Marginal and extended criteria liver donors, liver transplantation

1. Marginal and extended
criteria donors
Dr. Rohit K. Saini
Moderator – Dr. Neha Garg

2. Introduction
• Massive shortage of donors exist.
• Waiting list keeps on increasing.
• Unlike KTx where dialysis is available as an alternative,
removal from the list in LTx is tantamount to death
• Extended donor criteria – increases availability of organs.

3. Introduction
 No universal definition
• the use of increased risk donor organs (based on
demographic, clinical, lab and histological)
• liberalization of acceptance criteria
• higher potential of risk of graft failure

4. Marginal livers
• older donor livers (i.e. aged 70 or older),
• donation-after-circulatory-death (DCD) grafts,
• steatotic livers,
• livers from hepatitis C or B -positive donors,
• livers split between 2 recipients,
• livers that nobody wants

6. Elderly liver grafts
• Elderly donor livers, generally defined as >70 years, are
frequently discarded.
• Jan 2002 – sep 2014 : Total adult LTx (n – 71,926)
• 4.3% (3104) – elder donors (>70 years).

7. Unadjusted survival of patients receiving elderly graft
compared (>70) to those receiving all other donors (<70).
Significantly worse survival than younger donor
(p<0.0001)
K.J. Halazun, et al., Am. J. Transplant. 18 (3) (2018)

8. K.J.Halazun,et al., Am.J.Transplant.18(3)
(2018)
Eight independent negative
predictors of survival in recipients.

9. Adjusted recipient survival - Comparison of survival of “low risk
recipients of elderly grafts (>70)” vs. all recipients of grafts (<70)
(p=0.04)
K.J. Halazun, et al., Am. J. Transplant. 18 (3) (2018)

10. • Total 4127 liver grafts from older donors (2003-2016)
• 747 grafts were discarded and 3350 grafts were used.
• outcomes in recipients of grafts from older donors improved
over time (2010-2016 vs 2003-2009 )
• 40% lower graft loss risk (P < .001)
• 41% lower mortality risk (P < .001)
2019

11. Elderly liver grafts
• Several centers have even expanded the age limit and
published their results using livers from donors aged 80 or
greater with good outcomes.
Díaz FJL, et al. Gastroenterol Hepatol Bed Bench 2017.
Rabelo AV, et al. Transplantation Proceedings, 47, (2015)
• Optimal donor/recipient matching with elderly (septegenarian
and octogenarian ) livers showed that risk can be minimized
and liver grafts can be safely used.

12. Steatotic liver grafts
• Increasing prevalence of obesity and NAFLD, steatotic livers
offer another opportunity for donor pool expansion.
• Can be macro- or microvesicular (microvesicular - less
influence on graft function)
• HS can be further graded :
 mild (< 33%),
 moderate (33–66%),
 severe (> 66%)
• HS is associated with primary graft non function or early non
function

13. Steatotic liver grafts
• Historical : macrovesicular steatosis >30% (independent risk
factor for decreased survival).
• Recent studies support that these organs can be used when
other donor risk factors are minimized with equivalent
outcomes to non-steatotic livers.

14. Overtime change in donor characteristics.
Jackson KR, et al. Am J Transplant. 2020

15. Overtime change in recipients characteristics.

16. Discard rate :
•SDL : 58% (2005) to 43% (2017) (P < .001).
•non‐SDL : 8.2% (2005) to 7.5% (2017)
Utilization of SDL : 100 (2005) to max
260 (2016) (P = .004). [2.1% to 3.7%]
Jackson KR, et al. Am J Transplant. 2020

17. Posttransplant mortality for SDL vs
non‐SDL: 46% decreased in 2012‐2017
compared to 2005‐2007.
Posttransplant graft loss for SDL vs
non‐SDL: 47% decreased in 2012‐2017
compared to 2005‐2007.
Jackson KR, et al. Am J Transplant. 2020

18. Steatotic liver grafts
• Altogether, SDL with >30% macrovesicular steatosis from
healthier, younger donors (< 55 years) without prolonged CIT
(< 8 h) can be used for transplantation.
• Data exist safe use of livers with >60% steatosis, but should be
used after strict recipient selection.
• Ideal recipients should be in good clinical condition with a low
MELD score.
K.D. Chavin, et al. Clin. Transplant. 27 (5) (2013).

19. DCD liver grafts
• The DCD process increases WIT : higher rates of primary
nonfunction and ischemic cholangiopathy.
• Various scoring systems have been proposed to guide
appropriate donor/recipient matching and predict outcomes.
C.J. Callaghan et al. BMJ Open 3 (9) (2013)
J.C. Hong, et al. Arch. Surg. 146 (9) (2011).
A. Schlegel, et al. J. Hepatol. 68 (3) (2018).

20. 2018
•The new model is easy to calculate.
•It help to decide which risk combination will benefit from additional graft
treatment, or which should be declined

21. A. Schlegel, et al. J. Hepatol. 68 (3) (2018).

23. ECD DCD LTs
• Criteria - any one of following :
 Donor age >50 years
 Donor BMI >35 kg/m2
 Donor fWIT >30 min
 Donor macrosteatosis > 30%
• 2 eras : 2003-2011 and 2011-2018
• Optimisation protocol before 2nd era –
1. Thrombolytic donor flush
2. Decrease CIT.
P. Mihaylov, et al. Expanding the donor pool with the use of extended criteria
donation after circulatory death livers, Liver Transplant. (2019).

24. ECD DCD LTs
• Outcome :
o Increase use of ECD DCD LTs (from 39 to 52%)
o Decrease incidence of ischemic cholangiopathy from 17 to 5%
(0.03)
o Increase 1 year graft survival from 75 to 93% (0.07)
• With optimization of perioperative conditions, ECD DCD livers
can be successfully Tx to expand the donor pool.
P. Mihaylov, et al. Expanding the donor pool with the use of extended
criteria donation after circulatory death livers, Liver Transplant. (2019).

25. Hepatitis C liver grafts
• Traditionally, HCV viremic organs: declined and discarded.
• With development of DAAs, HCV treatment revolutionized.
• A landmark trial (2019): showed HCV transmission prevented
after hearts and lungs from HCV viremic donors transplanted
into 44 HCV-negative recipients on DAA therapy.
A.E. Woolley, et al. N. Engl. J. Med. 380 (17) (2019).

26. Hepatitis C liver grafts
• With DAA : Tx of HCV viremic livers into HCV-negative
recipients is increasing, with good short-term outcomes.
N. Kapila, et al. Hepatology (2019)
P.S. Ting, et al. Transpl. Infect. Dis. 21 (6) (2019)
K. Bari, et al. Hepatology 67 (5) (2018)
• With these encouraging results, HCV viremic organs are no
longer considered increased risk.

27. Hepatitis C liver grafts
• 26 HCV-negative recipients (2017-2019) received HCV-positive
donor livers combined with DAA therapy : normal graft
function and SVR at a median follow-up time of 8 months.
• However, 16% rate of acute cellular rejection: leading the
authors to hypothesize acute rejection may occur more
rapidly.
• Long-term follow-up is greatly anticipated to determine the
impact this treatment strategy.
P.S. Ting, et al. Transpl. Infect. Dis. 21 (6) (2019)

28. HBV Infection and Organ
Transplantation
• Grafts from HBV core antibody positive donors are acceptable
for recipients with HBV-related cirrhosis.
• does not affect graft or patient survival.
• However, HBV disease is 2.5 times more likely to recur. This
risk is mitigated by use of HBIg and antiviral therapy.
• The risk for transmission to HBV-naive recipients is
unacceptably high and is not reduced by administration of
HBIg and therefore should not be used.
Joya-Vazquez PP, et al. Transplantation. 2002
Walid S. Ayoub, et al. Gastroenterology & Hepatology. 2018

29. Walid S. Ayoub, et al. Gastroenterology & Hepatology. 2018

30. Split liver grafts
• The first split liver transplant (SLT) was performed in 1988.
• Two techniques :
1. Classic (ped-adult): split II, III seg and remaining I, IV – VIII
2. Full size split (adult-adult): I – IV and V – VIII.
• These organs are often retrieved from young, healthy donors
Hackl C., et al. World J. Transplant. 24 (47) (2018).
Yersiz H., et al. Ann. Surg. 238 (4) (2003).

31. Split liver grafts
• The incidence of biliary and vascular complications in
recipients of LLS grafts created by split LTx was not statistically
different.
SLT-LLS (dash), LD-LLS (interrupted),
and pediatric whole-organ recipients
(solid line). P - (0.12).
Yersiz H., et al. Ann. Surg. 238 (4) (2003).

32. livers that nobody wants (LNWs)
• McCormack and colleagues transplanted 26 LNWs.
• declined by at least three centers before acceptance: directed
to select recipients (underestimate by MELD scores).
2010

33. McCormack L., et al. HPB 2010

34. McCormack L., et al. HPB 2010

35. livers that nobody wants (LNWs)
• Transplantable livers are unnecessarily discarded by the
transplant community and improved methods for
donor/recipient matching are needed.
• practice in LNWs varies for each country
McCormack L., et al. HPB 2010
K.J. Halazun, et al. Ann. Surg. 266 (3) (2017).
G.C. Sotiropoulos, et al. Transplantation 80 (7) (2005).

36. Strategies to optimise ML before LTx
• Appropriate donor/recipient matching
• CIT as short as possible (<8 hours)
• Correction of donor hypernatremia (<155 meq/l)
• Prophylaxis: HBIg, antiviral(if anti HBc Ab positive donor)
• DAA (if HCV donors)
• Decrease I/R injury:
 Drugs (Urso-deoxycholic acid, Pentoxifylline, bezafibrate)
 Ischemic preconditioning
 Experimental (HSP preconditioning)
• Perfusion with fibrinolytic drugs
• Machine perfusion (hypo/normothermic)

37. Ex vivo liver perfusion
• Worldwide ex vivo organ perfusion is increasing. Marginal
lungs are now routinely “rescued” or “recovered” using ex
vivo technology and Tx with good short and midterm
outcomes.
• In 2016, the first successful transplantation of an initially
discarded liver after NMP was reported.
J. Reeb, M. Cypel, Clin. Transplant. 30 (3) (2016).
T. Perera, et al. Liver Transplant. 22 (2016).

38. Ex vivo liver perfusion

39. T. Perera, et al. Liver Transplant. 22 (2016).

40. Ex vivo liver perfusion
• Histologic assessment - maintenance of architectural structure
• replenishment of hepatocyte glycogen stores from 30% before
NMLP up to 80% after NMLP.
• accompanied with reduction in perfusate glucose
T. Perera, et al. Liver Transplant. 22 (2016).
Post LTx LFT.s

41. • Protocol to consider viable:
 metabolising lactate to ≤2.5 mmol/L within 4 hours of the
perfusion in combination with ≥2 of following:
 bile production,
 metabolism of glucose,
 hepatic arterial flow rate ≥150 mL/min
 portal venous flow rate ≥500 mL/min,
 pH ≥7.30
 maintain a homogeneous perfusion
2017

42. Ex vivo liver perfusion –
randomised trial
NMP (n-120) SCS (n-100) P – value
1. Discard rate 11.7% 24.1% 0.008
2. fWIT 21 min 16min 0.003
3. Total preservation
time
11hr 54min 7hr 45 min <0.001
4. PRS n = 15 n = 32 <0.001
5. LFT.s Rapidly decreased in NMP group CS
6. EAD N = 12 N = 29 <0.001
• No statistical difference:
bile duct complications
ICU/hospital stay
Post op RRT
graft survival or
survival of the patient
Nasralla D., et al. Nature 557 (7703) (2018)
Decreases discard rate

43. Malignancy
• Donors with untreated low-grade basal or squamous cell
malignancies, CIS.s and primary brain tumors with no
extracranial MTS can be considered.
• Donors with remote history of solid organ neoplasm: consider
biological behavior of tumor, stage and grade at diagnosis and
duration of the disease-free interval.
Nalesnik MA., et al. American Journal of Transplantation 2011

44. Nalesnik MA., et al. American Journal of Transplantation 2011

45. Domino Transplantation
• Explanted liver grafts from LT recipients - reuse for Tx.
• Conditions for domino Tx :
(1) a fully functional donor liver and
(2) an extrahepatic genetic defect.
• Examples:
1. Familial amyloid polyneuropathy
2. maple syrup urine disease (MSUD)
Yamamoto S, et al. Am J Transplant. 2007.
Mazariegos GV, et al. J Pediatr. 2012.

46. In last…
• Appropriate donor/recipient matching will
remain paramount for success.
• Revolutinize use of extended grafts and
salvage discarded grafts.