Premature Death in Kidney Transplant Recipients: The Time for Trials is Now.

Kidney transplantation improves survival and quality of life, and reduces health care costs compared with maintenance dialysis. With the development of better immunosuppressive drugs, antivirals, and patient care protocols, short-term outcomes have improved. However, kidney transplant (KT) recipients remain at increased risk for mortality, and achieve only 70%–75% of the life expectancy of age-matched individuals in the general population. Premature death despite kidney function is the leading cause of allograft loss after the first post-transplant year. The focus of KT research on immunosuppressant medications to decrease acute and chronic rejection has not translated into increased patient survival for KT recipients, and important nonimmunologic complications of transplantation are commonly overlooked. Uneven progress has been made globally, with most countries (including the United States) showing no improvement in long-term patient survival over the last two decades. Cardiovascular mortality is the leading cause of premature death despite kidney function. Although KT recipients have markedly lower cardiovascular disease (CVD) risk and mortality rates than patients on dialysis or the transplant waitlist, cardiovascular events occur 10–50 times more frequently than in the general population. CVD in KT recipients is partly due to traditional risk factors, including a high prevalence of diabetes, hypertension, obesity, preexisting ischemic heart disease, prior smoking, systemic atherosclerosis, reduced kidney function, and albuminuria. Transplant-related cardiovascular risk factors, including pretransplant dialysis duration, delayed graft function, acute rejection, chronic inflammation and side effects of immunosuppression, particularly post-transplant diabetes mellitus (PTDM) and dyslipidemia, also contribute to CVD burden. Reduced allograft function is particularly critical, with a 15% increased CVD mortality risk for each 5 ml/min per 1.73m drop below 45 ml/min per 1.73m. KT recipients experience a relatively higher incidence of arrhythmia than the general population, and CVD events are more likely to be fatal when they occur. Conventional risk prediction scores (e.g., the Framingham Risk Score) have been shown to greatly underestimate CVD risk in KT recipients, underscoring the need for research to better understand the pathogenetic mechanisms and risk predictors in this unique population. The general population has experienced major reductions in cardiovascular morbidity and mortality over the last 20 years, attributed to the use of evidence-based therapies to reduce risk. However, in KT recipients, most recommendations for CVD risk reduction are either on the basis of low-quality evidence from randomized controlled trials (RCTs) with insufficient power or inadequate follow-up time, observational studies, or evidence extrapolated from nontransplant populations. Few studies have effectively examined the role of conventional cardiovascular and kidney risk-factor management strategies and medical interventions in the transplant population (Table 1). Moreover, in the limited number of trials that have been completed, therapies reported to lower cardiovascular risk in the general and native CKD populations have not shown benefit in KT recipients. For example, statin therapy does not consistently reduce mortality in KT recipients. Similarly, a meta-analysis of eight trials of renin-angiotensin system blockade in KT recipients found that reninangiotensin system blockade did not significantly affect all-cause mortality, allograft loss, or creatinine level doubling, compared with control groups. Similar issues pertain to the care of KT recipients with new-onset PTDM. In the general population, there are established guidelines for the management of diabetes to reduce associated