Kidney Transplant Practice in Pandemic Times

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus disease 2019 (COVID-19) pandemic affected the entire kidney transplant system, from pretransplant evaluation, waitlist access, donation, organ utilization and transplantation through post-transplant outcomes, often in ways that exacerbated existing inequities.¹ Kidney transplant recipients with COVID-19, affected by underlying comorbidity and chronic immunosuppression, have higher morbidity and mortality than nontransplant patients with COVID-19.² As vaccines and treatment options for COVID-19 became available, outcomes improved overall, but complications remained high for kidney transplant recipients.¹ Thus, while an end to the pandemic may be in sight for the general population, transplant recipients will require better prevention and treatment regimens. Kidney transplant candidates and recipients want to know “When will we get back to normal? Who can we trust to navigate the rapidly, changing landscape?” What have we learned in this pandemic to improve future outcomes?

The Impact of the Pandemic on Kidney Transplantation Rates

During the first phase of the pandemic, as scarce hospital resources were directed to the care of patients with COVID-19, transplant practice was profoundly disrupted. Deceased donor kidney transplantation slowed, often limited to candidates with particular urgency. Living donor kidney transplantation, considered “elective” surgery in many centers, was generally halted to avoid risk of infection in living donors and recipients.³

Transplant programs made many adaptations to remain open. When critical transplant unit staff was redeployed to COVID-19 care units, remaining staff assumed wider responsibilities. Operating room time and availability, anesthesia services, and intensive care unit (ICU) beds all were severely limited. As the hospital emergency eased center by center, these resources were reconstituted. Determining the infectious status of donor organs and recipients was needed. A rebound in deceased donor kidney transplantation was facilitated when the Organ Procurement and Transplantation Network (OPTN) captured and reported organ donor SARS-CoV-2 testing results. Expanded online patient education and use of telehealth streamlined patient evaluation and follow-up in many centers.

In contrast with the recovery in deceased donor kidney transplantation, living donor kidney transplantation in 2020 and 2021 lagged behind 2019 levels, with particular disparities for Black patients.⁴

Lessons Learned

Decisions to continue or curtail transplantation during a pandemic or disaster should be evaluated continuously. Deceased donor kidney transplant should be considered an essential procedure to continue within the limits of local resources and patient safety. While living donor transplantation may be delayed in emergency times, vigilance is necessary to avoid exacerbating disparities in access to living donor transplantation.⁴ As knowledge and treatments evolve during an emergency such as a pandemic, transplant centers should continuously communicate with patients and general nephrologists. Critical transplant staff must be retained, even if temporarily reassigned to emergency duties, to ensure transplant program success during and after a pandemic or disaster.

SARS-CoV-2 Infection and Kidney Donation

Early in the pandemic, deceased donation and Organ Procurement Organizations processes fell dramatically. A decline in traumatic deaths nationally, and a dramatic rise in hospital and ICU admissions for COVID-19, limited opportunities for deceased organ donation. For the fewer available potential donor organs, obtaining consent from next-of-kin was challenged by limits on in-person contact. Inconsistent availability of COVID-19 testing in potential donors⁵ limited transplant surgery.

Before the advent of vaccines and effective antiviral therapy, COVID-19–positive donors were generally excluded from organ donation. Time-sensitive testing later informed organ procurement and placement, and cases of kidney allograft use from SARS-CoV-2–positive donors emerged.⁶ Short-term outcomes suggest that transplantation from well-selected SARS-CoV-2–infected donors may be as safe and effective as from noninfected donors.⁷ Emerging experience also demonstrates safety of kidney transplantation in select COVID-19 recovered patients.

Lessons Learned

Rapid development and availability of reliable and time-sensitive deceased donor infection testing, along with infection reporting by the OPTN, are critical to make organ acceptance decisions during a pandemic. In the future, prompt monitoring, data analysis, and reporting will help determine when organs from donors affected by novel infections can be safely used for kidney transplantation and when affected candidates can proceed to transplant.

Experiential Medicine versus Evidence-Based Medicine: Challenges and Innovations

Immunocompromised patients were excluded from every major COVID-19 clinical trial, including vaccines. Without safety and efficacy data for transplant patients, clinicians extrapolated from the general population with COVID-19.¹ Access to vaccination, medications, and general pandemic procedures varied by geography, which led to regional practice variations in immunosuppression modification, prophylactic interventions, and other treatments. Information sharing and collaboration among transplant institutions worldwide increased during the COVID-19 pandemic. This unparalleled cooperation helped guide individual practice when evidence was scarce.

With only limited short-term observational data on remdesivir for patients with kidney disease, this antiviral was initially considered contraindicated. More recent data suggest that remdesivir reduces ICU mortality without significant nephrotoxicity in kidney transplant recipients. Other empiric therapies were instituted that were often unhelpful and, sometimes, harmful.¹ Although the OPTN added COVID-19 as a cause of death, it did not capture patient-level information related to vaccinations, treatments, or changes in immunosuppression. This limited database made it difficult to correlate clinical care with outcomes. As clinicians did their best to draw conclusions, kidney transplant patients felt confused and asked for trusted sources of information.

Lessons Learned

When evidence is scarce during an emergency, collaboration among transplant institutions is extremely valuable. In the absence of randomized controlled trials and robust observational data, patient care must continue and patient questions must be answered. The use of “lesser quality” data from surveys of national practice patterns and experiential medicine, with continuous tracking and reporting, can generate best available information to inform practice. More robust and rigorous national registries and tools to rapidly analyze data may inform clinical practice sooner. Health care agencies and providers must provide ongoing authoritative information to patients in a rapidly changing landscape. The impact of building trust with the patient community is invaluable to get “buy-in” from the patients we serve, especially during times of uncertainty. In addition, we must recognize and manage the lasting mental health consequences of a pandemic for patients and providers.

Vaccination and Prophylactic Interventions

While the emergence of COVID-19 vaccines played a major role in reducing the risk and severity of COVID-19 in the population at large, transplant recipients had many questions regarding vaccine efficacy, safety, and reactogenicity. Because few immunocompromised patients participated in clinical trials, most data gathered in this population came from local registries and patient-initiated sharing. These data influenced our understanding of “fully vaccinated,” the need and timing of booster immunization, and need for pre-exposure prophylaxis in immunosuppressed transplant patients who may not have adequate immune responses to vaccination.

Data analysis now shows that vaccination is associated with reduced mortality in transplant patients.² Professional societies strongly recommend COVID-19 vaccination for transplant candidates before transplant and immunosuppression when possible⁸ and, given the ongoing emergence of new variants, continue to advise that vaccinated transplant recipients maintain personal measures to minimize SARS-CoV-2 exposure. While all US transplant programs encourage vaccination, programs exhibited significant heterogeneity in COVID-19 vaccination mandate policies, citing administrative opposition, legal prohibitions, and concern about equity in access to transplants.⁹

Lessons Learned

Preventative and treatment regimens for solid organ transplant recipients require careful application and re-evaluation during a pandemic. Transplant clinicians should communicate that understanding with our patients. Excluding immunocompromised patients and delays in funding drug and vaccine studies were major “misses” during this pandemic that need to change in the future. Immunocompromised individuals should be included in studies of new therapeutic agents.

Policy, Advocacy, and Regulatory Changes

The OPTN made proactive changes during the pandemic in response to community requests. Programs were allowed to apply for retroactive waiting time modification for candidates unable to obtain timely testing required for registration. The OPTN also allowed temporary inactivation of candidates for reasons related to COVID-19 precautions without loss of waiting time and temporarily paused some data form submission requirements. The Centers for Medicare & Medicaid Services facilitated ongoing transplant surgery through Tier 3b designation and temporary relaxation of telemedicine restrictions to facilitate access to care and reduce possible exposure to SARS-CoV-2 during in-person visits. The Scientific Registry of Transplant Recipients conducted a data “carve out” from performance reports from March 13, 2020, to June 12, 2020, when “all hands on deck” were devoted to clinical care rather than data acquisition.¹⁰

Lessons Learned

Regulators, payers, and policy makers must recognize that at times of emergencies, priority must focus on care and accessibility and adjust reporting requirements accordingly. Reporting waivers and telemedicine played major roles in making transplant care more accessible during the pandemic and should be repeated in future emergencies.

Summary

Kidney transplant recipients have a high risk of adverse outcomes during the COVID-19 pandemic and continue to be at risk. Immunocompromised patients were not included in studies of vaccines and therapeutics, so safety and efficacy were unknown. Survey and experiential data helped direct best care. For future pandemics, timely development of screening tools and wide availability of early testing will be invaluable in decisions for organ acceptance and transplantation. Drug and vaccine development should include this population. Legislators and regulators should work with clinicians to adapt health care policies and procedures to changing needs and remain trusted sources of information for patients and caregivers in future health care crises.

Disclosures

M.A. Josephson reports consultancy agreements with Exosome Diagnostics, IMMUCOR, Labcorp, Otsuka, UBC Pharmaceutical Support services for the mycophenolate pregnancy registry, and Vera Therapeutics; ownership interest in Seagen; research funding from Bucksbaum Institute and Gift of Hope; honoraria from ASN Board Review Course and ASN for Highlights; and is President-Elect for American Society of Nephrology. A.S. Kliger reports employment with Metabolism Associates, New Haven; consultancy agreements with ASN; multiple equity positions managed by UBS; advisory or leadership roles as American Society of Nephrology Chair of NTDS; Chair of EPC Advisory Committee and Co-Chair of COVID-19 Response Team; and other interests or relationships with American Society of Nephrology and Renal Physicians Association. V. Kumar reports research funding from NIH CTOT studies as sub investigator and United Therapeutics/Revivicor—XenoTransplantation as sub investigator, starting Jan 2022; honoraria from American Society of Nephrology/American Society of Transplantation for combined TNCC invited video lecture, American Society of Nephrology for the early course for ASN Kidney Week invited lecture, AREP for an educational webinar, ASN COVID 19 effort, Elsevier for a book chapter, and Medscape for a podcast, and NKF talks (travel and hotel, no honoraria); advisory or leadership roles as American Society of Transplantation - Elected Councilor American Society of Transplantation BOARD (no payment), exam item writer for ABIM (no honorarium), Member of DSMB for KIRA study (no honorarium), Region 3 UNOS living donor physician representation (no honorarium), and Veloxis Member of Delpi group examining the effectiveness of Envarsus in Kidney Transplant Recipients in an evidence based fashion with the ultimate goal of publication (honorarium deferred); and other interests or relationships with American Society of Transplantation (AST): Board Liaison to the Living Donor Community of Practice; AST Transplant Community and Community Education Committee; AST Cutting Edge in Transplantation Planning Committee (CeOT) 2022, Incoming Chair of Planning Committee; Member, AST Community Education Committee; UNOS Region 3 Representative to OPTN Living Donor Community; and Schwartz Center Rounds for compassionate Rounds - Facilitator. N. Leca reports consultancy agreements with CareDx, Veloxis, and Transplant Genomics and research funding from Angion, CareDx, CSL Behring, Natera, Novartis, Transplant Genomics, and Verici. K.A. Leigh reports employment with American Society of Nephrology. K.L. Lentine reports consultancy agreements with CareDx, Inc.; ownership interest in CareDx, Inc.; speakers bureau for Sanofi; and is a volunteer member of the ASN Policy and Advocacy Committee. R.B. Mannon reports consultancy agreements with Chinook Therapeutics and Olaris Inc.; research funding from Transplant Genomics, Inc. and Verici DX; honoraria from CSL Behring; patents or royalties from Eurofins; advisory or leadership roles for Steering Committee Verici Dx and Steering Committee of Vitaerris VKTX01 IMAGINE Trial; and other interests or relationships as Chair of ASN Policy and Advocacy Committee, Chair of Scientific Registry of Transplant Recipients (SRTR) Review Committee, Immediate Past-Chair of Women in Transplantation, member of ASN Grants Committee, Deputy Editor of American Journal of Transplantation, and member of DSMB for NIDDK/NIH. S. Mohan reports consultancy agreements with Angion Biomedica, eGenesis, and HSAG; advisory or leadership roles as Deputy Editor of Kidney International Reports (ISN), member of ASN Quality committee, member of SRTR Review Committee, National Faculty Chair of ETCLC, and Vice Chair of UNOS Data advisory committee; and research funding from Kidney Transplant Collaborative and NIH (NIDDK, NIHMD, and NIBIB). G. Roberts reports employment with Kidney Research Institute; ownership interest in Options Unlimited International (50%); speakers bureau for American Association of Kidney Patients; and other interests or relationships with American Association of Kidney Patients, APOLLO, APOLLO CAB, ASN COVID-19 Response Team and Transplant Subcommittee, ASN NTSD QAIE WG, Can-SOLVE CIRAC, CPATH BmDR Charter/Governance WG, HDU Advisory Committee, International Nephrology Society (ISN) Patient Group, KDIGO CKD & Complications in Dialysis WGs, KHI APOL1 Steering Committee, KHI PFPC, NKF Ambassador of KAC Diversity WG & Patient Education Series, and NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease. G. Roberts reports advisory or leadership roles for Center for Innovations in Cancer & Transplants, chair of Community Engagement (Eng.) Committee (Comm.), and Steering Comm.; KRI Patient Advisory Comm.; CDI Patient Advisory Board; Kidney Precision Medicine Project Community Engagement Committee; C-Path Patient Eng. Comm. & DIKI Project; CRIC study and Expert Patient Panel; and University of Minnesota's Office of Discovery and Translation: Reduce Medication-Related Disparities in African American Patients with Chronic Kidney Disease. G. Roberts's spouse reports consultancy agreements with Vortex. D.L. Sawinski reports ownership interest in CareDx; research funding from National Institutes of Health; advisory or leadership roles for American Journal of Kidney Diseases, Clinical Transplantation, and Councilor at Large of American Society of Transplantation Board of Directors; and other interests or relationships as UNOS Kidney Committee member and expert witness testimony. All remaining authors have nothing to disclose. The authors are volunteer members of the ASN COVID-19 Transplant Response Team.

Funding

None.

Author Contributions

A.S. Kliger, V. Kumar, K.L. Lentine, and S. Mohan conceptualized the study; V. Kumar provided supervision, was responsible for methodology and visualization, and wrote the original draft; V. Kumar and K.A. Leigh were responsible for project administration; V. Kumar, K.A. Leigh, and K.L. Lentine were responsible for resources; and M.A. Josephson, A.S. Kliger, V. Kumar, N. Leca, K.A. Leigh, K.L. Lentine, R.B. Mannon, S. Mohan, G. Roberts, and D.L. Sawinski reviewed and edited the manuscript.