EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: We compared survival outcomes among simultaneous liver-kidney transplants after model for end-stage liver disease (MELD) according to their specific diagnosis and hepatitis C virus versus non-hepatitis C virus.

Materials and Methods: Clinical data review was performed for all patients who underwent combined liver-kidney transplants at Johns Hopkins Hospital from January 31, 1995, to October 31, 2012. Differences in demographics and characteristics among 2 groups were compared using independent samples t test. Survival analysis and distributions were calculated using Kaplan-Meier and Mantel-Cox log-rank test.

Results: Of 48 combined liver-kidney transplants, 31 simultaneous liver-kidney transplants cases were included; nonsimultaneous liver-kidney transplants and patients with prior transplants were excluded. Proportions of age, sex, ethnicity, pre-MELD score, pretransplant renal replacement therapy requirement, hypertension, diabetes mellitus, and follow-up were similar in both groups. Median follow-up was 30 months. Overall and graft survival rates among simultaneous liver-kidney transplants recipients in the pre-MELD era were significantly superior to simultaneous liver-kidney transplants patients in the post-MELD era (P = .0473). However, overall and graft survival rates among simultaneous liver-kidney transplants recipients who had hepatitis C virus and non-hepatitis C virus causes were not statistically different.

Conclusions: We demonstrated a statistically significant difference in overall and kidney graft survival between the post-MELD era and the pre-MELD era. Subgroup analyses of this group showed no statistically significant difference in overall and kidney-graft survival when compared with their specific diagnosis of hepatitis C virus. This must be further studied and verified in a larger cohort of patients to fully identify the effect of hepatitis C virus infection in this group of patients because it can affect both liver and kidney grafts after transplant.

Since the United Network for Organ Sharing (UNOS) implemented model of end-stage liver disease (MELD) scoring system to determine liver graft allocation in 2002, the number of simultaneous liver-kidney transplants (SLK) has increased in the United States.^1-5 The MELD scoring system was initially developed to predict 90-day mortality in patients who had undergone a transjugular intrahepatic portosystemic shunt procedure.⁶ It then was found to be valuable in determining the survival in patients with end-stage liver disease in subsequent studies.⁷ The MELD score is now used by Eurotransplant and UNOS for prioritizing liver graft allocations instead of the Child-Pugh score.^8,9 The MELD score is calculated by using international normalized ratio, total bilirubin, and creatinine values, and renal insufficiency became a vital component in organ allocation. Renal dysfunction affects the survival among patients with liver transplant alone. With high MELD scores, liver transplant candidates with compensated cirrhosis and renal insufficiency may have a better chance at receiving liver and kidney grafts. Previous studies have shown that renal insufficiency is associated with poorer outcomes in liver transplant alone. A high serum creatinine level was the most important factor contributing to mortality.¹⁰

The first reported SLK was performed in Austria in 1983, and the patient survived longer than 9 years.¹¹ Numerous studies have been published evaluating the survival outcomes of SLK. Initial studies show that renal graft survival is greater in SLK than it is in kidney transplant alone. It is thought to be due to immune-protection provided by the liver graft.^12,13 However, there are conflicting data regarding the outcomes of SLK recipients.

In a 2008 study, an increase in 1-year patient and liver graft survival has been demonstrated only among patients who were on long-term dialysis (> 3 mo) before SLK, compared with liver transplant alone.² In a 2011 study, it was demonstrated that patient and liver graft survival among SLK recipients, who had kidney dysfunction without needing dialysis, was superior to recipients with liver transplant alone.¹⁴

Hepatitis C virus is linked with increased mortality among liver and kidney transplant recipients.^15,16 In one study comparing HCV (+) SLK, HCV (-) SLK, and HCV (+) liver transplant alone groups, patient survival rates among these groups were not significantly different.¹⁷ A recent study found that HCV was 1 of the 3 independent risk factors affecting survival among SLK recipients.¹⁸ This study sought to validate the superiority of patient and graft survival among SLK recipients in post-MELD era, and to compare outcomes of survival among SLK recipients, according to their specific diagnosis, HCV versus non-HCV.

Materials and Methods

After obtaining institutional review board approval, we performed a retrospective chart review of all patients who had undergone combined liver kidney transplants from January 1992 to November 2012 at the Johns Hopkins Hospital Liver Transplant Program. Only simultaneous SLK recipients were included in the study. Simultaneous liver-kidney transplants were defined as liver and kidney transplants that were performed within 24 hours. Combined but nonsimultaneous liver and kidney transplants were excluded. Simultaneous liver-kidney transplant recipients with prior liver and/or kidney transplants also were excluded. We collected the clinical data such as demographic characteristics of the patients, comorbidities, pretransplant and posttransplant laboratory values, follow-ups, and posttransplant outcomes. Follow-up was defined as time to death or time to date of last follow-up from the time of transplant. Follow-up was measured in months. All protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration.

Statistical analyses
Differences in patient demographics and characteristics were compared using the t test for continuous variables and Fisher exact test for categorical variables. Survival analyses and the distributions were calculated using Kaplan-Meier method and log-rank test. All statistical analyses were performed by using Stata 10 software.

A total of 48 combined liver-kidney transplant cases took place at Johns Hopkins Hospital from January 1992 to November 2012. Five combined liver kidney transplants, in which liver and kidney transplants were performed more than 24 hours apart were excluded. We identified 12 SLK cases which had prior liver and/or kidney transplants, and these cases also were excluded from the study. Thirty-one SLKs without prior liver and/or transplants were included in the final analysis. Of these 31 SLKs, there were 7 cases pre-MELD cases and 24 post-MELD cases. When cases were further divided according to their hepatitis C status, there were 11 HCV SLK cases and 20 non-HCV SLK cases. Figure 1 demonstrates the patient selection process.

Survival outcomes of pre-MELD SLK versus post-MELD SLK
The demographic characteristics of all patients were obtained and compared between the groups. The mean at age at transplant in pre-MELD group was 44 ± 16 years and post-MELD group was 50 ± 13 years. There were more female patients in post-MELD group; however, this difference was not statistically difference. There is a discrepancy between groups in terms of ethnicity. Interestingly, while all patients in pre-MELD group were white, 17% and 4% of post-MELD group were African-American and Hispanic. The mean pretransplant MELD score in pre-MELD group and post-MELD group were 23 and 28. The percentages of patients who had diabetes, hypertension, and pretransplant renal replacement therapy were similar in both groups. The mean follow-up in the pre-MELD group was 103 months, and it was 41 months in the post-MELD group. Table 1 shows the baseline characteristics of patients in the pre-MELD and post-MELD groups. Table 2 demonstrates the survival and mortality among SLK recipients in the pre-MELD and the post-MELD era.

Figures 2A, B, and C demonstrate the overall, liver, and kidney graft survival rates among the pre-MELD and the post-MELD groups. Overall survival among SLK recipients in pre-MELD era and post-MELD era were 43% and 88%. The survival among SLK recipients in pre-MELD era was significantly longer than SLK recipients in the post-MELD era (P = .0473). In the pre-MELD era, 1 patient died in 2 weeks from graft failure and sepsis, 2 other patients died in 6 months from similar problems, and 1 died after 7 years from metastatic squamous cell cancer. In contrast, in the post-MELD era, only 3 out of 24 patients died. Two patients died within 3 months of transplant from sepsis and 1 patient died from ischemic donor bile duct stricture, related complications, and sepsis.

Survival outcomes of HCV and non-HCV SLK recipients
The demographic characteristics of all patients were obtained and compared between the groups. Table 3 shows the baseline characteristic comparison among HCV and non-HCV patients who underwent SLK. The mean at age at transplant in HCV group was 53 ± 5 years and in the non-HCV group it was 47 ± 16 years. The mean pretransplant MELD scores in the HCV group and the non-HCV group were 28 and 26. The percentage of patients with diabetes, hypertension, and pretransplant renal replacement therapy was similar in both groups. The mean follow-up in the HCV group was 49 months, and it was 67 months in the non-HCV group. Overall survival and liver and kidney graft survival among HCV and non-HCV SLK recipients were similar. Figure 3 shows the causes of liver failure in non-HCV SLK patients. Figures 4A, B, and C show the graphs of the overall, liver, and kidney graft survival.

The effect of HCV in liver transplant is well known. Its recurrence is almost universal and active HCV RNA in serum can lead into advanced fibrosis/cirrhosis in 40% of the cases in a 5-year period. Posttransplant interferon administration is difficult to manage and especially not considered a successful option among HCV genotype 1 patients. With the recently approved (December 2013) non-interferon based oral HCV treatment options (eg, sofosbuvir and semeprevir), it is anticipated that HCV treatment before or after liver transplant can be considered. Currently, there is limited experience on this subject.¹⁹

The outcomes of HCV disease among SLK transplant recipients is not well known, but it is anticipated that HCV RNA activity may be more difficult to control among kidney graft recipients owing to a higher immunosuppression that is used during the initial induction. Therefore, more hepatitis activity is anticipated within the liver, causing graft compromise.

In this limited retrospective study, we demonstrated statistically significant improvement in patient survival in the post-MELD era compared with the pre-MELD era respecting SLK transplants. Of note, there is no demonstrated statistically significant difference in patient and graft survival among HCV and non-HCV SLK recipients. Therefore, HCV does not significantly affect patient and graft survival among SLK recipients. Our SLK population was not treated with conventional PEG interferon owing to the risk of renal graft rejection, leading to no control over the viral replication after the SLK transplant. Our current observation of no survival difference among HCV and non-HCV recipients must be further studied and verified in a larger cohort of patients to fully identify the effect of HCV on this group of patients with SLK grafts. The potential role of oral anti-viral HCV medications also must be further studied in this specific population.

Volume: 12 Issue: 1 March 2014 - Supplement - 1

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