​As dialysis carries a higher risk of infection and COVID-19-related mortality, kidney transplant programmes such as at the SingHealth Duke-NUS Transplant Centre have implemented measures to ensure that transplants are done safely. However, as kidney transplant recipients who are stable tend to see their general practitioners (GPs) for treatment of respiratory ailments, GPs are best-placed and valued partners in keeping these vulnerable patients safe with the approaches outlined below.

INTRODUCTION

Kidney transplant recipients make up the largest proportion of solid organ transplant recipients in Singapore. Furthermore, many of them, after passing their first year of transplantation, would be stable on chronic immunosuppression and may only be seen at the transplant centre two to three times a year.

As a result, it is not uncommon for a kidney transplant recipient to first consult a general practitioner (GP) for common medical conditions like respiratory tract infections.

Unfortunately, amidst the current COVID-19 pandemic, there is an increased likelihood of COVID-19 being the cause of respiratory tract symptoms for kidney transplant recipients. Hence, there is a need to update GPs on the characteristics and outcomes of COVID-19 in this group of patients.

THE IMPACT OF COVID-19 ON KIDNEY TRANSPLANTATION

The COVID-19 pandemic has had an adverse impact on organ donation and transplantation in Singapore. In 2020, the number of kidney transplants fell by over 50%, with only 46 kidney transplants performed compared to 89 in 2019. This would mean that a greater proportion of patients with end-stage kidney failure had to undergo dialysis instead.

Risks of kidney dialysis over kidney transplantation

Apart from dialysis-related morbidity, patients on dialysis also face higher risks of contracting a COVID-19 infection during the pandemic. This is due to their more frequent contact with healthcare facilities and the community.

In a systematic review, the incidence of COVID-19 was higher in patients receiving dialysis (105 per 10,000 person weeks) than patients with kidney transplants (23 per 10,000 person weeks).¹

Furthermore, COVID-19 related mortality was higher among dialysis patients with the unadjusted 28-day mortality risk being 33% higher than kidney transplant recipients.² This may be related to a higher comorbidity burden as they spend more time on dialysis.

ENSURING SAFETY IN TRANSPLANT CENTRES AMIDST THE PANDEMIC

Since dialysis is associated with higher incidence and mortality of COVID-19, it is reasonable for kidney transplant programmes to continue providing access to transplantation for patients with end-stage renal failure. As a result, transplant centres in Singapore have implemented a number of measures to ensure transplantation can be performed safely in pandemic conditions.

Adjusting transplantation activity levels

For example, the SingHealth Duke-NUS Transplant Centre has published guidelines on adjusting the level of transplantation activity based on: ^3,4

• National disease outbreak alert levels
• Prevailing COVID-19 transmission risk profiles
• Availability of resources
• Urgency for transplantation

Organ donor and transplant recipient screening protocols

Organ donor and transplant recipient screening protocols were also developed using polymerase chain reaction (PCR) testing, imaging and questionnaire checklists to minimise the risks of early posttransplant COVID-19 infections.⁵

Protected pathways to minimise exposure

Transplant programmes also developed telemedicine, medication delivery systems and protected pathways to ensure that outpatient care could be delivered safely without exposure to COVID-19.^6,7

Approaches to Reducing COVID-19 Risk for Transplant Recipients

Despite these measures, kidney transplant recipients remain vulnerable and experience high morbidity and mortality if they are infected with COVID-19.

In a meta-analysis and systematic review of 23 studies done at the SingHealth Duke-NUS Transplant Centre, it was reported that the pooled rate of mortality for kidney transplant recipients was 21.1%, which was higher than the 4.3% mortality rate observed in the general population.^8,9

COVID-19 infection in kidney transplant recipients also increased the risk of allograft loss as acute kidney injury and dialysis occurred in 38.9% and 12.4%, respectively.⁸

Therefore, it is imperative that everything possible should be done to reduce the risks of COVID-19 infections in kidney transplant recipients.

Approaches to accomplish this include:

1. COVID-19 vaccination
2. Early recognition and treatment
3. Lifestyle precautions

1. COVID-19 VACCINATION

COVID-19 vaccination is recommended for kidney transplant recipients, and most evidence about its safety and efficacy is based on experience using COVID-19 mRNA vaccines. Not surprisingly, immune responses to COVID-19 mRNA vaccines are poor in kidney transplant recipients who are on systemic immunosuppression.

In one study, the seroconversion rates after two doses of a COVID-19 mRNA vaccine were low at 27.2%, though seroconversion rates were even lower with the Sinovac vaccine at 18.8%.^10,11

Nevertheless, two doses of a COVID-19 mRNA vaccination still offer some protection, as one study of
904 vaccinated kidney transplant recipients reported that the breakthrough infection rate was only 0.8%.¹² More importantly, others have demonstrated that the mortality rate was reduced to 7.7% (compared to 12.6% among unvaccinated kidney transplant recipients).¹³

Given the low immunogenicity of two doses of a COVID-19 mRNA vaccine, a third vaccine dose is recommended and has been shown to further improve seroconversion rates to 60%.¹⁴

As for now, the primary COVID-19 vaccination schedule for kidney transplant recipients is three doses, with a booster dose to be given five months after the third dose.

2. EARLY RECOGNITION AND TREATMENT

There has been significant progress in the development of effective COVID-19 therapeutics since the pandemic started. In the United States, mortality among COVID-19-infected transplant recipients has declined over time, which has been attributed to improvement in care and changes in COVID-19-specific treatments.¹⁵

As a result, kidney transplant recipients infected with COVID-19 should be admitted back to their transplant centre hospital as soon as possible to receive treatment.

Therapies such as neutralising monoclonal antibodies (e.g., casirivimab/imedevimab or Regeneron), if administered during the early phase of COVID-19 infection, have been reported to be safe and effective in preventing progression of COVID-19.^16-20 This in turn would reduce the risks of death from COVID-19.

Remdesivir and immunomodulatory drugs such as tocilizumab have also been shown to reduce hospital stay and mortality among organ transplant recipients with more severe COVID-19 infections.²¹

Apart from receiving COVID-19 therapeutics, kidney transplant recipients would also need to have their immunosuppression adjusted, which can only be done safely in an inpatient setting. Transplant programmes have therefore disseminated advisories to their patients, instructing them to contact their transplant coordinators so that arrangements can be made for hospital admission in the event of being infected with COVID-19.

3. LIFESTYLE PRECAUTIONS

Regardless of the advances made in COVID-19 vaccination and therapeutics, kidney transplant recipients must also play their part by adhering to safe management measures. These include the proper wearing of masks, social distancing and accepting telemedicine consults whenever they are offered.

Kidney transplant recipients must also learn how to correctly perform antigen rapid testing whenever there is exposure or symptoms related to COVID-19.

It is even more important for the household contacts of kidney transplant recipients to adopt the same measures, as a common source of COVID-19 exposure in kidney transplant recipients is actually their household contacts.

CONCLUSION

Though the COVID-19 pandemic continues to challenge the healthcare system in Singapore, it has been resilient and effective against a common invisible enemy. Those at the frontline, such as GPs, are valued partners in protecting vulnerable transplant recipients from COVID-19. On behalf of the SingHealth Duke-NUS Transplant Centre, we express our gratitude to our GPs for being our vanguards.

REFERENCES

1. Chung EYM, Palmer SC, Natele P, et al. Incidence and outcomes of COVID-19 in patients with CKD: A systematic review and meta-analysis. Am J Kidney Dis 2021; 78(6): 804-815.

2. Goffin E, Candellier A, Vart P, et al. COVID-19-related mortality in kidney transplant and hemodialysis patients: a comparative, prospective registry-based study. Nephrol Dial Transplant 2021; 36(11): 2094-2105.

3. Chung SJ, Tan EK, Kee T, et al. Practical considerations for solid organ transplantation during the COVID-19 Global Outbreak. The Experience from Singapore. Transplant Direct 2020; 6(6): e554. doi: 10.1097/TXD.0000000000001002.

4. Ho QY, Chung SJ, Gan VHL, et al. High-immunological risk living donor renal transplant during the COVID-19 outbreak: Uncertainties and ethical dilemmas. Am J Transplant 2020; 20(7): 1949-1951.

5. Ho QY, Chung SJ, Low SCS, et al. Evaluating potential deceased donor renal transplant recipients for asymptomatic COVID-19. Transplant Direct 2020; 6(6): e559. doi: 10.1097/TXD.0000000000001010.

6. Kee T, Hi VG, Shimin JC, et al. Managing a renal transplant program during the COVID-19 Pandemic: practical experience from a Singapore transplant centre. Ann Acad Med Singapore 2020; 49(9): 652-660.

7. Liang EW, Tan JY, Chung JS, et al. Zero health-care associated respiratory viral infections among solid organ transplant recipients: Infection prevention outcomes during COVID-19 pandemic. Am J Transplant 2021; 21(6): 2311-2313.

8. Ho QY, Sultana R, Lee TL, et al. Coronavirus disease 2019 in kidney transplant recipients: a systematic review and meta-analysis. Singapore Med J 2021 Oct 24. doi: 10.11622/smedj.20211171. Online ahead of print.

9. Zhang JJY, Lee KS, Ang LW, et al. Risk factors for severe disease and efficacy of treatment in patients infected with COVID-19: A systematic review, meta-analaysis and meta-regression analysis. Clin Infect Dis 2020; 71(16):2199-2206.

10. Akyol M, Cevik E, Ucku D, et al. Immunogenicity of SARS-CoV-2 mRNA vaccine in dialysis and kidney transplant patients: a systematic review. Tuberk Toraks. 2021; 69(4): 547-560

11. Eren Sadioglu R, Demir E, Evren E, et al. Antibody response to two doses of inactivated SARS-CoV-2 vaccine (CoronaVac) in kidney transplant recipients. Transplant Infect Dis 2021; 23(6): e13740. doi: 10.1111/tid.13740

12. Tsapepas D, Paget K, Mohan S, et al. Clinically significant COVID-19 following SARS-CoV-2 vaccination in kidney transplant recipients. Am J Kidney Dis 2021; 78(2): 314-317

13. 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. Transplantation 2021; 105(11): e263-e264

14. Westhoff TH, Seibert FS, Anft M, et al. A third vaccine dose substantially improves humoral and cellular SARS-CoV-2 immunity in renal transplant recipients with primary humoral nonresponse. Kidney Int 2021; 100(5): 1135-1136

15. Heldman MR, Kates O, Safa K, et al. Changing trends in mortality among solid organ transplant recipients hospitalized for COVID-19 during the course of the Pandemic. Am J Transplant 2021 Oct 7:10.1111/ajt.16840. doi: 10.1111/ajt16840.

16. Dhand A, Lobo SA, Wolfe K, et al. Casirivimab-imdevimab for treatment of COVID-19 in solid organ transplant recipients: an early experience. Transplantation 2021; 105(71): e68-e69.

17. Del Bello A, Marion O, Vellas C, et al. Anti-SARS-CoV-2 monoclonal antibodies in solid organ transplant recipients. Transplantation 2021; 105(10): e146-e147.

18. Fernandes G, Devresse A, Scohy A, et al. Monoclonal antibody therapy for SARS-CoV-2 infection in kidney transplant recipients: a case series from Belgium. Transplantation 2022; 106(1): e107-e108

19. Klein EJ, Hardesty Aa, Vieira K, et al. Use of anti-spike monoclonal antibodies in kidney transplant recipients with COVID-19: Efficacy, ethnic and racial disparities. Am J Transplant 2021 Sept 30; 10.1111/ajt.16843. doi: 10.1111/ajt.16843.

20. Kutzler HL, Kuzaro HA, Serrano OK, et al. Initial experience of bamlanivimab monotherapy use in solid organ transplant recipients. Transpl Infect Dis 2021; 23(5): e13662. doi:10.1111/tid.13662.

21. Shafiekhani M, Shahabinezhad F, Niknam T, et al. Evaluation of the therapeutic regimen in COVID-19 in transplant patients: where do immunomodulatory and antiviral stands ? Virol J 2021; 18(1): 228. doi: 10.1186/s12985-021-01700-2.

Associate Professor Terence Kee is a Senior Consultant renal physician with an interest in renal transplantation. He obtained his MBBS at the Flinders University of South Australia in 1994, and by 2000 he completed the Singapore General Hospital (SGH) basic and advanced physician training programmes in general and renal medicine. He subsequently received a Singapore Government Health Manpower Development Plan award in 2004 to undergo a one-year fellowship in advanced renal transplantation under Professor Jeremy Chapman at the Westmead Hospital in Australia. He returned to SGH in 2005 and has since been an active member of the renal transplant team.

To find out more about our transplant programmes, GPs can contact the SingHealth Duke-NUS Transplant Centre:
Tel: 6312 2720
Email: [email protected]