Solid Organ Transplants
Lung Transplant and Lobar Lung Transplant
Solid organ transplants other than those addressed above are considered investigational. (See Related Policies)
If the member meets the criteria of the Transplant Center, the transplant may be considered medically necessary.
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)
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.
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.
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
According to the Organ Procurement and Transplantation Network (OPTN) using available U.S. data as of September 27, 2013, the 1-year survival rate after heart transplant was 88.0% for males and 86.2% for females.(15) Three-year survival rates were 79.3% for males and 77.2% for females, and 5-year survival rates were 73.2% for females and 69.0% for males.
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. (16) 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. (17) 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).
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%).
A retrospective analysis of OPTN data focusing on the adolescent population was published by Savia et al. in 2014. (18) 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. (19) 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.(20) 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. (21) 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.
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). (22) 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. (23) 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 recent representative study was published in 2013 by Saito et al. (24) 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.
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. (25) 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. (26) 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.
Concerns regarding a potential recipient’s history of cancer were based on the observation of significantly increased incidence of cancer in kidney transplant patients. (27) 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.(28) 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. (29, 30) 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. (31) 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 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 a research interest of some transplant centers, the minimal data regarding long-term outcome in these patients consist primarily 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 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). (32)
In 2006, the British HIV Association and the British Transplantation Society Standards Committee published guidelines for kidney transplantation in patients with HIV disease. (33) These criteria may be extrapolated to other organs:
However, concerns have been raised about the extrapolation of these criteria for lung transplants.
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. (34) 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. (35) 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.
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. (36-39) For example, De Santo et al. reported on 31 consecutive patients who had been diagnosed with unresponsive pulmonary hypertension at baseline right heart catheterization.(36) 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. (37) 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 literature, consisting of case series and registry data, describes outcomes in patients treated with heart transplant. Given the exceedingly poor survival without transplantation, this evidence 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.
Combined heart/lung transplantation is intended to prolong survival and improve function in patients with end-stage 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. (40)
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. (41) 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:
A 2014 analysis of data from the Organ Procurement and Transplantation Network reported on indications for pediatric heart/lung transplantation. (42) 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. (43) 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.
Repeat heart-lung transplant procedures have been performed; only 1 published study was found that reported on outcomes after repeat heart-lung transplants. The study, published by Shuhaiber and colleagues in 2008, involved a review of data from the UNOS registry. (44) 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.
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 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 is an accepted treatment of end-stage renal disease (ESRD) that results from a variety of etiologies, most commonly diabetic nephropathy. An insufficient supply of donor organs continues to be a challenge. A 2012 review article by Schold and Segev focused on strategies to increase the pool of organs available for kidney transplantation from deceased donors.(45) Interventions discussed included an “opt-out” policy in which persons are presumed to give consent to organ donation unless they specify nonconsent, expanded use of donors such as commercial sex workers who are considered to be at increased risk of disease transmission by using rigorous screening and expanded use of donors with documented infections in selected situations, e.g., transplantation of organs from HIV-positive donors to HIV-positive recipients.
Several articles 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. (46) 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 comorbidity-matched NHANES III participants for all patients and also stratified by age, sex, and race.
Mjoen et al. in Norway found that kidney donors are at increased risk of long-term mortality. (47) The investigators identified 1,901 kidney donors and compared them with a control group of 32,621 potentially eligible people who had participated in a population-based survey. The kidney transplants occurred between 1963 and 2007 and the median follow-up was 24.9 years. There were 224 (12%) deaths among kidney donors during the study period and 2425 (7%) deaths among controls. The unadjusted hazard ratio (HR) for death by any cause in kidney donors compared with controls was 2.49 (95% CI: 2.13 to 2.91; p<0.001). After adjusting for potential confounding variables, risk of morality remained elevated among donors (HR=1.48; 95% CI: 1.17 to 1.88; p<0.001).
Potential Contraindications to Kidney Transplant
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. (48) (These criteria may be extrapolated to other organs.)
A 2011 review article by European authors stated that there are adequate data suggesting that renal transplantation in adequately selected HIV-positive patients is safe in the short- and medium-term and that patient and graft survival rates are similar to those in HIV-negative patients. (49) Moreover, data do not suggest that immunosuppressive therapy has a negative impact on the course of HIV infection. However, rates of acute rejection after kidney transplantation are higher in HIV-positive patients. In addition, little is known about the management of coinfection with hepatitis C or about the optimal antiretroviral and immunosuppressive regimens. The authors concluded that more studies are needed to address these issues as well as long-term outcomes.
Several case series have evaluated outcomes of kidney transplantation in HIV-positive patients. For example, in 2010, Stock et al. published findings of the largest prospective study to date of outcomes following kidney and liver transplantation in HIV-positive recipients.(50) A total of 150 patients underwent kidney transplantation; 102 received kidneys from deceased donors and 48 from living donors. Twenty-eight (19%) of patients were also hepatitis C virus (HCV)-positive. Patients were followed for up to 3 years. The median follow-up of survivors was 1.7 years. The patient survival rate (SD) at 1 year was 94.6% (2.0%) and at 3 years was 88.2% (3.8%). Eleven patients died; the graft was still functioning at the time of death in 8 patients. There were 7 deaths among the 122 HCV-negative patients (6%) and 4 deaths among the 28 HCV-positive patients (14%); the p value for the difference in survival by HCV status was 0.09. Forty-nine of 150 (33%) patients had 67 acute rejection episodes. The cumulative incidence of allograft rejection was 31% (95% CI: 24 to 40) at 1 year and 41% (95% CI: 32 to 52) at 3 years. The time to first acute allograft rejection did not differ significantly among HCV-positive and HCV negative patients (p=0.36; exact numbers not reported). Infections requiring hospitalization were reported for 57 of 150 (38%) of patients. Patients who were HCV-positive had a higher rate of serious infection per follow-up year than those who were HCV-negative (0.8 and 0.5, respectively, p=0.02). The authors noted that that the rate of rejection was 2 to 3 times higher in this group of HIV-infected patients than in non-HIV-infected patients who participated in a larger study by the research team. They concluded that kidney transplantation is feasible in carefully selected HIV-infected patients and that better strategies are needed for minimizing rejection and for controlling infections in patients who are co-infected with HCV.
In 2011, a case-control study from France was published by Mazuecos et al. (51) Outcomes in 20 HIV positive patients who received kidney transplantation were compared with a matched cohort of 40 HIV negative patients. Matching was done on a number of variables including type of donor, donor and recipient age, pretransplantation laboratory values, hepatitis B and C status, and treatment at the same center within a short amount of time. There was a mean follow-up of 40.4 months among HIV-positive patients and 39.8 months among HIV-negative patients. Eight (40%) patients in the HIV-positive group and 9 (22.5%) in the HIV-negative group experienced acute rejection; this difference was not statistically significant (p=0.16). There were 4 graft failures (20%) in the HIV-positive group and 2 (5%) in the HIV negative group (p=0.89). One patient (5%) died in the HIV positive group, and there were no deaths in the HIV negative group.
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. (52) 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 HCV-positive patients may be due to chronic liver disease. In a meta-analysis of 9 studies, the risk of liver disease-related 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 2014, Pieloch et al. published a retrospective review of data from the Organ Procurement and Transplantation Network (OPTN) database.(53) 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).
A 2013 study by Gill et al. examined whether obese patients benefit from kidney transplantation. (54) The study compared outcomes in patients who underwent kidney transplant in the U.S. and those who were on the waiting list. In all BMI categories, risk of mortality at 1 year was significantly lower in patients who underwent transplantation than in those who remained on the waiting list. For example, among patients with a BMI of at least 40 kg/m2, who received organs from donors who met standard criteria, HR was 0.52 (95% CI: 0.37% to 0.72%). Moreover, among patients with BMI 35 to 39 kg/m2 who received organs from standard-criteria donors, HR was 0.34 (95% CI: 0.26 to 0.46). These data suggest that morbid obesity is not associated with an increased risk of adverse outcomes after kidney transplant.
According to data from the OPTN, rates of 1-, 3-, and 5-year survival are similar after a primary kidney transplant and a repeat transplant. (15) For example, for transplants performed between 2002 and 2004, the 1-year survival rate was 91.9% (91.6% to 92.1%) after primary transplantation and 89.7% (88.8% to 90.5%) after repeat transplantation. Among patients undergoing transplantation between 1997 and 2000, the 5-year survival rate was 72.0% (71.6% to 72.5%) after primary kidney transplantation and 66.9% (65.6% to 68.1%) after repeat kidney transplantation.
In 2009, Barocci et al. in Italy reported on long-term survival after kidney retransplantation.(55) 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.
A 2013 study by Johnston et al. compared outcomes in 3509 patients who underwent a preemptive second kidney transplant, defined as transplantation after fewer than 7 days of dialysis following graft failure, to outcomes in 14,075 patients who underwent a nonpreemptive second kidney transplant. (56) Data from the U.S. Renal Data System were reviewed. In the first year after retransplantation, there was a significantly lower risk of acute rejection in patients receiving a preemptive second transplant (12%) compared with those with a nonpreemptive second transplant (16%; p<0.001). In a multivariate analysis adjusting for demographic differences between groups, there was a significantly lower risk of allograft failure by any cause including death after preemptive second transplants compared with nonpreemptive second transplants (HR=0.88; 95% CI: 0.81 to 0.96).
Summary of Evidence for Kidney Transplant
Kidney transplant is an accepted treatment of end-stage renal disease (ESRD) in appropriately selected patients and thus may be considered medically necessary. Registry and national survey data suggest that live donors of kidneys for transplantation do not have an increased risk of mortality or ESRD.
Kidney retransplantation after a failed primary transplant may be considered medically necessary, as national data suggest similar survival rates after initial and repeat transplants.
Kidney transplantation is not medically necessary 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 kidney 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.
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.
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%). (57) Recurrence of HCV infection in transplant recipients has been nearly universal, and 10% to 20% of patients will develop cirrhosis within 5 years. (58) 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. (59) 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. (57)
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. (60) 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. (61-63) 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. (64-66) In December 2000, the National Institutes of Health (NIH) convened a workshop focusing on living-donor liver transplantation. A summary of this workshop was published in 2002. (67) 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 living-related 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. (67)
In 2000, the American Society of Transplant Surgeons issued the following statement (68):
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. (69) The following statistics were reported:
In 2002, NIH sponsored a conference on living-donor liver transplantation. (64) This report offered the following observations:
Living Donor Versus Deceased Donor
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. (71) These criteria may be extrapolated to other organs:
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. (72)1 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. (73) 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. (74) 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 (75) 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), (76) 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, (77) 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 (78) included 10 patients beyond pathologic Milan criteria but within UCSF criteria. Two-year 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, (79) 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, (76) 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. (80) 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. (81) 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. (82) 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. (83) 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. (84) 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. (85) Additionally; current UNOS criteria indicate a liver transplant candidate must not be eligible for resection. (86) 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. (87) 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. (86)
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), (88) 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. (89) 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. (90) 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.
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. (91) 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.
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. (92) 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. (93) 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. (94) 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 (95) 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 (96) 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. (97, 98) 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 5-year survival was 76%. The University of California, Los Angeles (UCLA)/Cedars-Sinai, (99) 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. (100) A German study of 24 patients reported the poorest results. (101) 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. (102) 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. (98) The series of 20 patients from the University of Pittsburgh experienced 67% 1-year tumor-free survival and a 31% 5-year rate. (99) The multicenter Spanish series reported crude recurrence rates of 53% and 36% for extrahepatic and intrahepatic cholangiocarcinoma, respectively. (96) The German center at Hannover found a crude recurrence rate of 63%.(101)
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. (103) 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. (104) 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.
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. (105) 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. (73) 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. (106) 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. (107) 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.
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. (108) 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. (109) 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. (110) 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). (111) 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.
In 2012, Bellido et al. reported on a retrospective cohort study of 68 consecutive adult liver retransplantations using registry data. (112) 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. (113) 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. (114) 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 living-related donors, with 1 lobe obtained from each of 2 donors (eg, mother and father) in cases when bilateral transplantation is required.
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. (115) 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 non- cytomegalovirus (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 (116)
In 2014, Kistler et al. reported on a systematic review of the literature on waitlist and posttransplant survival of idiopathic pulmonary fibrosis. (117) 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. (118) 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). (119) A significant decrease in survival was seen in single-lung transplant patients with a high LAS compared with double-lung 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. (120) (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. (121) 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. (122) 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).
In 2012, Benden et al. reviewed pediatric lung transplants that have been reported to the international registry. (123) 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
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. (115)
A 2012 study reported on outcomes in patients with lung cancer who were lung transplant recipients. (124) 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).
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.” (125)
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.
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. (126) 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. (127) 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). (128)
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. (129) 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. (130) 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, 3-year 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. (131) 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). (132) 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. (133) 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. (134) 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. (135) 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. (136) 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. (137) 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. (138) 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. (139) 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).
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. (115, 140, 141) 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). (115) 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. (140) 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.
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). (142) A 2001 TEC Assessment focused on the issue of pancreas retransplant. (143) 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.(144)
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. (145) 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. (146) 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. (147) 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. (148)
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. (149) 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. (150) 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). (151) 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. (152) 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.
The OPTN reported data on transplants performed between 1997 and 2004. (148) 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. (153) 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. (154) 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.” (155)
In 2006, the British HIV Association and the British Transplantation Society Standards Committee published guidelines for kidney transplantation in patients with HIV disease. (156) 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. (157) 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. (157)
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. (158) 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. (159) 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. (160) 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, (161) 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
Clinical Trials for Pancreas Transplant
Practice Guidelines and Position Statements
American College of Cardiology (ACC)/American Heart Association (AHA)
The accepted indications, probable indications, and contraindications for heart transplantation listed in the policy and guideline sections of this policy reflect the 2005 update of the American College of Cardiology (ACC)/American Heart Association (AHA) joint statement on diagnosis and management of chronic heart failure in the adult. They are unchanged in the 2009 update of the ACC/AHA statement. (3)
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 (162):
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 (163):
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 (164):
International Society for Heart and Lung Transplantation (ISHLT) - Cardiac Retransplantation
The 2010 guidelines from the ISHLT include the following recommendations on cardiac retransplantation (165):
International Society for Heart and Lung Transplantation (IHSLT)
Lung transplantation is now a generally accepted therapy for the management of a wide range of severe lung disorders…. However, the number of donor organs available remains far fewer than the number of patients with end-stage lung disease who might potentially benefit from the procedure. It is of primary importance, therefore, to optimize the use of this resource, such that the selection of patients who receive a transplant represents those with realistic prospects of favorable long-term outcomes. There is a clear ethical responsibility to respect these altruistic gifts from all donor families and to balance the medical resource requirement of one potential recipient against those of others in their society. These concepts apply equally to listing a candidate with the intention to transplant and potentially de-listing (perhaps only temporarily) a candidate whose health condition changes such that a successful outcome is no longer predicted.
Thus, for all patients, including those with end-stage cardiopulmonary disease and HIV infection, evaluation of a candidate for transplant needs to consider the probability of a successful transplant and the limited supply of organs available.
Multiple Professional Society Position Statement
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. (167)
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.(168) 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:
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).
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. (169) 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. (170) 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. (171) 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 life-threatening.
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. (85) 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 lower-level evidence and uniform consensus.
The NCCN guidelines on neuroendocrine tumors V1.2015 indicate liver transplantation for neuroendocrine tumor liver metastases is considered investigational. (172)
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. (173) 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. (174) 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. (166) See complete statement under Heart/Lung subheading above.
In 2014, the Board of Directors of the Organ Procurement and Transplantation Network issued an updated comprehensive list of transplant related policies. (175)
Each candidate registered on the pancreas waiting list must meet one of the following requirements:
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
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. (176)
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 transplantation is covered under Medicare when performed in a facility that is approved by Medicare as meeting institutional coverage criteria. (177) 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.
The Medicare Benefit Policy Manual includes a chapter on end stage renal disease. (178) 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.”
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. (179) The following conditions must be met for coverage of HCC:
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 CMS-approved 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. (180) 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.
Allogeneic pancreas transplant is covered under Medicare when performed in a facility that is approved by Medicare as meeting institutional coverage criteria. (181) The Centers for Medicare and Medicaid Services has made the following national coverage decision regarding pancreas transplant for Medicare recipients.
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.
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: (182)
The following procedure is not considered reasonable and necessary within the meaning of section 1862(a)(1)(A) of the Social Security Act:
Donor pneumonectomy(s) (including cold preservation), from cadaver donor
Lung transplant, single; without cardiopulmonary bypass
with cardiopulmonary bypass
Lung transplant, double (bilateral, sequential, or en bloc); without cardiopulmonary bypass
with cardiopulmonary bypass
Backbench standard preparation of cadaver donor lung allograft prior to transplantation, including dissection of allograft from surrounding soft tissues to prepare pulmonary venous/atrial cuff, pulmonary artery, and bronchus; unilateral
Donor cardiectomy-pneumonectomy (including cold preservation)
Backbench standard preparation of cadaver donor heart/lung allograft prior to transplantation, including dissection of allograft from surrounding soft tissues to prepare aorta, superior vena cava, inferior vena cava, and trachea for implantation
Heart-lung transplant with recipient cardiectomy- pneumonectomy
Donor cardiectomy (including cold preservation)
Backbench standard preparation of cadaver donor heart allograft prior to transplantation, including dissection of allograft from surrounding soft tissues to prepare aorta, superior vena cava, inferior vena cava, pulmonary artery, and left atrium for implantation
Heart transplant, with or without recipient cardiectomy
Prolonged extracorporeal circulation for cardiopulmonary insufficiency; initial 24 hours
Donor hepatectomy (including cold preservation), from cadaver donor
Liver allotransplantation; orthoptic; partial or whole, from cadaver or living donor, any age
heterotrophic, partial or whole, from cadaver or living donor, any age
Donor hepatectomy (including cold preservation), from living donor; left lateral segments only (segments II and III)
total left lobectomy (segments II, III, and IV)
total right lobectomy (segments V, VI, VII and VIII)
Backbench standard preparation of cadaver donor whole liver graft prior to allotransplantation, including cholecystectomy, if necessary, and dissection and removal of surrounding soft tissues to prepare the vena cava, portal vein, hepatic artery, and common bile duct for implantation; without trisegment or lobe split
with trisegment split of whole liver graft into two partial liver grafts (i.e., left lateral segment (segments II and III) and right trisegment (segments I and IV through VIII))
with lobe split of whole liver graft into two partial liver grafts (i.e., left lobe (segments II, III, and IV) and right lobe (segments I and V through VIII))
Backbench reconstruction of cadaver or living donor liver graft prior to allotransplantation; venous anastomosis, each
arterial anastomosis, each
Donor pancreatectomy (including cold preservation), with or without duodenal segment for transplantation
Backbench standard preparation of cadaver donor pancreas allograft prior to transplantation, including dissection of allograft from surrounding soft tissues, splenectomy, duodenotomy, ligation of bile duct, ligation of mesenteric vessels, and Y-graft arterial anastomoses from iliac artery to superior mesenteric artery and to splenic artery
Backbench reconstruction of cadaver donor pancreas allograft prior to transplantation, venous anastomosis, each
Transplantation of pancreatic allograft
Donor nephrectomy (including cold preservation); from cadaver, unilateral or bilateral
open from living donor
Backbench standard preparation of cadaver donor renal allograft prior to transplantation, including dissection and removal of perinephric fat, diaphragmatic, and retroperitoneal attachments, excision of adrenal gland, and preparation of ureter(s), renal vein(s), and renal artery(s), ligating branches, as necessary
Backbench standard preparation of living donor renal allograft (open or laparoscopic) prior to transplantation, including dissection and removal of perinephric fat, and preparation of ureter(s), renal vein(s), and renal artery(s), ligating branches, as necessary
Backbench reconstruction of cadaver or living donor renal allograft prior to transplantation; venous anastomosis, each
arterial anastomosis, each
ureteral anastomosis, each
Recipient nephrectomy (separate procedure)
Renal allotransplantation; implantation of graft; without recipient nephrectomy
with recipient nephrectomy
Laparoscopic, surgical; donor nephrectomy (including cold preservation), from living donor
Ultrasound, transplanted kidney, real time and duplex Doppler with image documentation
Extracorporeal circulation auxiliary to open heart surgery
Lobar lung transplantation
Donor lobectomy (lung) for transplantation, living donor
Simultaneous pancreas kidney transplantation
Type of Service
Place of Service
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 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.
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).