Premature Death in Kidney Transplant Recipients: The Time for Trials is Now
Authors: Amanda J. Vinson, Sunita Singh, Steven Chadban, David Cherney, Osama Gaber, John S. Gill, Erika Helgeson, Charles A. Herzog, Meg Jardine, Vivekanand Jha, Bertram L. Kasiske, Roslyn B. Mannon, Erin D. Michos, Amy K. Mottl, Kristin Newby, Prabir Roy-Chaudhury, Deirdre Sawinski, Adnan Sharif, Vikas S. Sridhar, Katherine R. Tuttle, David M. Vock, Arthur Matas
Journal: Journal of the American Society of Nephrology (2022)

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 creatively combined into an adaptive platform trial conducted with a single study protocol, with harmonization of inclusion/exclusion criteria and study end points. In addition to the gained efficiency of having a single control group, the platform trial could allow for comparison of multiple interventions simultaneously, and adaptive features such as dropping intervention arms for futility and/or adding new interventions during the study. KTR, kidney transplant recipients; HOPE-3, Heart Outcomes Prevention Evaluation-3; SHARP, Study of Heart and Renal Protection; ALERT, Assessment of LEscol in Renal Transplantation; MACE, major adverse cardiac event; HbA1c, hemoglobin A1c; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ACCORD, Action to Control Cardiovascular Risk in Diabetes; SPRINT, Systolic Blood Pressure Intervention Trial; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; ACR, albumin-creatinine ratio; FIDELIO-DKD, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease; FIGARO-DKD, Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease; GLP-1, glucagon-like peptide 1; GI, gastrointestinal; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes; REWIND, Researching Cardiovascular Events with a Weekly Incretin in Diabetes; AWARD-7, Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease; DKD, diabetic kidney disease; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.aAll studies will include adult KT recipients 6 months to 15 years post-transplant, no requirement for ACEi or ARB therapy before any trial given equipoise in this population (but if on an ACEi/ARB, dosing must be stable in the 4 weeks before randomization). All studies will exclude patients <3 months from a rejection episode, cardiac event, or stroke, or with a rapid decline in eGFR in the 3 months before screening. All proposed trials will require multinational collaboration to facilitate multisite recruitment and achieve adequate sample sizes.bAll studies will examine the composite outcome of MACE (including myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes), a sustained ≥40% drop in eGFR, or graft failure. 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. Disclosures A. Gaber reports having an ownership interest in financials, technology, and oil companies; reports receiving research funding from Amplyx Therapeutics, Angion, CareDx, Hansa Biopharma Medior Therapeutics, Novartis, Sanofi, and Veloxis; reports receiving honoraria from Optum Health and Sanofi; and reports other interests or relationships as Chairman for Nora's Life Gift Foundation. A. K. Matas reports receiving honoraria and consulting fees from Bayer and Veloxis; reports receiving research support from Alexion, Aurinia, Boehringer Ingelheim, Calliditas, CareDX, CSL Behring, Pfizer, Shire, and Veloxis; reports receiving honoraria from Bayer and UpToDate; and reports being a scientific advisor or member of Bayer, CareDx, and Jazz. A. Sharif reports having consultancy agreements with Hansa Pharmaceuticals; reports receiving research funding from Chiesi Pharmaceuticals; reports receiving honoraria from Chiesi Pharmaceuticals; reports being a scientific advisor or member of the advisory board meetings for Atara Biotherapeutics, Boehringer Ingelheim/Lilly Alliance, and Novartis Pharmaceuticals; and reports speakers bureau for meetings/symposia hosted by Astellas, Chiesi, and Novartis; and reports receiving funding from Boehringer Ingelheim/Lilly and Napp Pharmaceuticals. A. Vinson reports receiving consultancy and fellowship fees from Paladin Labs Inc. C. Herzog reports employment with Hennepin Healthcare System, Inc.; reports being a consultant for AbbVie, Amgen, AstraZeneca, Bayer, Corvidia, DiaMedica, FibroGen, Janssen, Merck, NxStage, Pfizer, Relypsa, Sanifit, and the University of Oxford; reports having an ownership interest with stock only (no other ownership role) in Boston Scientific, Bristol-Meyers Squibb, General Electric, Johnson & Johnson, Merck, and Pfizer; reports receiving research funding from Amgen, AstraZeneca, Bristol-Meyers Squibb, National Heart, Lung, and Blood Institute (NHLBI)/ National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (National Institutes of Health [NIH]), Relypsa, and the University of British Columbia; reports receiving honoraria from the American College of Cardiology (non-profit) and UpToDate (writing royalties); reports patents or royalties from UpToDate; reports having an advisory or leadership role with the American Heart Journal Editorial Board; and reports having other interests or relationships as Kidney Disease: Improving Global Outcomes: Planning Committee Co-Chair for the "CKD, Heart, and Vasculature" conference series, and as a participant in various nephrology-related controversies conferences for the ASN (Kidney Health Initiative workgroups). D. Cherney reports receiving honoraria from AbbVie, Astellas, AstraZeneca, Bayer, BMS, Boehringer Ingelheim-Lilly, CSL-Behring, Janssen, J&J, Maze, Merck, Mitsubishi-Tanabe, Novo-Nordisk, Otsuka, Prometic, and Sanofi; and reports receiving operational funding for clinical trials from AstraZeneca, Boehringer Ingelheim-Lilly, Janssen, Merck, Novo-Nordisk, and Sanofi; reports consultancy with AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim-Lilly, CSL Pharma, Janssen, Maze, Merck, Mitsubishi-Tanabe, NovoNordisk, Prometic, and Sanofi; and reports an advisory or leadership role with AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, and Sanofi. D. Sawinski reports having an ownership interest in CareDx; reports receiving research funding from the NIH; reports being a scientific advisor or member of the American Journal of Kidney Diseases and Clinical Transplantation; and reports having other interests/relationships as a United Network for Organ Sharing Kidney Committee member. E. D. Michos reports serving on the advisory boards for AstraZeneca, Amarin, Bayer, Boehringer Ingelheim, Esperion, Novartis, and Novo Nordisk; and reports being a scientific advisor or member as the Editor in Chief for the American Journal of Preventive Cardiology. J. Gill reports receiving honoraria from Takeda and Veloxis; reports having an advisory or leadership role with the American Society of Transplantation, and the Journal of the American Society of Nephrology; and reports receiving consultancy fees from Astellas and Volexis, and grant support from Astellas. K. Newby reports having consultancy agreements with Beckman-Coulter, Better Therapeutics, GlaxoSmithKline, and Medtronic; reports receiving research funding from the BioKier, Center for Disease Control, NIH (NIA and NHLBI), North Carolina Department of Health and Human Services, and Roche Diagnostics; reports receiving honoraria from Oregon ACC and the NHLBI; and reports being a scientific advisor or member of the AstraZeneca Healthcare Foundation (Board, uncompensated), David H. Murdock Research Institute (Board, uncompensated), and NHLBI Board of External Experts. K. R. Tuttle reports having consultancy agreements with AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, and Novo Nordisk; reports receiving research funding from Bayer, Goldfinch Bio, and Travere; reports receiving honoraria from Bayer, Boehringer Ingelheim, Gilead, and Novo Nordisk; and reports being a scientific advisor or member of CJASN, Kidney Health Initiative, Lancet Diabetes Endocrinology, Nature Reviews Nephrology, and NIDDK. M. J. Jardine is responsible for research projects that have received funding from Amgen, Baxter, CSL, Dimerix, Eli Lilly, Gambro, and Merck Sharp & Dohme Corp; has received Advisory, Steering Committee and/or speaker fees from Akebia, Amgen, Astra Zeneca, Baxter, Bayer, Boehringer Ingelheim, Chinook, CSL, Janssen, Merck, MSD, PeerVoice, Roche, and Vifor; with any consultancy, honoraria, or travel support paid to the institution; and reports being supported by a Medical Research Future Fund Next Generation Clinical Researchers Program Career Development Fellowship. P. Roy-Chaudhury reports consultancy with WL Gore, Medtronic/Covidien, BD-Bard, Cormedix, Humacyte, Akebia, Vifor-Relypsa, Bayer, Reata, and InRegen; ownership interest as Chief Scientific Officer and Founder of Inovasc LLC; research funding from NIH Small Business Grants as MPI or site PI with: Inovasc, Adgero, Cylerus and Eko; honoraria from WL Gore, Medtronic/Covidien, BD-Bard, Cormedix, Humacyte, Akebia, Vifor-Relypsa, Bayer, Reata, Chugai Pharmaceuticals, and InRegen; advisory or leadership role with ASN, Cardiorenal Society, Vascular Access Society of the America's, WL Gore, Medtronic/Covidien, BD-Bard, Cormedix, Humacyte, Akebia, Vifor-Relypsa, Bayer, Reata, InRegen, and Editorial Board of Journal of Vascular Access; and other interests or relationships - discussions with: Vasbio, Elucid Bio, and Outset Medical, and Research Contract while at University of Arizona with Kidney Research Institute Seattle. R. B. Mannon reports receiving grant funding from Verici Diagnostic; reports being a member of the Steering Committees for CSL-Behring IMAGINE Trial and Verici Diagnostics VDX20-1001 Study; reports receiving research funding from Astellas, CareDx, CSL Behring, Mallinckrodt, Quark Pharmaceuticals, and Transplant Genomics, Inc.; reports receiving honoraria from CSL Behring, Hansa, Novartis, Sanofi, and Vitaerris; reports patents and inventions with Eurofins; and reports other interests/relationships as the ASN Grants committee Chair, ASN Policy and Advocacy Committee, Chair Data Safety Monitoring Board, Chair Women in Transplantation, Co-Chair Scientific Registry of Transplant Recipients Review Committee, NIDDK/NIH, and Program Committee the Transplantation Society 2020, 2022. S. J. Chadban reports having a consultancy with CSL; reports receiving research funding from Baxter payments made to hospital, CSL, and Novartis; reports receiving honoraria from AstraZeneca and Novartis; and reports having an advisory or leadership role with CSL and Novartis. S. K. Singh reports receiving a drug supply from AstraZeneca for an investigator-initiated study (NCT04965935). V. Jha reports receiving grant funding from Baxter Healthcare, Biocon, and GSK; and reports receiving honoraria from AstraZeneca, Baxter, Boehringer Ingelheim, NephroPlus, and Zydus Cadilla, under the policy of all honoraria being paid to the organization. All remaining authors have nothing to disclose. Funding None.