6. Trend of living liver donors

As the experience grew with LDLT amongst the transplant surgeons, there was constant fine tuning of the technique for both the donor and recipient operations. The refinement of technique allowed for the donors who were once considered anatomically unfeasible to be much more openly accepted, further increasing the living liver donor pool available for transplant.

6.2. BMI and macrosteatosis

Hepatic steatosis marginalizes the quality of the allograft by compromising graft and patient survival in short and also long term [26, 27]. It is also associated with higher incidences of Primary Non-Function (PNF) [27] in DDLT. The positive predictive value of PNF after a DDLT based on a deceased donor liver biopsy can be as high as 90% [28], therefore transplant centers when accepting donor livers>30% macrosteatosis on liver biopsy are cautious, and control other variables that can jeopardize the outcomes, like cold ischemic time and warm ischemic time [29]. But, such detailed causal relationship of hepatic steatosis with PNF has not been well studied in LDLT. Furthermore, to establish the true level of hepatic steatosis, a liver biopsy is needed which carries although low but un-needed risks for the living donor, i.e. 5% risk of serious complication and 1% risk of significant bleeding and 1 in 10,000 risk of a fatality [30, 31]. Therefore, transplant centers tend to avoid routine liver biopsies in living liver donors during evaluation, but some, instead rely on the BMI as an indicator of hepatic steatosis [32]. But obesity has been rising in the last two decades across the world. In 2012, in United States, 69% people were overweight (BMI > 25) and 35% obese (BMI > 30) [33]. Therefore, in presence of the obesity epidemic, and the rising liver transplant waiting list, should transplant centers be selective in choosing living liver donors with BMI > 30, especially when it has been demonstrated that BMI > 30 is not a contraindication for live liver donation [34]. The yield of such a donation also had comparable results for donor safety and donor complications in both short and long term when compared with live liver donors with BMI < 30. Furthermore, the recipients also enjoy similar graft/patient survival both in short and long term (Figure 6) [34]. Therefore, when considering obese live liver donors, accepting Graft Recipient Weight Ratio (GRWR) of a higher value (1.42 vs. 1.17, p = 0.0001) can yield the desired donor safety and comparable recipient outcomes [34]. However, there is no ideal GRWR, that is considered optimal in an obese live liver donor, because values as low as 0.74 have successfully achieved comparable and good recipient outcomes [35]. It is also thought that various techniques for Graft Inflow Modulation (GIM) allows for accepting and safely transplanting a lower GRWR liver allograft in LDLT to minimize Small For Size Syndrome (SFSS) [36], whereas others are of

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Figure 5. Age distribution of living liver donors in the last three decades in the US [20].

#### 6.1. Donor age

The majority of living liver donors in United States are <50 year old patients. But in the three decades since the first successful LDLT in Chicago, the living liver donor pool for donors >50 years and also for >65 year old, has doubled (Figure 5), whilst reducing the percentage share of the living donor pool from <50 year old donors. This is largely due to the reduced no. of <50 year old live liver donors available, further complicating the increased burden on the liver transplant waiting list in United States. Therefore, this increased demand has somewhat driven the acceptance of extended age spectrum for living liver donors.

Increased donor age, i.e., above 50 years has profound negative impact on long term patient survival after a Deceased Donor Liver Transplant (DDLT) [21]. This is thought to be largely due to the poor tolerance of such liver allografts to longer cold ischemic times and the ischemia-reperfusion injury that follows. In LDLT too, donor age > 50 years negatively impacts recipient survival [22, 23], but not at a significant rate when compared to the DDLT experience with older donors. But the reduced patient survival is hard to explain, especially when LDLT has much shorter cold ischemic times which are significantly higher in a DDLT.

Liver allograft regeneration in LDLT has been shown to be impaired in older liver donor allografts [22], however this effect seems to disappear in a prospective study [24]. At a molecular level, activation of phosphorylated-Signal Transducer and Activator of Transcription 3 (p-STAT3) gene through signal transduction of cytokines protects hepatocytes from apoptosis and oxidative stress [25] and p-STAT 3 is under-expressed in LDLT from donors>50 years [25]. This imbalance of anti-apoptotic and anti-oxidative functions at the cellular level could explain the reduced graft and patient survival in living donor liver transplant from older donors.

Therefore, although LDLT is preferable from a younger donor, but LDLT from older donors, still confers a far superior survival advantage in comparison to waiting on the liver transplant wait-list.

Figure 5. Age distribution of living liver donors in the last three decades in the US [20].

#### 6.2. BMI and macrosteatosis

The encouraging growth in LDLT volume and its timed elective nature, yielded superior graft and patient survival when compared to DDLT (Figure 3) [18]. But it is noteworthy, the Adultto-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) group in United States showed that a low volume LDLT transplant center (center case no. <20) had far poorer outcomes when compared to DDLT (Figure 4) [19]. This echoes the learning curve that follows a novel surgical technique but also the updation of the infrastructure that a transplant center

As the experience grew with LDLT amongst the transplant surgeons, there was constant fine tuning of the technique for both the donor and recipient operations. The refinement of technique allowed for the donors who were once considered anatomically unfeasible to be much more openly accepted, further increasing the living liver donor pool available for transplant.

The majority of living liver donors in United States are <50 year old patients. But in the three decades since the first successful LDLT in Chicago, the living liver donor pool for donors >50 years and also for >65 year old, has doubled (Figure 5), whilst reducing the percentage share of the living donor pool from <50 year old donors. This is largely due to the reduced no. of <50 year old live liver donors available, further complicating the increased burden on the liver transplant waiting list in United States. Therefore, this increased demand has somewhat

Increased donor age, i.e., above 50 years has profound negative impact on long term patient survival after a Deceased Donor Liver Transplant (DDLT) [21]. This is thought to be largely due to the poor tolerance of such liver allografts to longer cold ischemic times and the ischemia-reperfusion injury that follows. In LDLT too, donor age > 50 years negatively impacts recipient survival [22, 23], but not at a significant rate when compared to the DDLT experience with older donors. But the reduced patient survival is hard to explain, especially when LDLT

Liver allograft regeneration in LDLT has been shown to be impaired in older liver donor allografts [22], however this effect seems to disappear in a prospective study [24]. At a molecular level, activation of phosphorylated-Signal Transducer and Activator of Transcription 3 (p-STAT3) gene through signal transduction of cytokines protects hepatocytes from apoptosis and oxidative stress [25] and p-STAT 3 is under-expressed in LDLT from donors>50 years [25]. This imbalance of anti-apoptotic and anti-oxidative functions at the cellular level could explain the reduced graft and patient survival in living donor liver transplant from older donors.

Therefore, although LDLT is preferable from a younger donor, but LDLT from older donors, still confers a far superior survival advantage in comparison to waiting on the liver transplant

driven the acceptance of extended age spectrum for living liver donors.

has much shorter cold ischemic times which are significantly higher in a DDLT.

needs during the initial experience.

172 Liver Research and Clinical Management

6. Trend of living liver donors

6.1. Donor age

wait-list.

Hepatic steatosis marginalizes the quality of the allograft by compromising graft and patient survival in short and also long term [26, 27]. It is also associated with higher incidences of Primary Non-Function (PNF) [27] in DDLT. The positive predictive value of PNF after a DDLT based on a deceased donor liver biopsy can be as high as 90% [28], therefore transplant centers when accepting donor livers>30% macrosteatosis on liver biopsy are cautious, and control other variables that can jeopardize the outcomes, like cold ischemic time and warm ischemic time [29]. But, such detailed causal relationship of hepatic steatosis with PNF has not been well studied in LDLT. Furthermore, to establish the true level of hepatic steatosis, a liver biopsy is needed which carries although low but un-needed risks for the living donor, i.e. 5% risk of serious complication and 1% risk of significant bleeding and 1 in 10,000 risk of a fatality [30, 31]. Therefore, transplant centers tend to avoid routine liver biopsies in living liver donors during evaluation, but some, instead rely on the BMI as an indicator of hepatic steatosis [32]. But obesity has been rising in the last two decades across the world. In 2012, in United States, 69% people were overweight (BMI > 25) and 35% obese (BMI > 30) [33]. Therefore, in presence of the obesity epidemic, and the rising liver transplant waiting list, should transplant centers be selective in choosing living liver donors with BMI > 30, especially when it has been demonstrated that BMI > 30 is not a contraindication for live liver donation [34]. The yield of such a donation also had comparable results for donor safety and donor complications in both short and long term when compared with live liver donors with BMI < 30. Furthermore, the recipients also enjoy similar graft/patient survival both in short and long term (Figure 6) [34]. Therefore, when considering obese live liver donors, accepting Graft Recipient Weight Ratio (GRWR) of a higher value (1.42 vs. 1.17, p = 0.0001) can yield the desired donor safety and comparable recipient outcomes [34]. However, there is no ideal GRWR, that is considered optimal in an obese live liver donor, because values as low as 0.74 have successfully achieved comparable and good recipient outcomes [35]. It is also thought that various techniques for Graft Inflow Modulation (GIM) allows for accepting and safely transplanting a lower GRWR liver allograft in LDLT to minimize Small For Size Syndrome (SFSS) [36], whereas others are of the belief that higher portal pressures on the contrary help in liver regeneration [35, 37] thereby avoiding the need for GIM.

The experience in the east was entirely different at the five-large volume Asian transplant centers (Seoul, Hong Kong, Taiwan, Kyoto and Tokyo), wherein 38% were left hepatic lobe donation versus 62% right lobe between 1990 and 2001, with lower complication rates for left lobe donation 7.5 vs. 28% [42]. Furthermore, when the transplant centers performed more left lobe hepatectomy as compared to the right (762 vs. 500), the lower donor complication rates for the left lobe liver allografts even reached statistical significance (18.8 vs. 44.2%, p < 0.05) [43]. In summation, the combined experience of living donor hepatectomy across the eastern and western world resonates, that the success of surgery with lower donor complication rates is heavily dependent on the experience of surgeons and their individual practice, than just the laterality of the hepatic lobectomy. Inherently, a living donor transplant carries high stakes, as a donor death or higher complication rate can significantly impact the LDLT practice of an entire nation. In 2001, United States performed a record no. of LDLTs, i.e., 524. But the infamous living liver donor death later that year, crippled the LDLT practice of US to this date,

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Donor Safety is paramount to the success of LDLT and also for the transplant program. Therefore, inadequate graft size is a major obstacle, considering the low number of donors willing and suitable to donate. Inadequate graft size along with portal hyper-perfusion can lead to Small For Size Syndrome (SFSS), a clinical syndrome characterized by postoperative coagulopathy and liver dysfunction. Various modes of GIM have been proposed to minimize the portal hyperperfusion and also minimize congestion, but little focus has been on how to encompass the low GRWR. Therefore, dual lobe liver transplant, a technical advancement to the standard LDLT has been described and safely practiced [44] by certain centers. Herein, dual allografts from two separate donors are transplanted heterotopically and orthotopically in one recipient; yielding higher liver volume for better recipient outcome and at the same time, be safer for the living donor(s) (Figure 7). Besides being a technically complex operation, it comes with immunological challenges of acute rejection between the two grafts and the recipient, and also between the

ABO-incompatible (ABO-i) living donor liver transplants have been in discussion and sparse use for almost three decades, and is reserved for urgent cases only. This is because the fiveyear patient survival rates in adults are abysmally low at 22% [45]. Therefore, ABO-i LDLT has unpopular amongst transplant surgeons. But in 2003, Rituximab, an anti-CD20 monoclonal antibody was introduced in liver transplantation with excellent graft and patient survival rates for ABO-i LDLT [46]. Since then, there have been various immune-modifications by adding plasmapheresis, splenectomy or immunoadsorption columns to Rituximab therapy, in order to

grafts itself, including the risk of Graft Versus Host Disease (GVHD).

7.2. ABO-i liver transplant and paired exchange

successfully cross the blood group incompatibility barrier.

annually averaging to only about 300 LDLTs.

7. Advances in LDLT

7.1. Dual lobe liver transplant

#### 6.3. The debate of right vs. left lobe donor hepatectomy

The very first few LDLTs performed were in pediatric patients, utilizing Left Lateral Segment (LLS) liver grafts. This was technically easier for the recipients, whilst offering higher level of donor safety. Both these factors were paramount in gaining the needed success and popularity of LDLT across the world. Meanwhile in adult recipients, right lobe versus left lobe LDLT was debated heavily for two decades. The debate aimed at balancing donor safety and recipient outcomes. Although, logic and ethics favored donor safety, but the recipient risks and outcome were equally important, thus feeding the debate. Normally, the right lobe of the liver is larger and denser than the left lobe, which is much smaller and flatter. Therefore, a left lobe hepatectomy generates a smaller allograft providing higher safety for the donor but limiting the choice of recipient. This blunted the popularity of LDLT in adult patients. But in 1997, the feasibility of using a right lobe liver graft safely in adults by overcoming the graft size matching, opened the gateway for adult LDLTs [38, 39].

In United States, right lobe living donor hepatectomy remained the choice for 95% adult LDLTs, between 1998 and 2009 [40]. Although the number of left lobe living liver donors were smaller for statistical inference, nonetheless, A2ALL consortium concluded, a higher rate of donor complications with left lobe donation. The Turkish group also noted similar findings, whereby performing 91% right lobe LDLTs between 2007 and 2011, they experienced higher donor complications for left lobe liver donation [41]. Arguably both in the US and Turkey, the number of left lobe liver donation was far smaller for a meaningful covariate analysis, instead, it hinted towards the importance of individual surgeon experience in right or left lobe donor hepatectomy.

Figure 6. LDLT patient survival based on BMI [34].

The experience in the east was entirely different at the five-large volume Asian transplant centers (Seoul, Hong Kong, Taiwan, Kyoto and Tokyo), wherein 38% were left hepatic lobe donation versus 62% right lobe between 1990 and 2001, with lower complication rates for left lobe donation 7.5 vs. 28% [42]. Furthermore, when the transplant centers performed more left lobe hepatectomy as compared to the right (762 vs. 500), the lower donor complication rates for the left lobe liver allografts even reached statistical significance (18.8 vs. 44.2%, p < 0.05) [43].

In summation, the combined experience of living donor hepatectomy across the eastern and western world resonates, that the success of surgery with lower donor complication rates is heavily dependent on the experience of surgeons and their individual practice, than just the laterality of the hepatic lobectomy. Inherently, a living donor transplant carries high stakes, as a donor death or higher complication rate can significantly impact the LDLT practice of an entire nation. In 2001, United States performed a record no. of LDLTs, i.e., 524. But the infamous living liver donor death later that year, crippled the LDLT practice of US to this date, annually averaging to only about 300 LDLTs.
