Use of a Pediatric End-stage Liver Disease Score for Deceased Donor Allocation: The United States Experience

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1 69 SYMPOSIUM : Gastroenterology & Hepatology Use of a Pediatric End-stage Liver Disease Score for Deceased Donor Allocation: The United States Experience Sue V. McDiarmid 1, Robert M. Merion, Dawn M.Dykstra and Ann M. Harper 1 Departments of Pediatrics and Surgery, David Geffen School of Medicine at University of California, Los Angeles Scientific Registry of Transplant Recipients/University Renal Research and Education Association, Ann Arbor, MI Departments of Research and Allocation Policy, United Network of Organ Sharing, 700 North Fourth St, Richmond, VA, [Received November 21, 06; Accepted December 01, 06] ABSTRACT The Pediatric end-stage liver disease (PELD) score was developed as a measure of the severity of chronic liver disease that would predict mortality or children awaiting liver transplant. From multivariate analyses a model was derived that included five objective factors which together comprise the PELD score. The factors are growth failure, age less than 1 year, international normalized ratio (INR), serum albumin and total bilirubin. [Indian J Pediatr 07; 74 (4) : ] smcdiarmid@mednet.ucla.edu Key words : Mortality; Score; Transplant; Pediatric Prior to 02 both children and adults awaiting liver transplantation in the United States were placed into 4 broad urgency categories and within each category deceased donor livers were allocated to those with the longest waiting time. Several analyses showed that this allocation system had the undesired affect of directing livers to patients who were not the most medically urgent, and in fact just by virtue of long waiting times a surrogate marker of a stable patient many patients of greater medical urgency were being by-passed. In order to best utilize the scare resource of deceased donor livers and follow the U.S. government s directive to transplant patients with the highest medical urgency first, the transplant community co-operated to develop grading scores measuring severity of chronic liver disease, so that every patient on the liver waiting list could be ranked by their score. The pediatric end-stage liver disease score (PELD) and the medical end stage liver disease (MELD) score for adults, were developed simultaneously to create an integrated system of deceased donor liver allocation based on the severity of chronic liver disease. 1, 2 The Correspondence and Reprint requests : Dr. S.V. McDiarmid M.D., UCLA Medical Center, Rm MDCC, Le Conte Ave, Los Angeles, CA, MELD and PELD scores rank children and adults alike on a single liver waiting list according to their probability of death within three months of listing. The PELD score was derived from a population of children enrolled in the Studies of Pediatric Liver Transplantation (SPLIT) database. 3 SPLIT is a consortium of more than 40 pediatric liver transplant centers in the US and Canada who participate in the voluntary submission of comprehensive data from the pre, peri and post -transplant periods to a centralized clinical coordinating center. The PELD score was developed from 884 registrants for a first liver only transplant in SPLIT. Similar underlying principles were used to develop the PELD and MELD scores. The parameters tested for inclusion in the models were required to be objective and measurable, and the same statistical method (area under the receiver operator curve) was used to test the accuracy of the models. From multivariate analyses of the SPLIT population, factors included in a model that predicted death, or death and/or moving to the intensive care unit (ICU), within 3 months of listing, were: INR, total bilirubin, serum albumin, age <1 year, and height <2 standard deviations from the mean for age and sex. The PELD score derived from this model was highly accurate in predicting both death and death/moving to ICU within three months of listing, Indian Journal of Pediatrics, Volume 74 April,

2 70 S.V. McDiarmid et al with a receiver operating characteristic (ROC) of 0.92 and 0.82 respectively. In addition, the PELD score was validated as an accurate predictor of death on the waiting list in a separate population of children at a large single center. (ROC=0.89). 4 The PELD equation is shown in Table 1. TABLE 1. Pediatric End-Stage Liver Disease (PELD) Scoring System PELD Score = (Age (<1 YR.)) Log e (albumin g/dl) Log e (total bilirubin mg/dl) Log e (INR) (Growth failure (<-2 Std. Deviations present)). Notes: Laboratory values less than 1.0 will be set to 1.0 for the purposes of the PELD score calculation. Growth failure will be calculated based on age and gender using the current CDC growth chart. Scores for patients listed for liver transplantation before the patient s first birthday continue to include the value assigned for age (<1 Year) until the patient reaches the age of 24 months. The PELD and MELD scores are derived from distinctly different equations. The factors included in MELD score calculation are bilirubin, INR and serum creatinine. As well, the populations in which the scores were developed were different. 5, 6 As shown in Fig. 1, the MELD curve and the original SPLIT derived PELD survival curve that predicted survival three months after listing for transplant, were clearly separate. For any given numerical score, children as compared to adults had a lower probability of dying awaiting liver transplantation. A major concern of the pediatric liver transplant community at the time of implementation of MELD and PELD, was that under the new allocation policy, children would have a reduced access to transplantation, particularly as children on the waiting list are outnumbered 17 to 1 by adults, a discrepancy which continues to increase. 7 A particularly vulnerable group of children are those under two years of age, especially whether the concept of the benefit of transplantation, as measured by life years gained with or without transplant should be incorporated into allocation policies for children will be addressed. Further Validation of PELD in the OPTN Database The implementation of PELD (and MELD) has allowed for on-going analyses of the accuracy of PELD to predict survival on the waiting list under the new allocation policy, as opposed to the survival curve generated retrospectively from the SPLIT database. Fig. 1 shows how the original curve derived from the SPLIT predicting survival by PELD score 3 months after listing, has changed with the implementation of MELD/PELD. The new curves shown are derived from data collected after implementation of PELD and MELD by the Scientific Registry for Transplant Recipients (SRTR), which analyzes the mandatory data submitted by all transplant centers in the U.S. For comparison, an updated MELD curve is also shown. Note that for a severity score 0-25, children in comparison to adults, now have a lower probability of survival 3 months after listing. This is in contrast to the original SPLIT derived curve which predicted children always had a higher chance of survival at any give score. Above a severity score of 25 the PELD curve moves to the right of both the MELD curve and the original SPLIT derived PELD curve, indicating that in this higher score range children have a better chance of survival waiting for transplant as compared to adults. Percent Survival 100% 90% 80% 70% 60% 50% 40% MELD (June 04) PELD (June 04) those less than 1 year of age, for whom the highest death 30% rate on the waiting list has been consistently reported in % the United Network for Organ Sharing (UNOS) Annual Reports. 8 10% This review will address how the PELD allocation system has selected children for transplantation, including comparisons between the pre and post PELD eras. Reasons for removal from the waiting list, rates of both transplantation and death on the waiting list, will be compared for children and adults. An analysis of children transplanted at status 1, and the effect on donor allocation of retaining status 1 for children with chronic liver disease, and by exception will be presented. The impact of the new policy for pediatric donor allocation to pediatric recipients will be compared to the pre MELD/PELD era, and broader sharing of pediatric donors will be discussed. Finally, 0% PELD: SPLIT patients PELD (June 04) Only PELD Less Than Severity Score Fig. 1. Predicted probability of waiting list death (% survival) at 3 months by severity scores. Effect on Liver Waiting List: Comparing Pre and Post MELD/PELD Eras An analysis was performed comparing the percentage of adults and children removed from the liver transplant waiting list (for reasons of: deceased donor transplant, death, too sick to transplant, living donor transplant or other ), 1 year before, and 1 year after MELD/PELD implementation. Fig. 2 shows this 388 Indian Journal of Pediatrics, Volume 74 April, 07

3 71 Use of a Pediatric End-Stage Liver Disease Score for Deceased Donor % Removals % Pediatric Donors 50 Percent at Listing 40 Percent at Transplant < Deceased Death Too sick Living donor Other Recipient Age (Years) donor Tx Tx Fig. 3. Percentage of children listed and transplanted at allocation (ie match) PELD score ranges. Pediatric (<18) pre-meld Pediatric (<18) post-meld Source: SRTR analysis 2/27/02-3/31/04. Adult (18 and up) pre-meld Adult (18 and up) post-meld Fig. 2. Reasons for removal from the liver waiting list before and 60 after implementation of MELD/PELD. 50 comparison for both adults and children for the pre MELD/PELD era (2/27/01-2/26/02) and the post MELD/PELD era (2/27/02-2/26/03). In the pre MELD/PELD era 9,909 adults and 1,035 children were added to the list in comparison to 8,751 adults and 856 children in the first year after implementation. In the MELD/PELD era, the percentage of deceased donor transplants increased form 49% to 53% compared to a 2% increase for adults. Importantly, for both children and adults, the percentage of patients who died on the liver waiting list decreased between the pre and post MELD/PELD eras. The utilization of living donors decreased for both adults and children after implementation of MELD/PELD, and removals from the list for reasons other increased for both age ranges. These initial data suggested that the access to deceased donors for both children and adults had not been adversely affected by the change in allocation policy, and that overall death on the waiting list was reduced. 90 day Outcomes on the Liver Waiting List As both the MELD and PELD scores rank patients according to their probability of death 3 months after listing, outcomes of patients 90 days after listing is a relevant time point for assessment. Comparing 14,272 adults to 896 children 90 days after listing, added to the liver only waiting list between 2/27/02 and 12/31/03, and excluding status 1 and exceptional cases, the rate of deceased donor transplantation for children was higher, 37.8% than for adults 24.7%. The death rates were similar 8.3%% and 8.2% for children and adults respectively. PELD Scores at Listing and at Transplantation Fig. 3 shows the percentage of children within ranges of the match PELD score at the time of listing and at the time of transplantation for the time period 2/27/02 to 3/31/04. Note that the largest percentage of children were transplanted at a PELD score <10. Fig. 4 shows the percentage of patients transplanted within MELD/ % Pediatric Donors MELD at Transplant 40 PELD at Transplant < Recipient Age (Years) Fig. 4. Percentage of children and adults transplanted at allocation (ie match) score ranges. Source: SRTR analysis 2/27/02-3/31/04. TABLE 2. Mean and Median Lab PELD at Listing by Age and Previous Transplant Mean PELD Median Age at PELD listing <1 Year Years Years Years Previous liver transplant No Yes Source: OPTN/SRTR Data as of May 04. Includes all nonstatus I listings between 2/27/02 and 3/31/04 PELD (match score) ranges comparing children and adults. Only 5.8% of adults were transplanted at a score of less than 10 compared to 34.4% of children. Table 2 shows the mean and median calculated and match PELD scores at listing and at transplant by age. The youngest children, those <1 year of age, had substantially higher PELD scores than older children. Deaths on the Waiting List Children <2 years of age, particularly those <1 year of age, have previously had the highest mortality on the waiting list compared to any other age group. 8 Death on the liver waiting list, adjusted for time waiting on the list (per 1000 patient years), was compared for 12 Indian Journal of Pediatrics, Volume 74 April,

4 72 S.V. McDiarmid et al months before and the 25 months after implementation of MELD/PELD. As shown in Fig. 5, the implementation of MELD/PELD has reduced the high death rates of children < 2 years of age. Death Rate per 1,000 Patient Years at Risk Pre-MELD/PELD Adult (18+ years) Children <2 years Post-MELD/PELD All Pediatric (<18 years) Children <1 years Fig. 5. Death adjusted per 1000 patient years on the liver waiting list before and after implementation of MELD/PELD. Source: SRTR analysis 2/27/01-2/26/02 (pre) and 2/27/ 02-3/31/04 (post) MELD/PELD. The Effect of Status 1 for Children Status 1 is defined as patients with severe liver disease at risk of death within 7 days. Adults must have acute liver failure, primary non function, hepatic artery thrombosis or acutely decompensated liver Wilsons disease to qualify for this category. Children meeting these criteria also qualify for status 1, but unlike adults, children with chronic liver disease meeting specific criteria, can also be listed at status 1. As well, until recently, children (and adults) can be granted status 1 by exception after prospective approval by their Regional Review Boards (RRB). The RRBs consist of groups of transplant physicians and surgeons that meet in 11 geographic regions of the country. Their function is to adjudicate requests for additional MELD/PELD points or status 1 requests for patients whose physicians do not believe their risk of death on the list is accurately reflected by their score. A recent analysis of the OPTN database examined the percent of children transplanted at status 1 comparing 18 months before and after implementation of the MELD/PELD policy. 9 Forty eight percent (n=339) of all children who received deceased donor grafts were status 1 before MELD/PELD, compared to 41% (n=306) after MELD/ PELD implementation. Of these 23.3% and 29.7% were transplanted at status 1 by exception in the pre and post MELD/PELD eras respectively. The percent of children at status 1 who received a living donor was similar between eras 8.6% and 10.3% for the pre and post MELD/PELD respectively. The percent of children transplanted at status1 showed wide variations across the 11 geographic regions, ranging from as low as 7% to as high as 75%. Those transplanted at status 1 by exception ranging from 2.5 to 43.3% between regions. Biliary atresia was the diagnosis of about a third of 390 children transplanted at status 1 irrespective of era. There was a significant difference between the mean calculated PELD scores for children with fulminant liver failure (PELD = 24.6), those with chronic liver disease meeting standard criteria for Status 1 (PELD = 19.6) and for those children listed by exception, (PELD = 14.0 (P<0.001). Death rates were examined for the ranges of PELD score and the different categories of status 1 for children: fulminant liver failure, PNF/HAT, chronic liver disease with PELD <25, chronic liver disease with PELD>25, and status 1 by exception, for children added to the waiting list from 2/27/02 to 9/30/03. The death rate was calculated by dividing the number of deaths in each category by the total number of patient years in each category. The results (Table 3) show that children with fulminant liver failure, PNF/HAT and those with chronic liver failure (meeting criteria for status 1 and PELD > 25) had similiar and substantially higher death rates than children with chronic liver disease and PELD<25, and particularly those children listed at status 1 by exception. TABLE 3. Death Rates/1000 Patient Years for Different Status 1 Categories Status 1 # of Patient Death Median Lab Category Years Rate PELD Pulminant 5.9 (24) PNF/HAT 3.0 (12) Other (All) 5.6 (17) Other (lab 1.5 (7) PELD 25) Other (lab 4.1 ( PELD <25) Exception 3.9 (2) Six month patient and graft survival was compared for all children transplanted, those meeting status 1 standard criteria, those transplanted at status 1 by exception, and those transplanted at non status 1 (Figs. 6a and b). No significant differences between each of the groups or when comparing the pre and post MELD/ PELD era were seen. Pediatric Donors Allocated to Pediatric Recipients The implementation of MELD/PELD required a change in the previously established policy that allowed preference for pediatric aged donors (<18 years) to be allocated to pediatric recipients within each of the four status definitions, following the local, regional and national algorithm. Under MELD/PELD within the population of adults and children with a MELD or PELD score predicting a greater than 50% probability of death within 3 months of listing ( a MELD of 32 and a PELD of 46 respectively) a pediatric donor would first be allocated to a pediatric patient and then allocated to Indian Journal of Pediatrics, Volume 74 April, 07

5 73 Use of a Pediatric End-Stage Liver Disease Score for Deceased Donor 100% 90.3% 93.0% 92.5% 92.8% 88.6% 86.1% 81.5% 80.7% pediatric donors transplanted into children <2 years of age. 50% Pre PELD Post PELD DISCUSSION 0% 100% 50% 0% Overall Status 1 Status 1 Non Status 1 Standard Exception 83.2% 83.0% Fig. 6a 77.9% 76.1% 72.5% 86.4% 85.1% 88.6% Overall Status 1 Status 1 Non Status 1 Standard Exception Pre PELD Post PELD Fig. 6b Figs. 6a and 6b. Patient (8a) and graft (8b) pre and post MELD/ PELD implementation for children comparing: overall survival, status 1 meeting standard criteria, status 1 by exception, non Status 1. Source: OPTN analysis. an adult patient within this range. If the pediatric donor was not placed it would then be allocated first to a child in the population of patients with a less than 50% probability of death within 3 months of listing. The age of recipients of pediatric donors for 1 year prior to implementation of MELD/PELD was compared to 1-year after implementation. As shown in Fig. 7, regardless of era, the majority (50-60%) of pediatric donors were allocated to adults. Comparing the two eras there was a small decrease in the number of pediatric donors allocated to adults in the post MELD/ PELD era and a small increase in the number of Recipient Age (Years) Fig. 7. Percentage of pediatric donors allocated to recipients by age range, comparing pre and post MELD/PELD eras. Source: SRTR analysis. 2/27/01-2/26/02 (pre): 2/27/02 3/31/04 (post). Comparing time periods before and after the introduction of MELD/PELD a similar percentage of children are being transplanted, the death rates for children listed are lower and transplant outcomes are similar. These findings are in agreement with results reported for adult patients. 10 While these results reassure that access for children to transplantation and outcome after transplant have not been adversely effected by the new allocation policy, a closer analysis of the results suggest improvements in the system are warranted. Most obvious, is the uneven allocation of donor livers across the PELD score ranges, with two extremes evident. Almost half of all children are transplanted at status 1, and of the remainder, half again, are transplanted at PELD score < 10. Are the authors' transplanting too many children at status 1, and are too many children transplanted too early? Within the status 1 category only a minority of children have acute liver failure, PNF or HAT. Most have either chronic liver disease or enter status 1 by exception. The observation that almost 1/3 of children are listed by exception, and have a low probability of death on the waiting list in comparison to any other status 1 subset, suggests that the status 1 by exception designation should be reconsidered. Continuing to allow children listed at status 1 by exception, (1/3 of all status 1 children), to compete equally for organs with other status 1 children, and adults either at status 1 or with very high MELD scores, all of whom have substantially higher death rates, contravenes the U.S. Government s Department of Health and Human Services mandate 11 that priority should be given to transplanting the patient with the highest probability of dying first. As well, adults or children with high MELD/PELD scores, can be bypassed in favor of a status 1 listed child with a much lower probability of dying waiting. It is also important to note, that within the chronic liver disease group, only children with a PELD score >25 have a similar death rate on the list compared to those children with acute liver failure. A re-definition of status 1 for both children and adults has recently been instituted. The changes adopted include prioritizing children with acute liver failure meeting strict definitions, (including PNF and HAT) above any other status 1 child), a more strict definition of the criteria for status 1 chronic liver disease criteria, including a threshold PELD of >25, and eliminating the status 1 by exception category all together. Indian Journal of Pediatrics, Volume 74 April,

6 74 S.V. McDiarmid et al On the other end of the spectrum, too many children appear to be transplanted too early. Preliminary SRTR analyses (unpublished, personal communication from author RMM) suggest that children transplanted at a PELD score <10 have a higher probability of death after a transplant as compared to remaining on the list. While the numbers are admittedly small in the current analyses, this trend needs to be carefully followed. The way in which the PELD score selects pediatric patients for transplant, does not seem to have changed overall patient and graft survival. This is supported by other studies that have shown that in multivariate analyses the PELD score at transplant has no statistically significant effect on post transplant patient and graft survival at 6 months. The concept of transplant benefit has not yet been well studied in children. In adult liver transplantation the benefit of transplantation, as measured by the life years gained with or without transplantation, is becoming incorporated into liver allocation policy for adults. 12 Adults transplanted with a MELD score 17, have a statistically important decrease in life years gained if transplanted as compared to remaining on the waiting list. 13 As noted above, although a similar effect was seen for children transplanted at a PELD score <10, the pediatric transplant community has been cautious about adopting a policy that would preclude access to liver transplantation for these children. Not only were the numbers small in the analyses, but pediatric hepatologists have long held the opinion that the benefit of transplantation for children should not be limited to survival as the only relevant outcome. The benefit of transplantation on growth, 14 development, future cognitive function, and overall quality of life should not be discounted. At present, the difficulty lies in defining transplantation benefits other than survival, developing the appropriate measures of these benefits, as well as the required data collection to allow appropriate models to be constructed. Developing such models is a priority on the agenda of the SRTR. CONCLUSION The PELD score can be used to accurately rank by severity of chronic liver disease children awaiting liver transplantation. Until recently, the large number of children with chronic liver disease listed and transplanted at status 1 (and therefore not listed by PELD score) precluded the accurate ranking and therefore the predictability of death on the waiting list for children with high PELD scores. The recent more rigorous definition of status 1 criteria for children with chronic liver disease, and elimination of exceptions should allow improved allocation to the most medically urgent children listed either at status 1 or listed with a high PELD score. As well, broader sharing of pediatric donors, should result in improved equity for access to deceased donor livers for both children and adults awaiting liver transplantation. REFERENCES 1. Wiesner RH, McDiarmid SV, Kamath PS, Edward EB, Malinchoc M, Kremers WK et al. Meld and Peld: Application of Survival Models to Liver Allocation. Liver Transplantation 01; 7 : Freeman RB Jr, Wiesner RH, Harper A, McDiarmid SV, Lake J, Edwards, E et al. The new liver allocation system: moving toward evidence-based transplantation policy. Liver Transplantation 02; 8(9) : McDiarmid SV, Anand R, And Lindblad A. Development of a pediatric end stage liver disease score to predict poor outcome awaiting liver transplantation. Transplantation 02; 4. Mazariegos, G. V., Anand, R, and McDiarmid, S. V. Validation of PELD Severity Score in a Pediatric Transplant Candidate Database. Amer J Transplantation 02; 2(3) : Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL et al. A model to predict survival in patients with end-stage liver disease. Hepatology 01; 33 : SPLIT Research Group. Studies of Pediatric Liver Transplantation (SPLIT) : Year 00 Outcomes. Transplantation 01; 72 : McDiarmid, S. New liver allocation policies and their potential effect on pediatric patients awaiting liver transplantation. Pediatric Transplantation 02; 6 : HHS/HRSA/OSP/DOT, UNOS, and URREA. 02 OPTN/SRTR Annual Report McDiarmid, SV, Harper AM. Are too many pediatric liver recipients transplanted at status 1? Amer J Transplantation 4[Suppl 8] Freeman RB, Wiesner RH, Edwards E, Harper A, Merion R, and Wolfe R. Results of the first year of the new liver allocation plan. Liver Transplantation 04; 10(1) : Organ Procument and Transplantation Network-HRSA. Final Rule with comment period. Federal Register 1998; 63 : Olthoff KM, Brown R, Delmonico F, Freeman R, McDiarmid S, Merion et al. Evolving concepts in liver allocation in the MELD/PELD era: Summary Report of a National Conference. Liver Transplantation 04; 13. Merion RM, Schaubel DE, Dykstra DM, Freeman RB, Port, FK, Wolfe, RA. The survival benefit of liver transplantation. Amer Soc Transplant Physicians 4[Suppl 8] : McDiarmid SV, Gornbein JA, DeSilva P, Goss JA, Vargas JH, Martin MG et al. Factors affecting growth after pediatric liver transplantation. Transplantation 1999; 67 : Indian Journal of Pediatrics, Volume 74 April, 07