ABSTRACT The current liver allocation system, introduced in 2002, decreased the importance of waiting time for allocation priorities; the number of active wait-listed candidates and median waiting times were immediately reduced. However, the total number of adult wait-listed candidates has increased since 2002, and median waiting time has increased since 2006. Pretransplant mortality rates have been stable, but the number of candidates withdrawn from the list as being too sick to undergo transplant nearly doubled between 2009 and 2011. Deceased donation rates have remained stable, with an increasing proportion of expanded criteria donors. Living donation has decreased over the past 10 years. Transplant outcomes remain robust, with continuously improving graft survival rates for deceased donor, living donor, and donation after circulatory death livers. Numbers of new and prevalent pediatric candidates on the waiting list have decreased. Pediatric pretransplant mortality has decreased, most dramatically for candidates aged less than 1 year. The transplant rate has increased since 2002, and is highest in candidates aged less than 1 year. Graft survival continues to improve for pediatric recipients of deceased donor and living donor livers. Incidence of acute rejections increases with time after transplant. Posttransplant lymphoproliferative disorder remains an important concern in pediatric recipients.
I am just so grateful for this amazing gift I received.
Halley, liver recipient
In 2011, 5,805 adult liver transplants were performed in the United States (Figure 4.1). These included transplant of 5,351 organs from donation after brain death donors, 266 from donation after circulatory death (DCD) donors, and 188 from living donors. Organs were procured across the country and transplanted at 131 transplant programs (from deceased organ donation chapter, Figure 1.3). For the organ recipients, these life-saving operations are expected to provide an unadjusted 1-year survival of 88.2% (data not shown). These extraordinary results are achieved by collaboration among transplant surgeons, physicians, and other health care providers, as well as organ procurement and allocation personnel. Conversely, during 2011, 2,456 patients died while on the waiting list, and 482 patients were removed from the list because they were too sick to undergo transplant (Figure 1.5).
The current allocation system, introduced in 2002, markedly decreased the importance of waiting time for liver allocation priorities. The number of active wait-listed liver transplant candidates was immediately reduced (Figure 1.1), as was the median waiting time (Figure 1.7). The proportion of wait-listed candidates who received an organ within 5 years of listing increased (Figure 1.9). Increasing proportions of candidates are older (Figure 1.2); the proportion of the largest age group, those aged 50 to 64 years, increased from 51.2% in 2001 to 63.7% in 2011. The proportion of male candidates increased gradually over time.
A gradually worsening donor shortage trend is recognizable. Since 2002, the total number of wait-listed candidates gradually increased (Figure 1.1); most are listed as active. The median pre-transplant waiting time increased gradually but consistently since 2006 (Figure 1.7). The proportion of candidates with model for end-stage liver disease (MELD) scores greater than 15 also increased (Figures 1.2, 1.3). While pre-transplant mortality rates have been relatively stable since 2007 (Figure 1.10), the number of candidates withdrawn from the list because they were too sick to undergo transplant nearly doubled between 2009 (260) and 2011 (482; Figure 1.5). These data raise concern that wait-list mortality, which has decreased since the MELD-based allocation system was implemented, may increase again.
Geographic disparity in organ availability remains notable. The proportion of adults receiving deceased donor organs within 5 years of listing varied from less than 50% in some donation service areas (DSAs) to more than 80% in others (Figure 1.8). Similarly, mortality within 90 days of listing, regardless of transplant status, varied substantially by DSA; 90-day mortality varied more than 2-fold between DSAs with the lowest and highest mortality (Figure 1.12). As expected, the likelihood of undergoing transplant tended to be lower in DSAs with higher mortality. One possible approach to reducing wait-list mortality is to expand organ sharing among candidates at highest risk of death, as is currently done with status 1A and 1B patients. Based on analyses illustrated in Figure 1.11, showing that mortality for end-stage liver disease patients with the highest MELD scores (35 or higher) is nearly comparable to mortality for status 1A and 1B patients, a policy proposal for regional sharing of organs for those patients has recently been approved.
Transplant, Deceased and Living Donation
In the past several years, deceased donor liver donation rates have remained stable (Figure 2.1). In response to the donor shortage, transplant surgeons continue their efforts to increase the donor pool.
An increasing proportion of deceased donors are expanded criteria donors. The proportion of DCD organs has increased compared with the 1990s and remains at approximately 6% (Figures 2.7, 4.4). The proportion of organs donated after anoxic brain death increased more than 2-fold in the past decade, and the proportion of organs donated after death due to head trauma decreased (Figure 2.8).
Geographic inequality in deceased donor liver donation rates remains substantial (Figure 2.2). Variability between states with the highest and lowest donation rates is approximately 4-fold. This variability is accompanied by geographic differences in deceased donor transplant rates; by DSA, rates vary from 15.3 to 258.5 per 100 patient-years on the waiting list (Figure 4.6). Use of DCD donors varies widely by DSA, from 0% to 22.2% of transplants performed in 2009–2011 (Figure 4.5). Median MELD scores in adults receiving deceased donor livers ranged from 18.5 to 36.0; the national median MELD score is 27 (Figure 4.8).
The number of donations from living donors reached a plateau at about 250, about half the number of a decade ago (Figure 3.1). The relatively low number of living donor transplants performed in the US is substantially less than the numbers performed in countries such as Japan and Korea, a disparity possibly reflecting more access to deceased donors in the US than in many parts of Asia. The gradual decrease in the number of living donors in the US over the past 10 years may be related to concerns about donor safety. Morbidity rates for living donors remain relatively low. Biliary complications in the first 6 weeks after donation are reported in less than 3% of living donors per year, except for 2007, when they were reported in 7.9% (Figure 3.8); most complications are reported as grade 1 or 2. Vascular complications in the first 6 weeks remain low, at less than 2% (Figure 3.9), and the frequency of reoperations in the first 6 weeks is low, at less than 4% (Figure 3.11).
Unfortunately, two donor deaths were reported in 2010 (Figure 3.12), and these deaths clearly affected the views of the transplant community regarding living donation. The number of left lobe transplants increased slightly (Figure 3.5). Since left lobe and left lateral lobe segment donation are generally regarded as safer for the donor (less volume of tissue taken), the slight increase in the number of these procedures compared with right lobe donation may reflect ongoing safety concerns in the transplant community. In general, living donor rates are higher in geographic areas with higher median MELD scores; the transplant community may be avoiding living donation unless the candidate has a MELD score less than 30.
Several important trends among liver transplant recipients are apparent. First, increasing proportions of recipients are older. Over the past decade, the proportion of recipients aged 50 years or older increased from 58.5% to 77.1%, and the proportion aged 35 to 49 years halved, from 35.1% to 16.9% from 2002 to 2011 (counts shown in Figure 4.2). Absolute numbers are small, but the proportion of recipients aged 65 years or older has gradually increased, from 7.6% in 2002 to 12.8% in 2011. The proportions of recipients with obesity and diabetes have also increased (Table 4.9). Second, liver transplant rates in female candidates are increasingly recognized to be lower than rates in male counterparts. Several potential explanations may apply, and the gap may be narrowing in the past 2 to 3 years (Figure 4.3). Third, an upward trend remains for combined transplant. This is most notable for simultaneous liver-kidney transplant; these procedures increased more than 2-fold in the past decade (Figure 2.4). Simultaneous liver-kidney transplant remains a contentious topic, and the criteria for determining who is most appropriate for the procedure have not been established and adopted.
Although liver transplant is being performed in increasingly challenging circumstances (more older recipients with more comorbidity undergoing transplant with high MELD scores and suboptimal donor organs), transplant outcomes in the US remain robust. In survival models with minimal adjustment (age, sex, race), the graft failure rate has continuously improved (Figure 6.2). Improvement in graft outcomes has occurred in deceased donor, living donor, and DCD transplants (Figure 6.1). As of June 30, 2011, 62,469 liver transplant recipients in the US were alive with a functioning graft (Figure 6.7).
Several factors affect graft survival after liver transplant, including recipient age, primary cause of disease, and status and MELD score at the time of transplant (Figures 6.4, 6.5). These factors have been well described and have relatively modest impact on absolute graft survival rates.
Successful liver transplant results are in part attributable to appropriate use of immunosuppression. Initial immunosuppression for most recipients is tacrolimus and mycophenolate mofetil (MMF), commonly in conjunction with steroids (Figure 7.1). Induction therapy is used infrequently (Figure 7.2). By 1 year after transplant, most patients are no longer taking steroids and are taking tacrolimus with or without MMF (Figure 7.3). With these immunosuppressive regimens, acute rejection occurs in less than 20% of recipients during the first year (Figure 6.8).
The number of new active pediatric candidates added to the liver transplant waiting list decreased from a peak of 969 in 2001 to 704 in 2011; few candidates were added as inactive (Figure 8.1). In a similar trend, the number of prevalent candidates on the waiting list has decreased. Since 2008, prevalent candidates with active status outnumber those with inactive status. The wait-list age distribution has changed little over the past decade; in 2011, 49.2% of listed candidates were aged 6 years or younger (Figure 8.2). The proportion of Hispanic wait-listed candidates increased from 14.8% in 1998 to 24.0% in 2011. The number of wait-listed candidates waiting for a retransplant decreased from 236 in 2001 to 76 in 2011 and represented 11.2% of wait-listed candidates (Figure 8.3). Among all wait-listed candidates in 2011, 8.2% of those aged 0 to 5 years were waiting for a re-transplant, as were 18.8% of those aged 6 to10 years and 15.3% of those aged 11 to 17 years. Pre-transplant mortality has steadily declined for candidates wait-listed for a liver-alone transplant, from 14.3 deaths per 100 wait-list years in 1998–1999 to 6.2 in 2010–2011; the most dramatic decline was in the group aged less than 1 year, where pre-transplant mortality was halved (Figure 8.7).
The number of deceased donor pediatric liver transplants peaked at 542 in 2008 and decreased to 477 in 2011. The number of living donor transplants decreased from a peak of 120 in 2000 to 59 in 2011 (Figure 8.8). The transplant rate has increased since 2002 to the current rate of 84.1 transplants per 100 patient-years on the waiting list (Figure 8.9). The transplant rate is highest for patients aged less than 1 year: 264 transplants per 100 patient-years on the waiting list. Over the past decade, the age, sex, and ethnic distributions of recipients have changed little (Figure 8.10). Cholestatic disease remains the leading cause of liver failure. More than 55% of patients who underwent transplant waited 60 days or fewer for transplant. Without taking into account exception scores provided by Organ Procurement and Transplantation Network (OPTN) policy, MELD/pediatric end-stage liver disease (PELD) scores at the time of transplant were 35 or higher for 14.7% of patients and less than 15 for 15.0%; the most common score range was 15 to 29. Most pediatric patients (63.6%) received a whole liver. The percentage of living donors declined from 19.4% during 1999–2001 to 10.6% during 2009–2011 (Figure 8.10). Use of DCD organs is rare in pediatric liver transplant, generally accounting for less than 1% (Figure 8.12).
Immunosuppression and Outcomes
In 2011, tacrolimus was reported as part of the initial maintenance immunosuppressive medication regimen for 95.4% of pediatric liver transplant recipients and MMF for 40.1% (Figure 8.15). Steroid use was reported for 87.3% of recipients at the time of transplant, but for only 38.7% of 2010 recipients at 1 year after transplant. Mammalian target of rapamycin (mTOR) inhibitors were reported for 1.4% of recipients at the time of transplant and for 5.3% at 1 year after transplant. In 2011, 68.8% of liver transplants were performed with no induction immunosuppression (Figure 8.15). Graft survival has continued to improve over the past decade for recipients of deceased donor and living donor livers. Graft failure was 10.1% at 6 months for deceased donor transplants performed in 2010, 14.4% at 1 year for transplants performed in 2009, 19.6% at 3 years for transplants performed in 2008, 25.0% at 5 years for transplants performed in 2006, and 35.8% at 10 years for transplants performed in 2001 (Figure 8.16). Incidence of acute rejection increases with time after transplant. For liver transplants performed in 2005–2010, acute rejection occurred for 20.0% by 6 months after transplant, 30.6% by 12 months, and 36.8% by 24 months (Figure 8.19). Post-transplant lymphoproliferative disorder (PTLD) is an important concern in pediatric transplantation. The highest risk for PTLD and Epstein-Barr virus (EBV) infection occurs in EBV-negative recipients. Incidence of PTLD was 6.2% at 5 years after transplant in EBV-negative recipients and 4.0% in EBV-positive recipients (Figure 8.14).
The OPTN Pediatric Transplantation and Liver and Intestinal Organ Transplantation Committees developed two proposals that were adopted by the OPTN Board of Directors in November 2011 and implemented on February 1, 2012: 1) to allow centers to seek permission to list all pediatric liver candidates with non-metastatic hepatoblastoma as status 1B, and 2) to eliminate the requirement that pediatric liver transplant candidates be in a hospital's intensive care unit to qualify as status 1A or 1B.