Comparative Effectiveness of Liver Transplant Strategies for End-Stage Liver Disease Patients on Renal Replacement Therapy

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1 LIVER TRANSPLANTATION 20: , 2014 ORIGINAL ARTICLE Comparative Effectiveness of Liver Transplant Strategies for End-Stage Liver Disease Patients on Renal Replacement Therapy Yaojen Chang, 1 Lorenzo Gallon, 2 Colleen Jay, 2 Kirti Shetty, 3 Bing Ho, 2 Josh Levitsky, 2 Talia Baker, 2 Daniela Ladner, 2 John Friedewald, 2 Michael Abecassis, 2 Gordon Hazen, 4 and Anton I. Skaro 2 1 Lombardi Comprehensive Cancer Center, Department of Oncology, Cancer Prevention and Control Program, Georgetown University School of Medicine, Washington, DC; 2 Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL; 3 Division of Gastroenterology and Hepatology, Sibley Memorial Hospital, Johns Hopkins Medicine, Washington, DC; and 4 Department of Industrial Engineering and Management Sciences, Northwestern University McCormick School of Engineering, Evanston, IL There are complex risk-benefit tradeoffs with different transplantation strategies for end-stage liver disease patients on renal support. Using a Markov discrete-time state transition model, we compared survival for this group with 3 strategies: simultaneous liver-kidney (SLK) transplantation, liver transplantation alone (LTA) followed by immediate kidney transplantation if renal function did not recover, and LTA followed by placement on the kidney transplant wait list. Patients were followed for 30 years from the age of 50 years. The probabilities of events were synthesized from population data and clinical trials according to Model for End-Stage Liver Disease (MELD) scores (21-30 and >30) to estimate input parameters. Sensitivity analyses tested the impact of uncertainty on survival. Overall, the highest survival rates were seen with SLK transplantation for both MELD score groups (82.8% for MELD scores of and 82.5% for MELD scores > 30 at 1 year), albeit at the cost of using kidneys that might not be needed. Liver transplantation followed by kidney transplantation led to higher survival rates (77.3% and 76.4%, respectively, at 1 year) than placement on the kidney transplant wait list (75.1% and 74.3%, respectively, at 1 year). When uncertainty was considered, the results indicated that the waiting time and renal recovery affected conclusions about survival after SLK transplantation and liver transplantation, respectively. The subgroups with the longest durations of pretransplant renal replacement therapy and highest MELD scores had the largest absolute increases in survival with SLK transplantation versus sequential transplantation. In conclusion, the findings demonstrate the inherent tension in choices about the use of available kidneys and suggest that performing liver transplantation and using renal transplantation only for those who fail to recover their native renal function could free up available donor kidneys. These results could inform discussions about transplantation policy. Liver Transpl 20: , VC 2014 AASLD. Received June 27, 2013; accepted April 9, See Editorial on Page 1017 Abbreviations: CI, confidence interval; ECD, extended criteria donor; ESLD, end-stage liver disease; KTA, kidney transplantation alone; LTA, liver transplantation alone; MELD, Model for End-Stage Liver Disease; NMH, Northwestern Memorial Hospital; OPTN, Organ Procurement and Transplantation Network; r, weekly rate; RRT, renal replacement therapy; SLK, simultaneous liver-kidney; SRTR, Scientific Registry of Transplant Recipients; t, 1 week. The authors have no conflicts of interest to declare. This research was supported in part by the Cancer Intervention and Surveillance Modeling Network (grant U01 CA from the National Cancer Institute) and the National Institute on Disability and Rehabilitation Research (grant H133P from the Department of Education). Address reprint requests to Yaojen Chang, Dr.P.H., M.S., M.P.H., Lombardi Comprehensive Cancer Center, Department of Oncology, Cancer Prevention and Control Program, Georgetown University School of Medicine, 3300 Whitehaven Street, Suite 4100, Washington, DC Telephone: ; FAX: ; yc377@georgetown.edu DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2014 American Association for the Study of Liver Diseases.

2 LIVER TRANSPLANTATION, Vol. 20, No. 9, 2014 CHANG ET AL Figure 1. Schematic diagram of the Markov simulation model used to compare survival rates for 50-year-old ESLD patients on pretransplant RRT by transplant strategy. Death could occur with any health state or SLK/LTA transplant surgery. There are approximately 15,000 individuals in the United States each year with end-stage liver disease (ESLD) who are on waiting lists for liver transplantation. 1 Many of these individuals also have associated renal impairment. Comorbid renal disease increases the risk of death while a person is on the liver transplant waiting list. 2-5 Moreover, those who undergo liver transplantation in the setting of cirrhosis with renal impairment have a particularly poor prognosis, especially when their renal function does not improve after liver transplantation. 6-8 Therefore, simultaneous liver-kidney (SLK) transplantation has been suggested as a strategy for improving posttransplant survival. 2,9,10 In fact, its use has increased 2-fold since criteria that consider both liver and kidney function [the Model for End-Stage Liver Disease (MELD) system] were implemented in 2002 for transplant waiting-list prioritization. 11 However, the increase in the number of SLK transplants could have other unintended consequences, such as increased wait-list times due to the need to have 2 matched organs and the use of kidneys that might not have been needed in patients destined to have improved renal function after liver transplantation. Sequential approaches have been proposed as alternatives: liver transplant is performed first, and renal transplant is then performed only for the subset of patients who do not experience renal recovery. For this group, however, the added time on the renal transplant waiting list after liver transplantation could increase mortality Because of the complexity of these alternative transplant strategies, they are difficult to compare directly in clinical trials. To our knowledge, no previous studies have compared the outcomes of these alternative transplant strategies or examined multiple approaches according to the severity of liver and kidney disease. Moreover, procedures and outcomes are not tracked in national registries with sufficient detail for outcomes to be directly estimated. 1,15 In such situations, in which there are different tradeoffs with the benefits and harms associated with various transplant scenarios, modeling can be a useful scientific method for comparing and quantifying the outcomes of alternative transplantation approaches. This study used simulation modeling to compare survival with 3 different transplant strategies for 2 groups of ESLD patients at the age of 50 years with renal disease who were already on pretransplant renal replacement therapy (RRT). The 2 groups were patients with MELD scores of 21 and 30 and patients with scores > 30 because, by definition, being on RRT means that individuals have a score of 21 or higher. Increasing scores indicate a higher risk of mortality. For each of these 2 groups, we examined (1) SLK transplantation, (2) liver transplantation alone (LTA) followed by placement on the wait list for renal transplantation according to the current allocation policy, and (3) LTA followed by kidney transplantation for recipients who did not recover native renal function. The results are intended to inform clinical decision making and policy discussions about US transplant strategies. PATIENTS AND METHODS Model Overview A Markov discrete-time state transition model was constructed with TreeAge Pro 2009 (version , TreeAge Software, Williamstown, MA) to evaluate the 3 strategies for 2 groups of 50-year-old patients (based on MELD scores) with ESLD (regardless of etiology); all patients were receiving pretransplant RRT (Fig. 1). We selected the age of 50 years to start the simulation because the largest proportion of ESLD patients are 50 to 64 years old. The model consisted of a finite number of mutually exclusive health states, which are called Markov states. 16,17 In each simulation, according to the strategy being evaluated, a patient moved through the model to experience events (eg, undergo liver-kidney transplant surgery) and transitioned between all the different health states that followed from that strategy (eg, graft rejection and recovery of renal function) until death or the end of a 30-year time horizon. Patients could move

3 1036 CHANG ET AL. LIVER TRANSPLANTATION, September 2014 TABLE 1. Values of Parameters Used in a Markov Simulation Model Comparing Transplant Strategies for 50-Year-Old ESLD Patients on Pretransplant RRT Parameter Base Case* Source Time to liver transplant by MELD score (days) OPTN/SRTR 15 (2008) ( ) ( ) > ( ) Time to kidney transplant for 50- to 64-year-old ( ) OPTN/SRTR 15 (2008) candidates under current allocation policy (days) Annual liver wait-list death rates per 1000 OPTN/SRTR 15 (2008) patient-years by MELD score > Annual kidney wait-list death rate per OPTN/SRTR 15 (2008) patient-years Annual dialysis death rate per 1000 patientyears 133 Wolfe et al. 19 (1999) LTA recipient survival without renal recovery at 64 Northup et al. 18 (2010) 90 days (%) LTA recipient survival without renal recovery at 15 Northup et al. 18 (2010) 1500 days (%) LTA recipient survival for group with MELD 78 Gonwa et al. 7 (2006) scores of after renal recovery at 5 years (%) LTA recipient survival for group with MELD 72 Gonwa et al. 7 (2006) scores > 30 after renal recovery at 5 years (%) SLK recipient survival for group with MELD 71.5 Gonwa et al. 7 (2006) scores of at 5 years (%) SLK recipient survival for group with MELD 68 Gonwa et al. 7 (2006) scores > 30 at 5 years (%) KTA recipient survival at 10 years with non OPTN/SRTR 15 (2008) ECD deceased donor kidneys (%) Probability of liver transplant operative mortality (%) 3 Llovet et al. 20 (1999), Jonas et al. 21 (2001), Mazzaferro et al. 22 (1996) Probability of kidney transplant operative 1.3 Hollingsworth et al. 23 (2007) mortality (%) Probability of SLK transplant operative mortality (%) 4.3 Llovet et al. 20 (1999), Jonas et al. 21 (2001), Mazzaferro et al. 22 (1996), Hollingsworth et al. 23 (2007) Probability of SLK acute graft failure (%) 1.3 NMH data Probability of post-lta renal recovery with pretransplant 70.8 Northup et al. 18 (2010) RRT for <30 days (%) Probability of post-lta renal recovery with pretransplant 56.3 Northup et al. 18 (2010) RRT for days (%) Probability of post-lta renal recovery with pretransplant 23.5 Northup et al. 18 (2010) RRT for days (%) Probability of post-lta renal recovery with pretransplant 11.5 Northup et al. 18 (2010) RRT for >90 days (%) Post-KTA renal graft survival at 3 months (%) 95.7 OPTN/SRTR 15 (2008) Post-LTA liver graft survival at 3 months (%) 88.1 OPTN/SRTR 15 (2008) Post-LTA liver graft survival at 5 years (%) 62.8 OPTN/SRTR 15 (2008) Post-LTA kidney graft survival at 10 years (%) 27 Ojo et al. 24 (2003) Post-SLK liver/renal graft survival at 97.3 NMH data 3 months (%) Post-SLK liver graft survival at 5 years (%) 62 Pham et al. 25 (2007) Post-SLK kidney graft survival at 5 years (%) 60 Pham et al. 25 (2007)

4 LIVER TRANSPLANTATION, Vol. 20, No. 9, 2014 CHANG ET AL TABLE 1. Continued Parameter Base Case* Source Post-KTA kidney graft survival at 10 years with 42.4 OPTN/SRTR 15 (2008) non-ecd deceased donor kidneys (%) *The data within parentheses are 95% CIs for the national median waiting times. Northwestern University Enterprise Data Warehouse. The declining exponential function was used to convert the parameter values in the literature into weekly values. To convert the rates into probabilities, the following equation was used: P e 2rt where r is the weekly rate and t is 1 week. The probability of post-lta renal recovery was terminated in the 12th posttransplant week in the model because the likelihood of recovering renal function more than 3 months after transplantation was very low. between states at 1-week intervals; this reflected how disease progression is tracked in the MELD score system. Thirty years was selected as the time horizon because few 50-year-old patients with ESLD will live beyond this span. This study was deemed exempt from IRB review due to only secondary, de-identified data used in the simulation model. At the start of the model, each patient followed 1 of the 3 transplant strategies. If the patient survived the transplant surgery, the new organ(s) could be accepted or rejected. Posttransplant renal recovery could occur or not occur. Because renal recovery or the development of renal graft function was unlikely to occur more than 3 months after transplantation, 18 patients who did not have recovery of renal function remained on RRT and were placed on the kidney transplant waiting list. They either died on the kidney waiting list or survived to undergo kidney transplantation alone (KTA). This kidney could either function or be rejected. Additionally, chronic liver and kidney failure could occur after transplantation and result in the patient being wait-listed for liver retransplantation, kidney retransplantation, or both, although this group would be expected to be small because of the high rates of chronic complications and wait-list mortality. Death could occur before any of the transplants while the patient was on the waiting list, during surgery, or at any time after transplantation; mortality was assumed to be due to liver-kidney disease and not unrelated causes. The primary outcome of the model was the survival rate for each transplant strategy. As noted previously, we grouped the patients into 2 groups on the basis of their MELD scores: 21 to 30 and >30. By definition, because our patient population had ESLD and was already on RRT, they all would have had MELD scores of 21 or more at the start of the simulation. Because RRT could be stopped and/or reinitiated while patients were on the waiting list, the model considered the probabilities of transitions between the initial MELD score and higher or lower scores over time. Transition probabilities occurred between states defined by MELD score quintiles. These new MELD scores, in turn, affected the wait-list position at any point in time. Data Sources The parameter values and ranges used in the model to estimate the probabilities of all transitions between states and the prevalence of events were estimated from multiple data sources. If available, data from clinical trials were used; otherwise, large populationbased observational data sets were used. Because all transplant candidates are represented in transplant registries, these data sources were considered as population estimates. Because all transition probabilities occurred in 1-week cycles, some data required a conversion from annual values to weekly values. The values and sources of all parameters are summarized on Table 1 and are highlighted in the following narrative. Waiting Time The number of days from listing to the date of liver transplantation was based on data from the 2008 Organ Procurement and Transplantation Network (OPTN)/Scientific Registry of Transplant Recipients (SRTR) annual report for each MELD score quintile. 15 The median was used as the point estimate, and the 95% confidence interval (CI) of the median was used to determine a range for testing the impact of the initial wait time on survival outcomes in sensitivity analyses. Waiting-list times for kidneys after liver transplantation without renal recovery were assumed to be 16 weeks because the recovery of native renal function was less likely to occur more than 3 months after transplantation. 18 Times on the waiting list for repeat liver or kidney transplantation after organ rejection were based on the national median waiting time for each MELD quintile. 15 We assumed an equal wait-list time within MELD score groups regardless of the type of liver transplant (ie, with or without a renal transplant) because the registries did not differentiate these procedures. We tested the impact of this assumption in a sensitivity analysis. For liver transplant candidates on the wait list, the probability of changing MELD score groups over time was estimated from data reported in the 2008 United Network for Organ Sharing/OPTN data set.

5 1038 CHANG ET AL. LIVER TRANSPLANTATION, September 2014 TABLE 2. Markov Model Estimates of Posttransplant Survival Rates for 50-Year-Old ESLD Patients on Pretransplant RRT by Transplant Strategy and MELD Scores Survival Rate by Transplant Strategy 1 Year 2 Years 3 Years 5 Years 10 Years MELD scores of SLK transplant with standard criteria donor kidneys Liver transplant and subsequent kidney transplant if needed with current allocation wait time Liver transplant and subsequent kidney transplant if needed with 16-week wait time MELD scores > 30 SLK transplant with standard criteria donor kidneys Liver transplant and subsequent kidney transplant if needed with current allocation wait time Liver transplant and subsequent kidney transplant if needed with 16-week wait time NOTE: The data are presented as percentages. Posttransplant Events Beyond operative mortality (discussed later), 2 posttransplant events affect survival: graft rejection and recovery of renal function. After transplantation, organ(s) can be acutely or chronically rejected. Because Markov model states do not have a memory of prior health, we made the simplifying assumption that the probability of acute and chronic liver and kidney graft failure was unaffected by previous MELD scores. We assumed that only standard criteria donor kidney grafts were used for KTA. Mortality Mortality can occur over time in several ways, including death due to organ failure or its complications while the patient is on the waiting list, operative mortality during transplantation, postoperative mortality due to complications, death due to acute or chronic organ rejection and failure, and death due to other causes related to the underlying ESLD. The mortality rate on the initial waiting list for each MELD score quintile was derived from the 2008 OPTN/SRTR annual report. 15 Operative mortality was based on the published literature The probabilities of posttransplant mortality were significantly affected by renal function. We assumed that the long-term survival of liver transplant recipients undergoing either simultaneous or single transplantation was based on a constant hazard of death. We also assumed that liver recipients who did not recover their native renal function had a much higher posttransplant mortality rate on the basis of observational data reported by Northup et al. 18 Analysis Simulations were replicated 500,000 times for each scenario, and the results were summarized with Stata 11 (StataCorp LP, College Station, TX). The primary outcome was the survival associated with each of the 3 transplant strategies by MELD score group. We examined the absolute 1-, 3-, 5-, and 10-year survival rates because these were felt to be the most relevant to clinical decision making for the respective transplant recipients. We did not examine survival beyond 10 years because of the shortage of long-term observed data for validating model outcomes. Results were also stratified by the time on pretransplant RRT. To fully reflect the impact of different waiting times (eg, subsequent kidney transplantation 52 weeks after liver transplantation) and dialysis durations (>90 days) on survival, we assessed the impact of these factors on 2-year survival. One-way sensitivity analyses were conducted to test the impact of uncertainty on parameter estimates for waiting times, renal recovery, and chronic renal graft survival after liver transplantation. Initial median waiting times for LTA varied over the 95% CI range because of variability at the regional, donor service area, and transplant center levels. Patients undergoing SLK transplantation could have different waitlist times than those undergoing LTA. Alternatively, because of the need to match 2 organs, the waitinglist time could be longer for SLK transplantation versus LTA. Therefore, we used wait-list times ranging from 50% to 200% of the national median wait-list time for SLK transplantation. We also varied the range of times for kidney transplants after LTA (16, 26, and 52 weeks). Renal recovery was varied and based on 50% to 200% of the values observed for each period of RRT duration (<30, 30-60, 60-90, and >90 days) 18 ; 50% to 200% of the baseline renal graft survival after liver transplantation was tested in the sensitivity analysis. 24 The results of these 1-way sensitivity analyses are summarized in tornado diagrams. In this format, the results are arranged from the largest impact to the least impact of varying a given parameter on survival rates. In this manner, the uncertainty of the parameter associated with the largest bar, the one at

6 LIVER TRANSPLANTATION, Vol. 20, No. 9, 2014 CHANG ET AL Figure 2. Survival rates for transplant recipients in the MELD score categories of 21 to 30 and >30 by transplant strategy. LTA indicates liver transplant recipients with the option of being placed on the kidney wait list when renal recovery failed; LTA_KTA16wk indicates liver transplant recipients with the option of subsequent kidney transplantation 16 weeks after transplantation when renal recovery failed; and SLK indicates SLK transplant recipients. TABLE 3. Markov Model Estimates of 1-Year Posttransplant Survival Rates for 50-Year-Old ESLD Patients on Pretransplant RRT by Transplant Strategy and MELD Scores Stratified by the Duration of Pretransplant RRT Pretransplant RRT Duration (Days) 1-Year Survival Rate < >90 MELD scores of SLK transplant with standard criteria donor kidneys Liver transplant and subsequent kidney transplant if needed with current allocation wait time Liver transplant and subsequent kidney transplant if needed with 16-week wait time MELD scores > 30 SLK transplant with standard criteria donor kidneys Liver transplant and subsequent kidney transplant if needed with current allocation wait time Liver transplant and subsequent kidney transplant if needed with 16-week wait time NOTE: The data are presented as percentages. the top of the chart, has the maximum impact on the survival result, with each successive parameter uncertainty (lower bars) having a lesser impact. RESULTS In this population of 50-year-old ESLD patients on pretransplant RRT, survival decreased over time with all 3 strategies, and it was lower for the patients in the more severe MELD score category (>30; Table 2). The scenario with the highest survival rate was SLK transplantation (Table 2 and Fig. 2), which was followed by LTA with the option of subsequent kidney transplantation at 16 weeks or placement on the kidney transplant wait list when renal recovery failed (77.3% and 75.1% at 1 year, respectively, for the lower MELD score group). This was true for both MELD score groups (82.8% and 82.5% with SLK transplantation for the lower and higher MELD score groups, respectively, at 1 year). However, when LTA was

7 1040 CHANG ET AL. LIVER TRANSPLANTATION, September 2014 Figure 3. Two-year survival rates for SLK transplant candidates and LTA candidates by the MELD score category with different assumptions about the waiting time. Figure 4. Two-year survival rates for LTA recipients in the MELD score categories of 21 to 30 and >30 when kidney transplantation for those who failed to recover renal function was subsequently performed at 16, 26, and 52 weeks or on the basis of the current kidney graft allocation policy. performed initially and renal recovery did not occur within the first 3 months, patients immediately undergoing renal transplantation had higher survival rates than those who were allocated kidneys according to routine policies. As shown in Table 2, the differ- ences in the survival rates of SLK transplant recipients and liver transplant recipients under the current kidney allocation policy were larger (8.2% and 7.7% at 1 year and 9.9% and 9.2% at 3 years for the MELD score categories of >30 and 21-30,

8 LIVER TRANSPLANTATION, Vol. 20, No. 9, 2014 CHANG ET AL Figure 5. One-year survival rates for liver transplant recipients in the MELD score categories of >30 and 21 to 30 when renal recovery during each period of RRT duration was varied in the range of 50% to 200% of the baseline values. respectively) than the differences between the other strategies. Also, we noted that the survival advantage of SLK transplantation versus liver transplantation with the option of subsequent kidney transplantation 16 weeks after liver transplantation was narrowed to 6.1% and 5.5% at 1 year, 5% and 4.4% at 3 years, and 3.9% and 3.2% at 5 years for the higher and lower MELD score groups, respectively. During the 30-year simulation period, the cumulative incidence of renal transplantation after LTA was 18.4% with the current kidney allocation policy/wait time (data not shown). When we considered the duration of pretransplant RRT (Table 3), the ranking of the strategies remained similar across all durations in terms of 1-year survival, with SLK transplantation leading to substantially higher survival than initial LTA. Additionally, there was little reduction in survival as the duration of pretransplant rental replacement therapy increased with the simultaneous transplant strategy. However, with LTA, survival decreased substantially with an increasing duration of prior renal support therapy. For instance, for the group with higher MELD scores, 1-year survival decreased from 74.3% to 52.8% as the duration of pretransplant RRT increased from <30 days to >90 days under the current kidney allocation policy. Sensitivity Analysis Survival after SLK transplantation was related to the uncertainty of the waiting time, with improved survival associated with waiting times 50% shorter than the national median and with reductions in survival associated with waiting times 200% greater than the national median (Fig. 3). The reduction in survival was less for those with MELD scores of 21 to 30 versus those with MELD scores > 30. However, survival rates varied by less than 63% when the waiting time was varied less dramatically over the 95% CI of the national median waiting time. Among those undergoing LTA and subsequent kidney transplantation, outcomes were also affected by the uncertainty of the waiting time (Fig. 4). Overall, across all strategies, patients had the best survival with the shortest transplant waiting times. When chronic renal graft survival after liver transplantation was varied from 50% to 200% of the baseline values, the changes in the 3- and 5-year survival rates were modest (20.64% to 10.41% and 21.24% to 10.81% for the group with MELD scores > 30 and 20.72% to 10.50% and 21.59% to 10.82% for the group with MELD scores of 21-30). A sensitivity analysis of the probability of renal recovery after liver

9 1042 CHANG ET AL. LIVER TRANSPLANTATION, September 2014 transplantation for each pretransplant RRT duration (<30, 30-60, 60-90, and >90 days) with MELD scores > 30 and MELD scores of 21 to 30 is displayed in Fig. 5. For instance, the 1-year survival rate for the liver transplant recipients with MELD scores > 30 receiving pretransplant RRT for <30 days changed in the range of 25.66% to 16.59% when the probability of renal recovery was varied from 50% to 200% of the baseline value. The various probabilities of renal recovery after liver transplantation had a significant impact on the survival of the liver transplant recipients. DISCUSSION This is the first study to use simulation modeling to directly compare and quantify the expected outcomes of current or proposed clinical transplantation strategies among middle-aged patients with ESLD who are on pretransplant renal support. Overall, the SLK transplant strategies led to higher survival rates than sequential transplantation approaches. There were no major differences between MELD score groups, but patients who had been on RRT for the longest period seemed to benefit the most with respect to survival from simultaneous transplantation versus sequential transplantation. Finally, performing liver transplantation first and then performing renal transplantation only for those who fail to recover their native renal function could free up available donor kidneys, and this could be a good alternative to simultaneous transplantation if waiting times are short. Our model results suggest that among the alternatives considered, SLK transplantation results in the greatest short- and long-term survival for liver transplant candidates receiving pretransplant RRT. This result is consistent with other analyses comparing LTA and SLK transplantation for dialysis-dependent patients. 7,8,26,27 The 1 study with a different conclusion included patients undergoing SLK transplantation or sequential liver-kidney transplantation when subsequent kidney transplants provided to liver transplant recipients and SLK transplants provided to ESLD patients on RRT were performed in the same period of time. 12 Thus, the 2 groups were getting very similar treatments that were essentially simultaneous transplants. Northup et al. 18 noted that ESLD patients on renal dialysis who undergo LTA have a very low survival rate (16% at 4 years) if they do not recover renal function. Because of the current wait time of multiple years for renal transplantation, many of these patients will not survive. However, our results suggest that SLK transplantation could prevent this wait-list mortality and dramatically increase survival (56%-64% at 5 years). The model results for SLK transplantation and liver transplantation among those receiving pretransplant renal support are very similar to those observed in clinical practice for this same group of patients. For instance, Gonwa et al. 7 reported survival rates for 632 SLK transplant recipients and 1103 liver transplant recipients at 1, 2, and 3 years after transplantation of 83.6%, 79%, and 74.8% and 75.2%, 71.2%, and 68.3%, respectively. These rates are within 65% of our model results. The consistency of our results with this large clinical series supports the validity of the model employed in our study. Additionally, our model results are consistent with clinical observational studies showing that the longer the duration of pretransplant RRT is, the greater the benefits will be from SLK transplantation. For example, Northup et al. 18 demonstrated an inverse doseresponse relationship between the pretransplant RRT duration and the probability of renal recovery after liver transplantation. However, 1 study did not observe better survival with simultaneous transplantation versus sequential transplantation for a subgroup on RRT for <3 months, 5 whereas our model results indicated survival benefits with SLK over LTA even when the pretransplant dialysis duration was <30 days. However, our model projected that the difference in the survival benefit observed between a pretransplant RRT duration < 30 days and a pretransplant RRT duration > 90 days would be substantial. In comparison with the current deceased donor kidney graft allocation policy, the strategy of subsequent kidney transplantation 16 weeks after liver transplantation improved the survival of liver transplant recipients who received pretransplant RRT. A more significant survival advantage with this strategy was found for the subgroup of liver transplant recipients with MELD scores of 21 to 30 who received pretransplant RRT for the longest duration (>90 days). On the other hand, the difference in survival between SLK transplant recipients and liver transplant recipients decreased when kidney transplantation was subsequently performed 16 weeks after transplantation for those who did not recover renal function. Because of the approximately 6% annual wait-list mortality rate among end-stage renal disease patients who are 50 to 64 years old and the likelihood of recovering native renal function after liver transplantation, liver transplantation with subsequent kidney transplantation at 16 weeks might be a very good alternative strategy for ESLD patients on pretransplant RRT. With this strategy, unnecessary SLK transplants can be avoided, and additional kidney grafts can be released to endstage renal disease patients on kidney transplant wait lists. Current MELD-based liver allocation has given priority to ESLD patients with renal impairment. Consequently, the number of SLK transplants has steadily increased since the implementation of the MELD system in As the number of kidney grafts allocated to SLK transplantation has increased, the kidney transplant waiting period has been lengthened, and more kidney wait-list deaths could occur. Thus, this comparison of liver-based transplant strategies underscores the dynamic tradeoffs between approaches and raises interesting allocation questions. The current model examined approaches for only a subset of ESLD patients, so we cannot fully

10 LIVER TRANSPLANTATION, Vol. 20, No. 9, 2014 CHANG ET AL address equity and allocation issues. Although it would be very complex, an examination of multiple conditions affected by organ allocation in future models would be interesting for placing liver disease strategies in a broader context. This work (and clinical decisions) could be facilitated by new data for accurately identifying ESLD patients who will not recover renal function after transplantation. There are many strengths of this modeling study, including the direct comparison of 3 alternative transplant strategies, the use of the best available data, the detailed assessment of the impact of parameter uncertainty on outcomes, and the robust conclusions that are consistent with clinical observations. Despite these strengths, there are also several limitations that should be considered in an evaluation of our results. First, the population targeted in this study was very narrowly defined, and the results will not apply to all ESLD patients, such as the 25% of those receiving SLK transplants who are not on pretransplant dialysis. Second, among the subset of patients who had been on RRT for <30 days, improvements in survival after SLK transplantation may not be related to the receipt of a new kidney. To the extent that this is true, we may have overestimated survival, although estimates for those on pretransplant RRT for longer durations are more likely to reflect true benefits from receiving a new kidney. Third, as noted previously, the model was restricted to outcomes among our target population and did not assess the effects of the different transplant strategies on organ allocation and availability for other groups of patients. Fourth, there were insufficient data to model intermediate outcomes that would be relevant to decision making and/or the assessment of costs, such as retransplantation rates. Finally, simulation modeling does not provide tests of statistical significance, nor does it determine levels of clinically meaningful improvements in survival rates. The United Network for Organ Sharing is developing SLK transplant guidelines in response to the dramatically increasing number of SLK transplants and the variations among transplant centers in indications for this procedure. 28 The proposed guidelines focus on offering SLK transplantation only to ESLD patients who are unlikely to regain renal function after liver transplantation (eg, on the basis of the length of time on dialysis and the baseline renal function). The results of our model support these guidelines because we have demonstrated that maximal gains in survival after SLK transplantation accrue to those who have high MELD scores (>30) and those who have been on RRT for >90 days. In conclusion, there are dynamic and complex tradeoffs in the risks and benefits of different transplantation strategies for middle-aged ESLD patients requiring renal support. This study used simulation modeling to compare and quantify the outcomes of 3 clinically prevalent transplant approaches for this population. Models allow direct comparisons of large numbers of individuals that might not be feasible in clinical trials. The results suggest that SLK transplantation yields higher survival rates than liver transplantation under the current kidney graft allocation policy. When kidney transplantation was subsequently available to those who failed to recover renal function 16 weeks after transplantation, differences in the survival rates associated with SLK transplantation and liver transplantation became limited. Liver transplantation with subsequent kidney transplantation might be an alternative strategy for decreasing the tradeoff between the mortality risk after liver transplantation and unnecessary SLK transplantation, but important equity allocation issues are raised. ACKNOWLEDGMENT The authors acknowledge Dr. Mandelblatt (Georgetown-Lombardi Cancer Center) for her assistance with manuscript editing. REFERENCES 1. Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR). OPTN/SRTR 2011 Annual Data Report. Rockville, MD: Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation; Testino G, Ferro C. 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