Outcomes of patients with hepatitis C undergoing simultaneous liver–kidney transplantation

Journal of Hepatology 51 (2009) 874–880 www.elsevier.com/locate/jhep

Outcomes of patients with hepatitis C undergoing simultaneous liver–kidney transplantationq Lisa B. Van Wagner1, Talia Baker2, Shubhada N. Ahya3, John P. Norvell1, Edward Wang2,4, Josh Levitsky1,2,* 2

1 Division of Hepatology, Medicine Northwestern University, Chicago, IL, USA Division of Organ Transplantation, Medicine Northwestern University, Feinberg School of Medicine, 675 N St. Clair St., Chicago, IL 60611, USA 3 Division of Nephrology, Medicine Northwestern University, Chicago, IL, USA 4 Division of Preventive Medicine Northwestern University, Chicago, IL, USA

See Editorial, pages 839–841

Background/Aims: The number of simultaneous liver–kidney transplants (SLK) has increased since the MELD era. Data on short- and long-term outcomes of hepatitis C virus positive (HCV+) SLK compared to HCV+ liver transplant alone (LTA) recipients are limited. Methods: A case-control study comparing outcomes of HCV+ SLK versus transplant year-matched HCV+ LTA (1:1) was performed. Results: 38 /142 (26.7%) SLK recipients were HCV+. LTA controls had lower MELD (17.4 ± 8.6) at transplant than SLK (34.5 ± 6.6) (p = 0.001). There were increased early post-transplant infection episodes in SLK (56.3%) versus LTA (21.6%) (p = 0.001) and a trend towards increased early mortality in the SLK group (p = 0.08). However, there was no difference in long-term patient and graft survival, time to HCV recurrence, % P stage 2 fibrosis, renal function, and graft function between the groups. Ten SLK recipients were treated for HCV recurrence with pegylated interferon + ribavirin: two had sustained virologic response, five stopped due to side effects, and three had no response. None had liver or kidney rejection on treatment. Conclusion: Our data represent the largest analysis of HCV+ SLK outcomes to date. We demonstrate increased early complications in SLK versus LTA recipients, likely due to being more critically ill at transplant (higher MELD) and complications unrelated to HCV within the first year. However, long-term outcomes, i.e. HCV recurrence, graft/renal dysfunction, are similar to LTA. In addition, while data are limited, treatment of HCV recurrence with interferon appeared safe in our SLK recipients. Ó 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Hepatitis C virus; Liver transplantation; Kidney transplantation; Simultaneous liver–kidney transplantation; Interferon; Recurrent disease

Received 19 March 2009; received in revised form 5 May 2009; accepted 27 May 2009; available online 12 June 2009 Associate Editor: P.-A. Clavien q The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. * Corresponding author. Tel.: +1 312 6954413; fax: +1 312 6950036. E-mail address: [email protected] (J. Levitsky). Abbreviations: SLK, simultaneous liver–kidney transplant; MELD, model for end-stage liver disease; HCV+, hepatitis C virus positive; LTA, liver transplant alone; IFN, interferon; RBV, ribavirin; RRT, renal replacement therapy; SVR, sustained viral response; ICU, intensive care unit; ECD, expanded criteria donor; ALT, alanine aminotransferase. 0168-8278/$36.00 Ó 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2009.05.025

L.B. Van Wagner et al. / Journal of Hepatology 51 (2009) 874–880

1. Introduction When the United Network for Organ Sharing changed its algorithm for liver allocation to the model for end-stage liver disease (MELD) system in 2002, highest priority shifted to patients with renal insufficiency as a major component of their end-stage liver disease [1]. Critics of the MELD system have suggested that because creatinine is given considerable weight in the MELD formula, liver grafts are being preferentially allocated to patients with renal insufficiency [2,3]. As such, the introduction of the MELD has coincided with a significant increase in the number of simultaneous liver–kidney transplants (SLK) performed annually [2]. However, data are conflicting within studies aimed at predicting which candidates will fail to recover renal function and need SLK, thus creating controversy over the role of SLK transplantation and a clear need for ongoing re-examination of outcomes [1,4–8]. With the impetus towards increased SLK transplants, data on outcomes are needed surrounding the current leading indication for liver transplantation in the United States – Hepatitis C Virus (HCV) [9]. Hepatitis C infection has been associated with the development of chronic kidney disease before and after transplantation, either due to immune complex injury, co-existing diabetes, or other factors [10–14]. What has not been clearly delineated is whether HCV+ SLK recipients have more rapid progression of HCV recurrence or have worse outcomes (rejection, infection, patient/graft survival) compared to liver transplant alone (LTA) recipients. In addition, the management of HCV recurrence in the SLK population is not well-defined or reported. Of concern are studies within the renal transplant literature that have shown an unacceptably high risk of precipitating renal allograft rejection with interferon (IFN) therapy [15–21]. More recent reports have demonstrated successful HCV treatment with pegylated IFN and ribavirin (RBV) in SLK recipients without development of renal rejection on therapy, although data are limited to small numbers of patients [22–24]. Therefore, the purpose of this study was to analyze outcomes of a cohort of patients with hepatitis C undergoing SLK compared to LTA in terms of patient and graft survival, rejection episodes, infectious complications and most importantly hepatitis C recurrence.

2. Patients and methods 2.1. Patients We performed a retrospective review of data in all HCV+ patients who underwent SLK (cases) at Northwestern Memorial Hospital from June 1, 1999 to January 1, 2007. Cases were matched 1:1 to LTA controls who were transplanted within the same year (randomly selected within the year), primarily to compare the occurrence and progression

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of HCV recurrence in both groups. Patient data were obtained by reviewing inpatient and outpatient medical records and our electronic transplantation database. Collected and analyzed data included age, sex, cause of liver and kidney diseases, dialysis requirements, MELD score, preoperative and postoperative laboratory results, donor age, infectious complications, post-transplant immunosuppressive regimens, liver and kidney rejections, need for retransplantation, documentation of hepatitis C recurrence (including treatment, outcomes and complications) and patient and graft survival. Patients received methylprednisolone 500 mg intravenously immediately post-operatively, followed by a prednisone taper over 3 months. Maintenance immunosuppression regimens varied to some degree within this period and are reported in the results. All documented episodes of rejection were based on biopsy. Hepatitis C recurrence was defined by standard histological criteria [25]. Liver biopsies were performed for either liver enzyme elevations or, in the majority, by protocol on a yearly basis. Allograft kidney biopsies were performed when clinically indicated. In the time period of the study, the allocation system allowed for the use of SLK transplantation based on the best clinical judgment of the transplant program. Therefore, with no reliable algorithms available to predict the reversibility of renal disease/injury in this patient population, we used a standard set of decision-making criteria in each patient regarding the need for combined transplant. These included a serum creatinine >1.5 mg/dl for >1 month (or 0.8 greater than baseline), risk factors for intrinsic renal disease (diabetes, hypertension), and the presence of significant proteinuria and/or the need for renal replacement therapy >3 weeks.

2.2. Definitions and statistical analysis Differences in patient characteristics and postoperative outcomes between SLK and LTA groups were compared using Student’s t-test for continuous variables and Fisher exact test or v2 analysis for categorical variables. Sustained virological response (SVR) was defined as an undetectable HCV RNA 24 weeks after cessation of therapy. Patient survival was defined as time from transplantation to death or last follow-up. Liver graft survival was defined as time from transplantation to death, last follow-up, or retransplantation. Kidney graft survival was defined as time from transplantation to death, last follow-up, or return to renal replacement therapy (RRT). Duration of RRT was defined as total inclusive days during which RRT (conventional or continuous) was required. Kaplan–Meier survival analysis and Cox proportional hazard model were conducted to compare patient and graft survival (uncorrected and corrected for age, gender, MELD) and HCV recurrence between SLK and LTA patients using SAS 9.2 (SAS Inc., Cary, NC). Significance was established at an alpha level of 0.05.

3. Results 3.1. Demographics and preoperative characteristics During the study time period, 142 patients underwent SLK. Thirty-eight (26.7%) of these patients were HCVpositive and 38 LTA patients served as controls. Compared to the LTA group (Table 1), the SLK group had a significantly higher percentage receiving preoperative RRT and previous liver transplantation, higher baseline creatinine and bilirubin, and higher MELD at transplantation. Other baseline characteristics did not differ significantly. 3.2. Patient and graft survival At the completion of the analysis, 15 (39%) SLK patients and 8 (21.5%) LTA patients had died. The

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Table 1 Comparison of patients with HCV undergoing SLK versus year-matched LTA. Characteristic

SLK (n = 38)

LTA (n = 38)

P value

Age, mean ± SD, years Sex, No (%) Male Female Ethnicity, No (%) Caucasian African–American Hispanic Other Preoperative MELD score, mean ± SD Previous liver transplant, No (%) Previous kidney transplant, No (%) Preoperative RRT, No (%) Time receiving RRT pre-transplantation, mean ± SD, days Baseline creatinine, mean ± SD Causes of kidney failure, No (%) Hepatorenal syndrome Alone Coexisting chronic renal insufficiency++ Acute tubular necrosis Alone Coexisting chronic renal insufficiency++ Chronic allograft rejection+ Calcineurin inhibitor toxicity+ Diabetes mellitus+ Other*,+ Baseline serum ALT, mean ± SD Baseline total serum bilirubin, mean ± SD Donor age, mean ± SD, years Immunosuppression, No (%) Tacrolimus alone Tacrolimus + mycophenolate mofetil Sirolimus regimen Cyclosporine regimen Induction agents (alemtuzumab or basiliximab) Follow-up,** mean ± SD months

54 ± 8.1

51.7 ± 6.1

0.1664 0.6344

23 (60.5) 15 (39.5)

25 (65.8) 13 (34.2)

27 (71.1) 3 (7.9) 7 (18.4) 2 (5.3) 34.6 ± 6.6 8 (21.1) 5 (13.2) 25 (65.8) 184.2 ± 470.9 3.6 ± 2.1

23 (60.5) 8 (21) 5 (13.1) 1 (0.3) 17.4 ± 8.6 2 (5.3) 0 (0) 0 (0) n/a 1.2 ± 0.5 n/a

0.1930

<.0001 0.0360 0.0272 <.0001 n/a <.0001

18 (47.4) 3 (7.9) 15 (39.5) 5 (13.2) 0 (0) 5 (13.2) 4 (10.5) 4 (10.5) 2 (5.3) 5 (13.2) 109.1 ± 225.1 14.1 ± 13.8 37.6 ± 16.1

84.2 ± 72.8 3.9 ± 3.4 40 ± 17.3

0.5212 <.0001 0.5472

17 (44.7) 17 (44.7) 4 (10.5) 0 (0) 4 (10.5) 34 ± 27

20 (52.6) 13 (34.2) 2 (5.3) 3 (7.9) 2 (5.3) 41 ± 27

0.0831 0.0831 0.1600 0.0831 0.1600 0.2472

Abbreviations: SLK, simultaneous liver and kidney transplant; LTA, liver transplant alone; SD, standard deviation; No, number; RRT, renal replacement therapy; MELD, model for end-stage liver disease; n/a, non-applicable. * Other: HCV-associated glomerulonephritis (GN) (n = 2)+, Wegener’s GN+, contrast nephropathy, Polycystic kidney disease. ** Follow up = time to death or time to date of last follow-up. + Biopsy proven diagnosis. ++ Unknown etiology of chronic renal insufficiency, defined by Cr P1.5 mg/dL for P1 month.

1-, 3-, and 5-year overall survival rates for the SLK group were 73.7%, 61.8%, and 68.1%, and in the LTA group, the rates were 91.9%, 78.8%, and 73.2%, respectively. Cause of death included recurrent HCV (4 SLK, 5 LTA), sepsis or multi-organ failure (5 SLK, 0 LTA), graft failure (3 SLK, 1 LTA), cardiac complications (2 SLK, 0 LTA), renal failure (1 SLK, 0 LTA) and recurrent hepatocellular carcinoma (0 SLK, 2 LTA). Kaplan–Meier survival analysis demonstrated a trend towards a lower survival in the SLK versus LTA groups (p = 0.07), particularly early after transplant (Fig. 1A). However, once adjusted for age, gender, and MELD, this trend was no longer apparent (p = 0.298). In the SLK group, the 1-, 3-, and 5-year liver graft survival rates were 73.7%, 61.8%, and 53%, respectively. In the LTA group, the 1-, 3-, and 5-year liver graft sur-

vival rates were 89.2%, 69.3%, and 64%, respectively. By Kaplan–Meier analysis, there was no difference in liver graft survival between SLK and LTA groups (Fig. 1B). The 1-, 3-, and 5-year kidney graft survival rates in the SLK group were 73.7%, 61.8%, and 53%, respectively. Seven (47%) of 15 grafts were lost because of death. The remaining eight kidney graft failures were due to acute tubular necrosis in 4 cases, primary graft nonfunction in 3 cases and chronic rejection in 1 case. None of these patients survived to retransplantation. 3.3. Postoperative complications Univariate analysis revealed a higher percentage of SLK recipients with early (0–6 month) infections (56.3%) compared to LTA recipients (21.6%) (p =

L.B. Van Wagner et al. / Journal of Hepatology 51 (2009) 874–880

Survival Distribution Function

A

(range, 2–444 days) from transplant. Four (33.3%) regained renal function and were alive at last followup (median 1019 days, range 511–1246). Of note, five (41.7%) of the 12 SLK patients requiring post-transplant RRT received expanded criteria donor (ECD) kidneys (e.g. donor age >65, stroke as cause of death, history of hypertension and serum creatinine >1.5 mg/dL prior to death) [26] compared to 1 (3.8%) of the 26 SLK patients not requiring post-transplant RRT (p = 0.03). All five of these SLK patients who received ECD kidneys died.

Log-rank test: X2 (1)=3.1, p=0.0783 1.00

0.75

0.50

0.25

Liver Transplant TransplantAlone Alone

Simultaneous Liver Simultaneous LiverKidney Kidney

0.00 0

1

2

3

4

5

6

7

8

9

10

4 3

4 1

0 0

0 0

Time (year) LTA ( n) : 38 SLK ( n) : 38

Survival Distribution Function

B

34 28

31 25

19 17

12 9

7 5

6 5

Log-rank test: X2 (1)=1.56, p=0.2111 1.00

0.75

0.50

0.25

Liver Liver Transplant Transplant Alone Alone Simultaneous Simultaneous Liver LiverKidney Kidney

0.00 0

1

2

3

4

5

6

7

8

9

10

4 3

4 1

0 0

0 0

Time (year) LTA ( n) : 38 SLK ( n) : 38

33 28

30 25

17 17

11 9

7 5

6 5

877

Fig. 1. (A) Kaplan–Meier patient survival curve. Kaplan–Meier survival analysis demonstrated a trend towards a higher death rate in the SLK group versus LTA (p = 0.078). However, when controlled for MELD there was no difference in survival between the groups (p = 0.986). (B) Kaplan–Meier graft survival curve. Kaplan–Meier survival curve for graft function showed no difference between the groups (p = 0.2111).

0.001). In addition, the SLK group had an increased number of intensive care unit (ICU) days (6.3 ± 8.2 p = 0.009) and total hospital days (11.1 ± 8.8, p = 0.002) when compared to LTA (2.5 ± 2.2 and 5.9 ± 4.4, respectively). Other outcomes and endpoints, i.e. rejection episodes, ALT, bilirubin and creatinine levels were not different over time (Table 2). Five (13.2%) SLK patients had six episodes of acute kidney rejection and one lost their graft. Twenty-five SLK patients (65.8%) were on renal replacement therapy (RRT) for a median of 30 pretransplant days (range, 1–1798). None in the LTA group required pre-transplant RRT, although four (10.5%) required RRT following LTA for a median of 31 days (range, 17–61 days). One LTA patient underwent subsequent SLK and three expired due to recurrent HCV. In contrast, in the SLK group, 12 (31.6%) patients required post-transplant RRT for a median of 116 days (range, 2–359 days). Of these, eight (66.6%) did not regain renal function and all eight expired at a median of 160 days

3.4. Hepatitis C recurrence Twenty-six (68.4%) SLK patients had liver biopsies following transplant versus 35 (92.1%) of LTA (p = 0.01). Of these, 17/26 (65.5%) SLK patients had documented HCV recurrence compared to 26/35 (74.3%) LTA patients (p = 0.47). Overall disease-free time was 1.04 ± 1.3 years for the SLK group and 1.01 ± 1.2 years for the LTA group (p = 0.4). There was no difference in HCV recurrence between SLK and LTA groups (Fig. 2). Of the 17 SLK recipients with HCV recurrence, 10 were treated with pegylated IFN and RBV (Table 3). Mean grade and stage prior to treatment were 1.2 ± 0.42 and 1.3 ± 1.47, respectively. Two patients achieved an SVR, three were non-responders, and five discontinued treatment due to pancytopenia or psychiatric effects. There were no episodes of liver or kidney rejection while on treatment. Of the 26 LTA recipients with recurrence, 14 were treated with pegylated IFN (alpha-2a or 2b) and RBV. Mean grade and stage prior to treatment were 1.36 ± 0.50 and 0.71 ± 1.2, respectively. Five achieved an SVR, seven were non-responders, and two discontinued therapy due to psychiatric effects. There was one documented episode of liver rejection while on treatment in this group, which resolved with methylprednisolone.

4. Discussion To our knowledge, our study represents the largest analysis of outcomes of patients with HCV undergoing SLK transplant. Our non-renal failure control subjects were selected to analyze the effect of HCV alone on outcomes between single and dual organ transplant recipients. Notably, the problem of HCV recurrence for SLK recipients was similar to LTA, despite the speculation that dual organ transplant recipients may be at an increased risk of HCV recurrence with more immunosuppressive therapy. While the overall percentage of recurrence was actually somewhat higher in the LTA patients, the time-to-recurrence or degree of histological injury (fibrosis) was not different among the groups. Confounding factors on the risk of HCV recurrence,

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Table 2 Comparison of outcomes of HCV positive patients undergoing SLK versus LTA. Outcome

SLK (n = 38)

LTA (n = 38)

P value

Intensive care unit days, mean ± SD Total hospital days post-operatively, mean ± SD Infectious complications, No (%) 0–1 Month 1–6 Months 1 Year Patients receiving post-operative RRT, No (%) Time receiving RRT post-transplantation, mean, days Creatinine at 1 year, mean ± SD Total bilirubin at 1 year, mean ± SD ALT at 1 year, mean ± SD Liver rejection episodes Kidney rejection episodes Hepatitis C recurrence, No (%) % P stage 2 fibrosis At 1 years At 2 years Liver Graft survival at 1 year, % Kidney Graft survival at 1 year, % Overall patient survival, % At 1 year At 2 years At 3 years At 5 years

6.26 ± 8.23 11.11 ± 8.78

2.47 ± 2.17 5.92 ± 5.38

0.0089 0.0019

17 (44.7) 15 (39.5) 5 (13.2) 12 (31.6) 146.33 ± 140.15 1.32 ± 0.51 2.5 ± 4.76 61.17 ± 51. 99 11 6 17 (44.74)

8 (21.1) 5 (13.2) 6 (15.8) 4 (10.5) 35.00 ± 19.95 1.19 ± 0.26 1.40 ± 2.36 84.58 ± 68.11 14 n/a 26 (68.42)

0.0222 0.0055 0.9510 0.0244 <.0001 0.1943 0.2581 0.1274 0.4638 n/a 0.0362

3 1 73.7 73.7

0 8 89.2 n/a

0.0332 0.2653 0.0557 n/a

73.7 71.1 61.8 61.8

91.9 89.2 78.8 73.2

0.0290 0.0344 0.0818 0.1365

Abbreviations: HCV, hepatitis C virus; SLK, simultaneous liver kidney; LTA, liver transplant alone; SD, standard deviation; No, number; RRT, renal replacement therapy; ALT, alanine aminotransferase; n/a, non-applicable.

such as differences in immunosuppressive regimens, liver rejection rates, and donor age were similar and well matched among the SLK and LTA groups, supporting our findings of comparable recurrence rates. Regarding HCV therapy, SVR rates in the SLK group were low in the small number treated, although there were no documented kidney or liver rejection episodes on interferon therapy. When we combine our 10 SLK patients with eight from previous case series, the overall SVR rate is 38.9% with no reported kidney rejection and one liver rejection on IFN [22–24]. The significant risk of kidney rejection and graft failure as well as inconsistent response

Survival Distribution Function

Log-rank test: X2(1)=1.25, p=0.2627 1.00

0.75

Liver LiverTransplant TransplantAlone Alone

0.50

Simultaneous SimultaneousLiver LiverKidney Kidney

0.25

0.00 0

1

2

3

4

5

6

7

8

Time (year) LTA ( n) : 34 SLK ( n) : 26

8 10

3 4

1 3

1 3

1 0

1 0

1 0

0 0

Fig. 2. Kaplan–Meier recurrence survival curve. Kaplan–Meier survival curve and Cox proportional Hazard models for recurrence showed no difference between the groups (p = 0.2627), even when controlled for age.

rates have impeded the regular use of IFN therapy for HCV after kidney transplantation [15–21,27]. However, none of these studies included SLK cohorts. There is well-documented evidence to support the theory that the liver transplant provides some level of immunologic protection to the kidney allograft [28,29]. This was first described in animal models by Calne et al. [30] and has been observed in human studies [31,32]. Therefore, it is reasonable to hypothesize that the lack of kidney (and liver) rejection with IFN-based treatment regimens in the SLK recipients reported here and elsewhere may be secondary to this postulated immunoprotection. Although there was a trend towards increased mortality early after SLK, there was no difference in longterm survival between the groups. The decrease in short-term survival was likely due to the increased rate of infection, as the majority of deaths were caused by sepsis and multi-organ failure. Along with a higher rate of infections, the SLK group had longer hospitalizations and time in the ICU compared to the LTA group. These findings underscore the inherent severity of illness in patients with dual organ failure (higher MELD) and the associated risks and complications immediately after transplantation. Although this finding is subject to Type II error given the small sample size, our results are supported by the fact that one would expect higher MELD renal failure patients to fare worse early after transplant than lower MELD non-renal failure LTA patients. In fact, this is a major concern in regard to the appropriateness of SLK [1,2,26,27]. However, in other studies

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Table 3 Comparison of patients treated for HCV recurrence with pegylated interferon/ribavirin. Characteristics Sex, No (%) Male Female Age, median (range), years Patients who had received treatment prior to transplant, No (%)* Interval time lapse between transplantation and treatment, median (range), months Creatinine prior to treatment, median (range) ALT prior to treatment, median (range) HCV genotype, No (%) 1 2 3 Unknown HCV RNA prior to treatment, median (range) Fibrosis stage at recurrence, No (%) Stage 0–1 Stage P2 Response, No (%) SVR NR Treatment stopped due to side effects Rejection episodes, liver or kidney

SLK (n = 10)

LTA (n = 14)

8 (80) 2 (20) 50.4 (43.2–67.5) 7 (70) 10 (1–50.6)

8 (57.1) 6 (42.9) 48.7 (43.5–66.3) 8 (57.1) 11.2 (1.7–27.2)

1.2 (0.8–2.3) 68 (10–712)

1.1 (0.9–1.4) 116.5 (44–399)

9 (90) 0 1 (10) 0 2,765,000 (520,000–>10,000,000)

7 (50) 1 (7.1) 3 (21.4) 3 (21.4) 1,506,115 (13,400–>10,000,000)

7 (70) 3 (30)

11 (78.6) 3 (21.4)

2 (20) 3 (30) 5 (50) 0

5 7 2 1

(35.7) (50) (14.3) (7.1)

Abbreviations: SLK, simultaneous liver kidney; LTA, liver transplant alone; SD, standard deviation; No, number; ALT, alanine aminotransferase; HCV, hepatitis C virus; SVR, sustained viral response; NR, nonresponder. * Pegylated interferon + ribavirin based regimens.

focused on SLK transplantation (all causes of liver disease), similar diminished short-term but preserved longterm survival have been reported [26–30]. The lack of difference in overall survival highlights the clinical importance of developing future studies to examine strategies to decrease peri-operative and post-operative complications and thus improve outcomes. We also established that SLK and LTA recipients who required post-transplant RRT have significant mortality with approximately two-thirds expiring in the study time period. Notably, within the SLK group, all of those receiving ECD kidneys required RRT and eventually died. With an overall shortage of organs, our preliminary data suggest that ECD kidneys might be delegated to those on the kidney transplant waiting list who have been shown to have better outcomes with ECD kidney transplantation compared to SLK patients [33]. Thus, when a decision is made to give a combined transplant to a critically ill patient on the LT waiting list, the quality of the grafts should take precedence in order to maximize survival. There are limitations of our analysis. The retrospective nature may have led to inherent biases involved in data collection and patient selection. As mentioned previously, in order to analyze HCV outcomes we chose only to control for the presence of HCV, thus accepting as a limitation that baseline variables between the cohorts may be different, and in fact, they were (higher MELD, higher creatinine and higher bilirubin) in the SLK cohort. However, we demonstrate that despite

the early worse outcomes for SLK recipients, long-term outcomes including HCV recurrence (our primary outcome measure), graft function and survival did not differ between the groups. Another limitation is that we do not routinely perform renal biopsies at our center prior to listing for SLK due to the concern of hemorrhagic complications that have been reported as high as 30% in one series [34]. Although we may not have accurately assessed the necessity of SLK in our patient population, allocation of a kidney allograft was based on clinical judgment and defined criteria, and now follows recommended guidelines [35]. Finally, protocol liver biopsies were not performed on all patient groups. Thus, it is possible that the HCV recurrence rate is underestimated and may be more pronounced in the SLK group who had fewer biopsies performed. We speculate that this difference may be attributed to the fact that our transplant clinicians may have been hesitant to perform protocol biopsies on SLK patients due to their reluctance to treat HCV recurrence (i.e. risk of kidney rejection). While compliance with protocol biopsies would have allowed for more accurate statistical comparisons, the available data do support similar histological progression and graft function among the groups. In conclusion, while early morbidity and mortality may be higher in HCV+ SLK patients, particularly those requiring RRT, long-term patient and graft survival and HCV recurrence rates are similar to that of HCV+ LTA patients. Based on the available data, antiviral treatment for HCV recurrence in SLK recipients

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appears safe. Additional prospective trials with larger patient populations and protocol biopsies for HCV recurrence are needed to further validate our findings.

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