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

• mortality
• cardiovascular disease
• evidence
• death with graft function
• death despite kidney function
• kidney transplantation
• transplant recipients
• premature mortality

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.¹ 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.² 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.^1,3

Cardiovascular mortality is the leading cause of premature death despite kidney function.^3,4 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.³ CVD in KT recipients is partly due to traditional risk factors, including a high prevalence of diabetes, hypertension, obesity, pre-existing ischemic heart disease, prior smoking, systemic atherosclerosis, reduced kidney function, and albuminuria.^3,4 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.^3,4 Reduced allograft function is particularly critical, with a 15% increased CVD mortality risk for each 5 ml/min per 1.73m² drop below 45 ml/min per 1.73m².⁵ 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.⁶ Conventional risk prediction scores (e.g., the Framingham Risk Score) have been shown to greatly underestimate CVD risk in KT recipients,⁷ 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.⁸ Similarly, a meta-analysis of eight trials of renin-angiotensin system blockade in KT recipients found that renin-angiotensin system blockade did not significantly affect all-cause mortality, allograft loss, or creatinine level doubling, compared with control groups.⁹

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 cardiovascular and kidney risk. Development of PTDM is a risk factor for premature death despite kidney function, yet to date there have been no long-term prospective trials examining optimal drug therapies in the transplant population. Recommendations for the medical management of PTDM are largely speculative, on the basis of retrospective observational data or extrapolation from other populations. As a result, the 2020 Kidney Disease: Improving Global Outcomes Diabetes and CKD guidelines did not specify glycemic therapies, targets, or monitoring for PTDM, and instead provided only ungraded Practice Points on the basis of the general CKD population. The United Kingdom has recently published PTDM specific national guidelines; however, these are similarly largely derived from results of nontransplant data; nearly 50% of recommendations were on the basis of evidence graded as low quality.¹⁰

The lack of evidence for primary and secondary preventative strategies for CVD in KT recipients may explain the poor uptake of potential disease-modifying therapies in this population. A retrospective analysis of the Patient Outcomes in Renal Transplantation study demonstrated that among KT recipients with a prior myocardial infarction, <75% of recipients received secondary prevention with an antiplatelet agent, and only 65% with a statin. Similarly, baseline data from the Folic Acid for Vascular Outcome Reduction in Transplantation trial assessing risk factors for CVD and mortality in KT recipients showed that 69% of participants did not meet National Kidney Foundation blood pressure targets, 18% had borderline or elevated LDL cholesterol (of which 60% were untreated), and 31% of patients with prevalent CVD were not taking an antiplatelet agent.¹¹ An additional explanation for the poor uptake in KT recipients of therapies with proven benefit in the general population may be the lack of defined responsibility among health care providers managing transplant recipients. Transplant physicians are undoubtedly responsible for managing immunosuppression, rejection, and transplant-related infections, but is it the transplant physician, the general nephrologist, or the primary care provider whose focus should be on optimizing CVD risk factors and primary prevention? Without clearly defined roles in the health care team, and close collaboration and coordination, opportunities to apply what little evidence exists may go unheeded.

Despite being the leading cause of transplant failure, there have been few controlled studies primarily aiming to decrease the outcome of premature death despite kidney function. Furthermore, KT recipients are often systematically excluded from trials examining strategies to minimize the risk of adverse CVD outcomes. For example, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have revolutionized kidney and CVD risk reduction in people with CKD and heart failure, regardless of diabetes status.¹² Small case series of off-label use in KT recipients suggest efficacy, justifying larger trials; however, all major trials of SGLT2i to date have excluded transplant recipients. Similarly, trials of glucagon-like peptide-1 receptor antagonists, mineralocorticoid receptor antagonists, and angiotensin receptor-neprilysin inhibitors, all of which significantly reduce mortality or major adverse cardiac events in at-risk populations, have also systematically excluded KT recipients. Table 2 provides examples of potential RCTs of six agents with benefit in other populations that could be conducted in the KT population.

Given the statistical power limitations that have plagued earlier KT studies, RCTs in KT recipients will require multinational collaboration and multisite recruitment to achieve adequate sample sizes and optimize generalizability. Recognizing the existing difficulties with funding and recruitment for trials in KT recipients, a standing platform design would improve efficiency and may help achieve enrolment targets. For example, a single protocol with harmonization of inclusion/exclusion criteria and study end points would allow several distinct RCTs to be conducted simultaneously, with coordinated follow-up and event adjudication (e.g., evaluation of SGLT2i, intensive glycemic control, and statin therapy simultaneously). Although the cost of a platform trial would be higher than an RCT for a single intervention, a platform design may engage federal and foundation granting agencies, and facilitate funding through multiple concurrent industry partners. Ultimately, this could be less expensive, requiring recruitment of fewer patients overall than multiple separate and unrelated, parallel studies with potentially conflicting inclusion/exclusion criteria further challenging recruitment.

Patients with severe CKD or dialysis dependency (groups with even greater CVD-attributable mortality than KT recipients) have likewise been systematically excluded from most cardiovascular trials, and when included, similarly appear to have a blunted response to many standard risk modifying therapies (e.g., statin therapy for patients on hemodialysis in the AURORA trial). Kidney disease is a spectrum from CKD to ESKD to transplantation. Improving cardiovascular outcomes for KT recipients will require improvements across the entire spectrum of kidney disease, including those on the transplant waitlist. To ignore these subgroups will create a survival bias, whereby only the healthiest candidates will survive to transplantation, with many patients who are waitlisted experiencing fatal or transplant precluding cardiac events, further widening existing socioeconomic and racial or ethnic disparities in access to transplantation.

Given the mechanistic differences in health and disease in immunosuppressed transplant recipients, extrapolation of results from nontransplant populations may be a flawed approach. To date, many therapies with a positive effect in other at-risk populations have failed to yield a meaningful benefit among KT recipients, or have not been sufficiently studied.^8,9 Hence, introduction of these therapies without clinical trial evidence will likely result in uneven implementation, or possible harm. Likewise, there is unrealized potential for enormous benefit if the observed CVD risk mitigation with newer agents in other at-risk populations is demonstrated in KT recipients. Until KT recipients are included in prospective trials to reduce CVD events and mortality, the status quo will not change; agents with clear benefit in other at-risk populations will remain underutilized in high-risk KT recipients. Despite well over 1 million prevalent KT recipients globally, the population appears to be simply too small to command the interest of pharmaceutical companies focused on the return on investment for the development of therapies for larger at-risk populations.

With the Advancing American Kidney Health Initiative, there is an expectation that transplantation rates will rise, alongside the increasing age and comorbidity burden in waitlisted transplant candidates, emphasizing the need for new data and new therapies for the care of these complex patients. Evidence to reduce or prevent premature death despite kidney function in the transplant population remains lacking, despite >50% of patients, caregivers, researchers, and health care providers citing “long-term medical complications of transplantation” as the highest research priority in the post-transplant period.¹³ We therefore need a call to action for the entire transplant community, governmental and nongovernmental funding agencies, patient advocacy groups, federal agencies, and industry partners, to galvanize research and innovation in this area to improve the survival (especially cardiovascular) of transplant recipients. We believe this must be a two-pronged effort. In addition to the development of immunosuppressive therapies with improved cardiovascular, infectious, and malignancy profiles, there is an urgent need to develop strategies to determine the risk-benefit ratio in KT recipients of new cardiorenal preventive therapies that have been shown to improve survival in other at-risk populations. This may be through dedicated RCTs in KT recipients as shown in Table 2, or through the generation and assembly of real-world evidence (including pragmatic trials) in the KT recipient population for implementation into practice.

• Copyright © 2022 by the American Society of Nephrology