MELD and PELD: application of survival models to liver allocation.
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Health Care Rationing↗
Biomedical subjects
E B Edwards
Publications and source records attributed to E B Edwards.
Can energetic expenditure be minimized by performing activity intermittently?
Previous research has shown that the energetic expense per unit distance traveled for one bout of short-duration activity is much greater than the energetic expense associated with long-duration activity. However, animals are often seen moving intermittently, with these behaviors characterized by brief bouts of activity interspersed with brief pauses. We hypothesized that, when multiple bouts of brief activity are performed intermittently, the energetic cost per unit distance is less than when only one short bout is performed. Mice were run 1, 2, 3, 5, 9 or 13 times for 15 s at their maximal speed within a 375 s period while enclosed in an open-flow respirometry system on a treadmill. The mice were also run continuously for 375 s. Following the last sprint and the continuous run, the mice remained in the respirometry chamber until their vO2 reached resting levels. Excess exercise oxygen consumption (EEOC), the excess volume of oxygen consumed during the exercise period, increased from 0.03+/-0.01 to 0.40+/-0.02 ml O2g(-)(1) (mean +/- s.e.m., N=9) with activity frequency. However, the excess post-exercise oxygen consumption (EPOC), or volume of oxygen consumed during the recovery period, was independent of activity frequency (range 0.91-1.16 ml O2g(-)(1)) and accounted for more than 80 % of the total metabolic cost when activity was performed intermittently. Lactate concentration was measured at rest, immediately after running and immediately after recovering from running 1, 5 and 13 times within the 375 s period. After running, [lactate] was significantly higher than resting values, but following recovery, [lactate] had reached resting values. The net cost of activity, C(act), calculated by summing EEOC and EPOC and then dividing by the distance run, decreased significantly from 132+/-38 to 6+/-1 ml O2g(-)(1 )km(-)(1) as activity frequency increased. When these values for C(act) were compared with the cost of running continuously for the same amount of time, the values were identical. Therefore, we conclude that animals can minimize energetic expenditure by performing brief behaviors more frequently, just as they can minimize these costs if they increase the duration of continuous behaviors.
Animals↗
Application of a continuous disease severity score to the OPTN liver waiting list.
In a move to establish measurable, objective criteria for cadaveric liver allocation, the United Network for Organ Sharing OPTN will implement the Model for End Stage Liver Disease (MELD) system in early 2002 as a replacement for the current Child-Turcotte-Pugh (CTP)-based Status 2A, 2B, and 3 categories for patients waiting for a cadaver donor liver transplant. The MELD is a continuous mortality risk score based on serum creatinine, bilirubin, and INR. Although originally developed in patients undergoing the transjugular intrahepatic portosystemic shunt (TIPS) procedure, analysis of OPTN data shows that the components of MELD (in particular, bilirubin) have a very strong correlation with mortality in liver transplant candidates. Univariate analyses showed that pretransplant mortality significantly increased when the MELD score was > 1.8. In the study cohort, 25% of the patients had a MELD score > 1.8. Multivariate analysis showed that the MELD score was an independent predictor of mortality, with a 2-unit increase multiplying the risk of mortality by a factor of 5.6. The MELD and CTP scores were correlated, but MELD scores varied widely for any given CTP score, indicating that some patients could be disadvantaged with the status-based system. The MELD score was validated in an independent dataset; concordance with 3-month mortality was 0.88. We conclude that the MELD score is a good indicator of disease severity and that implementation of this system should direct more livers to those patients in greatest need of transplantation.
Health Care Rationing↗
The OPTN waiting list, 1988-2000.
More patients in the United states are waiting for organ transplants that at any time in the past and the remarkable growth of the UNOS waiting list has become a key issue for the transplant community. 1. On October 31, 2001, there were 84,277, registrations on the combined UNOS waiting list. Among these, 63% were awaiting kidney transplantation, and 22% were awaiting liver transplantation. 2. The majority of patients on the UNOS waiting list on October 31, 2000, were of blood type O (52%), white (55%) and male (58%), and awaiting their first transplant (87%). 3. The percentage transplanted within one year of listing has been declining for most organs, although that percentage has been somewhat stable for heart and lung between 1998-2000. 4. Blood type and medical urgency have a significant impact upon the percent transplanted within one year of listing for most organ types. Patients awaiting heart, pancreas, and intestinal transplants experience the highest probability of receiving a transplant within one year. 5. Deaths per patients waiting have declined since 1988 for most patients awaiting life-saving organs and have remained relatively low for those awaiting a kidney, pancreas, or kidney-pancreas transplant. Deaths were highest for lung and heart-lung patients, but appear to be declining.
Adolescent↗
Improved graft survival of pediatric liver recipients transplanted with pediatric-aged liver donors.
BACKGROUND: Improving graft survival after liver transplantation is an important goal for the transplant community, particularly given the increasing donor shortage. We have examined graft survivals of livers procured from pediatric donors compared to adult donors. METHODS: The effect of donor age (<18 years or > or =18 years) on graft survivals for both pediatric and adult liver recipients was analyzed using data reported to the UNOS Scientific Registry from January 1, 1992 through December 31, 1997. Graft survival, stratified by age, status at listing, and type of transplant was computed using the Kaplan-Meier method. In addition, odds ratios of graft failure at 3 months, 1 year, and 3 years posttransplant were calculated using a multivariate logistic regression analysis controlling for several donor and recipient factors. Modeling, using the UNOS Liver Allocation Model investigated the impact of a proposed policy giving pediatric patients preference to pediatric donors. RESULTS: Between 1992 and 1997 pediatric recipients received 35.6% of pediatric aged donor livers. In 1998 the percent of children dying on the list was 7.4%, compared with 7.3% of adults. Kaplan-Meier graft survivals showed that pediatric patients receiving livers from pediatric aged donors had an 81% 3-year graft survival compared with 63% if children received livers from donors > or =18 years (P<0.001). In contrast, adult recipients had similar 3-year graft survivals irrespective of donor age. In the multivariate analysis, the odds of graft failure were reduced to 0.66 if pediatric recipients received livers from pediatric aged donors (P<0.01). The odds of graft failure were not affected at any time point for adults whether they received an adult or pediatric- aged donor. The modeling results showed that the number of pediatric patients trans planted increased by at most 59 transplants per year. This had no significant effect on the probability of pretransplant death for adults on the waiting list. Waiting time for children at status 2B was reduced by as much as 160 days whereas adult waiting time at status 2B was increased by at most 20 days. CONCLUSION: A policy that would direct some livers procured from pediatric- aged donors to children improves the graft survival of children after liver transplantation. The effect of this policy does not increase mortality of adults waiting. Such a policy should increase the practice of split liver transplantation, which remains an important method to increase the cadaveric donor supply.
Adolescent↗
Liver transplant waiting time does not correlate with waiting list mortality: implications for liver allocation policy.
Factors associated with the risk for mortality once placed on the liver transplant waiting list and how this risk relates to center-specific waiting time and transplant activity have not been adequately evaluated. We performed this study to determine the association between center-specific waiting time and waiting list mortality among liver transplant candidates stratified by medical urgency at the time of registration. A Cox proportional hazards model was used to calculate 2-year mortality risk for a cohort of 16, 414 registrants added to the United Network for Organ Sharing liver transplant waiting list between January 1, 1997, and December 31, 1997. After controlling for confounding variables, we calculated the mortality risk for centers, organ procurement organizations (OPOs), and states. The relation between center-specific waiting list mortality risk and median waiting time or transplant activity was determined by linear regression. In multivariate analyses, higher initial medical urgency status (relative risk [RR] = 12.8; P <.001), increasing age (P <.001), black ethnicity (RR = 1.29; P <.001), history of previous transplant (RR = 1.2; P =.009), certain liver diagnoses, and smaller center size (RR = 1.39; P =.008) were associated with significantly increased waiting list mortality. Candidates with blood type A (RR = 0.87; P <.001) and those with cholestatic cirrhosis as the primary diagnosis (RR = 0.73; P < 0. 001) had a reduced risk for dying. There were significant variations in 2-year waiting list mortality risk among centers, OPOs, and states. However, when stratified by medical urgency status at waiting list entry, center-specific waiting time and transplantation rates accounted for almost none of the center-specific waiting list mortality. Although there are variations in waiting list mortality risk among centers, OPOs, and states, there is very little relation between center-specific waiting list mortality and center-specific median waiting time or center-specific transplantation rates when stratified by medical urgency. Waiting time and center transplant rates should not influence liver allocation policy.
Cohort Studies↗
The effect of the volume of procedures at transplantation centers on mortality after liver transplantation.
BACKGROUND AND METHODS: For many complex surgical procedures there is an association between a low volume of procedures and an increased risk of death for the patients who undergo the procedures. We examined the effect of the volume of procedures at transplantation centers on the risk of death after liver transplantation. We analyzed all liver transplantations performed in the United States between October 1, 1987, and April 30, 1994. Because the results for 1987 to 1991 were largely similar to those from 1992 to 1994, we focused on the more recent period. RESULTS: Between January 1, 1992, and April 30, 1994, 47 centers performed 20 or fewer liver transplantations each per year (total, 837 transplantations) and were designated low-volume centers, and 52 centers performed more than 20 transplantations each per year (total, 6526) and were designated high-volume centers. The one-year mortality rate for the low-volume centers was 25.9 percent, as compared with 20.0 percent for the high-volume centers. Thirteen centers, all of which had low volumes, had one-year mortality rates of more than 40 percent. Low-volume centers that were affiliated with high-volume centers, such as pediatric transplantation programs, had results similar to those of the high-volume centers. The one-year mortality rate at unaffiliated low-volume centers was 28.3 percent, as compared with a rate of 20.1 percent for the group of all high-volume centers plus affiliated low-volume centers (P<0.001). CONCLUSIONS: As a group, liver-transplantation centers in the United States that perform 20 or fewer transplantations per year have mortality rates that are significantly higher than those at centers that perform more than 20 transplantations per year. Information regarding the outcome of liver transplantation at transplantation centers should be made widely available to the public in a timely manner.
Hospitals, Special↗
Center-specific graft and patient survival rates: 1997 United Network for Organ Sharing (UNOS) report.
CONTEXT: Multiple comprehensive, risk-adjusted studies evaluating short-term surgical mortality have been reported previously. This report analyzes short-term and long-term outcomes, both nationally and at each individual transplant program, for all solid organ transplantations performed in the United States. OBJECTIVES: To report graft and patient survival rates for all solid organ transplantations, both nationally and at each specific transplant program in the United States, and to compare the expected survival rate with the actual survival rate of each individual program. DESIGN AND SETTING: Multivariate regression analysis of donor and recipient factors affecting graft and patient survival of all kidney, liver, pancreas, heart, lung, and heart-lung transplants reported to the United Network for Organ Sharing from 742 separate transplant programs. PATIENTS: A cohort of 97587 solid organ transplantations performed on 92966 recipients in the United States from January 1988 through April 1994. MAIN OUTCOME MEASURES: Short-term and conditional 3-year national and individual transplant program graft and patient survival rates overall and from 2 separate eras (era 1, January 1988-April 1992; era 2, May 1992-April 1994); comparison of actual center-specific performance with risk-adjusted expected performance and identification of centers with better-than-expected or worse-than-expected survival rates. RESULTS: One-year graft follow-up exceeded 98% and conditional 3-year follow-up exceeded 91% for all organs. Graft and patient survival improved significantly in era 2 compared with era 1 for all cadaver organs except heart, which remained the same. One-year cadaveric graft survival ranged from 81.5% for heart to 61.9% for heart-lung and 3-year conditional graft survival ranged from 91.3% for pancreas to 74.7% for lung. The percentage of programs whose actual 1-year graft survival was not different from or was better than their risk-adjusted expected survival ranged from 98.3% for heart-lung to 75.7% for liver. Most kidney, liver, and heart programs whose actual survival was significantly less than expected performed small numbers (less than the national average) of transplantations per year. CONCLUSIONS: Graft and patient survival for solid organ transplantations showed improvement over time. Conditional 3-year graft and patient survival rates were approximately 90% for all organs except for lung and heart-lung. The conditional 3-year survival rates were better than 1-year survival rates, indicating the major risk after transplantation occurs in the first year. The majority of transplant programs achieved actual survival rates not significantly different from their expected survival rates. Center effects were most significant within the first year after transplantation and had much less influence on long-term survival outcomes.
Actuarial Analysis↗
Effect of diagnosis on survival benefit of lung transplantation for end-stage lung disease.
BACKGROUND: Although certain forms of end-stage lung disease are debilitating, whether the associated mortality rate exceeds that of transplantation is unclear. We undertook analysis to clarify the survival benefit of lung transplantation for various types of end-stage lung disease. METHODS: We analysed data for all patients listed for transplantation in the USA for emphysema, cystic fibrosis, or interstitial pulmonary fibrosis in the years 1992-94. The numbers of patients entered on the waiting list, post-transplantation, died waiting, and currently waiting were: emphysema group 1274, 843, 143, and 165; cystic fibrosis group 664, 318, 193, and 59; interstitial pulmonary fibrosis group 481, 230, 160, and 48. A time-dependent non-proportional hazard analysis was used to assess the risk of mortality after transplantation relative to that for patients on the waiting list. FINDINGS: The clearest survival benefit from lung transplantation occurred in the cystic fibrosis group. The relative risks of transplantation compared with waiting were 0.87, 0.61, and 0.61 at 1 month, 6 months, and 1 year (p = 0.008), respectively. For interstitial pulmonary fibrosis, the corresponding relative risks were 2.09, 0.71, and 0.67 (p = 0.09). No survival benefit was apparent in the emphysema group. The risks of transplantation relative to waiting were 2.76, 1.12, and 1.10 at 1 month, 6 months, and 1 year, respectively, and the relative risk did not decrease to below 1.0 during 2 years of follow-up. INTERPRETATION: These findings suggest that lung transplantation does not confer a survival benefit in patients with end-stage emphysema by 2 years of follow-up. Other benefits not accounted for in this analysis such as improved quality of life, however, may justify lung transplantation for these patients.
Adult↗
Transplantation with older donor hearts for presumed "stable" recipients: an analysis of the Joint International Society for Heart and Lung Transplantation/United Network for Organ Sharing Thoracic Registry.
BACKGROUND: We have previously demonstrated that the use of older donor hearts (>45 years) increases the odds of death nearly twofold in the early posttransplantation period when compared with the use of hearts from younger donors. Before excluding this segment of the donor pool, however, the mortality risk for remaining on the waiting list compared with that of receiving an older donor heart should also be considered. METHODS: We examined all adult status 2 patients added to the United Network for Organ Sharing heart transplant waiting list for primary transplantation between 1992 and 1995 (n = 4681). To account for the transient increased risk after transplantation, we used a time-dependent nonproportional hazards model with an exponential decay component for the analysis. For patients with an equal time since listing, the resulting risk ratios represent the ratio of mortality risk for a patient who receives an older donor heart to the mortality risk for a patient who remains on the waiting list. RESULTS: After 30 days posttransplantation, the risk of death for recipients of 45- to 49-year-old donor hearts was lower than if they had remained on the waiting list, and by 6 months the relative risk was 0.37 (95% confidence interval: 0.22, 0.62). For recipients of hearts from donors 50 years or older, the risk after transplantation was lower after 64 days, and by 6 months the relative risk was 0.48 (95% confidence interval: 0.31, 0.75). CONCLUSION: These results suggest that in spite of a high initial risk resulting from the transplant procedure, there was a clear long-term survival benefit for status 2 recipients of older donor hearts. Thus overall, in spite of the increased risk of death associated with receiving older donor hearts, the risk of death without a transplant was even greater. On the basis of this analysis we cannot support the exclusion of older donors from the donor pool.
Adolescent↗
Effect of HLA matching on the relative risk of mortality for kidney recipients: a comparison of the mortality risk after transplant to the mortality risk of remaining on the waiting list.
BACKGROUND: Patients must wait increasingly longer periods on the kidney waiting list (WL) before receiving a transplant. Although patients can be maintained on dialysis, many deaths occur while waiting. To determine whether the risk of mortality on the WL is different from that related to the transplant procedure, data from the Organ Procurement and Transplantation Network and Scientific Registry were used to analyze all adult patients entered on the United Network for Organ Sharing (UNOS) kidney WL for a primary transplant between April 1, 1994, and December 31, 1994 (n=9925). METHODS: To account for the time spent on the WL before transplant, a time dependent, nonproportional hazards model was used to assess the risk of mortality after transplant for both well-matched (zero to two HLA mismatches) and poorly-matched (three to six HLA mismatches) transplants compared with the mortality risk of remaining on the WL. This model incorporated an exponential decay component to account for the transient increased risk after kidney transplantation. Patients were stratified by age, race, creatinine level, panel-reactive antibody at listing, and blood group. RESULTS: Although there was an increased risk of mortality in the initial posttransplant period, the risk of mortality at 1 year for transplanted patients was 59% (three to six mismatches) to 67% (zero to two mismatches) less than that of patients who remained on the waiting list for an additional year. CONCLUSIONS: Kidney transplantation is more beneficial than remaining on the waiting list. Even poorly-matched kidneys provided a significant reduction in the risk of mortality by 6 months as compared with the mortality risk of continuing to wait. Patients receive the maximum benefit when transplanted with well-matched kidneys.
Adult↗
Antilymphocyte induction therapy in cadaver renal transplantation: a retrospective, multicenter United Network for Organ Sharing Study.
Antilymphocyte induction therapy in cadaver renal transplantation is controversial. The effectiveness of antilymphocyte therapy in the current era of cyclosporine and tacrolimus use has been questioned. The United Network for Organ Sharing data set for the Center-Specific Outcomes Analysis, which has been verified by the transplant centers, was used for this study. At the time information in the database was confirmed, all transplant centers were queried on their use of an antilymphocyte preparation at the time of transplantation, and whether it was used within 24 hr of transplant surgery, the duration of the specific reagent. This allowed us to analyze 24,191 cadaver transplant procedures performed between the October 1, 1987, and the January 31, 1991. Using Cox regression analysis, as well as semiparametric logistic regression models, we demonstrated improved allograft outcomes in patients who received either Minnesota antilymphocyte globulin for 5 days or more or OKT3 for 7 days or more. The relative risk was 0.82 for Minnesota antilymphocyte globulin and 0.86 for OKT3 (for both, P<0.001). Semiparametric models were then used to compare the effectiveness of the antilymphocyte preparation in both a patient with at least a three-antigen mismatch and patients who had a zero-antigen mismatch. The improvement in graft survival was seen in both match grades. These data demonstrate the improved outcomes with the use of antilymphocyte preparations during the early posttransplant period in the modern cyclosporine era.
Antibodies, Monoclonal↗
The impact of improvements in procurement and utilization on US liver recipients.
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Health Care Rationing↗
Influence of HLA matching on thoracic transplant outcomes. An analysis from the UNOS/ISHLT Thoracic Registry.
BACKGROUND: The benefit of matching donor organs and recipients for HLAs has been well established in renal transplantation and has been suggested for thoracic organ transplantation. To determine the effect of HLA matching in cardiac and single-lung transplantation, the following study was performed. METHODS AND RESULTS: Using the joint Thoracic Transplant Registry or the United Network for Organ Sharing and the International Society for Heart and Lung Transplantation, all adult primary heart and single-lung transplant procedures performed in the United States from October 1987 through December 1993 were analyzed to determine the effects of HLA matching on transplant mortality. Both total HLA matches and matches at individual HLA loci were considered. Including HLA matching, 16 potential risk factors for heart transplant outcome and 16 potential risk factors for lung transplant outcome were subjected to multivariate analysis. A total of 10752 heart transplants and 1239 lung transplants were included in the independent analyses for each organ. For heart transplantation, there was a progressive reduction in risk for greater matching (1 or 2 matches: risk ratio, 0.83; 3 matches: risk ratio, 0.67; 4 to 6 matches: risk ratio, 0.59; all P < or = .01). The primary benefit of matching appeared to be at the A and DR loci (risk ratios, 0.87 and 0.79, respectively; P < .001). For lung transplantation, any matching had an independent positive effect on outcome; however, the relationship between numbers of HLA matches and relative risk was not present and ranged from risk ratios of 0.71 to 0.87 (P = .01 and P = .47, respectively). In this analysis, only matching at the A locus appeared to statistically influence outcome (risk ratio, 0.76; P = .01). CONCLUSIONS: These data demonstrate that HLA matching independently impacts survival in both heart and single-lung transplantation.
Adult↗
Measurement of the flux of lead from bone to blood in a nonhuman primate (Macaca fascicularis) by sequential administration of stable lead isotopes.
To better understand the kinetics of the transfer of lead from bone to blood, we have developed and tested a method in which sequential doses of lead, each enriched with a different stable isotope, were administered in a nonhuman primate Macaca fascicularis whose skeleton had been previously labeled with lead of known isotopic composition. Lead isotopic ratios of blood and bone samples, analyzed by thermal ionization mass spectrometry (TIMS), were unmixed by isotope dilution techniques. The first label administered allows the contribution from historical bone stores to be measured. Subsequent labels allow measurement of both the historical bone stores and the previous labels that have become recently incorporated into bone. The method may be extended to studies of bone lead mobilization in pregnancy, lactation, menopause, or in disease states such as postmenopausal osteoporosis.
Animals↗
Facing organ shortage, should we revisit organ allocation?
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Cadaver↗
UNOS Scientific Registry: present and future. United Network for Organ Sharing.
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Cadaver↗