative step. Expansion of minimally invasive donor hepatectomy will hopefully enhance the utilization of LDLT as it did for a kidney transplant and is appealing to the public.4 We have advocated for the importance of adjusting preoperative risk factors that include actual graft size, graft quality, recipient disease severity, and intra-operative optimization of graft inflow and outflow.5 Ng pointed out a lower MELD score and less portal hypertension in LLG compared with those for the right lobe graft group in our study. The mean graft size and graft-to-recipient weight ratio (GRWR) of the LLG group were always smaller compared with the right lobe graft group.6–8 The lower MELD score and the lesser degree of portal hypertension in our LLG group are merely reflective of the risk adjustment made for the smaller graft size of the LLG group. In our graft selection algorithm, we believe an LLG that provides for only a 0.6% to 0.7% GRWR for a case with multiple other risk factors of the small-for-size syndrome (SFSS), is insufficient. In that case, we offer the right lobe graft option. With this graft selection process, our LLG rate still reached 47%. Our program launched this LLG first choice approach when LLG use was less than 5% of adult LDLT in the Adult-to-Adult Living Donor Transplant Cohort Study consortium of North American Centers.9 With the recent Organ Procurement and Transplantation Network/United Network for Organ Sharing registry data analysis of 2009–2018, Kitajima et al.3 reported a still low but slowly increasing LLG rate, accounting for 17.5% of adult LDLT. This large data analysis of 1486 LDLTs showed a result consistent with previous studies that a combination of high MELD score, moderate ascites, and the use of LLG was associated with worse outcomes. However, the United Network for Organ Sharing registry does not include data on SFSS, or surgical techniques to optimize inflow and outflow that can contribute to the recent improvement in outcomes. Therefore, a single, large-volume center study is necessary to assess the impact of these surgical innovations on post-LDLT outcomes. Our study presents an innovative outflow augmentation technique combined with the use of splenectomy for inflow modulation. This combined technique nearly eradicated SFSS and successfully controlled post-transplant ascites with only 10% of LLG recipients experiencing intractable ascites (more than 1 L/day on post-transplant day 14). As Ng et al. mentioned that the Juntendo University group in Tokyo, showed excellent graft survival after LDLT-LLG with limited use of splenic artery ligation in 11% of cases and no outflow augmentation.10 However, they did report intractable ascites in 31/59 (53%) patients.10,11 In this setting, more use of inflow modulation or our proposed outflow augmentation could have reduced the ascites production. In summary, our study demonstrated that with our surgical refinement of inflow modulation and outflow augmentation along with preoperative risk assessment for SFSS, an LLG can be utilized far more frequently than the current rate in Western countries. This approach can improve donor safety while further improving access to transplant for the patients on the waiting list. We hope it is another important step in challenging the perceived boundaries of safe LLG utilization. ACKNOWLEDGMENTS The authors thank Ms. Nancy Lapid for English language editing. 

Response to Comment on “Living Donor Liver Transplantation With Augmented Venous Outflow and Splenectomy: A Promised Land for Small Left Lobe Grafts”

Paired exchange Living donor Liver Transplantation: Indications, stumbling blocks, and future considerations

Technical challenges in LDLT - Overcoming small for size syndrome and venous outflow reconstruction.

Living donor liver transplantation (LDLT) using small grafts, especially left lobe grafts (H1234-MHV) (LLG), continues to be a challenge due to small-for-size syndrome (SFSS). We herein demonstrate that with surgical modifications, outcomes with small grafts can be improved.Between 2012 and 2020, we performed 130 adult LDLT using 61 (47%) LLG (H1234-MHV) in a single Enterprise. The median graft-to-recipient weight ratio was 0.84%, with graft-to-recipient weight ratio <0.7% accounting for 22%. Splenectomy was performed in 72 (56%) patients for inflow modulation before (n=50) or after (n=22) graft reperfusion. In LLG-LDLT, venous outflow was achieved using all three recipient hepatic veins. In right lobe graft (H5678) (RLG)-LDLT, the augmented graft right hepatic vein was anastomosed to the recipient's cava with a large cavotomy. Outcome measures include SFSS, early allograft dysfunction (EAD), and survival.Graft survival rates at 1, 3, and 5 years were 94%, 90%, and 83%, respectively, with no differences between LLG (H1234-MHV) and RLG (H5678). Splenectomy significantly reduced portal flow without increasing the complication rate. Despite the aggressive use of small grafts, SFSS and EAD developed in only 1 (0.8%) and 18 (13.8%) patients, respectively. Multivariable logistic regression revealed model for end-stage liver disease score and LLG (H1234-MHV) as independent risk factors for EAD and splenectomy as a protective factor (odds ratio: 0.09; P =0.03). For LLG (H1234-MHV)-LDLT, patients who underwent prereperfusion splenectomy tended to have better 1-year graft survival than those receiving postreperfusion splenectomy.LLG (H1234-MHV) are feasible in adult LDLT with excellent outcomes comparable to RLG (H5678). Venous outflow augmentation and splenectomy help lower the threshold of using small-for-size grafts without compromising graft survival. 

Enric Cuevas Ferrando

Papers

Living Donor Liver Transplantation With Augmented Venous Outflow and Splenectomy