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

Abstract

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 Table 1. - Existing evidence for management of cardiovascular risk in KT recipients (targets with proven benefit in the general population)a Cardiovascular Risk Factor Summary of Evidence in KT Recipients Study Design Number Follow-Up Time Positive Trial/Study Reference Dyslipidemia • ALERT Trial: fluvastatin versus placebo reduced LDL cholesterol, but not coronary intervention procedures or mortality. RCT 2102 5.1 years No Holdaas H, et al. Lancet 361: 2024–2031, 2003. • ALERT extension study: fluvastatin versus placebo with 2 additional years of follow-up showed a reduction in composite of cardiac death or nonfatal myocardial infarction (HR, 0.65; 95% CI, 0.48 to 0.88). RCT/follow-up 1652 6.7 years Yes Holdaas H, et al. Am J Trans- plant 5: 2929–2936, 2005. • FAVORIT trial: high-dose folic acid/B6/B12 versus placebo reduced homocysteine, but no improvement in composite of cardiovascular disease, all-cause mortality, or dialysis-dependent kidney failure. RCT 4110 4.0 years No Bostom AG, et al. Circulation. 2011;123(16):1763–1770 Post-transplant diabetes • No long-term prospective trials examining optimal glycemic targets. Cochrane Review 399 N/A N/A Clement L, et al. 2017 Feb; 2017(2): CD009966 Hypertension • Worse graft and patient survival with higher systolic blood pressures, but no long-term prospective trials examining optimal BP targets. Observational 815 120 months N/A Pagonas N, et al. Sci Rep 9: 10507, 2019. Observational 1666 9.4 years N/A Kasiske BL, et al. Am J Kidney Dis 43: 1071–1081, 2004 RAS blockade • Ramipril versus placebo: no reduction in composite of doubling serum creatinine, ESKD, or death. More adverse events in ramipril group. RCT 213 48 months No Knoll GA, et al. Lancet Diabetes Endocrinol. 2016;4(4):318–326 • SECRET trial: candesartan versus placebo no reduction in composite of all-cause mortality, cardiovascular morbidity and graft failure. RCT 502 20 months No Philipp T, et al. Nephrol Dial Transplant. 2010;25(3):967–976. • Losartan versus placebo: no reduction in composite of ESKD, death, or doubling of serum creatinine RCT 153 5 years No Ibrahim HN, et al. J AmSoc Nephrol.2013;24(2):320–327. • Meta-analysis of eight trials of RAS blockade versus placebo: no reduction in all-cause mortality, transplant failure, or doubling of serum creatinine Meta-Analysis 1502 1.5 years No Hiremath S, et al. Am J Kidney Dis. 2017;69(1):78–86 Anti-Platelet Therapy • Post-hoc analysis of FAVORIT trial: aspirin users versus nonusers no reduced risk for incident CVD, all-cause mortality, or kidney failure in patients with no history of CVD. Observational 1962 4 years No Dad T, et al. American Journal of Kidney Diseases. 2016;68(2): 277–28 SGLT-2i • Empagliflozin versus placebo in patients with post-transplant diabetes: reduction in HbA1c and body weight. Cardiovascular endpoints not examined. RCT 49 24 weeks N/A Halden TAS, et al. Diabetes Care 42: 1067–1074, 2019 Uptake of Therapies • Retrospective analysis of PORT study: Even in patients with a prior MI, <75% and 65% were receiving secondary prevention with an antiplatelet agent or a statin, respectively. Observational 14,236 N/A N/A Pilmore HL, et al. Transplantation. 2011;91(5):542–551. • Post-hoc analysis of FAVORIT trial: 69% were not meeting blood pressure targets, 18% had borderline or elevated LDL cholesterol (of which 60% were untreated), and 31% of patients with prevalent cardiovascular disease were not taking an anti-platelet agent. Observational 4107 N/A N/A Carpenter MA, et al. Clin Transplant. 2012;26(4):E438–446. ALERT, Assessment of LEscol in Renal Transplantation; HR, hazard ratio; 95% CI, 95% confidence interval; PORT, Patient Outcomes in Renal Transplantation; FAVORIT, Folic Acid for Vascular Outcome Reduction in Transplantation; RAS, renin-angiotensin system; HbA1c; hemoglobin A1c; MI, myocardial infarction; SECRET, Study on Evaluation of Candesartan Cilexetil after Renal Transplantation; RCT, randomized controlled trial.aA strategy for literature search in this field would include the following terms: kidney transplantation, death, mortality, and cardiovascular. 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. Table 2. - Potential future randomized controlled trials to examine management of cardiovascular risk in KT recipients (targets with proven benefit in the general population but clinical equipoise in the kidney transplant population) Cardiovascular Risk Factor Intervention Inclusion/Exclusion Criteriaa Safety Outcomesb Similar Trials and Results in the General Population/Non-KT Recipient Populations at Risk Notes Dyslipidemia • Lipid-lowering agent or combination agents versus placebo Inclusion• Recipients with and without diabetes• Intermediate-high CV risk Exclusion• Statin contraindication Safety outcomes:• Muscle weakness/pain• Myopathy• Rhabdomylosis• New onset diabetes HOPE-314• Significant reduction in CV events in the intermediate-risk non-KT recipient population without CV disease (rosuvastatin versus placebo). SHARP15• Significant reduction in major atherosclerotic events in the CKD population without CV disease (simvastatin + ezetimibe versus placebo). • The ALERT trial (fluvastatin versus placebo in KT recipients) was negative for the primary MACE end point, but showed a reduction in myocardial infarction and death with fluvastatin. ALERT included a relatively low-risk population with a mortality rate lower than expected; statistical power was thus lacking.• Although the HOPE-3 and SHARP trials included patients without CV disease, we propose including intermediate and high-risk patients to enrich the event rate and aid with statistical power given lessons from the ALERT trial. Diabetes • Standard glucose control versus intensive glucose control (HbA1c <6.5%) Inclusion• Type 2 diabetes Exclusion• Type 1 diabetes Safety Outcomes:• Severe hypoglycemia• Fluid retention• Weight gain >10kg ADVANCE16• Intensive glucose control reduced major macro and microvascular diabetic events, primarily driven by a reduction in nephropathy in the non-KT recipient population. • Importantly, in the ACCORD17 trial, intensive glucose control (HbA1c <6%) resulted in weight gain of >10kg from baseline and increased mortality compared with the standard therapy group (HbA1c 7%–7.9%). Hypertension • Systolic blood pressure target <120 mmHg versus <140 mmHg Inclusion• Recipients with and without diabetes Safety outcomes:• Hypotension• Injurious falls• Syncope• Electrolyte abnormalities• Acute kidney injury SPRINT18• Significant reduction in fatal and nonfatal major CV events and death with intensive blood pressure control shown in the non-KT recipient population. • The SPRINT trial excluded patients with diabetes given existing evidence in general diabetes populations. We propose stratifying randomization on the basis of diabetes status given the lack of evidence in people with functioning kidney transplants, in whom pathophysiological pathways may well differ from the general population. SGLT-2i • SGLT2 inhibition versus placebo Inclusion• eGFR ≥20• Recipients with and without diabetes Exclusion• Type 1 diabetes Safety outcomes:• Infection• Bone fracture• Diabetic ketoacidosis• Acute kidney injury• Acute rejection DAPA-CKD19• Significant reduction in cardio-renal events with SGLT-2i shown in the CKD population. CREDENCE20• Significant reduction in cardio-renal events with SGLT-2i shown in the DKD population. • Antifibrotic properties of SGLT-2i may have additional benefit in reducing transplant glomerulopathy. Nonsteroidal, selective mineralocorticoid receptor antagonists • Finerenone versus placebo Inclusion• Urinary ACR >30 mg/g• eGFR ≥25• Type 2 diabetes Exclusion• Type 1 diabetes Safety outcomes:• Hyperkalemia• Acute kidney injury FIDELIO-DKD21• Lower risk of CKD progression and CV events with finerenone in the general population with advanced baseline DKD. FIGARO-DKD22• Similar to FIDELIO except showed improvement in CV events with finerenone over a wider range of CKD (stage 2–4 and moderate albuminuria, or stage 1–2 with severe albuminuria). • The FIDELITY23 trial was a pooled analysis of FIDELIO and FIGARO and showed reduced risk of CV and kidney outcomes with Finerenone versus placebo across the spectrum of CKD in patients with type 2 diabetes.• A study of finerenone in KT recipients would likely include features of both FIDELIO and FIGARO. Glucagon-like peptide 1 analogs • GLP-1 receptor agonist versus placebo Inclusion• Type 2 diabetes• High CV risk Exclusion• Type 1 diabetes Safety outcomes:• Hypoglycemia• Acute gallstone disease• Injection site reaction• GI upset• Pancreatitis• Neoplasm LEADER, SUSTAIN-6 and REWIND, AWARD-7242526–27• Significant reduction in cardio-renal events with GLP-1 analogs added to usual care for type 2 diabetes shown in non-KTR with established CV disease or at high CV risk.• Kidney benefits most consistent in those with evidence of DKD at baseline. • Increased GI disturbance with GLP-1 agonists may be exaggerated in KT recipients.• LEADER showed a nonsignificant increase in pancreatic cancer with additional studies needed to assess longer-term exposure, especially in an immunosuppressed population at increased baseline malignancy risk. Dependent on funding to facilitate the necessary sample size and follow-up, the above proposed trials could be into an trial conducted with a study with of and study end In to the of a control the trial could for of interventions and features as intervention for interventions the kidney transplant Outcomes Study of and Renal ALERT, Assessment of LEscol in Renal Transplantation; major adverse cardiac hemoglobin A1c; in Diabetes and Vascular Disease: and to Cardiovascular Risk in Systolic Intervention and of Outcomes in Kidney and Renal in Diabetes with ratio; Finerenone in Kidney and in Diabetic Kidney Finerenone in Cardiovascular and in Diabetic Kidney glucagon-like peptide LEADER, and in Evaluation of Cardiovascular Outcome to Cardiovascular and Outcomes With in With Type 2 REWIND, Cardiovascular with a in versus in patients with type 2 diabetes and chronic kidney diabetic kidney angiotensin receptor studies include KT recipients months to years no for or therapy trial given equipoise in this population on an be in the 4 weeks studies patients months from a rejection cardiac or or with a in eGFR in the months proposed trials collaboration to facilitate and achieve sample studies examine the composite outcome of MACE (including myocardial infarction, other acute coronary heart failure, or death from cardiovascular a drop in or graft failure. the statistical power that have KT studies, RCTs in KT recipients collaboration and to achieve sample and the existing with funding and for trials in KT recipients, a would and may achieve targets. For example, a with of and study end would RCTs to be conducted with follow-up and event (e.g., of intensive glycemic and statin therapy Although the of a trial would be higher than an RCT for a a may and and facilitate funding this could be of patients than and studies with with severe CKD or dialysis with mortality than KT recipients) have been systematically excluded from most cardiovascular and when similarly to have a to standard risk therapies (e.g., statin therapy for patients on in the Kidney disease is a spectrum from CKD to to Improving cardiovascular outcomes for KT recipients across the spectrum of kidney disease, including those on the transplant these a survival only the to transplantation, with patients are fatal or transplant cardiac events, existing and or in to the in health and disease in immunosuppressed transplant recipients, extrapolation of results from nontransplant populations may be a therapies with a in other at-risk populations have to a benefit among KT recipients, or have not been of these therapies without clinical trial evidence likely in or there is potential for benefit the CVD risk with agents in other at-risk populations is demonstrated in KT recipients. KT recipients are included in prospective trials to reduce CVD events and mortality, the status not agents with benefit in other at-risk populations remain in high-risk KT recipients. Despite well over 1 prevalent KT recipients globally, the population to be to the of on the on for the development of therapies for larger at-risk populations. With the American Kidney there is an that transplantation rates the and in transplant the need for data and therapies for the care of these Evidence to reduce or premature death despite kidney function in the transplant population despite of and health care providers medical complications of as the research in the post-transplant We need a to for the transplant and funding patient and to research and in this to the survival of transplant recipients. We this be a In to the development of immunosuppressive therapies with and malignancy there is an need to strategies to the in KT recipients of therapies that have been shown to survival in other at-risk populations. may be RCTs in KT recipients as shown in Table or the and of evidence (including in the KT recipient population for into an in and receiving research funding from and receiving from and and other or as for receiving and from and receiving research from and receiving from and and being a or of and with receiving research funding from receiving from being a or of the for and and for by and and receiving funding from and receiving and from with being a for and the of an with only other in General and receiving research funding from National and National of Diabetes and and Kidney of and the of receiving from the American of and or from an or role with the American Journal and other or as Kidney Disease: Improving Global for the and and as a in for the receiving from and and receiving funding for clinical trials from and with and and an or role with and an in receiving research funding from the being a or of the American Journal of Kidney and Transplantation; and other as a United for Kidney on the for and and being a or as the in for the American Journal of receiving from and an or role with the American of and the Journal of the American of and receiving from and and from with and receiving research funding from the for and of and and receiving from and the and being a or of the Foundation and of with and receiving research funding from and receiving from and and being a or of Kidney Lancet Diabetes and is responsible for research that have received funding from and has received from and with or to the and being by a Development with and as and of research funding from Small as or site and from and or role with Vascular of the and of Journal of Vascular and other or - and and at of with Kidney receiving funding from being a of the for and receiving research funding from and Transplant receiving from and and with and other as the and Safety in of Transplant Recipients Review and the Transplantation a with receiving research funding from made to and receiving from and and an or role with and receiving a drug from for an study receiving funding from and and receiving from and the of all being to the have to

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