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Current status of combined liver-kidney transplantation
Journal Pre-proof Current status of combined liver-kidney transplantation Burcin Ekser, Alan G. Contreras, Wellington Andraus, Timucin Taner PII:
S1743-9191(20)30171-0
DOI:
https://doi.org/10.1016/j.ijsu.2020.02.008
Reference:
IJSU 5267
To appear in:
International Journal of Surgery
Received Date: 5 February 2020 Accepted Date: 7 February 2020
Please cite this article as: Ekser B, Contreras AG, Andraus W, Taner T, Current status of combined liver-kidney transplantation, International Journal of Surgery, https://doi.org/10.1016/j.ijsu.2020.02.008. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
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ABSTRACT Combined liver-kidney transplantation is a life-saving procedure for patients with end-stage liver disease and underlying chronic kidney disease, or prolonged acute kidney injury. Due to physiologic changes secondary to portal hypertension in patients with end-stage liver disease, kidney injury is common, and combined liver-kidney transplantation accounts for 10% of all the liver transplants performed in the United States. Recently implemented policy in the United States standardizes the medical criteria for eligibility, and introduces a 'safety net' for those who are transplanted with a liver graft alone, in order to be able to receive a kidney graft later. Increasing number of combined liver-kidney transplants provides a large cohort of patients to be studied in detail for identification of factors (both donor and recipient-related) associated with better outcomes. Data regarding the safety and efficacy of delaying the kidney transplant part of the combined liver-kidney transplantation, and the immunologic benefits of the multi-organ transplantations including the liver are emerging. Here, we review the most recent analyses, and provide our opinion regarding the best practices in combined liver-kidney transplantation based on the evidence. INTRODUCTION Liver transplantation (LT) is the ultimate therapy for patients with end-stage liver disease (ESLD). However, ESLD is frequently associated with portal hypertension and subsequent pooling of the portal blood in the splanchnic system, resulting in reduced circulating blood volume which increases the risk for renal dysfunction and acute kidney injury (AKI) [1]. Decompensated cirrhosis increases this risk further, and could lead to chronic kidney disease (CKD) due to; (i) hepatorenal syndrome, (ii) hypovolemia-induced renal failure, (iii) parenchymal renal disease, and (iv) drug-induced renal failure [1]. As such, CKD is a common complication in LT recipients, and is associated with reduced survival [2-3].
Combined liver-kidney transplantation (CLKT), first reported by Margreiter et al. [4] in order to
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overcome both ESLD and end-stage renal disease, has been performed increasingly since the introduction of Model for End-stage Liver Disease (MELD) scoring system in 2002 for organ allocation. Due to the magnitude of operation and significantly sicker patient population, initial outcomes of CLKT were poor, with 20-30% mortality within the first year following CLKT [5]. Currently, there are no standard criteria for CLKT eligibility and organ allocation around the globe, and each country employs their own allocation criteria (which varies from center to center within the given country). In 2017, United Network for Organ Sharing (UNOS) in the United States enacted the most comprehensive policy for CLKT which now defines the medical eligibility criteria for all transplant centers under the UNOS umbrella (Table 1) [6]. CLKT has now reached to almost 10% of all LT activity in the United States (Figure 1) [6].
This review summarizes recent practices in CLKT with ongoing discussions mainly in the United States and with very limited data around the world.
Changes in CLKT allocation policy Since early 2000s, several allocation criteria have been proposed for CLKT. In 2007, Davis et al. proposed iothalamate clearance ≤30mL/min for CKD and dialysis duration ≥6 weeks, or fixed renal damage on kidney biopsy for AKI [7]. In 2008, a consensus conference proposed similar criteria but also added serum creatinine ≥2mg/dl and dialysis of ≥8 weeks, including diabetes, hypertension, age ≥65 years, and proteinuria for AKI [8]. In 2012, Nadim et al. conducted a survey of 88 transplant centers that perform CLKT in the United States to determine practice patterns [9]. The majority of centers in this study (73%) used dialysis duration for AKI as a cutoff for CLKT listing, with duration varying between 4-8 weeks [9]. Although more detailed criteria were proposed in the subsequent consensus conferences, no unified criteria were accepted by all transplant centers. In 2017, UNOS enacted a policy for the allocation of CLKT based on
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medical eligibility (Table 1), and introduced the ‘safety net’ for patients with marginal renal function who receive LT alone, so that they have access to kidney transplantation (KT) should the renal function worsen after the LT (Table 2).
There is no standardized allocation policy around the world. The data in CLKT from Latin American Centers are scarce. For example, in Mexico there are currently 4 patients listed for CLKT [unpublished]. Brazil is the largest country in Latin America in regards to number of LT performed each year (~2200 LTs /year) [10]. In Brazil, although the number of CLKT was doubled from 2% to 4% of all LTs after the adaptation of MELD score in 2006, there is still no standardized allocation policy for CLKT [11]. Only European and outside of UNOS data-registrybased analyses focusing on CLKT were reported by Tinti et al using the transplant registry from the United Kingdom [12]. The rate of CLKT was only 2% (n=123) of all LTs performed between 200-2013 in the United Kingdom and there was no mention to allocation policy in CLKT [12].
After the implementation of this new policy in the United States in 2017, Luo et al. carefully studied center-level variations [13]. They found that among 4736 CLKT-eligible candidates, only 65% were listed for CLKT within 6 months of eligibility. However, most interestingly, the percentage of CLKT listing ranged from 0%-100% across centers. They also found that African American race, male sex, previous transplant history, diabetes, and hypertension were associated with a higher likelihood of CLKT listing, while older age was associated with a lower likelihood of CLKT listing [10].
Calluro et al. recently analyzed all patients listed for LT in the UNOS registry from May 2007 through July 2014 [14]. They found that of 40979 candidates, 1683 (4.1%) would have met the new CLKT allocation criteria compared to 2452 (6%) in old proposed criteria. They conclude that new CLKT allocation policy will increase the proportion of women and decrease the
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proportion of men who are listed for CLKT but may not improve post-transplant survival [14]. Therefore, there is still ongoing need for monitoring of CLKT outcomes after implementation of the new policy [14].
Discussions and efforts are ongoing to improve the outcomes of CLKT and to decrease the futility of kidneys. Future studies will show us whether the implementation of standardized CLKT listing practices may reduce center-level variations and optimize outcomes.
Optimization of outcomes Surgical issues and timing of the KT in CLKT CLKT necessitates consideration of surgical logistics for both the liver and the kidney allografts. LT recipients are often sick at the time of transplant with significant coagulopathy, and require vasopressor/inotropic agents intraoperatively. Thus, the hemodynamic status of the recipients is far than ideal for the newly implanted kidney allograft. Furthermore, in patients with hyperbilirubinemia, the bilirubin crystalizes in the tubules of kidneys, increasing the risk for AKI and further renal dysfunction of the kidney allograft.
To optimize the physiologic environment for kidney graft and patient outcomes, Ekser et al. [15] have performed delayed KT in CLKT, the so-called ‘Indiana Approach’. In Indiana Approach, LT is performed first while the kidney graft is placed on a hypothermic pulsatile perfusion machine [15]. Implantation of the kidney graft is delayed for 2 to 3 days post-LT [15,16,17]. This approach allows stabilization of LT patients’ hemodynamics and coagulopathy in the post-LT period, before implantation of the renal allograft. This delay also permits decompression of varices to minimize blood loss during KT, which may directly impact renal allograft outcome. Finally, planned delayed implantation of the kidney frequently provides time to completely wean vasopressors before KT, thus lowering the risk of pressor-related delayed graft function (DGF)
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and clearing post-liver reperfusion debris and bilirubin from the circulation. The same group also documented that DGF is the most important negative predictor of patient survival in CLKT. Moreover, they also showed that despite the belief of renal allograft damage and increased rate of DGF due to prolonged cold ischemia time (CIT) >48 hours, the rate of DGF and estimated glomerular filtration rate (eGFR) were much better, if KT of the CLKT was delayed >48 hours (Figure 2A) [15].
Lunsford et al. recently reported their results in delayed KT in CLKT (Indiana Approach) with improved patient and kidney survival and decreased kidney futility, despite higher MELD (>35) score, longer intensive care stay, prolonged intubation, and greater use of vasopressors [18]. This study showed that even in high-acuity patients, delayed KT should be the preferable approach in CLKT [18]. Lauterio et al. reported the first 2 cases of delayed KT in CLKT in Europe, demonstrating that the technique can be done by others with broader implications [19].
Kidney allograft quality The importance of the kidney-donor profile index (KDPI) was highlighted by several studies in CLKT [20,21]. Jay et al. analyzed the UNOS database showing the importance of renal allograft quality based on KDPI [20]. They reported that of 4207 CLKT, 6% were from KDPI >85% donors and recipients of those grafts had significantly increased mortality (HR=1.83, 95%CI=1.44-2.31) [20]. In a single center analysis, Ekser et al showed that excellent outcomes can be achieved in CLKT using the Indiana Approach and low KDPI kidneys (Figure 2B) [16].
Shekhtman et al. analyzed the UNOS database for combined dual KT-LT in the United States between 2002-2012 [22]. Of 3044 CLKTs, they identified only 22 cases of combined dual KT-LT (0.7%). The kidneys used in these patients were all from extended criteria donors (ECD), and
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their survival was 41% at 3-year post-CLKT compared to 68% ECD CLKT and 65% for high KDPI CLKT [22]. Although the approach could expand the donor pool for CLKT, the current outcomes in combined dual KT-LT should be ameliorated. Previously, in a case report of 2 cases, Ekser et al. reported dual KT after LT with long-term success [23], which could be an option for the use of dual KT for LT recipients instead of using them simultaneously.
Recent studies highlight the overall inferior outcomes with the use of ECD kidneys and dual KT in CLKT. Although there are reports showing good outcomes in dual KT with marginal donors [24] and very high KDPI kidneys [25] after careful selection, the decision to use such kidney allografts should be made carefully on a case-by-case basis. In our expert opinion, several factors should be considered for this decision: (i) Kidney DGF: Measures should be taken to avoid and/or minimize DGF, since the latter has been shown to be the most important negative predictor on patient survival in CLKT in both single center [5,15,18] and larger UNOS data analyses [26].
(ii) Kidney allograft quality: Although the goal of the new CLKT allocation policy with ‘safety net’ is to decrease kidney futility and allocate better KDPI kidneys to pediatric population, it was shown that KDPI impacts the outcomes in CLKT [16,20,21]. One way to expand the donor pool could be the use of delayed KT approach in CLKT in order to use high KDPI kidneys without DGF with better outcomes [16]. Another option could be the use of donation after circulatory death (DCD) grafts in CLKT, which was recently studied by Croome et al. [27]. In UNOS database analysis, these authors showed that DCD-CLKT offers similar outcomes compared to matched patients undergoing donation after brain death (DBD)-CLKT, especially when the era factor (Era 1 - 2000-2010 vs. Era 2 - 2011-2018 – Era 2 was better than Era 1) is considered [27]. However, in another recent UNOS database study, Vinson et al. showed that DCD-CLKT could be only beneficial to those patients with MELD >30 [28]. They claimed that waiting for
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DBD-CLKT is the preferred option for patients with MELD ≤30 [28]. (iii) Recipient factors: It should be acknowledged that patients waiting for CLKT are much sicker compared to those waiting for LT or KT alone. Although the percentage of CLKT has now reached to almost 10% of all deceased LT in the United States, national outcomes are not yet optimal [22,29,30]. While many factors contributing to prolonged survival post-CLKT could be improved in recipients before transplant, aging and age-related senescence are important factors that cannot be easily modified. The outcomes of CLKT in elderly (>65 years and >70 years) recipients have been studied, and demonstrated that elderly recipients of CLKT (≥65 years) had similar outcomes to those <65 years of age [31]. However, with the multivariate analysis, the same authors proposed that CLKT should be avoided in patients ≥65 years of age on mechanical ventilation prior to CLKT, and in patients ≥70 years of age with a MELD score ≥30 [31].
A recent report by Goldberg et al. [32] analyzed the UNOS database to investigate the outcomes of CLKT in elder patients with underlying CKD. Between 2002-2018, there was a total of 3146 CLKTs with CKD, of which 465 recipients (14.8%) were 65-69 years of age, and 93 (3.0%) were ≥70 years of age. The authors found that compared to recipients aged 50-64 years, CLKT recipients with CKD 65-69 and ≥70 years of age; (i) were more likely to be of white race, (ii) had higher incidence of NASH/cryptogenic cirrhosis, (iii) received higher KDPI kidneys, (iv) had higher incidence of diabetes, especially in age group ≥70 years, and (v) were less likely to be on dialysis before the transplant [32]. The unadjusted 5-year survival of CLKT in recipients ≥70 years of age with CKD was 58% as compared to 69% in CLKT recipients ≥70 years of age without CKD, and both were lower compared to other age groups, such as 40-49, 50-59, 60-64, and 65-69 years of age [32]. It is likely that with the aging population, both the LT and CLKT candidates in advanced age will continue to increase, highlighting the importance of optimization of outcomes in this age group [33].
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(iv) Timing of kidney transplantation: As discussed above, CLKT necessitates special consideration of physiological needs for both liver and kidney allografts. Therefore, delayed KT in CLKT (Indiana Approach) can offer hemodynamically more stable LT recipient at the time of KT, and the renal allograft is not affected by prolonged CIT [15-19]. While LT alone, followed by KT at a later date from a separate donor (Kidney after LT) is another option, it should be noted that a recent UNOS database analysis showed that the hazard of 1-year-graft loss in the LT alone–CKD group was 35% higher than CLKT (HR=1.348, 95%CI=1.157-1572, p<0.001), indicating CLKT for patient who meet the CKD criteria may significantly improve transplant outcomes [34].
Despite encouraging outcomes obtained in delayed KT in CLKT, a recent report by Lee et al discussed the ‘en-bloc’ simultaneous liver-kidney transplantation as an alternative approach [35]. In this approach, the liver and ‘right’ kidney are procured together with the renal vein kept attached to the inferior vena cava [35]. Right renal artery is reconstructed to the donor splenic artery and the celiac axis of the donor is anastomosed to the recipient hepatic artery [35]. This surgical technique allows single incision (for LT) and definitely lowers the CIT for the renal allograft and operative time. The limitation of this approach is that the use of left kidney as an ‘en-bloc’ simultaneous liver-kidney transplant is quite difficult. The use of right kidney with multiple arteries and the liver with aberrant arteries which need reconstruction is also not preferable. Another concern is the potential risk of thrombosis or stenosis impacting the both allografts. However, in limited cases, the advantage of this (en-bloc) approach can be highlighted for centers where there is no perfusion machine available to apply delayed KT, and especially when the transplant teams for KT and LT are not the same. It should be also noted that, Lee et al observed 23% DGF rate both in traditional simultaneous CLKT and ‘en-bloc’ simultaneous liver-kidney transplantation [35].
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Immunological considerations in CLKT There are ongoing discussions about the choice of induction therapy and maintenance immunosuppressive regimen in CLKT due to the antigen load that comes from both organs instead of KT alone or LT alone. A recent study by AbdulRahim et al. investigated different induction therapies in CLKT in a UNOS database analysis [36]. They compared 4722 CLKTs between 2002 to 2016 with no induction (n= 2333), interleukin 2-receptor antagonist induction (n= 1558), and rabbit antithymocyte globulin (r-ATG) induction (n= 831). They concluded that rATG induction is potentially harmful and increases mortality risk compared with no induction in CLKT (HR= 1.29; 95% CI=1.10-1.52; P = 0.002) [36]. In response to this study, Ekser et al. demonstrated that their cohort of ~100 CLKTs using r-ATG induction had excellent outcomes [37].
Recent evidence, based on protocolled, routine kidney allograft biopsies demonstrates that the incidence of both T-cell-mediated and antibody-mediated rejection of the renal allograft is lower in CLKT patients, compared to KT alone patients, due to the protective effect of the liver [38]. In a follow-up study, Taner et al. demonstrated that molecular markers of inflammation and T-cell activation are significantly less common in kidney biopsies of CLKT recipients compared to KT alone recipients with similar immunologic risk profiles [39]. The study was designed in four groups: 16 cross-match negative KT alone, 15 cross-match positive KT alone, 12 cross-match negative CLKTs, and nine cross-match-positive CLKTs. The authors found that CLKT can have a profound impact on the kidney allograft, not only by decreasing inflammation and avoiding endothelial cell activation in cross-match-positive recipients, but also by increasing processes associated with tissue integrity/metabolism [39]. In a more recent study, Taner et al. studied host alloimmune response measured by the donor-specific alloresponsiveness and phenotypes of peripheral blood cells after the first years following CLKT [40]. They studied the alloreactivity
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of transplant recipients’ T cells using cryopreserved donor cells as the stimulators (Figure 3). They showed that CLKT recipients’ T cells had a very homogeneous and diminished response to alloantigen stimulation compared to KT alone recipient T cells (Figure 3) [40]. The protective effect of the liver allograft on simultaneously transplanted organs from the same donor has been shown in other multi-organ transplants as well [41,42].
Another recent study reported the impact of delayed KT on cross-match-positive CLKTs whether liver allograft can be utilized to lower anti-HLA donor specific antibodies (DSA) [43]. Although the cohort was small with 10 CLKTs with pre-existing DSAs, the authors showed that 8 out of 10 patients had decrease in DSA with an average of 57% in mean fluorescence intensity. Decrease in Class I antibody was significantly higher than Class II. This brief report with a small cohort showed that delaying KT for 2-3 days allows quantifiable reduction in circulating DSA after LT, probably by the absorption of antibodies by the liver allograft prior to KT with and without plasma exchange, which resulted in excellent clinical outcomes in cross-match-positive CLKT [43].
Conclusions CLKT is a life-saving procedure for patients with ESLD and CKD. The absolute number of CLKTs and the percentage of CLKT among the LT recipients have been increasing constantly in the past 2 decades. These accumulating numbers, in turn, provides increasingly large data sets, allowing for better assessment of factors associated with improved outcomes after CLKT. In light of the relatively new allocation policy in the United States, future studies will also help demonstrate whether outcomes improve and futility decrease, as projected.
DISCLOSURE
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All authors declare no conflict of Interest including manuscript preparation or funding by a commercial organization.
Provenance and peer review Commissioned, externally peer-reviewed
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outcomes in combined liver-kidney transplantation: Impact of kidney donor profile index and delayed kidney transplantation, Liver Transpl. 24 (2018) 222-232. 17. B. Ekser, A.M. Chen, C.A. Kubal, et al., Delayed kidney transplantation after 83 hours of cold ischemia time in combined liver-kidney transplant, Transplantation. 103 (2019) e382-e383. 18. L.E. Lunsford, V.G. Agopian, S.G. Yi, et al., Delayed Implantation of Pumped Kidneys Decreases Renal Allograft Futility in Combined Liver-Kidney Transplantation, Transplantation. (2019) Oct 23. doi: 10.1097/TP.0000000000003040. [Epub ahead of print] 19. A. Lauterio, R. De Carlis, S. Di Sandro, V. Buscemi, E. Andorno, L. De Carlis, Delayed kidney transplantation in combined liver-kidney transplantation for polycystic liver and kidney disease, Transpl. Int. 32 (2019) 1336-1338 20. C. Jay, J. Pugh, G.A. Halff, et al., Graft quality matters: survival after simultaneous liverkidney transplant according to KDPI, Clin. Transplant. 31 (2017) e12933. 21. B. Ekser, R.S. Mangus, C.A. Kubal, et al., Graft quality matters: Impact of KDPI and delayed kidney transplantation in combined liver-kidney transplantation, Clin. Transplant. 31 (2017) doi: 10.1111/ctr.13056. 22. G. Shekhtman, E. Huang, G.M. Danovitch, P. Martin, S. Bunnapradist, Combined dualkidney liver transplantation in the United States: a review of United Network for Organ Sharing/Organ Procurement and Transplantation Network Data between 2002 and 2012, Liver Transpl. 24 (2018) 1570-1577 23. B. Ekser, L. Furian, N. Baldan, et al., Dual kidney transplantation after liver transplantation: a good option to rescue a patient from dialysis, Clin. Transplant. 23 (2009) 124-128. 24. B. Ekser, L. Furian, A. Broggiato, et al., Technical aspects of unilateral dual kidney transplantation from expanded criteria donors: experience of 100 patients, Am. J. Transplant. 10 (2010) 2000-2007 25. B. Ekser, J.A. Powelson, J.A. Fridell, W.C. Goggins, T.E. Taber, Is the kidney donor profile index (KDPI) universal or UNOS-specific? Am. J. Transplant. 18 (2018) 1031-1032 26. S.R. Weeks, X. Luo, C.E. Haugen, et al., Delayed graft function in simultaneous liver kidney transplantation, Transplantation (2019) Aug 8. doi: 10.1097/TP.0000000000002908. [Epub ahead of print] 27. K.P. Croome, S. Mao, L. Yang, et al., Improved national results with simultaneous liver and kidney transplantation using donation after cardiac death donors, Liver Transplant. (2019) Oct 9. doi: 10.1002/lt.25653. [Epub ahead of print]. 28. A.J. Vinson, B. Gala-Lopez, K. Tennakore, B. Kiberd, The use of donation after circulatory death organs for simultaneous liver-kidney transplant: to DCD or not to DCD? Transplantation.
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103 (2019) 1159-1167 29. E.L. Lum, A. Cardenas, P. Martin, S. Bunnapradist, Current status of simultaneous liverkidney transplantation in the United States, Liver Transpl. 25 (2019) 797-806 30. A. Singal, S. Ong, S.K. Satapathy, et al, . Simultaneous liver kidney transplantation, Transpl. Int. 32 (2019) 343-352 31. K.P. Croome, D.D. Lee, J.M. Burn, et al., Simultaneous liver and kidney transplantation in elderly patients: outcomes and validation of a clinical score for patient selection, Ann. Hepatol. 15 (2016) 870-880. 32. D.S. Goldberg, R.M. Vianna, E.F. Martin, et al., Simultaneous liver kidney transplant in elderly patients with chronic kidney disease: is there an appropriate upper age cutoff? Transplantation. (2020) in press 33. B. Ekser, Facing elderly recipients in combined liver-kidney transplantation, Transplantation. (2020) in press 34. S. Nagai, M. Safwan, K. Collins, et al., Liver alone or simultaneous liver-kidney transplant? Pretransplant chronic kidney disease and post-transplant outcomes–a retrospective study, Transpl. Int. 31 (2018) 1028-1040. 35. T.C. Lee, A.R. Cortez, A. Kassam, et al., Outcomes of en bloc simultaneous liver-kidney transplantation compared to the traditional technique, Am. J. Transplant. (2019) Oct 12. doi: 10.1111/ajt.15655. [Epub ahead of print] 36. N. AbdulRahim, L. Anderson, S. Kotla, et al., Lack of Benefit and Potential Harm of Induction Therapy in Simultaneous Liver-Kidney Transplants, Liver Transpl. 25 (2019) 411-424. 37. B. Ekser, C.A. Kubal, J.A. Fridell, et al., Lack of Benefit and Potential Harm of Induction Therapy in Simultaneous Liver-Kidney Transplants, Liver Transpl. 25 (2019) 667-668 38. T. Taner, J.K. Heimbach, C.B. Rosen, et al., Decreased chronic cellular and antibodymediated injury in the kidney following simultaneous liver-kidney transplantation, Kidney Int. 89 (2016) 909-917 39. T. Taner, W.D. Park, M.D. Stegall, Unique molecular changes in kidney allografts after simultaneous liver-kidney compared with solitary kidney transplantation, Kidney Int. 91 (2017) 1193-1202. 40. T. Taner, M.P. Gustafson, M.J. Hansen, et al., Donor-specifics hypo-responsiveness occurs in simultaneous liver-kidney transplant recipients after the first year, Kidney Int. 93 (2018) 14651474
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41. T.W. Wong, M.J. Gandhi, R.C. Daly, et al., Liver allograft provides immunoprotection for the cardiac allograft in combined heart-liver transplantation, Am. J. Transplant. 16 (2016) 35223531. 42. N. Abrol, C.C. Jadlowiec, T. Taner, Revisiting the liver’s role in transplant alloimmunity. World. J. Gastroenterol. 25 (2019) 3123-3135. 43. Z. Rokop, C. Kubal, B. Ekser, et al., Impact of Delayed Kidney Transplantation On Positive Crossmatch Liver Kidney Transplantation, Am. J. Transplant. 19 (suppl 3) (2019) https://atcmeetingabstracts.com/abstract/impact-of-delayed-kidney-transplantation-on-positivecrossmatch-liver-kidney-transplantation/. Accessed January 10, 2020.
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Table 1: Medical Eligibility Criteria for Combined Liver-Kidney Transplantation
Candidate’s Transplant Nephrologist Confirms a Diagnosis of
Transplant Program Must Document at least 1 of the following
CKD with a measured or calculated GFR ≤60mL/min for >3 months
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Candidate is on regular hemodialysis Candidate’s most recent GFR is ≤30mL/min at the time of registration for kidney transplant
Sustained AKI
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Candidate is on dialysis at least 6 weeks Candidate’s GFR is ≤25mL/min for at least 6 weeks (as documented in weekly measurements) Candidate has any combination of above 2 criteria for 6 weeks
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Metabolic disease
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Hyperoxaluria aHUS from mutations in factor H or I Familial nonneuropathic systemic amyloidosis Methylmalonic aciduria
Legend: CKD= chronic kidney disease, AKI = acute kidney injury. GFR= glomerular filtration rate, aHUS= atypical hemolytic uremic syndrome
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Table 2: “Safety-net” kidney transplantation allocation sequences for liver transplant recipients with non-recovery of renal function. Sequence A (KDPI ≤20%)
Sequence B (KDPI >20% <35%)
Sequence C (KDPI >35% <85%)
Sequence D (KDPI >85%)
Highly sensitized
Highly sensitized
Highly sensitized
Highly sensitized
O-ABDR mismatch
O-ABDR mismatch
O-ABDR mismatch
O-ABDR mismatch
Prior living donor KT
Prior living donor KT
Prior living donor KT
Local CLKT safety net
Local pediatrics
Local pediatrics
Local CLKT safety net
Local+regional
Local top 20% EPTS
Local CLKT safety net
Local candidates
National candidates
O-ABDR mismatch (all)
Local adults
Regional candidates
Local (all)
Regional pediatrics
National candidates
Regional pediatrics
Regional adults
Regional (to 20%)
National pediatrics
Regional (all)
National adults
National pediatrics National (top 20%) National (all) Legend: EPTS= estimated post-transplant survival, KDPI= kidney donor profile index score, CLKT= combined liver-kidney transplantation From https://optn.transplant.hrsa.gov/media/1192/0815-12_SLK_Allocation.pdf
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FIGURE LEGENDS Figure 1: Activity of combined liver-kidney transplantation in the United States 20012019. Legend: CLKT: combined liver-kidney transplantation, UNOS= united network for organ sharing, LT= liver transplantation. Right axis shows absolute number of CLKT performed in the United States each year-end. Left axis shows the percentage of CLKT in all deceased liver transplantation performed in the United States.
Figure 2A: Differences in estimated glomerular filtration rate (eGFR) between delayed kidney transplantation with <48 hours and >48 hours in combined liver-kidney transplantation. Legend: eGFR= estimated glomerular filtration rate, KT= kidney transplantation, CLKT= combined liver-kidney transplantation. (*) indicates statistically significant difference in eGFR. The figure is adopted from Ekser et al [15] with permission.
Figure 2B: Patient survival in combined liver-kidney transplantation using the delayed kidney transplant (Indiana Approach) based on the quality of kidney allograft. Legend: KDPI = kidney donor profile index. The figure is reproduced from Ekser et al [16] with permission.
Figure 3: Comparison of T cell activity in different types of transplants. Legend: Production of interferon-g spots by T cells of solitary kidney (KTA), simultaneous liverkidney (SLK = CLKT), or solitary liver transplant (LTA) recipients in response to their donor and third-party cells (3P). In the KTA group, patients who had not received T-cell depleting induction are represented as open circles (o). *P= 0.11, **P <0.0001, ***P= 0.0002, #P= 0.04, ##P= 0.26, ###P >0.99. The image was adopted by Taner et al [40] with permission.
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CURRENT STATUS OF COMBINED LIVER-KIDNEY TRANSPLANTATION
Burcin Ekser, MD, PhD1, Alan G. Contreras MD2, Wellington Andraus, MD, PhD3, Timucin Taner MD, PhD4
(1) Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; (2) Department of Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, México; (3) Digestive Organs Transplant Division, Gastroenterology Department, Sao Paulo University School of Medicine, Sao Paulo, Brazil (4) Departments of Surgery and Immunology, Mayo Clinic, Rochester, MN, USA
Running Title: combined liver-kidney transplantation
Address correspondence to: Burcin Ekser, MD, PhD Transplant Division, Department of Surgery Indiana University School of Medicine 550 University Blvd, Room 4601 Indianapolis, IN, 46202 Telephone: 317-948-3835; Fax 317-968-1254 Email: [email protected]
(Word counts: Abstract 179; main text 2976; Tables 2; Figures 3)
KEY WORDS Combined, simultaneous, liver and kidney transplantation Kidney transplantation Liver transplantation Outcome
ABBREVIATIONS CIT = cold ischemia time CLKT = combined liver-kidney transplantation DBD = donation after brain death DCD = donation after circulatory death DSA = donor-specific antibbodies DGF = delayed graft function ECD = extended criteria donor GFR = glomerular filtration rate KDPI = kidney-donor profile index KT = kidney transplantation LT = liver transplantation MELD = model for end-stage liver disease r-ATG = rabbit antithymocyte globulin UNOS = United Network for Organ Sharing
ORCIDs Burcin Ekser Alan G Contreras
0000-0003-0741-8007 ([email protected] ) ([email protected])
Wellington Andraus
0000-0002-5162-138X ([email protected])
Timucin Taner
0000-0003-0641-2930 ([email protected] )
HIGHLIGHTS
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Combined liver-kidney transplantation accounts for 10% of all the liver transplants done in the United States, and is the most common multi-organ transplantation
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While there is no standard criteria for eligibility globally, a recent policy adopted in the United States mandates that candidates of combined liver-kidney transplantation meet a set criteria
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Given the hemodynamic instability during liver transplantation, delaying the kidney transplant in combined liver-kidney transplantation may be safe and advantageous
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Histologic, genomic, and functional studies show that the liver allograft provides immunoprotection for the kidney allograft in combined liver-kidney transplantation
S1743-9191(20)30171-0
DOI:
https://doi.org/10.1016/j.ijsu.2020.02.008
Reference:
IJSU 5267
To appear in:
International Journal of Surgery
Received Date: 5 February 2020 Accepted Date: 7 February 2020
Please cite this article as: Ekser B, Contreras AG, Andraus W, Taner T, Current status of combined liver-kidney transplantation, International Journal of Surgery, https://doi.org/10.1016/j.ijsu.2020.02.008. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
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Burcin Ekser, MD, PhD
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ABSTRACT Combined liver-kidney transplantation is a life-saving procedure for patients with end-stage liver disease and underlying chronic kidney disease, or prolonged acute kidney injury. Due to physiologic changes secondary to portal hypertension in patients with end-stage liver disease, kidney injury is common, and combined liver-kidney transplantation accounts for 10% of all the liver transplants performed in the United States. Recently implemented policy in the United States standardizes the medical criteria for eligibility, and introduces a 'safety net' for those who are transplanted with a liver graft alone, in order to be able to receive a kidney graft later. Increasing number of combined liver-kidney transplants provides a large cohort of patients to be studied in detail for identification of factors (both donor and recipient-related) associated with better outcomes. Data regarding the safety and efficacy of delaying the kidney transplant part of the combined liver-kidney transplantation, and the immunologic benefits of the multi-organ transplantations including the liver are emerging. Here, we review the most recent analyses, and provide our opinion regarding the best practices in combined liver-kidney transplantation based on the evidence. INTRODUCTION Liver transplantation (LT) is the ultimate therapy for patients with end-stage liver disease (ESLD). However, ESLD is frequently associated with portal hypertension and subsequent pooling of the portal blood in the splanchnic system, resulting in reduced circulating blood volume which increases the risk for renal dysfunction and acute kidney injury (AKI) [1]. Decompensated cirrhosis increases this risk further, and could lead to chronic kidney disease (CKD) due to; (i) hepatorenal syndrome, (ii) hypovolemia-induced renal failure, (iii) parenchymal renal disease, and (iv) drug-induced renal failure [1]. As such, CKD is a common complication in LT recipients, and is associated with reduced survival [2-3].
Combined liver-kidney transplantation (CLKT), first reported by Margreiter et al. [4] in order to
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overcome both ESLD and end-stage renal disease, has been performed increasingly since the introduction of Model for End-stage Liver Disease (MELD) scoring system in 2002 for organ allocation. Due to the magnitude of operation and significantly sicker patient population, initial outcomes of CLKT were poor, with 20-30% mortality within the first year following CLKT [5]. Currently, there are no standard criteria for CLKT eligibility and organ allocation around the globe, and each country employs their own allocation criteria (which varies from center to center within the given country). In 2017, United Network for Organ Sharing (UNOS) in the United States enacted the most comprehensive policy for CLKT which now defines the medical eligibility criteria for all transplant centers under the UNOS umbrella (Table 1) [6]. CLKT has now reached to almost 10% of all LT activity in the United States (Figure 1) [6].
This review summarizes recent practices in CLKT with ongoing discussions mainly in the United States and with very limited data around the world.
Changes in CLKT allocation policy Since early 2000s, several allocation criteria have been proposed for CLKT. In 2007, Davis et al. proposed iothalamate clearance ≤30mL/min for CKD and dialysis duration ≥6 weeks, or fixed renal damage on kidney biopsy for AKI [7]. In 2008, a consensus conference proposed similar criteria but also added serum creatinine ≥2mg/dl and dialysis of ≥8 weeks, including diabetes, hypertension, age ≥65 years, and proteinuria for AKI [8]. In 2012, Nadim et al. conducted a survey of 88 transplant centers that perform CLKT in the United States to determine practice patterns [9]. The majority of centers in this study (73%) used dialysis duration for AKI as a cutoff for CLKT listing, with duration varying between 4-8 weeks [9]. Although more detailed criteria were proposed in the subsequent consensus conferences, no unified criteria were accepted by all transplant centers. In 2017, UNOS enacted a policy for the allocation of CLKT based on
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medical eligibility (Table 1), and introduced the ‘safety net’ for patients with marginal renal function who receive LT alone, so that they have access to kidney transplantation (KT) should the renal function worsen after the LT (Table 2).
There is no standardized allocation policy around the world. The data in CLKT from Latin American Centers are scarce. For example, in Mexico there are currently 4 patients listed for CLKT [unpublished]. Brazil is the largest country in Latin America in regards to number of LT performed each year (~2200 LTs /year) [10]. In Brazil, although the number of CLKT was doubled from 2% to 4% of all LTs after the adaptation of MELD score in 2006, there is still no standardized allocation policy for CLKT [11]. Only European and outside of UNOS data-registrybased analyses focusing on CLKT were reported by Tinti et al using the transplant registry from the United Kingdom [12]. The rate of CLKT was only 2% (n=123) of all LTs performed between 200-2013 in the United Kingdom and there was no mention to allocation policy in CLKT [12].
After the implementation of this new policy in the United States in 2017, Luo et al. carefully studied center-level variations [13]. They found that among 4736 CLKT-eligible candidates, only 65% were listed for CLKT within 6 months of eligibility. However, most interestingly, the percentage of CLKT listing ranged from 0%-100% across centers. They also found that African American race, male sex, previous transplant history, diabetes, and hypertension were associated with a higher likelihood of CLKT listing, while older age was associated with a lower likelihood of CLKT listing [10].
Calluro et al. recently analyzed all patients listed for LT in the UNOS registry from May 2007 through July 2014 [14]. They found that of 40979 candidates, 1683 (4.1%) would have met the new CLKT allocation criteria compared to 2452 (6%) in old proposed criteria. They conclude that new CLKT allocation policy will increase the proportion of women and decrease the
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proportion of men who are listed for CLKT but may not improve post-transplant survival [14]. Therefore, there is still ongoing need for monitoring of CLKT outcomes after implementation of the new policy [14].
Discussions and efforts are ongoing to improve the outcomes of CLKT and to decrease the futility of kidneys. Future studies will show us whether the implementation of standardized CLKT listing practices may reduce center-level variations and optimize outcomes.
Optimization of outcomes Surgical issues and timing of the KT in CLKT CLKT necessitates consideration of surgical logistics for both the liver and the kidney allografts. LT recipients are often sick at the time of transplant with significant coagulopathy, and require vasopressor/inotropic agents intraoperatively. Thus, the hemodynamic status of the recipients is far than ideal for the newly implanted kidney allograft. Furthermore, in patients with hyperbilirubinemia, the bilirubin crystalizes in the tubules of kidneys, increasing the risk for AKI and further renal dysfunction of the kidney allograft.
To optimize the physiologic environment for kidney graft and patient outcomes, Ekser et al. [15] have performed delayed KT in CLKT, the so-called ‘Indiana Approach’. In Indiana Approach, LT is performed first while the kidney graft is placed on a hypothermic pulsatile perfusion machine [15]. Implantation of the kidney graft is delayed for 2 to 3 days post-LT [15,16,17]. This approach allows stabilization of LT patients’ hemodynamics and coagulopathy in the post-LT period, before implantation of the renal allograft. This delay also permits decompression of varices to minimize blood loss during KT, which may directly impact renal allograft outcome. Finally, planned delayed implantation of the kidney frequently provides time to completely wean vasopressors before KT, thus lowering the risk of pressor-related delayed graft function (DGF)
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and clearing post-liver reperfusion debris and bilirubin from the circulation. The same group also documented that DGF is the most important negative predictor of patient survival in CLKT. Moreover, they also showed that despite the belief of renal allograft damage and increased rate of DGF due to prolonged cold ischemia time (CIT) >48 hours, the rate of DGF and estimated glomerular filtration rate (eGFR) were much better, if KT of the CLKT was delayed >48 hours (Figure 2A) [15].
Lunsford et al. recently reported their results in delayed KT in CLKT (Indiana Approach) with improved patient and kidney survival and decreased kidney futility, despite higher MELD (>35) score, longer intensive care stay, prolonged intubation, and greater use of vasopressors [18]. This study showed that even in high-acuity patients, delayed KT should be the preferable approach in CLKT [18]. Lauterio et al. reported the first 2 cases of delayed KT in CLKT in Europe, demonstrating that the technique can be done by others with broader implications [19].
Kidney allograft quality The importance of the kidney-donor profile index (KDPI) was highlighted by several studies in CLKT [20,21]. Jay et al. analyzed the UNOS database showing the importance of renal allograft quality based on KDPI [20]. They reported that of 4207 CLKT, 6% were from KDPI >85% donors and recipients of those grafts had significantly increased mortality (HR=1.83, 95%CI=1.44-2.31) [20]. In a single center analysis, Ekser et al showed that excellent outcomes can be achieved in CLKT using the Indiana Approach and low KDPI kidneys (Figure 2B) [16].
Shekhtman et al. analyzed the UNOS database for combined dual KT-LT in the United States between 2002-2012 [22]. Of 3044 CLKTs, they identified only 22 cases of combined dual KT-LT (0.7%). The kidneys used in these patients were all from extended criteria donors (ECD), and
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their survival was 41% at 3-year post-CLKT compared to 68% ECD CLKT and 65% for high KDPI CLKT [22]. Although the approach could expand the donor pool for CLKT, the current outcomes in combined dual KT-LT should be ameliorated. Previously, in a case report of 2 cases, Ekser et al. reported dual KT after LT with long-term success [23], which could be an option for the use of dual KT for LT recipients instead of using them simultaneously.
Recent studies highlight the overall inferior outcomes with the use of ECD kidneys and dual KT in CLKT. Although there are reports showing good outcomes in dual KT with marginal donors [24] and very high KDPI kidneys [25] after careful selection, the decision to use such kidney allografts should be made carefully on a case-by-case basis. In our expert opinion, several factors should be considered for this decision: (i) Kidney DGF: Measures should be taken to avoid and/or minimize DGF, since the latter has been shown to be the most important negative predictor on patient survival in CLKT in both single center [5,15,18] and larger UNOS data analyses [26].
(ii) Kidney allograft quality: Although the goal of the new CLKT allocation policy with ‘safety net’ is to decrease kidney futility and allocate better KDPI kidneys to pediatric population, it was shown that KDPI impacts the outcomes in CLKT [16,20,21]. One way to expand the donor pool could be the use of delayed KT approach in CLKT in order to use high KDPI kidneys without DGF with better outcomes [16]. Another option could be the use of donation after circulatory death (DCD) grafts in CLKT, which was recently studied by Croome et al. [27]. In UNOS database analysis, these authors showed that DCD-CLKT offers similar outcomes compared to matched patients undergoing donation after brain death (DBD)-CLKT, especially when the era factor (Era 1 - 2000-2010 vs. Era 2 - 2011-2018 – Era 2 was better than Era 1) is considered [27]. However, in another recent UNOS database study, Vinson et al. showed that DCD-CLKT could be only beneficial to those patients with MELD >30 [28]. They claimed that waiting for
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DBD-CLKT is the preferred option for patients with MELD ≤30 [28]. (iii) Recipient factors: It should be acknowledged that patients waiting for CLKT are much sicker compared to those waiting for LT or KT alone. Although the percentage of CLKT has now reached to almost 10% of all deceased LT in the United States, national outcomes are not yet optimal [22,29,30]. While many factors contributing to prolonged survival post-CLKT could be improved in recipients before transplant, aging and age-related senescence are important factors that cannot be easily modified. The outcomes of CLKT in elderly (>65 years and >70 years) recipients have been studied, and demonstrated that elderly recipients of CLKT (≥65 years) had similar outcomes to those <65 years of age [31]. However, with the multivariate analysis, the same authors proposed that CLKT should be avoided in patients ≥65 years of age on mechanical ventilation prior to CLKT, and in patients ≥70 years of age with a MELD score ≥30 [31].
A recent report by Goldberg et al. [32] analyzed the UNOS database to investigate the outcomes of CLKT in elder patients with underlying CKD. Between 2002-2018, there was a total of 3146 CLKTs with CKD, of which 465 recipients (14.8%) were 65-69 years of age, and 93 (3.0%) were ≥70 years of age. The authors found that compared to recipients aged 50-64 years, CLKT recipients with CKD 65-69 and ≥70 years of age; (i) were more likely to be of white race, (ii) had higher incidence of NASH/cryptogenic cirrhosis, (iii) received higher KDPI kidneys, (iv) had higher incidence of diabetes, especially in age group ≥70 years, and (v) were less likely to be on dialysis before the transplant [32]. The unadjusted 5-year survival of CLKT in recipients ≥70 years of age with CKD was 58% as compared to 69% in CLKT recipients ≥70 years of age without CKD, and both were lower compared to other age groups, such as 40-49, 50-59, 60-64, and 65-69 years of age [32]. It is likely that with the aging population, both the LT and CLKT candidates in advanced age will continue to increase, highlighting the importance of optimization of outcomes in this age group [33].
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(iv) Timing of kidney transplantation: As discussed above, CLKT necessitates special consideration of physiological needs for both liver and kidney allografts. Therefore, delayed KT in CLKT (Indiana Approach) can offer hemodynamically more stable LT recipient at the time of KT, and the renal allograft is not affected by prolonged CIT [15-19]. While LT alone, followed by KT at a later date from a separate donor (Kidney after LT) is another option, it should be noted that a recent UNOS database analysis showed that the hazard of 1-year-graft loss in the LT alone–CKD group was 35% higher than CLKT (HR=1.348, 95%CI=1.157-1572, p<0.001), indicating CLKT for patient who meet the CKD criteria may significantly improve transplant outcomes [34].
Despite encouraging outcomes obtained in delayed KT in CLKT, a recent report by Lee et al discussed the ‘en-bloc’ simultaneous liver-kidney transplantation as an alternative approach [35]. In this approach, the liver and ‘right’ kidney are procured together with the renal vein kept attached to the inferior vena cava [35]. Right renal artery is reconstructed to the donor splenic artery and the celiac axis of the donor is anastomosed to the recipient hepatic artery [35]. This surgical technique allows single incision (for LT) and definitely lowers the CIT for the renal allograft and operative time. The limitation of this approach is that the use of left kidney as an ‘en-bloc’ simultaneous liver-kidney transplant is quite difficult. The use of right kidney with multiple arteries and the liver with aberrant arteries which need reconstruction is also not preferable. Another concern is the potential risk of thrombosis or stenosis impacting the both allografts. However, in limited cases, the advantage of this (en-bloc) approach can be highlighted for centers where there is no perfusion machine available to apply delayed KT, and especially when the transplant teams for KT and LT are not the same. It should be also noted that, Lee et al observed 23% DGF rate both in traditional simultaneous CLKT and ‘en-bloc’ simultaneous liver-kidney transplantation [35].
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Immunological considerations in CLKT There are ongoing discussions about the choice of induction therapy and maintenance immunosuppressive regimen in CLKT due to the antigen load that comes from both organs instead of KT alone or LT alone. A recent study by AbdulRahim et al. investigated different induction therapies in CLKT in a UNOS database analysis [36]. They compared 4722 CLKTs between 2002 to 2016 with no induction (n= 2333), interleukin 2-receptor antagonist induction (n= 1558), and rabbit antithymocyte globulin (r-ATG) induction (n= 831). They concluded that rATG induction is potentially harmful and increases mortality risk compared with no induction in CLKT (HR= 1.29; 95% CI=1.10-1.52; P = 0.002) [36]. In response to this study, Ekser et al. demonstrated that their cohort of ~100 CLKTs using r-ATG induction had excellent outcomes [37].
Recent evidence, based on protocolled, routine kidney allograft biopsies demonstrates that the incidence of both T-cell-mediated and antibody-mediated rejection of the renal allograft is lower in CLKT patients, compared to KT alone patients, due to the protective effect of the liver [38]. In a follow-up study, Taner et al. demonstrated that molecular markers of inflammation and T-cell activation are significantly less common in kidney biopsies of CLKT recipients compared to KT alone recipients with similar immunologic risk profiles [39]. The study was designed in four groups: 16 cross-match negative KT alone, 15 cross-match positive KT alone, 12 cross-match negative CLKTs, and nine cross-match-positive CLKTs. The authors found that CLKT can have a profound impact on the kidney allograft, not only by decreasing inflammation and avoiding endothelial cell activation in cross-match-positive recipients, but also by increasing processes associated with tissue integrity/metabolism [39]. In a more recent study, Taner et al. studied host alloimmune response measured by the donor-specific alloresponsiveness and phenotypes of peripheral blood cells after the first years following CLKT [40]. They studied the alloreactivity
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of transplant recipients’ T cells using cryopreserved donor cells as the stimulators (Figure 3). They showed that CLKT recipients’ T cells had a very homogeneous and diminished response to alloantigen stimulation compared to KT alone recipient T cells (Figure 3) [40]. The protective effect of the liver allograft on simultaneously transplanted organs from the same donor has been shown in other multi-organ transplants as well [41,42].
Another recent study reported the impact of delayed KT on cross-match-positive CLKTs whether liver allograft can be utilized to lower anti-HLA donor specific antibodies (DSA) [43]. Although the cohort was small with 10 CLKTs with pre-existing DSAs, the authors showed that 8 out of 10 patients had decrease in DSA with an average of 57% in mean fluorescence intensity. Decrease in Class I antibody was significantly higher than Class II. This brief report with a small cohort showed that delaying KT for 2-3 days allows quantifiable reduction in circulating DSA after LT, probably by the absorption of antibodies by the liver allograft prior to KT with and without plasma exchange, which resulted in excellent clinical outcomes in cross-match-positive CLKT [43].
Conclusions CLKT is a life-saving procedure for patients with ESLD and CKD. The absolute number of CLKTs and the percentage of CLKT among the LT recipients have been increasing constantly in the past 2 decades. These accumulating numbers, in turn, provides increasingly large data sets, allowing for better assessment of factors associated with improved outcomes after CLKT. In light of the relatively new allocation policy in the United States, future studies will also help demonstrate whether outcomes improve and futility decrease, as projected.
DISCLOSURE
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All authors declare no conflict of Interest including manuscript preparation or funding by a commercial organization.
Provenance and peer review Commissioned, externally peer-reviewed
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outcomes in combined liver-kidney transplantation: Impact of kidney donor profile index and delayed kidney transplantation, Liver Transpl. 24 (2018) 222-232. 17. B. Ekser, A.M. Chen, C.A. Kubal, et al., Delayed kidney transplantation after 83 hours of cold ischemia time in combined liver-kidney transplant, Transplantation. 103 (2019) e382-e383. 18. L.E. Lunsford, V.G. Agopian, S.G. Yi, et al., Delayed Implantation of Pumped Kidneys Decreases Renal Allograft Futility in Combined Liver-Kidney Transplantation, Transplantation. (2019) Oct 23. doi: 10.1097/TP.0000000000003040. [Epub ahead of print] 19. A. Lauterio, R. De Carlis, S. Di Sandro, V. Buscemi, E. Andorno, L. De Carlis, Delayed kidney transplantation in combined liver-kidney transplantation for polycystic liver and kidney disease, Transpl. Int. 32 (2019) 1336-1338 20. C. Jay, J. Pugh, G.A. Halff, et al., Graft quality matters: survival after simultaneous liverkidney transplant according to KDPI, Clin. Transplant. 31 (2017) e12933. 21. B. Ekser, R.S. Mangus, C.A. Kubal, et al., Graft quality matters: Impact of KDPI and delayed kidney transplantation in combined liver-kidney transplantation, Clin. Transplant. 31 (2017) doi: 10.1111/ctr.13056. 22. G. Shekhtman, E. Huang, G.M. Danovitch, P. Martin, S. Bunnapradist, Combined dualkidney liver transplantation in the United States: a review of United Network for Organ Sharing/Organ Procurement and Transplantation Network Data between 2002 and 2012, Liver Transpl. 24 (2018) 1570-1577 23. B. Ekser, L. Furian, N. Baldan, et al., Dual kidney transplantation after liver transplantation: a good option to rescue a patient from dialysis, Clin. Transplant. 23 (2009) 124-128. 24. B. Ekser, L. Furian, A. Broggiato, et al., Technical aspects of unilateral dual kidney transplantation from expanded criteria donors: experience of 100 patients, Am. J. Transplant. 10 (2010) 2000-2007 25. B. Ekser, J.A. Powelson, J.A. Fridell, W.C. Goggins, T.E. Taber, Is the kidney donor profile index (KDPI) universal or UNOS-specific? Am. J. Transplant. 18 (2018) 1031-1032 26. S.R. Weeks, X. Luo, C.E. Haugen, et al., Delayed graft function in simultaneous liver kidney transplantation, Transplantation (2019) Aug 8. doi: 10.1097/TP.0000000000002908. [Epub ahead of print] 27. K.P. Croome, S. Mao, L. Yang, et al., Improved national results with simultaneous liver and kidney transplantation using donation after cardiac death donors, Liver Transplant. (2019) Oct 9. doi: 10.1002/lt.25653. [Epub ahead of print]. 28. A.J. Vinson, B. Gala-Lopez, K. Tennakore, B. Kiberd, The use of donation after circulatory death organs for simultaneous liver-kidney transplant: to DCD or not to DCD? Transplantation.
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103 (2019) 1159-1167 29. E.L. Lum, A. Cardenas, P. Martin, S. Bunnapradist, Current status of simultaneous liverkidney transplantation in the United States, Liver Transpl. 25 (2019) 797-806 30. A. Singal, S. Ong, S.K. Satapathy, et al, . Simultaneous liver kidney transplantation, Transpl. Int. 32 (2019) 343-352 31. K.P. Croome, D.D. Lee, J.M. Burn, et al., Simultaneous liver and kidney transplantation in elderly patients: outcomes and validation of a clinical score for patient selection, Ann. Hepatol. 15 (2016) 870-880. 32. D.S. Goldberg, R.M. Vianna, E.F. Martin, et al., Simultaneous liver kidney transplant in elderly patients with chronic kidney disease: is there an appropriate upper age cutoff? Transplantation. (2020) in press 33. B. Ekser, Facing elderly recipients in combined liver-kidney transplantation, Transplantation. (2020) in press 34. S. Nagai, M. Safwan, K. Collins, et al., Liver alone or simultaneous liver-kidney transplant? Pretransplant chronic kidney disease and post-transplant outcomes–a retrospective study, Transpl. Int. 31 (2018) 1028-1040. 35. T.C. Lee, A.R. Cortez, A. Kassam, et al., Outcomes of en bloc simultaneous liver-kidney transplantation compared to the traditional technique, Am. J. Transplant. (2019) Oct 12. doi: 10.1111/ajt.15655. [Epub ahead of print] 36. N. AbdulRahim, L. Anderson, S. Kotla, et al., Lack of Benefit and Potential Harm of Induction Therapy in Simultaneous Liver-Kidney Transplants, Liver Transpl. 25 (2019) 411-424. 37. B. Ekser, C.A. Kubal, J.A. Fridell, et al., Lack of Benefit and Potential Harm of Induction Therapy in Simultaneous Liver-Kidney Transplants, Liver Transpl. 25 (2019) 667-668 38. T. Taner, J.K. Heimbach, C.B. Rosen, et al., Decreased chronic cellular and antibodymediated injury in the kidney following simultaneous liver-kidney transplantation, Kidney Int. 89 (2016) 909-917 39. T. Taner, W.D. Park, M.D. Stegall, Unique molecular changes in kidney allografts after simultaneous liver-kidney compared with solitary kidney transplantation, Kidney Int. 91 (2017) 1193-1202. 40. T. Taner, M.P. Gustafson, M.J. Hansen, et al., Donor-specifics hypo-responsiveness occurs in simultaneous liver-kidney transplant recipients after the first year, Kidney Int. 93 (2018) 14651474
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41. T.W. Wong, M.J. Gandhi, R.C. Daly, et al., Liver allograft provides immunoprotection for the cardiac allograft in combined heart-liver transplantation, Am. J. Transplant. 16 (2016) 35223531. 42. N. Abrol, C.C. Jadlowiec, T. Taner, Revisiting the liver’s role in transplant alloimmunity. World. J. Gastroenterol. 25 (2019) 3123-3135. 43. Z. Rokop, C. Kubal, B. Ekser, et al., Impact of Delayed Kidney Transplantation On Positive Crossmatch Liver Kidney Transplantation, Am. J. Transplant. 19 (suppl 3) (2019) https://atcmeetingabstracts.com/abstract/impact-of-delayed-kidney-transplantation-on-positivecrossmatch-liver-kidney-transplantation/. Accessed January 10, 2020.
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Table 1: Medical Eligibility Criteria for Combined Liver-Kidney Transplantation
Candidate’s Transplant Nephrologist Confirms a Diagnosis of
Transplant Program Must Document at least 1 of the following
CKD with a measured or calculated GFR ≤60mL/min for >3 months
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Candidate is on regular hemodialysis Candidate’s most recent GFR is ≤30mL/min at the time of registration for kidney transplant
Sustained AKI
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Candidate is on dialysis at least 6 weeks Candidate’s GFR is ≤25mL/min for at least 6 weeks (as documented in weekly measurements) Candidate has any combination of above 2 criteria for 6 weeks
-
Metabolic disease
-
Hyperoxaluria aHUS from mutations in factor H or I Familial nonneuropathic systemic amyloidosis Methylmalonic aciduria
Legend: CKD= chronic kidney disease, AKI = acute kidney injury. GFR= glomerular filtration rate, aHUS= atypical hemolytic uremic syndrome
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Table 2: “Safety-net” kidney transplantation allocation sequences for liver transplant recipients with non-recovery of renal function. Sequence A (KDPI ≤20%)
Sequence B (KDPI >20% <35%)
Sequence C (KDPI >35% <85%)
Sequence D (KDPI >85%)
Highly sensitized
Highly sensitized
Highly sensitized
Highly sensitized
O-ABDR mismatch
O-ABDR mismatch
O-ABDR mismatch
O-ABDR mismatch
Prior living donor KT
Prior living donor KT
Prior living donor KT
Local CLKT safety net
Local pediatrics
Local pediatrics
Local CLKT safety net
Local+regional
Local top 20% EPTS
Local CLKT safety net
Local candidates
National candidates
O-ABDR mismatch (all)
Local adults
Regional candidates
Local (all)
Regional pediatrics
National candidates
Regional pediatrics
Regional adults
Regional (to 20%)
National pediatrics
Regional (all)
National adults
National pediatrics National (top 20%) National (all) Legend: EPTS= estimated post-transplant survival, KDPI= kidney donor profile index score, CLKT= combined liver-kidney transplantation From https://optn.transplant.hrsa.gov/media/1192/0815-12_SLK_Allocation.pdf
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FIGURE LEGENDS Figure 1: Activity of combined liver-kidney transplantation in the United States 20012019. Legend: CLKT: combined liver-kidney transplantation, UNOS= united network for organ sharing, LT= liver transplantation. Right axis shows absolute number of CLKT performed in the United States each year-end. Left axis shows the percentage of CLKT in all deceased liver transplantation performed in the United States.
Figure 2A: Differences in estimated glomerular filtration rate (eGFR) between delayed kidney transplantation with <48 hours and >48 hours in combined liver-kidney transplantation. Legend: eGFR= estimated glomerular filtration rate, KT= kidney transplantation, CLKT= combined liver-kidney transplantation. (*) indicates statistically significant difference in eGFR. The figure is adopted from Ekser et al [15] with permission.
Figure 2B: Patient survival in combined liver-kidney transplantation using the delayed kidney transplant (Indiana Approach) based on the quality of kidney allograft. Legend: KDPI = kidney donor profile index. The figure is reproduced from Ekser et al [16] with permission.
Figure 3: Comparison of T cell activity in different types of transplants. Legend: Production of interferon-g spots by T cells of solitary kidney (KTA), simultaneous liverkidney (SLK = CLKT), or solitary liver transplant (LTA) recipients in response to their donor and third-party cells (3P). In the KTA group, patients who had not received T-cell depleting induction are represented as open circles (o). *P= 0.11, **P <0.0001, ***P= 0.0002, #P= 0.04, ##P= 0.26, ###P >0.99. The image was adopted by Taner et al [40] with permission.
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CURRENT STATUS OF COMBINED LIVER-KIDNEY TRANSPLANTATION
Burcin Ekser, MD, PhD1, Alan G. Contreras MD2, Wellington Andraus, MD, PhD3, Timucin Taner MD, PhD4
(1) Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; (2) Department of Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, México; (3) Digestive Organs Transplant Division, Gastroenterology Department, Sao Paulo University School of Medicine, Sao Paulo, Brazil (4) Departments of Surgery and Immunology, Mayo Clinic, Rochester, MN, USA
Running Title: combined liver-kidney transplantation
Address correspondence to: Burcin Ekser, MD, PhD Transplant Division, Department of Surgery Indiana University School of Medicine 550 University Blvd, Room 4601 Indianapolis, IN, 46202 Telephone: 317-948-3835; Fax 317-968-1254 Email: [email protected]
(Word counts: Abstract 179; main text 2976; Tables 2; Figures 3)
KEY WORDS Combined, simultaneous, liver and kidney transplantation Kidney transplantation Liver transplantation Outcome
ABBREVIATIONS CIT = cold ischemia time CLKT = combined liver-kidney transplantation DBD = donation after brain death DCD = donation after circulatory death DSA = donor-specific antibbodies DGF = delayed graft function ECD = extended criteria donor GFR = glomerular filtration rate KDPI = kidney-donor profile index KT = kidney transplantation LT = liver transplantation MELD = model for end-stage liver disease r-ATG = rabbit antithymocyte globulin UNOS = United Network for Organ Sharing
ORCIDs Burcin Ekser Alan G Contreras
0000-0003-0741-8007 ([email protected] ) ([email protected])
Wellington Andraus
0000-0002-5162-138X ([email protected])
Timucin Taner
0000-0003-0641-2930 ([email protected] )
HIGHLIGHTS
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Combined liver-kidney transplantation accounts for 10% of all the liver transplants done in the United States, and is the most common multi-organ transplantation
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While there is no standard criteria for eligibility globally, a recent policy adopted in the United States mandates that candidates of combined liver-kidney transplantation meet a set criteria
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Given the hemodynamic instability during liver transplantation, delaying the kidney transplant in combined liver-kidney transplantation may be safe and advantageous
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Histologic, genomic, and functional studies show that the liver allograft provides immunoprotection for the kidney allograft in combined liver-kidney transplantation