- Email: [email protected]
Overview of the MELD Score and the UNOS Adult Liver Allocation System
CANDIDATES
Overview of the MELD Score and the UNOS Adult Liver Allocation System A.P. Martin, M. Bartels, J. Hauss, and J. Fangmann
ABSTRACT On February 27, 2002, the United Network for Organ Sharing (UNOS) introduced a new allocation policy for cadaveric liver transplants, based on the Model for End-Stage Liver Disease (MELD) score. This new policy stratifies the patients based on their risk of death while on the waiting list. We analyzed the background and main features of this new allocation policy to evaluate the effects on waiting list dynamics as well as the accuracy of MELD as a predictor of pretransplantation mortality and posttransplantation outcome. MELD has proved to be accurate as a predictor of waiting list mortality, but seems to be less accurate to predict posttransplantation outcome. Immediate effects of the new policy were a reduction in the waiting list, while organs were primarily directed to sicker patients with reduced waiting times. There was a statistically but not significantly reduced number of patients removed from the list due to death or severity of sickness. The balance between medical urgency and transplant benefit is still to be defined as is the relationship between pretransplantation criteria and posttransplantation outcomes, and the way this relationship should be included in the allocation policy.
S
INCE LIVER TRANSPLANTATION has become a universally accepted treatment for end-stage liver disease, the number of patients accumulating on the waiting list has gradually outweighed the scarce resources of available organs. Fair allocation of donor livers to patients with end-stage liver disease is a difficult task. The United States and Europe use prioritization systems based on waiting time and on the parameters of the Child-Turcotte-Pugh (CTP) score. However, these systems put too much emphasis on waiting time as a prioritization criterion. The transplant community, as well as the patient population, felt that there
was a lack of objective criteria to quantify the severity or progression of liver disease. Indeed, the CTP score was never prospectively validated as an accurate predictor of mortality for patients on the transplant waiting list.1 Also, it includes 2 subjective variables—ascites and encephalopathy—and From the Department of Visceral and Transplant Surgery, Universitetsklinik Leipzig, Leipzig, Sachsen, Germany. Address reprint requests to Adrian P. Martin, MD, Universita˙tsklinik Leipzig, Leibigstrasse 20a, Leipzig, Sachsen 04103, Germany. E-mail: [email protected]
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.04.025
Transplantation Proceedings, 39, 3169 –3174 (2007)
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MARTIN, BARTELS, HAUSS ET AL Table 1. The MELD and PELD Equations
MELD Score ⫽ 0.957 ⫻ Loge(creatinine mg/dL) ⫹ 0.378 ⫻ Loge(bilirubin mg/dL) ⫹ 1.120 ⫻ Loge (INR) ⫹ 0.643 The PELD equation includes corrections for growth failure (if growth is ⱕ2 SD than age equivalent growth parameters) and for age less than 1 year. Albumin, as marker of hepatic malfunction, has replaced creatinine from the adult equivalent MELD score. PELD Score ⫽ 0.436 (Age (⬍1 YR.)) ⫺ 0.687 ⫻ Loge(albumin g/dL) ⫹ 0.480 ⫻ Loge(total bilirubin mg/dL) ⫹ 1.857 ⫻ Loge(INR) ⫹ 0.667 [Growth failure (ⱕ2 Std. Deviations present)]
does not discriminate between patients with progressively altered laboratory values. HISTORY OF THE MODEL FOR END-STAGE LIVER DISEASE
Over time, increasing evidence suggested that a prioritization system should allocate organs based on the need for a transplant, rather than on the waiting time. In 1999, a Liver Disease Severity Score (LDSS) Committee was formed within the Organ Procurement and Transplantation Network (OPTN), an institution administered by the United Network for Organ Sharing (UNOS). This committee was assigned the task to define a model that would accurately predict mortality on the waiting list. The Model for EndStage Liver Disease (MELD) has been proposed as an objective quantification method (Table 1). This score had been previously validated as a predictor of mortality among patients with end-stage liver disease undergoing transjugular intrahepatic portosystemic shunt (TIPS) procedures.1 In the pediatric population, however, the MELD score was not found to be an accurate predictor of mortality. Accordingly, the Pediatric End-Stage Liver Disease (PELD) score has been developed, replacing the creatinine value with albumin, and incorporating variables for age and growth failure in the calculation (Table 1). After defining transition policies to assure that the implementation of the new allocation system did not affect patients already on the waiting list, the new policy took effect starting February 27, 2002. WHAT IS MELD?
The MELD score was first reported in 20002 to be a predictor of mortality risk among patients undergoing TIPS. It is an equation using 3 clinical laboratory measurements that were observed to have statistical impact on patient mortality risk (Table 1). The MELD score is currently considered to be the most accurate predictor of 90-day mortality risk for patients on the liver transplant waiting list. Before being validated and introduced in practice, the score was found to accurately predict mortality in several cohorts of patients with various disease etiologies.3–5 UNOS TERRITORY
UNOS is a private, nonprofit organization that was contracted by the US Government to regulate and manage the
organ allocation system in the United States. The territory of the United States is divided into 11 UNOS regions. Within each region, there are several Organ Procurement Agencies (OPO). Each OPO serves several transplant centers within their territory. The OPO centralizes the patients from the waiting lists of all centers within its territory and grants them priority by MELD score, so that available organs will first be allocated to the patients in descending order of MELD score within each specific OPO. Organ prioritization is denominated as “local” (within the OPO), “regional” (within a UNOS region), and “national.” HOW DOES THE ALLOCATION SYSTEM WORK?
Patients are prioritized on the waiting list within each blood type group by descending MELD score. This implies that the organs are basically allocated to the waitlisted patients with the highest mortality risk at the given time. Within each MELD score, livers are first allocated to blood typeidentical patients. To prevent inequitable distribution of organs, blood type O livers may only be attributed to blood type O recipients. The system allows patients with special situations (like very small size adult patients or AB type patients) to be listed for more than one blood type and thus be granted a higher chance of receiving a transplant. MELD scores have to be updated periodically (every 7 days for Status 1 patients and patients with MELD higher than 25). The UNOS algorithm for liver allocation is shown in Table 2. The organ allocation is first directed to local recipients (listed at centers within the OPO). Should there be no adequate recipient within the OPO, the offer is directed regionally and, ultimately, nationally. The impact of this policy is that cold ischemia time is reduced by shipping the organs within a limited territory. By reducing the cold ischemia time, and thus improving the quality of the transplanted organs, and by lowering the logistical and transportation expenses, the global costs of the procedure are also reduced. Attributing organs to regional patients with MELD higher than 15 before local patients with lower MELD is a measure that attempts to remove the inequity of sicker patients waiting longer, while patients with questionable transplant benefit are transplanted. Even so, differences and inequalities between regions and Table 2. Adult Donor Liver Allocation Policy 1. Local Status 1 patients in descending point order 2. Regional Status 1 patients in descending point order 3. Local patients with 3 MELD/PELD Scores ⱖ 15 in descending order of mortality risk scores (probability of candidate death) 4. Regional patients with MELD/PELD Scores ⱖ 15 in descending order of mortality risk scores (probability of candidate death) 5. Local patients with MELD/PELD Scores ⬍ 15 in descending order of mortality risk scores (probability of candidate death) 6. Regional patients with MELD/PELD Scores ⬍ 15 in descending order of mortality risk scores (probability of candidate death) 7. National Status 1 patients in descending point order Source: www.unos.org.
MELD AND UNOS LIVER ALLOCATION SYSTEM
between OPOs cannot be totally removed. The number, experience, and volume of transplant centers within OPOs, as well as the experience and efficacy of the OPOs themselves, differ within large ranges, resulting in differences of average transplantation MELD scores among OPOs and among regions. Schaffer et al,6 in a study involving 1 UNOS region with 3 OPOs, mentioned that within OPOs with competing transplant centers, patients received transplants at significantly higher MELD scores and using more MELD exceptions than within OPOs with single-center domination. Adult Status 1 patients may also be allocated pediatric livers; however, pediatric Status 1 patients have priority. By definition, adult Status 1 patients are those patients who fulfill 1 of the following criteria: (1) fulminant hepatic failure, with a life expectancy less than 7 days without a liver transplant; (2) primary nonfunction (PNF) of a transplanted liver within 7 days of implantation; (3) hepatic artery thrombosis (HAT) in a transplanted liver within 7 days of implantation; or (4) acute decompensated Wilson’s disease.
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thus, their MELD score cannot further be increased. Also, 40 is the maximal score that can be attributed to a patient; patients with MELD scores higher than 40, while not receiving any extra priority, can still be transplanted if deemed reasonable by the transplant center. MELD EXCEPTIONS
It is recognized that there are categories of patients whose MELD scores do not reflect the true urgency of their need for transplantation. Several categories of patients qualify under current regulations for various degrees of upgrading of their MELD scores to values that would allow them to undergo transplantation within a predictable time frame. Examples of exceptions include patients with hepatocellular carcinoma (HCC); biliary strictures; recurrent biliary sepsis; refractory upper gastrointestinal and variceal bleeding requiring transfusions and/or Blakemore tube insertion; refractory ascites and/or pleural effusions when TIPS is contraindicated; hepatopulmonary syndrome; metabolic diseases; severe polycystic liver disease; and pulmonary hypertension.
TOO HEALTHY VERSUS TOO SICK
One of the problems that has been raised is the balance between allocating the organs to the sickest patients (with the drawback of poorer posttransplantation outcome) versus allocating them to patients who would benefit most from transplantation by having the best survival rates. The interest of a liver transplant candidate is best served when the expected survival is higher than that without transplantation. It has been shown that among patients with MELD scores under 15, the mortality risk with transplantation is higher than the mortality risk without transplantation.7,8 There is, however, a certain death rate on the waiting list among these patients: 53 deaths per 1000 patient years. There are also isolated patients with low MELD scores who have significant complications of end-stage liver disease: 17% of transplantations in the period from February 2002 to August 2003 occurred in patients with MELD scores under 15.9 Imposing a minimal transplant score has been a widely debated topic. By applying this policy, organs would be directed toward patients with higher MELD scores; also, transplantation with low MELD scores and thus less benefit from the operation would be avoided. Recent UNOS policies have required a minimal transplant score of 15. Exceptions can be granted in selected cases (eg, for AB blood type or direct donation). At the other end of the disease spectrum, there are patients who are too sick to withstand liver transplantation. Allocating organs to these patients may not benefit them and may also be a waste of valuable organ resources. To limit this, 2 measures have been implemented. The creatinine value has been capped at 4 mg/dL. For patients with values above 4 mg/dL, as well as those undergoing hemodialysis, this maximal value is used in the calculation, and
TRANSPLANTATION OF PATIENTS WITH HCC
Prioritization of patients with HCC is one of the most debated topics. Under the previous organ allocation system, Yao et al10 found a 25% yearly dropout rate from the waiting list due to progressive disease. Still, putting these patients at advantage may diminish the chances of otherwise sicker candidates to receive an organ in time. Currently, T2 tumors (namely, 1 nodule 2.0 to 5.0 cm: 2 or 3 nodules, all ⬍3.0 cm as defined by the American Liver Tumor Study Group Modified Tumor-Node-Metastasis Staging Classification) are allocated 24 MELD points. Considering that T1 patients are at a relatively low risk of being removed from the list because of tumor progression, since April 2004, T1 patients do not receive extra MELD points.11 Based on data reporting good outcomes among patients transplanted with tumors larger than 5 cm,12 the review boards can accept well-documented lesions beyond T2 criteria to be granted 24 MELD points. MELD AND RETRANSPLANTATION
Retransplanted patients tend to have a poorer outcome than patients undergoing a first liver transplantation. Data reported by Edwards and Harper in a study based on OPTN data13 showed that the MELD scores of retransplanted patients were higher than those of first-transplant patients. Also, in patients with MELD scores higher than 20, the relative risk of death on the waiting list was higher for relisted patients at similar MELD scores. Similar data were reported by other authors.14 These patients seem to have a greater risk of dying than that reflected by the MELD score, and the accuracy of MELD as a predictor of waitlist mortality is thus somewhat lower in relisted patients.
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MARTIN, BARTELS, HAUSS ET AL
Fig 1. Correlation between MELD score and waitlist mortality. Source: Olthoff et al,9 with permission.
IMPROVING THE PREDICTIVE ACCURACY OF THE MELD SCORE
Several factors have been studied as potential elements to improve the estimation of pretransplantation mortality. There are data to suggest that the change in MELD or PELD scores over short periods may correlate with higher mortality risk on the waiting list.15,16 Ascites, encephalopathy, and variceal bleeding do not add significant improvement to the statistical performance of MELD. Serum sodium seems to be a reliable surrogate for ascites. In one single-center study, hyponatremia correlated well with the presence of ascites and was a predictor of 3-month mortality.17 Adding serum sodium to MELD may improve the predictive value of the score. Further data are needed to assess its practical value. TRANSPLANT STATISTICS IN THE MELD ERA
After the implementation of MELD as the basis of organ allocation, a large amount of statistical work has been done to follow the results of this change on organ distribution. Correlation With Waitlist Mortality and Posttransplantation Outcome
Analyzing the correlation of the MELD score on patients listed within 1 year after the implementation of the new allocation system, a linear relationship was observed between MELD score and waitlist mortality (Fig 1). While the MELD score was confirmed as an excellent predictor of waitlist mortality, its relationship with posttransplantation outcome was less consistent. Still, there was a correlation between the pretransplantation MELD score and patient survival after transplantation.13 The 2004 OPTN/SRTR Annual Report showed slightly lower 3-month and 1-year survivals for patients with MELD ⬎ 30.18 The same tendency was noted for graft survival. Olthoff et al9 cited data from The Mayo Clinic (Rochester, Minn) showing that patients with MELD ⬎ 30 displayed lower survival rates than those
with lower MELD. This tendency was based on a steep decrease in survival in the first year, while at 5 years the survival curves for all MELD scores overlapped (Fig 2). Graft survival decreased for patients with MELD ⬎ 30, while it was fairly equal among patients with lower MELD. Effects on the Waiting List
Before implementation of the current allocation system, the waiting time for a liver transplant grew constantly from an average of 225 days in 1994 to 1811 days in 1999. Adding patients early on to the transplant list based on the necessity to accrue waiting time, rather than on medical urgency, was one of the main reasons behind the continuous growth of the waiting lists. The new system drastically de-emphasizes the importance of waiting time and imposes minimal criteria for transplantation, leading to a significant reduction in overall waiting time.8 Between February 2002 and February 2003, there was a 12% reduction in waiting list registrations, especially among patients with low MELD scores, as an effect of a reduced urge to list patients to accrue waiting time. Thereafter the number of waitlisted patients has again been showing a slowly increasing trend.19 Among the waitlisted patients in 2003, 96% had MELD scores ⱕ 20 and 43% had MELD ⬍ 10.8 However, after implementation of the new organ allocation policy, the death rate on the waiting list did not significantly decrease. In an analysis of the first “afterMELD” year, Freeman et al1 found only a 4% (P ⫽ .076) decrease in waiting list mortality, possibly as a result of the listing dynamics, which balanced the quicker transplantation of sicker patients with an increased listing of sicker patients. This also meant a shifting of available organs toward patients in more need for a transplant. Effects on the Rate of Transplantation
An overall increased rate of transplantation was observed after implementation of the new allocation policy, in the
MELD AND UNOS LIVER ALLOCATION SYSTEM
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Fig 2. Correlation between MELD score and postoperative survival rate. Source Olthoff et al,9 with permission.
context of a better rate of usage of cadaveric donors (Table 3). The response might be related to the increased use of marginal donors in an era when, through the MELD score, one can better assess the probability of a patient to tolerate a less optimal organ. As seen from the data in Table 1, the increased rate of transplanted livers after 2002 cannot simply be attributed to a steadily increasing trend of the transplantation rate. Other factors that need to be taken into account to explain this growth include the higher rate of organ donor referrals and consent to donation. These increased by almost 10% and 5%, respectively, from 2002 to 2003.18 FUTURE TRENDS
Even if the new organ allocation policy is considered to be an improvement in comparison to the waiting time-based prioritization, it is still far from perfect. There are still many areas of concern and many discrepancies. Inter- and intraregional differences in number and size of transplant centers, as well as in the efficiency of OPOs, make a difference in the patients’ chances of receiving a transplant and in the average transplantation MELD scores.6,18 Thus, patients Table 3. Rate of Increase in the Absolute Number of Cadaveric Liver Transplantations in the United States Year
Cadaveric Liver Transplantations
Increase From Previous Year (%)
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
4020 4100 4424 4498 4595 4671 4969 5351 5846 6121
2 7.9 1.6 2.1 1.6 6.3 7.7 9.3 4.7
Source: OPTN data, May 18, 2006.
with equal MELD scores but located in different regions have different chances of receiving a transplant and different waiting times. Intraregional sharing of organs is a feature of interest for a more equitable allocation. Other areas of improvement are centered on the already mentioned concept of transplant benefit. The ultimate goal of organ allocation would be to allocate organs to patients who would have the best posttransplantation outcome, while at the same time reducing as much as possible the removal rate due to death or severity of sickness from the waiting list. MELD alone does not serve both these goals, and is especially vulnerable in the prediction of posttransplantation outcome. Improving this aspect would require adding donor- and center-dependent factors to the allocation algorithm, but further data are necessary to sustain such a change. Future developments may also be directed toward attempting to match donor organs and recipients through an elaborate information network. Such attempts have already been made at the University of Birmingham.20 In conclusion, the MELD score has proved to be effective as a predictor of pretransplantation mortality. It is currently the most reliable criterion to select waitlisted patients for liver transplantation. The applicability of MELD exceptions adds versatility and flexibility to the allocation algorithm. As time passes, further efforts to monitor the weaknesses and the strengths of this promising system must be undertaken. REFERENCES 1. Freeman RB, Wiesner RH, Harper A, et al, for the UNOS/ OPTN Liver Disease Severity Score, UNOS/OPTN Liver and Intestine, and UNOS/OPTN Pediatric Transplantation Committees: The New Liver Allocation System: Moving Toward EvidenceBased Transplantation Policy. Liver Transpl 8:851, 2002 2. Malinchoc M, Kamath PS, Gordon FD, et al: A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 31:864, 2000 3. Wiesner RH, McDiarmid SV, Kamath PS, et al: MELD and PELD: application of survival models to liver allocation. Liver Transpl 7:567, 2001
3174 4. Hanley JA, McNeil BJ: The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 143:29, 1982 5. Kamath PS, Wiesner RH, Malinchoc M, et al: A model to predict survival in patients with end stage liver disease. Hepatology 33:464, 2001 6. Schaffer RL III, Kulkarni S, Harper A, et al: The sickest first? Disparities with model for end-stage liver disease-based organ allocation: one region’s experience. Liver Transpl 9:1211, 2003 7. Merion RM, Schaubel DE, Dykstra DM, et al: The survival benefit of liver transplantation. Am J Transplant 5:307, 2005 8. Hanto DW, Fishbein TM, Wright Pinson C, et al: Liver and intestine transplantation: summary analysis 1994 –2003. Am J Transplant 5:916, 2005 9. Olthoff K, Brown RS, Delmonico FL, et al: Summary report of a national conference: evolving concepts in liver allocation in the MELD and PELD era. Liver Transpl 10:A6, 2004 10. Yao FY, Bass NM, Nikolai B, et al: Liver transplantation for hepatocellular carcinoma: analysis of survival according to the intention-to-treat principle and dropout from the waiting list. Liver Transpl 8:873, 2002 11. Sharma P, Balan V, Hernandez JL, et al: Liver transplantation for hepatocellular carcinoma: the MELD impact. Liver Transpl 10:36, 2004 12. Yao FY, Ferrell L, Bass NM, et al: Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 33:1394, 2001 13. Merion RM, Wolfe RA, Schaubel D, et al: Final analysis for SRTR data requests from the OPTN Liver Intestine Transplantation Committee Meeting of May 14 –15, 2003
MARTIN, BARTELS, HAUSS ET AL 14. Onaca N, Levy MF, Ueno T, et al: An outcome comparison between primary liver transplantation and retransplantation based on the pretransplant MELD score. Transpl Int 19:282, 2006 15. Merion RM, Wolfe RA, Dykstra DM, et al: Longitudinal assessment of mortality risk among candidates for liver transplantation. Liver Transpl 9:12, 2003 16. Report of the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee to the Board of Directors, June 26 –27, 2003 17. Ruf AD, Yanrorno SE, Descalzi VI, et al: Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone. A single center experience. Am J Transplant 4:438, 2004 18. 2004 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994 –2003. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, Md; United Network for Organ Sharing, Richmond, Va; University Renal Research and Education Association, Ann Arbor, Mich 19. 2005 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994 –2004. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, Md; United Network for Organ Sharing, Richmond, Va; University Renal Research and Education Association, Ann Arbor, Mich 20. Lucey M: How will patients be selected for transplantation in the future? Liver Transpl 10:S90, 2004
Overview of the MELD Score and the UNOS Adult Liver Allocation System A.P. Martin, M. Bartels, J. Hauss, and J. Fangmann
ABSTRACT On February 27, 2002, the United Network for Organ Sharing (UNOS) introduced a new allocation policy for cadaveric liver transplants, based on the Model for End-Stage Liver Disease (MELD) score. This new policy stratifies the patients based on their risk of death while on the waiting list. We analyzed the background and main features of this new allocation policy to evaluate the effects on waiting list dynamics as well as the accuracy of MELD as a predictor of pretransplantation mortality and posttransplantation outcome. MELD has proved to be accurate as a predictor of waiting list mortality, but seems to be less accurate to predict posttransplantation outcome. Immediate effects of the new policy were a reduction in the waiting list, while organs were primarily directed to sicker patients with reduced waiting times. There was a statistically but not significantly reduced number of patients removed from the list due to death or severity of sickness. The balance between medical urgency and transplant benefit is still to be defined as is the relationship between pretransplantation criteria and posttransplantation outcomes, and the way this relationship should be included in the allocation policy.
S
INCE LIVER TRANSPLANTATION has become a universally accepted treatment for end-stage liver disease, the number of patients accumulating on the waiting list has gradually outweighed the scarce resources of available organs. Fair allocation of donor livers to patients with end-stage liver disease is a difficult task. The United States and Europe use prioritization systems based on waiting time and on the parameters of the Child-Turcotte-Pugh (CTP) score. However, these systems put too much emphasis on waiting time as a prioritization criterion. The transplant community, as well as the patient population, felt that there
was a lack of objective criteria to quantify the severity or progression of liver disease. Indeed, the CTP score was never prospectively validated as an accurate predictor of mortality for patients on the transplant waiting list.1 Also, it includes 2 subjective variables—ascites and encephalopathy—and From the Department of Visceral and Transplant Surgery, Universitetsklinik Leipzig, Leipzig, Sachsen, Germany. Address reprint requests to Adrian P. Martin, MD, Universita˙tsklinik Leipzig, Leibigstrasse 20a, Leipzig, Sachsen 04103, Germany. E-mail: [email protected]
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.04.025
Transplantation Proceedings, 39, 3169 –3174 (2007)
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MARTIN, BARTELS, HAUSS ET AL Table 1. The MELD and PELD Equations
MELD Score ⫽ 0.957 ⫻ Loge(creatinine mg/dL) ⫹ 0.378 ⫻ Loge(bilirubin mg/dL) ⫹ 1.120 ⫻ Loge (INR) ⫹ 0.643 The PELD equation includes corrections for growth failure (if growth is ⱕ2 SD than age equivalent growth parameters) and for age less than 1 year. Albumin, as marker of hepatic malfunction, has replaced creatinine from the adult equivalent MELD score. PELD Score ⫽ 0.436 (Age (⬍1 YR.)) ⫺ 0.687 ⫻ Loge(albumin g/dL) ⫹ 0.480 ⫻ Loge(total bilirubin mg/dL) ⫹ 1.857 ⫻ Loge(INR) ⫹ 0.667 [Growth failure (ⱕ2 Std. Deviations present)]
does not discriminate between patients with progressively altered laboratory values. HISTORY OF THE MODEL FOR END-STAGE LIVER DISEASE
Over time, increasing evidence suggested that a prioritization system should allocate organs based on the need for a transplant, rather than on the waiting time. In 1999, a Liver Disease Severity Score (LDSS) Committee was formed within the Organ Procurement and Transplantation Network (OPTN), an institution administered by the United Network for Organ Sharing (UNOS). This committee was assigned the task to define a model that would accurately predict mortality on the waiting list. The Model for EndStage Liver Disease (MELD) has been proposed as an objective quantification method (Table 1). This score had been previously validated as a predictor of mortality among patients with end-stage liver disease undergoing transjugular intrahepatic portosystemic shunt (TIPS) procedures.1 In the pediatric population, however, the MELD score was not found to be an accurate predictor of mortality. Accordingly, the Pediatric End-Stage Liver Disease (PELD) score has been developed, replacing the creatinine value with albumin, and incorporating variables for age and growth failure in the calculation (Table 1). After defining transition policies to assure that the implementation of the new allocation system did not affect patients already on the waiting list, the new policy took effect starting February 27, 2002. WHAT IS MELD?
The MELD score was first reported in 20002 to be a predictor of mortality risk among patients undergoing TIPS. It is an equation using 3 clinical laboratory measurements that were observed to have statistical impact on patient mortality risk (Table 1). The MELD score is currently considered to be the most accurate predictor of 90-day mortality risk for patients on the liver transplant waiting list. Before being validated and introduced in practice, the score was found to accurately predict mortality in several cohorts of patients with various disease etiologies.3–5 UNOS TERRITORY
UNOS is a private, nonprofit organization that was contracted by the US Government to regulate and manage the
organ allocation system in the United States. The territory of the United States is divided into 11 UNOS regions. Within each region, there are several Organ Procurement Agencies (OPO). Each OPO serves several transplant centers within their territory. The OPO centralizes the patients from the waiting lists of all centers within its territory and grants them priority by MELD score, so that available organs will first be allocated to the patients in descending order of MELD score within each specific OPO. Organ prioritization is denominated as “local” (within the OPO), “regional” (within a UNOS region), and “national.” HOW DOES THE ALLOCATION SYSTEM WORK?
Patients are prioritized on the waiting list within each blood type group by descending MELD score. This implies that the organs are basically allocated to the waitlisted patients with the highest mortality risk at the given time. Within each MELD score, livers are first allocated to blood typeidentical patients. To prevent inequitable distribution of organs, blood type O livers may only be attributed to blood type O recipients. The system allows patients with special situations (like very small size adult patients or AB type patients) to be listed for more than one blood type and thus be granted a higher chance of receiving a transplant. MELD scores have to be updated periodically (every 7 days for Status 1 patients and patients with MELD higher than 25). The UNOS algorithm for liver allocation is shown in Table 2. The organ allocation is first directed to local recipients (listed at centers within the OPO). Should there be no adequate recipient within the OPO, the offer is directed regionally and, ultimately, nationally. The impact of this policy is that cold ischemia time is reduced by shipping the organs within a limited territory. By reducing the cold ischemia time, and thus improving the quality of the transplanted organs, and by lowering the logistical and transportation expenses, the global costs of the procedure are also reduced. Attributing organs to regional patients with MELD higher than 15 before local patients with lower MELD is a measure that attempts to remove the inequity of sicker patients waiting longer, while patients with questionable transplant benefit are transplanted. Even so, differences and inequalities between regions and Table 2. Adult Donor Liver Allocation Policy 1. Local Status 1 patients in descending point order 2. Regional Status 1 patients in descending point order 3. Local patients with 3 MELD/PELD Scores ⱖ 15 in descending order of mortality risk scores (probability of candidate death) 4. Regional patients with MELD/PELD Scores ⱖ 15 in descending order of mortality risk scores (probability of candidate death) 5. Local patients with MELD/PELD Scores ⬍ 15 in descending order of mortality risk scores (probability of candidate death) 6. Regional patients with MELD/PELD Scores ⬍ 15 in descending order of mortality risk scores (probability of candidate death) 7. National Status 1 patients in descending point order Source: www.unos.org.
MELD AND UNOS LIVER ALLOCATION SYSTEM
between OPOs cannot be totally removed. The number, experience, and volume of transplant centers within OPOs, as well as the experience and efficacy of the OPOs themselves, differ within large ranges, resulting in differences of average transplantation MELD scores among OPOs and among regions. Schaffer et al,6 in a study involving 1 UNOS region with 3 OPOs, mentioned that within OPOs with competing transplant centers, patients received transplants at significantly higher MELD scores and using more MELD exceptions than within OPOs with single-center domination. Adult Status 1 patients may also be allocated pediatric livers; however, pediatric Status 1 patients have priority. By definition, adult Status 1 patients are those patients who fulfill 1 of the following criteria: (1) fulminant hepatic failure, with a life expectancy less than 7 days without a liver transplant; (2) primary nonfunction (PNF) of a transplanted liver within 7 days of implantation; (3) hepatic artery thrombosis (HAT) in a transplanted liver within 7 days of implantation; or (4) acute decompensated Wilson’s disease.
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thus, their MELD score cannot further be increased. Also, 40 is the maximal score that can be attributed to a patient; patients with MELD scores higher than 40, while not receiving any extra priority, can still be transplanted if deemed reasonable by the transplant center. MELD EXCEPTIONS
It is recognized that there are categories of patients whose MELD scores do not reflect the true urgency of their need for transplantation. Several categories of patients qualify under current regulations for various degrees of upgrading of their MELD scores to values that would allow them to undergo transplantation within a predictable time frame. Examples of exceptions include patients with hepatocellular carcinoma (HCC); biliary strictures; recurrent biliary sepsis; refractory upper gastrointestinal and variceal bleeding requiring transfusions and/or Blakemore tube insertion; refractory ascites and/or pleural effusions when TIPS is contraindicated; hepatopulmonary syndrome; metabolic diseases; severe polycystic liver disease; and pulmonary hypertension.
TOO HEALTHY VERSUS TOO SICK
One of the problems that has been raised is the balance between allocating the organs to the sickest patients (with the drawback of poorer posttransplantation outcome) versus allocating them to patients who would benefit most from transplantation by having the best survival rates. The interest of a liver transplant candidate is best served when the expected survival is higher than that without transplantation. It has been shown that among patients with MELD scores under 15, the mortality risk with transplantation is higher than the mortality risk without transplantation.7,8 There is, however, a certain death rate on the waiting list among these patients: 53 deaths per 1000 patient years. There are also isolated patients with low MELD scores who have significant complications of end-stage liver disease: 17% of transplantations in the period from February 2002 to August 2003 occurred in patients with MELD scores under 15.9 Imposing a minimal transplant score has been a widely debated topic. By applying this policy, organs would be directed toward patients with higher MELD scores; also, transplantation with low MELD scores and thus less benefit from the operation would be avoided. Recent UNOS policies have required a minimal transplant score of 15. Exceptions can be granted in selected cases (eg, for AB blood type or direct donation). At the other end of the disease spectrum, there are patients who are too sick to withstand liver transplantation. Allocating organs to these patients may not benefit them and may also be a waste of valuable organ resources. To limit this, 2 measures have been implemented. The creatinine value has been capped at 4 mg/dL. For patients with values above 4 mg/dL, as well as those undergoing hemodialysis, this maximal value is used in the calculation, and
TRANSPLANTATION OF PATIENTS WITH HCC
Prioritization of patients with HCC is one of the most debated topics. Under the previous organ allocation system, Yao et al10 found a 25% yearly dropout rate from the waiting list due to progressive disease. Still, putting these patients at advantage may diminish the chances of otherwise sicker candidates to receive an organ in time. Currently, T2 tumors (namely, 1 nodule 2.0 to 5.0 cm: 2 or 3 nodules, all ⬍3.0 cm as defined by the American Liver Tumor Study Group Modified Tumor-Node-Metastasis Staging Classification) are allocated 24 MELD points. Considering that T1 patients are at a relatively low risk of being removed from the list because of tumor progression, since April 2004, T1 patients do not receive extra MELD points.11 Based on data reporting good outcomes among patients transplanted with tumors larger than 5 cm,12 the review boards can accept well-documented lesions beyond T2 criteria to be granted 24 MELD points. MELD AND RETRANSPLANTATION
Retransplanted patients tend to have a poorer outcome than patients undergoing a first liver transplantation. Data reported by Edwards and Harper in a study based on OPTN data13 showed that the MELD scores of retransplanted patients were higher than those of first-transplant patients. Also, in patients with MELD scores higher than 20, the relative risk of death on the waiting list was higher for relisted patients at similar MELD scores. Similar data were reported by other authors.14 These patients seem to have a greater risk of dying than that reflected by the MELD score, and the accuracy of MELD as a predictor of waitlist mortality is thus somewhat lower in relisted patients.
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MARTIN, BARTELS, HAUSS ET AL
Fig 1. Correlation between MELD score and waitlist mortality. Source: Olthoff et al,9 with permission.
IMPROVING THE PREDICTIVE ACCURACY OF THE MELD SCORE
Several factors have been studied as potential elements to improve the estimation of pretransplantation mortality. There are data to suggest that the change in MELD or PELD scores over short periods may correlate with higher mortality risk on the waiting list.15,16 Ascites, encephalopathy, and variceal bleeding do not add significant improvement to the statistical performance of MELD. Serum sodium seems to be a reliable surrogate for ascites. In one single-center study, hyponatremia correlated well with the presence of ascites and was a predictor of 3-month mortality.17 Adding serum sodium to MELD may improve the predictive value of the score. Further data are needed to assess its practical value. TRANSPLANT STATISTICS IN THE MELD ERA
After the implementation of MELD as the basis of organ allocation, a large amount of statistical work has been done to follow the results of this change on organ distribution. Correlation With Waitlist Mortality and Posttransplantation Outcome
Analyzing the correlation of the MELD score on patients listed within 1 year after the implementation of the new allocation system, a linear relationship was observed between MELD score and waitlist mortality (Fig 1). While the MELD score was confirmed as an excellent predictor of waitlist mortality, its relationship with posttransplantation outcome was less consistent. Still, there was a correlation between the pretransplantation MELD score and patient survival after transplantation.13 The 2004 OPTN/SRTR Annual Report showed slightly lower 3-month and 1-year survivals for patients with MELD ⬎ 30.18 The same tendency was noted for graft survival. Olthoff et al9 cited data from The Mayo Clinic (Rochester, Minn) showing that patients with MELD ⬎ 30 displayed lower survival rates than those
with lower MELD. This tendency was based on a steep decrease in survival in the first year, while at 5 years the survival curves for all MELD scores overlapped (Fig 2). Graft survival decreased for patients with MELD ⬎ 30, while it was fairly equal among patients with lower MELD. Effects on the Waiting List
Before implementation of the current allocation system, the waiting time for a liver transplant grew constantly from an average of 225 days in 1994 to 1811 days in 1999. Adding patients early on to the transplant list based on the necessity to accrue waiting time, rather than on medical urgency, was one of the main reasons behind the continuous growth of the waiting lists. The new system drastically de-emphasizes the importance of waiting time and imposes minimal criteria for transplantation, leading to a significant reduction in overall waiting time.8 Between February 2002 and February 2003, there was a 12% reduction in waiting list registrations, especially among patients with low MELD scores, as an effect of a reduced urge to list patients to accrue waiting time. Thereafter the number of waitlisted patients has again been showing a slowly increasing trend.19 Among the waitlisted patients in 2003, 96% had MELD scores ⱕ 20 and 43% had MELD ⬍ 10.8 However, after implementation of the new organ allocation policy, the death rate on the waiting list did not significantly decrease. In an analysis of the first “afterMELD” year, Freeman et al1 found only a 4% (P ⫽ .076) decrease in waiting list mortality, possibly as a result of the listing dynamics, which balanced the quicker transplantation of sicker patients with an increased listing of sicker patients. This also meant a shifting of available organs toward patients in more need for a transplant. Effects on the Rate of Transplantation
An overall increased rate of transplantation was observed after implementation of the new allocation policy, in the
MELD AND UNOS LIVER ALLOCATION SYSTEM
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Fig 2. Correlation between MELD score and postoperative survival rate. Source Olthoff et al,9 with permission.
context of a better rate of usage of cadaveric donors (Table 3). The response might be related to the increased use of marginal donors in an era when, through the MELD score, one can better assess the probability of a patient to tolerate a less optimal organ. As seen from the data in Table 1, the increased rate of transplanted livers after 2002 cannot simply be attributed to a steadily increasing trend of the transplantation rate. Other factors that need to be taken into account to explain this growth include the higher rate of organ donor referrals and consent to donation. These increased by almost 10% and 5%, respectively, from 2002 to 2003.18 FUTURE TRENDS
Even if the new organ allocation policy is considered to be an improvement in comparison to the waiting time-based prioritization, it is still far from perfect. There are still many areas of concern and many discrepancies. Inter- and intraregional differences in number and size of transplant centers, as well as in the efficiency of OPOs, make a difference in the patients’ chances of receiving a transplant and in the average transplantation MELD scores.6,18 Thus, patients Table 3. Rate of Increase in the Absolute Number of Cadaveric Liver Transplantations in the United States Year
Cadaveric Liver Transplantations
Increase From Previous Year (%)
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
4020 4100 4424 4498 4595 4671 4969 5351 5846 6121
2 7.9 1.6 2.1 1.6 6.3 7.7 9.3 4.7
Source: OPTN data, May 18, 2006.
with equal MELD scores but located in different regions have different chances of receiving a transplant and different waiting times. Intraregional sharing of organs is a feature of interest for a more equitable allocation. Other areas of improvement are centered on the already mentioned concept of transplant benefit. The ultimate goal of organ allocation would be to allocate organs to patients who would have the best posttransplantation outcome, while at the same time reducing as much as possible the removal rate due to death or severity of sickness from the waiting list. MELD alone does not serve both these goals, and is especially vulnerable in the prediction of posttransplantation outcome. Improving this aspect would require adding donor- and center-dependent factors to the allocation algorithm, but further data are necessary to sustain such a change. Future developments may also be directed toward attempting to match donor organs and recipients through an elaborate information network. Such attempts have already been made at the University of Birmingham.20 In conclusion, the MELD score has proved to be effective as a predictor of pretransplantation mortality. It is currently the most reliable criterion to select waitlisted patients for liver transplantation. The applicability of MELD exceptions adds versatility and flexibility to the allocation algorithm. As time passes, further efforts to monitor the weaknesses and the strengths of this promising system must be undertaken. REFERENCES 1. Freeman RB, Wiesner RH, Harper A, et al, for the UNOS/ OPTN Liver Disease Severity Score, UNOS/OPTN Liver and Intestine, and UNOS/OPTN Pediatric Transplantation Committees: The New Liver Allocation System: Moving Toward EvidenceBased Transplantation Policy. Liver Transpl 8:851, 2002 2. Malinchoc M, Kamath PS, Gordon FD, et al: A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 31:864, 2000 3. Wiesner RH, McDiarmid SV, Kamath PS, et al: MELD and PELD: application of survival models to liver allocation. Liver Transpl 7:567, 2001
3174 4. Hanley JA, McNeil BJ: The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 143:29, 1982 5. Kamath PS, Wiesner RH, Malinchoc M, et al: A model to predict survival in patients with end stage liver disease. Hepatology 33:464, 2001 6. Schaffer RL III, Kulkarni S, Harper A, et al: The sickest first? Disparities with model for end-stage liver disease-based organ allocation: one region’s experience. Liver Transpl 9:1211, 2003 7. Merion RM, Schaubel DE, Dykstra DM, et al: The survival benefit of liver transplantation. Am J Transplant 5:307, 2005 8. Hanto DW, Fishbein TM, Wright Pinson C, et al: Liver and intestine transplantation: summary analysis 1994 –2003. Am J Transplant 5:916, 2005 9. Olthoff K, Brown RS, Delmonico FL, et al: Summary report of a national conference: evolving concepts in liver allocation in the MELD and PELD era. Liver Transpl 10:A6, 2004 10. Yao FY, Bass NM, Nikolai B, et al: Liver transplantation for hepatocellular carcinoma: analysis of survival according to the intention-to-treat principle and dropout from the waiting list. Liver Transpl 8:873, 2002 11. Sharma P, Balan V, Hernandez JL, et al: Liver transplantation for hepatocellular carcinoma: the MELD impact. Liver Transpl 10:36, 2004 12. Yao FY, Ferrell L, Bass NM, et al: Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 33:1394, 2001 13. Merion RM, Wolfe RA, Schaubel D, et al: Final analysis for SRTR data requests from the OPTN Liver Intestine Transplantation Committee Meeting of May 14 –15, 2003
MARTIN, BARTELS, HAUSS ET AL 14. Onaca N, Levy MF, Ueno T, et al: An outcome comparison between primary liver transplantation and retransplantation based on the pretransplant MELD score. Transpl Int 19:282, 2006 15. Merion RM, Wolfe RA, Dykstra DM, et al: Longitudinal assessment of mortality risk among candidates for liver transplantation. Liver Transpl 9:12, 2003 16. Report of the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee to the Board of Directors, June 26 –27, 2003 17. Ruf AD, Yanrorno SE, Descalzi VI, et al: Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone. A single center experience. Am J Transplant 4:438, 2004 18. 2004 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994 –2003. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, Md; United Network for Organ Sharing, Richmond, Va; University Renal Research and Education Association, Ann Arbor, Mich 19. 2005 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994 –2004. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, Md; United Network for Organ Sharing, Richmond, Va; University Renal Research and Education Association, Ann Arbor, Mich 20. Lucey M: How will patients be selected for transplantation in the future? Liver Transpl 10:S90, 2004