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Open Access

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

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 and Arthur Matas
JASN April 2022, 33 (4) 665-673; DOI: https://doi.org/10.1681/ASN.2021111517
Amanda J. Vinson
1Division of Nephrology, Department of Medicine, Nova Scotia Health Authority, Nova Scotia, Canada
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Sunita Singh
2Division of Nephrology, Department of Medicine, Ajmera Transplant Centre, Toronto, Canada
3Department of Medicine, University of Toronto, Toronto, Canada
4Division of Nephrology, Department of Medicine, Toronto General Hospital, University Health Network, Toronto, Canada
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Steven Chadban
5Division of Nephrology, Department of Medicine, Kidney Centre, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia
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David Cherney
3Department of Medicine, University of Toronto, Toronto, Canada
4Division of Nephrology, Department of Medicine, Toronto General Hospital, University Health Network, Toronto, Canada
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Osama Gaber
6Department of Surgery, Houston Methodist Hospital, Houston, Texas
7Department of Surgery, Weill Cornell Medicine, New York, New York
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John S. Gill
8Division of Nephrology, University of British Columbia, Vancouver, Canada
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Erika Helgeson
9Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota
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Charles A. Herzog
10Department of Medicine, Hennepin Healthcare/University of Minnesota, Minneapolis, Minnesota
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Meg Jardine
11Division of Nephrology, Department of Medicine, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia
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Vivekanand Jha
12Division of Nephrology, Department of Medicine, George Institute for Global Health, University of New South Wales, New Delhi, India
13Division of Nephrology, Department of Medicine, School of Public Health, Imperial College, London, United Kingdom
14Division of Nephrology, Department of Medicine, Manipal Academy of Higher Education, Manipal, India
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Bertram L. Kasiske
10Department of Medicine, Hennepin Healthcare/University of Minnesota, Minneapolis, Minnesota
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Roslyn B. Mannon
15Division of Nephology, University of Nebraska Medical Center, Omaha, Nebraska
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Erin D. Michos
16Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Amy K. Mottl
17Division of Nephrology, Department of Medicine, University of North Carolina Kidney Center, Chapel Hill, North Carolina
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Kristin Newby
19Division of Cardiology, Duke University School of Medicine, Durham, North Carolina
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Prabir Roy-Chaudhury
17Division of Nephrology, Department of Medicine, University of North Carolina Kidney Center, Chapel Hill, North Carolina
18Division of Nephrology, Department of Medicine, WG (Bill) Hefner Veterans Affairs Medical Center, Salisbury, North Carolina
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Deirdre Sawinski
20Nephrology and Transplantation, Weill Cornell Medical College, New York, New York
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Adnan Sharif
21Division of Nephrology, Department of Medicine, University Hospitals Birmingham, Birmingham, United Kingdom
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Vikas S. Sridhar
2Division of Nephrology, Department of Medicine, Ajmera Transplant Centre, Toronto, Canada
3Department of Medicine, University of Toronto, Toronto, Canada
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Katherine R. Tuttle
22Nephrology Division and Kidney Research Institute, University of Washington, Seattle, Washington
23Division of Nephrology, Department of Medicine, Providence Medical Research Center, Spokane, Washington
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David M. Vock
9Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota
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Arthur Matas
24Division of Transplantation, University of Minnesota, Minneapolis, Minnesota
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  • 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

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Table 1.

Existing evidence for management of cardiovascular risk in KT recipients (targets with proven benefit in the general population)a

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.

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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)

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.

Author Contributions

A. Vinson conceptualized the manuscript; A. Matas and A. Vinson wrote the original draft; and all authors reviewed and edited the manuscript.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • Copyright © 2022 by the American Society of Nephrology

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Journal of the American Society of Nephrology: 33 (4)
Journal of the American Society of Nephrology
Vol. 33, Issue 4
April 2022
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Premature Death in Kidney Transplant Recipients: The Time for Trials is Now
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Premature Death in Kidney Transplant Recipients: The Time for Trials is Now
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
JASN Apr 2022, 33 (4) 665-673; DOI: 10.1681/ASN.2021111517

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Premature Death in Kidney Transplant Recipients: The Time for Trials is Now
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
JASN Apr 2022, 33 (4) 665-673; DOI: 10.1681/ASN.2021111517
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  • Looking Upstream–The Role of Primary Care in Addressing US Race Inequities in Kidney Health
  • United States Renal Data System Spotlight on Racial and Ethnic Health Equity: Progress, but Much Remains to Discover, Understand, and Improve
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Keywords

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