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Orthotopic liver transplantation (OLT) is a durable and the definitive lifesaving treatment modality for patients suffering from irreversible liver failure. Although thousands of patients receive liver transplants each year, the limited organ supply remains a reality, and many patients are not as fortunate. Since 1987 the rate of new registration for the United Network for Organ Sharing (UNOS) liver waiting list has far exceeded the growth of deceased donor liver organs. In 2011 there were 16,080 candidates on the liver waiting list, although only 6282 patients received transplants. Approximately 3000 patients died while on the waiting list for lack of donor organs or were removed from the list because they were too sick to undergo transplant (OPTN/SRTR 2011 Annual Data Report). The growing disparity between the available organs and OLT candidates are attributed to the following factors: (1) expansion of acceptable indications for OLT candidates as a result of increase in surgical experience and refinement of surgical techniques in the operative management of highly complex procedures, (2) advancement in the operative and perioperative care of critically ill patients, (3) improvement of posttransplant management and immunosuppression, (4) increased patient access to transplant centers, and (5) ongoing decline in the number of standard criteria donors (OPTN/SRTR 2011 Annual Data Report).
In general there are four major dynamic interrelated factors that ultimately determine the outcome after OLT: organ availability and timing of OLT, recipient characteristics, operative factors, and organ donor and graft type. Organ availability, allocation, and distribution play a critical factor in the timing of OLT and subsequently, outcomes after OLT. The system of organ allocation in the United States has evolved from what began as an informal, voluntary sharing among a few transplant centers into a national sharing system that aims to ensure equitable allocation of all organs for transplantation. Each solid organ has its own organ allocation system based upon either waiting time on the list or medical urgency. In contradistinction to patients suffering from other organ failure (i.e., renal, heart, lung), where mechanical devices are available to sustain life while on the waiting list, patients with end-stage liver disease solely depend on a timely OLT to survive. Thus the liver organ allocation system has been based on medical urgency, “sickest first,” rather than time on the waiting list. The Model for End-Stage Liver Disease/ Pediatric End-Stage Liver Disease (MELD/PELD) was implemented on February 27, 2002, to prioritize OLT for patients with high acuity of illness and to reduce waiting list mortality based on a continuous disease severity scale.
Although waiting list mortality has decreased with the MELD/PELD system, geographical disparity in organ availability remains notable. Based on analyses that the waiting list mortality for end-stage liver disease patients with the highest MELD scores (35 or higher) is comparable to mortality for status 1A and 1B patients, a policy for regional sharing of organs for patients with a MELD score of 35 or higher was implemented on June 18, 2013, to expand organ sharing among candidates at highest risk for death on the waiting list, as is currently done with status 1A and 1B patients. With the ongoing organ crisis, it is expected that the proportion of critically ill OLT candidates will continue to grow. Therefore it is paramount that patients listed for transplant receive the highest level of care to realize the maximum survival benefit from a scarce resource (deceased and live donors). This chapter aims to provide a review of recent data on predictors of graft failure-free survival after liver transplantation and to facilitate development of an objective approach to patient and organ selection to reduce transplant waiting list mortality, optimize utilization of the scarce resource, and ensure successful outcomes.
The advanced recipient illness and organ shortage have deleterious effects on posttransplant survival. A study from the University of California, Los Angeles (UCLA) that included more than 5300 transplants performed over the past 3 decades clearly demonstrated a change in recipient risk factors after implementation of the MELD system compared to pre-MELD era. The post-MELD recipients are older (54 versus 49 years, P < .01), more likely hospitalized (50% versus 47%, P = .03) and receiving pretransplant renal replacement (34% versus 12%, P < .01), and have a greater laboratory MELD score (28 versus 19, P < .01), longer waiting list times (270 versus 186 days, P < .01), and more pretransplant hospital days (10 days versus 8 days, P < .01). Multiple objective parameters such as recipient age, renal impairment, coagulation parameters, mechanical ventilation, and liver function have been associated with diminished outcomes after OLT.
Perhaps the most objective parameter indicating advanced liver disease is the degree of pretransplant renal impairment. The predictive value of preoperative renal function on postoperative OLT survival has been extensively investigated by the Baylor University Medical Center group. Data from 569 consecutive OLTs demonstrated that patients with hepatorenal syndrome (HRS) have significantly decreased actuarial survival 5 years after liver transplantation when compared with patients without HRS ( P < .03). Furthermore, end-stage renal disease developed in 10% of patients with HRS after OLT versus 0.8% of patients without HRS ( P < .05). Cuervas-Mons and coworkers, as well as the analysis of UNOS registry, found that preoperative serum creatinine level alone was the strongest predictor of early posttransplant sepsis and hospital death.
Although the MELD system is accurate at predicting 3-month waiting list mortality from liver disease, the MELD score alone is not able to accurately predict posttransplant deaths. Although early studies showed progressively lower patient survival benefits with rising MELD scores, recent studies have validated no direct correlation between MELD score and posttransplant survival. The MELD prediction of 3- month posttransplant mortality has a C statistic of only 0.62 (95% confidence interval, 0.55 to 0.69). Models with a C statistic value greater than 0.70 are considered clinically acceptable. Successful development of preoperative models that accurately predict patient survival after liver transplantation has therefore become a crucial concern of the liver transplant community. Such models will facilitate the clinical decision-making process by (1) balancing outcomes with severity of disease to avoid “futile” transplantation and (2) providing guidelines based on objective criteria for “delisting” of transplant candidates when expected OLT outcomes fall below an established survival threshold, as proposed by an amendment to the final rule of the Department of Health and Human Services (DHHS).
Several authors have proposed predictive models using the UNOS registry data. The survival outcomes following liver transplantation (SOFT) score used 18 risk factors (recipient, donor, and operative) to successfully predict 3-month recipient survival following OLT ( Tables 98-1 and 98-2 , Fig. 98-1 ). The most significant risk factors were a history of previous transplantation and the need for life support before transplantation. Another model, balance of risk (BAR) score, identified six strongest predictors of posttransplant survival: recipient MELD score, cold ischemia time, recipient age, previous OLT, and life support before transplant. Although these models may provide clinicians an overall guide, analysis of registry data suffers lack of granularity for the level of expertise of a particular transplant center in the medical and surgical care of patients with the highest acuity of illness. Therefore it is imperative that the implementation of clinical decision pathways be based on each transplant center’s medical capacity, experience and depth as well as the ability to match donor-recipient risk factors under the current organ allocation system to optimize outcomes after OLT.
Risk Factors | Points |
---|---|
P-SOFT (Preallocation) Score | |
Age > 60 yr | 4 |
Body mass index > 35 | 2 |
One previous transplant | 9 |
Two previous transplants | 14 |
Previous abdominal surgery | 2 |
Albumin level < 2 g/dL | 2 |
Dialysis pre-OLT | 3 |
Intensive care unit pre-OLT | 6 |
MELD score > 30 | 3 |
Life support pre-OLT | 4 |
Encephalopathy | 9 |
Portal vein thrombosis | 2 |
Ascites pre-OLT | 3 |
SOFT SCORE | |
P-SOFT score | Total from above |
Portal bleed 48 hr pre-OLT | 6 |
Donor age 10-20 yr | −2 |
Donor age > 60 yr | 3 |
Cause of donor death from cerebral vascular accident | 2 |
Donor serum creatinine level > 1.5 mg/dL | 2 |
National allocation | 2 |
Cold ischemia time 0-6 hr | −3 |
Risk Group | Point Range |
---|---|
P-SOFT (Preallocation) Score | |
Low | 0-5 |
Low-moderate | 6-15 |
High-moderate | 16-35 |
High | 36-40 |
Futile | >40 |
SOFT SCORE | |
Low | 0-5 |
Low-moderate | 6-15 |
High-moderate | 16-35 |
High | 36-40 |
Futile | >40 |
To date the balance between serving the sickest first, as stipulated in the DHHS final rule, strikes a delicate balance with avoiding futile transplantation. During the initial implementation of the MELD allocation system, a consensus was reached to cap the MELD score at a maximum of 40 points so that candidates with MELD scores higher than 40 do not receive additional priority. This policy allows transplant centers to attempt transplantation of desperately ill candidates without providing an additional advantage of organ allocation because it was thought that transplant candidates with MELD scores higher than 40 were at high risk for death at OLT.
Although patients with MELD scores of 40 or higher have the highest 3-month waiting list mortality rate (80% to 100%), these patients receive the greatest survival benefit from OLT, compared to patients with lower MELD scores. Allocation of organs to the sickest first has changed the characteristics of liver transplant recipients during the last decade and has brought new medical and economic challenges to bring these patients through OLT. Patients undergoing OLT today have more severe end-stage liver disease, are older, and have greater comorbidity, compared with the pre-MELD era. With implementation of broader sharing of deceased donor livers to patients with high acuity of illness, status 1, and MELD scores of 35 or higher, it is paramount to provide not only excellent medical care and achieve optimal outcomes in high-risk patients but also avoid futile transplantation in the face of organ crisis.
The UCLA group proposed that a cumulative futility risk score (UCLA Futility Risk Scoring System) that included disease-specific factors, including laboratory MELD score, cardiac risk, previous septic shock, and comorbidities, predicted posttransplant futility, rather than demographic, donor, or operative factors. Table 98-3 and Figure 98-2 show the cumulative UCLA Futility Risk Scoring System and long-term posttransplant patient survival outcomes. Cardiac risk and age-adjusted comorbidities were associated with the highest risk for futile outcome in the study. Cardiac risk factors that included elevated pretransplant serum troponin levels or history of cardiovascular disease and coronary artery disease were highly predictive of mortality and graft loss within 1 year after OLT, The scoring system included the Charlson Comorbidity Index (CCI), a validated instrument to assess whether a patient will live long enough to benefit from a specific screening measure or medical intervention. Age-adjusted CCI was highly predictive of futility, with no 5-year survivors among recipients with an age-adjusted CCI of 6 or higher. Another study also showed that both the CCI and individual comorbidities, including coronary artery disease, diabetes mellitus, chronic obstructive pulmonary disease, connective tissue disorders, and renal insufficiency, were associated with decreased posttransplant survival. Therefore cardiac and other aggravated comorbidities are probably the most important predictors of futile liver transplantation in the sickest patients.
Risk Factor | Points |
---|---|
MELD (per point) | 0.5 |
Pre-OLT septic shock | 3 |
Cardiac risk | 4 |
Age-adjusted Charlson Comorbidity Index ≥ 6 | 5 |
Based on the four identified independent futility predictors (MELD score, septic shock, cardiac risk, and age-adjusted CCI), the model had a good discriminatory ability with a C statistic of 0.75 compared to other established risk scores such as SOFT score (C statistic of 0.70), BAR score (C statistic of 0.68), and Donor Risk Index (DRI) (C statistic of 0.53). The proposed UCLA Futility Risk Score can be applied for risk stratification of the sickest patients considered for OLT. Liver transplant candidates with MELD scores of 40 or higher who have septic shock, cardiac risk, and significant comorbidities should not undergo liver transplantation because the predicted risk for futile outcome is greater than 75%. Based on this model excluding futility, the 5-year patient survival rate of our high MELD group at 75% was comparable to reported rates for all recipients in the United States (73%) and Europe (71%).
Although the long-term patient survival outcomes after primary OLT are excellent largely because of surgical innovations, advances in perioperative and intraoperative management, and immunosuppression regimens, 10% to 22% of OLT recipients require retransplantation of the liver (ReLT) for various reasons. For patients with failing hepatic grafts, ReLT is the only option for survival. In numerous studies, ReLT has been associated with lower survival rates than first transplantation and is considered a high-risk procedure because of the technical demands of the operation and the severity of illness of the ReLT candidates. Not only are there attendant medical and surgical problems, but these are also accompanied by financial and ethical issues because of the increased resource utilization of ReLT and the idea of denying patients awaiting their first transplant access to grafts. Nevertheless, good long-term survival has been demonstrated in select groups of retransplant recipients. Objectively, the decision of whether to retransplant a patient should involve the same considerations as the first time: the operative risk and the chances of long-term survival. Therefore it is important for clinicians to have tools to risk stratify ReLT candidates so that they can have an accurate predictor of survival after retransplantation of the liver.
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