Simultaneous Liver Kidney Allocation Policy: A Proposal to Optimize Appropriate Utilization of Scarce Resources

Transcription

1 American Journal of Transplantation 2016; 16: Wiley Periodicals Inc. Special Article Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: /ajt Simultaneous Liver Kidney Allocation Policy: A Proposal to Optimize Appropriate Utilization of Scarce Resources R. N. Formica 1, *, M. Aeder 2, G. Boyle 3, A. Kucheryavaya 3, D. Stewart 3, R. Hirose 4 and D. Mulligan 1 1 Yale University School of Medicine, New Haven, CT 2 University Hospitals Case Medical Center, CWRU, Cleveland, OH 3 United Network of Organ Sharing, Richmond, VA 4 University of California, San Francisco, San Francisco, CA *Corresponding author: Richard N. Formica, richard.formica@yale.edu The introduction of the Mayo End-Stage Liver Disease score into the Organ Procurement and Transplantation Network (OPTN) deceased donor liver allocation policy in 2002 has led to a significant increase in the number of simultaneous liver kidney transplants in the United States. Despite multiple attempts, clinical science has not been able to reliably predict which liver candidates with renal insufficiency will recover renal function or need a concurrent kidney transplant. The problem facing the transplant community is that currently there are almost no medical criteria for candidacy for simultaneous liver kidney allocation in the United States, and this lack of standardized rules and medical eligibility criteria for kidney allocation with a liver is counter to OPTN s Final Rule. Moreover, almost 50% of simultaneous liver kidney organs come from a donor with a kidney donor profile index of The kidneys from these donors could otherwise be allocated to pediatric recipients, young adults or prior organ donors. This paper presents the new OPTN and United Network of Organ Sharing simultaneous liver kidney allocation policy, provides the supporting evidence and explains the rationale on which the policy was based. Abbreviations: CKD, chronic kidney disease; DSA, donor service area; egfr, estimated GFR; KDPI, kidney donor profile index; MELD, Mayo End-Stage Liver Disease; OPO, Organ Procurement Organization; OPTN, Organ Procurement and Transplantation Network; SLK, simultaneous liver kidney; UNOS, United Network of Organ Sharing Received 25 September 2015, revised 01 November 2015 and accepted for publication 16 November 2015 Introduction The introduction of the Mayo End-Stage Liver Disease (MELD) score into the Organ Procurement and Transplantation Network (OPTN) deceased donor liver allocation policy in 2002 (1) has led to a significant increase in the number of simultaneous liver kidney (SLK) transplants in the United States (2) (Figure 1). Also contributing to the increasing trend is the fact that there are no medical criteria on which allocation of the kidney with a liver is based. This has resulted in heterogeneity in both numbers of SLK transplants performed in the different OPTN regions of the country and which patients receive them (3). The primary issue driving SLK allocation is increasing severity of illness of liver disease patients. Because the MELD score relies heavily on serum creatinine (4), as MELD score at transplantation has increased, there has been a coincident increase of renal disease in liver transplant candidates. The issue is compounded by the fact that despite multiple efforts, clinical science has not been able to reliably predict which liver candidates with renal insufficiency or disease will recover renal function or need a concurrent kidney transplant (5, 6). Moreover, data suggest that even in the highest risk patients, the development of end-stage renal disease in the first 6 mo after liver transplantation is a relatively rare occurrence (7). This is counterbalanced by the available evidence suggesting that renal disease requiring dialysis during the first year after liver transplantation results in an 5% decrease in 1-year patient survival compared with a liver transplant recipient without renal disease (8). Because of the difficulty in discriminating between those patients who will and will not require long-term dialysis after liver transplantation, the default position of physicians has been to err on the side of caution and transplant the kidney along with the liver. The problem facing the transplant community is that currently there are almost no medical criteria for candidacy for SLK allocation in the United States. OPTN policy states only that candidates registered for multiple organs must appear on the heart, lung or liver match run to be eligible to receive a heart, lung or liver. When multiorgan 758

2 Simultaneous Liver Kidney Allocation Policy Figure 1: Number of simultaneous liver kidney transplants by year. Based on Organ Procurement and Transplantation Network data as of June 12, Simultaneous liver kidney transplants with other organs were excluded from tabulations. candidates other than heart lung candidates are eligible to receive a heart, lung or liver, the second required organ will be allocated to the multiorgan candidate from the same donor if the donor s donor service area (DSA) is the same DSA where the multiorgan candidate is registered. Heart lung combinations are allocated according to Policy 6.5.E: Allocation of Heart-Lungs. (OPTN Policy 5.8 Allocation of Multi-Organ Combinations). This lack of standardized rules and medical eligibility criteria for kidney allocation with a liver is counter to the OPTN Final Rule, which states that allocation policies must be based on sound medical judgment and standardized criteria, must seek to achieve the best use of organs and must avoid futile transplants. Moreover, OPTN policy prioritizes multiorgan candidates before kidney-alone candidates if the candidate is in the same DSA as the donor. Because there are no medical criteria on which allocation is based, it is geographic proximity between the donor and candidate alone that is the determining factor. In fall 2014, representatives from the OPTN Kidney Transplantation, Liver and Intestinal Transplantation, Organ Procurement Organization (OPO), Ethics, Minority Affairs and Operations and Safety Committees ( working group ) began to develop an SLK allocation policy. The group thought the current policy was problematic because it does not base kidney allocation on medical criteria indicating which candidates are most in need. Because multiorgan allocation occurs before kidney-alone allocation, for example, highly sensitized patients (those with calculated panel reactive antibody of 98%, 99%, and 100%) are never offered these kidneys, although they are highly prioritized in kidney-alone allocation. (OPTN Policy 8: Allocation of Kidneys). Another significant concern is that the kidneys used in SLK allocation tend to come from donors with lower kidney donor profile index (KDPI) (9) and thus have longer expected longevity (UNOS unpublished data). Of the total number of SLK transplants, 49% of donor kidneys had a KDPI <35% and were prioritized for pediatric candidates in kidney-alone allocation. This diverts, on average, 250 kidneys per year that may have been potentially offered to pediatric patients, young adults or other prioritized groups. Past Work Several attempts have been made to address this problem over the past decade. In 2006, 2007, and 2012, several transplant societies held consensus conferences to discuss the topic and began to formulate medical criteria for SLK (3, 10, 11). In 2009, the Kidney Transplantation and Liver and Intestinal Transplantation Committees distributed a public comment proposal that was largely constructed from these recommendations. The 2009 proposal contained certain medical eligibility criteria pertaining to renal insufficiency for SLK allocation (3). This proposal also introduced the concept of a safety net to ensure that a liver transplant patient not offered the kidney initially and who remained on dialysis after liver transplantation would be highly prioritized for kidney offers. This proposal received broad support; however, several national professional groups opposed portions of the proposal for different reasons. Further complicating American Journal of Transplantation 2016; 16:

3 Formica et al the effort was the fact that many of the proposed changes involved very complex and expensive computer system programming, mostly due to the vast number of kidney allocation policy variances that existed at the time and the unknown factor of when the new kidney allocation system would be approved and implemented. A decision was made not to proceed until the new kidney allocation system was in place. Methods This study used data from OPTN as of January 3, 2015, unless stated otherwise. The OPTN data system includes data on all donors, waitlisted candidates and transplant recipients in the United States, submitted by the members of the OPTN, and has been described elsewhere. The Health Resources and Services Administration, U.S. Department of Health and Human Services, provides oversight of the activities of the OPTN contractor. OPTN data were supplemented with alternative sources of death data including Social Security Death Master File data as of December 19, 2014, and dialysis data from the Centers for Medicare and Medicaid Services database as of March 31, Analyses were performed for adult candidates added to the waiting list from March 1, 2002, through December 31, 2012, and for deceased donor adult transplants performed during that time. Unless stated otherwise, all multiorgan registrations and transplants and prior transplant recipients were excluded from analyses. Liver status 1A recipients were also excluded. Kidney registrations and transplants with a previous liver transplant were limited to those with liver functioning at the time of kidney registration or transplant. Waiting list analysis was performed on a patient level with all multiple registrations for the same organ (either kidney alone or both kidney and liver) for the same patient combined into one item. The SLK candidates group included (i) all candidates with liver and kidney registrations at the same center who had the same start and end dates and (ii) all candidates with a liver registration added to the waiting list first and then had kidney registration added at the same center within 30 days of the liver registration with both registrations ending on the same day. Waiting list deaths included all waiting list removals for death and removals for reasons other than transplant (or death during transplant procedure) if death occurred within 30 days of removal was found. Waiting list survival time was censored (i) at the time of removal from the waiting list for patients removed for transplant, (ii) at 30 days after removal from the waiting list for patients removed for reasons other than transplant of death, or (iii) on January 3, 2015 (database copy date) for patients still waiting as of that date. Renal failure was defined by pretransplant dialysis time of >2 mo or serum creatinine >2.5 mg/dl. For kidney graft survival analyses, a graft was considered to have failed if graft failure, return to chronic maintenance dialysis or patient death was reported to the OPTN contractor. Otherwise, graft survival time was considered to be censored as of the last date for which a graft was reported as still functioning. The Kaplan Meier method was used to generate waiting list, graft and patient survival curves. Survival curves were compared using the log-rank test. Comparisons of characteristics of recipients were made using the chi-square statistic for categorical variables and the Wilcoxon Mann Whitney test for continuous variables. Estimated GFR (egfr) was computed using the MDRD formula. Multivariable analyses were performed using Cox proportional hazards regression and included restricted cubic splines for continuous variables. Overall, p-values <0.05 were considered statistically significant. Results In an effort to develop a proposal that was based on evidence, the working group reviewed the medical literature on the topic of SLK allocation. In addition, the OPTN database was queried for the characteristics of SLK recipients, recipient survival with and with out kidney disease after liver transplantation, kidney waitlist survival for those waiting for primary kidney transplantation and those waiting for kidney transplantation after liver transplantation, and kidney graft survival for kidney alone and SLK patients. To better understand the degree of kidney disease that resulted in a net survival benefit of receiving a kidney accompanying the liver, those patients who received SLK transplant were characterized by presence or absence of dialysis prior to transplantation and its duration and, for those not on dialysis, serum creatinine at the time of listing chosen as a measure of kidney injury. The kidneys used in multiorgan transplants predominantly come from donors with lower KDPI. In the case of SLK transplant, 48.3% of donors had kidneys with a KDPI <0.35. In addition 37% of SLK recipients received no dialysis prior to transplantation, 22% received <2 mo of dialysis, 9% received between 2 and 6 mo of dialysis and 23% received >6 mo of dialysis (Figure 2). Of those patients who received no pretransplant dialysis, 40% had serum creatinine <2.5 mg/dl at the time of transplantation. Pretransplant dialysis time of >2 mo or serum creatinine >2.5 mg/dl were used as an approximate definition of renal impairment. Characteristics of patients meeting the definition of renal failure and those who did not are presented in Table 1. Among those patients meeting this definition, those who received an SLK transplant had an unadjusted survival curve that was significantly higher than those who received liver alone. Patient survival at 1 and 5 years was 86.2% and 70.1%, respectively, for those patients receiving SLK and 81.1% and 65.9%, respectively, for those receiving liver alone (Figure 3A). After multivariable adjustment, this significant difference remained, echoing results published by Fong et al (8) (Table 2). Interestingly, however, recipients without renal impairment had significantly worse (unadjusted) 1- and 760 American Journal of Transplantation 2016; 16:

4 Simultaneous Liver Kidney Allocation Policy Figure 2: Pretransplant dialysis and duration among simultaneous liver kidney recipients (March 1, 2002 to December 31, 2012). Table 1: Donor and recipient characteristics (March 1, 2002 to December 31, 2012) Renal failure Non renal failure SLK Liver alone p-value SLK Liver alone p-value Liver diagnosis Noncholestatic cirrhosis 74.8% 75.4% < % 60.7% <0.001 Malignant neoplasms 8.2% 8.0% 10.6% 23.4% Cholestatic liver disease/cirrhosis 3.8% 8.2% 5.3% 8.2% Metabolic disease 3.9% 2.9% 1.5% 2.5% Acute hepatic necrosis 1.6% 2.9% 2.1% 2.3% Benign neoplasms 4.0% 0.2% 1.7% 0.3% Other 3.7% 2.4% 3.0% 2.6% Ethnicity White 62.2% 71.5% < % 72.9% <0.001 Hispanic 17.1% 16.4% 17.3% 12.6% Black 15.3% 8.0% 14.0% 8.7% Asian 4.2% 3.1% 4.0% 4.7% Other 1.2% 1.1% 1.2% 1.1% Diabetes at listing 40.4% 27.8% < % 22.8% <0.001 Transplant year March % 20.0% % 24.3% < % 35.7% 46.0% 38.1% % 44.3% 39.1% 37.6% Recipient age (years) 56.0 ( ) 55.0 ( ) ( ) 55.0 ( ) <0.001 MELD lab score 27.0 ( ) 36.0 ( ) < ( ) 17.0 ( ) <0.001 Recipient weight (kg) 78.1 ( ) 83.5 ( ) < ( ) 83.0 ( ) <0.001 Donor/recipient sex Female/female 16.4% 17.7% % 14.9% Female/male 23.0% 22.2% 26.4% 25.6% Male/female 19.8% 22.0% 16.4% 15.0% Male/male 40.7% 38.1% 46.6% 44.5% KDPI (reference population ( ) 46.5 ( ) < ( ) 51.0 ( ) <0.001 Liver donor risk index 1.2 ( ) 1.4( ) < ( ) 1.4 ( ) <0.001 Renal failure was defined as 2 mo of dialysis or estimated GFR 25 prior to liver transplant. Continuous factors are expressed as median (5th 95th percentiles). KDPI, Kidney Donor Profile Index; MELD, Model for End-Stage Liver Disease; SLK, simultaneous liver kidney. American Journal of Transplantation 2016; 16:

5 Formica et al Figure 3: Unadjusted survival advantage of receiving SLK versus LI (March 1, 2002 to December 31, 2012). (A) Survival of SLK versus LI for patients with renal renal failure defined as 2 mo of dialysis or estimated GFR 25 ml/min. (B) Survival of SLK versus LI for patients not meeting the definition of renal failure. LI, liver alone; SLK, simultaneous liver kidney. 5-year survival if they received SLK (86.3% and 69.5%, respectively) as opposed to liver alone (89.9% and 73.9%, respectively) (Figure 3B). This survival decrement was not statistically significant (p = 0.25) after multivariable adjustment (Table 2). Nevertheless, these results suggest that liver-alone candidates with renal insufficiency stand to benefit most from SLK transplantation, whereas the benefit of receiving SLK is dubious and may potentially even be detrimental for patients without renal insufficiency. Because SLK is done with the goal of improving the utility of liver transplantation by improving the 1-year survival of the recipient, the SLK working group wanted to better understand the cost in terms of renal allograft outcome. The survival of the renal allograft was 83.3% for SLK recipients meeting the working definition of renal impairment and 84.6% for those not meeting the definition of renal failure. Both of these survival rates were significantly lower than the renal allograft survival rate of 91.3% for kidney-alone patients (Figure 4A). Allograft loss was primarily due to patient death. SLK patient survival at 1 year was 86.2% and 86.3% for those with and without the renal impairment, respectively, compared with 91.3% for kidney-alone recipients (Figure 4B). Finally, in an effort to develop an appropriate safety net for liver-alone recipients who do not regain sufficient renal function, survival rates for patients on the kidney transplant waiting list were compared for prior liver transplant recipients versus those listed for first kidney-alone transplant. Prior liver transplant recipients had much worse waitlist survival compared with kidney-alone candidates. Moreover, this decreased survival was noted even if they were listed in the first year after liver transplantation. Nevertheless, those prior liver transplant recipients who received a kidney transplant within 3 years of the liver transplant had long-term survival that was comparable to kidney-alone recipients. Those who waited >3 years had significantly worse survival, suggesting that liver-alone candidates whose kidney function does not return to normal should be transplanted relatively quickly after liver transplantation (Figure 5). Policy Proposal and Rationale The SLK working group used the past policy proposal and public comment as a framework for developing an updated proposal. The proposal has two components: medical eligibility criteria for SLK transplant and a safety net for liver recipients who end up needing a kidney shortly after liver-alone transplantation. In addition, the proposal also contains a plan to eliminate the conflict between the multiorgan policy and deceased donor liver policy with regard to a liver candidate s priority for regional liver and (for MELD 35 candidates) SLK allocation. 762 American Journal of Transplantation 2016; 16:

6 Simultaneous Liver Kidney Allocation Policy Table 2: Multivariable, risk-adjusted analyses of mortality within 5 years after transplant (March 1, 2002 to December 31, 2012) Risk factor Renal failure group Non-renal failure group Hazard ratio 95% Confidence limits p-value Hazard ratio 95% Confidence limits p-value SLK versus liver alone Liver diagnosis (reference group: noncholestatic cirrhosis) Malignant neoplasms Cholestatic liver disease/cirrhosis <0.001 Metabolic disease Acute hepatic necrosis Benign neoplasms < <0.001 Other Ethnicity (reference group: white) Hispanic <0.001 Black < <0.001 Asian <0.001 Other Donor/recipient sex (reference group: male/male) Female/female <0.001 Female/male Male/female Diabetes at listing < <0.001 Transplant year (reference group: ) March < < < <0.001 Recipient age <0.001 <0.001 MELD lab score <0.001 Recipient weight (kg) <0.001 Liver donor risk index <0.001 <0.001 Renal failure was defined as 2 mo of dialysis or estimated GFR 25 prior to liver transplant. Continuous factors are expressed as median (5th 95th percentiles). MELD, Model for End-Stage Liver Disease; SLK, simutaenous liver kidney. Medical eligibility criteria The medical eligibility criteria are divided into three categories: chronic kidney disease (CKD), sustained acute kidney injury and metabolic diseases requiring combined liver kidney transplantation. Under the proposal, if the liver candidate fits one of the specified categories, the candidate is eligible for both local and regional SLK allocation. Chronic kidney disease: This category includes both end-stage renal disease, as defined by the administration of chronic dialysis, and advanced medical renal disease. The advanced medical renal disease component posed the greatest challenge. Serum creatinine is a poor marker for renal dysfunction in the liver disease population and tends to overestimate renal function (12). The existing literature (6) suggests that patients with CKD and low GFR require combined liver kidney transplantation. The definition of CKD chosen was formulated by incorporating the current published literature with the observed characteristic of SLK patients discussed above. In addition, although the published literature is conflicting, it supports the clinical impression that in a patient with low GFR, the addition of calcineurin inhibitor to the medical regimen causes an 10 ml/min reduction in egfr (13 15). Consequently, CKD was defined as egfr of <60 ml/min for >90 days prior to listing and an egfr of <35 ml/min at the time of listing. Sustained acute kidney injury: In developing the definition of sustained acute kidney injury, the working group took into consideration the published literature, the characteristics of SLK patients discussed above and the clinical expertise of its members. The duration of acute dialysis required prior to needing a kidney transplant is not resolved, and different authors have argued for between 4 and 12 weeks (5, 10, 16). Six weeks was chosen because after 4 weeks of dialysis, the rate of renal recovery declines significantly (17). Moreover, recipients of SLK transplant have higher MELD scores (2), and the survival of these patients for >6 weeks is anticipated to be very low (18). In addition, for those patients not requiring dialysis and not having a prior diagnosis of CKD, an egfr of <25 ml/min for six or more consecutive weeks was added to the definition of sustained acute kidney injury. Finally, because many of these patients have kidney injury that exists on a continuum, a combination of dialysis and egfr < 25 ml/min for six consecutive weeks duration was included. American Journal of Transplantation 2016; 16:

7 Formica et al Figure 4: Kidney and recipient survival for SLK recipients versus KI recipients (March 1, 2002 to December 31, 2012). (A) Oneyear renal allograft survival for SLK patients with and without renal failure, defined as 2 mo of dialysis or estimated GFR 25, compared with KI transplants (prior liver recipients were excluded from the KI group.) (B) One-year patient survival for SLK recipients with and without renal failure compared with KI recipients. KI, kidney alone; SLK, simultaneous liver kidney. Figure 5: Kidney patient survival for those with and without prior LI Tx, separately for waiting list candidates and kidney transplant recipients (March 1, 2002 to December 31, 2012). LI tx, liver transplant. 764 American Journal of Transplantation 2016; 16:

8 Simultaneous Liver Kidney Allocation Policy Figure 6: Allocation sequence for kidney transplantation demonstrating where the proposed safety net for liver transplant recipients with nonrecovery of renal function would be placed. SLK, simultaneous liver kidney. Metabolic disease: The inclusion of those patients with metabolic diseases that require combined liver kidney transplantation was not controversial and has been accepted for some time. Consequently, no changes from existing practice were required. Safety net The development of a safety net was a critical component of this proposed policy. It is believed that the addition of this component to the policy may affect physician decision making by removing the concern that if a patient does not receive the SLK transplant, the patient will remain on dialysis and suffer a worse outcome. Any patient who receives a liver transplant and who is registered on the kidney waiting list between 60 and 365 days after liver transplant and either is on chronic hemodialysis or has an egfr 20 ml/min will qualify for increased priority (Figure 6). This will be a match classification priority and not an assignment of additional waiting time points. Once a patient qualifies for this priority, it will be retained until the patient receives a kidney transplant. This safety net will apply to liver-alone transplant recipients and to liver transplant recipients with other organs: heart, lung and/or intestine. It will not apply to SLK recipients unless they meet the definition of primary kidney nonfunction 90 days after SLK transplantation. Primary kidney nonfunction is defined as instances in which the kidney was removed, the patient is on chronic maintenance hemodialysis or the patient has an egfr 20 ml/min at 90 days after a kidney transplant. Regional sharing With the institution of the kidney allocation system on December 4, 2014, the payback provision for kidneys shared out of the local allocation unit was terminated. This change could have a significant impact on SLK allocation because patients requiring SLK transplant are likely to have MELD scores 35 (2) and thus qualify for regional sharing of livers; however, the current allocation policies do not require an OPO to allocate a kidney with a liver if it is outside of the local designation. This creates a difficult decision in which an OPO must choose whether or not to offer a kidney with the liver and/or a transplant center must choose between accepting a liver alone in a regional share for a patient requiring liver kidney transplantation or continuing to wait for a local SLK and the potential increased morbidity and mortality for the patient. Consequently, regional sharing of kidneys in SLK transplant for patients with MELD scores 35 was included in the policy. Discussion The development of a coherent and rational approach to combined liver kidney allocation establishes a template for the confused and often internally inconsistent approach that exists for allocation of other multiorgan combinations. Developing standardized medical eligibility criteria is only the beginning of the process of improving the organ allocation system in the United States. Still to be resolved is the fact that SLK transplantation is not accounted for in the Scientific Registry of Transplant Recipients metrics of program performance. This creates an incentive to add a kidney to a high-risk liver candidate to buffer a program s outcomes. The increasing tendency to allocate the kidney with the liver has highlighted another structural deficiency within the allocation system. In addition to the problems addressed American Journal of Transplantation 2016; 16:

9 Formica et al with this policy proposal, there is a larger conflict in considering multiorgan transplantation as a class. With potentially four primary organs pancreas, liver, heart and lung that can be paired with a kidney, OPOs must make a solomonic decision at the time of allocation regarding which match run will be used. This is because no policy exists regarding which organ should be allocated first. This fact puts multiorgan allocation in conflict with the Final Rule. Organ allocation must proceed based on the medical need of the recipient and his or her ability to wait for an organ; however, until now, there has not been an effort to determine medical need and the ability to wait regarding candidates for various multiorgan combinations and those awaiting solitary kidney transplantation. Development of fair and rational medical criteria for qualifying for SLK allocation that may be applicable to other organ with kidney combinations, along with a safety net to protect patients that are screened out but may be in need, is the first step toward developing a comprehensive organ allocation system based on medical need, the ability to wait and transparent rules. Disclaimer The data reported have been supplied by the United Network for Organ Sharing as the contractor for the Organ Procurement and Transplantation Network (OPTN). The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of or interpretation by the OPTN or the U.S. government. Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. References 1. Freeman RB Jr, Wiesner RH, Harper A, et al. The new liver allocation system: Moving toward evidence-based transplantation policy. Liver Transpl 2002; 8(9): Gonwa TA, McBride MA, Anderson K, Mai ML, Wadei H, Ahsan N. Continued influence of preoperative renal function on outcome of orthotopic liver transplant (OLTX) in the US: Where will MELD lead us? Am J Transplant 2006; 6(11): Nadim MK, Sung RS, Davis CL, et al. Simultaneous liver-kidney transplantation summit: Current state and future directions. Am J Transplant 2012; 12(11): Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003; 124(1): Locke JE, Warren DS, Singer AL, et al. Declining outcomes in simultaneous liver-kidney transplantation in the MELD era: Ineffective usage of renal allografts. Transplantation 2008; 85(7): Ruebner R, Goldberg D, Abt PL, et al. Risk of end-stage renal disease among liver transplant recipients with pretransplant renal dysfunction. Am J Transplant 2012; 12(11): Israni AK, Xiong H, Liu J, et al. Predicting end-stage renal disease after liver transplant. Am J Transplant 2013; 13(7): Fong TL, Khemichian S, Shah T, Hutchinson IV, Cho YW. Combined liver-kidney transplantation is preferable to liver transplant alone for cirrhotic patients with renal failure. Transplantation 2012; 94(4): Organ Procurement and Transplantation Network. A Guide to Calculating and Interpreting the Kidney Donor Profile Index (KDPI); Available from: Eason JD, Gonwa TA, Davis CL, Sung RS, Gerber D, Bloom RD. Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation (SLK). Am J Transplant 2008; 8(11): Charlton MR, Wall WJ, Ojo AO, et al. Report of the first international liver transplantation society expert panel consensus conference on renal insufficiency in liver transplantation. Liver Transpl 2009; 15(11): S1 S Francoz C, Glotz D, Moreau R, Durand F. The evaluation of renal function and disease in patients with cirrhosis. J Hepatol 2010; 52(4): Henny FC, Kleinbloesem CH, Moolenaar AJ, Paul LC, Breimer DD, van Es LA. Pharmacokinetics and nephrotoxicity of cyclosporine in renal transplant recipients. Transplantation 1985; 40(3): Klein IH, Abrahams A, van Ede T, Hene RJ, Koomans HA, Ligtenberg G. Different effects of tacrolimus and cyclosporine on renal hemodynamics and blood pressure in healthy subjects. Transplantation 2002; 73(5): Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 2009; 4(2): Davis CL, Feng S, Sung R, et al. Simultaneous liver-kidney transplantation: Evaluation to decision making. Am J Transplant 2007; 7(7): Network VNARFT; Palevsky PM, Zhang JH, O Connor TZ, et al. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med 2008; 359(1): Wiesner RH, McDiarmid SV, Kamath PS, et al. MELD and PELD: Application of survival models to liver allocation. Liver Transpl 2001; 7(7): American Journal of Transplantation 2016; 16: