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Ethical Issues in Kidney Transplant and Donation during COVID-19 pandemic

Open AccessPublished:July 15, 2022DOI:https://doi.org/10.1016/j.semnephrol.2022.07.006

      ABSTRACT

      The Covid-19 pandemic caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) has faced the transplant community with unprecedented clinical challenges in a highly vulnerable patient category. These were associated with many uncertainties for patients and healthcare professionals and prompted many ethical debates regarding safe delivery of kidney transplantation. In this paper, we highlight some of the most important ethical questions that were raised during the pandemic and attempt to analyse ethical arguments in the light of core principles of medical ethics to either suspend or continue kidney transplantation, to mandate vaccination in transplant patients and transplant candidates, and finally healthcare providers. We have come up with frameworks to deal responsibly with these ethical challenges, and formulated recommendations to cope with the issues imposed on patients and transplant professionals.

      INTRODUCTION

      The Covid-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been causing disruptions of an unprecedented magnitude in clinical practice in all areas including organ transplantation. The public health emergency poses ethical challenges for organ donation and transplantation healthcare professionals.
      • Ibrahim B
      • Dawson R
      • Chandler JA
      • et al.
      The COVID-19 pandemic and organ donation and transplantation: ethical issues.
      As in other areas of healthcare, the crisis of Covid-19 calls into question how to maintain the welfare of patients based on the ethical principles of justice, autonomy, beneficence, non-maleficence and accountability.
      The objective of this article is to summarize ethical issues associated with kidney transplantation during the Covid-19 pandemic. An ethical framework to address different questions will be provided. Key issues for kidney transplantation during the time of Covid-19 include keeping kidney and kidney transplant patients safe, the need to ration scarce medical resources and make recommendations for suspending or continuing transplant activity, and recommendations towards advising or mandating vaccination.

      ETHICAL CHALLENGES

      The challenging issues of kidney transplant patients and those on the waiting list for kidney transplantation have surfaced since the first wave before availability of the COVID-19 vaccine but remain critical following the delta and omicron waves.
      Data from the Scientific Registry of Transplant Recipients (SRTR) have illustrated the magnitude of impact. During the early part of the pandemic, there was a 2.2-fold increase in mortality for patients on the kidney transplantation waitlist in the United States.
      • Boyarsky BJ
      • Werbel WA
      • Durand CM
      • et al.
      Early national and center-level changes to kidney transplantation in the United States during the COVID-19 epidemic.
      At the same time, total mortality rate observed in kidney transplant recipients during the Covid-19 era has also been shown to exceed the expected deaths by 1.4-fold according to the SRTR data.
      • Massie AB
      • Werbel WA
      • Avery RK
      • Chiang TP
      • Snyder JJ
      • Segev DL.
      Quantifying Excess Deaths Among Solid Organ Transplant Recipients in the COVID-19 Era.
      The ratio of observed to expected deaths varied substantially by race or ethnicity even within the national study of the United States, being highest (82% above expected) among Hispanic solid organ transplant recipients.
      • Massie AB
      • Werbel WA
      • Avery RK
      • Chiang TP
      • Snyder JJ
      • Segev DL.
      Quantifying Excess Deaths Among Solid Organ Transplant Recipients in the COVID-19 Era.
      Based on meta-analyses of observational studies, the 30-day mortality of Covid-19 was 19% among kidney transplant recipients.
      • Gatti M
      • Rinaldi M
      • Bussini L
      • et al.
      Clinical outcome in solid organ transplant recipients affected by COVID-19 compared to general population: a systematic review and meta-analysis.
      ,
      • Jayant K
      • Reccia I
      • Bachul PJ
      • et al.
      The Impact of COVID-19 on Kidney Transplant Recipients in Pre-Vaccination and Delta Strain Era: A Systematic Review and Meta-Analysis.
      There was a trend towards lower mortality with time, approaching 14%
      • Heldman MR
      • Kates OS
      • Safa K
      • et al.
      Changing trends in mortality among solid organ transplant recipients hospitalized for COVID-19 during the course of the pandemic.
      during the second half of 2020 and as low as 2%
      • Cochran W
      • Shah P
      • Barker L
      • et al.
      COVID-19 Clinical Outcomes in Solid Organ Transplant Recipients During the Omicron Surge.
      during the omicron surge in 2022. The mortality of kidney transplant recipients from Covid-19 in low- and middle-income countries, such as Latin America, was higher, ranging from 14.3 to 35.4%.
      • Cristelli MP
      • Viana LA
      • Tedesco-Silva H
      • Medina-Pestana J.
      COVID-19 Among Kidney Transplant Recipients: A Look Into Latin America.
      Although Covid-19 vaccines are effective in curtailing cases and reducing mortality, ethical challenges come from the issue of vaccine equity. In many low-resource countries, critical shortages of vaccine fell short of achieving herd immunity to allow preparedness for sustaining kidney transplantation activity, or even dialysis service. Such an ongoing mismatch between demand and supply of vaccines would likely cause controversy and divided opinion whether booster dosing should wait until global distribution of vaccines is better achieved.
      • Schaefer GO
      • Leland RJ
      • Emanuel EJ.
      Making Vaccines Available to Other Countries Before Offering Domestic Booster Vaccinations.

      Challenge 1: Should kidney transplantation be continued or suspended during the pandemic?

      Of note, the pandemic has imposed significant stress on healthcare systems, requiring a shift of resources to combat the infection and temporary cessation of elective clinical activities.
      • Wu K
      • Smith CR
      • Lembcke BT
      • Ferreira TBD.
      Elective Surgery during the Covid-19 Pandemic.
      A substantial reduction in organ donation and transplantation has been reported worldwide
      • Weiss MJ
      • Lalani J
      • Patriquin-Stoner C
      • et al.
      Summary of International Recommendations for Donation and Transplantation Programs During the Coronavirus Disease Pandemic.
      • Loupy A
      • Aubert O
      • Reese PP
      • Bastien O
      • Bayer F
      • Jacquelinet C
      Organ procurement and transplantation during the COVID-19 pandemic.
      • Boyarsky BJ
      • Po-Yu Chiang T
      • Werbel WA
      • et al.
      Early impact of COVID-19 on transplant center practices and policies in the United States.
      , and not necessarily restricted to regions with the highest infection rates. Based on a nationwide analysis in the United States, there was a reduction of over 50% in deceased donor transplantation since the Covid-19 outbreak, mostly driven by reduced kidney transplantation.
      • Loupy A
      • Aubert O
      • Reese PP
      • Bastien O
      • Bayer F
      • Jacquelinet C
      Organ procurement and transplantation during the COVID-19 pandemic.
      Another survey in the United States reported that 72% of transplant institutions had completely suspended living donor kidney transplantation in early 2020, where restrictions to deceased donor kidney transplantation was imposed in 84% of centers.
      • Boyarsky BJ
      • Po-Yu Chiang T
      • Werbel WA
      • et al.
      Early impact of COVID-19 on transplant center practices and policies in the United States.
      A decrease in kidney retrieval was also evident in regions with low caseloads, indicative of a global and nationwide effect beyond the local Covid-19 incidence and prevalence.
      • Loupy A
      • Aubert O
      • Reese PP
      • Bastien O
      • Bayer F
      • Jacquelinet C
      Organ procurement and transplantation during the COVID-19 pandemic.
      To quantify the impact of Covid-19 on solid organ transplantation, international data should be collected. The most comprehensive international data leverage on the transplant activity from 22 countries, starting from the onset of the 100th cumulative Covid-19 cases through to the end of 2020.
      • Aubert O
      • Yoo D
      • Zielinski D
      • et al.
      COVID-19 pandemic and worldwide organ transplantation: a population-based study.
      Despite variation between countries, the most pronounced reduction was in kidney transplantation, with an overall decrease of 19%. Deceased and living kidney donor transplantation was decreased by 12% and 40% respectively.
      • Aubert O
      • Yoo D
      • Zielinski D
      • et al.
      COVID-19 pandemic and worldwide organ transplantation: a population-based study.
      The trend of reduced transplantation after 2020, including burnout in transplant workforces and the impact of increase in incidence of infection in kidney transplant recipients secondary to omicron variant, remains to be evaluated and monitored.
      • Nimmo A
      • Gardiner D
      • Ushiro-Lumb I
      • Ravanan R
      • Forsythe JLR.
      The Global Impact of COVID-19 on Solid Organ Transplantation: Two Years Into a Pandemic.
      ,
      • Villanego F
      • Vigara LA
      • Alonso M
      • et al.
      Trends in COVID-19 Outcomes in Kidney Transplant Recipients During the Period of Omicron Variant Predominance.
      Deferring elective surgical or medical procedures during the Covid-19 crisis is justified ethically to protect patients and healthcare workers (non-maleficence and distributive justice as resources and staff were not available for elective and even many emergency services). There was an unknown risk in the beginning of Covid-19 infection (pre-vaccination era) for immunosuppressed patients. We cannot ascertain if Covid-19 could be transmitted from donors to recipients. The fact that many hospitals where overwhelmed and operation theatres were converted to intensive care unit beds has substantial consequences. Anaesthetists and many other specialists had been deployed to work in intensive care units, dialysis units or areas other than the transplant programme. This could have implications for decision to keep or suspend transplant programme, and in many cases dictated by hospital directors.
      The rationale underscores the need to balance individual patients’ need and that of the community (again distributive justice). We have a duty to the communities, hospital employees and patients, in addition to the responsibility to individual waitlisted kidney transplant candidates. It amounts to an estimation of the reserve of personal protective equipment (PPE) availability and the utilization of PPE for kidney transplantation surgery and perioperative transplant care. Other factors include the population density and incidence of Covid-19 cases in the community, hospital bed and ICU bed surge capacity, in addition to staffing availability. When high-filtration N-95 masks are in short supply, suspending elective surgery or endoscopy is considered more appropriate than contingency measures such as reusing masks or downgrading protective gear requirements. Blood product availability is not a major concern for kidney transplantation (but still needs to be reserved for every case even though there rarely is a need to transfuse), as opposed to liver transplantation. Although blood donation rate is expected to be reduced during a pandemic (due to fear of being infected while donating blood and restricted freedom of blood collection teams to attend public places
      • Chegini A.
      Evaluating the Importance of Patient Blood Management During COVID-19 Pandemic.
      ), the demand for blood products may well turn out to be lower as the number of trauma patients falls secondary to lockdown-related travel restrictions. The same applies to the consideration of ventilator capacity, which should not be too much affected by kidney transplantation; most kidney transplant recipients do not require ventilator support postoperatively, although we might argue that there should always be an intensive care bed for ventilation standby.
      To aid in the decision making as to whether deceased and living donor kidney transplantation should be deferred/suspended during a region or hospital's Covid-19 response, there are several consequences to be considered. The first and foremost factor is the patients who need and benefit from kidney transplantation. That ethical principle is to strike a balance between equity and clinical results. While ethical values might inform the choice, one should distinguish between the situations when the position of a center is at the peak of the incidence curve versus those at the downslope stage
      • Stock PG
      • Wall A
      • Gardner J
      • et al.
      Ethical Issues in the COVID Era: Doing the Right Thing Depends on Location, Resources, and Disease Burden.
      , and between the pre-vaccination and post-vaccination era. Transplant programs should definitely also include patient factors regarding clinical risk. The question to address, in other words, is whether – and how long – the end-stage kidney disease (ESKD) patients can wait without transplantation. The waitlisted kidney transplant patients’ views should be given a prominent place in the decision-making process, as we learned that communication with kidney transplant candidates is of the utmost importance.
      • Thind AK
      • Beckwith H
      • Dattani R
      • et al.
      Resuming Deceased Donor Kidney Transplantation in the COVID-19 Era: What Do Patients Want?.
      The majority of surveyed patients favor receiving a kidney transplant despite the ongoing COVID-19 pandemic. Reactivation of candidates on the waitlist cannot be assumed, however, and should take an individualized approach, incorporating clinical risk with patient perspectives.
      • Clarke C
      • Lucisano G
      • Prendecki M
      • et al.
      Informing the Risk of Kidney Transplantation Versus Remaining on the Waitlist in the Coronavirus Disease 2019 Era.
      Given the imbalance between supply and demand for medical resources, the pertinent question is not whether to set priorities, but how to do so ethically and consistently.
      • Emanuel EJ
      • Persad G
      • Upshur R
      • et al.
      Fair Allocation of Scarce Medical Resources in the Time of Covid-19.
      ,
      • Luyckx VA
      • Moosa MR.
      Priority Setting as an Ethical Imperative in Managing Global Dialysis Access and Improving Kidney Care.
      The need to be consistent by no means implies a fixed answer because the risk-benefit ratio can be highly dynamic during different stages of kidney disease and the varying Covid-19 incidence in the community and disease burden. The best framework for pandemic resource allocation during Covid-19 has been constructed by medical ethicists previously (Table 1). In essence, four fundamental pillars appear in the proposed ethical considerations: maximizing the benefits produced by scarce resources, treating people equally, promoting and rewarding instrumental value, and giving priority to the worst off.
      • Emanuel EJ
      • Persad G
      • Upshur R
      • et al.
      Fair Allocation of Scarce Medical Resources in the Time of Covid-19.
      ,
      • Persad G
      • Wertheimer A
      • Emanuel EJ.
      Principles for allocation of scarce medical interventions.
      Table 1Ethical framework for guiding kidney transplantation management during Covid-19 pandemic.
      Ethical Values and Guiding PrinciplesApplication to kidney transplantation and Covid-19 pandemic
      Maximize total benefits: Utilitarianism

      Save the most lives

      Save the most life-years – maximize prognosis


      Receives the highest priority

      Receives the highest priority
      Treat people equally: Egalitarianism

      First-come, first-served

      Random selection


      Should not be used

      Used for selecting transplant recipients with similar HLA matching to donor
      Promote and reward social usefulness (reciprocity or benefit to others)

      Retrospective – priority to those who have made relevant contributions



      Prospective – priority to those who are likely to make relevant contributions


      Gives priority to previous organ donors when other factors such as maximizing benefits are equal

      Gives priority to vaccinated patients when other factors such as maximizing benefits are equal
      Give priority to the worst off: Prioritarianism

      Sickest first

      Youngest first


      Used when it aligns with maximizing benefits

      Used when it aligns with maximizing benefits such as preventing spread of the virus
      Table reproduced with permission from xxx.21,22
      Intuitively, one of the reasons for kidney transplantation to be the most affected by Covid-19 pandemic among all solid organ transplantation, is the perceived effective alternative to transplantation for managing kidney failure. Although dialysis is perceived as a reasonable alternative, it is important to note that there is an exceptionally high SARS-CoV-2 infection attack rate (the proportion of patients who become infected) among hemodialysis patients.
      • Brown EA
      • Perl J.
      Increasing Peritoneal Dialysis Use in Response to the COVID-19 Pandemic: Will It Go Viral?.
      ,
      • Quintaliani G
      • Reboldi G
      • Di Napoli A
      • et al.
      Exposure to novel coronavirus in patients on renal replacement therapy during the exponential phase of COVID-19 pandemic: survey of the Italian Society of Nephrology.
      Owing to difficulty for dialysis patients to self-isolate and practical challenges of implementing social distancing in the dialysis units
      • Corbett RW
      • Blakey S
      • Nitsch D
      • et al.
      Epidemiology of COVID-19 in an Urban Dialysis Center.
      , hemodialysis patients are subjected to an exceptionally high likelihood of infection. Furthermore, urgency of kidney transplantation varies between patients. Many patients can afford to wait longer when transplantation has to be suspended, whereas less fortunate patients need a kidney transplant within a short time to survive. Examples are those who have limited access to dialysis, who have exhaustion or imminent lack of vascular access and either have absolute contraindications to or technique failure of peritoneal dialysis.
      • Veras de Sandes-Freitas T
      • Gomes Ramalho de Oliveira J
      • Loiola de Alencar Dantas G
      • Lobo Mesquita L
      • Barbosa de Almeida ER
      • de Matos Esmeraldo R
      Clinical Characteristics and Outcomes of Kidney Transplantation under Urgency Priority Condition.
      Highly sensitized patients with high percentage panel reactive antibodies and impending dialysis technique failure could also be given priority status for kidney transplantation. Adoption of a broad-brush approach stopping all kidney transplantation could have significantly disadvantaged these high-priority waitlisted transplant candidates who will have the lowest life expectancy in the absence of a kidney transplant. Instead, priority setting is a more reasonable approach, even though priority-setting also entails trade-offs to be made.
      • Luyckx VA
      • Moosa MR.
      Priority Setting as an Ethical Imperative in Managing Global Dialysis Access and Improving Kidney Care.
      While acknowledging that priority is inherently a value-laden process, we should make decisions on the premise that fair and transparent priority setting would address both population health needs and an individual patient's urgency. As outlined in Table 1, it is highly justified to give priority to maximizing the number of patients that survive treatment with a reasonable life expectancy
      • Emanuel EJ
      • Persad G
      • Upshur R
      • et al.
      Fair Allocation of Scarce Medical Resources in the Time of Covid-19.
      . If we simply consider “save the most lives,” we should always save five lives rather than one. However, prognosis allocation is relevant too. That means incorporating estimated life-years into benefit estimation. The concept or metric of life-years, as initially introduced as epidemiological and economic indicator of disease burden, is now often used by bioethicists to assign priority. In other words, we should not simply aim to save the most lives and should aim to save the most life-years. Although not all appear to champion life-year approach
      • Gaurke M
      • Prusak B
      • Jeong KY
      • Scire E
      • Sulmasy DP.
      Life-Years & Rationing in the Covid-19 Pandemic: A Critical Analysis.
      , this approach is receiving most support from prognosis-based allocation perspective. Based on the estimation of reduced transplant activity during the Covid-19 pandemic compared with 2019, it has translated into a negative effect of 37,664 life-years lost for patients waitlisted for kidney, much higher than 7370 life-years lost for patients waitlisted for liver.
      • Aubert O
      • Yoo D
      • Zielinski D
      • et al.
      COVID-19 pandemic and worldwide organ transplantation: a population-based study.
      There is a certain logic to have different policies for kidney transplantation programme suspension and resumption. Within the domain of kidney transplantation, most patients with ESKD can wait until an organ becomes available. However, some patients cannot wait too long. Live kidney donation can be rescheduled, whereas deceased donor kidneys will be wasted (as they will also likely not be retrieved, not just discarded) if transplant services are suspended. Should a deceased donor kidney be considered suitable for an immunologically high-risk patient awaiting transplant, that kidney could have been the one and only chance for this challenging cohort of often long-waiting patients. Outcome studies of highly sensitized kidney transplant candidates
      • Jackson KR
      • Holscher C
      • Motter JD
      • et al.
      Posttransplant Outcomes for cPRA-100% Recipients Under the New Kidney Allocation System.
      ,
      • Lim WH
      • Chapman JR
      • Wong G.
      Peak panel reactive antibody, cancer, graft, and patient outcomes in kidney transplant recipients.
      further argues for prioritizing the transplant for them despite the pressures of the Covid-19 pandemic. A key finding of safety in using lymphocyte-depleting agents (associated with decrease in rejection and without increase in mortality) even during the pandemic era
      • Bae S
      • McAdams-DeMarco MA
      • Massie AB
      • et al.
      Early Changes in Kidney Transplant Immunosuppression Regimens During the COVID-19 Pandemic.
      ,
      • Willicombe M
      • Gleeson S
      • Clarke C
      • et al.
      Identification of Patient Characteristics Associated With SARS-CoV-2 Infection and Outcome in Kidney Transplant Patients Using Serological Screening.
      supports the argument to prioritize highly sensitized transplant candidates. The policy of complete cessation of transplant surgery for highly sensitized patients would have precluded the precious chance of getting a compatible kidney; they may not get a chance to get another suitable offer. Consideration of relevant factors in deciding the policy should include the supply-to-demand gap of organs. That means we should evaluate the impact of stopping kidney donation and transplantation. When stratifying urgency of resuming transplantation, it is reasonable to give higher priority to regions with lower organ donation rate.
      In the face of ethical dilemmas surrounding decision conundrums regarding deferring versus maintaining transplantation, a simulation of the outcomes using a Markov decision process model and probabilities can give additional information. That means an estimation of risk and benefit for different phenotype patients in different geographies, the latter referring to Covid-19 acquisition risks and case fatality rates. Besides the characteristics of the pandemic, the length of delay should be factored in, because the length of the pandemic could influence the waitlist and post-transplant mortality. According to simulation calculator developed for this purpose (http://www.transplantmodels.com/covid_sim), the best immediate survival benefits of kidney transplantation occur in areas where the case fatality rate from Covid-19 among the general population is low. On the other hand, kidney transplantation will result in harm only when case fatality rates are substantially higher for kidney transplant recipients (such as 50% or greater) than for waitlist patients (e.g. 30% or lower), and when the community risk of Covid-19 acquisition is medium or high.
      • Massie AB
      • Boyarsky BJ
      • Werbel WA
      • et al.
      Identifying scenarios of benefit or harm from kidney transplantation during the COVID-19 pandemic: A stochastic simulation and machine learning study.
      When the survival probability is assessed for waitlist patients, we have to also consider the survival benefit for patients receiving home dialysis.
      • Cozzolino M
      • Conte F
      • Zappulo F
      • et al.
      COVID-19 pandemic era: is it time to promote home dialysis and peritoneal dialysis?.
      ,
      • Li PK
      • Lu W
      • Mak SK
      • et al.
      Peritoneal Dialysis First Policy in Hong Kong for 35 years: Global impact.
      Increasingly concerned that patient autonomy should be respected, surveys should be conducted to assess transplant waitlisted patients’ attitudes and concerns toward transplantation during different periods of Covid-19. During the peak of Covid-19 and before availability of vaccination in Singapore, when safe distancing measures were strictly enforced and activities around the country were limited to essential activities only, a standardized telephone survey of patients awaiting transplant was conducted.
      • Tan EK
      • Koh YX
      • Kee T
      • et al.
      Waitlisted Transplant Candidates' Attitudes and Concerns Toward Transplantation During COVID-19.
      Nearly half of the respondents were waiting for kidney transplant. While most patients had initially responded that transplantation services should continue despite Covid-19, the opinion changed after the series of questions designed to introduce thoughts on the risk of infection to a transplanted patient. Careful consideration on the pre- and post-transplant care and the potential harm from donor-derived infection had influenced the willingness of patients to proceed with transplantation; the proportion of patients keen to proceed decreased by half.
      • Tan EK
      • Koh YX
      • Kee T
      • et al.
      Waitlisted Transplant Candidates' Attitudes and Concerns Toward Transplantation During COVID-19.
      A similar survey conducted in the United Kingdom, also before the era of SARS-CoV-2 vaccine, showed that the majority of kidney transplant candidates would like to be reactivated immediately on the transplant waitlist when transplant activity is resumed.
      • Thind AK
      • Beckwith H
      • Dattani R
      • et al.
      Resuming Deceased Donor Kidney Transplantation in the COVID-19 Era: What Do Patients Want?.
      Ideally, centers should decide the pragmatism and prioritising of living versus deceased donor transplantaion.
      • Stock PG
      • Wall A
      • Gardner J
      • et al.
      Ethical Issues in the COVID Era: Doing the Right Thing Depends on Location, Resources, and Disease Burden.
      Some transplant centers tend to defer deceased donor transplantation because the hospitalisation tends to be lengthier than for living donor transplant patients, and even more so if extended criteria donor kidneys are accepted. Resource utilisation and demands for deceased donor kidney transplant are also of concern when the recipient hospitals are heavily affected by the shortage of manpower including nursing staff, PPE, bed and testing capacity. Key consideration for proceeding with living donor kidney transplantation is particularly relevant in regions where dialysis capacity is constrained or not affordable.
      • Kulkarni S
      • Flescher A
      • Ahmad M
      • et al.
      Ethical analysis examining the prioritisation of living donor transplantation in times of healthcare rationing.
      Last but not least, we need to consider the ethical principle of accountability and safety of healthcare professionals, in addition to the benefit to the society and the transplant candidates. Even when a waitlisted candidate accepts the risk of infection and transplant, we have to be considerate of the risk for the medical team. This is even more relevant in the situations when PPE shortage occurs and the lack of resources to have universal screening.
      • Spoletini G
      • Bianco G
      • Graceffa D
      • Lai Q.
      Transplantation during the COVID-19 pandemic: nothing noble is accomplished without danger.
      Under such constraints, the rate of contagion among health-workers has been reported to increase, leading to a vicious circle of in-hospital nosocomial spread to patients and staff.
      • Spoletini G
      • Bianco G
      • Graceffa D
      • Lai Q.
      Transplantation during the COVID-19 pandemic: nothing noble is accomplished without danger.
      All in all, the ethical considerations would favour a “phased approach” rather than “all-or-none” approach.
      • Kumar D
      • Manuel O
      • Natori Y
      • et al.
      COVID-19: A global transplant perspective on successfully navigating a pandemic.
      That could either be a stepwise decreasing or stepwise ramping up transplant activity according to (clinical) risk assessments (Table 2). The varying degrees of reduction would therefore depend on risk stratification, namely, resource availability and medical urgency (Figure 1). In the United Kingdom, NHS Blood and Transplant has supported organ donation and transplantation with up-to-date national guidance and data collection.
      Table 2One of the proposed frameworks for phased approach to kidney transplantation activity during Covid-19 pandemic.
      Kidney transplant activity levelPriority level descriptionExamples (include but not limited to)
      25% reduction in transplant activityElective cases: patients whose conditions is not life threatening or can be managed with dialysis and for whom services can be deferred until the end of a pandemic wave (around 6 to 8 weeks)No living donor activity

      Deceased donor activity allowed
      50% reduction in transplant activityUrgent cases: patients who are deemed urgent and who need service within 14 days

      Services can be deferred for a few days, but not for the length of a pandemic wave
      No activity except highly sensitized cases (such as panel reactive antibody of 95% or above with suitable donor offer and negative donor specific antibody)
      75% reduction in transplant activityEmergency cases: patients who are deemed critical, whose condition is immediately life-threateningNo activity unless for medically urgent status (such as lack of dialysis access, uraemic cardiomyopathy)

      Combined kidney-pancreas transplant is not suggested
      100% reduction in transplant activity

      Health system is overwhelmed with Covid-19

      No intensive care unit or other capacity available

      Severe shortage of health personnel
      Complete cessation of all living and deceased donor transplant activity
      Table reproduced with permission from xxx.39
      Figure 1
      Figure 1Schematic diagram of factors in favor or against of maintaining kidney transplantation during Covid-19 pandemic.

      Challenge 2: Should vaccination of kidney transplant candidates be mandatory during pandemic?

      The concern about pandemic spread and transmission risk from donor to recipient and nosocomial transmission has been calling into question whether or not mandating Covid-19 vaccination was justified. Are there ethical, legal and scientific reasons for mandatory vaccination before candidates can be waitlisted or accepted for kidney transplantation? One important factor that should caution the decision is that vaccine-hesitant populations are often hard hit by Covid-19 itself in terms of ethnicity, socio-economic background and comorbidities, and in other words, a vulnerable group. By mandating vaccines, we would have fueled an act of discrimination.
      Before the spread of the delta variant of SARS-CoV-2, there have been optimistic indications that vaccines could eliminate transmission of the virus. With more data and experience with the vaccine efficacy especially in kidney patients and transplant patients, as well as the parade of variants, their transmissibility and antigenic changes affecting protection by vaccination, the vaccination landscape has changed. It is now believed that SARS-CoV-2 vaccines should be relied to prevent symptomatic infection, reduce Covid-19-associated morbidity and mortality, rather than a panacea.
      • Monto AS.
      The Future of SARS-CoV-2 Vaccination - Lessons from Influenza.
      As compared with previous variants, omicron variant demonstrates substantial immune-evasion capability, and more so among kidney transplant recipients.
      • Karaba AH
      • Johnston TS
      • Aytenfisu TY
      • et al.
      A Fourth Dose of COVID-19 Vaccine Does Not Induce Neutralization of the Omicron Variant Among Solid Organ Transplant Recipients With Suboptimal Vaccine Response.
      That being said, vaccination can still provide reasonably satisfactory reduction in viral shedding and infectivity, especially in vulnerable population in hospitals
      • Regev-Yochay G
      • Amit S
      • Bergwerk M
      • et al.
      Decreased infectivity following BNT162b2 vaccination: A prospective cohort study in Israel.
      and elderly care facilities.
      • Sasanami M
      • Kayano T
      • Nishiura H.
      The number of COVID-19 clusters in healthcare and elderly care facilities averted by vaccination of healthcare workers in Japan, February-June 2021.
      ,
      • McGarry BE
      • Barnett ML
      • Grabowski DC
      • Gandhi AD.
      Nursing Home Staff Vaccination and Covid-19 Outcomes.
      For the sake of protecting transplant candidates from Covid-19 infection, vaccinations should preferably be administered before transplantation. To draw the analogy with seasonal influenza vaccination, vaccination before kidney transplantation would confer better protection to patients than those who do not receive vaccine (or defer until after transplantation). The same phenomenon is even more pronounced for humoral response to SARS-CoV-2 vaccine.
      • Prendecki M
      • Thomson T
      • Clarke CL
      • et al.
      Immunological responses to SARS-CoV-2 vaccines in kidney transplant recipients.
      Pooled estimate of antibody response after two doses of mRNA vaccines was 35% for transplant recipients, much lower than that of 89% for dialysis patients.
      • Carr EJ
      • Kronbichler A
      • Graham-Brown M
      • et al.
      Review of Early Immune Response to SARS-CoV-2 Vaccination Among Patients With CKD.
      A detailed ethical framework to argue for or against mandating vaccination in kidney patients prior to activation or reactivation on transplant waiting list has previously been published (Table 3).
      • Gokmen R
      • Cronin A
      • Brown W
      • et al.
      Kidney transplantation and patients who decline SARS-CoV-2 vaccination: an ethical framework.
      ,
      • Hurst DJ
      • Potter J
      • Padilla LA.
      Organ transplant and Covid-19 vaccination: Considering the ethics of denying transplant to unvaccinated patients.
      One of the arguments against mandating vaccination is the uncertain vaccine efficacy, especially in transplant candidates or transplant recipients on immunosuppression.
      • Gokmen R
      • Cronin A
      • Brown W
      • et al.
      Kidney transplantation and patients who decline SARS-CoV-2 vaccination: an ethical framework.
      On the other hand, this is exactly the reason to strongly recommend for vaccination before and not after kidney transplantation, in order to ensure the optimal protection. Registry data have suggested reduced mortality risk from Covid-19 infection for vaccinated kidney transplant recipients when compared to unvaccinated patients.
      • Ravanan R
      • Mumford L
      • Ushiro-Lumb I
      • et al.
      Two Doses of SARS-CoV-2 Vaccines Reduce Risk of Death Due to COVID-19 in Solid Organ Transplant Recipients: Preliminary Outcomes From a UK Registry Linkage Analysis.
      ,
      • Callaghan CJ
      • Mumford L
      • Curtis RMK
      • et al.
      Real-world Effectiveness of the Pfizer-BioNTech BNT162b2 and Oxford-AstraZeneca ChAdOx1-S Vaccines Against SARS-CoV-2 in Solid Organ and Islet Transplant Recipients.
      Furthermore, the protection conferred by vaccination among transplant candidates and recipients can be enhanced by accelerated or fourth booster doses messenger RNA vaccines
      • Benotmane I
      • Bruel T
      • Planas D
      • Fafi-Kremer S
      • Schwartz O
      • Caillard S.
      A fourth dose of the mRNA-1273 SARS-CoV-2 vaccine improves serum neutralization against the Delta variant in kidney transplant recipients.
      ,
      • Caillard S
      • Thaunat O
      • Benotmane I
      • Masset C
      • Blancho G.
      Antibody Response to a Fourth Messenger RNA COVID-19 Vaccine Dose in Kidney Transplant Recipients: A Case Series.
      , even the fifth dose
      • Abedon AT
      • Teles MS
      • Alejo JL
      • et al.
      Improved Antibody Response After a Fifth Dose of a SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case Series.
      , and ring vaccination
      • Perkins GB
      • Tunbridge M
      • Salehi T
      • et al.
      Concurrent vaccination of kidney transplant recipients and close household cohabitants against COVID-19.
      (priority and booster dosing of close household contacts of kidney transplant recipients).
      Table 3Ethical arguments for or against mandatory vaccination before transplant waitlisting.
      Arguments for mandating vaccination in transplant waitlisted candidatesArguments against mandating vaccination in transplant waitlisted candidates
      Duty to protect patients: first do no harm

      High mortality of Covid-19 in transplant recipients

      Additional risk of mortality in immediate post-transplant period
      Autonomy and human rights

      Respect patient decision

      Clear difference between vaccination passport for tourism and access to life-saving transplantation

      Unfairness to less educated or health illiterate populations who are more likely to be misinformed by “fake news”
      Potential harm to others

      Ensure safety of others and the hospital as a whole
      Equity of access

      Damage to trust in medical profession
      Inappropriate use of a scarce resource

      Maximize the benefit derived from the scarce resource of donated organs

      Damage to public perceptions of organ donation
      Practical uncertainties

      Efficacy of SARS-CoV-2 vaccine

      Uncertain efficacy to limit infectivity and virus transmission, especially new virus variants
      Possible precedents

      Predicating transplantation listing on aspects of patient choice or behavior such as abstinence from alcohol for liver transplant

      Poor compliance behaviour before transplantation as a predictor for non-adherence after kidney transplant
      Table reproduced with permission from xxx.47,48
      The controversy of vaccine mandate
      • Ladin K
      • Flescher AM
      • Reese PP.
      Vaccine Mandates for Transplant Patients: Caring for Patients Versus Turning Them Away.
      ,
      • Ross LF.
      COVID-19 Vaccine Refusal and Organ Transplantation.
      has been shown in an electronic survey of 141 transplant centers in the United States
      • Hippen BE
      • Axelrod DA
      • Maher K
      • et al.
      Survey of current transplant center practices regarding COVID-19 vaccine mandates in the United States.
      , where mandatory vaccination before solid organ transplant was implemented only in 36% of the centers. The most commonly cited justifications for a mandate included stewardship (64%), public health obligations (52%), and desire to reduce transmission risks to healthcare personnel (40%), other patients, and family members (40%).
      • Hippen BE
      • Axelrod DA
      • Maher K
      • et al.
      Survey of current transplant center practices regarding COVID-19 vaccine mandates in the United States.
      Almost none of the centers required clinical evidence demonstrating vaccine responsiveness such as measurement of anti-SARS-CoV-2 spike protein antibodies (which are not universally available and not easy to interpret). To a certain extent, these results suggest that the predominant view is strong recommendation of vaccination as opposed to a mandatory policy. Most bioethicists oppose to mandatory vaccination as eligibility for transplant waitlisting
      • Ross LF
      • Opel DJ.
      The case against COVID-19 vaccine mandates in pediatric solid organ transplantation.
      ; this is to uphold patient autonomy and avoid forced medical treatment. To align with the principle of informed consent, waitlisted transplant candidates should be allowed time and room for decision, even when the current evidence favours vaccination. There is no doubt that when mentally competent patients decline to receive vaccine, compulsory vaccination before allowing kidney transplant violates the principle of autonomy. Although vaccination is in line with the principle of beneficence, denying transplantation has been considered to be in conflict with the principle of non-maleficence toward an individual transplant candidate who does not want to receive vaccination.
      • Kates OS
      • Diekema DS
      • Blumberg EA.
      Should Health Care Institutions Mandate SARS-CoV-2 Vaccination for Staff?.
      Respect for autonomy requires holding patients responsible for the consequences of their conscientious choice, which occasionally conflicts with other important ethical principles such as public interest and other patients’ safety concerns. The imperative to respect a transplant candidate's right of informed consent, however, is not necessarily violating the public interest. In fact, patients can opt for regular surveillance to be allowed hospitalisation for transplant surgery. Part of the problem for this argument justifying equal candidacy for organ transplantation irrespective of the SARS-CoV-2 vaccination status, of course, is the lack of evidence to support that regular surveillance can mitigate risk of infection to the hospital. Because the level of protection and optimal frequency of surveillance remains unknown, vaccination remains the safest and primary strategy to prevent SARS-CoV-2 (poor clinical outcomes of) infections from the patients awaiting transplantation.
      • Leon TM
      • Dorabawila V
      • Nelson L
      • et al.
      COVID-19 Cases and Hospitalizations by COVID-19 Vaccination Status and Previous COVID-19 Diagnosis - California and New York, May-November 2021.
      In that case, respecting the personal choice to forego vaccination could have violated the principle of non-maleficence because of the potential harm to the other patients.
      • Kuczewski M
      • Wasson K
      • Hutchison PJ
      • Dilling DF.
      Putting ethics and clinical decision making before politics: requiring COVID-19 immunization for Solid Organ Transplantation (SOT) Candidates and their Support Team.
      To turn the decision making from transplant centers to a transplant candidate: should he or she decline a kidney transplant offer and delay the transplantation in order to allow time for pre-transplant vaccination optimization? A similar strategy of deferring rituximab B-cell depletion therapy for 4 weeks after SARS-CoV-2 vaccination has been proposed.
      • Soy M
      • Keser G
      • Atagunduz P
      • et al.
      A practical approach for vaccinations including COVID-19 in autoimmune/autoinflammatory rheumatic diseases: a non-systematic review.
      As opposed to drug therapy, a kidney transplantation will be more complicated. To assess the benefit or harm of delays in transplantation to facilitate pre-transplant vaccination, a Markov microsimulation model has been created.
      • Yanev I
      • Gagnon M
      • Cheng MP
      • et al.
      Kidney Transplantation in Times of Covid-19: Decision Analysis in the Canadian Context.
      In general, scenario analysis suggested a benefit to short delays in deceased donor transplants to receive the SARS-CoV-2 vaccine in waitlisted patients older than 55 years. In fact, delaying transplants for 6 months before living donor transplant is estimated to yield effectiveness of 22.83 quality-adjusted life years (QALYS).
      • Yanev I
      • Gagnon M
      • Cheng MP
      • et al.
      Kidney Transplantation in Times of Covid-19: Decision Analysis in the Canadian Context.
      However, caution should be exercised when delay to access of transplantation is expected to exceed 3 years (as in the case for deceased donor transplantation), or with high Kidney Donor Risk Index of the eventual deceased donor transplantation.
      • Yanev I
      • Gagnon M
      • Cheng MP
      • et al.
      Kidney Transplantation in Times of Covid-19: Decision Analysis in the Canadian Context.
      Notably, this Markov model
      • Yanev I
      • Gagnon M
      • Cheng MP
      • et al.
      Kidney Transplantation in Times of Covid-19: Decision Analysis in the Canadian Context.
      included unadjusted probability of Covid-19 deaths (when the probability of dying from Covid-19 is more than two times higher in transplant recipients compared to dialysis patients). Another major criticism for the study is the (inappropriate) assumption that the probability of Covid-19 death in transplant recipients does not change according to vaccination status. In other words, the model could have underestimated the mortality in non-vaccinated transplant recipients.
      Another argument against a vaccine mandate for kidney transplant candidates, as a result of recent drug development, is the emergence of therapeutic monoclonal antibodies. The current monoclonal antibodies (casirivimab and imdevimab, cilgavimab and tixagevimab), however, have limited neutralizing activity against BA.1 and BA.2 omicron variants after administration to immunocompromised patients.
      • Bruel T
      • Hadjadj J
      • Maes P
      • et al.
      Serum neutralization of SARS-CoV-2 Omicron sublineages BA.1 and BA.2 in patients receiving monoclonal antibodies.
      Based on the suboptimal protection to protect kidney transplant recipients against infection, the arguments of moving from vaccine to monoclonal antibody as pre-exposure prophylaxis remain speculative. Regarding the use of monoclonal antibody such as cilgavimab and tixagevimab, another ethical issue would be the controversy of granting these drugs for transplant candidates who decline vaccination. Policy makers, transplant pharmacists and doctors need to make decisions concerning the appropriate prevention measures. In other words, should transplant candidates get priority for the monoclonal antibody treatment if they decline SARS-CoV-2 vaccines? To address this issue, consideration should be given to the supply of monoclonal antibodies, effectiveness of the monoclonal antibodies for the predominant variants circulating in the community, immune response of the patients to vaccines. From the standpoint of distributive justice, the weight assigned to the fair distribution of monoclonal antibodies to transplant candidates should be given due consideration of the inequalities that have already existed among this cohort of patients who have higher infection rates, higher mortality, and less access to the healthcare. According to the National Institutes of Health guidelines in the United States, however, the monoclonal antibodies should not be considered a substitute for Covid-19 vaccination and, in particular, should not be used in unvaccinated individuals in whom Covid-19 vaccination is recommended and who are anticipated to have an adequate response. On the other hand, many transplant candidates face significant emotional and existential threats; emotional support and dedicated pre-transplant patient education are fundamental to prepare and equip them with knowledge.
      • Hamid M
      • Rogers E
      • Chawla G
      • Gill J
      • Macanovic S
      • Mucsi I.
      Pretransplant Patient Education in Solid-organ Transplant: A Narrative Review.
      One ultimate and useful solution would be moving away from the language of mandated treatments and, instead, aiming to assess the risks and benefits on an individual basis.
      • Gokmen R
      • Cronin A
      • Brown W
      • et al.
      Kidney transplantation and patients who decline SARS-CoV-2 vaccination: an ethical framework.
      That would entail exploration and understanding the reasons behind any transplant candidates’ vaccine hesitancy. Vaccine acceptance has been found to decrease with financial hardship, lower age and education, and among those with suspected past Covid-19 infection.
      • Stead M
      • Jessop C
      • Angus K
      • et al.
      National survey of attitudes towards and intentions to vaccinate against COVID-19: implications for communications.
      Rather than a blanket policy of mandatory vaccination, doctors and transplant healthcare workers should aim to encourage, and not enforce vaccination. In tandem with respect for autonomy, mutual trust plays a key role in doctor-patient relationship, and more so in long term dialysis or transplant care. A growing body of literature suggests that one of the most effective means of communicating vaccine information to parents is through sharing anecdotes and nudging, in contrast to coercion.
      • Renosa MDC
      • Landicho J
      • Wachinger J
      • et al.
      Nudging toward vaccination: a systematic review.
      ,
      • Benecke O
      • DeYoung SE.
      Anti-Vaccine Decision-Making and Measles Resurgence in the United States.
      A more caring approach has been proposed. The approach, called patient-centered trauma-informed (PTCI) approach
      • Ladin K
      • Flescher AM
      • Reese PP.
      Vaccine Mandates for Transplant Patients: Caring for Patients Versus Turning Them Away.
      , refers to the need to acknowledge patient's past trauma and its impact on patient interactions and treatment decision-making. Instead of informing patients in terse letters that they were ineligible to receive kidney transplant until getting vaccinated, PTCI calls for compassion, trustworthiness, collaboration and dignity.
      • Ladin K
      • Flescher AM
      • Reese PP.
      Vaccine Mandates for Transplant Patients: Caring for Patients Versus Turning Them Away.
      As such, transplant healthcare workers and health authorities should work to improve health literacy of kidney transplant candidates, and should listen actively to patients regarding their concerns and vaccine hesitancy.
      • Dettori M
      • Arghittu A
      • Castiglia P.
      Knowledge and Behaviours towards Immunisation Programmes: Vaccine Hesitancy during the COVID-19 Pandemic Era.
      The bottom line is for the patients to meet trained clinicians and discuss their concerns. Other measures of protecting against infection, including proper hygiene and social distancing, should also be encouraged.

      Challenge 3: Should vaccination of transplant healthcare workers be mandatory during pandemic?

      The issue of mandating Covid-19 vaccination is less controversial for healthcare workers than patients, although such policy could have been in tension with the healthcare workers’ autonomy.
      • Kates OS
      • Stock PG
      • Ison MG
      • et al.
      Ethical review of COVID-19 vaccination requirements for transplant center staff and patients.
      As previously signed by more than 80 organizations, a joint statement representing physicians, nurses, pharmacists, physician assistants, nurse practitioners, epidemiologists, public health workers and long-term care workers, has called for universal vaccination of health workers.
      • Emanuel EJ
      • Skorton DJ.
      Mandating COVID-19 Vaccination for Health Care Workers.
      The rationale for such mandate is based on three important reasons.
      • Emanuel EJ
      • Skorton DJ.
      Mandating COVID-19 Vaccination for Health Care Workers.
      ,
      • Klompas M
      • Pearson M
      • Morris C.
      The Case for Mandating COVID-19 Vaccines for Health Care Workers.
      First, that is considered a general ethical duty of healthcare workers to protect others. Second, getting vaccinated is considered a special duty to achieve professional objective and be committed to putting patients first. Mandating health workers to have vaccine, in short, implies a policy of mandatory assignment to different tasks within the hospital. Whether it is ethically acceptable to dismiss the health workers because they refuse vaccination is another issue. Third, this is not new but an extension of well-established and historical practices such as getting vaccinated against influenza, hepatitis B and other infectious diseases. Indeed, large-scale longitudinal analysis of national data over 23 years has recently showed that state laws promoting influenza vaccination for hospital workers were associated with reductions in annual pneumonia and influenza mortality by 1.92 deaths per 100,000 persons in the general population.
      • Carrera M
      • Lawler EC
      • White C.
      Population Mortality and Laws Encouraging Influenza Vaccination for Hospital Workers.
      The magnitude of population mortality reduction was especially obvious among elderly persons. Mandating SARS-CoV-2 vaccination for transplant healthcare workers is expected to protect the lives of vulnerable populations and build trust with the public. Genomic and epidemiological investigation has previously confirmed rapid nosocomial outbreaks of SARS-CoV-2 dissemination within the hospital setting triggered by asymptomatic healthcare workers, amplified by healthcare worker transmission to healthcare workers and patients.
      • Borges V
      • Isidro J
      • Macedo F
      • et al.
      Nosocomial Outbreak of SARS-CoV-2 in a "Non-COVID-19" Hospital Ward: Virus Genome Sequencing as a Key Tool to Understand Cryptic Transmission.
      Healthcare workers have been repeatedly demonstrated to be the previously hidden link between contact clusters in hospital environments.
      • Ellingford JM
      • George R
      • McDermott JH
      • et al.
      Genomic and healthcare dynamics of nosocomial SARS-CoV-2 transmission.
      In addition to the abovementioned argument for healthcare workers to receive vaccination to protect the patients, we should also be mindful of the workers’ autonomy and concerns. Efforts should be made to address the vaccine hesitancy (and more so when this overlaps with other disadvantages in the workplace). Flexibility of implementation, including time frame for different types of employees (clinical staff versus clerical staff), grace period before enhanced education and vaccine acceptance, re-deployment of employees, could be considered and subjected to the difference in cultural and legal settings.

      CONCLUSIONS

      The guiding principles for resource allocation including the delivery of kidney transplantation during the Covid-19 pandemic are relatively well established and supported by an ethical framework (Table 1). The dichotomy of continuation versus suspension of transplant activity should best be replaced by a stepwise approach (Table 2). Decision to continue or suspend transplant activity during the Covid-19 pandemic requires a risk-stratified approach strongly incorporating patient views. The decision on mandatory vaccination for kidney transplant candidates (Table 3) is much more controversial, partly due to concerns regarding autonomy and violation of human rights. Arguments to mandate vaccination before transplant waitlisting are outweighed by arguments in favor of strongly recommending vaccination to patients but respecting their autonomous choices. We recommend moving away from coercion to encouragement of vaccination. After documented risk-benefit discussions are held, based on trusted patient-clinician relationships, and on individual risk assessment of morbidity and mortality risk after transplantation, kidney transplantation should not be declined for people who do not wish to be vaccinated. In contrast, we found a stronger, but not necessarily agreed by all, ground for mandatory vaccination for transplant healthcare workers. The mandate for healthcare workers seems indisputable given the need to protect themselves and others. The debate is contentious, however, if this is associated with loss of jobs and when perceived as coercion and loss of autonomy.

      Conflict of Interest

      none

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