Download 7.03.509 Solid Organ Transplants

MEDICAL POLICY
POLICY
RELATED POLICIES
POLICY GUIDELINES
CODING
DESCRIPTION
SCOPE
BENEFIT APPLICATION
RATIONALE
REFERENCES
APPENDIX
HISTORY
Solid Organ Transplants
Number
7.03.509
Effective Date
March 1, 2017
Revision Date(s) 04/18/17; 04/14/17; 02/14/17; 12/09/16; 10/11/16; 01/29/16;
01/12/16; 03/31/15; 02/10/14; 01/14/13; 01/06/12; 01/11/11;
02/09/10; 03/10/09; 05/13/08; 05/08/07; 05/09/06; 05/10/05;
05/11/04; 01/01/04; 05/13/03; 07/01/02
Replaces
7.03.500, 7.03.502; 7.03.503; 7.03.504, 7.03.505; 7.03.506
Policy
[TOP]
Heart Transplant
A human heart transplant may be considered medically necessary for patients with end-stage heart failure. “End
stage heart failure” commonly reflects New York classification stage 3 or 4. (These are functional classifications,
but describe scenarios that patients will be unlikely to return to normal level of function—without some
fundamental change in the physiology, and because of the dysfunction of the organ system in question, other
organ systems are showing signs of deterioration.)
Heart retransplantation after a failed primary heart transplant may be considered medically necessary in patients
who meet criteria for heart transplantation.
Heart transplants that require concurrent coronary artery bypass graft surgery of the donor heart are considered
investigational.
Heart/Lung Transplant
A combined heart/Lung transplant may be considered medically necessary for patients with end-stage cardiac
and end-stage pulmonary disease.
Heart/lung retransplantation after a failed primary heart/lung transplant may be considered medically necessary
in patients who meet criteria for heart/lung transplantation.
Kidney Transplant
Kidney transplants, using a deceased (cadaver) or living donor, may be considered medically necessary for
patients who have documented end-stage renal disease or imminent end-stage renal disease.
Kidney retransplant after a failed primary kidney transplant may be considered medically necessary.
Liver Transplant
Liver transplants, using a deceased (cadaver) or living donor, may be considered medically necessary for
patients with end-stage or imminent end-stage liver failure.
Lung Transplant and Lobar Lung Transplant
Lung transplants may be considered medically necessary for patients with end-stage pulmonary disease.
Lobar lung transplants from a living or deceased donor may be considered medically necessary for patients
including children and adolescents with end-stage pulmonary disease.
Pancreas Transplant
Pancreas transplant after a prior kidney transplant may be considered medically necessary in patients with
insulin dependent diabetes.
A pancreas transplant alone may be considered medically necessary in patients with severely disabling and
potentially life-threatening complications due to hypoglycemia unawareness and labile insulin dependent
diabetes.
Pancreas retransplants after a failed primary pancreas transplant may be considered medically necessary.
Pancreas retransplant after two or more prior failed pancreas transplants is considered investigational.
Pancreas/Kidney Transplant
A combined pancreas/kidney transplant may be considered medically necessary in insulin-dependent diabetic
patients.
Solid organ transplants other than those addressed above are considered investigational. (See Related
Policies)
Related Policies
[TOP]
7.03.11
Percutaneous Ventricular Assist Devices
7.03.04
Intestinal and Multivisceral Organ Transplant Surgery
8.01.505
Transcatheter Arterial Chemoembolization as a Treatment for Primary or Metastatic Liver
Malignancies
8.03.05
Outpatient Pulmonary Rehabilitation
Policy Guidelines
[TOP]
A Company Medical Director or his/her designee will review all solid organ transplants for medical necessity in
conjunction with the criteria of the Transplant Center.
If the member meets the criteria of the Transplant Center, the transplant may be considered medically necessary.
Coding
32851
32852
32853
32854
CPT
Lung transplant, single; without cardiopulmonary bypass
Lung transplant, single; with cardiopulmonary bypass
Lung transplant, double (bilateral sequential or en bloc); without cardiopulmonary bypass
Lung transplant, double (bilateral sequential or en bloc); with cardiopulmonary bypass
33945
47135
47136
47399
48554
50360
50365
S2060
S2065
S2152
Heart transplant, with or without recipient cardiectomy
Liver allotransplantation, orthotopic, partial or whole, from cadaver or living donor, any age
Liver allotransplantation; heterotopic, partial or whole, from cadaver or living donor, any age (Code
deleted effective 01/01/16, replaced with 47399)
Unlisted procedure, liver
Transplantation of pancreatic allograft
Renal allotransplantation, implantation of graft; without recipient nephrectomy
Renal allotransplantation, implantation of graft; with recipient nephrectomy
HCPCS
Lobar lung transplantation
Simultaneous pancreas kidney transplantation
Solid organ(s), complete or segmental, single organ or combination of organs; deceased or living donor
(s), procurement, transplantation, and related complications; including: drugs; supplies; hospitalization
with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services, and the
number of days of pre and posttransplant care in the global definition
Description
[TOP]
A solid organ transplant consists of replacing a diseased organ with a healthy donor organ. Transplantation is
used for patients with refractory end-stage organ disease.
For purposes of this medical policy, solid organ transplants include heart, heart/lung, kidney, liver, lung, lobar
lung, pancreas and pancreas/kidney transplants.
Small bowel, small bowel/liver and multivisceral transplants are addressed in a separate medical policy. (See
Related Policies)
Scope
[TOP]
Medical policies are systematically developed guidelines that serve as a resource for Company staff when
determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject
to the limits and conditions of the member benefit plan. Members and their providers should consult the member
benefit booklet or contact a customer service representative to determine whether there are any benefit limitations
applicable to this service or supply.
Benefit Application
[TOP]
See health plan contract language for organ transplant benefits; there may be contract limitations on transplants.
(See Scope). This policy does not apply to Medicare Advantage.
Rationale
[TOP]
A literature search based on the MEDLINE database was performed through December 2016. Key literature
follows for each solid organ transplant addressed in this policy.
Heart Transplant
Heart transplantation can potentially improve both survival and quality of life in patients with end-stage heart
failure. Heart failure may be due to a number of differing etiologies, including ischemic heart disease,
cardiomyopathy, or congenital heart defects. The leading indication for heart transplant has shifted over time from
ischemic to nonischemic cardiomyopathy. The demand for heart transplants far exceeds the availability of donor
organs, and the length of time patients are on the waiting list for transplants has increased. The chronic shortage
of donor hearts has led to the prioritization of patients awaiting transplantation to ensure greater access for
patients most likely to derive benefit. Prioritization criteria are issued by The United Network for Organ Sharing
(UNOS).
Prioritization of Candidates for Heart Transplant
Most heart transplant recipients are now hospitalized Status 1 patients at the time of transplant. This shift has
occurred due to the increasing demand on the scarce resource of donor organs resulting in an increased waiting
time for donor organs. Patients initially listed as a Status 2 candidates may deteriorate to a Status 1 candidate
before a donor organ becomes available. At the same time, as medical and device therapy for advanced heart
failure has improved, some patients on the transplant list will recover enough function to become delisted.
In 2007, Lietz and Miller reported on patient survival on the heart transplant waiting list, comparing the era
between 1990 and 1994 to the era of 2000 to 2005.(1) One-year survival for United Network for Organ Sharing
(UNOS) Status 1 candidates improved from 49.5% to 69.0%. Status 2 candidates fared even better, with 89.4%
surviving 1 year compared with 81.8% in the earlier time period.
In 2010, Johnson et al. reported on waiting list trends in the United States between 1999 and 2008.(2) The
proportion of patients listed as Status 1 continued to increase, even as waiting list and post-transplant mortality for
this group decreased. Meanwhile, Status 2 patients have decreased as a proportion of all candidates. Completed
transplants have trended toward the extremes of age, with more infants and patients older than age 65 years
having transplants in recent years.
As a consequence, aggressive treatment of heart failure has been emphasized in recent guidelines. Prognostic
criteria have been investigated to identify patients who have truly exhausted medical therapy and thus are likely to
derive the maximum benefit for heart transplantation. Maximal oxygen consumption (VO2max), which is
measured during maximal exercise, is one measure that has been suggested as a critical objective criterion of the
functional reserve of the heart. The American College of Cardiology (ACC) has adopted VO2max as 1 criterion for
patient selection.(3) Studies have suggested that transplantation can be safely deferred in those patients with a
VO2max of greater than 14 mL/kg/min. The importance of the VO2max has also been emphasized by an
American Heart Association Scientific Statement addressing heart transplant candidacy.(4) In past years, a left
ventricular ejection fraction of less than 20% or a New York Heart Association class III or IV status may have
been used to determine transplant candidacy. However, as indicated by the ACC criteria, these measurements
are no longer considered adequate to identify transplant candidates. These measurements may be used to
identify patients for further cardiovascular workup but should not be the sole criteria for transplant.
Methods other than maximal VO2 have been proposed as predictive models in adults.(5-8) The Heart Failure
Survival Scale and Seattle Heart Failure Model (SHFM) are 2 examples. In particular, the SHFM provides an
estimate of 1-, 2-, and 3-year survival with the use of routinely obtained clinical and laboratory data. Information
regarding pharmacologic and device usage is incorporated into the model, permitting some estimation of effects
of current, more aggressive heart failure treatment strategies. In 2006, Levy et al.(9) introduced the model using
multivariate analysis of data from the PRAISE1 heart failure trial (n=1125). Applied to the data of 5 other heart
failure trials, the SHFM correlated well with actual survival (r=0.98; standard error of the estimate, ±3). The SHFM
has been validated in both ambulatory and hospitalized heart failure populations (10-12) but with a noted
underestimation of mortality risk, particularly in blacks and device recipients.(13-14) None of these models has
been universally adopted by transplant centers.
Initial Heart Transplant
Survival
According to the Organ Procurement and Transplantation Network (OPTN), based on available U.S. data as of
October 30, 2015, the 1-year survival after heart transplant was 88.0% and 86.2% for men and women,
respectively.(15) Three-year survival rates were 79.3% and 77.2% for men and women, respectively, and 5-year
survival rates were 73.1% and 69.1% for men and women, respectively.
Rana et al conducted a retrospective analysis of solid organ transplant recipients registered in the UNOS
database from 1987 to 2012, including 54,746 patients who underwent a heart transplant.(16) Transplant
recipients were compared with patients listed for transplant but who did not receive a transplant after propensity
score matching based on a variety of clinical characteristics. After matching, the median survival was 9.5 years in
transplant recipients compared with 2.1 years in waiting list patients.
Several studies have analyzed factors associated with survival in heart transplant patients. For example, a 2012
Kilic et al analyzed prospectively collected data from the UNOS registry.(17) The analysis included 9404 patients
who had survived 10 years after heart transplant and 10,373 patients who had died before 10 years. Among
individuals who had died, mean survival was 3.7 years posttransplant. In multivariate analysis, statistically
significant predictors of surviving at least 10 years after heart transplant included age younger than 55 years
(odds ratio [OR]=1.24; 95% confidence interval [CI], 1.10 to 1.38), younger donor age (OR=1.01; 95% CI: 1.01 to
1.02), shorter ischemic time (OR=1.11; 95% CI: 1.05 to 1.18), white race (OR=1.35; 95% CI: 1.17 to 1.56), and
annual center volume of 9 or more heart transplants (OR=1.31; 95% CI: 1.17 to 1.47). Factors that significantly
decreased the likelihood of 10-year survival in multivariate analysis included mechanical ventilation (OR=0.53;
95% CI: 0.36 to 0.78) and diabetes (OR=0.67; 95% CI: 0.57 to 0.78).
A 2013 study examined characteristics of patients who survived longer than 20 years after heart transplantation at
a single center in Spain.(18) Thirty-nine heart transplant recipients who survived over 20 years posttransplant
were compared with 98 patients who died between 1 and 20 years posttransplant. Independent factors associated
with long-term survival were younger recipient age, i.e., younger than 45 years versus 45 years and older
(OR=3.9; 95% CI: 1.6 to 9.7) and idiopathic cardiomyopathy, i.e., versus other etiologies (OR=3.3; 95% CI: 1.4 to
7.8).
Pediatric Considerations
According to OPTN data, in 2013, 193 heart transplants were performed in children younger than 18 years. (15)
Five-year survival rates by age group were: less than 1 year: 71.7% (95% CI: 66.3% to 77.1%); 1-5 years: 74.6%
(95% CI: 68.6% to 80.6%); 6-10 years: 77.3% (95% CI: 70.2% to 84.5%); and 11-17 years: 72.1% (95% CI:
67.1% to 77.1%).
According to OPTN data, in 2014, 404 heart transplants were performed in children younger than 18 years.(15)
Five-year survival rates by age group were: less than 1 year: 68.1% (95% confidence interval [CI] 62.6% to
73.7%); 1 to 5 years: 70.8% (95% CI 64.7% to 76.9%); 6 to 10 years: 75.0% (95% CI 67.6% to 82.3%); and 11 to
17 years: 68% (95% CI 62.9% to 82.3%). Data from the Pediatric Heart Transplant Study, which includes data on
all pediatric transplants at 35 participating institutions, suggest that 5-year survival for pediatric heart transplants
has improved over time (76% for patients transplanted from 2000- 2004 vs 83% for patients transplanted from
2005-2009).(20)
A retrospective analysis of OPTN data focusing on the adolescent population was published by Savla et al. in
2014.(19) From 1987 to 2011, heart transplants were performed in 99 adolescents (age, 13-18) with myocarditis
and 456 adolescents with coronary heart disease (CHD). Among adolescent transplant recipients with
myocarditis, median graft survival was 6.9 years (95% CI: 5.6 to 9.6 years, which was significantly less than other
age groups (i.e., 11.8 years and 12.0 years in younger and older adults, respectively). However, adolescents with
CHD had a graft survival rate of 7.4 years (95% CI: 6.8 to 8.6 years), similar to that of other age groups.
In 2010, the International Society for Heart and Lung Transplantation (ISHLT), 532 heart transplants in children
younger than 18 years of age were reported worldwide in 2010.(23) In infants, the most common indications for
heart transplant were congenital heart disease (56%) and cardiomyopathy (40%). For children older than 10 years
of age, the most common indication was cardiomyopathy (63%). Median survival has varied with age of the
transplant recipient. Median survival was 19.2 years for infants, 15.6 years for 1 to 10 year-olds, and 11.9 years
for 11 to 17 year-olds.
Noting that children listed for heart transplantation have the highest waiting list mortality of all solid organ
transplant patients, Almond et al analyzed data from the U.S. Scientific Registry of Transplant Recipients to
determine if the pediatric heart allocation system, as revised in 1999, prioritizes patients optimally and to identify
high-risk populations that may benefit from pediatric cardiac assist devices.(21) Of 3098 children (<18 years of
age) listed between 1999 and 2006, a total of 1874 (60%) were listed as Status 1A. Of those, 30% were placed
on ventilation and 18% were receiving extracorporeal membrane oxygenation. Overall, 533 (17%) died, 1943
(63%) received transplants, 252 (8%) recovered, and 370 (12%) remained listed. The authors found that Status
1A patients are a heterogeneous population with large variation in mortality based on patient-specific factors.
Predictors of waiting list mortality included extracorporeal membrane oxygenation support (hazard ratio [HR]=3.1),
ventilator support (HR=1.9), listing status 1A (HR=2.2), congenital heart disease (HR=2.2), dialysis support
(HR=1.9), and nonwhite race/ethnicity (HR=1.7). The authors concluded that the pediatric heart allocation system
captures medical urgency poorly, specific high-risk subgroups can be identified, and further research is needed to
better define the optimal organ allocation system for pediatric heart transplantation.
A retrospective review of pediatric cardiac transplantation patients was published by Auerbach and colleagues in
2011.(22) A total of 191 patients who underwent primary heart transplantation at a single center in the United
States were included; their mean age was 9.7 years (range= 0 to 23.6 years). Overall graft survival was 82% at 1
year and 68% at 5 years; the most common causes of graft loss were acute rejection and graft vasculopathy.
Overall patient survival was 82% at one year and 72% at 5 years. In multivariate analysis, the authors found that
congenital heart disease (HR= 1.6, 95% CI=1.02-2.64) and requiring mechanical ventilation at the time of
transplantation (HR=1.6, 95% CI=1.13-3.10) were both significantly independently associated with an increased
risk of graft loss. Renal dysfunction was a significant risk factor in univariate analysis, but was not included in the
multivariate model due to the small study group. Limitations of the study include that it was retrospective and
conducted in only one center.
Heart Retransplantation
Survival
An analysis of OPTN data from 1995 to 2012 reported that 987 retransplants were performed (of 28,464 heart
transplants, 3.5% of all transplants).(24) Median survival among retransplant recipients was 8 years. The
estimated survival at 1, 5, 10, and 15 years following retransplant was 80%, 64%, 47% and 30%, respectively.
Compared with primary transplant recipients, retransplant patients had a somewhat higher risk of death (risk ratio
[RR]=1.27, 95% CI: 1.13 to 1.42).
A number of studies have reviewed clinical experience with heart retransplantation in adults. In 2008, Tjang et al.
published a systematic review of the literature on clinical experience with adult heart retransplantation that
identified 22 studies.(25) The most common indications for retransplantation were cardiac allograft vasculopathy
(55%), acute rejection (19%) and primary graft failure (17%). The early mortality rate in individual studies was
16% (range, 5%-38%). Some of the factors associated with poorer outcome after retransplantation were shorter
transplant interval, refractory acute rejection, primary graft failure and an initial diagnosis of ischemic
cardiomyopathy.
A representative study was published in 2013 by Saito et al.(26) This was a retrospective review of data on 593
heart transplants performed at their institution, 22 of these (4%) were retransplants. The mean interval between
initial and repeat transplant was 5.1 years. The indications for a repeat transplant were acute rejection in 7
patients (32%), graft vascular disease in 10 patients (45%), and primary graft failure in 5 patients (23%). Thirty
day mortality after cardiac retransplantation was 32% (7 of 22 patients).
Among patients who survived the first 30 days (n=15), 1-, 5-, and 10-year survival rates were 93.3%, 79% and
59%, respectively. Comparable survival rates for patients undergoing primary cardiac transplants at the same
institution (n=448) were 93%, 82%, and 63%, respectively. An interval of 1 year or less between the primary and
repeat transplantation significantly increased the risk of mortality. Three of 9 patients (33.3%) with less than a
year between the primary and retransplantation survived to 30 days. In comparison 12 of 13 patents (92%) with at
least a year between primary and retransplantation were alive at 30 days after surgery.
A 2014 study using data from the United Network for Organ Sharing (UNOS) reported that there were no survival
differences between 3rd and 2nd transplants (76% for 3rd transplant vs 80% for 2nd transplant at1 year; 62% for 3rd
transplant vs 58% for 2nd transplant at 5 years; 53% for 3rd transplant vs 34% for 2 transplant at 10 years,
P=0.73).(27) However, generalizing from this study’s results may be limited given the small number (n=25) of 3rd
heart transplants.
nd
Pediatric Considerations
As with initial heart transplants, children waiting for heart retransplantation have high waitlist mortality. A 2014
study by Bock et al evaluated data on 632 pediatric patients who were listed for a heart retransplant at least 1
year (median, 7.3 years) after the primary transplant.(28) Patients’ median age was 4 years at the time of the
primary transplant and 14 years when they were relisted. Median waiting time was 75.3 days and mortality was
25.2% (159 of 632). However, waitlist mortality decreased significantly after 2006 (31% before 2006 and 17%
after 2006, p<0.01).
Previously, in 2005, Mahle et al. reviewed data on heart retransplants in the pediatric population, using UNOS
data.(29) A total of 219 retransplantations occurring between 1987 and 2004 were identified. The median age at
initial transplant was 3 years-old, and the median age at retransplantation was 9 years-old. The median interval
between initial procedure and retransplantation was 4.7 years. The most common indications for retransplantation
were coronary allograft vasculopathy (n=111 [51%]), nonspecific graft failure (n=34 [18%]) and acute rejection
(n=19 [9%]). Retransplantation was associated with worse overall survival than initial transplantation. One- 5-, and
10-year survival rates were 83%, 70% and 58%, respectively, after primary transplantation and 79%, 53%, and
44%, respectively after retransplantation. The most common causes of death after retransplantation were acute
rejection (14%), coronary allograft vasculopathy (14%) and infection (13%).
In both the adult and pediatric studies, poorer survival after retransplantation than initial transplantation is not
surprising given that patients undergoing retransplantation experienced additional clinical disease or adverse
events. The increased mortality from retransplantation appears to be mainly from increased short-term mortality.
Longer-term survival rates after retransplantation seem reasonable, especially when patients with a higher risk of
poor outcomes, e.g., those with a shorter interval between primary and repeat transplantation, are excluded. Also,
patients with failed initial transplant have no other options besides a retransplantation.
Potential Contraindications to Heart Transplant
Individual transplant centers may differ in their guidelines, and individual patient characteristics may vary within a
specific condition. In general, heart transplantation is contraindicated in patients who are not expected to survive
the procedure or in whom patient-oriented outcomes, such as morbidity or mortality, are not expected to change
due to comorbid conditions unaffected by transplantation, e.g., imminently terminal cancer or other disease.
Further, consideration is given to conditions in which the necessary immunosuppression would lead to hastened
demise, such as active untreated infection. However, stable chronic infections have not always been shown to
reduce life expectancy in heart transplant patients.
Malignancy
Concerns regarding a potential recipient’s history of cancer were based on the observation of significantly
increased incidence of cancer in kidney transplant patients.(30) In fact, carcinogenesis, primarily skin cancers, is
2 to 4 times more common in heart transplant patients, likely due to the higher doses of immunosuppression
necessary for the prevention of allograft rejection.(31) The incidence of de novo cancer in heart transplant
patients approaches 26% at 8 years post-transplant. For renal transplant patients who had a malignancy treated
before transplant, the incidence of recurrence ranged from 0% to more than 25% depending on the tumor type
(32,33), with a mean incidence of cancer recurrence after heart transplant for all tumors reported at 11.5%.(34)
However, it should be noted that the availability of alternate treatment strategies informs recommendations for a
waiting period following high-risk malignancies: in renal transplant, a delay in transplantation is possible due to
dialysis; end-stage heart failure patients may not have another option. A small study (n=33) of survivors of
lymphoproliferative cancers who subsequently received cardiac transplant had 1-, 5-, and 10-year survival rates
of 77%, 64%, and 50%, respectively.(35) By comparison, overall 1-, 5-, and 10-year survival rates are expected to
be 88%, 74%, and 55%, respectively, for the general transplant candidate. The evaluation of a candidate who has
a history of cancer must consider the prognosis and risk of recurrence from available information including tumor
type and stage, response to therapy, and time since therapy was completed. Although evidence is limited,
patients in whom cancer is thought to be cured should not be excluded from consideration for transplant. UNOS
has not addressed malignancy in current policies.
Human Immunodeficiency Virus (HIV)
Solid organ transplant for patients who are HIV-positive was historically controversial, due to the long-term
prognosis for HIV positivity and the impact of immunosuppression on HIV disease. The availability of highly active
antiretroviral therapy (HAART) has markedly changed the natural history of the disease. A 2009 retrospective
case series reported favorable outcomes for 7 patients with HIV who received a heart transplant.(36) There is little
data directly comparing outcomes for patients with and without HIV.
As of February 2013, the OPTN policy on HIV-positive transplant candidates states: “A potential candidate for
organ transplantation whose test for HIV is positive should not be excluded from candidacy for organ
transplantation unless there is a documented contraindication to transplantation based on local policy” (Policy 4,
Identification of Transmissible Diseases in Organ Recipients).(37)
In 2006, the British HIV Association and the British Transplantation Society Standards Committee published
guidelines for kidney transplantation in patients with HIV disease.(38) These criteria may be extrapolated to other
organs:
 CD4 count greater than 200 cells/mL for at least 6 months
 Undetectable HIV viremia (less than 50 HIV-1 RNA copies/mL) for at least 6 months
 Demonstrable adherence and a stable HAART regimen for at least 6 months
 Absence of AIDS-defining illness following successful immune reconstitution after HAART.
However, concerns have been raised about the extrapolation of these criteria for lung transplants.
Older Age
A 2011 study by Daneshvar et al. examined data on 519 patients who underwent heart transplantation between
1988 and 2009 at a single institution, with a particular focus on survival differences by age group.(39) There were
37 patients who were at least 70 years-old (group 1), 206 patients between 60 and 69 years (group 2), and 276
patients younger than 60 years (group 3). Median survival was 10.9 years in group 1, 9.1 years in group 2, and
12.2 years in group 3 (nonsignificant difference among groups). The 5-year survival rate was 83.2% in group 1,
73.8% in group 2, and 74.7% in group 3.
In 2012, Kilic et al. analyzed data from UNOS on 5330 patients age 60 and older (mean age, 63.7 years) who
underwent heart transplantation between 1995 and 2004.(40) A total of 3492 patients (65.5%) survived to 5 years.
In multivariate analysis, statistically significant predictors of 5-year survival included younger age (OR=0.97; 95%
CI: 0.95 to 1.00), younger donor age (OR=0.99; 95% CI: 0.99 to 1.00), white race (OR=1.23; 95% CI: 1.02 to
1.49), shorter ischemic time (OR=0.93; 95% CI: 0.87 to 0.99), and lower serum creatinine (OR=0.92; 95% CI:
0.87 to 0.98). In addition, hypertension, diabetes, and mechanical ventilation each significantly decreased the
odds of surviving to 5 years. Patients with 2 or more of these factors had a 12% lower rate of 5-year survival than
those with none of them.
Pulmonary Hypertension
Findings of several studies published in 2012 and 2013 suggest that patients with pulmonary hypertension who
successfully undergo treatment can subsequently have good outcomes after heart transplant.(41-44) For
example, De Santo et al. reported on 31 consecutive patients who had been diagnosed with unresponsive
pulmonary hypertension at baseline right heart catheterization.(41) After 12 weeks of treatment with oral sildenafil,
right heart catheterization showed reversibility of pulmonary hypertension, allowing listing for heart transplant.
Oral sildenafil treatment resumed following transplant. One patient died in the hospital. A right heart
catheterization at 3 months posttransplant showed normalization of the pulmonary hemodynamic profile, thereby
allowing weaning from sildenafil in the 30 patients who survived hospitalization. The reversal of pulmonary
hypertension was confirmed at 1 year in the 29 surviving patients. Similarly, in a study by Perez-Villa et al., 22
patients considered high risk for heart transplant due to severe pulmonary hypertension were treated with
bosentan.(42) After 4 months of treatment, mean pulmonary vascular resistance (PVR) decreased from 5.6 to 3.4
Wood units. In a similar group of 9 patients who refused participation in the study and served as controls, mean
PVR during this time increased from 4.6 to 5.5 Wood units. After bosentan therapy, 14 patients underwent heart
transplantation and the 1-year survival rate was 93%.
Summary of Evidence for Heart Transplant
The evidence for the use of heart transplant in individuals with end stage heart failure includes case series and
registry data. Relevant outcomes include overall survival, symptoms, morbid events, and treatment-related
morbidity and mortality. Given the exceedingly poor survival without transplantation, of patients who have
exhausted other treatments, evidence of post-transplant survival is sufficient to demonstrate that heart
transplantation provides a survival benefit in appropriately selected patients. Despite an improvement in prognosis
for many patients with advanced heart disease, heart transplant remains a viable treatment for those who have
exhausted other medical or surgical remedies, yet are still in end-stage disease. Heart transplantation is
contraindicated in patients in whom the procedure is expected to significantly worsen comorbid conditions.
Similarly, evidence suggests that heart retransplantation after a failed primary heart transplant provides a survival
benefit in patients who still meet criteria for heart transplantation and do not have contraindications.
Heart/Lung Transplant
Combined heart/lung transplantation is intended to prolong survival and improve function in patients with endstage cardiac and pulmonary diseases. Most recipients have Eisenmenger syndrome (37%), followed by
idiopathic pulmonary artery hypertension (28%) and cystic fibrosis (14%). Eisenmenger syndrome is a form of
congenital heart disease in which systemic-to-pulmonary shunting leads to pulmonary vascular resistance.
Eventually, pulmonary hypertension may lead to a reversal of the intracardiac shunting and inadequate peripheral
oxygenation, or cyanosis.(45)
Patient Selection
Patients who are eligible for heart/lung transplantation can be listed under both the heart and lung allocation
systems in the United States. In 2005, United Network for Organ Sharing (UNOS) changed the method by which
lungs were allocated, from one based on length of time on the waiting list to a system that incorporates the
severity of the patient’s underlying disease, as well as likelihood of survival.(46) However, it has been noted that
the individual systems underestimate the severity of illness in patients with both end-stage heart and lung failure,
and modification of the lung allocation score can be appealed for patients who meet the following criteria:
 Deterioration on optimal therapy
 Right arterial pressure greater than 15 mm Hg
2
 Cardiac index less than 1.8 L/min/m .
Pediatric Considerations
A 2014 analysis of data from the Organ Procurement and Transplantation Network reported on indications for
pediatric heart/lung transplantation.(47) The number of pediatric heart/lung transplants has decreased in recent
years, i.e., 56 cases in 1993-1997; 21 cases in 2008-2013. The 3 most common indications for pediatric
heart/lung transplant were primary pulmonary hypertension (n=55), congenital heart disease (n=37), and
Eisenmenger syndrome (n=30). However, while 30 children received a heart/lung transplant for Eisenmenger
syndrome through 2002, none have been performed for this indication since then. Pediatric heart/lung transplants
have also been performed for other indications including alpha1 antitrypsin deficiency, pulmonary vascular
disease, cystic fibrosis, and dilated cardiomyopathy.
In 2012, the Registry of the International Society for Heart and Lung Transplantation (ISHLT) reported on pediatric
heart/lung transplant data collected through June 2011.(48) Overall, survival rates after heart/lung transplants are
comparable in children and adults (median half-life of 4.7 and 5.3 years, respectively). For pediatric heart/lung
transplants that occurred between January 1990 and June 2010, the 5-year survival rate was 49%. The 2 leading
causes of death in the first year after transplantation were non-cytomegalovirus infection and graft failure. Beyond
3 years post-transplant, the major cause of death was bronchiolitis obliterans syndrome. An updated report on
pediatric lung and heart-lung transplant from the same registry in 2014 did not include updated data on pediatric
heart-lung transplants due to the small number of patients available.(197)
Heart/Lung Retransplantation
Repeat heart-lung transplant procedures have been performed; a study, published by Shuhaiber and colleagues
in 2008, involved a review of data from the UNOS registry.(49) The authors identified 799 primary heart-lung and
19 repeat heart-lung transplants. According to Kaplan-Meier survival analysis, the observed median survival times
were 2.08 years after primary transplant and 0.34 years after repeat transplants. In addition, the authors analyzed
survival data in matched pairs of primary and repeat transplant patients, who were matched on a number of
potentially confounding demographic and clinical characteristics. Matches were not available for 4 repeat
transplant patients. For the 15 repeat transplant patients with primary transplant matches, survival time did not
differ significantly in the 2 groups. Being on a ventilator was statistically significantly associated with decreased
survival time. The main limitation of this analysis is the small number of repeat transplant procedures performed.
In 2014, Yusen et al reported outcomes for adult heart-lung transplants, with a focus on retransplantation, using
data from the Registry of the International society for Heart and Lung Transplantation.(50) Thirty-three
participating centers reported 75 adult heart-lung transplants in 2012, a decline from the peak year for heart-lung
transplants (1989) during which 226 heart-lung transplants were performed. From 1982-2012, 90 adults had a first
heart–lung retransplant after a previous heart–lung transplant. These 90 patients had a median survival of 0.3
year, with an unadjusted survival rate of 52%, 43%, 36%, and 27% at 3 months, 1 year, 3 years, and 5 years,
respectively. Those who survived to 1 year had a conditional mean survival of 7.9 years.
Potential Contraindications to Heart/Lung Transplant
The potential contraindications for heart/lung transplantation are the same as for a heart transplant alone and are
detailed in an earlier paragraph. Considerations for heart transplantation and lung transplantation alone may also
pertain to combined heart/lung transplantation. For example, cystic fibrosis accounts for most pediatric candidates
for heart/lung transplantation, and infection with Burkholderia species is associated with higher mortality in these
patients. And, experience with kidney transplantation in patients infected with HIV in the era of HAART has
opened discussion of transplantation of other solid organs in these patients.
Summary of Evidence for Heart/Lung Transplant
The evidence for combined heart-lung transplant in individuals who have end-stage cardiac and pulmonary
disease includes case series and registry data. Relevant outcomes include overall survival, symptoms, morbid
events, and treatment-related morbidity and mortality. The available literature, consisting of case series and
registry data, describes outcomes after heart/lung transplantation. Given the exceedingly poor expected survival
without transplantation, this evidence is sufficient to demonstrate that heart/lung transplantation provides a
survival benefit in appropriately selected patients. It may be the only option for some patients with end-stage
cardiopulmonary disease.
Heart/lung transplant is contraindicated in patients in whom the procedure is expected to be futile due to comorbid
disease or in whom post-transplantation care is expected to significantly worsen comorbid conditions. Based on
this evidence and established guidelines, heart/lung transplant may be considered medically necessary for those
who meet clinical criteria and do not have contraindications to the procedure. A very limited amount of data
suggest that, after controlling for confounding variables, survival rates after primary and repeat heart/lung
transplants is similar. Findings are not conclusive due to the small number of cases of repeat heart/lung
transplants reported in the published literature. Repeat heart/lung transplantation may be considered medically
necessary in patients with a failed prior transplant who meet the clinical criteria for heart/lung transplantation.
Kidney Transplant
Kidney transplant, a treatment option for end-stage renal disease (ESRD), involves the surgical removal of a
kidney from a cadaver, living-related donor, or living-unrelated donor and transplantation into the recipient.
Survival
According to an analysis of data from the Organ Procurement and Transplantation Network (OPTN), between
2008 and 2015, the 1-year survival of patients undergoing an initial kidney transplant was 97.0% (95% confidence
interval [CI], 96.8% to 97.1%). Five-year survival was 85.8% (95% CI, 85.5% to 86.1%).(51)
In 2015, Krishnan et al published a study of 17,681 patients in a U.K. transplant database who either received a
kidney transplant or were on a list to receive a kidney transplant.(52) Authors found significantly higher 1- and 5year survival in patients who underwent a kidney transplant compared with those who remained on dialysis.
(Authors did not report exact survival rates.)
Organ Donation
The United Network for Organ Sharing (UNOS) proposed an Expanded Criteria Donor (ECD) approach in 2002 to
include brain-dead donors over 60 years or between 50 and 59 years old with 2 or more of the following criteria:
serum creatinine level greater than 1.5 mg/dL, death caused by cerebrovascular accident, or history of high blood
pressure.(53) In 2016, Querard et al conducted a systematic review and meta-analysis of studies comparing
survival outcomes with Expanded Criteria Donor (ECD) versus Standard Criteria Donor (SCD) kidney transplant
recipients.(53) Reviewers identified 32 publications, 5 of which adjusted for potential confounding factors. A
pooled analysis of 2 studies reporting higher rates of patient-graft failure for ECD kidney recipients found a
significantly higher adjusted hazard ratio (HR) for patient-graft survival (HR=1.68; 95% CI; 1.32 to 2.12). Metaanalyses were not conducted for patient survival outcomes; however, 1 study (n=189) found a higher but
nonsignificant difference in patient survival with ECD and SCD (HR=1.97; 95% CI, 0.99 to 3.91) and another
(n=13,833) found a significantly increased risk of death with ECD versus SCD (HR=1.25; 95% CI, 1.12 to 1.40).
Several studies have reported on long-term outcomes in live kidney donors. The most appropriate control group
to evaluate whether donors have increased risks of morbidity and mortality are persons who meet the criteria for
kidney donation but who did not undergo the procedure. Studies of this type have had mixed findings. For
example, Segev et al. did not find that donors had an increased mortality risk.(54) The authors analyzed data from
a national registry of 80,347 live donors in the U.S who donated organs between April 1, 1994 and March 31,
2009 and compared them with data from 9364 participants of the National Health and Nutrition Examination
Survey (NHANES) (excluding those with contraindications to kidney donation). There were 25 deaths within 90
days of live kidney donation during the study period. Surgical mortality from live kidney donation was 3.1 per
10,000 donors (95% confidence interval [CI], 2.0 to 4.6) and did not change over time, despite differences in
practice and selection. Long-term risk of death was no higher for live donors than for age- and comorbiditymatched NHANES III participants for all patients and also stratified by age, sex, and race.
Potential Contraindications to Kidney Transplant
HIV Infection
In 2001, the Clinical Practice Committee of the American Society of Transplantation proposed that HIV
positive patients who meet the following criteria, could be considered candidates for kidney
transplantation.(55) (These criteria may be extrapolated to other organs.)





CD4 count >200 cells per cubic millimeter for >6 months
HIV-1 RNA undetectable
On stable antiretroviral therapy >3 months
No other complications from AIDS (e.g., opportunistic infection, including aspergillus, tuberculosis,
coccidiosis mycosis, resistant fungal infections, Kaposi’s sarcoma, or other neoplasm).
Meeting all other criteria for transplantation.
Several studies have evaluated outcomes of kidney transplantation in HIV-positive patients. In 2015, Locke et al
examined outcomes in 499 HIV-positive kidney transplant recipients identified in the Scientific Registry of
Transplant Recipients (SRTR).(56) Compared with early era transplants (2004-2007), patients transplanted in the
modern era (2008-2011) had a significantly lower risk of death (HR=0.59; 95% CI, 0.39 to 0.90). Five-year patient
survival was 78.2% for patients transplanted in the early era and 85.8% for modern era transplants. In another
article, Locke et al compared outcomes in 467 adult kidney transplant recipients and 4670 HIV-negative controls,
matched on demographic characteristics.(57) Compared with HIV-negative controls, survival among HIV-positive
transplant recipients was similar at 5 years posttransplant (83.5% vs 86.2%, p=0.06). At 10 years, HIV-positive
transplant recipients had a significantly lower survival rate than HIV-negative patients (51.6% and 72.1%,
respectively, p<0.001). The lower 10-year survival rate was likely due to HIV and hepatitis C virus (HCV)
coinfection; survival at 10 years in HIV-monoinfected patients and HIV-negative patients was similar (88.7% vs
89.1%, p=0.50). In a 2016 analysis, Locke et al found a significantly lower 5-year mortality rates in HIV-infected
patients with end-stage renal disease who had kidney transplants compared with continued dialysis (adjusted
relative risk [RR], 0.21; 95% CI, 0.10 to 0.42; p<0.001).(58)
In addition, in 2015, Sawinski et al conducted an analysis of survival outcomes in patients infected with HIV,
hepatitis C infection (HCV), or HIV and HCV.(59) The analysis included 492 HIV-infected patients, 5605 HCVinfected patients, 147 dually infected patients, and 117,791 noninfected patients. In a multivariate analysis,
compared with noninfected patients, HIV-infected patients did not have an increased risk of death (HR=0.90; 95%
CI, 0.66 to 1.24). However, HCV infection (HR=1.44; 95% CI, 1.33 to 1.56) and HIV and HCV coinfection
(HR=2.26; 95% CI, 1.45 to 3.52) were both significantly associated with an increased risk of death.
Hepatitis C Infection
A 2014 meta-analysis by Fabrizi et al. identified 18 observational studies comparing kidney transplant outcomes
in patients with and without HCV infection.(60) The studies included a total of 133,350 transplant recipients. In an
adjusted analysis, the risk of all-cause mortality was significantly higher in HCV-positive versus HCV-negative
patients (relative risk [RR], 1.85; 95% CI: 1.49 to 2.31). Risks were elevated in various study subgroups examined
by the investigators. When the analysis was limited to the 4 studies from the U.S., the adjusted RR was 1.29
(95% CI: 1.15 to 1.44). In an analysis of 10 studies published since 2000, RR was 1.84 (95% CI: 1.45 to 2.34). An
analysis of disease specific mortality suggested that at least part of the increased of risk of mortality among HCVpositive patients may be due to chronic liver disease. In a meta-analysis of 9 studies, the risk of liver diseaserelated mortality was highly elevated in patients infected with HCV versus uninfected patients: the odds ratio (OR)
was 11.6 (95% CI: 5.54 to 24.4).
In the analysis by Sawinski (described above), HCV infection was associated with an increased risk of mortality in
kidney transplant patients compared with noninfected patients.(59)
Obesity
Several studies have found that morbid obesity is not associated with an increased risk of adverse outcomes after
kidney transplant. In a 2015 analysis of kidney transplant data from the U.K., body mass index (BMI) data were
available for 13,536 patients.(52) The authors devised several BMI categories (ie, <18.5 kg/m 2, 18.5 to <25 kg/m2,
25 to <30 kg/m2, 30 to <35 kg/m2, and 35 to <40 kg/m2). For each BMI category, patient survival was significantly
higher in individuals who underwent kidney transplants compared with individuals who remained on a waiting list.
In a similar analysis of U.S. data, published by Gil et al in 2013, risk of mortality at 1 year was significantly lower in
patients who underwent transplantation than in those who remained on the waiting list for all BMI categories.(61)
For example, among patients with a BMI of at least 40 kg/m 2, who received organs from donors who met standard
criteria (HR=0.52; 95 CI, 0.37 to 0.72); and moreover, among patients with BMI 35 to 39 kg/m 2 who received
organs from standard-criteria donors (HR=0.34; 95% CI, 0.26 to 0.46).
In 2014, Pieloch et al. published a retrospective review of data from the Organ Procurement and Transplantation
Network (OPTN) database.(62) The sample included 6055 morbidly obese patients (i.e., body mass index [BMI],
35-40 kg/m2) and 24,077 normal-weight patients who underwent kidney transplant between 2001 and 2006. After
controlling for potentially confounding factors, the overall 3-year patient mortality did not differ significantly among
obese and normal-weight patients (HR=1.03; 05% CI: 0.96 to 1.12). Similar results were found for 3-year graft
failure (HR=1.04; 95% CI: 0.98 to 1.11). In subgroup analyses, obese patients who were nondialysis dependent,
nondiabetic, younger, received living-donor transplants, and needed no assistance with daily living activities had
significantly lower 3-year mortality rates compared with normal-weight patients who were dialysis dependent,
diabetic, had poor functional status, and received a deceased-donor transplant, respectively (p<0.01). In the
comparison of mortality in nondiabetic obese and normal-weight patients, the OR was 0.53 (95% CI: 0.44 to
0.63).
Section Summary: Kidney Transplant
A large number of kidney transplants have been performed worldwide. Available data have demonstrated a
reasonably high survival rate after kidney transplant for appropriately selected patients and significantly higher
survival rates for patients undergoing kidney transplant compared with those who remained on a waiting list. HIV
infection and obesity have not been found to increase the risk of adverse events after kidney transplantation.
Some data have suggested that kidney transplant recipients with HCV have worse outcomes than those without
hepatitis C infection; however, data have not shown that patients with hepatitis C infection do not benefit from
kidney transplants.
Kidney Retransplantation
Survival
According to an analysis of data from the OPTN between 2008 and 2015, the 1-year survival of patients
undergoing a repeat kidney transplant was 97.1% (95% CI, 96.7% to 97.5%). Five-year patient survival after a
repeat kidney transplant was 87.6% (95% CI, 86.8% to 88.4%).(51)
In 2015, Gupta et al retrospectively analyzed OPTN data, focusing on patients who had an initial kidney transplant
as children.(63) A total of 2281 patients were identified who had their first transplant when they were younger than
18 years and a second kidney transplant at any age. In multivariate analysis, length of first graft survival and age
at second graft were significantly associated with second graft survival. Specifically, first graft survival time of
more than 5 years was associated with better second graft survival. Moreover, patients who were between 15 and
20 years old at second transplant were at increased risk of second kidney graft failure compared with patients in
other age groups.
In 2009, Barocci et al. in Italy reported on long-term survival after kidney retransplantation.(64) There were 100
(0.8%) second transplants of 1302 kidney transplants performed at a single center between January 1983 and
June 2007. Among the second kidney recipients, 1-, 5-, and 10-year patient survival was 100%, 96%, and 92%,
respectively. Graft survival rates at 1, 5, and 10 years were 85%, 72%, and 53%, respectively.
In 2016, Shelton et al evaluated outcomes in HIV-infected patients undergoing kidney retransplantation.(65) In an
adjusted survival analysis, HIV-infected retransplant patients had a significantly increased risk of death compared
with HIV-negative patients (HR=3.11; 95% CI, 1.82 to 5.34). Other factors significantly associated with increased
risk of death after kidney retransplantation included recipient infection with HCV (HR=1.77; 95% CI, 1.32 to 2.38)
and grafts from older donors (HR=1.01; 95 CI, 1.00 to 1.02). The analysis included only 22 HIV-infected patients
and this number of patients is too small to draw conclusions about the appropriateness of kidney retransplantation
in HIV-infected individuals.
Section Summary: Kidney Retransplant
Data have demonstrated a reasonably high survival rate after kidney retransplant for appropriately selected
patients (e.g., 5-year patient survival rates ranging from 87% to 96%).
Summary of Evidence for Kidney Transplant
For individuals who have ESRD without contraindications to kidney transplant who receive kidney transplant from
a living donor or deceased (cadaveric) donor, the evidence includes registry data and case series. Relevant
outcomes are overall survival, morbid events, and treatment-related mortality and morbidity. Data from large
registries have demonstrated a reasonably high survival rate after kidney transplant for appropriately selected
patients and significantly higher survival rates for patients undergoing kidney transplant compared with those who
remained on a waiting list. Kidney transplantation is contraindicated for patients in whom the procedure is
expected to be futile due to comorbid disease or in whom posttransplantation care is expected to significantly
worsen comorbid conditions. The evidence is sufficient to determine that the technology results in a meaningful
improvement in the net health outcome.
For individuals who have a failed kidney transplant without contraindications to kidney transplant who receive
kidney retranplant from a living donor or deceased (cadaveric) donor, the evidence includes registry data and
case series. Relevant outcomes are overall survival, morbid events, and treatment-related mortality and morbidity.
Data have demonstrated a reasonably high survival rate after kidney retransplant for appropriately selected
patients (eg, 5-year patient survival rates ranging from 87% to 96%). Kidney retransplantation is contraindicated
for patients in whom the procedure is expected to be futile due to comorbid disease or in whom
posttransplantation care is expected to significantly worsen comorbid conditions. The evidence is sufficient to
determine that the technology results in a meaningful improvement in the net health outcome.
Liver Transplant
Liver transplantation is now routinely performed as a treatment of last resort for patients with end-stage liver
disease. Liver transplantation may be performed with liver donation after brain or cardiac death or with a liver
segment donation from a living donor. Patients are prioritized for transplant by mortality risk and severity of illness
criteria developed by the Organ Procurement and Transplantation Network (OPTN) and the United Network of
Organ Sharing (UNOS). The severity of illness is determined by the model for end-stage liver disease (MELD)
and pediatric end-stage liver disease (PELD) scores.
Recent literature continues to address expanded criteria for transplantation for hepatocellular carcinoma,
predictors of recurrence, the role of neoadjuvant therapy in patients with hepatocellular carcinoma, expanded
donor criteria, transplantation and retransplantation for hepatitis C, and living donor transplantation.
Overview
Relevant outcomes for studies on liver transplantation include waiting time duration, dropout rates, survival time,
and recurrence. As experience with liver transplant has matured, patient selection criteria have broadened to
include a wide variety of etiologies. The most controversial etiologies include viral hepatitis and primary
hepatocellular cancer (HCC). In particular, the presence of hepatitis B virus (HBV) and hepatitis C virus (HCV)
have been controversial indications for liver transplantation because of the high potential for recurrence of the
virus and subsequent recurrence of liver disease. However, registry data indicate a long-term survival rate (7
years) of 47% in HBV-positive transplant recipients, which is lower than that seen in other primary liver diseases
such as primary biliary cirrhosis (71%) or alcoholic liver disease (57%).(66) Recurrence of HCV infection in
transplant recipients has been nearly universal, and 10% to 20% of patients will develop cirrhosis within 5
years.(67) Although these statistics raise questions about the most appropriate use of a scarce resource (donor
livers), the long-term survival rates are significant in a group of patients who have no other treatment options.
Similarly, the long-term outcome in patients with primary hepatocellular malignancies was poor (19%) in the past
compared with the overall survival of liver transplant recipients. However, recent use of standardized patient
selection criteria, such as the Milan criteria (a solitary tumor with a maximum tumor diameter of 5 cm or less, or
up to 3 tumors 3 cm or smaller and without extrahepatic spread or macrovascular invasion), has dramatically
improved overall survival rates.
In a systematic review of liver transplant for HCC in 2012, Maggs et al. found 5-year overall survival rates ranged
from 65% to 94.7% in reported studies.(68) Nevertheless, transplant represents the only curative approach for
many of these patients who present with unresectable organ-confined disease, and expansion of patient selection
criteria, bridging to transplant or downstaging of disease to qualify for liver transplantation is frequently studied.
Liver transplant cannot be considered curative in patients with locally extensive or metastatic liver cancer or in
patients with isolated liver metastases with extrahepatic primaries or in cholangiocarcinoma.(66)
Living Donors
Due to the scarcity of donor organs and the success of living donation, living donor liver transplantation has
become accepted practice. The living donor undergoes hepatectomy of the right lobe, the left lobe, or the left
lateral segment, which is then transplanted into the recipient. Because hepatectomy involves resection of up to
70% of the total volume of the donor liver, the safety of the donor has been the major concern. For example, the
surgical literature suggests that right hepatectomy of diseased or injured livers is associated with mortality rates of
about 5%. However, initial reports suggest that right hepatectomy in healthy donors has a lower morbidity and
mortality. The Medical College of Virginia reported the results of their first 40 adult-to-adult living donor liver
transplantations, performed between June 1998 and October 1999.(69) There were an equal number of related
and unrelated donors. Minor complications occurred in 7 donors. The outcomes among recipients were similar to
those associated with cadaveric donor livers performed during the same period of time. However, in the initial
series of 20 patients, 4 of the 5 deaths occurred in recipients who were classified as 2A. In the subsequent 20
patients, recipients classified as 2A were not considered candidates for living-donor transplant. Other case series
have reported similar success rates.(70-72) Reports of several donor deaths reemphasize the importance of
careful patient selection based in part on a comprehensive consent process and an experienced surgical
team.(73-75) In December 2000, the National Institutes of Health (NIH) convened a workshop focusing on livingdonor liver transplantation. A summary of this workshop was published in 2002.(76) According to this document;
the risk of mortality to the donor undergoing right hepatectomy was estimated to be approximately 0.2% to 0.5%.
Based on survey results, the workshop reported that donor morbidity was common; 7% required reexploration,
10% had to be rehospitalized, and biliary tract complications occurred in 7%. The median complication rate
reported by responding transplant centers was 21%.
Due to the potential morbidity and mortality experienced by the donor, the workshop also noted that donor
consent for hepatectomy must be voluntary and free of coercion; therefore, it was preferable that the donor have
a significant long-term and established relationship with the recipient. According to the workshop summary, “At
the present time, nearly all centers strive to identify donors who are entirely healthy and at minimal risk during
right hepatectomy. As a result, only approximately one third of persons originally interested in becoming a living
liver donor complete the evaluation process and are accepted as candidates for this procedure.”
Criteria for a recipient of a living-related liver are also controversial, with some groups advocating that livingrelated donor livers be only used in those most critically ill; while others state that the risk to the donor is
unacceptable in critically ill recipients due to the increased risk of postoperative mortality of the recipient.
According to this line of thought, living-related livers are best used in stable recipients who have a higher
likelihood of achieving long-term survival.(76)
In 2000, the American Society of Transplant Surgeons issued the following statement(77):
Living donor transplantation in children has proven to be safe and effective for both donors and recipients
and has helped to make death on the waiting list a less common event. Since its introduction in 1990,
many of the technical and ethical issues have been addressed and the procedure is generally applied.
The development of left or right hepatectomy for adult-to-adult living donor liver transplantation has been
slower. Because of the ongoing shortage of cadaver livers suitable for transplantation, adult-to-adult living
donor liver transplantation has been undertaken at a number of centers. While early results appear
encouraging, sufficient data are not available to ascertain donor morbidity and mortality rates. There is
general consensus that the health and safety of the donor is and must remain central to living organ
donation.
Brown et al reported on the results of a survey focusing on adult living-related recipients in the United States.(78)
The following statistics were reported:
 The survey encompasses 449 adult-to-adult transplantations.
 Half of the responding programs already had performed at least 1 adult-to-adult living-donor liver
transplantation, and 32 of the remaining 41 centers were planning to initiate such surgery.
 14 centers had performed more than 10 such transplantations, and these centers accounted for 80% of
these transplants.
 A total of 45% of those evaluated for living donation subsequently donated a liver lobe; 99% were
genetically or emotionally related to the recipient.
 Complications in the donor were more frequent in the centers that performed the fewest living- related
donor transplantations.
 There was 1 death among the donors, but complications were relatively common, ie, biliary
complications in 6% and reoperation in 4.5%.
In 2002, NIH sponsored a conference on living-donor liver transplantation.(73) This report offered the following
observations:
 The incidence and type of complications encountered and mortality associated with living-donor liver
transplant in both donors and recipients need to be determined and compared with those for patients
undergoing cadaveric transplantation.
 The question of whether all U.S. transplant programs should perform this operation or this complex
procedure should be limited to only a few select centers needs to be addressed.
Living Donor Versus Deceased Donor
In 2013, Grant et al. reported on a systematic review and meta-analysis of 16 studies to compare recipient
outcomes between living donor liver transplants and deceased donor liver transplants for HCC.(79) For diseasefree survival after living donor liver transplantation, the combined hazard ratio (HR) was 1.59 (95% confidence
interval [CI], 1.02 to 2.49) compared with deceased donor liver transplantation. For overall survival, the combined
HR was 0.97 (95% CI: 0.73 to 1.27). The studies included in the review were mostly retrospective and considered
to be of low quality. Further study is needed to determine any differences between living and deceased liver
transplantation outcomes.
HIV-Positive Patients
This subgroup of recipients has long been controversial, due to the long-term prognosis for HIV positivity, the
impact of immunosuppression on HIV disease, and the interactions of immunosuppressive therapy with
antiretroviral therapy in the setting of a transplanted liver. For example, most antiretroviral agents are metabolized
through the liver and can cause varying degrees of hepatotoxicity. HIV candidates for liver transplantation are
frequently coinfected with hepatitis B or C, and viral coinfection can further exacerbate drug-related
hepatotoxicities. Nevertheless, HIV positivity is not an absolute contraindication to liver transplant due to the
advent of highly active antiretroviral therapy (HAART), which has markedly changed the natural history of the
disease and the increasing experience with liver transplant in HIV-positive patients. Furthermore, the United
Network of Organ Sharing (UNOS) states that asymptomatic HIV-positive patients should not necessarily be
excluded for candidacy for organ transplantation, stating “A potential candidate for organ transplantation whose
test for HIV is positive but who is in an asymptomatic state should not necessarily be excluded from candidacy for
organ transplantation, but should be advised that he or she may be at increased risk of morbidity and mortality
because of immunosuppressive therapy.” In 2001, the Clinical Practice Committee of the American Society of
Transplantation proposed that the presence of AIDS could be considered a contraindication to kidney transplant
unless the following criteria were present.(80) These criteria may be extrapolated to other organs:
 CD4 count greater than 200 cells/mm3 for more than 6 months
 HIV-1 RNA undetectable
 On stable antiretroviral therapy more than 3 months
 No other complications from AIDS (e.g., opportunistic infection, including aspergillus, tuberculosis,
coccidioses mycosis, resistant fungal infections, Kaposi’s sarcoma, or other neoplasm).
 Meeting all other criteria for transplantation.
It is likely that each individual transplant center will have explicit patient selection criteria for HIV-positive patients.
In 2011, Cooper et al. conducted a systematic review to evaluate liver transplantation in patients coinfected with
HIV and hepatitis.(81) The review included 15 cohort studies and 49 case series with individual patient data. The
survival rate of patients was 84.4% (95% CI: 81.1% to 87.8%) at 12 months. Patients were 2.89 (95% CI: 1.41 to
5.91) times more likely to survive when HIV viral load at the time of transplantation was undetectable compared
with those with detectable HIV viremia.
Terrault et al reported on a prospective, multicenter study to compare liver transplantation outcomes in 3 groups:
patients with both HCV and HIV (n=89), patients with only HCV (n=235), and all transplant patients age 65 or
older.(82) Patient and graft survival reductions were significantly associated with only 1 factor: HIV infection. At 3
years, in the HCV only group, patient and graft survival rates were significantly better at 79% (95% CI: 72% to
84%) and 74% (95% CI: 66% to 79%), respectively, than the group with both HIV and HCV infection at 60% (95%
CI: 47% to 71%) and 53% (95% CI: 40% to 64%). While HIV infection reduced 3-year survival rates after liver
transplantation in patients also infected with HCV, there were still a majority of patients experiencing long-term
survival.
Hepatocellular Carcinoma (HCC)- Selection Criteria
Patient selection criteria for liver transplantation for HCC have focused mainly on the number and size of tumors.
In 1996 Mazzafaro et al. identified patient criteria associated with improved outcomes after liver transplantation for
HCC with cirrhosis.(83) This patient selection criteria became known as the Milan criteria and specifies patients
may have either a solitary tumor with a maximum tumor diameter of 5 cm or less, or up to 3 tumors 3 cm or less.
An editorial by Llovet(84) noted that the Milan criteria is considered the criterion standard for selecting transplant
candidates. Patients with extrahepatic spread or macrovascular invasion have a poor prognosis. UNOS adopted
the Milan criteria, combined with 1 additional criteria (no evidence of extrahepatic spread or macrovascular
invasion), as its liver transplantation criteria. Interest in expanding liver transplant selection criteria for HCC and
other indications is ongoing. A 2001 paper from the University of California, San Francisco (UCSF),(85) proposed
expanded criteria to include patients with a single tumor 6.5 cm or less in diameter, 3 or fewer tumors 4.5 cm or
less, and a total tumor size of 8 cm or less. It should be noted that either set of criteria can be applied
preoperatively (with imaging) or with pathology of the explanted liver at the time of intended transplant.
Preoperative staging often underestimates what is seen on surgical pathology. To apply pathologic criteria, a
backup candidate must be available in case preoperative staging is inaccurate. Given donor organ scarcity, any
expansion of liver transplant selection criteria has the potential to prolong waiting times for all candidates.
Important outcomes in assessing expanded criteria include waiting time duration, death, or deselection due to
disease progression while waiting (dropout), survival time, and time to recurrence (or related outcomes such as
disease-free survival). Survival time can be estimated beginning when the patient is placed on the waiting list,
using the intention-to-treat principal, or at the time of transplantation. Llovet stated that 1-year dropout rates for
patients meeting Milan criteria are 15% to 30%, and 5-year survival rates not reported by intention-to-treat should
be adjusted down by 10% to 15%.
A limited body of evidence is available for outcomes among patients exceeding Milan criteria but meeting UCSF
criteria. The largest series was conducted in 14 centers in France,(86) including an intention-to-treat total of 44
patients based on preoperative imaging at the time of listing and a subset of 39 patients meeting pathologic UCSF
criteria. The median waiting time was 4.5 months, shorter than the typical 6 to 12 months in North America.
Dropouts comprised 11.4% of total. Posttransplant overall patient 5-year survival at 63.6%, was more favorable
than the intention-to-treat probability (45.5%) but less favorable than among larger numbers of patients meeting
Milan criteria. Similar findings were seen for disease-free survival and cumulative incidence of recurrence. Three
centers in Massachusetts(87) included 10 patients beyond pathologic Milan criteria but within UCSF criteria. Twoyear survival posttransplant was 77.1%, with 2 patients dying and 8 alive after a median of 32 months. A group of
74 patients meeting preoperative Milan criteria had a 2-year survival probability of about 73%, but it is inadvisable
to compare different preoperative and pathologic staging criteria. From the series of patients who developed the
expanded UCSF criteria,(88) 14 satisfied those criteria on pathology but exceeded the Milan criteria. UCSF
investigators did not provide survival duration data for this subgroup, but noted that 2 patients died. A center in
Essen, Germany reported on 4 patients. Although the French series suggests that outcomes among patients
exceeding Milan criteria and meeting UCSF criteria are worse than for patients meeting Milan criteria, it is unclear
whether the latter group still achieves acceptable results. A benchmark of 50% 5-year survival has been
established in the liver transplant community,(85) and the French study meets this by posttransplant pathologic
staging results (63.6%) and falls short by preoperative intention-to-treat results (45.5%).
In their 2008 review, Schwartz et al. argue that selection based exclusively on the Milan criteria risks prognostic
inaccuracy due to the diagnostic limitations of imaging procedures and the surrogate nature of size and number of
tumors.(89) They predict that evolution of allocation policy will involve the following: 1. the development of a
reliable prognostic staging system to help with allocation of therapeutic alternatives; 2. new molecular markers
that might improve prognostic accuracy; 3. aggressive multimodality neoadjuvant therapy to downstage and limit
tumor progression before transplant and possibly provide information about tumor biology based on response to
therapy; and, 4. prioritization for transplantation should consider response to neoadjuvant therapy, time on waiting
list, suitability of alternative donor sources. Two papers describe work on identifying predictors of survival and
recurrence of disease. Ioannou and colleagues analyzed UNOS data pre- and post-adoption of the MELD
allocation system finding a 6-fold increase in recipients with hepatocellular carcinoma and that survival in the
MELD era was similar to survival to patients without HCC.(90) The subgroup of patients with larger (3-5 cm)
tumors, serum alpha-fetoprotein level >455 mg/mL, or a MELD score 20 or greater, however, had poor
transplantation survival. A predicting cancer recurrence scoring system was developed by Chan et al based on a
retrospective review and analysis of liver transplants at 2 centers to determine factors associated with recurrence
of HCC.(91) Of 116 patients with findings of hepatocellular carcinoma in their explanted livers, 12 developed
recurrent hepatocellular carcinoma. Four independent significant explant factors were identified by stepwise
logistic regression: size of 1 tumor greater than 4.5 cm, macroinvasion, and bilobar tumor were positive predictors
of recurrence, and the presence of only well-differentiated hepatocellular carcinoma was a negative predictor.
Points were assigned to each factor in relation to its odds ratio. The accuracy of the method was confirmed in 2
validation cohorts.
In 2010, Guiteau et al. reported on 445 patients transplanted for HCC in a multicenter, prospective study in UNOS
Region 4.(92) On preoperative imaging, 363 patients met Milan criteria, and 82 patients were under expanded
Milan criteria consisting of 1 lesion less than 6 cm, 3 or less lesions, none greater than 5 cm and total diameter
less than 9 cm. Patient allograft and recurrence-free survival at 3 years did not differ significantly between
patients meeting Milan criteria versus patients under the expanded criteria (72.9% and 77.1%, 71% and 70.2%
and 90.5% and 86.9%, all respectively). While preliminary results showed similar outcomes when using expanded
Milan criteria, the authors noted their results were influenced by waiting times in Region 4 and that similar
outcomes may be different in other regions with different waiting times. Additionally, the authors noted that a
report from a 2010 national HCC consensus conference on liver allocation in HCC patients does not recommend
expanding Milan criteria nationally and encourages regional agreement.(93) The report addressed the need to
better characterize the long-term outcomes of liver transplantation for patients with HCC and to assess whether it
is justified to continue the policy of assigning increased priority for candidates with early-stage HCC on the
transplant waiting list in the United States. Overall, the evidence base is insufficient to permit conclusions about
health outcomes after liver transplantation among patients exceeding Milan criteria and meeting expanded UCSF
or other criteria.
Liver Transplantation Versus Liver Resection for HCC
Liver transplantation is the criterion standard treatment for HCC meeting Milan criteria in decompensated livers
such as Child-Pugh class B or C (moderate to severe cirrhosis). Liver resection is generally used for early HCC in
livers classified as Child-Pugh class A.(94) Additionally; current UNOS criteria indicate a liver transplant candidate
must not be eligible for resection.(95) However, the best treatment approach for early HCC in well-compensated
livers is controversial. In 2013, Zheng et al. reported on a meta-analysis of 62 cohort studies (n=10,170 total
patients) comparing liver transplantation to liver resection for HCC.(96) Overall 1-year survival was similar
between procedures (OR=1.08; 95% CI, 0.81 to 1.43; p=0.61). However, overall 3- and 5-year survival
significantly favored liver transplantation over resection (OR=1.47; 95% CI: 1.18 to 1.84; p<0.001; OR=1.77; 95%
CI: 1.45 to 2.16; p<0.001, respectively). Disease-free survival in liver transplant patients was 13%, 29%, and 39%
higher than in liver resection patients at 1, 3, and 5 years, all respectively (p<0.001). Recurrence rates were also
30% lower in liver transplantation than resection (OR=0.20; 95% CI: 0.15 to 0.28; p<0.001). While liver
transplantation outcomes appear favorable compared with liver resection, a shortage of donor organs may
necessitate liver resection as an alternative to liver transplantation.(95)
In patients who have a recurrence of HCC after primary liver resection, salvage liver transplantation has been
considered a treatment alternative to repeat hepatic resection, chemotherapy, or other local therapies such as
radiofrequency ablation, transarterial chemoembolization, percutaneous ethanol ablation, or cryoablation.
Several systematic reviews have evaluated the evidence on outcomes of salvage transplant compared with
primary transplant. In a 2013 meta-analysis of 14 nonrandomized comparative studies by Zhu et al., (n=1272 for
primary transplant, n=236 for salvage),(97) overall survival at 1, 3, and 5 years and disease-free survival at 1 and
3 years was not significantly different between groups. Disease-free survival, however, was significantly lower at 5
years in salvage liver transplantation compared with primary transplantation (OR=0.62; 95% CI: 0.42 to 0.92;
p=0.02). There was insufficient data to evaluate outcomes in patients exceeding Milan criteria, but in patients
meeting Milan criteria, survival outcomes were not significantly different suggesting salvage liver transplantation
may be a viable option in these patients.
In a 2012 meta-analysis, Li et al. compared primary liver transplantation to salvage liver transplantation (liver
transplantation after liver resection) for HCC.(98) Included in the meta-analysis were 11 case-controlled or cohort
studies totaling 872 primary liver transplants and 141 salvage liver transplants.
Overall survival and disease-free survival rates between primary liver transplantation and salvage liver
transplantation were not statistically significant at 1, 3, and 5 years (p>0.05). Survival rates of patients who
exceeded the Milan criteria at 1, 3, and 5 years were also not significantly different between the 2 groups (1-year
OR=0.26; 95% CI: 0.01 to 4.94; p=0.37; 3-year OR=0.41; 95% CI: 0.01 to 24.54; p=0.67; 5-year OR=0.55; 95%
CI: 0.07 to 4.48; p=0.57).
In 2013, Chan et al. systematically reviewed 16 nonrandomized studies (n=319) on salvage liver transplantation
after primary hepatic resection for HCC.(99) The authors found that overall and disease-free survival outcomes
with salvage liver transplantation were similar to reported primary liver transplantation outcomes. The median
overall survival for salvage liver transplantation patients was 89%, 80% and 62% at 1, 3, and 5 years,
respectively. Disease-free survival was 86%, 68% and 67% at 1, 3, and 5 years, respectively. Salvage liver
transplantation studies had median overall survival rates of 62% (range, 41%-89%) compared with a range of
61% to 80% in the literature for primary liver transplantation. Median disease-free survival rates for salvage liver
transplantation were 67% (range, 29-100%) compared with a range of 58% to 89% for primary liver
transplantation. Given a limited donor pool and increased surgical difficulty with salvage liver transplantation,
further studies are needed. UNOS criteria indicate liver transplant candidates with HCC who subsequently
undergo tumor resection must be prospectively reviewed by a regional review board for the extension application.
Nonalcoholic Steatohepatitis
Liver transplantation is a treatment option for patients with nonalcoholic steatohepatitis (NASH) who progress to
liver cirrhosis and failure. In a 2013 systematic review and meta-analysis, Wang et al evaluated 9 studies
comparing liver transplantation outcomes in patients with and without NASH.(100) Patients with NASH had similar
1-, 3-, and 5-year survival outcomes after liver transplantation as patients without NASH. Patients with NASH also
had lower graft failure risk than those without NASH (OR=0.21; 95% CI: 0.05 to 0.89; p=0.03). However, NASH
liver transplant patients had a greater risk of death related to cardiovascular disease (OR=1.65; 95% CI: 1.01 to
2.70; p=0.05) and sepsis (OR=1.71; 95% CI: 1.17 to 2.50; p=0.006) than non-NASH liver transplant patients.
Cholangiocarcinoma
Reports on outcomes after liver transplantation for cholangiocarcinoma, or bile duct carcinoma generally
distinguish between intrahepatic and extrahepatic tumors, the latter including hilar or perihilar tumors. Recent
efforts have focused on pretransplant downstaging of disease with neoadjuvant radiochemotherapy.
In 2012, Gu et al. reported on a systematic review and meta-analysis of 14 clinical trials on liver transplantation
for cholangiocarcinoma.(101) Overall 1-, 3-, and 5-year pooled survival rates from 605 study patients were 0.73
(95% CI: 0.65 to 0.80), 0.42 (95% CI: 0.33 to 0.51), and 0.39 (95% CI: 0.28 to 0.51), respectively. When patients
received adjuvant therapies preoperatively, 1-, 3-, and 5-year pooled survival rates improved and were 0.83 (95%
CI: 0.57 to 0.98), 0.57 (95% CI: 0.18 to 0.92), and 0.65 (95% CI: 0.40 to 0.87), respectively.
In 2012, Darwish Murad et al. reported on 287 patients from 12 transplant centers treated with neoadjuvant
therapy for perihilar cholangiocarcinoma followed by liver transplantation.(102) Intention-to-treat survival (after a
loss of 71 patients before liver transplantation) was 68% at 2 years and 53% at 5 years, and recurrence-free
survival rates posttransplant were 78% at 2 years and 65% at 5 years. Survival time was significantly shorter for
patients who had a previous malignancy or did not meet UNOS criteria by having a tumor size greater than 3 cm,
metastatic disease, or transperitoneal tumor biopsy (p<0.001).
The European Liver Transplant Registry was cited by a review article.(103) Among 186 patients with intrahepatic
cholangiocarcinoma, 1-year survival was 58%, and 5-year survival was 29%. In 169 patients with extrahepatic
cholangiocarcinoma, the probabilities were 63% and 29%, respectively. The Cincinnati Transplant Registry(104)
reported on 207 patients with either intrahepatic or extrahepatic cholangiocarcinoma, finding a 1-year survival of
72% and a 5-year rate of 23%. The multicenter Spanish report(105) included 36 patients with hilar tumors and 23
with peripheral intrahepatic disease. One-year survival was 82% and 77%, while 5-year survival was 30% and
23% in the 2 groups, respectively.
Among the individual centers, the Mayo Clinic in Minnesota has the most experience and most favorable results
for patients with cholangiocarcinoma.(106,107) Between 1993 and 2006, 65 patients underwent liver
transplantation for unresectable perihilar cholangiocarcinoma or had perihilar tumor due to primary sclerosing
cholangitis. Unresectable patients underwent neoadjuvant radiochemotherapy. One-year survival was 91% and 5year survival was 76%. The University of California, Los Angeles (UCLA)/Cedars-Sinai,(108) reported on 25
cases of both intrahepatic and extrahepatic cholangiocarcinoma. One-year survival was 71% and 3-year survival
was 35%. The University of Pittsburgh found 1-year survival of 70% and 5-year survival of 18% among 20
patients with intrahepatic cholangiocarcinoma.(109) A German study of 24 patients reported the poorest
results.(110) In 2011, Friman et al reported on 53 patients who received liver transplants for cholangiocarcinoma
during the period of 1984-2005, in Norway, Sweden, and Finland.(111) The 5-year survival rate was 25% overall,
36% in patients with TNM stage 2 or less, and 10% in patients with TNM greater than 2. On further analysis using
only data from those patients transplanted after 1995, the 5-year survival rate increased to 38% versus 0% for
those transplanted before 1995. Additionally, the 5-year survival rate increased to 58% in those patients
transplanted after 1995 with TNM stage 2 or less and a CA 19-9 100 or less. The authors suggest transplantation
may have acceptable outcomes in select patients.
Some articles have reported recurrence data using survival analysis techniques. In a series of 38 patients from
the Mayo Clinic, cumulative recurrence was 0% at 1 year, 5% at 3 years, and 13% at 5 years.(107) The series of
20 patients from the University of Pittsburgh experienced 67% 1-year tumor-free survival and a 31% 5-year
rate.(108) The multicenter Spanish series reported crude recurrence rates of 53% and 36% for extrahepatic and
intrahepatic cholangiocarcinoma, respectively.(105) The German center at Hannover found a crude recurrence
rate of 63%.(110)
Mayo Clinic has reported promising results after liver transplantation for cholangiocarcinoma. Five-year patient
survival among 65 patients who received neoadjuvant radiochemotherapy was 76%. No other center or group of
centers reported 5-year survival above 30%. The Mayo Clinic found a 5-year cumulative recurrence rate of 13%
among 38 patients and additional recurrence data are quite limited. While a single center’s results are
encouraging, it is important to see if other centers can produce similar findings before forming conclusions about
outcomes after liver transplantation for cholangiocarcinoma.
In a 2008 review , Heimbach considers the published outcomes of the combined protocol in the context of recent
data on outcomes for surgical resection and concludes that outcomes of neoadjuvant chemoradiotherapy with
subsequent liver transplantation for patients with early-stage hilar cholangiocarcinoma, which is unresectable, or
arising in the setting of primary sclerosing cholangitis are comparable to transplantation for patients with
hepatocellular carcinoma and other chronic liver diseases and superior to resection.(112) The author describes
intraoperative challenges attributable to the neoadjuvant therapy including severe inflammatory changes and
dense fibrosis and suggests that key principles to be considered by centers considering use of the combined
protocol include a multidisciplinary approach, pretransplant staging, inclusion of only patients without lymph node
metastasis, replacement of irradiated vessels (when possible) and monitoring for postoperative vascular
complications. Wu et al describe an extensive surgical procedure combined with radiotherapy.(113) They
retrospectively review their experience with surveillance and early detection of cholangiocarcinoma (CC) and en
bloc total hepatectomy-pancreaticoduodenectomy-orthotopic liver transplantation (OLT-Whipple) in a small series
of patients with early stage CC complicating primary sclerosing cholangitis. Surveillance involved endoscopic
ultrasound and endoscopic retrograde cholangiopancreatography and cytological evaluation. Patients diagnosed
with CC were treated with combined extra-beam radiotherapy, lesion-focused brachytherapy, and OLT-Whipple.
CC was detected in 8 of the 42 patients followed up according the surveillance protocol between 1988 and 2001,
and 6 patients underwent OLT-Whipple. One died at 55 months after transplant of an unrelated cause without
tumor recurrence, and 5 are without recurrence at 5.7–10.1 years.
Hepatitis C
Mukherjee and Sorrell, reviewing controversies in liver transplantation for hepatitis C, indicate that the greatest
opportunity for hepatitis C virus (HCV) eradication is pretransplant before hepatic decompensation.(114)
Challenges of treatment post-transplantation include immunosuppressive drugs and abnormal hematologic,
infectious, and liver function parameters. The authors list the following factors associated with poor outcomes in
liver transplantation for recurrent HCV: high HCV-RNA level pretransplant, non-caucasian ethnicity, advanced
donor age, T-cell depleting therapies, inappropriate treatment of Banff A1 ACR with steroid boluses,
cytomegalovirus disease, and year of transplantation (worse with recent transplants). They cite the International
Liver Transplantation Society Consensus on Retransplantation, which states that the following are associated with
worse outcomes of retransplantation: total bilirubin level >10mg/dL, creatinine level >2 mg/dL, age >55 years,
development of cirrhosis in the first post-transplant year, and donor age >40 years.
As noted above, Terrault et al. reported on a prospective, multicenter study to compare liver transplantation
outcomes in 3 groups: patients with both HIV and HCV infection (n=89), patients with only HCV (n=235), and all
transplant patients age 65 and older.(82) HCV status was not significantly associated with reduced patient and
graft survival. In the HCV-only group, patient and graft survival rates were significantly better at 79% (95% CI:
72% to 84%) and 74% (95% CI: 66% to 79%), respectively, than the group with HIV and HCV at 60% (95% CI:
47% to 71%) and 53% (95% CI: 40% to 64%). While HIV infection reduced 3-year survival rates after liver
transplantation in patients also infected with HCV, there were still a majority of patients experiencing long-term
survival.
Metastatic Neuroendocrine Tumors
Neuroendocrine tumors (NETs) are relatively rare neoplasms that are generally slow-growing but rarely cured
when metastatic to the liver. Treatment options to control or downstage the disease include chemotherapy and
debulking procedures, including hepatic resection. In select patients with nonresectable, hormonally active liver
metastases refractory to medical therapy, liver transplantation has been considered as an option to extend
survival and minimize endocrine symptoms.
In 2014, Fan et al. reported on a systematic review of 46 studies on liver transplantation for NET liver metastases
of any origin.(115) A total of 706 patients were included in the studies reviewed. Reported overall 5-year survival
rates ranged from 0 to 100%, while 5-year disease-free survival rates ranged from 0 to 80%. In studies with more
than 100 patients, the 5-year overall survival rate and disease-free survival rate averaged about 50% and 30%,
respectively. Frequent and early NET recurrences after liver transplantation were reported in most studies.
In 2011 Mathe et al. conducted a systematic review of the literature to evaluate patient survival after liver
transplant for pancreatic NETs.(116) Data from 89 transplanted patients from 20 clinical studies were included in
the review. Sixty-nine patients had primary endocrine pancreatic tumors, 9 patients were carcinoids, and 11
patients were not further classified. Survival rates at 1, 3, and 5 years were 71%, 55%, and 44%, respectively.
The mean calculated survival rate was 54.45 (6.31) months, and the median calculated survival rate was 41
months (95% CI: 22 to 76 months). While there may be centers that perform liver transplantation on select
patients with NETs, further studies are needed to determine appropriate selection criteria. The quality of available
studies is currently limited by their retrospective nature and heterogeneous populations.
Pediatric Hepatoblastoma
Hepatoblastoma is a rare malignant primary solid tumor of the liver that occurs in children. Treatment consists of
chemotherapy and resection; however, often tumors are not discovered until they are unresectable. In cases of
unresectable tumors, liver transplantation with pre- and/or postchemotherapy is a treatment option with reports of
good outcomes and high rates of survival.(117) UNOS guidelines list nonmetastatic hepatoblastoma as a
condition eligible for pediatric liver transplantation.4 In 2011 Barrena et al reported on 15 children with
hepatoblastoma requiring liver transplantation.(118) Overall survival after liver transplant was 93.3% (6.4%) at 1,
5, and 10 years. In 2010, Malek et al. reported on liver transplantation results for 27 patients with primary liver
tumor identified from a retrospective review of patients treated between 1990 and 2007.(119) Tumor recurrence
occurred in 1 patient after liver transplantation, and overall survival was 93%. In 2008 Browne et al reported on 14
hepatoblastoma patients treated with liver transplantation. Mean follow-up was 46 months, with overall survival in
10 of 14 patients (71%). Tumor recurrence caused all 4 deaths. In the 10 patients receiving primary liver
transplantation, 9 survived while only 1 of 4 patients transplanted after primary resection survived (90% vs 25%,
p=0.02).(120) While studies on liver transplantation for pediatric hepatoblastoma are limited, case series have
demonstrated good outcomes and high rates of long-term survival. Additionally, nonmetastatic pediatric
hepatoblastoma is included in UNOS criteria for patients eligible for liver transplantation. Therefore, liver
transplantation for nonmetastatic pediatric hepatoblastoma may be considered medically necessary.
Liver Retransplantation
In 2012, Bellido et al. reported on a retrospective cohort study of 68 consecutive adult liver retransplantations
using registry data.(121) Survival probability using Kaplan-Meier curves with log-rank tests to compare 21 urgent
versus 47 elective retransplantations were calculated. Overall survival rates were significantly better in patients
undergoing urgent procedures (87%), which were mostly due to vascular complications than elective procedures
(76.5%), which were mostly related to chronic rejection.
In 2011, Remiszewski et al. examined factors influencing survival outcomes in 43 liver retransplantation
patients.(122) When compared with primary liver transplantation patients, retransplantation patients had
significantly lower 6-year survival rates (80% vs 58%, respectively; p<0.001). The authors also reported low
negative correlations between survival time and time from original transplantation until retransplantation and
between survival time and patient age. Survival time and cold ischemia time showed a low positive correlation.
Hong et al., in 2011, reported on a prospective study of 466 adults to identify risk factors for survival after liver
retransplantation.(123) Eight risk factors were identified as predictive of graft failure, including age of recipient,
MELD score greater than 27, more than 1 prior liver transplant, need for mechanical ventilation, serum albumin of
less than 2.5 g/dL, donor age older than 45 years, need for more than 30 units of packed red blood cells
transfused intraoperatively, and time between prior transplantation and retransplantation between 15 and 180
days. The authors propose this risk-stratification model can be highly predictive of long-term outcomes after adult
liver retransplantation and can be useful in patient selection.
Summary of Evidence for Liver Transplantation
Liver transplant is an accepted treatment of end-stage liver disease that provides a survival benefit in
appropriately selected patients and thus, may be considered medically necessary for the indications listed in the
Policy Statement and in those otherwise meeting United Network of Organ Sharing (UNOS) criteria. Liver
transplantation is investigational in patients in whom the procedure is expected to be futile due to comorbid
disease or in whom posttransplantation care is expected to significantly worsen comorbid conditions. Case series
and case-control data indicate that HIV infection is not an absolute contraindication to liver transplant; for patients
who meet selection criteria, these studies have demonstrated patient and graft survival rates are similar to those
in the general population of kidney transplant recipients.
Recent literature continues to address expanded criteria for transplantation for hepatocellular carcinoma (HCC),
predictors of recurrence, the role of neoadjuvant therapy in patients with HCC, expanded donor criteria,
transplantation and retransplantation for hepatitis C, and living donor transplantation. Further study is needed
before liver transplant selection criteria can be expanded for HCC. Additionally, further study is needed to address
salvage liver transplantation for HCC recurrence after primary liver resection.
Liver transplantation for hilar cholangiocarcinoma is performed at some transplant centers, and long-term survival
has been reported in select patients with unresectable disease. For metastatic NET, cure of disease is not
achieved, and 5-year survival is generally not high. However, there have been reports of survival benefit in
patients receiving liver transplantation for unresectable neuroendocrine tumor metastasis confined to the liver.
Based on survival data and clinical vetting input, transplantation in patients with hilar cholangiocarcinoma who
meet strict eligibility criteria may be considered medically necessary; transplantation for NET metastatic to the
liver is considered investigational.
The literature on liver transplantation for pediatric hepatoblastoma is limited, but case series have demonstrated
good outcomes and high rates of long-term survival. Additionally, nonmetastatic pediatric hepatoblastoma is
included in UNOS criteria for patients eligible for liver transplantation. Therefore, liver transplantation for
nonmetastatic pediatric hepatoblastoma may be considered medically necessary.
Case series have demonstrated favorable outcomes with liver retransplantation in certain populations, such as
when criteria for an original liver transplantation are met for retransplantation. While some evidence suggests
outcomes after retransplantation may be less favorable than for initial transplantation in some patients, long-term
survival benefits have been demonstrated. There was support from clinical vetting for retransplantation following
primary graft nonfunction, hepatic artery thrombosis, ischemic biliary injury after donation after cardiac death,
chronic rejection or certain recurrent nonneoplastic diseases resulting in end-stage liver failure in a primary
transplant. As a result, retransplantation after initial failed liver transplant may be considered medically necessary
in these situations.
Lung and Lobar Lung Transplant
End-stage lung disease may be the consequence of a number of different etiologies. The most common
indications for lung transplantation are chronic obstructive pulmonary disease (COPD), idiopathic pulmonary
fibrosis, cystic fibrosis, alpha1-antitrypsin deficiency, and idiopathic pulmonary arterial hypertension. Before the
consideration for transplant, patients should be receiving maximal medical therapy, including oxygen
supplementation, or surgical options, such as lung-volume reduction surgery for COPD. Lung or lobar lung
transplantation is an option for patients with end-stage lung disease despite these measures.
A lung transplant refers to single-lung or double-lung replacement. In a single-lung transplant, only 1 lung from a
deceased donor is provided to the recipient. In a double-lung transplant, both the recipient's lungs are removed
and replaced by the donor's lungs. In a lobar transplant, a lobe of the donor’s lung is excised, sized appropriately
for the recipient’s thoracic dimensions, and transplanted. Donors for lobar transplant have primarily been livingrelated donors, with 1 lobe obtained from each of 2 donors (e.g., mother and father) in cases when bilateral
transplantation is required.
Survival
The Registry of the International Society for Heart and Lung Transplantation (ISHLT) contains data from 42,069
adult recipients who had lung transplantation (including lung retransplantations) before 2012.(124) Reports from
132 transplant centers around the world were obtained on 3640 lung transplants performed. In 2011, the overall
median survival of patients who underwent lung transplantation between 1994 and June 2010 was 5.5 years. In
the first 30 days after transplantation, the major reported causes of mortality were graft failure and noncytomegalovirus (CMV) infections, while non-CMV infections became the major cause of death for the remainder
of the first year. Beyond the first year, the most common reported causes of mortality were bronchiolitis obliterans,
graft failure (lung rejection or bronchiolitis obliterans) and non-CMV infections. Over time, the proportion of
patients who died from malignancies increased; malignancies accounted for 15% of all deaths between 5 and 10
years after transplant. Authors of a 2009 review of the current status of lung transplantation observed that while
transplantation can prolong survival, survival statistics for lung transplantation are not as favorable as in patients
receiving other solid organ transplants (125)
In 2014, Kistler et al. reported on a systematic review of the literature on waitlist and posttransplant survival of
idiopathic pulmonary fibrosis.(126) Estimated median survival of idiopathic pulmonary fibrosis patients
posttransplantation is estimated at 4.5 years and is lower than other underlying pretransplant diagnoses. From
ISHLT and the Organ Procurement and Transplantation Network (OPTN) data, 1-year survival ranged from 75%
to 81%; 3-year, 59% to 64%, and 5-year, 47% to 53%. Limited data were available on posttransplant morbidity
outcomes.
In 2009, Thabut et al. reported on a comparison of patients undergoing single- and double-lung transplantation for
idiopathic pulmonary fibrosis.(127) A retrospective review was conducted of 3327 patients with data in the UNOS
registry. More patients underwent single-lung compared with double-lung transplant (64.5% vs. 35.5%,
respectively). Median survival time was greater for the double-lung group at 5.2 years (95% confidence interval
[CI], 4.3 to 6.7 years) versus 3.8 years (95% CI: 3.6 to 4.1 years; p<0.001). After adjustment for baseline
differences, however, survival times were not statistically different.
The authors concluded that overall survival (OS) did not differ between the 2 groups: single-lung transplants
offered improved short-term survival but long-term harm, whereas double-lung transplant increased short-term
harm but was associated with a long-term survival benefit. In 2014, Black et al. reported on LAS and single versus
double lung transplant in 8778 patients (8050 had an LAS less than 75 and 728 had an LAS 75 or higher). (128) A
significant decrease in survival was seen in single-lung transplant patients with a high LAS compared with doublelung transplant patients with a high LAS, even though operative morbidity was higher (p<0.001).
Patient Selection for Lung Transplantation
In 2008, Kozower et al. performed a retrospective cohort study using data from 5 academic medical centers to
evaluate the impact of a new lung allocation score on short-term outcomes after lung transplantation.(129) (This
lung allocation score was implemented in May 2005 by OPTN.) This new score changed lung allocation from a
system based on waiting time to an algorithm based on the probability of survival for 1 year on the transplant list
and survival 1-year posttransplantation. Results were compared for 170 patients who received transplants on the
basis of the new lung allocation scores (May 4, 2005-May 3, 2006) with those of 171 patients who underwent
transplants the preceding year before implementation of the scoring system. Waiting time decreased from 681 to
445.6 days (p<0.001). Recipient diagnoses changed, with an increase (15% to 25%) in idiopathic pulmonary
fibrosis cases and decreases in emphysema (46% to 34%) and cystic fibrosis (23% to 13%). Hospital mortality
and 1-year survival were the same between groups (5.3% vs. 5.3% and 90% vs. 89%, respectively). Presumably
due to increased severity of illness, the incidence of primary graft dysfunction and postoperative intensive care
unit length of stay increased in the year after implementation of the scoring system; graft dysfunction grew from
14.8% (24/170) to 22.9% (39/171); (p=0.04) and length of stay rose from 5.7 to 7.8 days.
In 2010, Yusen et al. reviewed the effect of the LAS on lung transplantation by comparing statistics for the period
before and after its implementation in 2005.(130) Other independent changes in clinical practice, which may affect
outcomes over the same period of time, include variation in immunosuppressive regimens, an increased supply of
donor lungs, changes in diagnostic mix, and increased consideration of older recipients. Deaths on the waiting list
declined following implementation of the LAS system, from approximately 500 per 5000 patients to 300 per 5000
patients. However, it is expected that implementation of LAS affected patient characteristics of transplant
applicants. One-year survival posttransplantation did not improve after implementation of the LAS system: patient
survival data before and after are approximately 83%. Long-term survival data are not yet available for
comparison.
In 2014, Shafii et al. reported on a retrospective evaluation of the LAS and mortality in 537 adults listed for lung
transplantation and 426 who underwent primary lung transplantation between 2005 and 2010.(131) Patients on
the waitlist who had a higher LAS had a higher rate of mortality (p<0.001). In the highest quartile of LAS, ranging
from 47 to 95, within 1 year of listing, there was a 75% mortality rate. Higher LAS was also associated with early
posttransplant survival (p=0.05) but not late posttransplant survival (p=0.4). When other predictive factors of early
mortality were accounted for, pretransplant LAS was not independently related to posttransplant mortality
(p=0.12).
Pediatric Considerations
In 2012, Benden et al. reviewed pediatric lung transplants that have been reported to the international
registry.(132) Pediatric patients are defined as those younger than 18 years of age. The authors noted an
increase in the number of pediatric lung transplants in recent years; there were 126 transplants in 2010 compared
with 73 in 2000. In contrast to adult patients, the most common indication for pediatric patients was cystic fibrosis,
accounting for 54% of lung transplants in 6- to 11-year-olds and 72% of lung transplants in 12- to 17-year-olds
that occurred between 1990 and June 2011. Survival has improved in the recent era, and 5-year survival is not
significantly different from adult recipients. The half-life, estimated time at which 50% of recipients have died, was
4.7 years for children and 5.3 years for adults. For children receiving allografts between 2002 and June 2010, the
5-year survival rate was 54% and 7-year survival was 44%. Patients aged 1 to 11 years had a significantly better
survival rate than those between the ages of 12 and 17 years (half-life of 6.2 years and 4.3 years, respectively). In
the first year after lung transplantation, non-CMV infection and graft failure were the 2 leading causes of death.
Bronchiolitis obliterans syndrome was the major cause of death beyond 3 years after transplantation
Potential Contraindications
Malignancy
Malignancies are common after lung transplantation with 21% and 40% of patients reporting 1 or more
malignancies at 5 and 10 years posttransplantation, respectively.4 Skin cancer occurred most frequently and
lymphoproliferative disorders were the malignancies most associated with morbidity posttransplantation.(124)
A 2012 study reported on outcomes in patients with lung cancer who were lung transplant recipients.(133) Ahmad
and colleagues identified 29 individuals in the UNOS database who underwent lung transplantation for advanced
bronchoalveolar carcinoma (BAC). These patients represented 0.13% of the 21,553 lung transplantations during
the study period. BAC and general lung transplant recipients had similar survival rates: the 30-day mortality rate
was 7% versus 10% (p=0.44) and 5-year survival rate was 50% versus 57% (p=0.66).
HIV
Solid organ transplant for patients who are HIV‒positive has been controversial, due to the long-term prognosis
for HIV positivity and the impact of immunosuppression on HIV disease. Although HIV-positive transplant
recipients may be of research interest at some transplant centers, the minimal data regarding long-term outcome
in these patients primarily consist of case reports and abstract presentations of liver and kidney recipients.
Nevertheless, some transplant surgeons would argue that HIV positivity is no longer an absolute contraindication
to transplant due to the advent of highly active antiretroviral therapy (HAART), which has markedly changed the
natural history of the disease.
As of October 2013, the OPTN policy on HIV status in recipients states: “A potential candidate for organ
transplantation whose test for HIV is positive should not be excluded from candidacy for organ transplantation
unless there is a documented contraindication to transplantation based on local policy.”(134)
In 2006, the British HIV Association and the British Transplantation Society Standards Committee published
guidelines for kidney transplantation in patients with HIV disease.15 These criteria may be extrapolated to other
organs.
Other Infections
Infection with Burkholderia cenocepacia is associated with increased mortality in some transplant centers, a factor
that may be taken into account when evaluating overall risk for transplant survival.(135) Two papers published in
2008 evaluated the impact of infection with various species of Burkholderia on outcomes for lung transplantation
for cystic fibrosis. In a study published by Murray et al., multivariate Cox survival models assessing hazard ratios
(HRs) were applied to 1,026 lung transplant candidates and 528 transplant recipients.(136) Of the transplant
recipients, 88 were infected with Burkholderia. Among transplant recipients infected with B cenocepacia, only
those infected with nonepidemic strains (n=11) had significantly greater posttransplant mortality than uninfected
patients (HR=2.52; 95% CI, 1.04 to 6.12; p=0.04). Transplant recipients infected with Burkholderia gladioli (n=14)
also had significantly greater posttransplant mortality than uninfected patients (HR=2.23; 95% CI: 1.05 to 4.74;
p=0.04). When adjustments for specific species/strains were included, lung allocation scores of Burkholderia
multivoransinfected transplant candidates were comparable with uninfected candidate scores, and scores for
patients infected with nonepidemic B cenocepacia or B gladioli were lower. In a smaller study of 22 patients
colonized with Burkholderia cepacia complex who underwent lung transplantation in 2 French centers, the risk of
death by univariate analysis was significantly higher for the 8 patients infected with B cenocepacia than for the
other 14 colonized patients (11 of whom had B multivorans).(137)
In 2012, Shields et al. reported on infections in 596 consecutive lung transplant recipients treated at a single
center occurring in the first 90 days after transplantation.(138) A total of 109 patients (18%) developed 138
Staphylococcus aureus infections. The most common type of infection was pneumonia (66 of 138, 48%) followed
by tracheobronchitis (36/138 [26%]) and bacteremia (17/138 [12%]). Thirteen of 109 (12%) patients with S aureus
infection died within 90 days of the onset of infection. The 1-year mortality rate was higher for patients with S
aureus pneumonia (19/ 66 [29%]) but not S aureus tracheobronchitis (8/36 [22%]) compared with uninfected
patients (85/487 [17%]).
Pinney et al. published a retrospective review of invasive fungal infection rates in lung transplantation patients
without cystic fibrosis treated at a single center.(139) Patients were followed for a median of 34 months. Invasive
fungal infections were identified in 22 of 242 (9.1%) patients. Aspergillus infections were most common, occurring
in 11 of 242 (4.5%) of patients. There were also 7 cases (3%) of Candida infection. Survival rates did not differ
significantly in patients with invasive fungal infections compared with the entire cohort of patients. For example, 3year survival was 50% among patients with invasive fungal infection and 66% in the entire cohort (p=0.66). The
authors did not compare survival in patients with invasive fungal infections with survival only in those without
invasive fungal infections.
In 2013, Lobo et al. reported on 13 lung transplant patients with Mycobacterium abscessus in cystic fibrosis.(140)
Survival rates were 77%, 64%, and 50% after transplant at 1, 3, and 5 years, respectively. These results were not
significantly different when compared with 154 cystic fibrosis patients treated with lung transplantation who did not
have M abscessus (p=0.8).
Coronary Artery Disease
Castleberry et al. reported on a retrospective cohort study of lung transplantation with concurrent coronary bypass
(CAB) or preoperative percutaneous coronary intervention (PCI).(141) Of 898 lung transplants performed during
the period between 1997 and 2010, 49 patients also had concurrent CAB and 38 patients had preoperative PCI.
All of the intervention groups, including revascularization, had similar rates of perioperative mortality, overall
unadjusted survival, and adjusted hazard ratio for cumulative risk of death. Postoperative major adverse cardiac
event rates were also similar among groups, although postoperative length of stay, intensive care unit time and
need for ventilator support increased in patients receiving concurrent CAB with lung transplantation.
In 2011, Sherman et al. reported on outcomes in 27 patients with coronary artery disease (CAD) at a single center
who underwent lung transplantation and coronary revascularization.(142) Patients needed to be otherwise
considered good candidates for transplantation and have discrete coronary lesions (at least 50% in the left main
artery or at least 70% in other major vessels) and preserved ejection fraction. Thirteen patients had single-lung
transplantation and 14 had double-lung transplantation. Outcomes were compared with a control group of 81
patients without CAD who underwent lung transplantation; patients were matched for age, diagnosis, lung
allocation score and type of procedure. During a mean follow-up of 3 years, 9 of 27 (33%) patients with CAD and
28 of 81 (35%) without CAD died (p=0.91). Bronchiolitis obliterans and infection were the primary causes of
death. There was no significant difference between groups in a composite outcome of adverse cardiac events
(defined as acute coronary syndrome, redo revascularization, or hospital admissions for heart failure) (p=0.80).
Lobar Lung Transplantation
Several case series have reported outcomes after lobar lung transplants in both children and adults. In 2005, Barr
et al reported on experience performing living donor lobar lung transplants in the United States.(143) Ninety
patients were adults and 43 were children. The primary indication for transplantation (86%) was cystic fibrosis. At
the time of transplantation, 67% of patients were hospitalized and 20% were ventilator dependent. Overall
recipient actuarial survival at 1, 3, and 5 years was 70%, 54%, and 45%, respectively. There was not a
statistically significant difference in actuarial survival between adults and children who underwent transplantation.
Moreover, survival rates were similar to the general population of lung transplant recipients. The authors also
reported that rates of postoperative pulmonary function in patients surviving more than 3 months posttransplant
were comparable with rates in cadaveric lung transplant recipients.
In 2014 Date et al. reported on a retrospective study comparing 42 living-donor lobar lung transplants and 37
cadaveric lung transplants.(144) Survival rates at 1 and 3 years were not significantly different between the
groups (89.7 and 86.1% vs. 88.3 and 83.1%, respectively, p=0.55), despite living-donor lobar lung transplant
patients having poorer health status preoperatively. In 2012, a program in Japan reported on 14 critically ill
patients who had undergone single living-donor lobar lung transplants; there were 10 children and 4 adults.(145)
Patients were followed for a mean 45 months. The 3-year survival rate was 70% and the 5-year survival was
56%. Severe graft dysfunction occurred in 4 patients. Mean forced vital capacity (FVC) was found to be lower in
patients experiencing severe graft dysfunction compared with the other patients, mean FVC was 54.5% and
66.5%, respectively. The authors stated that this suggests size mismatching in the patients with severe graft
dysfunction. Also in 2012, Inci et al. published data on 23 patients in Switzerland who received bilateral lobar lung
transplants.(146) The mean age was 41 years (range, 13-66). Survival at 1 and 2 years was 82% and 64%,
respectively; survival rates were comparable with 219 patients who underwent bilateral lung transplantation during
the same time period (p=0.56).
A review article by Date stated that, as of 2011, approximately 400 living-donor lobar lung transplants have been
performed worldwide.(147) Procedures in the United States decreased after 2005 due to changes in the lung
allocation system. The author stated that size matching between donor and recipient is important and that, to
some extent, size mismatching (oversized or undersized grafts) can be overcome by adjusting surgical technique.
In 2014 Slama et al. reported on a comparison of outcomes in 138 cadaveric lobar lung transplants (for size
discrepancies) to 778 patients who received cadaveric whole-lung transplants, 239 of whom had downsizing by
wedge resection of the right middle lobe and/or the left lingula.(148) Survival in the lobar lung transplant group at
1 and 5 years was 65.1% and 54.9% versus 84.8% and 65.1% in the whole lung and downsized by wedge
resection group (p<0.001). The lobar lung transplantation group experienced significantly inferior early
postoperative outcomes, but in patients who were successfully discharged, survival rates were similar to standard
lung transplantation (p=0.168).
Lung Retransplantation
Registry data and case series reports have demonstrated favorable outcomes with lung retransplantation in
certain populations, such as in patients who meet criteria for initial lung transplantation.(124,149,150) The ISHLT
Registry contains data on 970 retransplantation patients for the period of January 1995 to June 2012 (2.6% of all
lung transplantations during this period). Lung retransplantation occurred most commonly for bronchiolitis
obliterans syndrome in 568 patients, while 402 patients received retransplantation for other reasons.4 In an
analysis of lung transplantation during the period of January 1999 to June 2011, retransplantation was associated
with an increased risk of death within 1 year after lung transplantation (HR=1.69; 95% CI, 1.38 to 2.07;
p<0.001).(124) However, for patients surviving at least 1 year, the risk of death was no longer associated with
retransplantation.
In 2013, Kilic et al. evaluated data on 390 adult lung retransplantation patients from the UNOS database.(149)
Patients received lung retransplantation during the period May 2005 to December 2010, which was after the LAS
selection criteria were implemented. Patients with reduced functional status were found to have poorer outcomes
than patients with better functional status before retransplantation. Using the Karnofsky scale to stratify patients
into functional status groups, the authors found the overall 1-year survival of 56% for patients requiring total
assistance before retransplantation was significantly lower than the overall 1-year survival of 82% for patients who
only required some assistance before retransplantation (p<0.001). The 1-year mortality rate after risk adjustment
was also increased significantly for patients requiring total assistance before retransplantation (odds ratio, 3.72;
p=0.02). While additional patient selection criteria may be useful for lung retransplantation, current LAS criteria
are now used.
Summary of Evidence for Lung and Lobar Lung Transplantation
The literature on lung and lobar lung transplantation, which consists of case series and registry data,
demonstrates that lung and lobar lung transplantation provides a survival benefit in appropriately selected patients
and thus may be considered medically necessary. It may be the only option for some patients with end-stage lung
disease.
The literature on lung retransplantation is limited but is accumulating in registry data. As in lung transplantation,
lung retransplantation may be the only option for patients with failed lung transplantation.
Pancreas Transplant
The information about pancreas transplants is taken in part from a 1998 TEC Assessment, which focused on
pancreas graft survival and health outcomes associated with both pancreas transplant alone (PTA) and pancreas
after kidney transplant (PAK).(151) A 2001 TEC Assessment focused on the issue of pancreas retransplant.(152)
The assessments and subsequent evidence offer the observations and conclusions that follow.
Pancreas Transplant after Kidney Transplant (PAK)
PAK transplantation allows the uremic patient the benefits of a living-related kidney graft, if available and the
benefits of a subsequent pancreas transplant that is likely to result in improved quality of life compared with a
kidney transplant alone. Uremic patients for whom a cadaveric kidney graft is available, but a pancreas graft is not
simultaneously available benefit similarly from a later pancreas transplant. Based on International Pancreas
Registry data reported in 2011, the patient survival rate after PAK was 83% at 5 years posttransplant.(153)
In 2009, Fridell et al. reported a retrospective review (n=203) of a single center’s experience with PAK and SPK
since 2003, when current induction/tacrolimus immunosuppressive strategies became standard. (154) Of the
cases studied, 61 (30%) were PAK and 142 (70%) were SPK. One-year patient survival rates were 98% and 95%
(PAK and SPK, respectively; p=0.44). Pancreas graft survival rates at 1 year were observed to be 95% and 90%,
respectively (p=0.28). The authors concluded that in the modern immunosuppressive era, PAK should be
considered as an acceptable alternative to SPK in candidates with an available living kidney donor.
In 2012, Bazarbachi et al. reviewed a single center’s experience with PAK and SPK.(155) Between 2002 and
2010, 172 pancreas transplants were performed in diabetic patients; 123 SPK and 49 PAK. The median length of
time between kidney and pancreas transplantation in the PAK group was 4.8 years. Graft and patient survival
rates were similar in the 2 groups. Death-censored pancreas graft survival rates for SPK and PAK were 94% and
90% at 1 year, 92% and 90% at 3 years, and 85% and 85% at 5 years (all, p=0.93). Patient survival rates
(calculated beginning at the time of pancreas transplantation) in the SPK versus PAK groups were 98.3% and
100% after 1 year, 96.4% and 100% after 3 years, and 94.2% and 100% after 5 years (all, p=0.09).
Kleinclauss et al. retrospectively examined data from diabetic kidney transplant recipients (N=307) from a single
center and compared renal graft survival rates in those who subsequently received a pancreatic transplant with
those who did not.(156) The comparative group was analyzed separately depending on whether they were
medically eligible for pancreas transplant, but chose not to proceed for financial or personal reasons, or were
ineligible for medical reasons. The ineligible (n=57) group differed significantly at baseline from both the PAK
group (n=175) and the eligible group (n=75) with respect to age, type of diabetes, and dialysis experience; kidney
graft survival rates were lower than either of the other groups, with 1-, 5-, and 10-year rates of 75%, 54%, and
22%, respectively (p<0.001). The authors compared 1-, 5-, and 10-year kidney graft survival rates in PAK patients
with those in the eligible group: 98%, 82%, and 67% versus 100%, 84%, and 62%, respectively, and concluded
that the subsequent transplant of a pancreas after a living donor kidney transplant does not adversely affect
patient or kidney graft survival rates.
Simultaneous Pancreas/Kidney (SPK) Transplant
According to International Registry data through 2005, recent 5-year graft survival rates for SPK transplants were
72% for the pancreas and 80% for the kidney.(9) Ten-year graft survival rates reached almost 60% for SPK
transplants. The U.S.-based Organ Procurement and Transplant Network (OPTN) reported a 5-year survival rate
of 85.5% (95% confidence interval [CI]: 84.3% to 86.7%) for SPK procedures performed between 1997 and
2000.(157)
Pancreas transplant has been found to improve mortality in patients with type 1 diabetes. In 2014, van Dellen et
al. in the U.K. reported a retrospective analysis of data on 148 SPK patients and a wait-list control group of 120
patients.(158) All patients had uncomplicated type 1 (insulin dependent) diabetes. (The study also included 33
patients who had PAK and 11 PTA patients.) Overall mortality (mortality at any time point) was 30% (30/120
patients) on the waiting list and 9% (20/193 patients) in transplanted patients; the difference between groups was
statistically significant (Fisher’s exact test; p<0.001). One year mortality was 13% (n=16) on the waiting list and
4% (n=8) in the transplant group (Fisher’s exact test; p<0.001).
There are some data on outcomes in patients with type 2 compared with type 1 diabetes. In 2011, Sampaio and
colleagues published an analysis of data from the United Network for Organ Sharing (UNOS) database.(159) The
investigators compared outcomes in 6,141 patients with type 1 diabetes and 582 patients with type 2 diabetes
who underwent SPK between 2000 and 2007. In adjusted analyses, outcomes were similar in the 2 groups. After
adjusting for other factors such as body weight; dialysis time; and cardiovascular comorbidities, type 2 diabetes
was not associated with an increased risk of pancreas or kidney graft survival, or mortality compared to type 1
diabetes.
Pancreas Transplant Alone
PTA graft survival has improved in recent years. According to International Registry data 1-year graft function
increased from 51.5% in 1987-1993 to 77.8% in 2006-2010 (p<0.001).(160) One-year immunologic graft loss
remained higher (6%) after PTA than PAK (3.7%) or SPK (1.8%). In carefully selected patients with insulin
dependent diabetes mellitus (IDDM) and severely disabling and potentially life-threatening complications due to
hypoglycemia unawareness and persistent labile diabetes despite optimal medical management, benefits of PTA
were judged to outweigh the risk of performing pancreas transplantation with subsequent immunosuppression.
Most patients undergoing PTA are those with either hypoglycemic unawareness or labile diabetes. However,
other exceptional circumstances may exist where nonuremic IDDM patients have significant morbidity risks due to
secondary complications of diabetes (e.g., peripheral neuropathy) that exceed those of the transplant surgery and
subsequent chronic immunosuppression. Because virtually no published evidence regarding outcomes of medical
management in this very small group of exceptional diabetic patients exists, it is not possible to generalize about
which circumstances represent appropriate indications for pancreas transplantation alone. Case-by-case
consideration of each patient’s clinical situation may be the best option for determining the balance of risks and
benefits.
Noting that nephrotoxic immunosuppression may exacerbate diabetic renal injury after PTA, Scalea et al. (2008)
reported a single institutional review of 123 patients who received 131 PTA for development of renal failure.(161)
Mean graft survival was 3.3 years (range, 0-11.3), and 21 patients were lost to follow-up. At mean follow-up of 3.7
years, mean estimated glomerular filtration rate was 88.9 mL/min/1.73 m2 pretransplantation versus 55.6
mL/min/1.73 m2 posttransplantation. All but 16 patients had a decrease in estimated glomerular filtration rate.
Thirteen developed end-stage renal disease, which required kidney transplantation at a mean of 4.4 years. The
authors suggested that patients should be made aware of the risk and only the most appropriate patients offered
PTA. Future updates of this policy will continue to follow this clinical topic.
Pancreas Retransplantation
The OPTN reported data on transplants performed between 1997 and 2004.(157) Patient survival rates after
repeat transplants were similar to survival rates after primary transplants. For example, 1-year survival was 94%
(95% CI: 93% to 95%) after a primary pancreas transplant and 96% (95% CI: 93% to 99%) after a repeat
pancreas transplant. The numbers of patients transplanted were not reported, but OPTN data stated that 1217
patients were alive 1 year after primary transplant and 256 after repeat transplants. Three-year patient survival
was 90% (95% CI: 88% to 91%) after primary transplants and 90% (95% CI:86% to 94%) after repeat transplants.
One-year graft survival was 78% (95% CI: 76% to 81%) after primary pancreas transplant and 70% (95% CI: 65%
to 76%) after repeat transplant.
Data are similar for patients receiving combined kidney/pancreas transplants, but follow-up data are only available
on a small number of patients who had repeat kidney/pancreas transplants so estimates of survival rates in this
group are imprecise. Three-year patient survival as 90% (95% CI: 89% to 91%) after primary combined transplant
and 80% (95% CI: 64% to 96%) after a repeat combined transplant. The number of patients who were living 3
years after transplant was 2907 after a primary combined procedure and 26 after a repeat combined procedure.
Several centers have published outcomes after pancreas retransplantation. In 2014, Seal et al. reported on 96
consecutive PTA patients treated at a single center in Canada; 78 were initial transplants, and 18 were
retransplants.(162) Pancreas graft survival was similar for primary transplants and retransplants at 1 year (88% vs
100%, p=0.88) and 3 years (85% in both groups, p=0.99). Patient survival rates were also similar in the 2 groups
at 1 year (96% and 100%, p=0.95) and 3 years (93% and 100%, p=0.93). In 2013, Buron et al. reported on their
experience with pancreas retransplantation in France and Geneva.(163) Between 1976 and 2008, 568 pancreas
transplants were performed at 2 centers, including 37 repeat transplants. Patient survival after a repeat pancreas
transplant was 100% after 1 year and 89% after 5 years. Graft survival was 64% at 1 year and 46% at 5 years.
Among the 17 patients who underwent a second transplant in a later time period i.e., between 1995 and 2007,
graft survival was 71% at 1 year and 59% at 5 years. In this more recently transplanted group, graft survival rates
were similar to primary pancreas transplants, which was 79% at 1 year and 69% at 5 years.
Pancreas Transplant in HIV-Positive Transplant Recipients
Current OPTN policy on Identification of Transmissible Diseases states that OPTN permits HIV test positive
individuals as organ candidates if permitted by the transplant hospital.”(164)
In 2006, the British HIV Association and the British Transplantation Society Standards Committee published
guidelines for kidney transplantation in patients with HIV disease.(165) As described earlier, these criteria may be
extrapolated to other organs.
Age as a Potential Contraindication to Pancreas Transplant
Recipient age over 50 years has in the past been considered a relative contraindication for pancreas transplant.
In the past 5 to 10 years, several analyses of outcomes by patient age group have been published and there is
now general agreement among experts that age should not be a contraindication; however, age-related
comorbidities are important to consider when selecting patients for transplantation.
In the largest study of pancreas outcomes by recipient age, Siskind et al. (2014) used data from the UNOS
database. (166) Investigators included all adult patients who received SPK or PTA between 1996 and 2012
(n=20,854). There were 3160 patients between the ages of 50 and 59 years, and 280 patients age 60 or older.
Overall, Kaplan-Meier survival analysis found statistically significant differences in patient survival (p<0.001) and
graft survival (p<0.001) among age categories. Graft survival was lowest in the 18-to-29 age group at 1, 5, and 10
years, which the authors noted might be due to early immunological graft rejection due to more robust immune
responses. However, 10 and 15 year graft survival was lowest in the 60 and older age group. Patient survival
rates decreased with increasing age, and the differential between survival in older and younger ages increased
with longer follow-up intervals. Lower survival rates in patients 50 and older could be due in part to comorbidities
at the time of transplantation. Also, as patient age, they are more likely to die from other causes. Still, patient
survival at 5 and 10 years was relatively high.(166)
Among previous studies on pancreas outcomes in older patients, Shah et al. (2013) reviewed data on 405
patients who underwent PTA between 2003 and 2011.(167) One-year patient survival was 100% for patients
younger than age 30, 98% for patients age 30 to 39 years, 94% for patients 40 to 49 years, 95% for patients 50 to
59 years, and 93% for patients age 60 or older. There was not a statistically significant difference in patient
survival by age (p=0.38). Findings were similar for 1-year graft survival; there was not a statistically significant
difference in outcomes by age of transplant recipients (p=0.10).
A 2011 study by Afaneh et al. reviewed data on 17 individuals at least 50 years-old and 119 individuals younger
than 50 years who had a pancreas transplant at a single institution in the United States.(168) The 2 groups had
similar rates of surgical complications, acute rejection, and nonsurgical infections. Overall patient survival was
similar. Three- and 5-year survival rates were 93% and 90%, respectively, in the younger group, and 92% and
82%, respectively, in the older group. Schenker et al. (2011) in Germany compared outcomes in 69 individuals at
least 50 years-old and 329 individuals younger than 50 years who had received pancreas transplants. (169) Mean
duration of follow-up was 7.7 years. One-, 5-, and 10-year patient and graft survival rates were similar in the 2
groups. For example, 5-year patient survival was 89% in both groups. Five-year pancreas graft survival was 76%
in the older group and 72% in the younger group. The authors of both studies, as well as the authors of a
commentary accompanying the Schenker article,(170) agreed that individuals age 50 years and older are suitable
candidates for pancreas transplantation.
Summary of Evidence for Pancreas Transplant
The literature, consisting primarily of case series and registry data, demonstrate graft survival rates comparable
with other solid organ transplants, as well as attendant risks associated with the immunosuppressive therapy
necessary to prevent allograft rejection. No randomized controlled trials have compared any form of pancreas
transplant with insulin therapy. Pancreas transplant may be considered medically necessary in patients who are
undergoing, or have undergone, kidney transplantation for renal failure. It may also be considered medically
necessary as a stand-alone treatment in patients with hypoglycemia unawareness and labile diabetes, despite
optimal medical therapy and in whom severe complications have developed.
Ongoing and Unpublished Clinical Trials for Various Solid Organ Transplants
Clinical Trials for Liver Transplant




NCT00301379 Washington State University is conducting a prospective registry study of neoadjuvant
chemoradiation in conjunction with liver transplantation for cholangiocarcinoma. There is an estimated
enrollment of 20 and an estimated completion date of November 2015.
NCT01549795 A study on liver transplantation for hilar cholangiocarcinoma began in March 2012 in Italy.
This study will enroll 33 patients, is still recruiting and had a primary completion date of July 2013. Status
of this study is unknown, last verified in July 2012.
NCT01201096 Liver transplantation for metastatic NET is being evaluated in a German study. In this
observational study, patients will receive neoadjuvant peptide receptor-mediated radiotherapy with 177
lutetium about 9 months prior to liver transplantation. This study is expected to enroll 50 patients and is
scheduled for completion in September 2018. This study was last verified in September 2010.
NCT01387503 A study on liver transplantation after downstaging HCC exceeding the Milan Criteria is
ongoing in Italy. This study is evaluating 260 patients and is expected to be completed in January 2014.
The status of this study is unknown, last verified in June 2011.
Clinical Trials for Pancreas Transplant

NCT01067950 The Pancreas Allotransplantation for Diabetic Nephropathy and Mild Chronic Renal
Failure Stage (PANCREAS) Study is currently recruiting participants at Nantes University in France. The
stated objective of the open-label RCT study is to assess the superiority of isolated pancreas transplant
to intensive insulin therapy in Type 1 diabetes patients with overt proteinuric nephropathy and mildly
reduced renal function. The primary combined endpoint is to be patient mortality and renal function
impairment at five years. If completed, this would represent the first RCT comparing pancreas transplant
to insulin therapy. The study was scheduled to start in 2010; no updates are available as of December
2014.
Practice Guidelines and Position Statements
Heart Transplant
American College of Cardiology (ACC)/American Heart Association (AHA)
Guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) on the
diagnosis and management of chronic heart failure, updated in 2005 and then in 2009, provide statements about
the accepted indications, probable indications, and contraindications for heart transplantation:(6)
Adult Patients
Accepted Indications for Transplantation
 Hemodynamic compromise due to heart failure demonstrated by any of the following 3 bulleted items,
o
Maximal VO2 (oxygen consumption) <10 mL/kg/min with achievement of anaerobic metabolism
o
Refractory cardiogenic shock
o
Documented dependence on intravenous inotropic support to maintain adequate organ
perfusion, or
 Severe ischemia consistently limiting routine activity not amenable to bypass surgery or angioplasty, or
 Recurrent symptomatic ventricular arrhythmias refractory to ALL accepted therapeutic modalities.
Probable Indications for Cardiac Transplantation
 Maximal VO2 <14 mL/kg/min and major limitation of the patient’s activities, or
 Recurrent unstable ischemia not amenable to bypass surgery or angioplasty, or
 Instability of fluid balance/renal function not due to patient noncompliance with regimen of
 weight monitoring, flexible use of diuretic drugs, and salt restriction
The following conditions are inadequate indications for transplantation unless other factors as listed above are
present.
 Ejection fraction <20%
 History of functional class III or IV symptoms of heart failure
 Previous ventricular arrhythmias
 Maximal VO2 >15 mL/kg/min
Pediatric Patients
Patients with heart failure with persistent symptoms at rest who require one or more of the following:
 Continuous infusion of intravenous inotropic agents, or
 Mechanical ventilatory support, or
 Mechanical circulatory support.
Patients with pediatric heart disease with symptoms of heart failure who do not meet the above criteria but who
have:
 Severe limitation of exercise and activity (if measurable, such patients would have a peak maximum
oxygen consumption <50% predicted for age and sex); or
 Cardiomyopathies or previously repaired or palliated congenital heart disease and significant growth
failure attributable to the heart disease; or
 Near sudden death and/or life-threatening arrhythmias untreatable with medications or an implantable
defibrillator; or
 Restrictive cardiomyopathy with reactive pulmonary hypertension; or
 Reactive pulmonary hypertension and potential risk of developing fixed, irreversible elevation of
pulmonary vascular resistance that could preclude orthotopic heart transplantation in the future; or
 Anatomical and physiological conditions likely to worsen the natural history of congenital heart disease in
infants with a functional single ventricle; or
 Anatomical and physiological conditions that may lead to consideration for heart transplantation without
systemic ventricular dysfunction.
International Society for Heart and Lung Transplantation (ISHLT)- Pediatric
In a 2004 statement, International Society for Heart and Lung Transplantation (ISHLT) recommended that
children with the following conditions should be evaluated for heart transplantation(171):
 Diastolic dysfunction that is refractory to optimal medical/surgical management because they are at high
risk of developing pulmonary hypertension and of sudden death (based on level of evidence B [a single
randomized trial or multiple nonrandomized trials]).
Advanced systemic right ventricular failure (Heart Failure Stage C described as patients with underlying structural
or functional heart disease and past or current symptoms of heart failure) that is refractory to medical therapy
(level of evidence C [primarily expert consensus opinion]).
In 2014, the ISHLT issued updated guidelines on the management of pediatric heart failure.(196) These
guidelines do not provide updated guidance about transplantation listing because the IHSLT was in the process of
updating its overall guidance about heart transplantation listing criteria.
International Society for Heart and Lung Transplantation (ISHLT) – Potential
Contraindications
ISHLT’s 2006 Guidelines for the Care of Cardiac Transplant Candidates included the following statements on
potential contraindications to heart transplantation(172):
 “Patients should be considered for cardiac transplantation if they are ≤70 years of age.” “Carefully
selected patients >70 years of age may be considered for cardiac transplantation.”
 For patients with preexisting neoplasms, “cardiac transplantation should be considered when tumor
recurrence is low based on tumor type, response to therapy and negative metastatic work-up.”
 For obese patients, “it is reasonable to recommend weight loss to achieve a BMI of <30 kg/m2 or percent
BMI of <140% of target before listing for cardiac transplantation.”
 “Diabetes with end-organ damage other than nonproliferative retinopathy or poor glycemic control
(glycosylated hemoglobin [HbA1C] >7.5) despite optimal effort is a relative contraindication for
transplant.”
 “It is reasonable to consider the presence of irreversible renal dysfunction (eGFR <40 mL/min) as a
relative contraindication for heart transplantation alone.”
 “Peripheral vascular disease may be considered as a relative contraindication for transplantation when
its presence limits rehabilitation and re-vascularization is not a viable option.”
 “It is reasonable to consider active tobacco smoking as a relative contraindication to transplantation.
Active tobacco smoking during the previous 6 months is a risk factor for poor outcomes after
transplantation.”
 “A structured rehabilitative program may be considered for patients with a recent (24 months) history of
alcohol abuse if transplantation is being considered.... Patients who remain active substance abusers
(including alcohol) should not receive heart transplantation.”
 “Mental retardation or dementia may be regarded as a relative contraindication to transplantation.” (Level
of Evidence: C).
 “Patients who have demonstrated an inability to comply with drug therapy on multiple occasions should
not receive transplantation.”
The AHA Council on Cardiovascular Disease in the Young
The AHA Council on Cardiovascular Disease in the Young; the Councils on Clinical Cardiology, Cardiovascular
Nursing, and Cardiovascular Surgery and Anesthesia; and the Quality of Care and Outcomes Research
Interdisciplinary Working Group stated in 2007 that, based on level B (nonrandomized studies) or level C
(consensus opinion of experts), heart transplantation is indicated for pediatric patients as therapy for the following
indications(173):
 Stage D heart failure (interpreted as abnormal cardiac structure and/or function, continuous infusion of
intravenous inotropes, or prostaglandin E1 to maintain patency of a ductus arteriosus, mechanical
ventilatory and/or mechanical circulatory support) associated with systemic ventricular dysfunction in
patients with cardiomyopathies or previous repaired or palliated congenital heart disease,
 Stage C heart failure (interpreted as abnormal cardiac structure and/or function and past or present
symptoms of heart failure) associated with pediatric heart disease and severe limitation of exercise and
activity, in patients with cardiomyopathies or previously repaired or palliated congenital heart disease
and heart failure associated with significant growth failure attributed to heart disease, pediatric heart
disease with associated near sudden death and/or life-threatening arrhythmias untreatable with
medications or an implantable defibrillator, or in pediatric restrictive cardiomyopathy disease associated
with reactive pulmonary hypertension;
 The guideline states that heart transplantation is feasible in the presence of other indications for heart
transplantation, in patients with pediatric heart disease and an elevated pulmonary vascular resistance
index >6 Woods units/m2 and/or a transpulmonary pressure gradient >15 mm Hg if administration of
inotropic support or pulmonary vasodilators can decrease pulmonary vascular resistance to <6 Woods
units/m2 or the transpulmonary gradient to <15 mm Hg.
International Society for Heart and Lung Transplantation (ISHLT) - Cardiac
Retransplantation
The 2010 guidelines from the ISHLT include the following recommendations on cardiac retransplantation(174):
 “Retransplantation is indicated in children with at least moderate systolic heart allograft dysfunction
and/or severe diastolic dysfunction and at least moderate CAV (cardiac allograft vasculopathy).”
 “It is reasonable to consider listing for retransplantation those adult HT [heart transplant] recipients who
develop severe CAV not amenable to medical or surgical therapy and symptoms of heart failure or
ischemia.”
 “It is reasonable to consider listing for retransplantation those HT recipients with heart allograft
dysfunction and symptomatic heart failure occurring in the absence of acute rejection.”
 “It is reasonable to consider retransplantation in children with normal heart allograft function and severe
CAV.”
Heart/Lung Transplant
International Society for Heart and Lung Transplantation (IHSLT)
The Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation issued
consensus-based guidelines on the selection of lung transplant recipients in 1998, 2006, and most recently
updated in 2014.(198)
For combined heart-lung transplant, the guidelines state:
 “Most commonly, patients with irreversible myocardial dysfunction or congenital defects with irreparable
defects of the valves or chambers in conjunction with intrinsic lung disease or severe PAH [pulmonary
arterial hypertension] are considered for heart-lung transplantation.
 “PAH and elevated PVR [pulmonary vascular resistance], defined as a PVR > 5 Woods units, a PVR
index > 6, or a transpulmonary pressure gradient 16 to 20 mm Hg, should be considered as relative
contraindications to isolated cardiac transplantation. If the pulmonary artery systolic pressure is >60 mm
Hg in conjunction with any of these 3 variables, the risk of right heart failure and early death is increased.
 “If the PVR can be reduced to <2.5 with a vasodilator but the systolic blood pressure falls to <85 mm Hg,
the patient remains at high risk of right heart failure and mortality after isolated cardiac transplantation.
Mechanical circulatory support may be considered to improve these indices and still enable cardiac
transplantation and obviate the need for heart-lung transplantation.
 “In most patients with pulmonary hypertension associated with right ventricular failure, isolated bilateral
lung transplantation is associated with comparable or better results than heart-lung transplantation.”
Kidney Transplant
European Renal Best Practice
In 2016, the European Renal Best Practice advisory group published guidance on managing older patients (age
>65 years) with chronic kidney disease stage 3b or higher (estimated glomerular filtration rate [eGFR] <45
mL/min/1.73 m2).(175) One of the clinical questions in the guidance involved the criteria and appropriateness of
transplantation in older patients with end stage renal failure. Because older patients are often excluded from trials,
evidence is limited and the panel issued a separate narrative on the topic.(176) The position statement asserted
that patients should not be deemed ineligible for renal transplantation based on age alone, and that for select
elderly patients, transplantation is superior to dialysis in increasing survival. Before elderly patients should be
considered for transplantation, psychological testing and assessments of comorbidities (in particular, cardiac
evaluation and malignancy testing) should be performed.
British Transplantation Society
In 2014, the British Transplantation Society published a guideline on the management of the failed kidney
transplant.(177) Among other recommendations, the guideline stated that appropriate patients with failing kidney
transplants can undergo retransplantation when the graft eGFR falls to 10 to 15 mL/min. In addition, the guideline
included a suggestion that joint transplant or advanced kidney care be initiated at least 6 to 12 months before the
expected need for dialysis or retransplantation, or when the eGFR is less than 20 mL/min. The authors noted that
these recommendations were based on low-quality evidence.
American Society of Transplant Surgeons et al
In 2011, the American Society of Transplant Surgeons, American Society of Transplantation, Association of
Organ Procurement Organizations, and the United Network for Organ Sharing issued a position statement
recommending the modification of the National Organ Transplant Act of 1984. Their recommendation was that the
potential pool of organs from HIV-infected donors be explored. With modern antiretroviral therapy, the use of
these previously banned organs would open an additional pool of donors to HIV-infected recipients. The
increased pool of donors has the potential to shorten waiting times for organs and decrease the number of waiting
list deaths. The organs from HIV infected deceased donors would be used for transplant only with patients
already infected with HIV. In 2013 the HIV Organ Policy Equity (HOPE) Act was passed allowing the use of this
group of organ donors.(179)
British HIV Association and the British Transplantation Society
In 2006, the British HIV Association and the British Transplantation Society Standards Committee published
guidelines for kidney transplantation in patients with HIV disease.(180) The guidelines recommend that any
patient with end stage renal disease with a life expectancy of at least 5 years is considered appropriate for
transplantation under the following conditions:
 CD4 >200 cells/mL for at least 6 months
 Undetectable HIV viremia (<50 HIV-1 RNA copies/mL) for at least 6 months
 Demonstrable adherence and a stable HAART [highly active antiretroviral therapy] regimen for at
 least 6 months
 Absence of AIDS-defining illness following successful immune reconstitution after HAART.
The document lists general and disease-specific exclusion criteria and immunosuppressant protocols. These
recommendations are based on level III evidence (observational studies and case reports).
Liver Transplant
Multiple Professional Society Position Statement
In December 2010, 10 international liver diseases or transplantation societies held an international consensus
conference on liver transplantation for HCC.(181) Consensus criteria for selecting candidates for liver
transplantation were developed at the conference. Milan criteria was recommended for use as the benchmark for
patient selection, although it is noted the Milan criteria may be modestly expanded based on data from expansion
studies that demonstrate outcomes that are comparable to outcomes from studies using the Milan criteria.
Candidates for liver transplantation should also have a predicted survival of 5 years or more. The consensus
criteria indicate alpha-fetoprotein concentrations may be used with imaging to assist in determining patient
prognosis.
In regard to liver retransplantation, the consensus criteria issued a weak recommendation indicating
retransplantation after graft failure of a living donor transplant for HCC is acceptable in patients meeting regional
criteria for a deceased donor liver transplant. A strong recommendation was issued indicating liver
retransplantation with a deceased donor for graft failure for patients exceeding regional criteria is not
recommended. And the consensus criteria issued a strong recommendation that liver retransplantation for
recurrent HCC is not appropriate. However, a de novo HCC may be treated as a new tumor and retransplantation
may be considered even though data to support this are limited.
American Association for the Study of Liver Diseases (AASLD)
In 2005, the American Association for the Study of Liver Diseases (AASLD) issued guidelines on evaluating
patients for liver transplant.(182) These guidelines state liver transplantation is indicated for acute or chronic liver
failure from any cause after all effective medical treatments have been attempted. Furthermore, AASLD
guidelines indicate patients should be assessed by a transplantation center to determine whether liver
transplantation is appropriate. While AASLD guidelines indicate liver transplant may be appropriate in patients
with cholangiocarcinoma and metastatic neuroendocrine tumors, these recommendations and many of the
recommendations in AASLD guidelines are based on opinion.
The European Neuroendocrine Society (ENETS)
The European Neuroendocrine Society (ENETS) issued consensus guidelines in 2008 and updated in 2012 for
the management of patients with liver metastases from neuroendocrine tumors.(183) ENETS guidelines indicate,
in a “minimal consensus” statement, that liver transplantation may be considered for diffuse unresectable
neuroendocrine tumor metastases or when hormonal disturbances that are refractory to medical therapy are lifethreatening.
National Comprehensive Cancer Network (NCCN)
The National Comprehensive Cancer Network (NCCN) guidelines on hepatobiliary cancers V1.2015 recommends
referral to a liver transplant center or bridge therapy for patients with HCC meeting UNOS criteria of a single
tumor 5 cm or less, or 2 to 3 tumors 3 cm or less with no macrovascular involvement or extrahepatic disease.(94)
Patients should be referred to the transplant center before biopsy. In patients meeting UNOS criteria who are
ineligible for transplant and in select patients with Child-Pugh class A or B liver function with tumors that are
resectable, NCCN indicates resection is the preferred treatment option or locoregional therapy may be
considered. Patients with unresectable HCC should be evaluated for liver transplantation and if the patient is a
transplant candidate, then referral to a transplant center should be given or bridge therapy should be considered.
The NCCN guidelines on hepatobiliary cancers also indicate liver transplant is appropriate in select patients with
extrahepatic cholangiocarcinoma, which is unresectable, but biliary and hepatic function is otherwise normal or
when underlying chronic liver disease precludes surgery. These are level 2A recommendations based on lowerlevel evidence and uniform consensus.
The NCCN guidelines on neuroendocrine tumors V1.2015 indicate liver transplantation for neuroendocrine tumor
liver metastases is considered investigational.(184)
Council of the British Transplant Society
Liver transplantation guidelines for nonalcoholic steatohepatitis (NASH) were developed by the Council of the
British Transplant Society and approved by the British Society of Gastroenterology, the British Association for the
Study of Liver and NHS Blood and Transplant in 2012. These guidelines indicate liver transplantation may be
considered for the treatment of NASH cirrhosis with end-stage liver disease or HCC. (185) These guidelines are
based primarily on consensus of expert opinion.
American Association for the Study of Liver Diseases (AASLD) and the American
Society of Transplantation
AASLD and the AST issued a 2013 guideline for the long-term medical management of the pediatric patient after
liver transplant.(186) The guideline makes the following statement regarding liver transplant in children:
Pediatric liver transplant has dramatically changed the prognosis for many infants and children with liver
failure and metabolic disease. As survival increases, long-term maintenance resources exceed
perioperative care requirements. The most common indication for liver transplant in children is biliary
atresia which accounts for 50% of all children requiring transplant in the U.S. and 74% in Europe.
Lung and Lobar Lung Transplant
International Society for Heart and Lung Transplantation (IHSLT)
In 2006 the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation
published guidelines for the selection of lung transplant candidates. (178) See complete statement under
Heart/Lung subheading above.
Pancreas Transplant
In 2014, the Board of Directors of the Organ Procurement and Transplantation Network issued an updated
comprehensive list of transplant related policies.(187)
Each candidate registered on the pancreas waiting list must meet one of the following requirements:



Be diagnosed with diabetes
Have pancreatic exocrine insufficiency
Require the procurement or transplantation of a pancreas as part of a multiple organ transplant for
technical reasons
The policy also delineated pancreas, kidney-pancreas, and islet allocation, classifications, and rankings.
U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force has not addressed solid organ transplantation.
Medicare National Coverage
Heart Transplant
Cardiac transplantation is covered under Medicare when performed in a facility that is approved by Medicare as
meeting institutional coverage criteria, approximately 108 programs across the nation.(188)
The Centers for Medicare and Medicaid Services has stated that under certain limited cases, exceptions to the
heart transplant criteria may be warranted if there is justification and if the facility ensures safety and efficacy
objectives.
Heart/Lung Transplant
Heart/lung transplantation is covered under Medicare when performed in a facility that is approved by Medicare
as meeting institutional coverage criteria.(189) The Centers for Medicare and Medicaid Services has stated that
under certain limited cases, exceptions to the criteria may be warranted if there is justification and if the facility
ensures safety and efficacy objectives.
Kidney Transplant
The Medicare Benefit Policy Manual includes a chapter on end stage renal disease.(190) In a section on
identifying candidates for transplantation (140.1), it states, “After a patient is diagnosed as having ESRD, the
physician should determine if the patient is suitable for transplantation. If the patient is a suitable transplant
candidate, a live donor transplant is considered first because of the high success rate in comparison to a
cadaveric transplant. Whether one or multiple potential donors are available, the following sections provide a
general description of the usual course of events in preparation for a live-donor transplant.”
Liver Transplant
Medicare covers adult liver transplantation for end-stage liver disease and HCC when performed in a facility that
is approved by the Centers for Medicare and Medicaid Services (CMS) as meeting institutional coverage criteria
for liver transplants.(191) The following conditions must be met for coverage of HCC:
 The patient is not a candidate for subtotal liver resection;
 The patient's tumor(s) is less than or equal to 5 cm in diameter;
 There is no macrovascular involvement; and
 There is no identifiable extrahepatic spread of tumor to surrounding lymph nodes, lungs, abdominal
organs or bone.
Beginning June 21, 2012, on review of this national coverage decision for new evidence, Medicare began offering
coverage for adult liver transplantation, at Medicare administrative contractor discretion, for extrahepatic
unresectable cholangiocarcinoma, liver metastases due to a neuroendocrine tumor and hemangioendothelioma.
Adult liver transplantation is excluded for other malignancies.
Pediatric liver transplantation is covered for children (younger than age 18 years) when performed in a CMSapproved pediatric hospital for extrahepatic biliary atresia or any other form of end-stage liver disease, except that
coverage is not provided for children with a malignancy extending beyond the margins of the liver or those with
persistent viremia.
Lung and Lobar Lung Transplant
Lung transplantation is covered under Medicare when performed in a facility that is approved by Medicare as
meeting institutional coverage criteria.(192) The Centers for Medicare and Medicaid Services have stated that
under certain limited cases, exceptions to the facility-related criteria may be warranted if there is justification and
the facility ensures safety and efficacy objectives.
Pancreas Transplant
Allogeneic pancreas transplant is covered under Medicare when performed in a facility that is approved by
Medicare as meeting institutional coverage criteria.(193) The Centers for Medicare and Medicaid Services has
made the following national coverage decision regarding pancreas transplant for Medicare recipients.
A. General – Pancreas transplantation is performed to induce an insulin-independent, euglycemic state in
diabetic patients. The procedure is generally limited to those patients with severe secondary
complications of diabetes, including kidney failure. However, pancreas transplantation is sometimes
performed on patients with labile diabetes and hypoglycemic unawareness.
B. Nationally Covered Indications – Effective for services performed on or after July 1, 1999, whole organ
pancreas transplantation is nationally covered by Medicare when performed simultaneous with or after a
kidney transplant. If the pancreas transplant occurs after the kidney transplant, immunosuppressive
therapy begins with the date of discharge from the inpatient stay for the pancreas transplant.
Effective for services performed on or after April 26, 2006, pancreas transplants alone (PA) are
reasonable and necessary for Medicare beneficiaries in the following limited circumstances:(194)
1. PA will be limited to those facilities that are Medicare-approved for kidney transplantation.
 Patients must have a diagnosis of type I diabetes
 Patient with diabetes must be beta cell autoantibody positive; or
2. Patient must demonstrate insulinopenia defined as a fasting C-peptide level that is less than or
equal to 110% of the lower limit of normal of the laboratory's measurement method. Fasting
Cpeptide levels will only be considered valid with a concurrently obtained fasting glucose ≤225
mg/dL;
3. Patients must have a history of medically-uncontrollable labile (brittle) insulin-dependent
diabetes mellitus with documented recurrent, severe, acutely life-threatening metabolic
complications that require hospitalization. Aforementioned complications include frequent
hypoglycemia unawareness or recurring severe ketoacidosis, or recurring severe hypoglycemic
attacks;
4. Patients must have been optimally and intensively managed by an endocrinologist for at least 12
months with the most medically-recognized advanced insulin formulations and delivery systems;
5. Patients must have the emotional and mental capacity to understand the significant risks
associated with surgery and to effectively manage the lifelong need for immunosuppression;
and,
6. Patients must otherwise be a suitable candidate for transplantation.
C. Nationally Noncovered Indications – The following procedure is not considered reasonable and
necessary within the meaning of section 1862(a)(1)(A) of the Social Security Act:
Transplantation of partial pancreatic tissue or islet cells (except in the context of a clinical trial
[see section 260.3.1 of the National Coverage Determinations Manual]).
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Hepatology. Jun 2005;41(6):1407-1432. PMID 15880505
183.Steinmuller T, Kianmanesh R, Falconi M, et al. Consensus guidelines for the management of patients
with liver metastases from digestive (neuro)endocrine tumors: foregut, midgut, hindgut, and unknown
primary. Neuroendocrinology. 2008;87(1):47-62. PMID 18097131
184.National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Neuroendocrine
Tumors. V1.2015. http://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Accessed
February 2017.
185.Newsome PN, Allison ME, Andrews PA, et al. Guidelines for liver transplantation for patients with nonalcoholic steatohepatitis. Gut. Apr 2012;61(4):484-500. PMID 22234978
186.American Association for the Study of Liver Diseases and the American Society of Transplantation.
Guideline for the long-term medical management of the pediatric patient after liver transplant. 2013;
https://www.aasld.org/publications/practice-guidelines-0 Accessed February 2017.
187.Organ Procurement and Transplantation Network (OPTN). Policies and Bylaws: Deceased Donor Organ
Procurement. https://optn.transplant.hrsa.gov/governance/policies/ Accessed February 2017.
188.Centers for Medicare and Medicaid Services (CMS). National Coverage Determination (NCD) for HEART
TRANSPLANTs (260.9). https://www.cms.gov/Regulations-andGuidance/Guidance/Manuals/downloads/ncd103c1_Part4.pdf. Accessed February 2017.
189.Center for Medicare and Medicaid Services (CMS). Decision Memo for TRANSPLANT Centers: ReEvaluation of Criteria for Medicare Approval (CAG-00061N) http://www.cms.gov/medicare-coveragedatabase/details/nca-decision-memo.aspx?NCAId=75&NcaName=Transplant+Centers*3a%24+ReEvaluation+of+Criteria+for+Medicare+Approval&CoverageSelection=National&KeyWord=transplant&Key
WordLookUp=Title&KeyWordSearchType=And&bc=gAAAABAAEAAA&. Accessed February 2017.
190.Medicare Benefit Policy Manual. Chapter 11- End Stage Renal Disease (ESRD). Available online at:
http://www.cms.gov/manuals/Downloads/bp102c11.pdf. Accessed February 2017.
191.Centers for Medicare and Medicaid Services. National Coverage Determination (NCD) Pub. 100.3 Liver
Transplantation. NCD Section 260.1 (adult) and 260.2 (pediatric).
192.Medicare approved lung transplant centers. http://www.cms.gov/Medicare/Provider-Enrollment-andCertification/CertificationandComplianc/downloads/ApprovedTransplantPrograms.pdf. Accessed February
2017.
193.Centers for Medicare and Medicaid Services (CMS). Medicare approved pancreas and kidney/pancreas
transplant centers.
http://www.cms.gov/CertificationandComplianc/Downloads/ApprovedTransplantPrograms.pdf. Accessed
February 2017.
194.Centers for Medicare and Medicaid Services (CMS). National Coverage Determination (NCD) for
pancreas Transplants (260.3). Effective 4/26/2006. https://www.cms.gov/medicare-coveragedatabase/details/ncd-details.aspx?NCDId=107&ncdver=3&DocID=260.3&bc=IAAAABAAAAAA&.
Accessed February 2017.
195.Blue Cross and Blue Shield Association. Medical Policy Reference Manual, Kidney Transplant policy No.
7.03.01, 2014; Pancreas Transplant policy No. 7.03.02, 2015; Liver Transplant policy No. 7.03.06, 2015;
Lung and Lobar Lung Transplant policy No. 7.03.07, 2015; Heart/Lung Transplant policy No. 7.03.08,
2014; Heart Transplant policy No. 7.03.09, 2014.
196.Kirk R, Dipchand AI, Rosenthal DN, et al. The International Society of Heart and Lung Transplantation
197.Guidelines for the management of pediatric heart failure: Executive summary. J Heart Lung Transplant.
Sep 2014;33(9):888-909. PMID 25110323Benden C, Goldfarb SB, Edwards LB, et al. The registry of the
International Society for Heart and Lung Transplantation: seventeenth official pediatric lung and heartlung transplantation report--2014; focus theme: retransplantation. J Heart Lung Transplant. Oct
2014;33(10):1025-1033.
198. Weill D, Benden C, Corris PA, et al. A consensus document for the selection of lung transplant
candidates: 2014--an update from the Pulmonary Transplantation Council of the International Society for
Heart and Lung Transplantation. J Heart Lung Transplant. Jan 2015;34(1):1-15.
Appendix
[TOP]
N/A
History
[TOP]
Date
07/01/02
05/13/03
01/01/04
05/11/04
09/01/04
05/10/05
02/06/06
05/09/06
05/26/06
02/26/07
05/08/07
05/21/07
05/13/08
03/10/09
02/09/10
01/11/11
01/06/12
12/03/12
01/29/13
02/12/13
05/30/13
02/10/14
03/11/14
03/31/15
Reason
Add to Surgery Section - New Policy. Replaces other transplant policies (PR.7.03.100, 102, 103,
104, 105, and 106)
Replace Policy - Scheduled review. References added and CPT code table updated.
Replace Policy - CPT code updates only.
Replace Policy - Policy reviewed by Nancy Aceto no changes needed at this time; new review date
only. Appendices removed—no value.
Replace Policy - Policy renumbered from PR.7.03.109. No changes to dates.
Replace Policy - Scheduled review. References added. No change to policy statement.
Codes updated - No other changes.
Replace Policy - Scheduled review. References added; no change to policy statement.
Scope and Disclaimer Updates - No other changes.
Codes Updated - No other changes.
Replace Policy - Policy updated with literature review; reference added. No change in policy
statement.
References Updated - Policy updated with information on Medicare coverage of heart transplants.
Replace Policy - Policy updated with literature search. Policy statement to include using a cadaver
or living donor under kidney transplants as a medically necessary indication. Also to include
“imminent end-stage liver failure” for patients under liver transplants as medically necessary.
Replace Policy - Policy updated with literature search; references added. No change to policy
statement.
Replace Policy - Policy updated with literature search. No change to policy statement.
Replace Policy - Policy updated with literature search. No change to policy statement.
Replace Policy – Policy updated with literature search; references added. No change to policy
statement.
Update title to Related Policy 7.03.11.
Replace policy. Policy updated with literature search. No change to policy statement. References
updated.
Update Related Policies, change title for 8.02.02.
Update Related Policies. Change title for 7.03.510.
Replace policy. Retransplant policy statements added to kidney, heart, heart/lung. Literature
updated. References 35-39 added. ICD-9 Diagnosis codes were listed for informational purposes
only and have been removed from the policy.
Coding Update. Codes 33.50, 33.51, 33.52, 33.6, 37.5, 50.4, 50.51, 50.59, 52.80, 52.81, 52.82,
52.83, and 55.69 were removed per ICD-10 mapping project; these codes are not utilized for
adjudication of policy.
Annual Review. Alphabetized names of organ transplants in policy statements. Related policy
08/19/15
09/24/15
01/12/16
01/29/16
10/11/16
12/09/16
02/14/17
04/14/17
04/18/17
7.03.05 added. Rationale section extensively reorganized by alphabetizing organ transplants and
updated based on a literature review through December, 2014. References extensively
renumbered and some references removed. Policy statements unchanged.
Update Related Policies. Remove 7.03.510 and 8.02.02 then add 8.03.05 and 7.03.04.
Coding update. ICD-9 Procedure codes removed; these are informational only.
Annual Review. Policy updated with literature search; references added. No change to the policy
statement.
Coding update. Added HCPCS code S2152.
Update related policies. Removed 7.03.05 from related policies section as it was deleted (contents
moved to 7.03.04).
Coding Update. Transplant benefit-related codes removed. Coding table moved to Policy
Guidelines section. Updated titles of some Related Policies.
Annual review. Policy updated with literature review through October 25, 2016; references
renumbered. Policy statements unchanged.
Coding update; added HCPCS code S2060.
Coding update; added HCPCS code S2065.
Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts
policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical
technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in
their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific
medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
©2017 Premera All Rights Reserved.
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ជាមានព័ត៌មានយា៉ងសំខាន់អំពីទរមង់ែបបបទ ឬការរា៉ប់រងរបស់អនកតាមរយៈ
Premera Blue Cross ។ របែហលជាមាន កាលបរ ិេចឆ ទសំខាន់េនៅកនុងេសចកត ីជូន
ដំណឹងេនះ។ អន ករបែហលជារតូវការបេញច ញសមតថ ភាព ដល់កំណត់ៃថង ជាក់ចបាស់
នានា េដើមបីនឹងរកសាទុកការធានារា៉ប់រងសុខភាពរបស់អនក ឬរបាក់ជំនួយេចញៃថល ។
អន កមានសិទធិទទួ លព័ត៌មានេនះ និងជំនួយេនៅកនុងភាសារបស់អនកេដាយមិនអស
លុយេឡើយ។ សូ មទូ រស័ពទ 800-722-1471 (TTY: 800-842-5357)។
ਪੰ ਜਾਬੀ (Punjabi):
ਇਸ ਨੋਿਟਸ ਿਵਚ ਖਾਸ ਜਾਣਕਾਰੀ ਹੈ. ਇਸ ਨੋਿਟਸ ਿਵਚ Premera Blue Cross ਵਲ ਤੁਹਾਡੀ
ਕਵਰੇਜ ਅਤੇ ਅਰਜੀ ਬਾਰੇ ਮਹੱ ਤਵਪੂਰਨ ਜਾਣਕਾਰੀ ਹੋ ਸਕਦੀ ਹੈ . ਇਸ ਨੋਿਜਸ ਜਵਚ ਖਾਸ ਤਾਰੀਖਾ
ਹੋ ਸਕਦੀਆਂ ਹਨ. ਜੇਕਰ ਤੁਸੀ ਜਸਹਤ ਕਵਰੇਜ ਿਰੱ ਖਣੀ ਹੋਵੇ ਜਾ ਓਸ ਦੀ ਲਾਗਤ ਜਿਵੱ ਚ ਮਦਦ ਦੇ
ਇਛੁੱ ਕ ਹੋ ਤਾਂ ਤੁਹਾਨੂੰ ਅੰ ਤਮ ਤਾਰੀਖ਼ ਤ ਪਿਹਲਾਂ ਕੁੱ ਝ ਖਾਸ ਕਦਮ ਚੁੱ ਕਣ ਦੀ ਲੋ ੜ ਹੋ ਸਕਦੀ ਹੈ ,ਤੁਹਾਨੂੰ
ਮੁਫ਼ਤ ਿਵੱ ਚ ਤੇ ਆਪਣੀ ਭਾਸ਼ਾ ਿਵੱ ਚ ਜਾਣਕਾਰੀ ਅਤੇ ਮਦਦ ਪ੍ਰਾਪਤ ਕਰਨ ਦਾ ਅਿਧਕਾਰ ਹੈ ,ਕਾਲ
800-722-1471 (TTY: 800-842-5357).
‫( فارسی‬Farsi):
‫اين اعالميه ممکن است حاوی اطالعات مھم درباره فرم‬. ‫اين اعالميه حاوی اطالعات مھم ميباشد‬
‫ به تاريخ ھای مھم در‬.‫ باشد‬Premera Blue Cross ‫تقاضا و يا پوشش بيمه ای شما از طريق‬
‫شما ممکن است برای حقظ پوشش بيمه تان يا کمک در پرداخت ھزينه‬. ‫اين اعالميه توجه نماييد‬
‫شما حق‬. ‫ به تاريخ ھای مشخصی برای انجام کارھای خاصی احتياج داشته باشيد‬،‫ھای درمانی تان‬
‫ برای کسب‬.‫اين را داريد که اين اطالعات و کمک را به زبان خود به طور رايگان دريافت نماييد‬
‫( تماس‬800-842-5357 ‫ تماس باشماره‬TTY ‫ )کاربران‬800-722-1471 ‫اطالعات با شماره‬
.‫برقرار نماييد‬
Polskie (Polish):
To ogłoszenie może zawierać ważne informacje. To ogłoszenie może
zawierać ważne informacje odnośnie Państwa wniosku lub zakresu
świadczeń poprzez Premera Blue Cross. Prosimy zwrócic uwagę na
kluczowe daty, które mogą być zawarte w tym ogłoszeniu aby nie
przekroczyć terminów w przypadku utrzymania polisy ubezpieczeniowej lub
pomocy związanej z kosztami. Macie Państwo prawo do bezpłatnej
informacji we własnym języku. Zadzwońcie pod 800-722-1471
(TTY: 800-842-5357).
Português (Portuguese):
Este aviso contém informações importantes. Este aviso poderá conter
informações importantes a respeito de sua aplicação ou cobertura por meio
do Premera Blue Cross. Poderão existir datas importantes neste aviso.
Talvez seja necessário que você tome providências dentro de
determinados prazos para manter sua cobertura de saúde ou ajuda de
custos. Você tem o direito de obter esta informação e ajuda em seu idioma
e sem custos. Ligue para 800-722-1471 (TTY: 800-842-5357).
Fa’asamoa (Samoan):
Atonu ua iai i lenei fa’asilasilaga ni fa’amatalaga e sili ona taua e tatau
ona e malamalama i ai. O lenei fa’asilasilaga o se fesoasoani e fa’amatala
atili i ai i le tulaga o le polokalame, Premera Blue Cross, ua e tau fia maua
atu i ai. Fa’amolemole, ia e iloilo fa’alelei i aso fa’apitoa olo’o iai i lenei
fa’asilasilaga taua. Masalo o le’a iai ni feau e tatau ona e faia ao le’i aulia le
aso ua ta’ua i lenei fa’asilasilaga ina ia e iai pea ma maua fesoasoani mai ai
i le polokalame a le Malo olo’o e iai i ai. Olo’o iai iate oe le aia tatau e maua
atu i lenei fa’asilasilaga ma lenei fa’matalaga i legagana e te malamalama i
ai aunoa ma se togiga tupe. Vili atu i le telefoni 800-722-1471
(TTY: 800-842-5357).
Español (Spanish):
Este Aviso contiene información importante. Es posible que este aviso
contenga información importante acerca de su solicitud o cobertura a
través de Premera Blue Cross. Es posible que haya fechas clave en este
aviso. Es posible que deba tomar alguna medida antes de determinadas
fechas para mantener su cobertura médica o ayuda con los costos. Usted
tiene derecho a recibir esta información y ayuda en su idioma sin costo
alguno. Llame al 800-722-1471 (TTY: 800-842-5357).
Tagalog (Tagalog):
Ang Paunawa na ito ay naglalaman ng mahalagang impormasyon. Ang
paunawa na ito ay maaaring naglalaman ng mahalagang impormasyon
tungkol sa iyong aplikasyon o pagsakop sa pamamagitan ng Premera Blue
Cross. Maaaring may mga mahalagang petsa dito sa paunawa. Maaring
mangailangan ka na magsagawa ng hakbang sa ilang mga itinakdang
panahon upang mapanatili ang iyong pagsakop sa kalusugan o tulong na
walang gastos. May karapatan ka na makakuha ng ganitong impormasyon
at tulong sa iyong wika ng walang gastos. Tumawag sa 800-722-1471
(TTY: 800-842-5357).
ไทย (Thai):
ประกาศนี ้มีข้อมูลสําคัญ ประกาศนี ้อาจมีข้อมูลที่สําคัญเกี่ยวกับการการสมัครหรื อขอบเขตประกัน
สุขภาพของคุณผ่าน Premera Blue Cross และอาจมีกําหนดการในประกาศนี ้ คุณอาจจะต้ อง
ดําเนินการภายในกําหนดระยะเวลาที่แน่นอนเพื่อจะรักษาการประกันสุขภาพของคุณหรื อการช่วยเหลือที่
มีค่าใช้ จ่าย คุณมีสิทธิที่จะได้ รับข้ อมูลและความช่วยเหลือนี ้ในภาษาของคุณโดยไม่มีค่าใช้ จ่าย โทร
800-722-1471 (TTY: 800-842-5357)
Український (Ukrainian):
Це повідомлення містить важливу інформацію. Це повідомлення
може містити важливу інформацію про Ваше звернення щодо
страхувального покриття через Premera Blue Cross. Зверніть увагу на
ключові дати, які можуть бути вказані у цьому повідомленні. Існує
імовірність того, що Вам треба буде здійснити певні кроки у конкретні
кінцеві строки для того, щоб зберегти Ваше медичне страхування або
отримати фінансову допомогу. У Вас є право на отримання цієї
інформації та допомоги безкоштовно на Вашій рідній мові. Дзвоніть за
номером телефону 800-722-1471 (TTY: 800-842-5357).
Tiếng Việt (Vietnamese):
Thông báo này cung cấp thông tin quan trọng. Thông báo này có thông
tin quan trọng về đơn xin tham gia hoặc hợp đồng bảo hiểm của quý vị qua
chương trình Premera Blue Cross. Xin xem ngày quan trọng trong thông
báo này. Quý vị có thể phải thực hiện theo thông báo đúng trong thời hạn
để duy trì bảo hiểm sức khỏe hoặc được trợ giúp thêm về chi phí. Quý vị có
quyền được biết thông tin này và được trợ giúp bằng ngôn ngữ của mình
miễn phí. Xin gọi số 800-722-1471 (TTY: 800-842-5357).