I m p ro v i n g L o n g - Ter m Outc ome s A f t er L i ver Tra n s p l a n t a t i o n Michael R. Charlton,
MBBS, FRCP
KEYWORDS Liver transplantation Metabolic syndrome Immunosuppression Graft rejection KEY POINTS About two-thirds of deaths after the first year following liver transplantation are unrelated to graft dysfunction. Although chronic rejection is an unusual cause of graft loss and mortality, treated acute cellular rejection is associated with attenuated patient and graft survival for patients with hepatitis C virus infection. Obesity and components of the metabolic syndrome are important risk factors for many of the most common causes of mortality following liver transplantation. The frequency of malignancies is greatly increased among liver transplant recipients, who are at risk of a distinct spectrum of neoplasia. Liver transplant recipients should undergo specific screening and management protocols to screen and treat features of the metabolic syndrome and neoplasia. Because of the central role of immunosuppression in common causes of morbidity and mortality following liver transplantation, the minimum degree of immunosuppression needed to achieve excellent allograft function should be sought for recipients.
INTRODUCTION
Professor Thomas Starzl performed 5 human liver transplants (LTs) between March and October of 1963. The longest patient survival was 21 days. Shortly after Starzl’s initial procedures, surgeons in Boston and Paris made single, failed attempts at LT. In the wake of these poor results, the medical community agreed to a moratorium on LTs that lasted for 3 years. The subsequent evolution of LT from an experimental procedure to a nearly routine operation, limited only by the number of available donor organs, has been one of the most remarkable achievements in medicine. The Scientific Registry of Transplant Recipients reports that more than 60,000 LT recipients are
Disclosure: None. Department of Medicine, Intermountain Medical Center, 5169 South Cottonwood Street, Murray, UT 84107, USA E-mail address: [email protected] Clin Liver Dis 18 (2014) 717–730 http://dx.doi.org/10.1016/j.cld.2014.05.011 1089-3261/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
liver.theclinics.com
718
Charlton
alive with a functioning graft in the United States alone. Currently, overall 3-year patient survival following LT in the United States is 80%, with a 10-year survival rate of approximately 50% (http://www.unos.org). Patient and graft survival rates continue to improve year to year (Fig. 1) despite steady increases in the severity of illness (as measured by model for end-stage liver disease [MELD] score) and increasing recipient and donor age at time of transplantation. The sequential improvement in patient and graft survival following LT have been contributed to by many factors. They also have been inversely related to the frequency of steroid-resistant rejection, which now accounts for less than 4% of long-term graft loss.1 Specific disease etiologies with recurrence of original liver diseases, such as primary sclerosing cholangitis (PSC) and hepatitis C virus (HCV), are the basis of one-third of late posttransplant deaths.2 As LT recipients live longer, the impact of long-term side effects of highly effective calcineurin inhibitor (CNI)-based immunosuppression has become more important. Understanding graft and nongraft-related causes of long-term mortality is critical to enhancing long-term outcomes. CAUSES OF DEATH AFTER LT
The most robust data regarding medium and long-term causes of mortality after LT were generated by the National Institute of Diabetes and Digestive and Kidney Diseases prospective multicenter study.2 Causes of death beyond the first postoperative year were 28% hepatic, 22% malignancy, 11% cardiovascular, 9% infection, and 6% renal failure (Fig. 2).2 Renal-related death increased dramatically over time. Recurrence of hepatitis C is, by far, the most common cause of late hepatic-related mortality. Risk factors for overall mortality beyond the first postoperative year include male gender, age, pretransplant and posttransplant diabetes, posttransplant hypertension, posttransplant renal insufficiency, retransplantation, pretransplant malignancy, and metabolic liver disease. Optimal management of cardiovascular disease, diabetes, hypertension, malignancy, and renal insufficiency are thus all necessary to reduce long-term mortality for LT recipients. Although considerable attention has been given to center-specific variability in 1-year posttransplant survival, there is much greater center-to-center variation in long-term outcomes, for example, 3 years Immunosuppression and Patient Survival by Era 100 90 80 70 60
%
50
3 yr patient survival
40
steroid res rejn
30 20 10 0 1970
1975
1980
1985
1990
1995
2000
2005
2009
2011
Fig. 1. Changes in 3-year patient survival after LT in the United States are shown. Increased 3-year survival has been mirrored by fall in steroid-resistant rejection, reflecting increasing efficacy of immunosuppression. (Data from Scientific Registry of Transplant Recipients. Available at: www.SRTR.org.)
Long-Term Outcomes After Liver Transplantation
Fig. 2. Causes of death at 1 and 12 years after LT are shown, as described by the NIH Liver Transplant Database Study. Only 4% of late mortality is secondary to chronic rejection. Almost all of the late causes of mortality are contributed to by immunosuppression. CV, cardiovascular disease.
posttransplantation (data source Scientific Registry for Transplant Recipients [SRTR], http://www.srtr.org/). The great majority of variation in long-term outcomes between centers cannot be accounted for recipient or donor-specific parameters, suggesting wide variation and impact of center-specific approaches to the long-term care of LT recipients. THE IMPACT OF IMMUNOSUPPRESSION AND REJECTION ON OUTCOMES
The development of effective immunosuppressive agents, primarily the advent of CNIs, played a major role in the transformation of posttransplant outcomes. Currently, more than 95% of LT recipients receive immunosuppression with a CNI-based protocol. The decline in the frequency of chronic rejection has closely mirrored the sequential overall improvements in 3-year patient survival (see Fig. 1). Contemporary randomized controlled trials of the most widely used immunosuppression combination (tacrolimus and corticosteroids mycophenolate) have reported the incidence of treated, biopsy-proven acute cellular rejection (tBPAR) to be 12% to 15% in the first 2 postoperative years.3,4 The great majority of tBPAR occurs in the first postoperative year (>95%) and the great majority of tBPAR in the first postoperative year occurs in the first 6 postoperative weeks.3,4,5 Impact of Acute Cellular Rejection on Overall Patient and Graft Survival Varies with Underlying Liver Disease
The National Institutes of Health (NIH) Liver Transplant Database observed that a single episode of early (first 6 postoperative weeks) tBPAR was associated with superior long-term patient survival when compared with recipients with no episodes of tBPAR (P 5 .05).5 Graft survival also was superior for patients with a single episode of tBPAR,
719
720
Charlton
although the difference was not statistically significant (relative risk [RR] 0.82, P 5 .21). Probably because the highest rates of tBAPR occur among the healthiest recipients (eg, rejection is more common in well-nourished patients with good kidney function), acute rejection was not significantly associated with either patient or graft survival in multivariate analysis, although the RRs were less than 1.0 (patient survival: RR 0.78, P 5 .25; retransplantation-free survival: RR 0.86, P 5 .44). The impact of acute cellular rejection on outcomes appears to vary with etiology of liver disease. In a subsequent analysis of the same cohort of patients (n 5 764 adult recipients: 166 HCV-infected and 602 HCV-negative), the NIH Liver Transplant Database study group analyzed the impact of tBPAR according to etiology of liver disease. HCV-infected transplant recipients were seen to experience similar frequencies of acute cellular and steroidresistant rejection as patients undergoing LT for most other indications. Importantly, the mortality risk was significantly increased (RR 2.4; P 5 .03) for HCV-infected transplant recipients who developed early tBPAR compared with HCV-negative transplant recipients. These cumulative observations suggest that, although an episode of early acute cellular rejection is associated with a lower risk of mortality among HCV-negative transplant recipients, HCV-infected transplant recipients are at an increased risk for mortality after an episode of early tBPAR. The adverse impact of early acute cellular rejection on patient survival among recipients with HCV infection has been an important consideration in management and development of primary immunosuppression and acute cellular rejection for HCV-infected transplant recipients. The impact, as measured by hazard ratio (HR) for mortality, of events, including acute cellular rejection, is shown in Fig. 3. Whether this relationship between tBPAR and mortality for patients with HCV will persist in the era of highly effective antiviral therapy remains to be seen. The severity of tBPAR is an important factor in long-term patient and graft survival. Patients who experience a severe histologic acute rejection episode have twice the 1-year rate of combined mortality and graft loss as those who experience a mild episode (12% vs 23%).5
Predictors of Posttransplant Mortality Factor Associated With Mortality
Odds Ratio (95% CI) 2.4
Treated ACR in HCV pos 0.73 Treated ACR in HCV neg
1.5 Diabetes pre-LT 3.75 Renal failure pre or post-LT 1.24 Recipient age per decade >20
0.1
1.0
10.0
Fig. 3. HRs for causes of mortality associated with rejection (ACR), pretransplantation diabetes, renal failure, and age are shown. The importance of minimizing immunosuppression to avoid renal insufficiency, and diabetes is suggested.
Long-Term Outcomes After Liver Transplantation
Immunosuppression in Patients with HCV Infection Corticosteroids
Although treatment of tBPAR has been definitively shown to increase mortality and graft loss in LT recipients with HCV infection, the impact of corticosteroid avoidance and minimization are less clear. By far the best data were generated in a large (n 5 312) randomized controlled study, that included a steroid-free arm of immunosuppression. This study, in which steroids were used in modest doses and tapered off in the first postoperative year, found no difference in the rate of recurrence of HCV or in patient or graft survival between steroid-free and steroid-using arms.6 Calcineurin inhibitors
The most reliable data concerning the relative impact of cyclosporine and tacrolimus on recurrence of HCV, graft loss, and mortality come from randomized controlled trials and large database analyses. The largest prospective randomized controlled study (n 5 495) found no difference in the histologic recurrence rate of hepatitis C at 12 months posttransplantation between patients receiving cyclosporine and tacrolimus.7 A meta-analysis of studies comparing the 2 CNIs, however, found a patient and graft survival benefit associated with tacrolimus as maintenance immunosuppression (graft loss: HR 0.73, 95% confidence interval [CI] 0.61–0.86).8 This observation is supported by analyses of the United Network for Organ Sharing (UNOS)/SRTR. In one, risk factors specific for the combined outcomes of death and graft loss among patients with hepatitis C included cyclosporine (increased risk, HR 1.10, CI 0.96–1.27, P 5 .16), tacrolimus (decreased risk, HR 0.70, CI 0.62–0.79, P
MBBS, FRCP
KEYWORDS Liver transplantation Metabolic syndrome Immunosuppression Graft rejection KEY POINTS About two-thirds of deaths after the first year following liver transplantation are unrelated to graft dysfunction. Although chronic rejection is an unusual cause of graft loss and mortality, treated acute cellular rejection is associated with attenuated patient and graft survival for patients with hepatitis C virus infection. Obesity and components of the metabolic syndrome are important risk factors for many of the most common causes of mortality following liver transplantation. The frequency of malignancies is greatly increased among liver transplant recipients, who are at risk of a distinct spectrum of neoplasia. Liver transplant recipients should undergo specific screening and management protocols to screen and treat features of the metabolic syndrome and neoplasia. Because of the central role of immunosuppression in common causes of morbidity and mortality following liver transplantation, the minimum degree of immunosuppression needed to achieve excellent allograft function should be sought for recipients.
INTRODUCTION
Professor Thomas Starzl performed 5 human liver transplants (LTs) between March and October of 1963. The longest patient survival was 21 days. Shortly after Starzl’s initial procedures, surgeons in Boston and Paris made single, failed attempts at LT. In the wake of these poor results, the medical community agreed to a moratorium on LTs that lasted for 3 years. The subsequent evolution of LT from an experimental procedure to a nearly routine operation, limited only by the number of available donor organs, has been one of the most remarkable achievements in medicine. The Scientific Registry of Transplant Recipients reports that more than 60,000 LT recipients are
Disclosure: None. Department of Medicine, Intermountain Medical Center, 5169 South Cottonwood Street, Murray, UT 84107, USA E-mail address: [email protected] Clin Liver Dis 18 (2014) 717–730 http://dx.doi.org/10.1016/j.cld.2014.05.011 1089-3261/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
liver.theclinics.com
718
Charlton
alive with a functioning graft in the United States alone. Currently, overall 3-year patient survival following LT in the United States is 80%, with a 10-year survival rate of approximately 50% (http://www.unos.org). Patient and graft survival rates continue to improve year to year (Fig. 1) despite steady increases in the severity of illness (as measured by model for end-stage liver disease [MELD] score) and increasing recipient and donor age at time of transplantation. The sequential improvement in patient and graft survival following LT have been contributed to by many factors. They also have been inversely related to the frequency of steroid-resistant rejection, which now accounts for less than 4% of long-term graft loss.1 Specific disease etiologies with recurrence of original liver diseases, such as primary sclerosing cholangitis (PSC) and hepatitis C virus (HCV), are the basis of one-third of late posttransplant deaths.2 As LT recipients live longer, the impact of long-term side effects of highly effective calcineurin inhibitor (CNI)-based immunosuppression has become more important. Understanding graft and nongraft-related causes of long-term mortality is critical to enhancing long-term outcomes. CAUSES OF DEATH AFTER LT
The most robust data regarding medium and long-term causes of mortality after LT were generated by the National Institute of Diabetes and Digestive and Kidney Diseases prospective multicenter study.2 Causes of death beyond the first postoperative year were 28% hepatic, 22% malignancy, 11% cardiovascular, 9% infection, and 6% renal failure (Fig. 2).2 Renal-related death increased dramatically over time. Recurrence of hepatitis C is, by far, the most common cause of late hepatic-related mortality. Risk factors for overall mortality beyond the first postoperative year include male gender, age, pretransplant and posttransplant diabetes, posttransplant hypertension, posttransplant renal insufficiency, retransplantation, pretransplant malignancy, and metabolic liver disease. Optimal management of cardiovascular disease, diabetes, hypertension, malignancy, and renal insufficiency are thus all necessary to reduce long-term mortality for LT recipients. Although considerable attention has been given to center-specific variability in 1-year posttransplant survival, there is much greater center-to-center variation in long-term outcomes, for example, 3 years Immunosuppression and Patient Survival by Era 100 90 80 70 60
%
50
3 yr patient survival
40
steroid res rejn
30 20 10 0 1970
1975
1980
1985
1990
1995
2000
2005
2009
2011
Fig. 1. Changes in 3-year patient survival after LT in the United States are shown. Increased 3-year survival has been mirrored by fall in steroid-resistant rejection, reflecting increasing efficacy of immunosuppression. (Data from Scientific Registry of Transplant Recipients. Available at: www.SRTR.org.)
Long-Term Outcomes After Liver Transplantation
Fig. 2. Causes of death at 1 and 12 years after LT are shown, as described by the NIH Liver Transplant Database Study. Only 4% of late mortality is secondary to chronic rejection. Almost all of the late causes of mortality are contributed to by immunosuppression. CV, cardiovascular disease.
posttransplantation (data source Scientific Registry for Transplant Recipients [SRTR], http://www.srtr.org/). The great majority of variation in long-term outcomes between centers cannot be accounted for recipient or donor-specific parameters, suggesting wide variation and impact of center-specific approaches to the long-term care of LT recipients. THE IMPACT OF IMMUNOSUPPRESSION AND REJECTION ON OUTCOMES
The development of effective immunosuppressive agents, primarily the advent of CNIs, played a major role in the transformation of posttransplant outcomes. Currently, more than 95% of LT recipients receive immunosuppression with a CNI-based protocol. The decline in the frequency of chronic rejection has closely mirrored the sequential overall improvements in 3-year patient survival (see Fig. 1). Contemporary randomized controlled trials of the most widely used immunosuppression combination (tacrolimus and corticosteroids mycophenolate) have reported the incidence of treated, biopsy-proven acute cellular rejection (tBPAR) to be 12% to 15% in the first 2 postoperative years.3,4 The great majority of tBPAR occurs in the first postoperative year (>95%) and the great majority of tBPAR in the first postoperative year occurs in the first 6 postoperative weeks.3,4,5 Impact of Acute Cellular Rejection on Overall Patient and Graft Survival Varies with Underlying Liver Disease
The National Institutes of Health (NIH) Liver Transplant Database observed that a single episode of early (first 6 postoperative weeks) tBPAR was associated with superior long-term patient survival when compared with recipients with no episodes of tBPAR (P 5 .05).5 Graft survival also was superior for patients with a single episode of tBPAR,
719
720
Charlton
although the difference was not statistically significant (relative risk [RR] 0.82, P 5 .21). Probably because the highest rates of tBAPR occur among the healthiest recipients (eg, rejection is more common in well-nourished patients with good kidney function), acute rejection was not significantly associated with either patient or graft survival in multivariate analysis, although the RRs were less than 1.0 (patient survival: RR 0.78, P 5 .25; retransplantation-free survival: RR 0.86, P 5 .44). The impact of acute cellular rejection on outcomes appears to vary with etiology of liver disease. In a subsequent analysis of the same cohort of patients (n 5 764 adult recipients: 166 HCV-infected and 602 HCV-negative), the NIH Liver Transplant Database study group analyzed the impact of tBPAR according to etiology of liver disease. HCV-infected transplant recipients were seen to experience similar frequencies of acute cellular and steroidresistant rejection as patients undergoing LT for most other indications. Importantly, the mortality risk was significantly increased (RR 2.4; P 5 .03) for HCV-infected transplant recipients who developed early tBPAR compared with HCV-negative transplant recipients. These cumulative observations suggest that, although an episode of early acute cellular rejection is associated with a lower risk of mortality among HCV-negative transplant recipients, HCV-infected transplant recipients are at an increased risk for mortality after an episode of early tBPAR. The adverse impact of early acute cellular rejection on patient survival among recipients with HCV infection has been an important consideration in management and development of primary immunosuppression and acute cellular rejection for HCV-infected transplant recipients. The impact, as measured by hazard ratio (HR) for mortality, of events, including acute cellular rejection, is shown in Fig. 3. Whether this relationship between tBPAR and mortality for patients with HCV will persist in the era of highly effective antiviral therapy remains to be seen. The severity of tBPAR is an important factor in long-term patient and graft survival. Patients who experience a severe histologic acute rejection episode have twice the 1-year rate of combined mortality and graft loss as those who experience a mild episode (12% vs 23%).5
Predictors of Posttransplant Mortality Factor Associated With Mortality
Odds Ratio (95% CI) 2.4
Treated ACR in HCV pos 0.73 Treated ACR in HCV neg
1.5 Diabetes pre-LT 3.75 Renal failure pre or post-LT 1.24 Recipient age per decade >20
0.1
1.0
10.0
Fig. 3. HRs for causes of mortality associated with rejection (ACR), pretransplantation diabetes, renal failure, and age are shown. The importance of minimizing immunosuppression to avoid renal insufficiency, and diabetes is suggested.
Long-Term Outcomes After Liver Transplantation
Immunosuppression in Patients with HCV Infection Corticosteroids
Although treatment of tBPAR has been definitively shown to increase mortality and graft loss in LT recipients with HCV infection, the impact of corticosteroid avoidance and minimization are less clear. By far the best data were generated in a large (n 5 312) randomized controlled study, that included a steroid-free arm of immunosuppression. This study, in which steroids were used in modest doses and tapered off in the first postoperative year, found no difference in the rate of recurrence of HCV or in patient or graft survival between steroid-free and steroid-using arms.6 Calcineurin inhibitors
The most reliable data concerning the relative impact of cyclosporine and tacrolimus on recurrence of HCV, graft loss, and mortality come from randomized controlled trials and large database analyses. The largest prospective randomized controlled study (n 5 495) found no difference in the histologic recurrence rate of hepatitis C at 12 months posttransplantation between patients receiving cyclosporine and tacrolimus.7 A meta-analysis of studies comparing the 2 CNIs, however, found a patient and graft survival benefit associated with tacrolimus as maintenance immunosuppression (graft loss: HR 0.73, 95% confidence interval [CI] 0.61–0.86).8 This observation is supported by analyses of the United Network for Organ Sharing (UNOS)/SRTR. In one, risk factors specific for the combined outcomes of death and graft loss among patients with hepatitis C included cyclosporine (increased risk, HR 1.10, CI 0.96–1.27, P 5 .16), tacrolimus (decreased risk, HR 0.70, CI 0.62–0.79, P
