1

Impact of Body Mass Index in Liver Transplantation for Nonalcoholic Fatty Liver

Disease and Alcoholic Liver Disease

Running title

Impact of Body Mass Index in Liver Transplantation

Authors

Stephen O'Neill; Transplant Surgery Registrar1

Sara Napetti, Consultant Hepatobiliary Surgeon1

Sorina Cornateanu, Consultant Transplant Surgeon1

Andrew I Sutherland; Consultant Transplant Surgeon1

Stephen Wigmore; Professor of Transplantation Surgery and Honorary Consultant Surgeon1

Gabriel C Oniscu; Consultant Transplant Surgeon and Honorary Clinical Senior Lecturer1

Anya Adair; Consultant Transplant and Hepatobiliary Surgeon and Honorary Clinical Senior

Lecturer1

Institutions

1Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK, Royal

Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA

Corresponding author

Anya Adair, Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK,

Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA

Tel.0044-7968711417

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E-mail: anyaadair@nhs.net

Sources of financial support

None

Type of article for submission

Original article

Conflicts of interest

None

Word count text

2655

Word count abstract

200

Author contribution

Each author has made a substantial contribution to the conception, design, drafting and

critical revision of this article for important intellectual content; and has given final approval

of the version to be published. Specific roles are summarised below:

SON – analysis, writing of manuscript

SN - data extraction, analysis, drafting of manuscript

SC - data extraction, drafting of manuscript

AIS – data extraction, analysis, drafting of manuscript

GO – conception, design, analysis, drafting of manuscript

AA - conception, design, analysis, drafting of manuscript

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Abstract

Background: This study evaluates long-term outcomes and body mass index (BMI)

following liver transplantation (LT) for non-alcoholic fatty liver disease (NAFLD) in

comparison with alcoholic liver disease (ALD).

Methods: Patient and graft survival were compared using Kaplan Meier curves and log rank

test. Multivariable analysis of recipient and donor characteristics was performed as

determinants of patient survival. BMI at listing was compared with BMI post-LT.

Results: Patient survival at 1-, 3-, 5- and 10 years post-LT was similar in the ALD group

(n=195) compared with the NAFLD group (n=84) (93% vs. 93%, 91% vs. 89%, 86% vs.

77%, 64% vs. 66% respectively, p=0.21). One patient in the NAFLD group was re-

transplanted and none in the ALD group therefore graft survival was also similar (p=0.20).

Multivariable analysis didn’t identify any significant predictors of reduced survival. In

comparison with the ALD group, BMI was significantly higher in the NAFLD group at

listing (31 vs. 27, p<0.001), 3-months post-LT (28 vs. 26, p<0.05) and 6-months post-LT (29

vs. 27, p<0.05) but was equivalent by 5-years post-LT (29 vs. 30, p=0.80).

Conclusions: NAFLD patients had similar patient and graft survival post-LT compared to

ALD. NAFLD patients returned to listing BMI by one-year post-LT but by 5-years post-LT

there was no difference in BMI between the groups.

Key words

Liver Transplantation, Nonalcoholic Fatty Liver Disease

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Introduction

Due to the obesity epidemic non-alcoholic fatty liver disease (NAFLD) is increasing in

prevalence worldwide and is now the second leading cause of liver transplantation (LT) in the

United States (1). In the United Kingdom, 12% of patients placed on the LT waiting list are

categorised as having NAFLD (2). Currently 25% of LTs performed per year in the Scottish

Liver transplant Unit are for NAFLD and it is now the second most common indication for

LT in Scotland. Due to the increasing prevalence of obesity and diabetes worldwide it is

likely that in the future NAFLD will become the leading indication for LT both in Europe and

in United States (3). The increase in NAFLD related LTs is anticipated to have a significant

impact on liver transplantation workload, and raises difficult questions regarding the optimal

allocation of scarce organ resources.

Given the relatively recent increase in the proportion of LTs performed for NAFLD, there is

very little evidence of long-term outcomes following LT including 10-year graft and patient

survival. Indeed, there have been recent calls for comprehensive follow-up studies to be

conducted in NAFLD patients following LT to better understand long-term outcomes and

disease recurrence in this group (3). Alcoholic liver disease (ALD) is an established

indication for LT, and similar to NAFLD, lifestyle choices play an important role in the

pathogenesis of ALD. Therefore to better appreciate the long-term outcomes of LT in

NAFLD patients, the ALD population is a rational comparator group (4).

A recent systematic review and meta-analysis that examined 9 studies and 717 patients after

LT for NAFLD found similar 1-, 3-, and 5-year survival between NAFLD and other causes of

liver failure (5). In a review of the United Network for Organ Sharing a superior survival of

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patients undergoing LT for NAFLD was identified when compared with patients undergoing

LT for ALD (6). In a single centre study, however, a non-significant trend toward lower

survival post-LT was identified in the NAFLD group when compared with ALD patients (4).

In a further single centre analysis, obese and overweight patients did not have reduced patient

or graft survival following LT but had increased morbidity with longer lengths of intensive

care and hospitalisation (7). A body mass index (BMI) of >35 kg/m2 was identified as a

significant risk factor for mortality following LT (8), whilst patients with a BMI > 40 kg/m2

had significantly worse 5-year graft and patient survival (9). In a further study patients with

BMI of 35.1-40 kg/m2 also had lower patient and graft survival (10). A recent meta-analysis

has found that BMI does not reduce patient survival overall post-LT but that obese patients

have reduced survival when compared with non-obese patients with similar causes of liver

disease (11).

This study aims to evaluate long-term outcomes including patient and graft survival and BMI

changes following LT for NAFLD, and compare these outcomes with patients undergoing a

LT for ALD.

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Methods

This study retrospectively reviewed a prospectively collected database of patients undergoing

LT in the Scottish Liver transplant Unit between November 2002 and May 2015. The

demographics of patients and outcome measures including patient and graft survival, and

body mass index (BMI) throughout the post-LT period were compared between patients

undergoing LT for a primary indication of NAFLD and patients undergoing LT for a primary

indication of ALD. Graft survival was defined as death or re-transplantation and BMI as

weight (kg)/height (meters)2. In the Scottish Liver Transplant Unit there is no upper limit of

BMI beyond which patients are not considered for LT. Patients were also not excluded if they

had evidence of ascites or sarcopenia. Histologically proven recurrences of NAFLD on liver

biopsy are described in patients that had selective liver biopsies performed.

In this study, parametric data are presented as mean +/- standard deviation and non-

parametric data as median and range. Statistical comparisons of continuous parametric data

and non-parametric data were performed using student’s t-test and Mann-Whitney-U test

respectively. Statistical comparisons of categorical data were performed using Pearson’s Chi-

square test. Kaplan-Meier curves were constructed to evaluate patient survival probabilities

with differences compared using the log-rank test. Survival percentages are given with 95%

confidence intervals in parentheses. Multivariable survival analysis was performed using a

Cox proportional hazard regression model. All comparisons were performed on R v3.1.3 (R

Foundation for Statistical Computing) with p<0.05 considered statistically significant.

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Results

During the study period 866 LTs were undertaken. As the study progressed the number of

LTs performed for ALD and NAFLD increased year on year, but the most marked increase

occurred in the NAFLD group after 2011 (Figure 1). In total 84 patients who had a LT for

NAFLD and 195 for ALD were identified. In the NAFLD group 22 patients had a history of

alcohol use but none of the patients in the ALD group had a history of NAFLD. The NAFLD

group was significantly older and had a significantly higher BMI at listing but was otherwise

non-significantly different to the ALD group in terms of sex distribution, incidence of

hepatocellular carcinoma (HCC), model for end stage liver disease (MELD) score, follow up,

resource utilisation and donor characteristics including age, sex and graft type (Table 1).

Patients in the NAFLD group were followed up for a median of 4 years (range 0 – 13) during

which time 17 patients died. The cause of death was known for 14 of these patients and

included pneumonia (n=2), HCC recurrence (n=2), NAFLD recurrence (n=1), myocardial

infarction (n=1), sepsis (n=1), chronic obstructive pulmonary disease (n=1), colon cancer

(n=1), lung cancer (n=1), intra-abdominal haemorrhage (n=1), liver failure secondary to acute

rejection (n=1) and pulmonary fibrosis (n=1). One patient in the NAFLD group had normal

liver function tests at the time of death. The overall patient survival at 1-, 3-, 5- and 10 years

was 93% (88 - 99), 89% (82 - 96), 77% (67 – 90) and 66% (50 – 87) respectively. There was

one patient re-transplanted in the NAFLD group for primary-non-function therefore the

overall graft survival at 1-, 3-, 5- and 10 years was 93% (87 - 99), 89% (83 - 96), 77% (66 –

90) and 66% (50 – 87) respectively.

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Patients in the ALD group were followed up for a median of 5 years (range 0 – 14) during

which time 40 patients died. The cause of death was known for 34 of these patients and

included chronic obstructive pulmonary disease (n=5), cerebrovascular accident (n=4), liver

failure (n=4), pneumonia (n=4), sepsis (n=4), malignancy (n=4), haemorrhage (n=2), accident

(n=1), elevated pulmonary vascular resistance (n=1), myocardial infarction (n=1), pulmonary

embolus (n=1), recurrent HCC (n=1), respiratory failure (n=1) and sclerosing peritoneal

disease (n=1). Three patients in the ALD group had normal liver function tests at the time of

death. This gave an overall patient survival at 1-, 3-, 5- and 10 years of 93% (90 - 97), 91%

(87 - 95), 86% (81 – 91) and 64% (53 – 77). None of the ALD group was re-transplanted

therefore patient and graft survival was identical in the ALD group. Overall the patient

survival (Figure 2) and graft survival (Figure 3) was similar in the ALD group compared with

the NAFLD group. Multivariable survival analysis of recipient (age, sex, presence of

hepatocellular carcinoma, MELD) and donor characteristics (age, donor type) did not identify

any significant predictors of patient survival (Table 2).

In the NAFLD group there was a significant decrease in BMI at three and six months post-LT

(31 +/- 5 vs. 28 +/- 4, p<0.001 and 30 +/- 5 vs. 29 +/- 4, p<0.05 respectively) compared with

BMI at listing, but BMI returned to pre-transplant levels by the end of the first year following

LT (Figure 4). In the ALD group there was no significant decrease in BMI, but by 2 years

after LT there was a significant increase in BMI compared with the time of adding to the

waiting list (27 +/- 5 vs. 29 +/- 5, p<0.01), which was sustained up to 5 years after LT (27 +/-

5 vs. 30 +/- 6, p<0.05) (Figure 4). In comparison with the ALD group, BMI was significantly

higher in the NAFLD group at listing (31 +/- 5 vs. 27 +/- 5, p<0.001), 3 months post-LT (28

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+/- 4 vs. 26 +/- 4, p<0.05), 6 months post-LT (29 +/- 4 vs. 27 +/- 4, p<0.05) and 3 years

post-LT (32 +/- 6 vs. 29 +/- 5, p<0.05) but not at the other time points including 2 years, 4

years and 5 years post-LT (Table 1, Figure 4). None of the patients included in this study

underwent bariatric surgery at any time point.

Twenty patients in the NAFLD group underwent a selective liver biopsy for persistently

deranged liver function tests during follow up and disease recurrence of NAFLD was

histologically identified in four patients.

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Discussion

This was an exploratory study driven by the upsurge in NAFLD related disease in the LT

population in Scotland. This study has identified that patient survival is similar in NAFLD

patients compared with ALD patients after LT. In addition, after controlling for other donor

and recipient factors NAFLD was not an independent predictor of mortality post-LT. The

overall patient survival rate at 1-, 3-, and 5-years following LT for NAFLD reported in this

study (93%, 89% and 78% respectively) are comparable with other reports (3). The survival

rate reported from other single centre studies, which have diverse patient numbers (ranging

from 9 to 144) and severity of illness (mean MELD ranging from 9-33), varies from 78-90%,

73-88% and 60-85% at 1-, 3- and 5-year respectively (3). Larger database studies (n= 1840)

conducted by the Scientific Registry of Transplant Recipients (12), and United Network for

Organ Sharing (n=1810, mean MELD 21) (6) also report comparable survival rates post-LT

in NAFLD patients as observed in this study (84-88 % at 1 year, 78-82 % at 3 years and 77 %

at 5 years). The European Liver Transplant Registry reports a 63% survival at 10-years post

LT for NAFLD compared with 66% in this study.

ALD is a long-recognized indication for LT and it is well established that excellent outcomes

are possible if patients refrain from alcohol relapse (13). The reasons why the ALD

population was selected as a comparator group was because similar to NAFLD, lifestyle

choices play an important role in the pathogenesis of ALD. However, it is appreciated that

differences exist between the groups, as the NAFLD population has previously been

associated with a higher frequency of cardiovascular events and ALD patients have more

potential for malignant tumour development (3, 14). The Scottish Liver Transplant Unit

routinely conducts rigorous pre-assessment of ALD patients and carefully selects candidates

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to be listed for LT. This is reflected in the excellent outcomes reported in the ALD group

with overall patient survival at 1-, 3-, 5- and 10 years of 93%, 91%, 86% and 64%

respectively. In comparison, the European Liver Transplant Registry reports lower 1-, 5-, and

10-year patient survival rates of 86%, 73%, and 59% for ALD patients after LT (15).

NAFLD patients have previously been considered to be higher risk surgical candidates in the

short-term following LT particularly with regards cardiovascular events (3). In a study of 115

patients who underwent LT for NAFLD, it was found that they were significantly more likely

than patients with ALD (127 patients) to experience an adverse cardiac event one year after

transplant, even after risk adjustment (odds ratio 4.12; 95 % CI 1.91–8.90) (16). However, in

this study the outcomes in the NAFLD group tended to be similar in the longer term as well

as the first year post-transplant, this may reflect our policy of intensive pre-operative

cardiovascular investigation in this group.

The NAFLD population in this study, despite having a reduction in BMI early following LT,

regained their pre-transplant BMI by one year. In a review of 159 patients with a diagnosis of

HCC, higher BMI increased the risk for complications and led to a poorer oncologic outcome

following LT (17). It is unclear whether a lack of sustained BMI reduction contributed to

poorer longer-term transplant outcomes across the NAFLD group in this current study but

based on the evolution of BMI post-LT it would seem unlikely since there were no significant

differences in BMI compared to the ALD population in the longer term. However, BMI does

not take into account the fact that NAFLD is known to be associated with a six-fold increase

in sarcopenic obesity in the LT population (18). Sarcopenia, which was not assessed in this

study, strongly correlates with mortality following LT (19).

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Despite having cachexia, patients with chronic liver failure that have ascites or peripheral

oedema may have elevated BMI secondary to fluid overload rather than obesity (20). Pre-

transplant BMI can be corrected for ascites by subtracting the volume of ascites from the

patient weight (21). Corrected BMI was not utilised in this study and BMI may therefore

have been overestimated, particularly at the listing stage when ascites was more likely to be

present. However, this would have affected both the NAFLD and ALD groups.

Furthermore, BMI does not exclude the possibility of disease recurrence, which was evident

in 20% (4/20) of patients that had a post-LT biopsy. This finding could also be an

underestimation, as protocol biopsies are not routinely performed in the Scottish Liver

Transplant Unit, and are generally only considered in patients with steatosis on ultrasound

and/or persistently deranged liver function tests (22). The literature would suggest that

recurrent NAFLD varies between 25-60% following LT (3). Indeed, evaluation of recurrence

via liver biopsies in a cohort of 88 patients transplanted for NAFLD found recurrence in 39%

(23). Therefore clinicians could consider performing liver biopsies or undertake Fibroscans

for these patients at more regular intervals and aggressively seek to reduce risk factors for

recurrence including BMI (24).

Weight gain is common after LT and 30%–70% of patients become overweight or obese (3).

In a study of BMI following LT in 597 patients, by 1 and 3 years post LT, 24% and 31% of

LT patients had a BMI >30 kg/m2 with weight gain significantly greater in patients aged >50

years and those transplanted for chronic liver disease compared to fulminant liver failure

(25). It has been suggested that chronic fatigue and the metabolic effects of

immunosuppression make sustained reduction of weight difficult leading to progressively

increasing BMIs after LT (22). Current guidance makes no specific recommendation for the

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prevention or treatment of NAFLD in LT recipients other than the correction and

optimisation of individual components of the metabolic syndrome and cardiovascular risk

factors (2, 26). However, it seems sensible that longer-term nutritional programs could be

advantageous, especially for NAFLD patients (3). Minimising dietary cholesterol intake,

consumption of 2 or more cups of coffee per day and a Mediterranean diet, including

approximately 60 mL/d of olive oil have all been advocated in a recent review (22).

Medically supervised weight loss alone can be relatively ineffectual in the general

population, and this is also true in the transplant clinic where patients are found to regain

weight, acquire diabetes, and develop recurrent steatosis (27). This could also be a

component of steroid and calcineurin induction of diabetes and not just obesity. In a recent

randomised controlled trial, evorolimus with reduced exposure to tacrolimus showed reduced

post liver transplantation weight gain at 1 and 2 years post-transplant in comparison to a

standard tacrolimus immunosuppression regimen (28).

More radical approaches to weight management such as bariatric surgery could be considered

in the NAFLD population but the optimal timing of such intervention needs clarified. In an

analysis of the United States Nationwide Inpatient Sample patients with decompensated liver

disease had a higher risk of mortality following bariatric surgery (16.3%) compared to those

with compensated liver disease (0.9%) or no liver disease (0.3%) (28). In a systematic review

22 cases of bariatric surgery following LT were reported with a complication rate following

the procedure of 32% and an overall mortality rate of 13.6% (29). A recent study from the

Mayo Clinic reported sustained weight loss (from a mean BMI of 48 kg/m2 to a mean BMI of

29 kg/m2) and no mortality following seven combined LT and sleeve gastrectomy procedures

(27). Therefore combined LT with bariatric surgery may represent the most acceptable of

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these options in terms of timing but larger studies are required to confirm the safety and

efficacy of this approach.

The strengths of this current study include the current importance of NAFLD along with the

long-term follow up of patients. Weaknesses include the retrospective nature of the study and

disease overlap with 22 patients in the NAFLD group having a history of alcohol use. The

NAFLD group was also mainly transplanted later in the study period and the study does not

take into account NAFLD patients listed but not transplanted. Future research in this area

could focus on metabolic profiling and identifying strategies to sustain reduction in BMI in

the NAFLD population after LT, in order to assess whether this impacts upon outcomes in the

longer term. There are currently no Food and Drug Administration–approved therapies for

NAFLD but it has been suggested that vitamin E could be considered in all patients with

histologically proven recurrence of NAFLD, with Pioglitazone considered in patients with

recurrence of NAFLD in the presence of type 2 diabetes mellitus (22). Increased average

steroid dose at 6 months post-LT has been correlated with increased NAFLD recurrence (23)

as has cumulative steroid use (29). Therefore tapering steroid dose earlier in the NAFLD

population could represent an attractive strategy if the immunosuppressive status of the

patient permits. It is our practice to discontinue steroids 3 months post-LT and continue with

Tacrolimus and Mycophenolate Mofetil in the longer term.

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Conclusion

In the experience of the Scottish Liver Transplant Unit, NAFLD patients had similar long-

term patient and graft survival after LT compared with ALD patients. After controlling for

other donor and recipient factors NAFLD was not an independent predictor of mortality after

LT. In NAFLD patients post transplant BMI dropped initially but returned to pre-transplant

levels within one year of transplant. However, there was no difference in long-term BMI at 4

and 5-years following LT in the NAFLD and ALD groups.

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Figure legends

Figure 1: LTs for NAFLD per year (2003 – 2014). Note the study period was November 2002

to May 2015. Therefore this graph excludes one ALD case from 2002, seven ALD cases from

2015 and one NAFLD case from 2015.

Figure 2: Kaplan-Meier curve to evaluate patient survival probabilities in patients receiving

LTs for NAFLD and ALD.

Figure 3: Kaplan-Meier curve to evaluate graft survival probabilities in patients receiving

LTs for NAFLD and ALD.

Figure 4: BMI of patients receiving a LT for NAFLD and ALD at time of listing and on

follow up.

Table legends

Table 1: Characteristics of recipients receiving LT for NAFLD and ALD as well as donor

characteristics. Results are expressed as overall count with percentage in parentheses, as

mean +/- standard deviation or median with range in parentheses.

*Data missing for 4 donors

**Normothermic regional perfusion used in 1 donor

***Normothermic regional perfusion used in 2 donors

Table 2: Cox regression analysis of recipient (age, sex, presence of hepatocellular carcinoma,

MELD) and donor characteristics (age, sex, donor type) as determinants of patient survival.

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Abbreviations: NAFLD = Non-alcoholic fatty liver disease, ALD = alcoholic liver disease,

HCC = hepatocellular carcinoma, MELD = model for end stage liver disease, DBD =

donation after brain death, DCD = donation after circulatory death, BMI = body mass index

Table 1 |

Recipient characteristics NAFLD (n=84) ALD (n=195) P value

Recipient male: female 52: 32

(62%: 38%)

147: 48

(75%: 25%)

0.03

Recipient age 62 (27-73) 58 (27-72) <0.001

HCC 26 (31%) 50 (26%) 0.44

MELD 17 (7-30) 19 (6-34) 0.12

Follow up 4 (0-13) 5 (0-14) 0.16

Donor characteristics

Donor age 53 (16-75) 50 (16-80) 0.47

Donor male: female 45: 39

(54%: 46%)

106: 85

(55%: 45%)*

0.87

Graft type

DBD 75 (89%) 180 (92%) 0.55

DCD 9 (11%)** 15 (8%)*** 0.55

Split LT 3 (4%) 18 (9%) 0.16

Resources

Operating time (minutes) 375 (200-570) 377 (179-900) 0.97

Packed red cells (units) 2 (0-22) 3 (0-49) 0.05

Fresh frozen plasma (units) 3 (0-20) 4 (0-24) 0.09

Platelets (units) 2 (0-6) 1 (0-9) 0.99

Cryoprecipitate (units) 0 (0-14) 0 (0-8) 0.09

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Length of stay (days) 18 (10-71) 16 (5-144) 0.38

BMI

At listing 31 (5) 27 (5) <0.001

3 months post-LT 28 (4) 26 (4) 0.01

6 months post-LT 29 (4) 27 (5) 0.01

1 year post-LT 29 (5) 28 (5) 0.12

2 years post-LT 30 (5) 29 (5) 0.13

3 years post-LT 32 (6) 29 (5) 0.02

4 years post-LT 31 (4) 29 (5) 0.22

5 years post-LT 29 (6) 30 (6) 0.78

Table 2 |

Factor Hazard ratio Lower 95% CI Upper 95% CI P value

NAFLD 1.85 0.89 3.86 0.10

Recipient age 1.02 0.98 1.07 0.36

Recipient sex

(male)

1.21 0.56 2.62 0.63

HCC 0.87 0.39 1.96 0.74

MELD 0.99 0.93 1.05 0.74

Donor age 1.00 0.98 1.02 0.75

Graft (DCD) 0.29 0.03 2.22 0.24

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