Author + information
- Received October 10, 2017
- Accepted October 16, 2017
- Published online November 27, 2017.
- Richa Gupta, MD, MPH,
- Kelly Schlendorf, MD and
- JoAnn Lindenfeld, MD∗ ()
- Heart Failure and Transplantation Section, Vanderbilt Heart and Vascular Institute, Nashville, Tennessee
- ↵∗Address for correspondence:
Dr. JoAnn Lindenfeld, Heart Failure and Transplantation Section, Vanderbilt Heart and Vascular Institute, Medical Center East, South Tower, 1215 21st Avenue South, Suite 5209, Nashville, Tennessee 37232-8802.
Heart transplantation remains the preferred treatment for patients with advanced heart failure refractory to medical therapies. Over the past few decades, heart transplant volumes are on the rise and the median survival post-transplant continues to improve, from 8.5 years in the 1980s to 11.9 years in the 2000s (1). This improvement in survival is mainly attributable to a reduction in mortality during the first year post-transplant as a result of improvements in surgical techniques, perioperative management, and immunosuppressive therapies directed at acute graft rejection.
Interestingly, median survival conditional on survival to 1 year does not show a similar trend for improvement; mortality rates have been relatively constant at 3% to 4% per year over the past 2 decades (1). This phenomenon may in part be due to an excess of mortality related to the effects of immunosuppression (IS) as time from transplant accrues. During the first post-transplant year, the leading cause of death is graft failure, followed by infection and multiple organ failure (1). After the first year, infection and malignancy become increasingly important causes of death, whereas rejection is no longer as common. Data from 2009 to 2015 show malignancy actually surpasses graft failure as the leading cause of death after 3 to 5 years post-transplant (1). Moreover, while infection becomes a less important contributor to mortality immediately after the first post-transplant year, its contribution to death remains greater than that of acute rejection, coronary allograft vasculopathy (CAV), and multiple organ failure from 1 year onward. Cumulatively, graft failure, infection, and malignancy are the 3 leading contributors to mortality post-transplant (1).
Notably, cause of death after transplant appears to be determined largely by age. Weaver-Pinzon et al. conducted a retrospective study of 52,995 adult patients transplanted between January 1995 and August 2011. There was a significantly higher mortality among recipients 60 to 69 years of age and ≥70 years of age at time of transplant compared with those 50 to 59 years of age and 18 to 29 years of age. Recipients 30 to 39 years of age and 40 to 49 years of age exhibited lower mortality relative to recipients 50 to 59 years of age and 18 to 29 years of age. Figure 1 depicts the hazard ratio for the risk of cause-specific mortalities as a function of recipient age, as compared with the reference group (50 to 59 years of age). The hazard ratio for deaths related to acute rejection, CAV, and graft failure decreases with increasing recipient age, with mortality from these causes being highest in the group 18 to 29 years of age and lowest in the group 60 to 69 years of age. Compared with the reference group, younger recipients had an increased risk of acute rejection-related death that ranged from a 32% higher risk in the 40- to 49-year-old group to a more than 4-fold increased risk in the 18- to 29-year-old group. In contrast, the hazard ratios for deaths related to malignancy, renal failure, and infection increase with increasing recipient age. Recipients ≥70 years of age had a 2-fold increased risk of infection-related mortality compared with the reference group, and those 18 to 29 years of age had the lowest infection-related mortality. Similarly, older recipients exhibited significantly higher risk of malignancy-related death, whereas younger recipients (18 to 49 years of age) had a 71% lower risk of malignancy-related death compared with the reference group. Importantly, this study found that differences in IS regimens among recipient age groups were minor. In summary, while mortality of younger recipients is driven by acute rejection, CAV, and graft failure, that of older recipients is driven by infection, malignancy and renal failure.
These data invite the observation that, particularly among older transplant patients, complications of IS represent important causes of morbidity and mortality. Table 1 lists the major medical complications following cardiac transplantation, the vast majority of which, including neoplasia, infection, chronic kidney disease, diabetes, gout, osteoporosis, and drug-drug interactions, are exacerbated by an excess of IS. Immune mechanisms influence these morbidities, and the increased susceptibility of older recipients as compared with younger recipients is likely due in part to changes in the immune response that occur with aging. Although CAV and graft dysfunction may be related to too little IS, a recent randomized study using rituximab immediately following cardiac transplant demonstrated increased intimal hyperplasia in the rituximab group (2). These data further call into question our already tenuous understanding of the relationship of IS to graft dysfunction and CAV, the latter of which is a form of chronic allograft injury mediated by both immune and nonimmune mechanisms.
Hypogammaglobulinemia (HGG), independent of other factors, significantly increases the risk of infections and is present in 49% of heart transplant recipients (3). In a meta-analysis by Florescu et al. (3) that included 1,756 patients from 18 studies who were status post–solid organ transplant, those with severe HGG (immunoglobulin G [IgG] <400 mg/dl) had a 2.46 times higher odds of infection compared with those with IgG >400 mg/dl. This risk remained consistently high in subset analysis by type of infection (cytomegalovirus, Aspergillus, fungal, and respiratory infections) for the severe HGG group. Moreover, the odds of death at 1 year for patients with IgG <400 mg/dl and IgG <700 mg/dl were 21.91 and 2.71 times higher, respectively, than were the odds of death for patients with IgG >400 mg/dl and >700 mg/dl (p = 0.005 and 0.04, respectively) (3). HGG appears to be associated with age (4), and the combination of age and HGG may prove useful in directing the reduction of IS regimens in transplant recipients.
Mycophenolate mofetil (MMF) remains among the preferred agents for maintenance IS in heart transplant recipients, and its use has been increasing since the 2000s (1). MMF is a prodrug and cell cycle inhibitor that blocks T- and B-cell proliferation and reduces activated leukocytes within a transplanted organ. Low IgG is associated with the use of MMF as a result of significant B-cell dysfunction, which profoundly depletes immunoglobulin levels (5). A small randomized clinical trial of MMF compared with azathioprine among renal transplant recipients showed that MMF was associated with significant HGG (primarily IgG) as well as increased risk of recurrent urinary tract infections, and that conversion of MMF to azathioprine both increased IgG concentrations over 3 months and eliminated recurrent infections (5). These findings further suggest that IgG may be a useful biomarker to predict risk of severe infection and guide IS therapy, especially in older patients.
The link between IS and malignancy is well established. The rate of any de novo cancer following heart transplantation is about twice that of the general population. Interestingly, however, there has been a steady decline in malignancy rates with respect to transplant year such that with the exception of lung cancer, there is decreasing disparity in malignancy rates between cardiac transplant recipients and the normal population (6). This trend is explained largely by a shift among transplant centers in recent years toward lower IS doses, and away from some of the more toxic agents used for maintenance and rescue IS. This observation begs the question of whether the level of IS, including levels of IgG, is related to the incidence of cancer post-transplant.
In light of the significant associations between older age, HGG and cause of death post-transplant, there is a strong case to be made for personalization of IS regimens aimed at reduction of IS as patients age, guided in part by levels of IgG. Many questions, however, remain unanswered surrounding quantification of recipient risk beyond age. Currently no data exist about the prevalence of HGG in later years following heart transplant. In addition, HGG is just 1 biomarker of humoral immunity among many that may be potentially useful in identifying recipients at high risk for infection or malignancy. Furthermore, although it is likely that rates of neoplasia and infection will decrease with reductions in IS, it is unclear what the impact will be on primary graft dysfunction or on CAV.
Nonetheless, the vastly different causes of death by age group in heart transplant recipients are difficult to ignore: over-IS is playing a much bigger role in mortality than previously thought. As long as we proceed carefully, we have an opportunity to improve outcomes, particularly in older recipients, by reducing IS as patients age.
Dr. Lindenfeld is a consultant for Novartis, Abbott, Relypsa, Amgen, CVRx, and VWave; and has grant funding from Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received October 10, 2017.
- Accepted October 16, 2017.
- 2017 American College of Cardiology Foundation
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